Advisory
Committee
on
Human
Radiation
Experiments
NATIONAL IjVSTITi
NIHLIBR
JAN 2 2
BLDG 10, 10 CENTER DR
BETHESDA, MD 20892-1150
Advisory Committee
on Human Radiation
Experiments
Final Report
October 1995
Additional copies of the Final Report of the Advisory Committee on Human
Radiation Experiments (stock number 061-000-00-848-9) as well as copies of the
Executive Summary and Guide to Final Report (stock number 061-000-00849-7)
and the three supplemental volumes (061-000-00850-1, 061-000-00851-9, and
061-000-00852-7) may be purchased from the Superintendent of Documents, U.S.
Government Printing Office.
All telephone orders should be directed to:
Superintendent of Documents
U.S. Government Printing Office
Washington, D.C. 20402
(202) 512-1800
FAX (202) 512-2250
8 a.m. to 4 p.m., Eastern time, M-F
All mail orders should be directed to:
U.S. Government Printing Office
P.O. Box 371954
Pittsburgh, PA 15250-7954
An Internet site containing ACHRE information (replicating the Advisory
Committee's original gopher) will be available at George Washington University.
The site contains complete records of Advisory Committee actions as approved;
complete descriptions of the primary research materials discovered and analyzed;
complete descriptions of the print and non-print secondary resources used by the
Advisory Committee; a copy of the Interim Report of October 21, 1994, and a
copy of the Final Report; and other information. The address is
http://www.seas.gwu.edu/nsarchive/radiation. The site will be maintained by the
National Security Archive at GWU.
Printed in the United States of America
Contents
PREFACE 1
INTRODUCTION The Atomic Century 19
PART I Ethics of Human Subjects Research: A Historical Perspective
Overview 81
1 Government Standards for Human Experiments: The 1940s and 1950s 83
2 Postwar Professional Standards and Practices for Human Experiments .... 130
3 Government Standards for Human Experiments: The 1960s and 1970s .... 171
4 Ethics Standards in Retrospect 196
PART II Case Studies
Overview 227
5 Experiments with Plutonium, Uranium, and Polonium 233
6 The AEC Program of Radioisotope Distribution 283
7 Nontherapeutic Research on Children 320
8 Total-Body Irradiation: Problems When Research and Treatment Are
Intertwined 366
9 Prisoners: A Captive Research Population 42 1
10 Atomic Veterans: Human Experimentation in Connection with Bomb
Tests 454
1 1 Intentional Releases: Lifting the Veil of Secrecy 506
12 Observational Data Gathering 563
13 Secrecy, Human Radiation Experiments, and Intentional Releases 619
PART III Contemporary Projects
Overview 669
14 Current Federal Policies Governing Human Subjects Research 675
1 5 Research Proposal Review Project 694
16 Subject Interview Study 724
Discussion of Part III 758
PART IV Coming to Terms with the Past, Looking Ahead to the Future
Overview 769
1 7 Findings 777
18 Recommendations 801
Statement By Committee Member Jay Katz 847
Official Documents
Executive Order 857
Charter | 862
Appendices
Acronyms and Abbreviations 869
Glossary 878
Selected Bibliography 886
Public Comment Participants 892
A Citizen's Guide to the Nation's Archives: Where the Records Are
and How to Find Them 897
iii
advisory committee on human radiation Experiments
1726 M STREET, N.W., SUITE 600
WASHINGTON, D.C. 20036 _ . innc
October 1995
To the Members of the Human Radiation Interagency Working Group:
Secretary Hazel O'Leaiy, Department of Energy
Secretary William Perry, Department of Defense
Attorney General Janet Reno, Department of Justice
Secretary Donna Shalala, Department of Health and Human Sen-ices
Secretary Jesse Brown. Department of Veterans Affairs
Director Alice Rivlin, Office of Management and Budget
Director John Deutch, Central Intelligence Agency
Administrator Daniel Goldin, National Aeronautics and Space Administration
On behalf of the Advisory Committee on Human Radiation Experiments, it is my
privilege to transmit to you our Final Report.
Since the Committee's first meeting in April 1994 we have been able to conduct
an intensive inquiry into the history of government-sponsored human radiation
experiments and intentional environmental releases of radiation that occurred between
1944 and 1974. We have studied the ethical standards of that time and of today and have
developed a moral framework for evaluating these experiments. Finally, we have
examined the extent to which current policies and practices appear to protect the rights
and interests of today's human subjects. This report documents our findings and makes
recommendations for your consideration.
The committee listened to the testimony of more than 200 public witnesses who
appeared before us. We are deeply grateful to all these witnesses, who overcame the
obstacles of geography and emotions to assist us.
Our work and this report would not have been possible without the extraordinary
effort the President and you put forward to open the government's records to our inquiry
and thus to the nation. We are especially pleased that, through our joint efforts, the
American people now have access to the tens of thousands of documents that bear on this
important history.
None of our conclusions came easily. We endeavored, both as individuals and as
a committee, to live up to the responsibility with which we were entrusted. This report
represents the consensus of fair-minded people who gave the best they had to offer to
their fellow citizens.
We thank President Clinton for this opportunity and for his courage and
leadership in appointing the Advisory Committee.
Ruth R. Faden
Chair, Advisory Committee
on Human Radiation Experiments
®
Printed with soy ink on recycled paper
Advisory Committee on Human Radiation Experiments
Ruth R. Faden. Ph.D.. M.RH.-Chair
Philip Franklin Wagley Professor of Biomedical Ethics and Director
The Bioethics Institute
Johns Hopkins University
Baltimore, Maryland
Senior Research Scholar
Kennedy Institute of Ethics
Georgetown University
Washington, D.C.
Kenneth R. Feinberg, J.D.
Kenneth R. Feinberg & Associates
Washington, D.C.
Eli Glatstein, M.D.
Professor and Chair
Department of Radiation Oncology
The University of Texas
Southwestern Medical Center at Dallas
Dallas, Texas
Jay Katz, M.D.
Elizabeth K. Dollard Professor Emeritus
of Law, Medicine and Psychiatry
Harvey L. Karp Professorial Lecturer in Law
and Psychoanalysis
Yale Law School
New Haven, Connecticut
Patricia A. King, J.D.
Professor of Law
Georgetown University Law Center
Washington, D.C.
Susan E. Lederer, Ph.D.
Associate Professor
Department of Humanities
The Pennsylvania State University College of Medicine
Hershey, Pennsylvania
Ruth Macklin, Ph.D.
Professor of Bioethics
Department of Epidemiology & Social Medicine
Albert Einstein College of Medicine
Bronx, New York
Nancy L. Oleinick, Ph.D.
Professor of Radiation Biochemistry
Division of Radiation Biology
Case Western Reserve University School of Medicine
Cleveland, Ohio
Henry D. Royal, M.D.
Professor of Radiology
Associate Director; Division of Nuclear Medicine
Mallinckrodt Institute of Radiology
Washington University Medical Center
St. Louis, Missouri
Philip K. Russell, M.D.
Professor, Department of International Health
Johns Hopkins University
School of Hygiene and Public Health
Baltimore, Maryland
Mary Ann Stevenson, M.D., Ph.D.
Assistant Professor of Radiation Oncology
Joint Center for Radiation Therapy
Harvard Medical School
Boston, Massachusetts
Deputy Chief
New England Deaconess Hospital
Department of Radiation Oncology
Boston, Massachusetts
Duncan C. Thomas, Ph.D.
Director, Biostatistics Division
Department of Preventive Medicine
University of Southern California School of Medicine
Los Angeles, California
Lois L. Norris
Second Vice President of Omaha National Bank
and Omaha National Corporation (Retired)
Omaha, Nebraska
Reed V. Tuckson, M.D.
President
Charles Drew University of Medicine and Science
Los Angeles, California
Advisory Committee on Human Radiation Experiments
Jeffrey Kahn
Associate Director
Dan Guttman
Executive Director
Anna Mastroianni
Associate Director
Stephen Klaidman
Director of Communications
Counselor to the Committee
Sarah Flynn
Editor
Staff*
Senior Policy and Research Analysts
Barbara Berney
James David
John Harbert
Gregg Herken
Jonathan Moreno
Ronald Neumann
Gary Stem
Jeremy Sugarman
Donald Weightman
Gilbert Whittemore
Research Analysts
Jonathan Engel
Patrick Fitzgerald
Mark Goodman
Deborah Holland
Denise Holmes
Michael Jasny
Gail Javitt
Wilhelmine Miller
Patricia Perentesis
Kathy Taylor
Sandra Thomas
Faith Weiss
Research Associates
Miriam Bowling
Praveen Fernandes
Sara Chandros Hull
Valerie Hurt
John Kruger
Ellen Lee
Shobita Parthasarathy
Noel Theodosiou
Information Services
David Saumweber, Director
Robin Cochran, Librarian
Tom Wisner, Senior Technology
Consultant
Communications and Outreach
Lanny Keller
Kristin Crotty
Committee and Staff Affairs
Jerry Garcia
Jeanne Kepper
Consultants
Jeffrey Botkin
Allen Buchanan
Gwen Davis
Gail Geller
Steve Goodman
Jon Harkness
Rebecca Lowen
Suzanne White Junod
Nancy Kass
Charles McCarthy
Monica Schoch-Spana
Patricia Stewart-Henney
John Till
E.W. Webster
*includes both full-time and part-time staff
acknowledgments
T t
he Committee's work over the past year and a half would have been
impossible without the assistance of an extraordinary number of individuals and
groups from all corners of the United States, and beyond. We wish to express the
depth of our gratitude to the many people who assisted, informed, and advised us.
Some of these people are identified by name elsewhere in this report and
its supplemental volumes. An appendix in this volume lists the more than 200
witnesses who appeared before the Committee at our public meetings in
Washington, D.C., Cincinnati, Knoxville, San Francisco, Santa Fe, and Spokane.
The supplemental volumes identify the dozens of individuals who agreed to
formal, taped interviews in connection with the Committee's oral history projects.
We thank all these people and many more:
• The hundreds of people who contacted the Committee with information
about their own experiences or the experiences of their family members.
Many of these people shared not only their personal stories but also the
information they had collected in the course of conducting their own
research into government archives.
• The representatives of many groups whose interests coincided with the
work of the Committee. These include organizations of former subjects of
biomedical radiation experiments (and their families), downwinders,
atomic veterans, uranium miners, and workers in and around atomic
energy communities. These groups, as well, shared the accumulated
information and perspective of years of experience and research.
• The numerous professionals in fields related to our research who gave of
their time and expertise to provide information or comment on the myriad
factual, technical, and policy questions before the Committee. These
experts provided help in understanding areas ranging from military and
human rights law to the laws of the atom, from the history of the
government's use of secrecy to the history of radiation science.
• The dozens of universities and independent hospitals, located in all
regions of the country, that willingly provided us with the documents we
needed to conduct our Research Proposal Review Project.
vn
A ckn o wledgm en (s
The nearly 1,900 individuals who graciously participated in our Subject
Interview Study, and the university hospitals, veterans hospitals, and
community hospitals that permitted us to conduct the study.
The numerous chairs of institutional review boards and radiation safety
committees who were kind enough to share with us their views about the
current status of human subject protections.
Archivists at public and private libraries, universities, and research
institutions, who assisted the Committee in our search for information.
The many journalists and scholars who have previously researched and
written about the subjects covered in this report, for sharing the
knowledge and wisdom embodied in their own many years of inquiry and
reflection.
A variety of state and local agencies for sharing with the Committee the
results of their own reviews of activities that we explored.
Members of Congress and congressional staff, including the staffs of the
General Accounting Office and the Office of Technology Assessment, for
sharing the product of their own prior inquiries into many of the areas
discussed in this report.
The members of the Human Radiation Interagency Working Group, who
provided invaluable assistance. We are particularly grateful to the many
employees at the Department of Energy, the Department of Defense, the
Department of Health and Human Services, the Department of Veterans
Affairs, the National Aeronautics and Space Administration, and the
Central Intelligence Agency, who aided us in the search and retrieval of
the many thousands of documents that provide the backbone for the
Committee's review of human radiation experiments that took place
between 1944 and 1974 and the history of government requirements for
the conduct of that research. We are also grateful to the staffs of the
Nuclear Regulatory Commission and the National Archives and Records
Administration for their invaluable assistance. Many of the same people,
as well as others, also provided advice and information as we undertook
our evaluation of the conduct of research involving human subjects today.
We wish to thank both the professional and administrative members of our
staff who worked so hard and showed such dedication to our task. Their talent,
energy, and commitment provided the foundation for our work. It is impossible
to overstate our gratitude and appreciation for their extraordinary efforts.
Finally, we wish to acknowledge our indebtedness to President Clinton for
the honor he bestowed upon us when he selected us to serve on the Advisory
Committee.
Vlll
Documentary Note
In fulfilling its mandate, the Advisory Committee on Human Radiation
Experiments (ACHRE) relied on several thousand separate sources: primary and
secondary published monographs, journal articles, historical records and
manuscripts, original correspondence and surveys, interviews, specially
constructed databases, searches of public and commercial databases, and
documentary films. Only a fraction of these, however, is represented in the final
report. More extensive information may be found in the supplemental volume
Sources and Documentation, which contains a full account of the ACHRE
research program, a finding aid to the complete research document collection, a
bibliography of published sources used, an index to significant documents and
identified experiments, and other auxiliary materials. Further information both
about the sources used by the Advisory Committee generally and about the
particular sources cited in this volume should be sought there.
The unpublished documents referenced in this report are identified by
their places in the ACHRE Research Document Collection. These identifiers, or
ACHRE document numbers, have four parts: originating institution, date of
receipt, order of receipt, and document number. For example, DOE-05 1094-A-
123 is the 123d document described in the first ("A") Department of Energy
("DOE") shipment (or accession) received on May 10, 1994 ("051094"). One of
the appendices, A Citizen's Guide to the Nation's Archives, provides instructions
for using references to the ACHRE collection to find documents there and in the
collections of the National Archives and at the agencies.
IX
FINAL REPORT
Preface
Un January 15, 1994, President Clinton created the Advisory Committee
on Human Radiation Experiments in response to his concern about the growing
number of reports describing possibly unethical conduct of the U.S. government,
and institutions funded by the government, in the use of, or exposure to, ionizing
radiation in human beings at the height of the Cold War. He directed us to
uncover the history of human radiation experiments and intentional environmental
releases of radiation; to identify the ethical and scientific standards for evaluating
these events; and to make recommendations to ensure that whatever wrongdoing
may have occurred in the past cannot be repeated.
The Advisory Committee is composed of fourteen members: a citizen
representative and thirteen experts in bioethics, radiation oncology and biology,
epidemiology and statistics, public health, history of science and medicine,
nuclear medicine, and law. We report to a Cabinet-level group convened by the
President (the Human Radiation Interagency Working Group), whose members
are the secretaries of defense, energy, health and human services, and veterans
affairs; the attorney general; the administrator of the National Aeronautics and
Space Administration; the director of the Central Intelligence Agency; and the
director of the Office of Management and Budget.
On April 21, 1994, at the end of the first day of our opening meeting,
President Clinton invited us to the White House to personally communicate his
commitment to the process we were about to undertake. He urged us to be fair,
thorough, and unafraid to shine the light of truth on this hidden and poorly
understood aspect of our nation's past. Our most important task, he said, was to
tell the full story to the American public. At the same time, we were also to
examine the present, to determine how the conduct of human radiation research
today compares with that of the past and to assess whether, in the light of this
inquiry, changes need to be made in the policies of the federal government to
better protect the American people. This report and the accompanying
1
Preface
supplemental volumes constitute the Committee's attempt to tell the story of the
past and to report on our inquiry into the present.
WHY THE COMMITTEE WAS CREATED
Past research with human subjects, including human radiation research,
has been a source of life-saving knowledge. Research involving human subjects
continues to be essential to the progress of medical science, since most advances
in medicine must at some point in their development be tested in human subjects.
Every one of us who has been either a patient or a loved one of a patient has
benefited from knowledge gained through research with human subjects. But
medical science, like all science, does not proceed or progress without the taking
of risks. In medical research, these risks often fall on the human subject, who
sometimes does not stand to benefit personally from the knowledge gained. This
is the source of the moral tension at the core of the enterprise of research
involving human subjects. In order to secure important collective goods-
scientific knowledge and advances in medicine-individuals are put in harm's
way. The moral challenge is how to protect the rights and interests of these
individuals while enabling and encouraging the advancement of science.
The Committee had its origins when public controversy developed
surrounding human radiation experiments that were conducted half a century
ago. In November 1993, the Albuquerque Tribune published a series of articles
that, for the first time, publicly revealed the names of Americans who had been
injected with plutonium, the man-made material that was a key ingredient of the
atom bomb. Reporter Eileen Welsome put a human face to what had previously
been anonymous data published in official reports and technical journals. As
World War II was ending, she wrote, doctors in the United States injected a
number of hospitalized patients with plutonium, very likely without their
knowledge or consent. The injections were part of a group of experiments to
determine how plutonium courses through the human body. The experiments,
and the very existence of plutonium, were shrouded in secrecy. They were
conducted at the direction of the U.S. government, with the assistance of
university researchers in Berkeley, Chicago, and Rochester (New York), with the
expectation that the information gained could be used to limit the hazards to the
thousands of workers laboring to build the bomb.
On reading the articles, Secretary of Energy Hazel O'Leary expressed
shock, first to her staff, and then in response to a question posed at a press
conference. She was particularly concerned because the Department of Energy
had its earliest origins in the agencies responsible for building the atomic bomb
and sponsoring the plutonium experiments. During the Cold War, these agencies
had continued to do much of their work in the twilight zone between openness
and secrecy. Now, the Cold War was over. The time had come, Secretary
Preface
O'Leary determined, to make public anything that remained to be told about the
plutonium experiments.
Subsequent press reports soon noted that the plutonium injections were
not the only human radiation experiments that had been conducted during the war
and the decades that followed. In Massachusetts, the press reported that members
of the "science club" at the Fernald School for the Retarded had been fed oatmeal
containing minute amounts of radioactive material. In Ohio, news articles revived
an old controversy about University of Cincinnati researchers who had been
funded by the Defense Department to gather data on the effects of "total-body
irradiation" on cancer patients. In the Northwest, the papers retold the story of
Atomic Energy Commission funding of researchers to irradiate the testicles of
inmates in Oregon and Washington prisons in order to gain knowledge for use in
government programs. The virtually forgotten 1986 report prepared by a
subcommittee headed by U.S. Representative Edward Markey, "American
Nuclear Guinea Pigs: Three Decades of Radiation Experiments on U.S.
Citizens," was also recalled to public attention. 1
Coincidentally, the fact that the environment had also been used as a
secret laboratory became a subject of controversy. A November 1993
congressional report uncovered thirteen cases in which government agencies had
intentionally released radiation into the environment without notifying the
affected populations. 2 At various times, tests were conducted in Tennessee, Utah,
New Mexico, and Washington state. This report had been prepared at the request
of Senator John Glenn in his capacity as chair of a committee that had undertaken
a comprehensive oversight investigation of the nuclear weapons complex. As a
young marine in 1945, the senator was in a squadron being trained for possible
deployment to Japan when the atomic bomb ended the war; as an astronaut, he
had been the subject of constant testing and medical monitoring by space
administration flight surgeons; as a senator he was at the center of the country's
efforts to understand and control nuclear weapons. Senator Glenn understood the
importance of national security, but he found it "inconceivable . . . that, even at
the height of the communist threat, some of our scientists and doctors and military
and perhaps political leaders approved some of these experiments to be conducted
on an unknowing and unwitting public." 3
In the immediate aftermath of Secretary O'Leary's press conference and
the further press reports, thousands of callers flooded the Department of Energy's
phone lines to recount their own experiences and those of friends and family
members.
Underlying the outrage and concern expressed by government officials
and members of the public were many unanswered questions. How many human
radiation experiments were conducted? No one knew if the number was closer to
100 or 1,000. Were all the human radiation experiments done in secret, and were
any of them still secret? Are any secret or controversial studies still ongoing?
Preface
Scientists and science journalists pointed out that some of the highly publicized
experiments had long ago been the subject of technical journal articles, even press
accounts, and were old news; other commentators countered that, for most of the
public, articles in technical journals might as well be secret.
How, why, and from what population groups were subjects selected for
experiments? Some suspected that subjects were disproportionately chosen from
the most vulnerable populations-children, hospitalized patients, the retarded, the
poor—those too powerless to resist the government and its researchers.
Did the experiments benefit the American people through the
advancement of science and the enhancement of the ability to treat disease?
How many intentional releases took place, and how many people were
unknowingly put at risk? The answer here was sketchy; the releases identified in
the November 1993 Glenn report had all been performed in secret, and much
information about them was still secret.
How great were the risks to which people were exposed? Many pointed
out that radiation is not only present in our natural environment, but that, as a
result of biomedical research, most people routinely rely on radiation as a means
of diagnosing and treating disease. Others noted that while this is so, radiation
can be abused, and the potential dangers of low-level exposure are still not well
understood.
What did our government and the medical researchers it sponsored do to
ensure that the subjects were informed of what would be done to them and that
they were given meaningful opportunities to consent? Today, federal government
rules require the prior review of proposed experiments, to ensure that the risks
and potential benefits have been considered and that subjects will be adequately
informed and given the opportunity to consent. But the standards of today, many
historians and scholars of medical ethics noted, are not those of yesterday.
Others, however, declared that it was self-evident that no one should be
experimented upon without his or her voluntary consent. Indeed, it was pointed
out that this very principle was proclaimed aloud to the world in 1947, as the
plutonium experiments were coming to a close. It was the American judges at the
international war crimes trials in Nuremberg, Germany, who invoked the
principle in finding doctors guilty of war crimes for their vile experiments on
inmates of Nazi concentration camps. How could yesterday's standard have been
less strict than that of today? How, moreover, could the standard not have been
known by the government that sponsored the experiments and the researchers
who conducted them?
Finally, there were questions about how human experiments are
conducted today. Insofar as wrong things happened in the past, how confident
should we be that they could not happen again? Have practices changed? Do we
have the right rules, and are they implemented and enforced?
4
Preface
THE PRESIDENT'S CHARGE
The Advisory Committee was created under the Federal Advisory
Committee Act of 1972, which provides that committee meetings and basic
decision making be conducted in the open. The Committee's charter 4 defined
human radiation experiments to include
(1) experiments on individuals involving intentional exposure to
ionizing radiation. This category does not include common and
routine clinical practices. . . .
(2) experiments involving intentional environmental releases of
radiation that (A) were designed to test human health effects of
ionizing radiation; or (B) were designed to test the extent of human
exposure to ionizing radiation.
The Committee was mandated to review experiments conducted between
1944 and 1974, the latter being the year that the U.S. Department of Health,
Education, and Welfare issued rules for the protection of human subjects of
federally sponsored research. The Committee was asked to determine the ethical
and scientific standards by which to evaluate the pre- 1974 experiments and the
extent to which these experiments were consistent with such standards. We were
also to "consider whether (A) there was a clear medical or scientific purpose for
the experiments; (B) appropriate medical follow-up was conducted; and (C) the
experiments' design and administration adequately met the ethical and scientific
criteria, including standards of informed consent, that prevailed at the time of the
experiments and that exists today." The charter also directed that, upon
completing our review, the Committee may recommend that subjects (or families)
be notified of potential health risks and the need for medical follow-up and also
that we "may recommend further policies, as needed, to ensure compliance with
recommended ethical and scientific standards for human radiation experiments."
In order to inform the public about the conduct of research involving
human subjects taking place today, we were authorized to sample and consider
examples of research with human subjects currently under way.
In essence, we were to answer several fundamental questions: (1) What
was the federal government's role in human radiation experiments conducted from
1944 to 1974? (2) By what standards should the ethics of these experiments be
evaluated? and (3) What lessons learned from studying past and present research
standards and practices should be applied to the future?
In addition, while the Committee was not expressly charged with
considering issues relating to remedies, including financial compensation, we
have felt obliged to address the type of remedies that we believe the government,
Preface
as an ethical matter, should provide to subjects of experiments where the
circumstances warranted such a response.
THE COMMITTEES APPROACH
When those of us selected by President Clinton to serve on the Committee
read about human radiation experiments in our hometown newspapers during the
1993 holiday season, none of us imagined that within months we would be
embarking on such an intense and challenging investigation of an important
aspect of our nation's past and present, requiring new insights and difficult
judgments about enduring ethical questions.
On April 2 1 and 22, 1 994, the Committee held its first meeting, and most
of us met each other for the first time. As we listened to opening statements by
Cabinet members and members of Congress, as well as the first witness from the
general public, it became clear how daunting a task we were undertaking. We
realized that our ability to reconstruct the story of past radiation experiments
required both the capacity to join with the agencies in the search through
thousands of boxes for documents and the intuition to recognize which documents
were important. We knew that the ability to tell that story depended on our ability
to understand the full range of technically complex, often emotionally charged
issues related to human radiation experiments. We could not understand, much
less tell, the story until we sought out all who could enhance our understanding, a
difficult job because the voices to which we had to listen spoke in the varied
languages of medicine, a multiplicity of scientific disciplines, the military,
policymakers, philosophers, patients, healthy subjects, family members of former
subjects, and individuals in a variety of other roles.
Finally, we were also convinced that an important determinant of our
success in keeping faith with the American people would be to understand not
only how human subject research was conducted in the past but also how it is
being conducted in the present.
Reaching In and Reaching Out
As we began our work, Committee members first sought to educate one
another. Early meetings included basic presentations on such topics as research
ethics, radiation, the history of human experimentation, the law of remedies, and
the debate over the effects of low levels of radiation.
Then we determined to search broadly for those who could contribute to
our understanding. We hired a staff with the expertise and experience need for
the Committee's myriad tasks. Finally, we sought to make ourselves available to
those who wanted to speak to us directly, especially people who felt they or their
loved ones were harmed, or might have been harmed, by human radiation-related
Preface
research or exposure. Each of the Committee's meetings reserved a period for
public comment. Since April 1994, the full Committee held sixteen public
meetings, each of two to three days' duration. Fifteen of those meetings were held
in Washington, D.C., and one was in San Francisco. In addition,; subsets of
Committee members presided over public forums in Cincinnati, Knoxville, Santa
Fe and Spokane. We traveled to these different cities in order to hear from
people who could not come to Washington, D.C., and lived in communities
where, or near where, experiments or intentional releases of interest to the
Committee had taken place. We further sought to reach out to those who could
not attend our meetings. By phone, mail, and personal visit, we and our staff
communicated with members of the public, researchers, attorneys, investigative
reporters, authors, and representatives of dozens of groups of interested people
who shared some aspect of the Committee's concern.
The Records of Our Past: The Search for Documents
One of the most difficult tasks before the Committee was determining how
many federally sponsored human radiation experiments occurred between 1944
and 1974 and who conducted them. When President Clinton established the
Committee, he also directed the Human Radiation Interagency Working Group to
provide us with all relevant documentary information in each of the agencies
files Teams were formed to identify the hundreds of government sites where
relevant documents might be located. We discovered there was no easy way to
identify how many experiments had been conducted, where they took place and
which government agencies had sponsored them. The location and retrieval of
documents thus required an extraordinary effort, and we appreciate the assistance
of all our collaborators. . , ...
We began with documents that were assembled during the 1980s and that
provided the basis for the Markey report. But review of those materials
confirmed that, even for this relatively well-known group of u ex P^ m ^ ; basic
information was lacking. We found that the Department of Health ; an Humm
Services (DHHS), which is the primary government sponsor of research involving
human subjects, reported that, as permitted by federal records laws it had long
since discarded files on experiments performed decades ago. Furthermore, the
capsule descriptions of research that remained sometimes did not make clear
whether the subjects of research had been humans or animals To complicate
matters further, the DHHS also pointed out that much research documentation had
originated and been retained only in the files of nonfederal grantee institutions
and investigators. Other agencies did provide some lists of experiments, in many
cases however, there was no information on basic questions of concern (tor
example, who the subjects were and what, if anything, they were told).
What rules or policies, if any, existed to govern federally sponsored
Preface
experiments in the pre- 1974 period? The prevailing assumption was that, with a
few notable exceptions, it was not until the mid-1960s that federal agencies began
to develop such policies in any significant way. Most scholarship focused on
divisions of the (then) Department of Health, Education, and Welfare. Little was
known about approaches to human experimentation at the Atomic Energy
Commission and the Department of Defense. Yet it was clear from the outset of
our inquiry that these agencies, as well as the DHEW, were central to the story of
human radiation experiments and that many of the experiments of interest
predated by decades the mid-1960s' interest in human subject protections.
As we began our search into the past, we found that it was necessary to
reconstruct a vanished world. The Committee and the agencies had to collect
information scattered in warehouses throughout the country. At the same time,
we had to create and test the framework needed to ensure that there would be a
"big picture" into which all the pieces of the puzzle would fit.
After a few months, the outlines of a world that had been almost lost
began to reemerge. Working with the Defense Department, we discovered that
long-forgotten government entities had played central roles in the planning of
midcentury atomic warfare-related medical research and experimentation. These
groups, the piecing together of long-lost or forgotten records would show,
debated the ethics of human experimentation and discussed possible human
radiation experimentation: Similarly, working with the Department of Energy, we
pieced together the minutes, and even many transcripts, of the key medical
advisory committee to the Atomic Energy Commission. We sought to mine
agency histories, when th£y existed: for example, at the Committee's request, the
Defense Nuclear Agency (the heir to the part of the Manhattan Project that was
transferred to the Defense Department) made public portions of the more than 500
internal histories that chronicle its story, most of which had previously been
available only to those with security clearances.
Despite these successes, it became evident that the records of much of our
nation's recent history had been irretrievably lost or simply could not be located.
The Department of Energy told the Committee that all the records of the
Intelligence Division of its predecessor, the Atomic Energy Commission, had
been destroyed— mainly during the 1970s, but in some cases as late as 1989. The
CIA explained, as had been previously reported, that records of the program
known as MK.ULTRA, in which unwitting subjects were experimented upon with
a variety of substances, had been destroyed during the 1970s, when the program
became a widely publicized scandal. Though documents related to the program
referred to radiation, the CIA concluded that human experiments using ionizing
radiation never took place under that program, based on currently available
evidence.
We also turned to nongovernmental archives throughout the country.
Cryptic notes and fragments of correspondence located in private and university
8
Preface
archives were fitted into our growing outline. For example, a copy of an
important 1954 Army surgeon general research policy statement, referenced in
Defense Department documents, was found at Yale University among the papers
of a Nobel laureate. . ,
Bv the end of our term, the Committee had received, organized, and
reviewed hundreds of thousands of pages of documents from public and private
archives This collection will be available to individuals and scholars who wish
to pursue the great many stories that remain to be told, and we view this as one of
our most significant contributions.
The Records of Our Past: The Memories of the People
The Committee listened to the testimony of more than 200 public
witnesses who appeared before us. We heard from people or their family
members who had been subjects in controversial radiation experiments, including
the plutonium injections, total-body irradiation experimen ts and ex Penments
involving the use of radioactive tracers with institutionalized children. We heard
from "atomic veterans": soldiers who had been marched to ground zero at atomic
bomb tests, sailors who had walked the decks of ships contaminated by
radioactive mist, and pilots who had flown through radioactive mushroom clouds.
We also heard from their widows. We heard from people who lived "downwind
from nuclear weapons tests in Nevada and intentional releases of radioactive
material in Washington state. We heard from Navajo miners who had served the
Country in uranium mines filled with radioactive dust, from native Alaskans who
had been experimented upon by a military cold weather research . lab, and I from
Marshall Islanders, whose Pacific homeland had been contaminated by fallout
after a 1954 hvdrogen bomb test.
We heard from officials and researchers responsible for human t research
today and from those who were present at or near the dawn of the Cold War. We
heard from individuals who, on their own time, had long been seeking to piece
together the story of human radiation experiments and offered to share their
findings. We heard from scholars, from members of Congress, and from people
who wanted to bear witness for those who could no longer speak We heard from
a woman who, as a high-school student intern decades ago, attended at the
bedside while a terminally ill patient was injected with uranium and from a
powerfully spoken veteran of the nuclear weapons work force who told of the
"bodv snatching" of dead friends in the name of science.
Most important, we heard from many people who believed that something
involving the government and radiation happened to them or their loved ones
decades ago; most had been unable to find out exactly what had happened, or
whv and now they wanted to know the truth. These witnesses spoke eloquent y
of their pain, their frustration, and the reasons they do not trust the government.
Preface
Their very appearance before the Committee testified to a commitment to the
country and to the value of the nation's effort to understand its past. We are
deeply grateful to all of these witnesses, who overcame the obstacles of
geography and emotions to participate in this work.
We combined our public meetings with additional efforts to interview, and
record for the nation's archives, those who could shed light on Cold War human
radiation experiments and on the ethics of biomedical experimentation. Dozens
of interviews were conducted with former government officials responsible for
programs that included radiation research, as well as with radiation researchers.
In Mississippi we talked with a retired general who served as a military
assistant to secretaries of defense in the 1940s and 1950s; in Berkeley, we talked
with the chemist who was one of the discoverers of plutonium; in Rhode Island
we talked with the physicist who served as the link between the civilian health
and safety agencies and the Cold War military research efforts; in Florida we
talked with a pioneer in health physics, a discipline created to provide for the
safety of nuclear weapons workers; in San Francisco and Washington, D.C., we
talked to the lawyers who advised the Atomic Energy Commission at its postwar
creation; in New York we talked with the Navy radiation researcher who was
rousted from his Maryland laboratory to respond to the emergency created by the
exposure of the Marshall Islanders; in San Diego we talked with a researcher
whose own career and massive history of radiation research had covered much of
the Committee's territory.
We also launched a special effort, called the Ethics Oral History Project,
to learn from eminent physicians who were beginning their careers in academic
medicine in the 1940s and 1950s about how research with human subjects was
then conducted. The Ethics Oral History Project also included interviews with
two people who had been administrators of the National Institutes of Health
during the 1950s, since they were intimately involved with ethical and legal
aspects of research involving human subjects at the time.
We listened to all these people and more, and through their testimony, this
report is informed.
Bounds of Our Inquiry
In the course of listening to public testimony, it became clear to us that
confusion exists about what an experiment is and whether it can be distinguished
from other activities in which people are put at risk and information is gathered
about them. The biomedical community, for example, struggles with the
distinction between scientific research and related activities. In a medical setting,
it is sometimes hard to distinguish a formal experiment designed to test the
effectiveness of a treatment from ordinary medical care in which the same
treatment is being administered outside of a research project. The patient
10
Preface
receiving the treatment may discern no difference between the two but the
Sn is relevant to questions of ethics. The physician-investigator may face
conflicts between the obligation to do what is best for each individual patient .and
the requirements of scientific research, whereas the physician involved only in
clinical care has a responsibility solely to the patient.
Similarly, in an occupational setting in which employees are put at risk, it
is often difficult to distinguish formal scientific efforts to study effects on the
health of employees fromroutine monitoring of employees exposure to hazards
in the work place for purposes of ensuring worker safety. In the first case, the
r^les of research ethics apply; in the second they do not. And yet here too, the
worker may discern no difference between the two activities. A further
complication for the Committee to consider was the fact that research in
occupational settings rarely takes the form of a classic experiment, in which the
investigator controls the variable under study and then randomly assigns subjects
to be in the "treatment" or "control" group. Instead, most occupational research
employs observational and statistical methods, drawing most heavily from the
field of epidemiology. These distinctions were unimportant, however to Mhe
representatives of atomic veterans, uranium miners, and residents of the Marshall
Islands, who told us of their belief that they, or those they spoke for, were
subjects of research. j-„*:„„
The Committee struggled with how strictly to define human radiation
experiments for purposes of our inquiry. There is no sin gle clear definition of an
experiment that is widely subscribed to by every member of the biomedical
community. Even our description above of a classic experiment is open to
contest Today, as well as in the past, the scientific community has rarely
employed the term experiment in discussions of biomedical research; other terms,
not necessarily synonymous-such as clinical study, clinical investigation, quasi
Zeriment, and case control study--** all used. We concluded that it was not
possible to interpret our charge by stipulating an artificial definition of human
radiation experiment. Instead, in keeping with the realities of bl0 ™ e ? ical
research, we decided to interpret our charge broadly, as including both research
involving human subjects in which the research design called for exposing
subjects to ionizing radiation and research designed to study the effects of
radiation exposure resulting from nonexpenmental activities.
This latter category includes the research involving uranium miners and
Marshall Islanders. In these cases we quickly determined that it was in some
respects impossible to isolate the ethical questions raised by the research from the
ethics of the context in which the research was conducted. A centra issue was
the exposure of people to risk, regardless of whether they were clearly understood
to be subjects of research. This characterization is true, as well, of the experience
of atomic veterans. As a consequence, we considered events that might be said to
be on the boundary between research and some other activity. Our inquiry
11
Preface
underscored the importance for social policy of the need to keep focused on
questions of risk and well-being regardless of what side of that boundary the
activity producing the risk falls.
Human Experimentation Today
In tandem with the reconstruction of the past, we undertook three projects
to examine the current state of human radiation experiments.
First, we studied how each agency of the federal government that
currently conducts or funds research involving human subjects regulates this
activity and oversees it. We surveyed what the operative rules are, how they are
implemented, and how they are enforced.
Second, from among the very large number of research projects involving
human subjects currently supported by the federal government, we randomly
selected 125 research projects for scrutiny by the Committee. For each of these
projects, we reviewed all available relevant documentation to assess how well it
appeared the rights and interests of the subjects participating in these projects
were being protected. The success of this review required the cooperation of
private research institutions all over the country, on whom we were dependent for
access to important documents. We had expected that perhaps no more than half
of those asked to cooperate would agree to do so, but with little hesitation, all of
the research centers that we approached agreed to cooperate.
Third, to learn from the subjects themselves, the Committee interviewed
almost 1,900 patients receiving medical care in outpatient facilities of private and
federal hospitals throughout the country. We asked patients about their attitudes
toward medical research with human subjects and about the meaning they attach
to the different terms used to explain medical research to potential subjects. We
ascertained, and attempted to verify, how many of these patients were currently or
ever had been subjects of research. Patient-subjects were asked about their
reasons for agreeing to join research projects; patients who reported having
refused offers to enter research projects were asked why they had decided against
participating.
In all three of these projects, we focused not only on human radiation
experiments but on human research generally. In critical (but not all) respects,
the government regulations that apply to human radiation research do not differ
from those that govern other kinds of research involving human subjects.
Moreover, the underlying ethical principles that should guide the conduct of
research are identical, whether one is considering human radiation research or all
research with human subjects. Finally, the Committee hoped to learn whether, in
practice, there are any differences between the conduct of radiation and
nonradiation experiments.
12
Preface
LESSONS FROM HISTORY: LOOKING TO THE FUTURE
What we have found is a story about the government's attempt to serve
two critical purposes: safeguarding national security and advancing medical
knowledge. One-half century ago, the U.S. government and its experts in the
fields of radiation and medicine were seeking to learn more about radiation in
order to protect workers, service personnel, and the general public against
potential atomic war and individuals against the menace of disease.
Toward these laudable ends, the government used patients, workers,
soldiers, and others as experimental subjects. It acted through the experts to
whom we regularly entrust the well-being of our country and our selves: elected
officials, civil servants, generals, physicians, and medical researchers.
Moreover, the government acted with full knowledge that the use of
individuals to serve the ends of government raises basic ethical questions. If, as
we look back, there could be doubt about the importance of the matter to the
leaders of the time, we need only look to the appearance before the U.S. Senate of
David Lilienthal, who had been nominated to serve as the first chairman of the
Atomic Energy Commission, the civilian successor to the Manhattan Project and
the predecessor to today's Department of Energy. In his testimony, Lilienthal
forcefully stated:
... all Government and private institutions must be
designed to promote and protect and defend the
integrity and the dignity of the individual. . . . Any
forms of government . . . which make men means
rather than ends in themselves ... are contrary to
this conception; and therefore I am deeply opposed
to them. . . . The fundamental tenet of communism
is that the state is an end in itself, and that therefore
the powers which the state exercises over the
individual are without any ethical standards to limit
them. This I deeply disbelieve. 6
What did happen when individuals were sometimes used as means to
achieve national goals? How well were the national goals of preserving the peace
and advancing medical science reconciled with the equally important end of
respect for individual dignity and health? What rules were followed to protect
people, and how well did they work? Was the public let in on the balancing of
collective and individual interest? In what sense did the public, in general, and
individuals, in particular, know what was happening and have the opportunity to
provide their meaningful consent?
In this report we try to convey our understanding of how, when only good
13
Preface
was sought, when its pursuit was entrusted to the experts on whom we most
relied, and when missions were substantially accomplished, distrust, as well as
accomplishment, remains.
We focus on the ways in which the government and its experts recognized
the interest of individual dignity and sought to strike a balance with the national
interests being pursued. We focus equally on the extent to which the public was
privy to this balancing. In particular, we try to show how individuals'
understanding and participation were limited by the conjunction of government
secrecy and expert knowledge.
All Americans should experience immense satisfaction in the strides that
have been made toward accomplishing both our national security and our medical
research goals. However, as attested to by the many thousands of letters and calls
that led to the Committee's creation, and the eloquent statements of the witnesses
who appeared before us, this pride is diluted by a bitter aftertaste-distrust by
many Americans of the federal government and those who served it.
The government has the power to create and keep secrets of immense
importance to us all. Secret keeping is a part of life. Secret keeping by the
government may be in the national interest. However, if government is to be
trusted, it is important to know, at the very least, the basic rules of secrecy and to
know that they are reasonable and that they are being followed.
Similarly, experts, by training and experience, have knowledge that
individual people must, as a practical matter, rely on. However, legitimate
questions arise when experts wear multiple hats or when they are relied on in
areas beyond their expertise.
Where official secrecy is coupled with expert authority, and both are
focused on a public that is not privy to secrets and does not speak the languages
of experts, the potential for distrust is substantial.
In telling the story, and asking the questions, we have kept our eyes open
for ways in which lost trust can be restored. It might be presumed that the past
we report on here is so different from the present that it will be of little use in
understanding research involving human subjects today. In fact, as we shall see,
basic questions posed by the story of human radiation experiments conducted
during the 1944-1974 period are no less relevant today. Then, as now, there were
standards; the question is how they worked to protect individuals and the public.
Then, as now, the ethical impulse was complexly alloyed with concerns for legal
liability and public image. Then, as now, the most difficult questions often
concerned the scope and practical meaning of ethical rules, rather than their
necessity. The country has come to recognize, from its experience of the past half
century, that tinkering with the regulations that govern publicly supported
institutions, imposing ethical codes on experts, and altering the balance between
secrecy and openness are important but not always sufficient means of reform.
The most important element is a citizenry that understands the limits of these
14
Preface
activities. That is why the purpose of this story is not simply to leam which
changes to make in rules or policies that apply to government or professionals,
but to begin to learn something more about how the Cold War world worked, as
the most important means to making the world of tomorrow work better.
HOW THIS REPORT IS ORGANIZED
Though this report is addressed largely to those who can affect future
policy in light of the information the Advisory Committee has gathered,
specifically the Human Radiation Interagency Working Group, it has been written
in such a way that it should be accessible to a wide range of interested readers.
We begin with an introduction, titled "The Atomic Century," which
describes the intersection of several developments: the birth and remarkable
growth of radiation science; the parallel changes in medicine and medical
research; and the intersection of these changes with government programs that
called on medical researchers to play important new roles beyond that involved in
the traditional doctor-patient relationship. The introduction concludes with a
section titled "The Basics of Radiation Science" for the lay reader.
The remainder of the text is divided into four parts. Each part is preceded
by an overview.
Part I, "Ethics of Human Subjects Research: A Historical Perspective,"
which contains four chapters, explores how both federal government agencies and
the medical profession approached human experimentation in the period 1944
through 1974. We begin with the story of the principles stated at midcentury at
the highest levels of the Cold War medical research bureaucracies and what we
have ascertained about whether these principles were translated into federal rules
or requirements. We then turn to the norms and practices engaged in at the time
by medical researchers themselves. It is in this chapter that we report the results
of our Ethics Oral History Project. In chapter 3, we review the development of
formal and public regulations concerning research involving human subjects in
the 1960s and 1970s. In the last chapter in part I we present our framework for
evaluating the ethics of human radiation experiments, grounded in both history
and philosophical analysis.
Part II, "Case Studies," approaches particular experiments from several
angles, each of which raises overlapping ethical questions. The chapters on the
plutonium injections and total-body irradiation consider the use of sick patients to
provide data needed to protect the health of workers engaged in the production of
nuclear weapons; the chapter on prisoners considers the use of healthy subjects
for this purpose; the chapter on children considers experimentation with
particularly vulnerable people; and the chapter on the AEC program of
radioisotope distribution considers the institutional safeguards that underlay the
conduct of thousands of human radiation experiments. The chapters on
15
Preface
intentional releases, atomic veterans, and observational studies consider, in
common, situations in which entire groups of people were exposed to risk as a
consequence of government-sponsored Cold War programs. The section
concludes with a review of the degree to which secrecy impaired, and may still
impair, our ability to understand human radiation experiments and intentional
releases conducted in the 1944-1974 period.
Part III, "Contemporary Projects," reports the findings of our three
inquiries into the present. We begin by describing what we have learned about
how the different federal agencies that sponsor human research regulate and
oversee this activity. Next, we report the results of our Research Proposal
Review Project, followed by the results of our Subject Interview Study. Part III
concludes with the Committee's synthesis of the implications of the results of all
three of these projects for the current state of human subject research.
Part IV, "Coming to Terms with the Past, Looking Ahead to the Future,"
reports the Committee's findings and recommendations.
A FINAL NOTE
The Committee's findings and recommendations represent our best efforts
to distill almost eighteen months of inquiry into, debate about, and analysis of
human radiation experiments. But what they cannot fully express is the
appreciation we developed for how much damage was done to individuals and to
the American people during the period we investigated and how this damage
endures today. The damage we speak of here is not physical injury, although this
too did occur in some cases. Rather, the damage is measured in the pain felt by
people who believe that they or their loved ones were treated with disrespect for
their dignity and disregard for their interests by a government and a profession in
which they had placed their trust. It is measured in a too-often cynical citizenry,
some of whom have lost faith in their government to be honest brokers of
information about risks to the public and the purposes of government actions.
And it is measured in the confusion among patients that remains today about the
differences between medical research and medical care— differences that can
impede the ability of patients to determine what is in their own best interest.
In the period that we examined, extraordinary advances in biomedicine
were achieved and a foundation was laid for fifty years without a world war. At
the same time, however, it was a time of arrogance and paternalism on the part of
government officials and the biomedical community that we would not under any
circumstances wish to see repeated.
As we listened to the heart-rending testimony of many public witnesses,
we came to feel great sorrow about the suffering they described. Our most
difficult task was determining what to recommend as the appropriate national
response to these emotions and the events that stimulated them. What can best
16
Preface
precipitate the healing of wounds and the restoration of trust? Appropriate
remedies for those who were wronged or harmed were of critical importance, but
remedies alone speak only to the past, not the future. It is equally important that,
the historical record having been spelled out and appropriate remedies identified,
we as a nation move forward and take action to prevent similar occurrences from
happening in the future. In the end, if trust in government is to be restored, those
in power must always act in good faith in their dealings with the citizenry. At the
same time, however, we must recognize that unless we have expectations of
honesty and fairness from our government and unless we are vigilant in holding
the government to those expectations, trust will never be restored.
Finally, we hope that this report conveys the sense of gratitude and honor
that we experienced as citizens serving on the Advisory Committee. We were
provided by the President with extraordinary access to the records of our past and
given complete liberty to deliberate on what we found. Although some of what
we report is a matter for national regret, our freedom of inquiry, and the
cooperation we received from officials and fellow citizens of all perspectives,
confirms that our nation's highest traditions are not things of the past but live very
much in the present.
17
ENDNOTES
1 . U.S. House of Representatives, Committee on Energy and Commerce,
Subcommittee on Energy Conservation and Power, November 1986, "American Nuclear
Guinea Pigs: Three Decades of Radiation Experiments on U.S. Citizens" (ACHRE No.
CON-050594-A-1).
2. U.S. Senate, Committee on Governmental Affairs, 1 1 November 1993,
"Nuclear Health and Safety: Examples of Post World War II Radiation Releases at U.S.
Nuclear Sites," GAO/RCED-94-51-FS (ACHRE No. CON-042894-A-4).
3. Advisory Committee on Human Radiation Experiments, proceedings of 21
April 1994, transcript, 112-113.
4. The full text of the Committee's charter appears at the end of this report. See
table of contents for page number.
5. For further information on access to this collection, see "A Citizen's Guide to
the Nation's Archives" at the end of this report.
6. David E. Lilienthal, The Journals of David E. Lilienthal: 1945-1950, 2 vols.
(New York: Harper and Row, 1964), as quoted in David McCullough, Truman (New
York: Simon and Schuster, 1992), 537-538.
18
INTRODUCTION
The Atomic Century
One hundred years ago, a half century before the atomic bombing of
Hiroshima and Nagasaki, the discovery of x rays spotlighted the extraordinary
promise, and peril, of the atom. From that time until 1942, atomic research was in
private hands. The Second World War and the Manhattan Project, which planned
and built the first atomic bombs, transformed a cottage industry of researchers
into the largest and one of the most secretive research projects ever undertaken.
Scientists who had once raced to publish their results learned to speak in codes
accessible only to those with a "need to know." Indeed, during the war the very
existence of the man-made element plutonium was a national secret.
After the war's end, the network of radiation researchers, government and
military officials, and physicians mobilized for the Manhattan Project did not
disband. Rather, they began working on government programs to promote both
peaceful uses of atomic energy and nuclear weapons development.
Having harnessed the atom in secret for war, the federal government
turned enthusiastically to providing governmental and nongovernmental
researchers, corporations, and farmers with new tools for peace-radioisotopes-
mass-produced with the same machinery that produced essential materials for the
nation's nuclear weapons. Radioisotopes, the newly established Atomic Energy
Commission (AEC) promised, would create new businesses, improve agricultural
production, and through "human uses" in medical research, save lives.
From its 1947 creation to the 1974 reorganization of atomic energy
activities, the AEC produced radioisotopes that were used in thousands of human
radiation experiments conducted at universities, hospitals, and government
facilities.' This research brought major advances in the understanding of the
19
Introduction
workings of the human body and the ability of doctors to diagnose, prevent, and
treat disease.
The growth of radiation research with humans after World War II was part
of the enormous expansion of the entire biomedical research enterprise following
the war. Although human experiments had long been part of medicine, there had
been relatively few subjects, the research had not been as systematic, and there
were far fewer promising interventions than there were in the late 1940s.
With so many more human beings as research subjects, and with
potentially dangerous new substances involved, certain moral questions in the
relationship between the physician-researcher and the human subject—questions
that were raised in the nineteenth century-assumed more prominence than ever:
What was there to protect people if a researcher's zeal for data gathering
conflicted with his or her commitment to the subjects' well-being? Was the age-
old ethical tradition of the doctor-patient relationship, in which the patient was to
defer to the doctor's expertise and wisdom, adequate when the doctor was also a
researcher and the procedures were experimental?
While these questions about the role of medical researchers were fresh in
the air, the Manhattan Project, and then the Cold War, presented new ethical
questions of a different order.
In March 1946, former British Prime Minister Winston Churchill told an
audience in Fulton, Missouri, that an "iron curtain" had descended between
Eastern and Western Europe—giving a name to the hostile division of the
continent that had existed since the end of World War II. By the following year.
Cold War was the term used to describe this state of affairs between the United
States and its allies on the one hand and the Soviet bloc on the other. A quick
succession of events underscored the scope of this conflict, as well as the stakes
involved: In 1948 a Soviet blockade precipitated a crisis over Berlin; in 1949, the
American nuclear monopoly ended when the Soviet Union exploded its first
atomic bomb; in 1950, the Korean War began.
The seeming likelihood that atomic bombs would be used again in war,
and that American civilians as well as soldiers would be targets, meant that the
country had to know as much as it could, as quickly as it could, about the effects
of radiation and the treatment of radiation injury.
This need for knowledge put radiation researchers, including physicians,
in the middle of new questions of risk and benefit, disclosure and consent. The
focus of these questions was, directly and indirectly, an unprecedented public
health hazard: nuclear war. In addressing these questions, medical researchers
had to define the new roles that they would play.
As advisers to the government, radiation researchers were asked to assist
military commanders, who called for human experimentation to determine the
effects of atomic weapons on their troops. But these researchers also knew that
human experimentation might not readily provide the answers the military
needed.
20
The Atomic Century
As physicians, they had a commitment to prevent disease and heal. At the
same time, as government advisers, they were called upon to participate in
making decisions to proceed with weapons development and testing programs
that they knew could put citizens, soldiers, and workers at risk. As experts they
were asked to ensure that the risks would not be excessive. And as researchers
they saw these programs as an opportunity for gathering data.
As researchers, they were often among the first to volunteer to take the
risks that were unavoidable in such research. But the risks could not always be
disclosed to members of the public who were also exposed. In keeping with the
tradition of scientific inquiry, these researchers understood that their work should
be the subject of vigorous discussion, at least among other scientists in their field.
But, as government officials and advisers, they understood that their public
statements had to be constrained by Cold War national security requirements, and
they shared in official concern that public misunderstanding could compromise
government programs and their own research.
Medical researchers, especially those expert in radiation, were not
oblivious to the importance of the special roles they were being asked to play.
"Never before in history," began the 1949 medical text Atomic Medicine, "have
the interests of the weaponeers and those who practice the healing arts been so
closely related." 2 This volume, edited by Captain C. F. Behrens, the head of the
Navy's new atomic medicine division, was evidently the first treatise on the topic.
It concluded with a chapter by Dr. Shields Warren, the first chief of the AEC's
Division of Biology and Medicine, who would become a major figure in setting
policy for postwar biomedical radiation research. While the atomic bomb was not
"of medicine's contriving," the book began, it was to physicians "more than to any
other profession" that atomic energy had brought a "bewildering array of new
problems, brilliant prospects, and inescapable responsibilities." The text, a
prefatory chapter explained, treats "not of high policy, of ethics, of strategy or of
international control [of nuclear materials], as physicians these matters are not for
us." 3 Yet what many readers of Atomic Medicine could not know in 1949 was
that Behrens, along with Warren and other biomedical experts, was already
engaged in vigorous but secret discussions of the ethics underlying human
radiation experiments. At the heart of these discussions lay difficult choices at
the intersection of geopolitics, science, and medicine that would have a
fundamental impact on the federal government's relationship with the American
people.
This chapter provides a brief survey of the development of radiation
research and the changing roles of the biomedical researcher, from the discovery
of x rays by a single individual to the complex world of government-sponsored
human radiation experimentation. Finally, at the end of this chapter, an aid to the
reader titled "The Basics of Radiation Science" provides information needed to
understand technical concepts in this report.
21
Introduction
BEFORE THE ATOMIC AGE: "SHADOW PICTURES,"
RADIOISOTOPES, AND THE BEGINNINGS OF HUMAN
RADIATION EXPERIMENTATION
Radiation has existed in nature from the origins of the universe, but was
unknown to man until a century ago. Its discovery came by accident. On a
Friday evening, November 8, 1895, the German physicist Wilhelm Roentgen was
studying the nature of electrical currents by using a cathode ray tube, a common
piece of scientific equipment. When he turned the tube on, he noticed to his
surprise that a glowing spot appeared on a black paper screen coated with
fluorescent material that was across the room. Intrigued, he soon determined that
invisible but highly penetrating rays were being produced at one end of the
cathode ray tube. The rays could expose photographic plates, leaving shadows of
dense objects, such as bone.
After about six weeks of experimenting with his discovery, which he
called x rays, Roentgen sent a summary and several "shadow pictures" to a local
scientific society. The society published the report in its regular journal and
wisely printed extra copies. News spread rapidly; Roentgen sent copies to
physicists throughout Europe. One Berlin physicist "could not help thinking that
I was reading a fairy tale . . . only the actual photograph proved to everyone that
this was a fact." 4
Physicians immediately recognized these rays as a new tool for diagnosis,
a window into the interior of the body. The useless left arm of German Emperor
Wilhelm II was x-rayed to reveal the cause of his disability, while Queen Amelia
of Portugal used x rays of several of her court ladies to vividly display the
dangers of "tightlacing." 5 Physicians began to use x rays routinely for examining
fractures and locating foreign objects, such as needles swallowed by children or
bullets shot into adults. 6 During World War I, more than 1.1 million wounded
soldiers were treated with the help of diagnostic x rays. 7
In 1 896, Roentgen's insight led to the discovery of natural radioactivity.
Henri Becquerel, who had been studying phosphorescence, discovered that
shadow pictures were also created when wrapped photographic plates were
exposed to crystals partly composed of uranium. Could this radioactive property
be concentrated further by extracting and purifying some as-yet-unknown
component of the uranium crystals? Marie and Pierre Curie began laborious
chemical analyses that led to the isolation of the element polonium, named after
Marie's native Poland. 8 Continuing their work, they isolated the element radium.
To describe these elements' emission of energy, they coined the word radio-
activity!'
As with x rays, popular hopes and fears for natural radioactivity far
exceeded the actual applications. One 1905 headline captures it all: "Radium, as
a Substitute for Gas, Electricity, and as a Positive Cure for Every Disease." 10
22
The Atomic Century
Following initial enthusiasm that radiation could, by destroying tumors, provide a
miracle cure for cancer, the reappearance of irradiated tumors led to
discouragement. Despite distressing setbacks, research into the medical uses of
radiation persisted. In the 1920s French researchers, performing experiments on
animals, discovered that radiation treatments administered in a series of
fractionated doses, instead of a single massive dose, could eliminate tumors
without causing permanent damage. With the new method of treatment, doctors
began to report impressive survival rates for patients with a variety of cancers.^
Fractionation became, and remains, an accepted approach to cancer treatment.
Along with better understanding of radiation's benefits came a better
practical appreciation of its dangers. Radiation burns were quickly apparent, but
the greater danger took longer to manifest itself. Doctors and researchers were
frequently among the victims. Radiation researchers were also slow to take steps
to protect themselves from the hidden danger. One journal opened its April 1914
issue by noting that "[w]e have to deplore once more the sacrifice of a radiologist,
the victim of his art." 12
Clear and early evidence of tragic results sharpened both expert and public
concern. By 1924, a New Jersey dentist noticed an unusual rate of deterioration
of the jawbone among local women. On further investigation he learned that all
at one time had jobs painting a radium solution onto watch dials. Further studies
revealed that as they painted, they licked their brushes to maintain a sharp point.
Doing so, they absorbed radium into their bodies. The radium gradually revealed
its presence in jaw deterioration, blood disease, and eventually, a painful,
disfiguring deterioration of the jaw. 13 There was no question that radium was the
culprit. The immediate outcome was a highly publicized crusade, investigation,
lawsuits, and payments to the victims. Despite the publicity surrounding the dial
painters, response to the danger remained agonizingly slow. Patent medicines
containing radium and radium therapies continued. 14
The tragedy of the radium dial painters and similar cases of patients who
took radium nostrums have provided basic data for protection standards for
radioactive substances taken into the body. One prominent researcher in the new
area of radiation safety was Robley Evans. Evans was drawn into the field by the
highly publicized death in 1932 of Eben Byers, following routine consumption of
the nostrum Radiothor. Byers's death spurred Evans, then a California Institute of
Technology physics graduate student, to undertake research that led to a study of
the effects on the body of ingesting radium; this study would continue for more
than half a century. 15
Evans's study and subsequent studies of the effects of radium treatments
provided the anchor in human data for our understanding of the effects of
radiation within the human body. As the dangers of the imprudent use of x rays
and internal radiation became clear, private scientific advisory committees sprang
up to develop voluntary guidelines to promote safety among those working with
radiation. When the government did enter the atomic age, it often referred to the
23
Introduction
guidelines of these private committees as it developed radiation protection
standards."'
The Miracle of Tracers
In 1913, the Hungarian chemist Georg von Hevesy began to experiment
with the use of radioactive forms of elements (radioisotopes) to trace the behavior
of the normal, nonradioactive forms of a variety of elements. Ten years later
Hevesy extended his chemical experiments to biology, using a radioisotope of
lead to trace the movement of lead from soil into bean plants. In 1943, Hevesy
won the Nobel Prize for his work on the use of radioisotopes as tracers.
Previously, those seeking to understand life processes of an organism had
to extract molecules and structures from dead cells or organisms, and then study
those molecules by arduous chemical procedures, or use traceable chemicals that
were foreign to the organism being studied but that mimicked normal body
chemicals in some important way. Foreign chemicals could alter the very
processes being measured and, in any case, were often as difficult to measure
precisely as were normal body constituents. The radioactive tracer— as Our
Friend the Atom, a book written by Dr. Heinz Haber for Walt Disney productions,
explained in 1956 to readers of all ages—was an elegant alternative: "Making a
sample of material mildly radioactive is like putting a bell on a sheep. The
shepherd traces the whole flock around by the sound of the bell. In the same way
it is possible to keep tabs on tracer-atoms with a Geiger counter or any other
radiation detector." 17
By the late 1920s the tracer technique was being applied to humans in
Boston by researchers using an injection of dissolved radon to measure the rate of
blood circulation, an early example of using radioactivity to observe life
processes. 18 However, research opportunities were limited by the fact that some
of the elements that are most important in living creatures do not possess
naturally occurring radioactive isotopes.
The answer to this problem came simultaneously at faculty clubs and
seminars in Berkeley and Boston in the early 1930s. Medical researchers realized
that the famed "atom smasher," the cyclotron invented by University of California
physicist Ernest Lawrence, could be used as a factory to create radioisotopes for
medical research and treatment. "Take an ordinary needle," Our Friend the Atom
explained, "put it into an atomic reactor for a short while. Some of the ions
contained in the steel will capture a neutron and be transformed into a radio-
isotope of iron. . . . Now that needle could be found in the proverbial haystack
without any trouble." 19
In 1936, two of Lawrence's Berkeley colleagues, Drs. Joseph Hamilton
and Robert Stone, administered radiosodium to treat several leukemia patients. In
1937, Ernest Lawrence's brother, physician John Lawrence, became the first to
use radiophosphorus for the treatment of leukemia. This application was
24
The Atomic Century
extended the following year to the treatment of polycythemia vera, a blood
disease. This method soon became a standard treatment for that disease. In 1938,
Hamilton and Stone also began pioneering work in the use of cyclotron-produced
neutrons for the treatment of cancer. The following year, not long before the war
in Europe began, Ernest Lawrence unveiled a larger atom smasher, to be used to
create additional radioisotopes and hence dubbed the "medical cyclotron." 20 The
discovery that some radioisotopes deposited selectively in different parts of the
body—the thyroid, for example-inspired a spirited search for a radioactive "magic
bullet" that might treat, or even cure, cancer and other diseases.
In Cambridge, the age of "nuclear medicine" is said to have begun in
November 1936 with a lunchtime seminar at Harvard, at which MIT President
Karl Compton talked on "What Physics Can Do for Biology and Medicine."
Robley Evans, by that time at MIT, is reported to have helped prepare the portion
of the talk from which medical researchers at the Massachusetts General
Hospital's thyroid clinic came to realize that MIT's atom smasher could produce a
great research tool for their work—radioisotopes. Soon, doctors at the thyroid
clinic began a series of experiments, including some involving humans, that
would lead to the development of radioiodine as a standard tool for diagnosing
and treating thyroid disease. 21
In late 1938, the discovery of atomic fission in Germany prompted
concern among physicists in England and the United States that Nazi Germany
might be the first to harness the power of the atom— as a propulsion method for
submarines, as radioactive poison, or most worrisome of all, as a bomb capable of
unimagined destruction. In the United States, a world-famous physicist, Albert
Einstein, and a recent emigre from Hungary, Leo Szilard, alerted President
Franklin D. Roosevelt to the military implications of the German discovery in an
August 1939 letter.
Assigning his own science adviser, Vannevar Bush, to the task of
determining the feasibility of an atomic bomb, Roosevelt's simple "O.K.,"
scrawled on a piece of paper, set in motion the chain of events that would lead to
the largest and most expensive engineering project in history. Soon, Ernest
Lawrence's Radiation Laboratory and its medical cyclotron were mobilized to aid
in the nationwide effort to build the world's first atomic bomb. In a related effort,
Drs. Stone and Hamilton, and others, would turn their talents to the medical
research needed to ensure the safety of those working on the bomb.
THE MANHATTAN PROJECT: A NEW AND SECRET
WORLD OF HUMAN EXPERIMENTATION
In August 1942, the Manhattan Engineer District was created by the
government to meet the goal of producing an atomic weapon under the pressure
of ongoing global war. Its central mission became known as the Manhattan
Project. Under the direction of Brigadier General Leslie Groves of the Army
25
Introduction
Corps of Engineers, who recently had supervised the construction of the
Pentagon, secret atomic energy communities were created almost overnight in
Oak Ridge, Tennessee, at Los Alamos, New Mexico, and in Hanford,
Washington, to house the workers and gigantic new machinery needed to produce
the bomb. The weapon itself would be built at the Los Alamos laboratory, under
the direction of physicist J. Robert Oppenheimer.
Plucked from campuses around the country, medical researchers came
face to face with the need to understand and control the effect upon the thousands
of people, doctors included, of radioactive materials being produced in previously
unimaginable quantities.
In November 1942 General Groves, through the intermediation of an
Eastman Kodak official, paid a call on University of Rochester radiologist
Stafford Warren. Rochester, like MIT and Berkeley, was another locale where
radiation research had brought together physicists and physicians. "They wanted
to know what I was doing in radiation. So I discussed the cancer work and some
of the other things," Warren told an interviewer in the 1960s. Then "[w]e got
upstairs and they looked in the closet and they closed the transom and they looked
out the window. . . . Then they closed and locked the door and said, 'Sit down.'" 22
Soon thereafter, Dr. Warren was made a colonel in the U.S. Army and the
medical director of the Manhattan Project. As his deputy, Warren called on Dr.
Hymer Friedell, a radiologist who had worked with Dr. Stone in California. Dr.
Stone himself had meanwhile moved to the University of Chicago, where he
would play a key role in Manhattan Project-related medical research.
Initially, researchers knew little or nothing about the health effects of the
basic bomb components, uranium, plutonium, and polonium. 23 But, as a secret
history written in 1946 stated, they knew the tale of the radium dial painters:
The memory of this tragedy was very vivid in the
minds of people, and the thoughts of potential
dangers of working in areas where radiation hazards
existed were intensified because the deleterious
effects of radiation could not be seen or felt and the
results of over-exposure might not become apparent
for long periods after such exposure. 24
The need for secrecy, Stafford Warren later recalled, compounded the
urgency of understanding and controlling risk. Word of death or toxic hazard
could leak out to the surrounding community and blow the project's cover. 25
The need to protect the Manhattan Project workers soon gave rise to a new
discipline, called health physics, which sought to understand radiation effects and
monitor and protect nuclear worker health and safety. The Project was soon
inundated with data from radiation-detection instruments, blood and urine
samples, and physical exams. The "clinical study of the personnel," Robert Stone
26
The Atomic Century
wrote in 1943, "is one vast experiment. Never before has so large a collection of
individuals been exposed to so much radiation." 26 Along with these data-
gathering efforts came ethical issues.
Would disclosure of potential or actual harm to the workers, much less the
public, impair the program? For example, a July 1945 Manhattan Project memo
discussed whether to inform a worker that her case of nephritis (a kidney disease)
may have been due to her work on the Project. The issue was of special import
because, the memo indicated, the illness might well be a precursor of more cases.
The worker, the memo explained, "is unaware of her condition which now shows
up on routine physical check and urinalysis." 27
As this memo showed, there was an urgent need for decisions on how to
protect the workers, while at the same time safeguard the security of the project:
"The employees must necessarily be rotated out, and not permitted to resume
further exposure. In frequent instances no other type of employment is available.
Claims and litigation will necessarily flow from the circumstances outlined."
There were also, the memo concluded, "Ethical considerations":
The feelings of the medical officers are keenly
appreciated. Are they in accordance with their
canons of ethics to be permitted to advise the
patient of his true condition, its cause, effect, and
probable prognosis? If not on ethical grounds, are
they to be permitted to fulfill their moral obligations
to the individual employees in so advising him? If
not on moral grounds, are those civilian medical
doctors employed here bound to make full
disclosure to patients under penalty of liability for
malpractice or proceeding for revocation of license
for their failure to do so? 28
It is not clear what was decided in this case. However, the potential
conflict between the government doctors' duty to those working on government
projects and the same doctors' obligations to the government would not disappear.
Following the war, as we see in chapter 12, this conflict would be sharply posed
as medical researchers studied miners at work producing uranium for the nation's
nuclear weapons.
Another basic question was the extent to which human beings could or
should be studied to obtain the data needed to protect them. The radium dial
painter data served as a baseline to determine how the effects of exposures in the
body could be measured. But this left the question of whether plutonium,
uranium, and polonium behaved more or less like radium. Research was needed
to understand how these elements worked in the body and to establish safety
levels. A large number of animal studies were conducted at laboratories in
27
Introduction
Chicago, Berkeley, Rochester, and elsewhere; but the relevance of the data to
humans remained in doubt.
The Manhattan Project contracted with the University of Rochester to
receive the data on physical exams and other tests from Project sites and to
prepare statistical analyses. While boxes of these raw data have been retrieved, it
is not clear what use was made of them. 29 Accidents, while remarkably few and
far between, became a key source of the data used in constructing an
understanding of radiation risk. But accidents were not predictable, and their
occurrence only enhanced the immediacy of the need to gain better data.
In 1944, the Manhattan Project medical team, under Stafford Warren and
with the evident concurrence of Robert Oppenheimer, made plans to inject
polonium, plutonium, uranium, and possibly other radioactive elements into
human beings. As discussed in chapter 5, the researchers turned to patients, not
workers, as the source of experimental data needed to protect workers. By the
time the program was abandoned by the government, experimentation with
plutonium had taken place in hospitals at the Universities of California, Chicago,
and Rochester, and at the Army hospital in Oak Ridge, and further
experimentation with polonium and uranium had taken place at Rochester.
The surviving documentation provides little indication that the medical
officials and researchers who planned this program considered the ethical
implications of using patients for a purpose that no one claimed would benefit
them, under circumstances where the existence of the substances injected was a
wartime secret. Following the war, however, the ethical questions raised by these
experiments would be revisited in debates that themselves were long kept secret.
In addition to experimentation with internally administered radioisotopes,
external radiation was administered in human experiments directed by Dr. Stone
at Chicago and San Francisco and by others at Memorial Hospital in New York
City. Once again, the primary subjects were patients, although some healthy
subjects were also involved. In these cases, the researchers may have felt that the
treatment was of therapeutic value to the patients. But, in addition to the question
of whether the patients were informed of the government's interest, this research
raised the question of whether the government's interest affected the patients'
treatment. As discussed in chapter 8, these questions would recur when,
beginning in 1 95 1 , and for two decades thereafter, the Defense Department would
fund the collection of data from irradiated patients.
Ensuring safety required more, however, than simply studying how
radioactive substances moved through and affected the human body. It also
involved studying how these substances moved through the environment. While
undetectable to the human senses, radiation in the environment is easily
measurable by instruments. When General Groves chose Hanford, on the
Columbia River in Washington state, as a site for the plutonium production
facility, a secret research program was mounted to understand the fate of
radioactive pollution in the water, the air, and wildlife. 30
28
The Atomic Century
Outdoor research was at times improvisational. Years after the fact,
Stafford Warren would recall how Manhattan Project researchers had deliberately
"contaminated the alfalfa field" next to the University of Rochester medical
school with radiosodium, to determine the shielding requirements for radiation-
measuring equipment. Warren's associate Dr. Harold Hodge recalled that a
shipment of radiosodium was received by plane from Robley Evans at MIT,
mixed with water in a barrel, and poured into garden sprinklers:
We walked along and sprinkled the driveway. This
was after dark. . . . The next thing, we went out and
sprayed a considerable part of the field. ... It was
sprayed and then after a while sprayed again, so
there was a second and third application. We were
all in rubber, so we didn't get wet with the stuff . . .
then Staff [Warren] said that one of the things we
needed was to see what would be the effect on the
inside of a wooden building. So we took the end of
the parking garage, and we sprinkled that up about
as high as our shoulders, and somebody went inside
and made measurements, and we sprinkled it again.
Then we wanted to know about the inside of a brick
building, and so we sprinkled the side of the animal
house. ... I had no idea what the readings were. . . I
hadn't the foggiest idea of what we were doing,
except that obviously it was something
radioactive. 31
Outdoor releases would put at risk unsuspecting citizens, even
communities, as well as workers. There were no clear policies and no history of
practice to guide how these releases should be conducted. As we explore in
chapter 1 1, this would be worked out by experts and officials in secret, on behalf
of the workers and citizens who might be affected.
THE ATOMIC ENERGY COMMISSION AND POSTWAR
BIOMEDICAL RADIATION RESEARCH
On August 6, 1945, when the atomic bomb was dropped on Hiroshima,
the most sensitive of secrets became a symbol for the ages. A week later, the
bomb was the subject of a government report that revealed to the public the uses
of plutonium and uranium. 32 Immediately, debate began over the future of atomic
energy. Could it be controlled at the international level? Should it remain
entirely under control of the military? What role would industry have in
developing its potential? Although American policymakers failed to establish
29
Introduction
international control of the bomb, they succeeded in creating a national agency
with responsibility for the domestic control of atomic energy.
The most divisive question in the creation of the new agency that would
hold sway over the atom was the role of the military. Following congressional
hearings, the Atomic Energy Commission was established by the 1946 McMahon
Act, to be headed by five civilian commissioners. President Truman appointed
David Lilienthal, former head of the Tennessee Valley Authority, as the first
chairman of the AEC, which took over responsibilities of the Manhattan Engineer
District in January 1947.
Also in 1947, under the National Security Act, the armed services were
put under the authority of the newly created National Military Establishment
(NME), to be headed by the secretary of defense. In 1949 the National Security
Act was amended, and the NME was transformed into an executive department—
the Department of Defense. 33 The Armed Forces Special Weapons Project, which
would coordinate the Defense Department's responsibilities in the area of nuclear
weapons, became the military heir to the Manhattan Engineer District. The
Military Liaison Committee was also established as an intermediary between the
Atomic Energy Commission and the Defense Department; it was also to help set
military requirements for the number and type of nuclear weapons needed by the
armed services.
Even before the AEC officially assumed responsibility for the bomb from
the Manhattan Project, the Interim Medical Advisory Committee, chaired by
former Manhattan Project medical director Stafford Warren, began meeting to
map out an ambitious postwar biomedical research program. Former Manhattan
Project contractors proposed to resume the research that had been interrupted by
the war and to continue wartime radiation effects studies upon human subjects. 34
In May 1947, Lilienthal commissioned a blue-ribbon panel, the Medical
Board of Review, that reported the following month on the agency's biomedical
program. In strongly recommending a broad research and training program, the
board found the need for research "both urgent and extensive." The need was
"urgent because of the extraordinary danger of exposing living creatures to
radioactivity. It is urgent because effective defensive measures (in the military
sense) against radiant energy are not yet known." The board, pointing to the
AEC's "absolute monopoly of new and important tools for research and important
knowledge," noted the commensurate responsibilities-both to employees and
others who could suffer from "its negligence or ignorance" and to the scientific
world, with which it was obliged to "share its acquisitions . . . whenever security
considerations permit." 35 In the fall of 1947, as recommended by the Medical
Board of Review, the AEC created a Division of Biology and Medicine (DBM) to
coordinate biomedical research involving atomic energy and an Advisory
Committee for Biology and Medicine (ACBM), which reported directly to the
AEC's chairman. 36
Not surprisingly, the DBM and ACBM became gathering places for the
30
The Atomic Century
luminaries of radiation science. The ACBM was headed by a Rockefeller
Foundation official, Dr. Alan Gregg. It settled on Dr. Shields Warren, a Harvard-
trained pathologist, to serve as the first chief of the DBM. Warren, as we shall
see, would play a central role in developments related to radiation research and
human experimentation. In the 1930s, focusing on cancer research, and
influenced by the work of Hevesy and the pioneering radioisotope work being
done in Berkeley and Boston, Warren turned to the question of the effects of
radiation on animals and the treatment of acute leukemia, the "most hopeless . . .
of tumors at that time." As the war neared, Warren enlisted in the Naval Reserve.
He continued medical work for the Navy, turning down an invitation to join
Stafford Warren (no relation) on "a project . . . that he couldn't tell me anything
about [the Manhattan Project].""
While most of the AEC's budget would be devoted to highly secret
weapons development and related activities, the biomedical research program
represented the commission's proud public face. Even before the AEC opened its
doors, Manhattan Project officials and experts had laid the groundwork for a bold
program to encourage the use of radioisotopes for scientific research, especially in
medicine. This program was first presented to the broad public in a September
1946 article in the New York Times Magazine. The article began dramatically by
describing the use of "radioactive salt" to measure circulation in a crushed leg, so
that a decision on whether to amputate below or above the knee could be made.
By November 1946, the isotope distribution program was well under way,
with more than 200 requests approved, about half of which were designated for
"human uses." From the beginning, the AEC's Isotope Division at Oak Ridge had
in its program director, Paul Aebersold, a veritable Johnny Appleseed for
radioelements. 39 In presentations before the public and to researchers, Aebersold,
dubbed "Mr. Isotope," touted the simplicity and low cost with which scientists
would be provided with radioisotopes: "The materials and services are made
available . . . with a minimum of red tape and under conditions which encourage
their use." 40 At an international cancer conference in St. Louis in 1947, the AEC
announced that it would make radioisotopes available without cost for cancer
research and experimental cancer treatment. This, Shields Warren later recalled,
had a "tremendous effect" and "led to a revolution in the type of work done in this
field." 41 c . .__,
To AEC administrators, Aebersold emphasized the benefits to the AhC s
public image: "Much of the Commission's success is judged by the public and
scientists ... on its willingness to carry out a wide and liberal policy on the
distribution of materials, information, and services," he wrote in a memo to the
AEC's general manager. 42
The AEC biomedical program as a whole also provided for funding ot
cancer research centers, research equipment, and numerous other research
projects. Here, too, were advances that would save many lives. Before the war,
radiotherapy had reached a plateau, limited by the cost of radium and the inability
31
Introduction
of the machines of the time to focus radiation precisely on tumors to the exclusion
of surrounding healthy tissue. AEC facilities inherited from the Manhattan
Project could produce radioactive cobalt, a cheaper substitute for radium. As
well, the AEC's "teletherapy" program funded the development of new equipment
capable of producing precisely focused high-energy beams. 43
The AEC's highly publicized peacetime medical program was not immune
to the pressures of the Cold War political climate. Even the lives of young
researchers in the AEC Fellowship Program conducting nonclassified research
were subject to Federal Bureau of Investigation review despite protests from
commission members. Congressionally mandated Cold War requirements such as
loyalty oaths and noncommunist affidavits, Chairman Lilienthal declared, would
have a chilling effect on scientific discussion and could damage the AEC's ability
to recruit a new generation of scientists. 44 The reach of the law, the Advisory
Committee for Biology and Medicine agreed, was like a "blighting hand; for
thoughtful men now know how political domination can distort free inquiry into a
malignant servant of expediency and authoritarian abstraction." 45 Nonetheless,
the AEC accepted the congressional conditions for its fellowship program and
determined to seek the program's expansion. 46
The AEC's direct promotional efforts were multiplied by the success of
Aebersold and his colleagues in carrying the message to other government
agencies, as well as to industry and private researchers. This success led, in turn,
to new programs.
In August 1947, General Groves urged Major General Paul Hawley, the
director of the medical programs of the Veterans Administration, to address
medical problems related to the military's use of atomic energy. Soon thereafter,
Hawley appointed an advisory committee, manned by Stafford Warren and other
medical researchers. The advisers recommended that the VA create both a
"publicized" program to promote the use of radioisotopes in research and a
"confidential" program to deal with potential liability claims from veterans
exposed to radiation hazards. 47 The "publicized" program soon mushroomed,
with Stafford Warren, Shields Warren, and Hymer Friedell among the key
advisers. By 1974, according to VA reports, more than 2,000 human radiation
experiments would be performed at VA facilities, 48 many of which would work in
tandem with neighboring medical schools, such as the relationship between the
UCLA medical school, where Stafford Warren was now dean, and the Wadsworth
(West Los Angeles) VA Hospital.
While the AEC's weapons-related work would continue to be cloaked in
secrecy, the isotope program was used by researchers in all corners of the land to
achieve new scientific understanding and help create new diagnostic and
therapeutic tools. It was, however, only a small part of an enormous institution.
By 1951 the AEC would employ 60,000 people, all but 5,000 through contractors.
Its land would encompass 2,800 square miles, an area equal to Rhode Island and
Delaware combined. In addition to research centers throughout the United States,
32
The Atomic Century
its operations "extended] from the ore fields of the Belgian Congo and the Arctic
region of Canada to the weapons proving ground at Enewetak Atoll in the Pacific
and the medical projects studying the after-effects of atomic bombing in . . .
Japan " 49 The Isotope Division, however, would employ only about fifty people
and, when reactor production time was accounted for, occupy only a fraction of
its budget and resources. 50
THE TRANSFORMATION IN GOVERNMENT-SPONSORED
RESEARCH
The AEC's decision to proceed with a biomedical research program was
part of an even greater transformation, in which government continued and
expanded wartime support for research in industry and at universities. Before
World War II, biomedical research was a small enterprise in which the federal
government played a minor role. During the war, however, large numbers of
American biomedical researchers were mobilized by the armed forces. These
researchers played an important role in advancing military medicine in a wide
range of areas, including blood substitutes, antimalarial drugs and, as noted
above in nurturing the infant science of nuclear medicine.
' As the war was drawing to a close, President Roosevelt asked for advice
from his Office of Scientific Research and Development (OSRD) on how to
convert the nation's military research effort to a peacetime footing, and whether
the government should take an activist role in promoting research. The OSRD,
under Vannevar Bush, responded in July 1945, after Roosevelt's death, with a
report called "Science, the Endless Frontier." Bush and his colleagues
recommended among other things the establishment of a National Science
Foundation (NSF) to support basic research in all areas including the biomedical
sciences. While the principle that the federal government should fund medical
research came to seem self-evident, this was hardly the case at the time. In a
personal reminiscence published in 1970, Bush wrote:
To persuade the Congress of these pragmatically
inclined United States to establish a strong
organization to support fundamental research would
seem to be one of the minor miracles. We in this
country have supported well those pioneers who
have created new gadgetry for our use or our
amusement. But we have not had during our
formative years the respect for scientific endeavors,
for scholarship generally, to the extent it had been
present in Europe. 51
Congress worked Bush's small miracle and passed relevant legislation, but
33
Introduction
President Harry Truman vetoed the bill. When the bill passed again, however,
Bush persuaded Truman to sign it. 52
At the new AEC, and elsewhere, a key element of the support for science
was the determination to fund extramural research, that is, research outside the
agency. Prior to the war, federal support for private researchers was limited. The
Manhattan Project was only one of several wartime efforts that drew private
researchers into government service and that provided federal funds for those who
remained in private research centers. Following the war, as researchers returned
to universities, laboratories, and hospitals, the continued federal support of their
efforts transformed the relationship between government and science and the
dimensions of the scientific effort. 53
During the war, the Committee on Medical Research (CMR) of the OSRD
operated entirely by funding external research. In 1 944, Congress empowered the
surgeon general of the Public Health Service to make grants to universities,
hospitals, laboratories, and individuals, which provided the legislative basis for
the postwar National Institute of Health (NIH) extramural program. 54 In 1948,
Congress authorized the National Heart Institute to join the decade-old National
Cancer Institute, and NIH became the National Institutes of Health.
By the late 1960s, the annual appropriations of NIH exceeded $1 billion. 55
Research involving medical uses of radioisotopes and external radiation was
among the newer fields benefiting from the increased funding. As discussed in
more detail in chapter 6, government-supported radioisotope research has proved
profoundly important in the development of techniques for medical diagnosis and
treatment.
Federal research funding has also continued to be essential to the
development of the use of external sources of radiation. For example, the crude
images made possible by Roentgen's discovery of x rays have been replaced by
higher resolution, three-dimensional pictures, such as those produced by
computerized tomographic (CT) scanning and magnetic resonance imaging
(MRI).
Today, the benefits of federally sponsored medical research are often
taken for granted. To many of those in the midst of the postwar planning and
advocacy, however, the result was not foreordained. "Fortunately," Shields
Warren recalled years later, postwar "momentum" kept AEC research budgets on
track until, in 1957, the Soviet launch of Sputnik (the first space satellite) jolted
the American people into a renewed commitment to the support of scientific
research. 56
34
The Atomic Century
THE AFTERMATH OF HIROSHIMA AND NAGASAKI: THE
EMERGENCE OF THE COLD WAR RADIATION RESEARCH
BUREAUCRACY
While promoting the beneficial uses of radiation, the government also
wished to continue and expand research on its harmful effects. Three days after
the destruction of Hiroshima, Robert Stone wrote two letters to Stafford Warren's
deputy, and Stone's former student, Hymer Friedell. The first expressed hope that
the contribution of medical researchers could now be made public, so that people
would know what they had done during the war. 57 The second letter described
Stone's "mixed feelings" at the success that had been achieved and his fear that
the lingering effects of radiation from the bomb had been underestimated: "I
could hardly believe my eyes," Stone wrote, "when I saw a series of news releases
said to be quoting Oppenheimer, and giving the impression that there is no
radioactive hazard. Apparently all things are relative." 58
Friedell and other researchers, including Stafford Warren and Shields
Warren, soon traveled to Hiroshima and Nagasaki to begin what became an
extensive research program on survivors. The data from that project quickly
became and still remain the essential source of information on the long-term
effects of radiation on populations of human beings. It was not long, however,
before there were additional real-life data on the bomb, from postwar atomic tests.
In 1946, the United States undertook the first peacetime nuclear weapons tests at
Bikini Atoll in the Marshall Islands. Operation Crossroads, conducted before
journalists and VIPs from around the world, was intended to test the ability of a
flotilla of unmanned ships to withstand the blast. Since most of the ships
remained afloat, the Navy declared Crossroads a triumph. 59
Behind the scenes, however, Crossroads medical director Stafford Warren
expressed horror at the level of contamination on the ships due to the underwater
atomic blast. 60 When the ships returned to the West Coast from the Pacific, they
were extensively studied to assess the damage and contamination from the atomic
bombs. The government created the Naval Radiological Defense Laboratory
(NRDL) to study the effects of atomic bombs on ships and to design ways to
protect them. "Crossroads," according to an NRDL history, "left no doubt that
man was faced with the necessity for coping with strange and unprecedented
problems for which no solutions were available." 6 '
Hiroshima and Nagasaki, it now seemed, were only the beginning, not the
end, of human exposure to bomb-produced radiation. As Crossroads confirmed
with the lingering problem of contaminated ships, what the bomb did not
obliterate it might still damage by radiation over the course of days or years. It
was no longer enough to know about the effects of radioactive materials on
American nuclear weapons workers; now there was the urgent need to understand
the effects on American soldiers, sailors, and even citizens as well.
Largely invisible to the public, an ad hoc bureaucracy sprang up to
35
Introduction
address the medical and radiation research problems of atomic warfare. This
bureaucracy brought together former wartime radiation researchers, who were
joined by junior colleagues, to advise, and participate in, the government's
growing radiation research program. Other, already established groups-such as
the AEC's Division of Biology and Medicine and its advisory committee-also
had important places in the new network.
Beyond considering fallout from the testing of atomic bombs, these groups
also looked at how radiation itself might be used as a weapon. During the war,
scientists like J. Robert Oppenheimer had speculated on the possibility that fission
products (radioactive materials produced by the bomb or by reactors) could be
dispersed in the air and on the ground to kill or incapacitate the enemy. In 1946,
the widespread contamination of ships at Crossroads by radioactive mist gave
dramatic evidence of the potential of so-called radiological warfare, or RW. In
1947, the military created a committee of experts to study the problem. The
following year, a blue-ribbon panel of physicians and physicists looked at the
prospects, both offensive and defensive, of what the Pentagon termed "Rad War."
The work of these panels would lead to dozens of intentional releases of radiation
into the environment at the Army's Dugway, Utah, testing grounds from the late
1940s to the early 1950s. The very fact that the government was engaged in RW
tests was a secret. Indeed, the records of the RW program-including, as we shall
see in chapter 1 1, the debate on what the public should be told about the
program-would remain largely secret for almost fifty years.
In 1 949, a military program to build a nuclear-powered airplane led to a
set of proposed human radiation experiments. The NEPA (Nuclear Energy for the
Propulsion of Aircraft) program had its origins in 1946 as a venture that included
the Manhattan Project's Oak Ridge site, the military, and private aircraft
manufacturers. Robert Stone, as we shall see in chapter 8, was a leading
proponent of experiments involving healthy volunteers, as a key to answering
questions about the radiation hazard faced by the crew of the proposed airplane.
The NEPA and RW groups considered important, but still discrete,
projects. Where did the "big picture" discussions take place? The Advisory
Committee has pieced together the records of the Armed Forces Medical Policy
Council, the Committee on Medical Sciences, and the Joint Panel on the Medical
Aspects of Atomic Warfare." These three Defense Department groups, all
chaired by civilian doctors, guided the government on both the broad subject of
military-related biomedical research and the new and special problems posed by
atomic warfare.
If the surviving records are an indication, from its creation in 1949 to its
evident demise with the reorganization of the Defense Department in 1953, the
Joint Panel quickly became the hub of atomic warfare-related biomedical
research. The Joint Panel gathered information about relevant research from all
corners of the government, provided guidance for Defense Department programs,
36
The Atomic Century
and reviewed and coordinated policy in the matter of human experimentation
using atomic energy.
By charter, the group was to be headed by a civilian. Harvard's Dr. Joseph
Aub, a long-standing member of the Boston-based medical research community
who had worked with Robley Evans on the study of the radium dial painters and
had also studied lead toxicity, served as chair. Those who served with Aub
included Evans, Hymer Friedell, and Louis Hempelmann, Oppenheimer's
Manhattan Project medical aide. Other government participants came from the
AEC, the Public Health Service, the National Institutes of Health, the Veterans
Administration, and the CIA. (The charter provided that the Joint Panel should
collect information on relevant research conducted abroad, which the CIA
evidently provided.) 63
This bureaucracy provided the venue for secret discussions that linked the
arts of healing and war in ways that had little precedent. At one and the same
time, for example, doctors counseled the military about the radiation risk to troops
at the site of atomic bomb tests, advised on the need for research on the
"psychology of panic" at such bomb tests, and debated the need for rules to
govern atomic warfare-related experimentation. (See chapter 10.)
The records of the Joint Panel show that, during the height of the Cold
War, the resources of civilian agencies were part of the mobilization of resources
to serve national security interests. For example, Dr. Howard Andrews, trained as
a physicist, was the National Institutes of Health's representative to the Joint
Panel, and in the 1950s he worked with the DOD and the AEC in monitoring
safety measures and measuring fallout from nuclear tests. 64
In 1950 President Truman ordered federal agencies, including the Public
Health Service and NIH, to focus their resources on activities that would benefit
national security needs. On paper, at least, PHS and NIH policymakers sought to
direct resources to questions of radiation injury, civil defense, and worker health
and safety. 65 For example, a 1952 internal planning memo explained that NIH
"will not wait for formal requests by the armed forces ... to undertake research
which NIH staff knows to be of urgent military and civilian defense significance.
Limited selective conversion of research to work directly related to biological
warfare, shock, radiation injury and thermal burns will begin immediately. . . ." 66
The fragmentary surviving documentation, however, does not show the extent to
which PHS- and NIH-funded researchers actually redirected their investigations
or merely recast the purpose of ongoing work.
NEW ETHICAL QUESTIONS FOR MEDICAL
RESEARCHERS
As medical researchers became fixtures in the Cold War research
bureaucracy, they assumed roles that, if not entirely new, raised ethical questions
with which they had rarely dealt before. The surviving records of the period
37
Introduction
reveal that frank and remarkable discussions took place among military and
civilian officials and researchers, all of whom had to balance the benefits of
gaining knowledge needed to fight and survive an atomic war with the risks that
had to be taken to gain this knowledge. They had to consider, and even debated,
whether human radiation experimentation was justified, what kinds of risks entire
populations could be exposed to, and what the public could and should be told.
Whether to Experiment with Humans: The Debate Is Joined
Spurred by proposals for human radiation experiments connected with the
nuclear-powered airplane (NEPA) project, AEC and DOD medical experts in
1949 and 1950 engaged in debate on the need for human experimentation. The
transcript of a 1950 meeting among AEC biomedical officials and advisers and
military representatives provides unique insight into the mix of moral principles
and practical concerns. 67
The participants in the debate included many of the key medical figures in
the Manhattan Project and the postwar radiation research bureaucracy. For the
Navy, for example, Captain Behrens, the editor of Atomic Medicine, made the
point that an atomic bomb might contaminate, but not sink, ships. The Navy
would need to know the risk of sending rescue or salvage parties into the
contaminated area. There were questions of "calculated risk which all of the
services are interested in, and not only the services but probably the civilians as
well." 68 Brigadier General William H. Powell, Jr., of the Office of the Air Force
Surgeon General, added further questions: How does radiation injure tissue? Can
equipment protect against the bomb's effects? Is there a way to treat radiation
injury? How should mass casualties be handled? 69
These questions were hardly abstract. Operation Crossroads had
demonstrated that postblast contamination of Navy ships was a serious hazard.
The use of the atomic bomb as a tactical weapon, declared Brigadier General
James Cooney of the AEC's Division of Military Applications, "has now gone
beyond the realm of possibility and into the realm of probability." 70 This meant
that "we have a responsibility that is tremendous," Cooney added. "If this weapon
is used tactically on a corps or division, and we have, say, 5,000 troops who have
received 100 Roentgens] radiation, the Commander is going to want from me, 'Is
it all right for me to reassemble these men and take them into combat?' I don't
know the answer to that question." 71 Commanders needed to know "How much
radiation can a man take?" 72
Cooney argued that human experimentation was necessary. He invoked
the military's tradition of experimentation with healthy volunteers, dating back to
Walter Reed's famous work on yellow fever at the turn of the century. Cooney
urged that the military seek volunteers within its ranks--"both officer and
enlisted"--to be exposed to as much as 150 R of whole-body radiation. 73
The AEC's Shields Warren took the other side in this debate. Warren
38
The Atomic Century
raised two basic points in response to Cooney. First, human experimentation was
not essential because animal research would be adequate to find the answers.
Second, data from human experimentation would likely be scientifically useless.
"We have," Warren declared, "learned enough from animals and from humans at
Hiroshima and Nagasaki to be quite certain that there are extraordinary variables
in this picture. There are species variables, genetics variables within species,
variations in condition of the individual within that species." The danger of
failing to provide data had to be weighed against the danger of providing
misleading data: "It might be almost more dangerous or misleading to give an
artificial accuracy to an answer that is of necessity an answer that spreads over a
broad range in light of these variables." 74
There were, moreover, political obstacles to the program Cooney had
proposed. Satisfactory answers, Warren concluded, would require "going to tens
of thousands of individuals." But America was not the Soviet Union: "If we were
considering things in the Kremlin, undoubtedly it would be practicable. I doubt
that it is practicable here." 75
At the heart of Warren's objections to Cooney's proposal was a concern
about employing "human experimentation when it isn't for the good of the
individual concerned and when there is no way of solving the problem." 76 To
Cooney's invocation of Walter Reed, Warren responded that, in the case of yellow
fever, humans were needed as subjects because there was no nonhuman host to
Cooney did not disagree with Warren "that statistically we will prove
nothing." But, he pointed out, "[G]enerals are hard people to deal with If we
had 200 cases whereby we could say that these men did or did not get sick up to
150 R, it would certainly be a great help to us." 77
Even then, Warren rejoined, the data might not be of great use: "I can
think in terms of times when even if everybody on a ship was sea-sick, you would
still have to keep the ship operating." 78
The 1950 debate over NEPA provides clear evidence that midcentury
medical experts gave thought before engaging in human experimentation that
involved significant risk and was not intended to benefit the subject. On paper,
the debate was decided in Shields Warren's favor. Following Warren's and
DBM's opposition, Cooney and the military agreed that "human experimentation"
on healthy volunteers would not be approved. However, even as this policy was
declared, the Defense Department, with Warren's apparent acquiescence,
proceeded to contract with private hospitals to gather data on sick patients who
were being treated with radiation. The government's use of sick patients for
research, as we shall see in chapter 8, raised difficult ethical questions of its own.
Whether to Put Populations at Risk: The Debate Continues
As the medical experts debated the issue of whether to put individual
39
Introduction
human subjects at risk in radiation experiments on behalf of NEPA, they were
also engaged in secret discussions about whether to proceed with the testing of
nuclear weapons, which might put whole populations at risk.
It was also in 1950 that the decision was made to carry out atomic bomb
testing at a site in the continental United States. President Truman chose the
Nevada desert as the location for the test site. Shields Warren's Division of
Biology and Medicine was assigned the job of considering the safety of early
tests. Like the earlier transcript, an account of a May 1951 meeting at Los
Alamos, convened by Warren, provides a window onto the balancing of risks and
benefits by medical researchers.
The meeting focused on the radiological hazards to populations downwind
from underground testing planned at the Nevada Test Site. Those in attendance
realized that the testing could be risky. "I would almost say from the discussion
this far," Warren summarized, "that in light of the size and activity of some of
these particles, their unpredictability of fallout, the possibility of external beta
burns is quite real." 79 Committee members considered the testing a "calculated
risk" for populations downwind, but they thought that the information they could
gain made the risk worthwhile. According to the record of the meeting, Warren
summarized the view of Dr. Gioacchino Failla, a Columbia University
radiological physicist: "[T]he time has come when we should take some risk and
get some information ... we are faced with a war in which atomic weapons will
undoubtedly be used, and we have to have some information about these
things ... if we look for perfect safety we will never make these tests." 80 Worried
about the potential consequences of miscalculation, the AEC's Carrol Tyler
observed, "We have lost a continental site no matter where we put it." Still, Tyler
argued, "If we are going to gamble it might as well be done where it is
operationally convenient." 1 " A proposed deep underground test did not take place,
and a test evidently considered less risky was substituted. Ultimately, in a
summary prepared at the end of the 1951 test series, the Health Division leader of
the AEC's Los Alamos Laboratory recorded that perhaps only good fortune had
averted significant contamination: "Thanks to the kindness of the winds, no
significant activity was deposited in any populated localities. It was certainly
shown however," he wrote, "that significant exposures at considerable distances
could be acquired by individuals who actually were in the fallout while it was in
progress." 82
The NEPA debate and the advent of nuclear testing confronted biomedical
experts with a set of conflicting, and even contradictory, objectives. First, they
were called upon to offer advice on decisions that might inevitably put people at
some risk. The risk had to be balanced against the benefit, which in most
instances was defined as connected with the nation's security. In many cases, the
experts agreed, it was better to bear the lesser risk now, in order to avoid a greater
risk later. Second, these experts were also called upon, as in the 1951 Nevada
test, to provide advice on minimizing risk. Third, as in the Nevada test, these
40
The Atomic Century
same experts saw the tests as opportunities to gather data that might ultimately be
used to reduce risk for all.
Whether and What the Public Should Be Told About Government-Created
Radiation Risk
Scientific research had a long and celebrated tradition of open publication
in the scientific literature. But several factors caused Cold War researchers to
limit their public disclosures. These included, preeminently, concern with
national security, which necessarily required secrecy. But they also included the
concern that the release of research information would undermine needed
programs because the public could not understand radiation or because the
information would embarrass the government.
The tension between the publicizing of information and the limits on
disclosure was a constant theme in Cold War research. When, in June 1 947, the
Medical Board of Review appointed by David Lilienthal reported on the AEC's
biomedical program, it declared that secrecy in scientific research is "distasteful
and in the long run contrary to the best interests of scientific progress." 83 As
shown by its organization of the medical isotope program, the AEC acted quickly
to make sure that the great preponderance of biomedical research done under its
auspices would be published in the open literature.
However, recently retrieved documents show that the need for secrecy was
also invoked where national security was not endangered. At the same time that
biomedical officials, such as those on the Medical Board of Review, spoke openly
of the need to limit national security restrictions, internally they sometimes sided
with those who would restrict information from the public even where release
admittedly would not directly endanger national security. Thus, as we shall see in
chapter 13, Shields Warren and other AEC medical officials agreed to withhold
data on human experiments from the public on the grounds that disclosure would
embarrass the government or could be a source of legal liability.
A further important qualification to what the public could know related to
research connected with the atomic bomb-including the creation of a worldwide
network to gather data on the effects of fallout from nuclear tests. In 1949, the
AEC undertook Project Gabriel, a secret effort to study the question of whether
the tests could threaten the viability of life on earth. In 1953, Gabriel led to
Project Sunshine, a loose confederation of fallout research projects whose human
data-gathering efforts, as we see in chapter 13, operated in the twilight between
openness and secrecy.
Finally, while documents show that medical experts and officials shared
an acute awareness of the importance of public support to the success of Cold
War programs, this awareness was coupled with concern about the American
public's ability to understand the risks that had to be borne to win the Cold War.
The concern that citizens could not understand radiation risk is illustrated by a
41
Introduction
recently recovered NEPA transcript. In July 1949, the nuclear airplane project
gathered radiation experts and psychologists to consider psychological problems
connected to radiation hazard. To the assembled experts the greatest unknown
was not radiation itself, but the basis for public fear and misunderstanding of
radiation.
"I believe," General Cooney proposed, "that the general public is under
the opinion that we don't know very much about this condition [radiation]. . . . We
know," he ventured, "just about as much about it as we do about many other
diseases that people take for granted . . . even tuberculosis." 84
Yet, said the Navy's Captain Behrens, "there are some peculiar ideas
relative to radiation that are related to primitive concepts of hysteria and things in
that category. . . . There is such a unique element in it; for some it begins to
border on the mystical." 85 A good deal of the public's fear of radiation, declared
Berkeley's Dr. Karl M. Bowman, a NEPA medical adviser, "is essentially the fear
of the unknown. The dangers have been enormously magnified." As Dr.
Bowman and others noted, the public's perception was not without reason, for "we
have emphasized for purposes of getting funds for research how little we know." 86
The perspective expressed in the NEPA transcript would lead, as shown in
chapter 10, to the use of atomic bomb tests to perform human research on the
psychology of panic and, as shown in other case studies, to decisions to hold
information closely out of concern that its release could create public
misunderstanding that would imperil important government programs.
CONCLUSION
In the atomic age, Captain Behrens's Atomic Medicine pointed out,
radiation research was both the agent and the beneficiary of dramatic
developments at the intersection of government and medicine. When ethical
questions were raised by these developments, radiation researchers would be on
the front line in having to deal with them. The burgeoning government- funded
biomedical research, including human radiation research, required a
reexamination of the traditional doctor-patient relationship. At the same time, the
evolving role of medical researchers as government officials and advisers also
posed questions about the place of doctors, and more generally of scientists, in
service to government.
42
The Atomic Century
The Basics of Radiation Science
The ethical and historical issues of human radiation experiments cannot be
understood without a basic grasp of the underlying science. This requires more
than a glossary defining technical terms. At least an intuitive understanding of
the natural laws and scientific techniques of radiation science is necessary.
Obviously, acquiring a professional level of knowledge would require far more
time than most readers can afford; indeed, entire careers are devoted to studying
just one aspect of the field. To serve the interests of democracy in a technological
world, however, we must provide sufficient technical background for all citizens
to become active participants in considering the ethical and political dimensions
of scientific research.
What follows is an attempt to provide such a background for the events
and issues discussed in this report, directed toward those readers less familiar
with "the basics" of radiation science. This task was deemed important enough to
deserve a distinct section of this Introduction.
What Is Ionizing Radiation?
What is radiation!
Radiation is a very general term, used to describe any process that
transmits energy through space or a material away from a source. Light, sound,
and radio waves are all examples of radiation. When most people think of
radiation, however, they are thinking of ionizing ra<//arto«--radiation that can
disrupt the atoms and molecules within the body. While scientists think of these
emissions in highly mathematical terms, they can be visualized either as
subatomic particles or as rays. Radiation's effects on humans can best be
understood by first examining the effect of radiation on atoms, the basic building
blocks of matter.
What is ionization!
Atoms consist of comparatively large particles (protons and neutrons)
sitting in a central nucleus, orbited by smaller particles (electrons): a miniature
solar system. Normally, the number of protons in the center of the atom equals
the number of electrons in orbit. An ion is any atom or molecule that does not
have the normal number of electrons. Ionizing radiation is any form of radiation
that has enough energy to knock electrons out of atoms or molecules, creating
ions.
How is ionizing radiation measured?
Measurement lies at the heart of modern science, but a number by itself
conveys no information. Useful measurement requires both an instrument for
measurement (such as a stick to mark off length) and an agreement on the units to
43
Introduction
be used (such as inches, meters, or miles). The units chosen will vary with the
purpose of the measurement. For example, a cook will measure butter in terms of
tablespoons to ensure the meal tastes good, while a nutritionist may be more
concerned with measuring calories, to determine the effect on the diner's health.
The variety of units used to measure radiation and radioactivity at times
confuses even scientists, if they do not use them every day. It may be helpful to
keep in mind the purpose of various units. There are two basic reasons to
measure radiation: the study of physics and the study of the biological effects of
radiation. What creates the complexity is that our instruments measure physical
effects, while what is of interest to some are biological effects. A further
complication is that units, as with words in any language, may fade from use and
be replaced by new units.
Radiation is not a series of distinct events, like radioactive decays, which
can be counted individually. Measuring radiation in bulk is like measuring the
movement of sand in an hourglass; it is more useful to think of it as a continuous
flow, rather than a series of separate events. The intensity of a beam of ionizing
radiation is measured by counting up how many ions (how much electrical
charge) it creates in air. The roentgen (named after Wilhelm Roentgen, the
discoverer of x rays) is the unit that measures the ability of x rays to ionize air; it
is a unit of exposure that can be measured directly. Shortly after World War II, a
common unit of measurement was the roentgen equivalent physical (rep), which
denoted an ability of other forms of radiation to create as many ions in air as a
roentgen of x rays. It is no longer used, but appears in many of the documents
examined by the Advisory Committee.
What are the basic types of ionizing radiation?
There are many types of ionizing radiation, but the most familiar are
alpha, beta, and gamma/x-ray radiation. Neutrons, when expelled from atomic
nuclei and traveling as a form of radiation, can also be a significant health
concern.
Alpha particles are clusters of two neutrons and two protons each. They
are identical to the nuclei of atoms of helium, the second lightest and second most
common element in the universe, after hydrogen. Compared with other forms of
radiation, though, these are very heavy particles—about 7,300 times the mass of
an electron. As they travel along, these large and heavy particles frequently
interact with the electrons of atoms, rapidly losing their energy. They cannot even
penetrate a piece of paper or the layer of dead cells at the surface of our skin. But
if released within the body from a radioactive atom inside or near a cell, alpha
particles can do great damage as they ionize atoms, disrupting living cells.
Radium and plutonium are two examples of alpha emitters.
Beta particles are electrons traveling at very high energies. If alpha
particles can be thought of as large and slow bowling balls, beta particles can be
visualized as golf balls on the driving range. They travel farther than alpha
44
The Atomic Century
particles and, depending on their energy, may do as much damage. For example,
beta particles in fallout can cause severe burns to the skin, known as beta burns.
Radiosotopes that emit beta particles are present in fission products produced in
nuclear reactors and nuclear explosions. Some beta-emitting radioisotopes, such
as iodine 131, are administered internally to patients to diagnose and treat disease.
Gamma and x-ray radiation consists of packets of energy known as
photons. Photons have no mass or charge, and they travel in straight lines. The
visible light seen by our eyes is also made up of photons, but at lower energies.
The energy of a gamma ray is typically greater than 100 kiloelectron volts (keV—
"k" is the abbreviation for kilo, a prefix that multiplies a basic unit by 1 ,000) per
photon, more than 200,000 times the energy of visible light (0.5 eV). If alpha
particles are visualized as bowling balls and beta particles as golf balls, photons
of gamma and x-radiation are like weightless bullets moving at the speed of light.
Photons are classified according to their origin. Gamma rays originate from
events within an atomic nucleus; their energy and rate of production depend on
the radioactive decay process of the radionuclide that is their source. X rays are
photons that usually originate from energy transitions of the electrons of an atom.
These can be artificially generated by bombarding appropriate atoms with high-
energy electrons, as in the classic x-ray tube. Because x rays are produced
artificially by a stream of electrons, their rate of output and energy can be
controlled by adjusting the energy and amount of the electrons themselves. Both
x rays and gamma rays can penetrate deeply into the human body. How deeply
they penetrate depends on their energy; higher energy results in deeper
penetration into the body. A 1 MeV ("M" is the abbreviation for mega, a prefix
that multiplies a basic unit by 1,000,000) gamma ray, with an energy 2,000,000
times that of visible light, can pass completely through the body, creating tens of
thousands of ions as it does.
A final form of radiation of concern is neutron radiation. Neutrons, along
with protons, are one of the components of the atomic nucleus. Like protons, they
have a large mass; unlike protons, they have no electric charge, allowing them to
slip more easily between atoms. Like a Stealth fighter, high-energy neutrons can
travel farther into the body, past the protective outer layer of the skin, before
delivering their energy and causing ionization.
Several other types of high-energy particles are also ionizing radiation.
Cosmic radiation that penetrates the Earth's atmosphere from space consists
mainly of protons, alpha particles, and heavier atomic nuclei. Positrons, mesons,
pions, and other exotic particles can also be ionizing radiation.
What Is Radioactivity?
What causes radioactivity?
As its name implies, radioactivity is the act of emitting radiation
spontaneously. This is done by an atomic nucleus that, for some reason, is
45
Introduction
unstable; it "wants" to give up some energy in order to shift to a more stable
configuration. During the first half of the twentieth century, much of modern
physics was devoted to exploring why this happens, with the result that nuclear
decay was fairly well understood by 1 960. Too many neutrons in a nucleus lead
it to emit a negative beta particle, which changes one of the neutrons into a
proton. Too many protons in a nucleus lead it to emit a positron (positively
charged electron), changing a proton into a neutron. Too much energy leads a
nucleus to emit a gamma ray, which discards great energy without changing any
of the particles in the nucleus. Too much mass leads a nucleus to emit an alpha
particle, discarding four heavy particles (two protons and two neutrons).
How is radioactivity measured?
Radioactivity is a physical, not a biological, phenomenon. Simply stated,
the radioactivity of a sample can be measured by counting how many atoms are
spontaneously decaying each second. This can be done with instruments
designed to detect the particular type of radiation emitted with each "decay" or
disintegration. The actual number of disintegrations per second may be quite
large. Scientists have agreed upon common units to use as a form of shorthand.
Thus, a curie (abbreviated "Ci" and named after Pierre and Marie Curie, the
discoverers of radium 87 ) is simply a shorthand way of writing "37,000,000,000
disintegrations per second," the rate of disintegration occurring in 1 gram of
radium. The more modern International System of Measurements (SI) unit for the
same type of measurement is the becquerel ( abbreviated "Bq" and named after
Henri Becquerel, the discoverer of radioactivity), which is simply a shorthand for
"1 disintegration per second."
What is radioactive half-life"!
Being unstable does not lead an atomic nucleus to emit radiation
immediately. Instead, the probability of an atom disintegrating is constant, as if
unstable nuclei continuously participate in a sort of lottery, with random drawings
to decide which atom will next emit radiation and disintegrate to a more stable
state. The time it takes for half of the atoms in a given mass to "win the lottery"--
that is, emit radiation and change to a more stable state—is called the half-life.
Half-lives vary greatly among types of atoms, from less than a second to billions
of years. For example, it will take about 4.5 billion years for half of the atoms in
a mass of uranium 238 to spontaneously disintegrate, but only 24,000 years for
half of the atoms in a mass of plutonium 239 to spontaneously disintegrate.
Iodine 131, commonly used in medicine, has a half-life of only eight days.
What is a radioactive decay chain?
Stability may be achieved in a single decay, or a nucleus may decay
through a series of states before it reaches a truly stable configuration, a bit like a
Slinky toy stepping down a set of stairs. Each state or step will have its own
46
The Atomic Century
unique characteristics of half-life and type of radiation to be emitted as the move
is made to the next state. Much scientific effort has been devoted to unraveling
these decay chains, not only to achieve a basic understanding of nature, but also
to design nuclear weapons and nuclear reactors. The unusually complicated
decay of uranium 238, for example— the primary source of natural radioactivity on
earth— proceeds as follows:" 8
U-238 emits an alpha
I
Thorium 234 emits a beta
I
Protactinium 234 emits a beta
I
Uranium 234 emits an alpha
1
Thorium 230 emits an alpha
1
Radium 226 emits an alpha
I
Radon 222 emits an alpha
!
Polonium 2 1 8 emits an alpha
1
Lead 214 emits a beta
1
Bismuth 214 emits a beta
I
Polonium 214 emits an alpha
I
Lead 210 emits a beta
1
Bismuth 210 emits a beta
1
Polonium 210 emits an alpha
I
Lead 206, which is stable
How can radioactivity be caused artificially?
Radioactivity can occur both naturally and through human intervention.
An example of artificially induced radioactivity is neutron activation. A neutron
fired into a nucleus can cause nuclear fission (the splitting of atoms). This is the
basic concept behind the atomic bomb. Neutron activation is also the underlying
47
Introduction
principle of boron-neutron capture therapy for certain brain cancers. A solution
containing boron is injected into a patient and is absorbed more by the cancer than
by other cells. Neutrons fired at the area of the brain cancer are readily absorbed
(captured) by the boron nuclei. These nuclei then become unstable and emit
radiation that attacks the cancer cells. Simple in its basic physics, the treatment
has been complex and controversial in practice and after half a century is still
regarded as highly experimental.
What Are Atomic Number and Atomic Weight?
What is an element?
Chemical behavior is what originally led scientists to classify matter into
various elements. Chemical behavior is the ability of an atom to combine with
other atoms. In more technical terms, chemical behavior depends upon the type
and number of the chemical bonds an atom can form with other atoms. In
classroom kits for building models of molecules, atoms are usually represented by
colored spheres with small holes for pegs and the bonds are represented by the
small pegs that can connect the spheres. The number of peg holes signifies the
maximum number of bonds an atom can form; different types of bonds may be
represented by different types of pegs. Atoms that have the same number of peg
holes may have similar chemical behavior. Thus, atoms that have identical
chemical behavior are regarded as atoms of the same element. For example, an
atom is labeled a "carbon atom" if it can form the same number, types, and
configurations of bonds as other carbon atoms. Although the basics are simple to
explain, how atoms bind to each other becomes very complex when studied in
detail; new discoveries are still being made as new types of materials are formed.
What is atomic number?
An atom may be visualized as a miniature solar system, with a large
central nucleus orbited by small electrons. The bonding capacity of an atom is
determined by the electrons. For example, atoms that in their normal state have
one electron are hydrogen atoms and will readily (and sometimes violently) bond
with oxygen. This bonding capacity of hydrogen was the cause of the explosion
of the airship Hindenburg in 1937. Atoms that in their normal state have two
electrons are helium atoms, which will not bond with oxygen and would have
been a better choice for filling the Hindenburg.
We can pursue the question back one step further: What determines the
number of electrons? The number of protons in the nucleus of the atom. Here,
the analogy between an atom and the solar system breaks down. The force that
holds the planets in their orbits is the gravitational attraction between the planets
and the sun. However, in an atom what holds the electrons in their orbit is the
electrical attraction between the electrons and the protons in the nucleus. The
48
The Atomic Century
basic rule is that like charges repel and opposite charges attract. Although a
proton has more mass than an electron, they both have the samf amount of
electrical charge, but opposite in kind. Scientists have designated electrons as
having a negative charge and protons as having a positive charge. One positive
proton can hold one negative electron in orbit. Thus, an atom with one proton in
its nucleus normally will have one electron in orbit (and be labeled a hydrogen
atom); an atom with ninety-four protons in its nucleus will normally have ninety-
four electrons orbiting it (and be labeled a plutonium atom).
The number of protons in a nucleus is called the atomic number and
always equals the number of electrons in orbit about that nucleus (in a nonionized
atom). Thus, all atoms that have the same number of protons~the atomic
number— are atoms of the same element.
What is atomic weight?
The nuclei of atoms also contain neutrons, which help hold the nucleus
together. A neutron has no electrical charge and is slightly more massive than a
proton. Because a neutron can decay into a proton plus an electron (the essence
of beta decay), it is sometimes helpful to think of a neutron as an electron and a
proton blended together, although this is at best an oversimplification. Because a
neutron has no charge, a neutron has no effect on the number of electrons orbiting
the nucleus. However, because it is even more massive than a proton, a neutron
can add significantly to the weight of an atom. The total weight of an atom is
called the atomic weight. It is approximately equal to the number of protons and
neutrons, with a little extra added by the electrons. The stability of the nucleus,
and hence the atom's radioactivity, is heavily dependent upon the number of
neutrons it contains.
What notations are used to represent atomic number and weight?
Each atom, therefore, can be assigned both an atomic number (the number
of protons equals the number of electrons) and an atomic weight (approximately
equaling the number of protons plus the number of neutrons). A normal helium
atom, for example, has two protons and two neutrons in its nucleus, with two
electrons in orbit. Its chemical behavior is determined by the atomic number 2
(the number of protons), which equals the normal number of electrons; the
stability of its nucleus (that is, its radioactivity) varies with its atomic weight
(approximately equal to the number of protons and neutrons). The most well-
known form of plutonium, for example, has an atomic number of 94, since it has
94 protons, and with the 145 neutrons in its nucleus, an atomic weight of 239 (94
protons plus 145 neutrons). In World War II, its very existence was highly
classified. A code number was developed: the last digit of the atomic number
(94) and the last digit of the atomic weight (239). Thus, in some of the early
documents examined by the Advisory Committee, the term 49 refers to
plutonium.
49
Introduction
Styles of notation vary, but usually isotopes are written as:
atcic numb e r Chemical abbreviation at ™8 ht
or as
atomic weight chemical abbreviation
Thus, the isotope of plutonium just discussed would be written as:
94
Pu 239 or as 239 Pu
Since the atomic weight is what is often the only item of interest, it might also be
written simply as Pu-239, plutonium 239, or Pu 239 .
Radioisotopes: What Are They and How Are They Made?
What are isotopes?
The isotopes of an element are all the atoms that have in their nucleus the
number of protons (atomic number) corresponding to the chemical behavior of
that element. However, the isotopes of a single element vary in the number of
neutrons in their nuclei. Since they still have the same number of protons, all
these isotopes of an element have identical chemical behavior. But since they
have different numbers of neutrons, these isotopes of the same element may have
different radioactivity. An isotope that is radioactive is called a radioisotope or
radionuclide. Two examples may help clarify this.
The most stable isotope of uranium, U-238, has an atomic number of 92
(protons) and an atomic weight of 238 (92 protons plus 146 neutrons). The
isotope of uranium of greatest importance in atomic bombs, U-235, though, has
three fewer neutrons. Thus, it also has an atomic number of 92 (since the number
of protons has not changed) but an atomic weight of 235 (92 protons plus only
143 neutrons). The chemical behavior of U-235 is identical to all other forms of
uranium, but its nucleus is less stable, giving it higher radioactivity and greater
susceptibility to the chain reactions that power both atomic bombs and nuclear
fission reactors.
Another example is iodine, an element essential for health; insufficient
iodine in one's diet can lead to a goiter. Iodine also is one of the earliest elements
whose radioisotopes were used in what is now called nuclear medicine. The most
common, stable form of iodine has an atomic number of 53 (protons) and an
atomic weight of 127 (53 protons plus 74 neutrons). Because its nucleus has the
"correct" number of neutrons, it is stable and is not radioactive. A less stable
form of iodine also has 53 protons (this is what makes it behave chemically as
50
The Atomic Century
iodine) but four extra neutrons, for a total atomic weight of 131 (53 protons and
78 neutrons). With "too many" neutrons in its nucleus, it is unstable and
radioactive, with a half-life of eight days. Because it behaves chemically as
iodine, it travels throughout the body and localizes in the thyroid gland just like
the stable form of iodine. But, because it is radioactive, its presence can be
detected. Iodine 131 thus became one of the earliest radioactive tracers.
How can different isotopes of an element be produced?
How can isotopes be produced-especially radioisotopes, which can serve
many useful purposes? There are two basic methods: separation and synthesis.
Some isotopes occur in nature. If radioactive, these usually are
radioisotopes with very long half-lives. Uranium 235, for example, makes up
about 0.7 percent of the naturally occurring uranium on the earth.* 9 The challenge
is to separate this very small amount from the much larger bulk of other forms of
uranium. The difficulty is that all these forms of uranium, because they all have
the same number of electrons, will have identical chemical behavior: they will
bind in identical fashion to other atoms. Chemical separation, developing a
chemical reaction that will bind only uranium atoms, will separate out uranium
atoms, but not distinguish among different isotopes of uranium. The only
difference among the uranium isotopes is their atomic weight. A method had to
be developed that would sort atoms according to weight.
One initial proposal was to use a centrifuge. The basic idea is simple:
spin the uranium atoms as if they were on a very fast merry-go-round. The
heavier ones will drift toward the outside faster and can be drawn off. In practice
the technique was an enormous challenge: the goal was to draw off that very
small portion of uranium atoms that were lighter than their brethren. The
difficulties were so enormous the plan was abandoned in 1942. 90 Instead, the
technique of gaseous diffusion was developed. Again, the basic idea was very
simple: the rate at which gas passed {diffused) through a filter depended on the
weight of the gas molecules: lighter molecules diffused more quickly. Gas
molecules that contained U-235 would diffuse slightly faster than gas molecules
containing the more common but also heavier U-238. This method also presented
formidable technical challenges, but was eventually implemented in the gigantic
gas diffusion plant at Oak Ridge, Tennessee. In this process, the uranium was
chemically combined with fluorine to form a hexafluoride gas prior to separation
by diffusion. This is not a practical method for extracting radioisotopes for
scientific and medical use. It was extremely expensive and could only supply
naturally occurring isotopes.
A more efficient approach is to artificially manufacture radioisotopes.
This can be done by firing high-speed particles into the nucleus of an atom.
When struck, the nucleus may absorb the particle or become unstable and emit a
particle. In either case, the number of particles in the nucleus would be altered,
creating an isotope. One source of high-speed particles could be a cyclotron. A
51
Introduction
cyclotron accelerates particles around a circular race track with periodic pushes of
an electric field. The particles gather speed with each push, just as a child swings
higher with each push on a swing. When traveling fast enough, the particles are
directed off the race track and into the target.
A cyclotron works only with charged particles, however. Another source
of bullets are the neutrons already shooting about inside a nuclear reactor. The
neutrons normally strike the nuclei of the fuel, making them unstable and causing
the nuclei to split (fission) into two large fragments and two to three "free"
neutrons. These free neutrons in turn make additional nuclei unstable, causing
further fission. The result is a chain reaction. Too many neutrons can lead to an
uncontrolled chain reaction, releasing too much heat and perhaps causing a
"meltdown." Therefore, "surplus" neutrons are usually absorbed by "control
rods." However, these surplus neutrons can also be absorbed by targets of
carefully selected material placed in the reactor. In this way the surplus neutrons
are used to create radioactive isotopes of the materials placed in the targets.
With practice, scientists using both cyclotrons and reactors have learned
the proper mix of target atoms and shooting particles to "cook up" a wide variety
of useful radioisotopes.
How Does Radiation Affect Humans?
Radiation may come from either an external source, such as an x-ray
machine, or an internal source, such as an injected radioisotope. The impact of
radiation on living tissue is complicated by the type of radiation and the variety of
tissues. In addition, the effects of radiation are not always easy to separate from
other factors, making it a challenge at times for scientists to isolate them. An
overview may help explain not only the effects of radiation but also the
motivation for studying them, which led to much of the research examined by the
Advisory Committee.
What effect can ionizing radiation have on chemical bonds?
The functions of living tissue are carried out by molecules, that is,
combinations of different types of atoms united by chemical bonds. Some of
these molecules can be quite large. The proper functioning of these molecules
depends upon their composition and also their structure (shape). Altering
chemical bonds may change composition or structure. Ionizing radiation is
powerful enough to do this. For example, a typical ionization releases six to
seven times the energy needed to break the chemical bond between two carbon
atoms. 91 This ability to disrupt chemical bonds means that ionizing radiation
focuses its impact in a very small but crucial area, a bit like a karate master
focusing energy to break a brick. The same amount of raw energy, distributed
more broadly in nonionizing form, would have much less effect. For example, the
amount of energy in a lethal dose of ionizing radiation is roughly equal to the
52
The Atomic Century
amount of thermal energy in a single sip of hot coffee. 92 The crucial difference is
that the coffee's energy is broadly distributed in the form of nonionizing heat,
while the radiation's energy is concentrated in a form that can ionize.
What is DNA?
Of all the molecules in the body, the most crucial is DNA (deoxyribose
nucleic acid), the fundamental blueprint for all of the body's structures. The DNA
blueprint is encoded in each cell as a long sequence of small molecules, linked
together into a chain, much like the letters in a telegram. DNA molecules are
enormously long chains of atoms wound around proteins and packed into
structures called chromosomes within the cell nucleus. When unwound, the DNA
in a single human cell would be more than 2 meters long. It normally exists as
twenty-three pairs of chromosomes packed within the cell nucleus, which itself
has a diameter of only 10 micrometers (0.00001 meter). 93 Only a small part of
this DNA needs to be read at any one time to build a specific molecule. Each cell
is continually reading various parts of its own DNA as it constructs fresh
molecules to perform a variety of tasks. It is worth remembering that the
structure of DNA was not solved until 1953, nine years after the beginning of the
period studied by the Advisory Committee. We now have a much clearer picture
of what happens within a cell than did the scientists of 1944.
What effect can ionizing radiation have on DNA?
Ionizing radiation, by definition, "ionizes," that is, it pushes an electron
out of its orbit around an atomic nucleus, causing the formation of electrical
charges on atoms or molecules. If this electron comes from the DNA itself or
from a neighboring molecule and directly strikes and disrupts the DNA molecule,
the effect is called direct action. This initial ionization takes place very quickly,
in about 0.000000000000001 of a second. However, today it is estimated that
about two-thirds of the damage caused by x rays is due to indirect action. This
occurs when the liberated electron does not directly strike the DNA, but instead
strikes an ordinary water molecule. This ionizes the water molecule, eventually
producing what is known as zfree radical. A free radical reacts very strongly
with other molecules as it seeks to restore a stable configuration of electrons. A
free radical may drift about up to 10,000,000,000 times longer than the time
needed for the initial ionization (this is still a very short time, about 0.00001 of a
second), increasing the chance of it disrupting the crucial DNA molecule. This
also increases the possibility that other substances could be introduced that would
neutralize free radicals before they do damage. 94
Neutrons act quite differently. A fast neutron will bypass orbiting
electrons and occasionally crash directly into an atomic nucleus, knocking out
large particles such as alpha particles, protons, or larger fragments of the nucleus.
The most common collisions are with carbon or oxygen nuclei. The particles
created will themselves then set about ionizing nearby electrons. A slow neutron
53
Introduction
will not have the energy to knock out large particles when it strikes a nucleus.
Instead, the neutron and the nucleus will bounce off each other, like billiard balls.
In so doing, the neutron will slow down, and the nucleus will gain speed. The
most common collision is with a hydrogen nucleus, a proton that can excite or
ionize electrons in nearby atoms. 95
What immediate effects can ionizing radiation have on living cells?
All of these collisions and ionizations take place very quickly, in less than
a second. It takes much longer for the biological effects to become apparent. If
the damage is sufficient to kill the cell, the effect may become noticeable in hours
or days. Cell "death" can be of two types. First, the cell may no longer perform
its function due to internal ionization; this requires a dose to the cell of about 100
gray (10,000 rad). (For a definition of gray and rad, see the section below titled
"How Do We Measure the Biological Effects of Radiation?") Second,
"reproductive death" (mitotic inhibition) may occur when a cell can no longer
reproduce, but still performs its other functions. This requires a dose of 2 gray
(200 rad), which will cause reproductive death in half the cells irradiated (hence
such a quantity is called a "mean lethal dose.") 96 Today we still lack enough
information to choose among the various models proposed to explain cell death in
terms of what happens at the level of atoms and molecules inside a cell. 97 If
enough crucial cells within the body totally cease to function, the effect is fatal.
Death may also result if cell reproduction ceases in parts of the body where cells
are continuously being replaced at a high rate (such as the blood cell-forming
tissues and the lining of the intestinal tract). A very high dose of 100 gray
( 1 0,000 rad) to the entire body causes death within twenty-four to forty-eight
hours; a whole-body dose of 2.5 to 5 gray (250 to 500 rad) may produce death
within several weeks. 98 At lower or more localized doses, the effect will not be
death, but specific symptoms due to the loss of a large number of cells. These
effects were once called nonstochastic; they are now called deterministic.™ A
beta burn is an example of a deterministic effect.
What long-term effects can radiation have?
The effect of the radiation may not be to kill the cell, but to alter its DNA
code in a way that leaves the cell alive but with an error in the DNA blueprint.
The effect of this mutation will depend on the nature of the error and when it is
read. Since this is a random process, such effects are now called stochastic.™
Two important stochastic effects of radiation are cancer, which results from
mutations in nongerm cells (termed somatic cells), and heritable changes, which
result from mutations in germ cells (eggs and sperm).
How can ionizing radiation cause cancer?
Cancer is produced if radiation does not kill the cell but creates an error in
the DNA blueprint that contributes to eventual loss of control of cell division, and
54
The Atomic Century
the cell begins dividing uncontrollably. This effect might not appear for many
years. Cancers induced by radiation do not differ from cancers due to other
causes, so there is no simple way to measure the rate of cancer due to radiation.
During the period studied by the Advisory Committee, great effort was devoted to
studies of irradiated animals and exposed groups of people to develop better
estimates of the risk of cancer due to radiation. This type of research is
complicated by the variety of cancers, which vary in radiosensitivity. For
example, bone marrow is more sensitive than skin cells to radiation-induced
cancer. 101
Large doses of radiation to large numbers of people are needed in order to
cause measurable increases in the number of cancers and thus determine the
differences in the sensitivity of different organs to radiation. Because the cancers
can occur anytime in the exposed person's lifetime, these studies can take seventy
years or more to complete. For example, the largest and scientifically most
valuable epidemiologic study of radiation effects has been the ongoing study of
the Japanese atomic bomb survivors. Other important studies include studies of
large groups exposed to radiation as a consequence of their occupation (such as
uranium miners) or as a consequence of medical treatment. These types of
studies are discussed in greater detail in the section titled "How Do Scientists
Determine the Long-Term Risks from Radiation?"
How can ionizing radiation produce genetic mutations?
Radiation may alter the DNA within any cell. Cell damage and death that
result from mutations in somatic cells occur only in the organism in which the
mutation occurred and are therefore termed somatic or nonheritable effects.
Cancer is the most notable long-term somatic effect. In contrast, mutations that
occur in germ cells (sperm and ova) can be transmitted to future generations and
are therefore called genetic or heritable effects. Genetic effects may not appear
until many generations later. The genetic effects of radiation were first
demonstrated in fruit flies in the 1920s. Genetic mutation due to radiation does
not produce the visible monstrosities of science fiction; it simply produces a
greater frequency of the same mutations that occur continuously and
spontaneously in nature.
Like cancers, the genetic effects of radiation are impossible to distinguish
from mutations due to other causes. Today at least 1,300 diseases are known to
be caused by a mutation. 102 Some mutations may be beneficial; random mutation
is the driving force in evolution. During the period studied by the Advisory
Committee, there was considerable debate among the scientific community over
both the extent and the consequences of radiation-induced mutations. In contrast
to estimates of cancer risk, which are based in part on studies of human
populations, estimates of heritable risk are based for the most part upon animal
studies plus studies of Japanese survivors of the atomic bombs.
The risk of genetic mutation is expressed in terms of the doubling dose:
55
Introduction
the amount of radiation that would cause additional mutations equal in number to
those that already occur naturally from all causes, thereby doubling the naturally
occurring rate of mutation.
It is generally believed that mutation rates depend linearly on dose and
that there is no threshold below which mutation rates would not be increased.
Spontaneous mutation (unrelated to radiation) occurs naturally at a rate of
approximately 1/10,000 to 1/1,000,000 cell divisions per gene, with wide
variation from one gene to another.
Attempts have been made to estimate the contribution of ionizing
radiation to human mutation rates by studying offspring of both exposed and
nonexposed Japanese atomic bomb survivors. These estimates are based on
comparisons of the rate of various congenital defects and cancer between exposed
and nonexposed survivors, as well as on direct counting of mutations at a small
number of genes. For all these endpoints, no excess has been observed among
descendants of the exposed survivors.
Given this lack of direct evidence of any increase in human heritable
(genetic) effects resulting from radiation exposure, the estimates of genetic risks
in humans have been compared with experimental data obtained with laboratory
animals. However, estimates of human genetic risks vary greatly from animal
data. For example, fruit flies have very large chromosomes that appear to be
uniquely susceptible to radiation. Humans may be less vulnerable than previously
thought. Statistical lower limits on the doubling dose have been calculated that
are compatible with the observed human data. Based on our inability to
demonstrate an effect in humans, the lower limit for the genetic doubling dose is
thought to be less than 100 rem. 103
How Do We Measure the Biological Effects of External Radiation?
The methods of measuring radiation and radioactivity, purely physical
events, were discussed earlier. In studying the effect of radiation on living
organisms, a biological event, the crucial data are the amount of energy absorbed
by a specific amount and type of tissue. This requires first measuring the amount
of energy left behind by the radiation in the tissue and, second, the amount and
type of tissue.
What is an absorbed dose of radiation?
The risk posed to a human being by any radiation exposure depends partly
upon the absorbed dose, the amount of energy absorbed per gram of tissue.
Absorbed dose is expressed in rad. A rad is equal to 100 ergs of energy
absorbed by 1 gram of tissue. The more modern, internationally adopted unit is
the gray (named for the English medical physicist L. H. Gray); one gray equals
100 rad. Almost all the documents from the time period studied by the Advisory
Committee use the term rad rather than gray. It is important to realize that
56
The Atomic Centwy
absorbed dose refers to energy per gram of absorbing tissue, not total energy.
Someone absorbing 1 gray (100 rad) in a small amount of tissue, such as a thyroid
gland, will absorb much less total energy than someone absorbing 1 gray (100
rad) throughout his or her entire body. Thus, when speaking of absorbed dose, it
is crucial to know the amount of tissue being exposed, not simply the number of
gray or rad.
What is an equivalent dose of radiation?
Even the rad or gray, though, are still units that measure a purely physical
event: the amount of energy left behind in a gram of tissue. It does not directly
measure the biological effect of that radiation. The biological effect of the same
amount of absorbed energy may vary according to the type of radiation involved.
This biological effect can be computed by multiplying the absorbed dose (in rad
or gray) by a number indicating the quality factor of the particular type of
radiation. For photons and electrons the quality factor is defined to be 1; for
neutrons it ranges from 5 to 20 depending on the energy of the neutron; for alpha
particles it is 20. m Thus, 1 gray (100 rad) of alpha particles is currently judged to
have an effect on living tissue that is twenty times more than 1 gray ( 1 00 rad) of x
rays. Multiplying the absorbed dose (in rad or gray) by the quality factor (also
known as the radiation weighting factor) produces what is called the equivalent
dose. For the period studied by the Advisory Committee, this was expressed in
terms of a unit called the rem, an acronym for roentgen equivalent man. 105 (The
term equivalent simply meant that an absorbed dose expressed in rem would have
equivalent biological effects, regardless of the type of radiation. Thus, 10 rem of
x rays should have the same biological effect as 10 rem of neutrons absorbed by
the same part of the body.) The modern unit is the sievert (abbreviated Sv and
named for the prominent Swedish radiologist, Rolf Sievert), which is equal to 100
rem. Thus, an equivalent dose of 200 rem would today be expressed as 2 sievert.
What is an effective dose of radiation?
Finally, the biological effect of radiation depends on the type of tissue
being irradiated. As with different types of radiation, a weighting or quality
factor is introduced depending on the type of tissue. The more sensitive the tissue
is to radiation, the higher the factor. The effective dose is the sum of the
equivalent doses of the various types of irradiated tissue, each properly weighted
for its sensitivity to radiation. Tissue weighting factors are determined from the
relative incidence of cancers in different tissues in the Japanese survivors of the
atomic bombs.
Calculating the effective dose makes it possible to readily compare
different exposures, as illustrated by the accompanying graphs.
57
Experimental and Nonexperimental Doses*
Thyroid Studies with lodine-131
Effective Dose Equivalant (millirems, thyroid excluded)
350
Study 1 Study 2 Study 3 Study 4 Background
Largest Dose
Smallest Dose
Thyroid Studies with lodine-131
Dose to Thyroid Gland (rads)
600
Study 1 Study 2 Study 3
■ Largest Thyroid Dose H
Study 4 Medical Scan
Smallest Thyroid Dose
*The experiments themselves are discussed in chapter 7. These graphs are reproduced with permission
from Task Force on Human Subject Research, Commonwealth of Massachusetts Department of Mental
Retardation, April 1994, "A Report on the Use of Radioactive Materials in Human Subject Research that
Involved Residents of State-Operated Facilities within the Commonwealth of Massachusetts from 1942-
1973" (ACHRENo. MASS-072194-A), 17, and the Working Group on Human Subject Research,
Commonwealth of Massachusetts Department of Mental Retardation, June 1994, "The Thyriod Studies:
A Follow-up Report on the Use of Radioactive Materials in Human Subject Research that Involved
Residents of State-Operated Facilities within the Commonwealth of Massachusetts from 1942-1973"
(ACHRENo. MASS-072194-A), 14.
Fernald School Nutrition Study: Ca Tracer
Effective Dose Equivalent (millirems)
500
Smallest Dose Largest Dose
|H Annual Natural Background |
Denver Resident
Study
Fernald School Nutrition Study: Fe Tracer
Effective Dose Equivalent (millirems)
500
Smallest Dose Largest Dose Denver Resident
MB Annual Natural Background H] Study
Common Medical Procedures
Whole Body Effective Dose Equivalent (millirems)
1000
Chest X-Ray BackX-Ray Colon X-Ray Brain Scan
H| Annual Natural Background HH Procedure
Introduction
How Do We Measure the Biological Effects of Internal Emitters?
The general principles just described require further refinement when
applied to doses from internal emitters.
What information is needed to calculate absorbed dose of a
radionuclide inside the body?
Calculating the absorbed dose from a radionuclide inside the body is
complex since it involves both the physics of radioactive decay and the biology of
the body's metabolism. Six important factors that must be considered are these:
1. The amount of the radionuclide administered.
2. The type of radiation emitted during the decay process.
3. The physical half-life of the radionuclide.
4. The chemical form of the radionuclide.
5. The fraction of the radionuclide that accumulates in each organ.
6. The length of time that the radionuclide remains in the organ (the
biological half-life).
How varied are the types of radiation that different radionuclides
emit?
Radionuclides can emit several types of radiation (e.g., gamma rays, beta
or alpha particles). Each radionuclide emits its own unique mixture of radiations;
indeed, scientists identify radioactive materials by using these unique mixtures as
if they were fingerprints. The mix of radiations for a specific radionuclide is
always the same, regardless of whether the radionuclide is located on a bench in a
physicist's laboratory or inside the human body. This means that the type of
radiation of each radionuclide can be measured outside the body with great
precision by laboratory instruments. A quality factor, discussed earlier, is used to
adjust for the difference in the biological effects of different types of radiation.
What determines how long a radionuclide will irradiate the body?
The combination of the physical and biological half-life (the effective
half-life) determines how long a radionuclide will continue to pump out energy
into surrounding tissue. If the physical and biological half-lives of a particular
chemical form of a radionuclide are very long, the radionuclide will continue to
expose an individual to radiation over his or her lifetime. The total lifetime
radiation exposure, expressed in rem, is called the committed dose equivalent.
The physical half-life is the length of time it will take for half of the atoms
in a sample to decay to a more stable form. The physical half-life of each
radionuclide can be measured precisely in the laboratory. A shorter half-life
means that the miniature power source will "run down" sooner. Sometimes,
however, a radionuclide will not decay immediately to a stable form, but to a
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The Atomic Century
second, still unstable, form. A full calculation, therefore, must also include the
types of radiation and physical half-lives of any decay products.
The biological half-life does not depend on the radionuclide but rather on
the chemical form of the radionuclide. One chemical form of the radionuclide
might be rapidly eliminated from the body whereas other chemical forms may be
slowly eliminated.
To measure the biological half-life of a particular chemical form of a
radionuclide, that chemical form needs to be studied in animals. Since the
biological processes of different animals vary considerably, an accurate
determination of the biological half-life requires that each chemical form of the
radionuclide be studied in each animal of interest. Prior to studying a chemical
form of a radionuclide in a human being, animal studies are performed to get
some idea of what to expect.
Once the results of animal studies are available, scientists are able to
predict what amount of that chemical form of the radionuclide can be safely
injected into humans. An accurate determination of what fraction of each
chemical form of the radionuclide accumulates in each organ and how long it
stays in each organ in humans can only be determined by studying humans.
These type of studies are called biodistribution studies.
What is the tissue weighting factor?
Some chemical forms of radionuclides are highly concentrated in one
small organ (e.g., iodine in the thyroid gland). When this happens, that organ will
absorb most of the radiated energy, and little energy will be deposited in the
remainder of the body. Thus, for each chemical form of a radionuclide, there is
an organ that will receive the highest dose from that radionuclide. Since organs
also vary greatly in their sensitivity to radiation, the biological consequences of
the radiation dose differ depending on the organ. This difference in sensitivity to
radiation is represented by what is called a tissue weighting factor.
What is the difference between committed equivalent dose and
committed effective dose?
An estimate of the risk posed by a radionuclide in the body depends on its
chemical form, its biodistribution, its physical properties (how it decays), and the
sensitivity of the organs exposed. When all these factors are considered in the
calculation of risk for a single radionuclide, the total lifetime exposure is called
the committed equivalent dose. If more than one radioisotope is present, the sum
of all the committed equivalent doses is called the committed effective dose. Both
are expressed in rem or the more modern units sieverts. m These calculations
provide a basis for comparing the risk posed by different isotopes.
How do radiation risks compare with chemical risks?
It should be noted that radiation is not the only possible hazard resulting
61
Introduction
from the medical use of radionuclides. Few radioisotopes, whether intentionally
or accidentally introduced into the body, enter in a chemically pure form. The
radioactive atoms are usually part of a larger chemical compound. The chemical
form of the radioisotope may pose its own hazards of chemical toxicity. Chemical
toxicity depends upon the chemical effect of the compound on the body, quite
independent of any effects of radiation. Determining chemical toxicity is an
entire field of science on its own.
How Do Scientists Determine the Long-Term Risks from Radiation?
Where did the risk estimates in this report come from?
Throughout this report, the reader will find numerous statements
estimating the risks of cancer and other outcomes to individuals exposed to
various types of radiation. These estimates were obtained from various scientific
advisory committees that have considered these questions in depth. 107 Their
estimates in turn are based on syntheses of the scientific data on observed effects
in humans and animals.
How are risk estimates expressed?
Epidemiologists usually express the risk of disease in terms of the number
of new cases {incidence rate) or deaths (mortality rate) in a population in some
period of time. For example, an incidence rate might be 100 new cases per
100,000 people per year; a mortality rate might be 15 deaths per 100,000 people
per year. These rates vary widely by age, conditions of exposure, and various
other factors. To summarize this complex set of rates, government regulatory
bodies often consider the lifetime risk of a particular outcome like cancer. When
relating a disease, such as cancer, to one of its several causes, a more useful
concept is the excess lifetime risk expected from one particular pattern of
exposure, such as continuous exposure to 1 rad per year.
It is well established that cancer rates begin to rise above the normal
background rate only some time after exposure, the latent period, which varies
with the type of cancer and other factors such as age. Even after the latent period
has passed and radiation effects begin to appear, not all effects are due to
radiation. The excess rate may still vary by age, latency, or other factors, but for
many cancers it tends to be roughly proportional to the rate in the general
population. This is known as the constant relative risk model, and the ratio of
rates at any given age between exposed and unexposed groups is called the
relative risk. Many advisory committees have based their risk estimates on
models for the relative risk as a function of dose and perhaps other factors. Other
committees, however, have based their estimates on the difference in rates
between exposed and unexposed groups, a quantity known as the absolute risk.
This quantity also varies with dose and other factors, but when this variation is
appropriately accounted for, either approach can be used to estimate lifetime risk.
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The Atomic Century
What are the types of data on which such estimates are based?
Human data are one important source, discussed below. Two other
important sources of scientific data are experiments on animals and on cell
cultures. Because both types of research are done in laboratories, scientists can
carefully control the conditions and many of the variables. For the same reason,
the experiment can be repeated to confirm the results. Such research has
contributed in important ways to our understanding of basic radiobiological
principles. It also has provided quantitative estimates of such parameters as the
relative effectiveness of different types of radiation and the effects of dose and
dose rate. In some circumstances, where human data are limited or nonexistent,
such laboratory studies may provide the only basis on which risks can be
estimated.
Why are human data preferable to data on animals or tissue cultures
for most purposes?
Most scientists prefer to base risk estimates for humans on human data
wherever possible. This is because in order to apply animal or tissue culture data
to humans, scientists must extrapolate from one species to another or from simple
cellular systems to the complexities of human physiology. This requires adjusting
the data for differences among species in life span, body size, metabolic rates, and
other characteristics. Without actual human data, extrapolation provides no
guarantee that there are no unknown factors also at work. It is not surprising that
there is no clear consensus as to how to extrapolate risk estimates from one
species to another. This problem is not unique to radiation effects; there are
countless examples of chemicals having very different effects in different species,
and humans can differ quite significantly from animals in their reaction to toxic
agents.
How have human data been obtained?
There are serious ethical issues with conducting experiments on humans,
as discussed elsewhere in the report. However, most of the human data that are
used to estimate risks, not just risk from radiation, come from epidemiologic
studies on populations that already have been exposed in various ways. For
radiation effects, the most important human data come from studies of the
Japanese atomic bomb survivors carried out by the Radiation Effects Research
Foundation (formerly the Atomic Bomb Casualty Commission) in Hiroshima.
Other valuable sources of data include various groups of medically exposed
patients (such as radiotherapy patients) and occupationally exposed workers (such
as the uranium miners, discussed in chapter 12). I08
63
Introduction
Why is it necessary to compare exposed populations with unexposed
populations?
Unlike a disease caused by identifiable bacteria, no "signature" has yet
been found in cancerous tissue that would link it definitively to prior radiation
exposure. Radiogenic cancers are identical in properties, such as appearance
under a microscope, growth rate, and potential to metastasize, to cancers
occurring in the general population. Finding cancers in an exposed population is
not enough to prove they are due to radiation; the same number of cancers might
have occurred due to the natural frequency of the disease. The challenge is to
separate out the effects of radiation from what would otherwise have occurred. A
major step in this direction is to develop follow-up (or cohort) studies, in which
an exposed group is followed over time to observe their disease rates, and these
rates are then compared with the rates for the general population or an unexposed
control group. 109
Why is the analysis of epidemiologic data so complicated?
Simply collecting data on disease rates in exposed and control populations
is not enough; indeed, casual analysis may lead to serious errors in understanding.
Sophisticated data-collection techniques and mathematical models are needed to
develop useful risk estimates for several reasons:
1 . Random variation due to sample size.
2. Multiple variables.
3. Limited time span of most studies.
4. Problems of extrapolation.
In addition, individual studies may also be biased in their design or
implementation.
What is random variation?
The observed proportion of subjects developing disease in any randomly
selected subgroup (sample) of individuals with similar exposures is subject to the
vagaries of random variation.
A simple-minded example of this is the classic puzzle of determining, in a
drawer of 100 socks, how many are white and how many are black, by pulling out
one sock at a time. Obviously, if we pull out all the socks, we know for certain.
In most areas of study, though, "pulling out all the socks" is far too expensive and
time-consuming. But if we pull only 10, with what degree of confidence can we
predict the color of the others? If we pull 20, we will have more confidence. In
other words, the larger the sample, the greater our confidence. Using statistical
techniques, our degree of confidence can be calculated from the size of the entire
population (in this case 100 socks) and the size of the actual sample. The result is
popularly called the margin of error.
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The Atomic Century
The most common examples of this in everyday life are the public opinion
polls continually quoted in the news media. As can be seen in the simple example
of the drawer of socks, the highest degree of confidence can be achieved simply
by pulling all the socks out of the drawer. For public opinion polls, this would be
far too expensive; instead, a small sample is selected at random from the
population. Nowadays it is common to report not only the actual results, but also
the sample size and the margin of error. The margin of error depends not only on
the sample size, but also on how high a degree of confidence we desire. The
degree of confidence is the probability that our sample has provided a true picture
of the entire population. For example, the margin of error will be smaller for 80
percent degree of confidence than for 95 percent. Even where a study covers an
entire exposed population, such as the atomic bomb survivors, the issue of
random variation remains when we wish to generalize the findings to other
populations.
What are multiple variables'!
The effects of radiation will depend upon, or vary, with the dose of
radiation received. However, these effects also may vary with other factors-
other variables-thai are not dependent upon the radiation dose itself. Examples
of such variables are age, gender, latency (time since exposure), and smoking.
Data on these other variables must be collected as well as data on the basic
elements of radiation dose and disease. The challenge is to then distinguish
between disease rates due to radiation and those due to other factors. For
example, if the population studied were all heavy smokers, this might explain in
part a higher rate of lung cancer. Much of the science of epidemiology is devoted
to choosing what factors to collect data on and then developing the multivariate
mathematical models needed to separate out the effect of each variable.
Radiation effects vary considerably across subgroups and over time or age.
Because of this, direct estimates of risk for particular subgroups would be very
unstable. Mathematical models must be used. These models allow all the data to
be used to develop risk estimates that, while based on sufficiently large estimates
to be stable, will be applicable to particular subgroups.
A more subtle problem is mis specification of the model finally chosen to
calculate risks. The model may weigh selected factors in a manner that best fits
the data from a statistical viewpoint. This model, while fitting the data, may not
actually be a "correct" view of nature; another model that does not fit the data
quite as well may actually better describe the as-yet-unknown underlying
mechanisms.
Why does a limited time span reduce the value of a study?
The most pronounced effects of large exposures to radiation manifest
themselves quickly in symptoms loosely termed radiation sickness.
However, another concern is understanding the effects of much lower
65
Introduction
levels of radiation. Unlike the more acute effects of large exposures, these may
not appear for some time. Some cancers, for example, do not appear until many
years after the initial exposure. These latent effects may continue to appear in a
population throughout their entire lifetimes. Calculating the lifetime risk of an
exposure requires following the entire sample until all its members have died.
Thus far, none of the exposed populations have yet been followed to the ends of
their lives, although the radium dial painter study for the group painting before
1930 essentially has been completed, and the follow-up has been closed out."
Why does extrapolation among human populations pose problems?
As discussed earlier, extrapolating results from one species to another is
problematic due to differences in how species respond to radiation.
Even though humans are all members of the same species, there are
similar problems when extrapolating results from one group of humans to another
group. Within the human species, different groups can have different rates of
disease. For example, stomach cancer is much more common and breast cancer
much rarer among Japanese than among U.S. residents.
How then should estimates of the radiation-induced excess of cancer
among the atomic bomb survivors be applied to the U.S. population?
Assumptions are needed to "transport" risk estimates from one human population
to another human population that may have very different "normal" risks.
Why does extrapolation from high to low doses pose problems?
Acquiring high-quality human data on low-dose exposure is difficult. Past
studies indicate that the effects of low doses are small enough to be lost in the
"noise" of random variation. In other words, the random variation due to sample
size may be greater than the effects of the radiation. Thus, to estimate the risks of
low doses, it is necessary to extrapolate from the effects of high doses down to
the lower range of interest. As with extrapolation among species or among
human populations, assumptions must be made.
The basic assumption concerns the dose effect. Is the effect of a dose
linear? This would mean that half the dose would produce half the effect; one-
tenth of the dose would produce one-tenth of the effect, and so forth. Nature is
not always so reasonable, however. There are many instances in nature of
nonlinear relationships. A nonlinear dose effect, for example, could mean that
half the dose would produce 75 percent of the effects. Or, going in the other
direction, a nonlinear dose effect could mean that half the dose would produce
only 10 percent of the effect. Reliable data are too sparse to settle the issue
empirically. Much of the ongoing controversy over low-dose effects concerns
which dose effect relationship to assume. Concerning dose response, most
radiation advisory committees assume that radiation risks are linear in doses at
low levels, although these risks may involve nonlinear terms at higher doses.
Another assumption concerns the effect of dose rate. It is generally
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The Atomic Century
agreed that the effect of high-dose x rays is reduced if the radiation is received
over a period of time instead of all at once. (This reduction in acute effects, due
to the cell's ability to repair itself in between exposures, is one of the reasons that
modern protocols for radiotherapy use several fractionated doses.) The degree to
which this also happens at low doses is less clear. There are few human data on
the effect of dose rate on cancer induction. Most estimates of the effect come
from animal or cell culture experiments. There is also evidence of quite different
dose-rate effects for alpha radiation and neutrons.
How can a specific study be biased?
When applied to an epidemiologic study, the term bias does not refer to
the personal beliefs of the investigators, but to aspects of the study design and
implementation. There are several possible sources of bias in any study.
What is called a confounding bias may result if factors other than radiation
have affected disease rates. Such factors, as mentioned earlier, might be a rate of
smoking higher than the general population.
A selection bias may result if the sample was not truly a random selection
from the population under study. For example, the results of a study that includes
only employed subjects might not be applicable to the general population, since
employed people as a group are healthier than the entire population.
An information bias may result from unreliability in a source of basic
data. For example, basing the amount of exposure on the memory of the subjects
may bias the study, since sick people may recall differently than healthy people.
Dose, in particular, can be difficult to determine when studies are conducted on
populations exposed prior to the study, since there usually was no accurate
measurement at the time of exposure. Sometimes when dose measurements were
taken, as in the case of the atomic veterans, the data are not adequate by today's
standards." 1
Finally, any study is subject to the random variation discussed earlier,
which depends on how large the sample is. This is more important for low-dose
than for high-dose studies, since the low-dose effects themselves are small
enough to be lost amid random variations if the sample is too small.
To summarize, multiple studies may produce somewhat different results
because there is an actual difference in the response between populations or
because studies contain spurious results due to their own inadequacies. In
addition, it must be recognized that the entire body of scientific literature is itself
subject to a form of bias known as publication bias, meaning an overreporting of
findings of excess risk. This is because studies that demonstrate an excess risk
may be more likely to be published than those that do not.
67
Introduction
In view of all these uncertainties, what risk estimates did the
Committee choose?
Despite all these uncertainties, it must be pointed out that more is known
about the effects of ionizing radiation than any other carcinogen.
The BEIR V Committee of the National Academy of Sciences estimated
in 1990 that the lifetime risk from a single exposure to 10 rem of whole-body
external radiation was about 8 excess cancers (of any type) per 1,000 people.
(This number is actually an average over all possible ages at which an individual
might be exposed, weighted by population and age distribution.) For continuous
exposure to 0.1 rem per year throughout a lifetime, the corresponding estimate
was 5.6 excess cancers (that is, over and above the rate expected in a similar, but
nonexposed population) per 1 ,000 people. It is widely agreed that for x rays and
gamma rays, this latter figure should be reduced by some factor to allow for a
cell's ability to repair DNA, but there is considerable uncertainty as to what figure
to use; a figure of about 2 or 3 is often suggested." 2
The estimates of lifetime risk from the BEIR V report have a range of
uncertainty due to random variation of about 1.4-fold. The additional
uncertainties, due to the factors discussed earlier, are likely to be larger than the
random variation.
In comparison, for most chemical carcinogens, the uncertainties are often
a factor of 10 or more. This agreement among studies of radiation effects is quite
remarkable and reflects the enormous amount of scientific research that has been
devoted to the subject, as well as the large number of people who have been
exposed to doses large enough to show effects.
68
ENDNOTES
1 . In 1974 the AEC's regulatory activities for civilian nuclear power and the use
(including medical research) of radioisotopes produced in nuclear reactors were
transferred to the Nuclear Regulatory Commission and its research and weapons-
development activities to the Energy Research and Development Administration
(ERDA) In 1 977 ERDA was incorporated into the new Department of Energy.
2. Captain C. F. Behrens, ed., Atomic Medicine (New York: Thomas Nelson and
Sons, 1949), 3.
3. Ibid., 7.
4 Otto Glasser, William Conrad Roentgen and the Early History oj the
Roentgen Rays (Springfield, 111., and Baltimore: Charles C. Thomas, 1934), 29; Glasser is
quoting O. Lummer of Berlin.
5. Ibid., 271.
6. Ibid., 244-282.
7. Robert Reid, Marie Curie (New York: E. P. Dutton, 1974), 241.
8. Ibid., 86-87.
9. P. Curie and M. S. Curie, "Radium: A New Body, Strongly Radio-Active,
Contained in Pitchblende," Scientific American (28 January 1899): 60. The term
hyperphosphorescence was suggested by Silvanus Thompson. Reid, Marie Curie, 87.
See also Susan Quinn, Marie Curie: A Life (New York: Simon and Schuster, 1995).
10. New York Journal, 21 June 1905, reproduced in David J. DiSantis, M.D.,
and Denise M. DiSantis, "Radiologic History Exhibit: Wrong Turns on Radiology's Road
of Progress," Radiographics (1991): 1 121-1 138, figure 17.
11. Henry S. Kaplan, "Historic Milestones in Radiobiology and Radiation
Therapy," Seminars in Oncology 6, no. 4 (December 1979): 480.
12. "Autopsy of a Radiologist," Archives of the Roentgen Ray 18
(April 1914): 393. .
13 Reid, Marie Curie, 274; Barton C. Hacker, The Dragon's Tail: Radiation
Safety in the Manhattan Project, 1942-1946 (Berkeley, Calif: University of California
Press, 1987), 22-23.
14. The marketing of one nostrum containing radium, Radiothor, was not
officially shut down by the Federal Trade Commission until 1932. "With the institution
of regulations, the radioactive patent medicine industry collapsed overnight." Roger M.
Macklis, "The Great Radium Scandal," Scientific American 269 (March 1993): 94-99.
In the 1920s, the use of capsules containing radium inserted into the nose was introduced
as a means of shrinking lymphoid tissue in children to treat middle ear obstructions and
infections. During World War II this procedure was used on submariners and Air Force
personnel as treatment and, in the case of several hundred submariners, on an
experimental basis to test the effectiveness of nasopharyngeal irradiation in shrinking
lymphoid tissue and equalizing external and middle ear pressure. In the late 1940s, the
observation that no controlled study had ever been conducted to test the treatment's
effectiveness in preventing deafness in children led Johns Hopkins researchers to begin
the experimental treatment of several hundred children. As the Advisory Committee
began its work in 1994, controversy over the long-term effects of this treatment still
swirled. Samuel Crane, "Irradiation of Nasopharynx," Annals of Otology, Rhinology, and
Laryngology 55 (1946): 779-788; H. L. Holmes and J. D. Harris, "Aerotitis Media in
69
Submariners," Annals of Otology, Rhinology, and Laryngology 55 (1946): 347-371. See
chapter 7 and ACHRE Briefing Book, vol. 13, tab E, April 1995, for fuller discussion.
15. Macklis, "The Great Radium Scandal," 94-99.
16. The National Council on Radiation Protection began as the American
Committee on X Ray and Radium Protection in 1928, under the aegis of the International
Congress of Radiology. A private organization, its members were physicians, physicists,
and representatives of the equipment manufacturers. Prior to World War II its main
function was to issue recommendations on radiological safety, which were published by
the National Bureau of Standards (a federal agency). At times this arrangement created
confusion, leading people to believe the publications were official recommendations.
After the war, the private group was revived as the National Committee on Radiation
Protection. In 1956 it was renamed the National Committee on Radiation Protection and
Measurements. In the early 1 960s, it received a congressional charter and was renamed
the National Council on Radiation Protection and Measurements. Throughout its history
it has coordinated its activities with other groups, such as the International Commission
on Radiological Protection' and committees of the National Academy of Sciences (known
as the BEAR and BEIR Committees). The most complete record of the NCRP's activities
is Lauriston S. Taylor, Organization for Radiation Protection: The Operations of the
ICRPandNCRP, 1928-1974 (Washington, D.C.: Office of Technical Information, U.S.
Department of Energy.) Lauriston Taylor, a physicist at the National Bureau of
Standards, served as the executive director of the organization from its founding in 1 928
to 1974. For further background on the history of radiation protection, see Daniel P.
Serwer, The Rise of Radiation Protection: Science, Medicine and Technology in Society,
1896-1935 (Ph.D. diss, in the History of Science, Princeton University, 1976) (Ann
Arbor: University Microfilms 77-14242, 1977); Gilbert F. Whittemore, The National
Committee on Radiation Protection, 1928-1960: From Professional Guidelines to
Government Regulation (Ph.D. diss, in the History of Science, Harvard University, 1986)
(Ann Arbor: University Microfilms 87-04465, 1987); J. Samuel Walker, "The
Controversy Over Radiation Safety: A Historical Overview," Journal of the American
Medical Association 262 (1989): 664-668; D. C. Kocher, "Perspective on the Historical
Development of Radiation Standards," Health Physics 61, no. 4 (October 1994).
17. Heinz Haber, The Walt Disney Story of Our Friend the Atom (New York:
Simon and Schuster, 1956), 152. The German-born Dr. Haber had come to the United
States in 1947 to work for the Air Force School of Aviation Medicine and was a
cofounder of the field of space medicine. In the early 1950s he joined the faculty of the
University of California at Los Angeles. As Spencer Weart, a historian of the images of
the atomic age has recorded, the accompanying Walt Disney movie Our Friend the Atom,
which was shown on television and in schools beginning in 1957, was probably the most
effective of educational films on the perils and potential of atomic energy. "The great
storyteller introduced the subject as something 'like a fairy tale,' indeed the tale of a genie
released from a bottle. The cartoon genie began as a menacing giant. . . . But scientists
turned the golem into an obedient servant, who wielded the 'magic power' of
radioactivity. . . ." Spencer R. Weart, Nuclear Fear: A History of Images (Cambridge,
Mass.: Harvard University Press, 1988), 169.
18. Marshall Brucer, Chronology of Nuclear Medicine (St. Louis: Heritage
Publications, 1990), 199-200. Radon is a gas at room temperature. Doctors developed
an innovative system for capturing radon from used cancer therapy vials and dissolving
it in a saline solution, which was then injected.
70
19. Haber, Our Friend the Atom, 152.
20. J. L. Heilbron and Robert W. Seidel, Lawrence and His Laboratory: A
History of the Lawrence Berkeley Laboratoiy, vol. 1 (Los Angeles: University of
California Press, 1989). The birth and development of nuclear medicine at the University
of California's Berkeley and San Francisco branches is the subject of a case study in a
supplemental volume to this report.
21. John Stanbury, A Constant Ferment (Ipswich, N.Y.: Ipswich Press, 1991),
57-67.
22. Stafford Warren, interview by Adelaide Tusler (Los Angeles: University of
California), 23 June 1966 in An Exceptional Man for Exceptional Challenges, Vol. 2
(Los Angeles: University of California, 1983) (ACHRE No. UCLA-101794-A-1), 421-
422.
23. Manhattan Project researchers focused on polonium in the development of
the initiator for the bomb. See Richard Rhodes, The Making of the Atomic Bomb (New
York: Simon and Schuster, 1986), 578-580.
24. Manhattan District Program, 31 December 1946 (book 1, "General," volume
7, "Medical Program") (ACHRE No. NARA-052495-A-1), 2.2.
25. Stafford Warren in Radiology in World War II, ed. Arnold Lorentz Ahnfeldt
(Washington, D.C.: GPO, 1966), 847.
26. Robert Stone, 10 May 1943 ("Health Radiation and Protection") (ACHRE
No. DOE-011195-B-1).
27. Philip J. Close, Second Lieutenant, JAGD, to Major C. A. Taney, Jr., 26
July 1945 ("Determination of Policy on Cases of Exposure to Occupational Disease")
(ACHRE No. DOE-120894-E-96), 1.
28. Ibid., 3.
29. Response to ACHRE Request No. 012795-B, Oak Ridge Associated
Universities, D. M. Robie to A. ("Tony") P. Polendak, 15 June 1979 ("Storage of records-
-Shipment 1161").
30. The story of this early Hanford research is told in Neal D. Hines, Proving
Ground: An Account of the Radiobiological Studies in the Pacific 1946-61 (Seattle:
University of Washington Press, 1962). As Hines explains, the initial study of the effect
of radioactivity on aquatic organisms was undertaken by a University of Washington
researcher. The program could not be identified with the Columbia River, and the
research was to be conducted in a normal campus setting. The project's name ("Applied
Fisheries Laboratory") was selected to disguise its work. The primary researcher initially
did not know the true purpose, and the university accepted the work for undisclosed
purpose on the assurance that national security required it.
3 1 . Harold Hodge, interview by J. Newell Stannard, transcript of audio
recording, 22 October 1980 (ACHRE No. DOE-061794-A-4), 21-22. Stafford Warren,
interview by J. Newell Stannard, transcript of audio recording, 7 February 1979 (ACHRE
No. DOE-061794-A), 3.
32. Henry DeWolf Smyth, Atomic Energy for Military Purposes: The Official
Report on the Development of the Atomic Bomb under the Auspices of the United States
Government, 1940-45 (Princeton, N.J.: Princeton University Press, 1945).
33. The organizational history of the Department of Defense is chronicled in
The Department of Defense: Documents on Establishment and Organization 1944-1978,
eds. Alice C. Cole, Alfred Goldberg, Samuel A. Tucker, Rudolf A. Winnacker
(Washington, D.C.: Office of the Secretary of Defense, Historical Office, 1978).
71
34. The program expanded from the base of Manhattan Project research sites
such as Oak Ridge, Hanford, Chicago, and the Universities of California, Chicago, and
Rochester to take in a growing portion of the university research establishment. The
minutes of the January 1947 meeting record an ambitious program to focus on the
physical measurement of radiation, the biological effects of radiation, methods for the
detection of radiation damage, methods for the prevention of radiation injury, and
protective measures. There followed an itemized list of the work to be done at Argonne
National Laboratory, Los Alamos, Monsanto, Columbia University, and the Universities
of Michigan, Rochester, Tennessee, California, and Virginia.
The University of Rochester was to be the largest university contractor, receiving
more than $1 million, followed by the University of California (about one-half million
for UCLA, where Stafford Warren was dean of the new medical school, and Berkeley, to
which Stone had returned to join Hamilton), Western Reserve (to which Warren's deputy
Hymer Friedell was headed), and Columbia (more than $100,000). Argonne received an
amount comparable to Rochester; other labs, including Los Alamos National Laboratory
and Clinton Laboratories (now Oak Ridge National Laboratory), were scheduled for
$200,000 or less. Stafford Warren, Interim Medical Committee, proceedings of 23-24
January 1947 (ACHRE No. UCLA-1 1 1094-A-26). See also ACHRE Briefing Book, vol.
3, tab F, document H.
35. "Report of the Board of Review," 20 June 1947, attached to letter from
David Lilienthal, Chairman, AEC, to Dr. Robert F. Loeb, Chairman, AEC Medical Board
of Review, 27 June 1947 ("At the conclusion of the deliberations . . .") (ACHRE No.
DOE-051094-A-191), 3-4.
36. The Advisory Committee has assembled the minutes of the meetings, and
such transcripts as have been retrieved.
37. Shields Warren, interview by Dr. Peter Olch, National Library of Medicine,
transcript of audio recording, 10-11 October 1972, 59.
38. Harry H. Davis, "The Atom Goes to Work for Medicine," New York Times
Magazine, 26 September 1946 (ACHRE No. DOE-051094-A-408).
39. Marshall Brucer, M.D., Chairman, Medical Division, Oak Ridge Institute
for Nuclear Studies, wrote:
Paul Aebersold's isotopes division was the only safely nonsecret part of
AEC. Aebersold had unlimited funds, unlimited radioisotopes, and
seemingly unlimited energy to promote the unlimited cures that had been
held back from the American public for too long. The liberal
establishment was in the depths of shame for having ended the war by
killing people. Radioisotopes didn't kill people; they cured cancer.
Aebersold spoke at every meeting of one person or more that had one
minute or more available on its program. No matter what the meeting's
subject, Aebersold's topic was always the same. He sold isotopes.
Marshall Brucer, "Nuclear Medicine Begins with a Boa Constrictor," Journal of Nuclear
Medicine 19, no. 6 (1978): 595.
40. Isotopes Division, prepared for discussion with general manager, "Present
and Future Scope of Isotope Distribution," 4 March 1949 (ACHRE No. DOE-01 1895-B-
1).
41. Interview with Shields Warren, 10-11 October 1972, 76.
72
42. Isotopes Division, 4 March 1949, 2.
43. See Kaplan, "Historic Milestones," 480.
44. "Summary of Congressional Hearings on Fellowship Issue," 16 May 1949
(ACHRE No. DOE-061395-D-1).
45. Advisory Committee for Biology and Medicine, proceedings of 10
September 1949 (ACHRE No. DOE-072694-A), 18.
46. Ibid, 19.
47. For a further discussion of the contemplated secret record keeping by the
VA, see chapter 10. As noted there, a VA investigation concluded that the "confidential"
division was never activated.
48. The VA provided the Advisory Committee with capsule descriptions of
experiments, which appeared in periodic VA reports of the time. In fact, the number of
descriptions exceeded 3,000 for the portion of the 1944-74 period the reports covered.
However, further information on the vast majority of the experiments was typically
unavailable, and the VA noted that some of the descriptions may be redundant (or reflect
refunding of a single experiment), and some may not have involved humans. Therefore,
the "more than 2,000" reflects a very rough estimate adjusted for these considerations.
49. Paul C. Aebersold, address before Rocky Mountain Radiological Society, 9
August 1951 ("The United States Atomic Energy Program: Part I-Overall Progress")
(ACHRE No. TEX- 101294- A- 1), 6.
50. By 1955 the program was receiving 8,000 applications a year, including
hundreds from abroad. A July 1955 Aebersold summary of accomplishments pronounced
that, as a result of the program, there were now 1 00 companies in the radiation instrument
business, two dozen suppliers of commercially labeled compounds, pharmaceutical
companies, hundreds of isotope specialists, a half-dozen waste disposal firms, and ten
safety monitoring companies. Also, 2,693 U.S. institutions had received isotope
authorization, including 1,126 industrial firms, 1,019 hospitals and private physicians,
220 colleges and universities, 244 federal and state laboratories, and 47 foundations.
"Capsule Summary of Isotopes Distribution Program," July 1955 (ACHRE No. TEX-
101294-A-2).
5 1 . Vannevar Bush, Pieces of the Action (New York: William Morrow and
Company, 1970), 65.
52. Ibid.
53. In addition to direct grants to private institutions the AEC pioneered the
creation of research consortia. In 1946, for example, the University of Tennessee and a
consortium of southeastern universities urged the Manhattan Project to establish the Oak
Ridge Institute of Nuclear Studies (ORINS). Following the creation of the AEC, ORINS
operated under AEC contract to train researchers and to operate a clinical research facility
focused on cancer. In 1966 ORINS became known by the name of its operating
contractor, the Oak Ridge Associated Universities, and the research facility is now known
as the Oak Ridge Institute for Science and Education (ORISE).
54. Donald C. Swain, "The Rise of a Research Empire: NIH, 1930 to 1950,"
Science 138, no. 3546 (14 December 1962): 1235. The National Institutes of Health
began as the Laboratory of Hygiene in 1887. It was renamed the National Institutes of
Health in 1948.
55. Assistant Director, Office of Extramural Research, National Institutes of
Health, to Anna Mastroianni, Advisory Committee, 16 July 1995 ("Comments on Draft
Chapters of ACHRE Final Report").
73
56. Interview with Shields Warren, 10-1 1 October 1972, 78.
57. Robert S. Stone, M.D., to Lieutenant Colonel H. L. Friedell, U.S. Engineer
Corps, Manhattan District, 9 August 1945 ("In reading through the releases . . .")
(ACHRE No. DOE-121494-D-2).
58. Robert S. Stone, M.D., to Lieutenant Colonel H. L. Friedell, U.S. Engineer
Corps, Manhattan District, 9 August 1945 ("As you and many others are aware, a great
many of the people . . .") (ACHRE No. DOE-121494-D-1).
59. Jonathan M. Weisgall, Operation Crossroads: The Atomic Tests at Bikini
Atoll (Annapolis, Md.: Naval Institute Press, 1994). For a contemporary account by a
doctor who served as a radiation monitor, see David Bradley, No Place to Hide (Boston:
Little, Brown and Co., 1948).
60. Weisgall, Operation Crossroads, 266-270.
61. "History of the U.S. Naval Radiological Defense Laboratory, 1946-58"
(ACHRE No. DOD-071494-A-1), 1.
62. The Joint Panel was the child of the Committee on Medical Science and
Committee on Atomic Energy (hence the term Joint), both of which, in turn, were
committees of the Defense Department's Research and Development Board. That board
served as the secretary of defense-level coordinator of departmentwide R&D.
63. The Committee has assembled the charter, agenda, reports, and available
minutes of the Joint Panel. ACHRE Research Collection Series, Library File,
Compilation of the Minutes of the Joint Panel on Medical Aspects of Atomic Warfare,
1948-1953(1994).
64. Howard Andrews, interview by Gilbert Whittemore (ACHRE staff),
transcript of audio recording, 3 December 1994 (ACHRE Reseach Project, Interview
Series, Targeted Interview Project).
65. In a February 1950 paper, the Public Health Service explained its role in
national defense:
During and since WW II, science and technology have
introduced new weapons and whole new industries
whose effects on human health have not been precisely
determined and effective methods against these hazards
have not yet been developed.
If, for example, an atomic bomb were to burst over a
large city in this country, tens of thousands of burned and
injured people could not be given effective treatment
because science has not yet found the practical means. . . .
The operation of atomic piles and related facilities also
presents a variety of problems as to human tolerance of
radiation and the disposition of radioactive substances.
"The U.S. Public Health Service and National Defense," February 1950 (ACHRE No.
HHS-071394-A-2), 1.
66. National Institutes of Health, 2 August 1952 ("Assumptions Underlying
NIH Defense Planning") (ACHRE No. HHS-071394-A-1).
67. Advisory Committee for Biology and Medicine, transcript (partial) of
proceedings of 10 November 1950 (ACHRE No. DOE-012795-C-1). While the
document is undated, discussion of the meeting appears in the November 1950 ACBM
74
minutes (12); a letter from Alan Gregg, Chairman, ACBM, to Gordon Dean, Chairman,
AEC, 30 November 1950 ("The Advisory Committee for Biology and Medicine held
their twenty-fourth . . .") (ACHRE No. DOE-072694-A); and a letter from Marion W.
Boyer, AEC General Manager, to Honorable Robert LeBaron, Chairman, Military
Liaison Committee, 10 January 1951 ("As you know, one of the important problems . .
.") (ACHRE No. DOE-040395-A-1).
68. Behrens, transcript, proceedings of 10 November 1950, 2.
69. Powell, transcript, proceedings of 10 November 1950, 8-10.
70. Cooney, transcript, proceedings of 10 November 1950, 6.
71. Ibid., 7.
72. Ibid., 6.
73. Ibid., 7-8.
74. Warren, transcript, proceedings of 10 November 1950, 13.
75. Ibid., 14.
76. Ibid., 15.
77. Cooney, transcript, proceedings of 10 November 1950, 15.
78. Ibid., 16.
79. "Notes on the Meeting of a Committee to Consider the Feasibility and
Conditions for a Preliminary Radiological Safety Shot for Operation 'Windsquall,'" 2 1 -
22 May 1951 (ACHRE No. DOE-030195-A-1), 41.
80. Ibid., 40.
81. Ibid., 19.
82. T. L. Shipman, Health Division Leader, to Alvin Graves, J-Division Leader,
27 December 1951 ("Summary Report Rad Safe and Health Activities at Buster- Jangle")
(ACHRE No. DOE-033195-B-1).
83. [AEC] Board of Review to the Atomic Energy Commission, 20 June 1947
("Report of the Board of Review") (ACHRE No. DOE-071494-A-4), 10.
84. NEPA Medical Advisory Panel, Subcommittee No. IX, "An Evaluation of
Psychological Problem of Crew Selection Relative to the Special Hazards of Irradiation
Exposure," 22 July 1949 (ACHRE No. DOD-121494-A-2), 20.
85. Ibid., 27.
86. Ibid., 22.
87. Definition of "curie," The Compact Edition of the Oxford English Dictionaiy
(Oxford, England: Oxford University Press, 1971), 3937.
88. J. Newell Stannard, Radioactivity and Health: A History (Oak Ridge, Tenn.:
Office of Scientific and Technical Information, 1988), 9.
89. Hanson Blatz, ed., Radiation Hygiene Handbook (New York: McGraw-Hill
Book Co., 1959), 6-185.
90. Richard G. Hewlett and Oscar E. Anderson, The New World: A Histo>y of
the Atomic Energy Commission, Vol. I: 1939-1946 (Berkeley: University of California
Press, 1990), reprint of 1962 edition, 107-108.
91. Eric Hall, Radiobiology for the Radiologist, 4th ed. (Philadelphia: J. B.
Lippincott, 1994), 3.
92. Ibid., 5.
93. The DNA strand would be about 5 centimeters (cm) long; the average cell
diameter is about 20 microns (0.002 cm). Bruce Alberts et al., eds., Molecular Biology of
the Cell (New York: Garland, 1983), 385-388.
94. Hall, Radiobiology for the Radiologist, 4th ed., 9-10.
75
95.
Ibid.
96.
Ibid.,
30.
97.
Ibid.,
32-33.
98.
Ibid.,
312.
99.
Ibid.,
324.
100
. Ibid
101. International Commission on Radiological Protection, Recommendations:
ICRP Publication No. 60 (New York: Pergamon Press, 1991), cited in Hall,
Radiobiology for the Radiologist, 4th ed., 456.
102. Hall, Radiobiology for the Radiobiologist, 4th ed., 355.
103. Committee on the Biological Effects of Ionizing Radiation, National
Research Council, Health Effects of Exposure to Low Levels of Ionizing Radiation: BEIR
V (Washington, D.C.: National Academy Press, 1990), 2-4.
104. International Commission on Radiological Protection, Recommendations:
ICRP Publication No. 60, quoted in Hall, Radiobiology for the Radiologist, 4th ed., 455.
105. ". . . roentgen equivalent man, or mammal (rem). The dose of any ionizing
radiation that will produce the same biological effect as that produced by one roentgen of
high-voltage x-radiation." Blatz, ed., Radiation Hygiene Handbook, 2-19.
106. Hall, Radiobiology for the Radiobiologist, 4th ed., 458.
107. These include the National Council on Radiation Protection and
Measurement (NCRP), the International Commission on Radiation Protection (ICRP), the
United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR),
the Committee on the Biological Effects of Ionizing Radiation (BEIR) of the National
Research Council, and the Environmental Protection Agency (EPA).
108. In addition, there have been a number of studies of people exposed to low
levels of radiation, including military personnel and residents subject to fallout from
nuclear weapons testing, workers at and residents near nuclear facilities, patients given
diagnostic x rays, and regions with high natural background radiation. Most of these
either have not produced convincing positive results or are unsuitable for risk assessment
because of the statistical instability of their estimates.
109. Some indirect estimates have been based on "case control" studies, in which
diseased cases are compared with unaffected controls to look for differences in their past
exposures that could account for their different outcomes.
General reference works include D. G. Kleinbaum, W. Kupper, and H.
Morgenstern, Epidemiologic Research: Principles and Quantitative Methods (Belmont,
Calif.: Lifetime Learning Publications, 1982), and J. D. Boice, Jr., and J. E. Fraumeni, Jr.,
Radiation Carcinogenesis: Epidemiology and Biological Significance (New York: Raven
Press, 1984).
110. Dr. Shirley Fry to Bill LeFurgy, 31 August 1995 ("HRE Draft Final
Report"), 8, contained in Ellyn Weiss, Special Counsel and Director, Office of Human
Radiation Experiments, DOE, to Anna Mastroianni, ACHRE, 1 1 September 1995.
111. "[T]he NTPR dose data are not suitable for dose-response analysis."
Institute of Medicine, "A Review of the Dosimetry Data Available in the Nuclear Test
Personnel Review (NTPR) Program, An Interim Letter Report of the Committee to Study
the Mortality of Military Personnel Present at Atmospheric Tests of Nuclear Weapons to
the Defense Nuclear Agency" (Washington, D.C.: Institute of Medicine, May 15, 1995),
2.
76
1 12. Committee on the Biological Effects of Ionizing Radiation, National
Research Council, Health Effects of Exposure to Low Levels of Ionizing Radiation: BEIR
V (Washington, D.C.: National Academy Press, 1990), 22, 162.
77
Part I
ETHICS OF HUMAN SUBJECTS
RESEARCH: A HISTORICAL
PERSPECTIVE
PartI
Overview
W hen the Advisory Committee began work in April 1994 we were
charged with determining whether "the [radiation] experiments' design and
administration adequately met the ethical and scientific standards, including
standards of informed consent, that prevailed at the time of the experiments and
that exist today" and also to "determine the ethical and scientific standards and
criteria by which it shall evaluate human radiation experiments."
Although this charge seems straightforward, it is in fact difficult to
determine what the appropriate standards should be for evaluating the conduct
and policies of thirty or fifty years ago. First, we needed to determine the extent
to which the standards of that time are similar to the standards of today. To the
extent that there were differences we needed to determine the relative roles of
each in making moral evaluations.
In chapter 1 we report what we have been able to reconstruct about
government rules and policies in the 1940s and 1950s regarding human
experiments. We focus primarily on the Atomic Energy Commission and the
Department of Defense, because their history with respect to human subjects
research policy is less well known than that of the Department of Health,
Education, and Welfare (now the Department of Health and Human Services).
Drawing on records that were previously obscure, or only recently declassified,
we reveal the perhaps surprising finding that officials and experts in the highest
reaches of the AEC and DOD discussed requirements for human experiments in
the first years of the Cold War. We also briefly discuss the research policies of
DHEW and the Veterans Administration during these years.
In chapter 2 we turn from a consideration of government standards to an
exploration of the norms and practices of physicians and medical scientists who
conducted research with human subjects during this period. We include here an
81
Part I
analysis of the significance of the Nuremberg Code, which arose out of the
international war crimes trial of German physicians in 1947. Using the results of
our Ethics Oral History Project, and other sources, we also examine how
scientists of the time viewed their moral responsibilities to human subjects as well
as how this translated into the manner in which they conducted their research. Of
particular interest are the differences in professional norms and practices between
research in which patients are used as subjects and research involving so-called
healthy volunteers.
In chapter 3 we return to the question of government standards, focusing
now on the 1960s and 1970s. In the first part of this chapter, we review the well-
documented developments that influenced and led up to two landmark events in
the history of government policy on research involving human subjects: the
promulgation by DHEW of comprehensive regulations for oversight of human
subjects research and passage by Congress of the National Research Act. In the
latter part of the chapter we, review developments and policies governing human
research in agencies other than DHEW, a history that has received comparatively
little scholarly attention. We also discuss scandals in human research conducted
by the DOD and the CIA that came to light in the 1970s and that influenced
subsequent agency policies.
With the historical context established in chapters 1 through 3, we turn in
chapter 4 to the core of our charge. Here we put forward and defend three kinds
of ethical standards for evaluating human radiation experiments conducted from
1944 to 1974. We embed these standards in a moral framework intended to
clarify and facilitate the difficult task of making judgments about the past.
82
Government Standards for
Human Experiments:
The 1940s and 1950s
W hen the Advisory Committee began its work, a central task was the
reconstruction of the federal government's rules and policies on human
experiments from 1944 through 1974. The history of research rules at the
Department of Health, Education, and Welfare (DHEW) was well known, at least
from 1953 on, when DHEW's National Institutes of Health (NIH) adopted a
policy on human subjects research for its newly opened research hospital, the
Clinical Center. In the 1960s, the DHEW and some other executive branch
agencies undertook regulation of research involving human subjects. These were
early steps of a process that culminated, in 1991, in the comprehensive federal
policy known as the "Common Rule."' The historical background of this process,
including a well-publicized series of incidents and scandals that motivated it, was
also widely known and much discussed (see chapter 3). 2
By contrast to DHEW, much less was known about the history of research
rules for other agencies also involved in research with human subjects during this
period, including the Department of Defense (DOD), the Atomic Energy
Commission (AEC), and the Veterans Administration (VA). From the
perspective of the charge to the Advisory Committee, these agencies were at least
as important as DHEW. It was known that in 1953 the secretary of defense
issued, in Top Secret, a memorandum on human subjects based on the Nuremberg
Code. 3 In 1947 an international tribunal had declared the Nuremberg Code the
standard by which a group of doctors in Nazi Germany should be judged for their
83
Parti
horrific wartime experiments on concentration camp inmates. However, the
actual impact of the Nuremberg Code on the biomedical community in the United
States, both inside and outside of government, is a matter of some disagreement
(see chapter 2). The general view was that, despite some developments in the
1940s and 1950s, there was little activity within the federal government on issues
of human subjects research before the 1960s.
But while scholars have known of the 1953 secretary of defense
memorandum, which was declassified in 1975, other relevant Department of
Defense documents remained classified or had lain buried in archives. Moreover,
relevant records of the Atomic Energy Commission were largely unexplored and
in some cases still classified. These records are important because, from its
creation in 1947, the AEC distributed radioisotopes that would be used in
thousands of human radiation experiments, and it was a funding source for many
other experiments (see Introduction). Along with the DOD, also created in 1 947,
the AEC was searching for biomedical information needed to understand the
effects of radiation as it prepared for the possibility of atomic warfare. Although
the AEC was thus the catalyst for a considerable amount of human
experimentation after World War II, there has been literally no scholarship on the
AEC's position on the use of human beings in radiation-related research.
Now that previously obscure, even classified, records are being made
public, it appears that in the first years of the Cold War, officials and experts in
the AEC and DOD did discuss the requirements for human experiments. In this
chapter we tell what we have learned about those discussions.
We begin by telling the story of the AEC general manager's early
declarations on human research, which included a requirement that consent be
obtained from patient-subjects. This story requires a careful look at a series of
letters and memorandums exchanged in the late 1940s. Together these documents
paint a clearly important but nonetheless confusing picture of a new agency's
attempts to come to grips with the complexities of human experimentation. We
consider not only what these documents say, but what we can piece together
about what they meant in the context of the times. Central questions include the
precise scope of the activities covered by the requirements and whether and how
these 1 947 statements were communicated and put into effect in the AEC's
burgeoning contract research and radioisotope distribution programs.
We turn next to the Department of Defense, where we trace the history of
rules on the use of healthy "normal volunteer" subjects in military research from
the time of Walter Reed through the secretary of defense's 1953 memorandum,
and beyond. This memorandum is the earliest known instance in which a federal
agency that sponsored human experiments adopted the Nuremberg Code. What is
known about how the memorandum was interpreted and implemented by the
military establishment takes up much of the rest of this chapter. Here, as in the
case of the AEC, key questions concern the scope of the activities covered by
requirements and the extent to which they were put into effect.
84
Chapter 1
Finally, we briefly discuss how research involving human subjects was
addressed at the National Institutes of Health and the Veterans Administration in
the 1950s. The evolution of policies governing human research at DHEW has
been well documented and is only summarized here. 4 We now know that NIH's
1953 policy was not the earliest federal requirement that consent be obtained from
patients as well as healthy subjects. However, in contrast with the 1940s
declarations by the AEC, it was a far more visible statement issued by an agency
that was emerging as the leading sponsor of human subjects research. In contrast
with what is known about NIH, the extent to which there were research rules at
the VA in the 1940s and 1950s remains unclear.
A recurring theme in this chapter is the uncertainty about the significance
within government agencies of many of the official statements that are discussed.
While these statements emanated from high and responsible officials and
committees, often they cannot be linked to fuller expressions of commitment by
the agencies. Some of these statements were not widely disseminated, and there
were no implementing guidelines or regulations and no sanctions for failures to
abide by them. Thus, it is sometimes unclear what formal, legal significance
these statements had. We are no less interested, however, in what these
statements can tell us about how government officials and advisers saw human
research at the time and how they understood the obligations surrounding it.
THE ATOMIC ENERGY COMMISSION: A REQUIREMENT
FOR "CONSENT" IS DECLARED AT THE CREATION
Even before the AEC came into existence on January 1, 1947, Manhattan
Project researchers and officials had begun to lay the groundwork for the
expansion of the government's support of biomedical radiation research
conducted under federal contract. By the time the AEC began operations, the
parallel program to distribute federally produced radioisotopes to research
institutions throughout the country was already well under way.
The planning for these undertakings required both reflection on high-level
matters of policy and attention to matters of small but critical legal and
bureaucratic detail. Both legal rules and administrative processes were uncharted.
For example, who would be responsible if things went awry and subjects were
injured? When could the government tell private doctors or researchers how to
conduct treatment or research? The need for rules seemed obvious, but the
particular rules that would be arrived at were not.
In April 1947 and again in November, Carroll Wilson, the general
manager of the new agency, wrote letters first to Stafford Warren and then to
Robert Stone, both of whom played prominent roles in Manhattan Project medical
research, Warren as medical director, and Stone as a key member of the Chicago
branch of the project. In these letters, Wilson maintained that "clinical testing"
with patients could go forward only where there was a prospect that the patient
85
Part I
could benefit medically and only after that patient had been informed about the
testing and there was documentation that the patient had consented. What was the
origin of this position, and what was its reach? It appears that these letters were
the products of an agency that was not only seeking to devise rules for new
programs but also was trying to glean lessons from the experience with the secret
research that had been conducted during the Manhattan Project. In the course of
setting rules for the future, the AEC and its research community had to confront
whether and how to proceed with human experimentation in the face of human
experiments, including plutonium injections, conducted under the auspices of the
Manhattan Project, experiments that were conducted in secret and that had the
potential for both negative public reaction and litigation.
The First Wilson Letter
General Manager Wilson's first 1947 letter on human research, dated April
30, was, at least in part, a straightforward effort to define the rules according to
which the AEC would provide contractors with research funding. The need for
such rules had been discussed by the AEC's Interim Medical Advisory
Committee, chaired by Stafford Warren, in January 1 947 when it met to consider
whether "clinical testing" should be part of the AEC contract research program.
The report of the meeting records projects involving human subjects at the
University of Rochester and the University of California at Berkeley, and perhaps
others. 5 In a January 30 letter to General Manager Wilson, Stafford Warren
reported the committee's conclusion that in the study of health hazards and the use
of fissionable and radioactive materials, "final investigations by clinical testing of
these materials" would be needed. Warren therefore requested that the AEC legal
department determine the "financial and legal responsibility" of the AEC when
such "clinical investigations" are carried out under AEC-approved and -financed
programs. 6 (The term experiment was not used, and the precise meaning of
clinical testing is not clear.)
A month later, in early March, Warren met with Major Birchard M.
Brundage, chief of the AEC's Medical Division, and two AEC lawyers to consider
the terms for the resumption of "clinical testing." In a memorandum for the
record, the lawyers summarized the meeting. In the case of "clinical testing" the
lawyers
expressed the view that it was most important that it
be susceptible of proof that any individual patient,
prior to treatment, was in an understanding state of
mind and that the nature of the treatment and
possible risk involved be explained very clearly and
that the patient express his willingness to receive
the treatment. 7
86
Chapter 1
Initially, the lawyers had proposed that researchers obtain a "written
release" from patients. However, "on Dr. Warren's recommendation," the lawyers
agreed that it would be sufficient if "at least two doctors certify in writing to the
patient's state of mind to the explanation furnished him and to the acceptance of
the treatment.""
In his April 30 letter to Stafford Warren, Wilson announced that the AEC
had approved Warren's committee's recommendations for a "program for
obtaining medical data of interest to the Commission in the course of treatment of
patients, which may involve clinical testing." 9 Wilson's letter spelled out ground
rules that were agreed upon. The commission understood that "treatment (which
may involve clinical testing) will be administered to a patient only when there is
expectation that it may have therapeutic effect." In addition, the commission
adopted the requirement for documentation of consent agreed upon in Warren's
meeting with the lawyers:
[I]t should be susceptible of proof from official
records that, prior to treatment, each individual
patient, being in an understanding state of mind,
was clearly informed of the nature of the treatment
and its possible effects, and expressed his
willingness to receive the treatment. 10
The commission deferred to Warren's request that written releases from
the patient not be required. However,
it does request that in every case at least two
doctors should certify in writing (made part of an
official record) to the patient's understanding state
of mind, to the explanation furnished him, and to
his willingness to accept the treatment."
Carroll Wilson's April letter was sent to Stafford Warren as head of the
Interim Medical Advisory Committee, which was responsible for advising the
AEC on its contract research program, and forwarded to Major Brundage at the
Oak Ridge office. 12 Stafford Warren was at this point dean of the medical school
at the University of California at Los Angeles, one of the dozen research
institutions involved in the AEC contract research program. With one exception
the Advisory Committee on Human Radiation Experiments did not locate
documentation that the letter or its contents were communicated to any other
research institutions involved with the AEC's contract research program. The
exception is the University of California at San Francisco, where there is indirect
evidence that someone at that institution had been apprised of Wilson's April
letter. Of the eighteen plutonium injections, only the last one, that involving
87
Parti
Elmer Allen, or "CAL-3," took place after the April letter. In Mr. Allen's
medical chart, there is a notation signed by two physicians indicating that the
"experimental nature" of the procedure was explained and that the patient
"agreed." 13 Although the note in Mr. Allen's chart suggests an effort on the part
of the researchers to comply with Wilson's April letter, the researchers did not
comply with the other provision of the Wilson letter, that "treatment (which may
involve clinical testing) will be administered to a patient only when there is
expectation that it may have therapeutic effect." 14 As is discussed in more detail
in chapter 5, there was no expectation at the time that Mr. Allen would benefit
medically from an injection of plutonium. 15
The Second Wilson Letter
The context of the second Wilson letter, as well as its precise terms, further
indicates that the April 1947 letter was given little distribution and effect. In the
fall of 1947, the AEC laboratory at Oak Ridge requested advice from Carroll
Wilson's office on the rules for experiments involving human subjects. Just as the
AEC's Washington headquarters had embarked on the funding of a new research
program, Oak Ridge was also in the midst of considering the rules governing the
expansion of its own medical research program and the distribution of isotopes,
which was then headquartered at Oak Ridge. In September 1 947, the manager of
Oak Ridge Operations wrote to Wilson, asking, "What responsibilities does the
AEC bear for human administration of isotopes (a) by private physicians and
medical institutions outside the Project, and (b) by physicians within the project. . .
What are the criteria for future human use?" 16
Two weeks later. Oak Ridge sent a memorandum to the Advisory
Committee for Biology and Medicine (ACBM). The ACBM had succeeded both
Stafford Warren's Interim Medical Advisory Committee and the Medical Board of
Review, a group appointed by AEC Chairman David Lilienthal to review the
AEC's medical program. The memorandum emphasized the need for "medico-
legal criteria" for "future human tracer research" because some of that research
would be "of no immediate therapeutic value to the patient." The memorandum
outlined the pros and cons of "tracer studies":
Pro -
( 1 ) Tracer research is fundamental to toxicity
studies.
(2) The adequacy of the health protection which we
afford our present employees may in a large
measure depend upon information obtained using
tracer techniques.
(3) New and improved medical applications can
88
Chapter 1
only be developed through careful experimentation
and clinical trial.
(4) Tracer techniques are inherent in the
radioisotope distribution program.
Con -
(1) Moral, ethical and medico-legal objections to
the administration of radioactive material without
the patient's knowledge or consent.
(2) There is perhaps a greater responsibility if a
federal agency condones human guinea pig
experimentation.
(3) Publication of such researches in some
instances will compromise the best interests of the
Atomic Energy Commission.
(4) Publication of experiments done by Atomic
Energy Commission contractor's personnel may
frequently be the source of litigation and be
prejudicial to the proper functioning of the Atomic
Energy Commission Insurance Branch. 17
The questions raised by Oak Ridge were discussed by the ACBM at its
October 11, 1947, meeting, which decided to give the "matter more study." 18 The
minutes of the October 1 1 meeting record that "human experimentation" was then
discussed in the context of a request by Dr. Robert Stone to release "classified
papers containing certain information on human experimentation with
radioisotopes conducted within the AEC research program." 19 The request was
part of a continuing effort by Stone and other scientists to obtain permission to
publish the research, including the plutonium experiments, that they had
conducted in secret during the Manhattan Project. Earlier in 1947, the AEC had
reversed a decision to declassify a report on the plutonium injections, citing the
potential for public embarrassment and legal liability (see chapter 5). The
question of what to do with these requests continued to fester.
The minutes explain that the "problem" raised by Stone had been dealt
with by Chairman Lilienthal's Medical Board of Review in June. In a cryptic
statement, the minutes record the ACBM's agreement that papers on human
experiments "should remain classified unless the stipulated conditions laid down
by the Board of Review were complied with." 20
The "stipulated conditions" referred to are contained in General Manager
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Part I
Wilson's November 5, 1947, letter to Stone. According to Wilson's letter, at a
June meeting the Medical Board of Review concluded that "the matter of human
experimentation" would remain classified where certain "conditions" were not
satisfied. Wilson then quoted from the "preliminary unpublished and restricted
draft of the [Medical Board] report read to the Commissioners" as follows:
The atmosphere of secrecy and suppression makes
one aspect of the medical work of the Commission
especially vulnerable to criticism. We therefore
wish to record our approval of the position taken by
the medical staff of the AEC in point of their
studies of the substances dangerous to human life.
We [the Medical Board of Review] believe that no
substances known to be, or suspected of being,
poisonous or harmful should be given to human
beings unless all of the following conditions are
fully met: (a) that a reasonable hope exists that the
administration of such a substance will improve the
condition of the patient, (b) that the patient give his
complete and informed consent in writing, and (c)
that the responsible next of kin give in writing a
similarly complete and informed consent, revocable
at any time during the course of such treatment
[emphasis added]. 21
In other words, the opinion of the Medical Board of Review was presented
by Wilson in his November letter as both a prescription for the future conduct of
human experiments and a presentation of the criteria that must be met for the
declassification of past research. Wilson again referenced these conditions in a
letter to ACBM Chairman Alan Gregg, also on November 5. "I am sure," Wilson
wrote Gregg, "that this information will assist Dr. Stone in evaluating the present
problem and inform him as to the conditions that must be met in future
experiments." 22 Thus, as discussed in more detail in chapters 5 and 13, the
requirement that research proceed only with consent appears to have been
coupled with the decision to withhold from the public information about
experiments that failed to meet that standard.
Two points should be made about the term informed consent, which
appears in the November letter from Wilson to Stone. First, it is not clear what
meaning Wilson and the members of the Medical Board of Review attributed to
the term. No further explanation was given. Second, it is nevertheless a matter of
some historical interest that this term is used at all. Previous scholarship had
attributed its first official usage to a landmark legal opinion in a medical
malpractice case that was issued a decade later. 23 -
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Chapter 1
The April and November 1947 Wilson letters have some common
elements, in spite of their differences in detail. They both provided that research
with humans proceed (1) only where there is reasonable hope of therapeutic effect;
and (2) with documentary proof that the patient-subject was informed of the
treatment and its possible effects and had consented to its administration.
But there are many remaining mysteries about the AEC's 1947 statements.
In interviews with Advisory Committee staff, Joseph Volpe, who served as an
AEC attorney in its early days and became general counsel in 1949, explained
that a letter authored by General Manager Wilson could state AEC policy and
confidently recollected that informed consent from research subjects would have
been required by the first AEC general counsel. This requirement, Volpe
maintained, should be reflected in the commission's minutes. 24 However,
Committee and DOE review of the commission's minutes did not reveal evidence
that the "consent" policy was expressly addressed.
Even more troubling is that both Wilson letters precluded research that did
not offer patient-subjects a prospect of direct medical benefit. In the context of
the concern about the plutonium injections and the other "nontherapeutic"
research conducted during the Manhattan Project experiments, this provision
readily makes sense. Yet, as Oak Ridge's inquiry to Washington noted,
nontherapeutic research in the form of tracer studies had been, and would
continue to be, a mainstay of AEC-sponsored isotope research. How could it be
that the Wilson letters were intended to ban exactly the kind of research that at the
same time the AEC was so actively promoting? It is conceivable that the
requirement of the isotope distribution program for risk review prior to the human
use of radioisotopes was a means of addressing this notion. However, if the
equation between that risk review procedure and the provision in the November
Wilson letter seems implicit, the documentary evidence does not provide an
express link between the requirement stated in the Wilson letter and the rules of
the isotope distribution program.
From Statements to Policy: A Failure of Translation
Despite the fact that they were developed in response to a need for clarity
in the way that human research should be conducted, we have found little
evidence of efforts to communicate or implement the rules stated by Wilson in
coordination with the AEC's biomedical advisory groups and other AEC officials.
In some cases the evidence described in the following paragraphs suggests that
policies for consent from subjects were established and implemented, while in
other cases it suggests that, if there were any such policies, they were unknown or
lost. Taken together, however, this evidence further supports the view that the
ideas present in General Manager Wilson's 1947 statements were available to
those working in the field during this time, albeit perhaps in a primitive form.
Consider, for example, a 1951 exchange between the AEC's Division of
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Parti
Biology and Medicine (DBM), which directed the AEC's medical research
program, and the commission's Los Alamos Laboratory, which was in routine
contact with Washington. An information officer at Los Alamos, Leslie Redman,
who was charged to review papers that involved human experimentation, asked
the DBM for a "definite AEC policy" on "human experimentation." In the course
of his work, Redman wrote, he had been advised by "various persons" at Los
Alamos that "regulations or policies of the AEC" on human experimentation were
available, but he had been unable to locate more than general information about
these regulations. According to his letter, his understanding was that
these regulations are comparable to those of the
American Medical Association: that an experiment
be performed under the supervision of an M.D.,
with the permission of the patient, and for the
purpose of seeking a cure. 25
Redman's characterization of the American Medical Association's guidelines, as
we shall see in chapter 2, is partly incorrect. The requirement of a therapeutic
intent is absent from the AM A guidelines. The possibility of direct therapeutic
benefit for the patient was, however, a condition of research according to both of
General Manager Wilson's 1947 letters.
Shields Warren, the DBM chief, responded to Redman by citing Wilson's
November 5, 1947, letter to Stone and by excerpting the conditions quoted
above. 26 But Warren did not term these conditions "standards" or "requirements."
Rather, Warren's response to Los Alamos "urges" compliance with these "guiding
principles." 27
Though Los Alamos was provided with the criteria stated by Wilson in
November 1947, General Manager Wilson's statements were not routinely
communicated in response to requests for guidance from non-AEC researchers.
In an April 1948 letter to the DBM, a university researcher explained that the
Isotopes Division had approved his request to use phosphorus 32 for
"experimental procedures in the human . . . simply for investigational purposes
and not for treatment of disease." What, the researcher wanted to know, should
be done about "medical-legal aspects" and "permission forms"? 28 The request
could have been answered by referring to Wilson's 1 947 statements about
consent. Instead, the DBM simply referred the researcher to the Isotopes Division
at Oak Ridge. 29 In its response, the Isotopes Division did not indicate that consent
should be solicited, as Wilson had stipulated. The Isotopes Division, stating it
could be "of little assistance," declined to provide "legal advice," save to note that
"we understand that most hospitals do require patients to sign general releases
before entering into treatment." 30
From 1947 onward, the AEC had ample opportunity to disseminate a
research policy. The AEC routinely provided educational and administrative
92
Chapter 1
materials to applicants for AEC funding and to the far greater number of
ZlTcan s foTAEC-produced radioisotopes. The isotopes distribution program,
np Sat included a sophisticated structure of regulation, repkte with ; review
oSmttees, training courses, and informational brochures (see chapter -t ) At the
federal level this included the Subcommittee on Human Applications of the
Cotmi ^ilitopc Distribution, whose very purpose was "to review all initial
« for radioisotopes to be used experimentally or otherwise in human beings
remohasis added]." 31 The AEC Subcommittee on Human Applications was
supplemented by similar committees at the research institutions where the work
WaS C °fn U p C nnciple, there does not seem to be any reason these local committees
could not have been instructed by the Isotopes Division on consent
eautemenL- Some evidence suggests that in March 1948 the Subcommittee on
Human Applications discussed consent requirements for healthy subjects and
"Sheets. In a document dated March 29, 1948, the Subcommittee on
Human Applications appeared to resolve that
1 Radioactive materials should be used in experiments
involving human subjects when information obtained will
have diagnostic value, therapeutic significance, or will
contribute to knowledge on radiation protection.
2. Radioactive materials may be used in normal human
subjects provided
a. The subject has full knowledge of
the act and has given his consent to
the procedure.
b. Animal studies have established
the assimilation, distribution,
selective localization and excretion
of the radioisotope or derivative in
question.
3. Radioactive materials may be used in patients
suffering from diseased conditions of such nature
that there is no reasonable probability of the
radioactivity employed producing manifest injury
provided:
a. Animal studies have established the
assimilation, distribution, selective
93
Part I
localization and excretion of the
radioisotope or derivative in
question.
b. The subject is of sound mind, has
full knowledge of the act and has
given his consent to the procedure. . . .
4. Investigations are approved ( 1 ) by medical
director or his equivalent at the installation
responsible for the investigation, (2) by the
Director, Division of Biology and Medicine, and (3)
full written descriptions of experimental procedures
and calculated estimates of radiation to be received
by body structure and organs must be submitted. 31
We were unable to locate any further references to this document and do not
know whether it represented a policy that was adopted. Perhaps it represents the
consensus of the Subcommittee on Human Applications, as it had met shortly
before that, or perhaps it is simply a draft document prepared by staff.
Whatever the ultimate disposition of this document, it provides some idea
of the problems that were under consideration at the time and indicates that views
on human use were unsettled. The first numbered item, for example, appears to
recommend human radiation experiments when they will offer diagnostic value
and therapeutic significance or knowledge about radiation protection. If the
document had in fact been adopted, the recognition that isotope experimentation
could be undertaken to "contribute to knowledge" (item 1) would appear to revise
the Wilson letters' prohibition of nontherapeutic experimentation. The third item
also addresses consent and risk of injury to patient-subjects without indicating
that there should be any potential benefit. Another peculiarity is found in the
second item, which refers to consent from normal human subjects but does not
rule out experiments that present risk to the subject.
In any event, at a 1948 meeting the Subcommittee on Human Applications
articulated a consent requirement as part of a decision to permit patients suffering
from serious diseases to receive "larger doses for investigative purposes." 34 This
requirement was disseminated to all radioisotope purchasers in 1949. 35 The
subcommittee allowed investigators to administer "larger doses" to seriously ill
patients but only with the patient's consent. While it is possible that the basis for
permitting larger doses was an assumption that smaller ones would be of no
potential benefit to subjects, item 3 of the just-quoted March 1948 document
suggests the assumption was rather that in seriously ill patients other disease
processes would be more likely to take their course before radiation injury was
manifested.
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Chapter 1
There is evidence that at least one AEC-funded entity did routinely
provide some form of disclosure and consent in the early 1950s. From its opening
in 1950 the AEC-sponsored Oak Ridge Institute for Nuclear Studies (ORINS), a
research hospital, advised incoming patients that procedures were experimental.
Additionally, patients were given written information that advised them that
"probable benefit, if any, cannot always be predicted in advance." 36 Patients were
also asked to sign a form that indicated that they were "fully advised" about the
"character and kind of treatment and care," which would be "for the most part
experiments with no definite promise of improvement in my physical
condition." 37 Thus, at least in the case of ORINS, and perhaps at other AEC
facilities, a local process was instituted apart from any known communication of
the statements by AEC officials.
Nonetheless, there is other evidence that the AEC did not communicate
the requirements detailed in General Manager Wilson's 1 947 letters to its own
contract research organizations, which, as in the cases of Argonne, Los Alamos,
Brookhaven, and Oak Ridge, ;had significant biomedical programs and were
engaged in human research. When the Division of Biological and Medical
Research at Argonne National Laboratory met in January 1951 to discuss
beginning a program of human experimentation in cancer research, one of its
members asserted that the ACBM had not established a "general policy
concerning human experimentation." The minutes of the meeting at Argonne
record that the ACBM "has been approached several times in the past for a
general policy and has refused to formulate one." 38
In 1956, Los Alamos asked the DBM to "restate its position on the
experimental use of human volunteer subjects" for tracer experiments. 39 The
DBM responded by stating that tracer doses might be administered under certain
conditions, which included the provision that subjects be volunteers who were
fully informed. The focus of this position seems to have been research with
healthy people and not patients, and no reference was made to the provisions of
the Wilson letters. 40 The DBM's 1956 formulation was given "staff distribution"
by Los Alamos and restated in 1962. 4 '
Also in 1956, the Isotopes Division did state a requirement for healthy
subjects. All subjects were to be informed volunteers. As part of its
"Recommendations and Requirements" guidebook for the medical uses of
radioisotopes, which was distributed to all medical users of radioisotopes, the
Isotopes Division stated:
Uses of radioisotopes in normal subjects for
experimental purposes shall be limited to:
a. Tracer doses which do not exceed the
permissible total body burden for the radioisotope
95
Part I
in question. In all instances the dose should be kept
as low as possible.
b. Volunteers to whom the intent of the study and
the effects of radiation have been outlined.
c. Volunteers who are unlikely to be exposed to
significant additional amounts of radiation. 42
These requirements apparently applied to all uses of AEC radioisotopes, whether
government or private researchers were involved. The "experimental or
nonroutine" use of radioisotopes in any human subjects was limited to
institutional programs where local review committees existed to oversee the risk
to which subjects were exposed. In stating these requirements, the AEC reiterated
that "patients" in whom "there is no reasonable probability of producing manifest
injury" may be used in some experiments not normally permitted, but did not
reiterate the requirement that consent should be obtained from these patients, as
was stated in 1948.
What, then, can be said about the rules and policies of the AEC in the
1940s and 1950s? General Manager Wilson's 1947 letters clearly stipulate a
requirement of "informed consent" from patient-subjects, at least where
potentially "poisonous or harmful" substances are involved. But with the
exception of ORINS there is little indication that this requirement was imposed as
binding policy on any AEC facility, contractor, or recipient of radioisotopes. By
contrast, later requirements that healthy subjects be informed volunteers and that
seriously ill patients be permitted to receive higher doses only with their consent
appear to have been more broadly communicated and enforced. The only
evidence of general attention to matters of consent from patient-subjects comes
from ORINS, whose policies and practices show a striking similarity to those that,
as we shall see, were being contemporaneously employed at another facility
essentially devoted to experimental work, the NIH's Clinical Center. At the same
time, there is evidence of considerable attention in both policy and practice to
issues of safety and acceptable risk (see chapter 6). Questions of subject
selection, as in the case of seriously ill patients, emerge only in this context of
safety; there is no evidence that issues of fairness or concerns about exploitation
in the selection of subjects figured in AEC policies or rules of the period.
THE DEPARTMENT OF DEFENSE: CONSENT IS
FORMALIZED
The story of research involving human subjects in the U.S. military began
at least a century ago. Well before 1944, the beginning of the period of special
interest to the Advisory Committee, the military needed healthy subjects to test
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Chapter 1
means to prevent and treat infectious diseases to which military personnel might
be exposed. The notion that consent should be obtained from human subjects was
clearly part of this tradition; less clear is how consistently this was applied and
what consent actually meant to those in authority.
The most famous example of the early use of subject consent in the
military took place at the turn of the century. Walter Reed's successful research
on yellow fever, the mosquito-borne disease that bedeviled Panama Canal
construction efforts, employed healthy subjects who signed forms indicating their
agreement. Whether the practice was required by the Army or self-imposed by
Reed is unknown. In 1925 an Army regulation to promote infectious disease
research noted that "volunteers" should be used in "experimental" research. 43
The Navy also provided early requirements for human subject research.
In 1932, the secretary of the Navy granted permission for the conduct of an
experiment involving divers on condition that the subjects were "informed
volunteers." 44 In 1943 the secretary of the Navy also required that all
investigators seeking to conduct research with service personnel obtain prior
approval from the secretary. 45
As we have noted in the Introduction, during World War II, federally
funded biomedical research related to the war effort (outside the Manhattan
Project) was coordinated by the Committee on Medical Research (CMR) of the
Office of Scientific Research and Development, which was part of the Executive
Office of the President. The CMR supported a program of human research,
during which the question of the rules for the conduct of human research was
addressed. In 1942 a University of Rochester researcher, seeking to "work out a
human experiment on the chemical prophylaxis of gonorrhea," asked the CMR for
"an opinion that such human experimentation is desirable." 46 In an October 9,
1942, response, the CMR's chairman offered the following general statement,
which was endorsed by the full committee:
[HJuman experimentation is not only desirable, but
necessary in the study of many of the problems of
war medicine which confront us. When any risks
are involved, volunteers only should be utilized as
subjects, and these only after the risks have been
fully explained and after signed statements have
been obtained which shall prove that the volunteer
offered his services with full knowledge and that
claims for damage will be waived. An accurate
record should be kept of the terms in which the
risks involved were described. 47
In spite of the CMR's statement in response to this researcher's query, it supported
other experiments that involved subjects whose capacity to give valid consent to
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Part I
participation was doubtful, including institutionalized people with cognitive
disabilities. 4 *
During the war, the Navy used consent forms in wartime experiments
using prisoners and conscientious objectors, as a proposal for research on an
influenza vaccine with prisoners at San Quentin in 1943 shows. 49 The form used
in this case indicates that the subject is "acting freely and voluntarily without any
coercion on the part of any person whomever." 50 To be sure, the forms located by
the Advisory Committee were called "waiver" or "release" rather than "consent"
forms. Thus, the attestation to voluntary participation was punctuated by the
release of experimenters from liability. However, at a time when free young men
were routinely conscripted into the military, the requirement that subjects,
including prisoners and conscientious objectors, must be volunteers seems
remarkable.
In sharp contrast with these procedures, the Navy, too, sometimes
functioned in a manner inconsistent with a voluntary consent policy for healthy
subjects. Surviving subjects have reported that harmful mustard gas experiments
on naval personnel at the Naval Research Laboratory in Washington, D.C., during
World War II failed to adequately inform subjects and seem to have involved
manipulation or coercion of "volunteers." 51 The lack of medical follow-up on the
subjects of these experiments was sharply criticized in a 1993 report by the
Institute of Medicine of the National Academy of Sciences. 52
The NEPA Debate on the Ethics of Prisoner Experiments
Many of the researchers and officials who had been involved in Manhattan
Project human experiments during the war and then in the 1947 AEC
deliberations about human research policy also were engaged in 1949 and 1950 in
discussions of the ground rules for research with human subjects in the
development of new military technology. This time the forum was the joint AEC-
DOD project on Nuclear Energy for the Propulsion of Aircraft (NEPA). The
DOD convened an advisory panel of private and public officials to determine how
to obtain data needed to answer questions such as whether the air crew would be
put at undue risk by the nuclear-powered engine. The participants in the
discussion included university researchers Hymer Friedell, Stafford Warren,
Robert Stone, and Joseph Hamilton, and AEC officials Shields Warren and Alan
Gregg. Shields Warren argued that human experimentation was not appropriate
because the research could be done on animals and human data was not likely to
produce scientifically valid results (see Introduction).
Robert Stone, the recipient of the November 1947 letter in which AEC
General Manager Wilson called for "informed consent," emerged as the primary
proponent of human experiments. In a January 1950 discussion paper, he focused
on the "ethics of human experimentation." 53 After a recitation of a tradition that
included Walter Reed's experience and the historical use of prisoners and medical
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Chapter 1
students as research subjects, Stone cited requirements that had been publicized
by the American Medical Association in 1946. These rules provided that subjects
must give voluntary consent, that animal experimentation must precede human
experimentation, and that human experiments should be "performed under proper
medical protection and management." 54 (See chapter 2.) Stone argued that it
would be possible to conduct NEPA-related experiments with prisoners in
compliance with all three of these requirements.
Stone's proposal generated considerable discussion among DOD and AEC
experts and officials. In April 1950, the DOD's Joint Panel on the Medical
Aspects of Atomic Warfare endorsed the use of prisoners of "true volunteer
status" as meeting "the requirements of accepted American standards for the use
of human subjects for research purposes." 55
However, AEC officials were less than enthusiastic. "Doesn't the prisoner
proposal," ACBM Chairman Alan Gregg asked a military official in the course of
one discussion, "fall in the category of cruel and unusual punishment?" 5 "Not,"
the official replied, "if they would carry out the work as they proposed It
would be on an absolutely voluntary basis, and under every safety precaution that
could be built up around it ... it didn't strike me as being cruel and unusual." To
which Shields Warren retorted: "It's not very long since we got through trying
Germans for doing exactly the same thing." 57
In December 1950 the AEC convened a panel to discuss what was known
about potential radiation effects on service personnel and whether human research
was needed. Joseph Hamilton, Robert Stone's colleague at the University of
California, was unable to attend the meeting, and in his regrets he offered his
thoughts on the matter. In a letter to Shields Warren, he noted that the proposal to
use prisoner volunteers "would have a little of the Buchenwald touch" and
reported that he had no "very constructive ideas as to where one would turn for
such volunteers should this plan be put into effect." 58 He suggested using large
primates, even though, from a purely scientific viewpoint, the data collected
would not be as useful as data from humans. 59
Apparently Stone lost the debate. A decision was made not to conduct
experiments with prisoners or other healthy subjects in connection with the NEPA
project. However, as will be discussed in more detail in chapter 8, the military
contracted with a private hospital to study patients who were being irradiated for
cancer treatment, in the hopes of answering the same kinds of questions that
would have been addressed if NEPA research with prisoners had gone forward.
Congress Provides for DOD Contractor Indemnification in the Case of
Injury
In the aftermath of World War II, the military continued its long-standing
program of infectious disease research using human subjects. During the late
1940s and early 1950s the Army Epidemiological Board (AEB) and its 1949
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Parti
successor, the Armed Forces Epidemiological Board (AFEB), which was
established to advise on medical research funded by the DOD and to direct some
research undertaken with Army funds, sponsored studies with healthy subjects
that focused on hepatitis, dengue fever, and other infectious diseases. Consistent
with military tradition, at least some AEB-sponsored researchers were using
written permission forms. The forms, frequently referred to as an "Agreement
with Volunteer," or a "release," outlined the study and the risks to the subject and
protected the DOD from liability. 60
In the late 1 940s, some university researchers expressed concern that they
were not adequately protected from liability in the case of injury or death of their
prisoner-subjects. The ensuing dialogue provides a window on the role of the
written releases and the understanding of the rules governing human subject
research. In response to a researcher's request to be reimbursed by the Army for a
disability policy for the subjects, the Army lawyers replied that the Army could
not provide indemnification in the absence of clear congressional authority.
Army legal advisers recommended that the researcher "protect himself, the State
of New Jersey [the research locale], and the Government by means of the usual
waiver." 61
In a February 1948 letter, the AEB director, John R. Paul, explained that
the "world situation" had placed the rules for human experimentation up for
grabs. 62
At this stage in the world situation one should
proceed cautiously, until standards are set by what
ever body is in 'authority.' I am not sure just what
the rules are but I understand that . . . some type of
vigilance committee has laid down certain
principles about volunteers in order to protect this
country from the criticisms brought up in Germany
during the Nuremberg trials. . . . During the war we
more or less made our own policies on this, but I
am not sure that this is possible today. . . , 63
The allusion to a "vigilance committee" is unclear. It may be a reference to a
committee established by the governor of Illinois to examine the use of prisoners
as research subjects in that state and chaired by Andrew Ivy, the principal expert
witness for the prosecution at the Nuremberg Medical Trial (see chapter 2).
Given the date of the letter, February 18, 1948, it seems likely that Paul had just
skimmed through his new copy of the Journal of the American Medical
Association— the report of Ivy's committee was published in the February 14,
1948, issue. 64
In April 1948, an AEB official made it plain to the researchers that the fact
that state authorities or the prison warden gave permission for the experiment
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Chapter 1
should be of little comfort to them. In case of a lawsuit, responsibility "would
devolve entirely upon the individual experimenter." 65 Only Congress could
provide a solution, but it would be a "dangerous course" to raise the matter
publicly. "I have," the AEB official wrote,
given considerable thought to the matter of whether
it would be advisable to approach individuals or
groups in Congress with the idea of having laws
passed relating to payment of compensation for
disability or release of the experimenter from
liability. I am afraid that this would be a dangerous
course, and that it might in fact injure clinical
investigations generally. There is a very real
possibility that unfavorable publicity would quickly
result. 66
It appears that the relief sought by researchers was provided by Congress
in 1952, however, under the umbrella of a law that provided indemnification for
DOD research and development activities as a whole. In October 1952, following
the death of a prisoner-subject in an AFEB-sponsored hepatitis study 67 and
questions raised by the Army Chemical Corps about release forms for "human
'guinea pigs,'" 68 the AFEB administrator queried the DOD Legal Office about a
recently passed federal law. The law provided authority for the military to
indemnify contractors for risks undertaken in "research and development
situations." Did the new law "afford relief to the immediate dependents of
prison volunteers when as [a] result of these experiments they should die[?]" 6
The answer was yes, but only by providing relief to the researchers first. "From
the wording of the law, and from ... the legislative history," the Legal Office
replied, "it is a direct indemnification to the contractor and not to the individual
human guinea pig." 70
Thus, what appears to have been the first Cold War congressional
enactment to deal with human subjects of research addressed the government's
obligation to its contractors, not the government's and its researchers' obligations
to the subjects. Moreover, the record indicates that a more direct approach was
not sought by the DOD because of concerns about public relations. At the same
time Congress was acting, however, the DOD itself was secretly debating a new
policy for human experiments.
The Secretary of Defense Issues the Nuremberg Code in Top Secret
As the Korean War began in mid- 1950, the military's interest in human
experimentation-in connection with chemical and biological as well as atomic
and radiation warfare-intensified. The need for a DOD-wide policy on the use of
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Part I
human subjects in research was noted by Colonel George Underwood, the
director of the Office of the Secretary of Defense, in a February 1953
memorandum to the incoming administration of Dwight D. Eisenhower: "There
is no DOD policy on the books which permits this type of research [human
experiments in the field of atomic, biological, and chemical warfare]." 71
From 1950 to 1953 discussions about human research and human research
policy were held in several high-level DOD panels, including the Armed Forces
Medical Policy Council (AFMPC), the Committee on Medical Sciences (CMS),
and the Joint Panel on the Medical Aspects of Atomic Warfare. These groups
were headed by civilian researchers, and, in at least the latter two cases, included
representatives of the AEC, CIA, NIH, VA, and Public Health Service.
At its September 8, 1952, meeting, the AFMPC heard a presentation from
the chief of preventive medicine of the Army Surgeon General's Office on the
topic of biological warfare research:
It was pointed out that the research had reached a
point beyond which essential data could not be
obtained unless human volunteers were utilized for
such experimentation. . . . Following detailed
discussion, it was unanimously agreed that the use
of human volunteers in this type of research be
approved. 72
At its October 13, 1952, meeting the AFMPC again took up the question
of human experimentation. "It was resolved," the chairman wrote to the secretary
of defense, "that the ten rules promulgated at the Nuremberg trials be adopted as
the guiding principles to be followed. An eleventh rule [barring experiments with
prisoners of war] was added by the legal advisor to the Council, Mr. Stephen S.
Jackson." 73
DOD attorney Jackson evidently was responsible for the inclusion of the
Nuremberg Code in the AFMPC's proposed policy. In an October 13, 1952,
memo to the chairman of the AFMPC, Jackson
recommended: that the attached principles and
conditions for human experimentation, which were
laid down by the Tribunal in the Nuremberg Trials,
be adopted instead of those previously submitted by
me. 74
As an addendum to the Nuremberg Code, Jackson proposed a requirement
that "consent be expressed in writing before at least one witness." This
recommendation followed from the suggestion of Anna Rosenberg, assistant
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Chapter 1
The Nuremberg Code
1. The voluntary consent of the human subject is absolutely essential.
This means that the person involved should have legal capacity to give consent; should be so
situated as to be able to exercise free power of choice, without the intervention of any element of
force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and
should have sufficient knowledge and comprehension of the elements of the subject matter
involved as to enable him to make an understanding and enlightened decision. The latter element
requires that before the acceptance of an affirmative decision by the experimental subject there
should be made known to him the nature, duration, and purpose of the experiment; the method and
means by which it is to be conducted; all inconveniences and hazards reasonably to be expected;
and the effects upon his health or person which may possibly come from his participation in the
experiment. The duty and responsibility for ascertaining the quality of the consent rest upon each
individual who initiates, directs or engages in the experiment. It is a personal duty and
responsibility which may not be delegated to another with impunity.
2. The experiment should be such as to yield fruitful results for the good of society,
unprocurable by other methods or means of study, and not random and unnecessary in nature.
3. The experiment should be so designed and based on the results of animal
experimentation and a knowledge of the natural history of the disease or other problem under
study that the anticipated results will justify the performance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physical and
mental suffering and injury.
5. No experiment should be conducted where there is an a priori reason to believe that
death or disabling injury will occur; except, perhaps, in those experiments where the experimental
physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the
humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to protect the
experimental subject against even remote possibilities of injury, disability, or death.
8. The experiment should be conducted only by scientifically qualified persons. The
highest degree of skill and care should be required through all stages of the experiment of those
who conduct or engage in the experiment.
9. During the course of the experiment the human subject should be at liberty to bring the
experiment to an end if he has reached the physical or mental state where continuation of the
experiment seems to him to be impossible.
10. During the course of the experiment the scientist in charge must be prepared to
terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the
good faith, superior skill, and careful judgment required of him, that a continuation of the
experiment is likely to result in injury, disability, or death to the experimental subject.
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secretary of defense for manpower and personnel, who was an expert on labor
relations. 75
A letter written by the administrator of the Armed Forces Epidemiological
Board documents Mr. Jackson's role and motivation:
It was on Mr. Jackson's insistence that the
'Nuremberg Principles' were used in toto in the
document, since he stated, these already had
international judicial sanction, and to modify them
would open us to severe criticism along the line—
"see they use only that which suits them." 76
Thus, the DOD's counsel cited the 1947 Nuremberg military tribunal
ruling as establishing an international legal precedent to which American
researchers should be held.
It appears that in succeeding months the AFMPC proposal was received
unenthusiastically by other DOD committees that reviewed it. In a November 12,
1952, memorandum, the executive director of the Committee on Medical Sciences
pointed out that "human experimentation has been carried on for many years." He
contended that
to issue a policy statement on human
experimentation at this time would probably do the
cause more harm than good; for such a statement
would have to be "watered down" to suit the
capabilities of the average investigator. 77
"Human experimentation," the CMS executive director asserted, "has, in
years past, and is at present governed by an unwritten code of ethics," which is
"administered informally by fellow workers in the field [and] is considered to be
satisfactory. ... To commit to writing a policy on human experimentation would
focus unnecessary attention on the legal aspects of the subject." 78
Notwithstanding the reservations of the CMS and others, 79 the Nuremberg
Code proposal had the support of President Truman's secretary of defense, Robert
A. Lovett. 80 However, the secretary's aide, George V. Underwood, wrote in
January 1953, "Since consequences of this policy will fall upon Mr. Wilson
[President Eisenhower's nominee for secretary of defense, Charles Wilson], it
might be wise to pass to him as a unanimous recommendation from the
'alumni.'" 81
In a January 13, 1953, memorandum for the new secretary, the AFMPC
"strongly recommended that a policy be established for the use of human
volunteers (military and civilian employees) in experimental research at Armed
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Chapter 1
Forces facilities." The policy would render the research "subject to the principles
and conditions laid down as a result of the Nuremberg trials." 82
The Wilson Memorandum
26 Feb 1953
Memorandum for the Secretary of the Army
Secretary of the Navy
Secretary of the Air Force
Subject: Use of Human Volunteers in Experimental Research
1. Based upon a recommendation of the Armed Forces Medical Policy Council, that
human subjects be employed, under recognized safeguards, as the only feasible means for realistic
evaluation and/or development of effective preventive measures of defense against atomic,
biological or chemical agents, the policy set forth below will govern the use of human volunteers
by the Department of Defense in experimental research in the fields of atomic, biological and/or
chemical warfare.
2. By reason of the basic medical responsibility in connection with the development of
defense of all types against atomic, biological and/or chemical warfare agents. Armed Services
personnel and/or civilians on duty at installations engaged in such research shall be permitted to
actively participate in all phases of the program, such participation shall be subject to the
following conditions:
a. The voluntary consent of the human subject is absolutely essential.
( 1 ) This means that the person involved should have legal capacity to
give consent; should be so situated as to be able to exercise free power of choice,
without the intervention of any element offeree, fraud, deceit, duress, over-
reaching, or other ulterior form of constraint or coercion; and should have
sufficient knowledge and comprehension of the elements of the subject matter
involved as to enable him to make an understanding and enlightened decision.
This latter element requires that before the acceptance of an affirmative decision
by the experimental subject there should be made known to him the nature,
duration, and purpose of the experiment; the method and means by which it is to
be conducted; all inconveniences and hazards reasonably to be expected; and the
effects upon his health or person which may possibly come from his
participation in the experiment.
(2) The concept [sic] of the human subject shall be in writing; his
signature shall be affixed to a written instrument setting forth substantially the
aforementioned requirements and shall be signed in the presence of at least one
witness who shall attest to such signature in writing.
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(a) In experiments where personnel from more than one
Service are involved the Secretary of the Service which is exercising
primary responsibility for conducting the experiment is designated to
prepare such an instrument and coordinate it for use by all the Services
having human volunteers involved in the experiment.
(3) The duty and responsibility for ascertaining the quality of the
consent rests upon each individual who initiates, directs or engages in the
experiment. It is a personal duty and responsibility which may not be delegated
to another with impunity.
b. The experiment should be such as to yield fruitful results for the good of
society, unprocurable by other methods or means of study, and not random and
unnecessary in nature.
c. The number of volunteers used shall be kept at a minimum consistent with
item b., above.
d. The experiment should be so designed and based on the results of animal
experimentation and a knowledge of the natural history of the disease or other problem
under study that the anticipated results will justify the performance of the experiment.
e. The experiment should be so conducted as to avoid all unnecessary physical
and mental suffering and injury.
f. No experiment should be conducted where there is an a priori reason to
believe that death or disabling injury will occur.
g. The degree of risk to be taken should never exceed that determined by the
humanitarian importance of the problem to be solved by the experiment.
h. Proper preparation should be made and adequate facilities provided to protect
the experimental subject against even remote possibilities of injury, disability, or death.
i. The experiment should be conducted only by scientifically qualified persons.
The highest degree of skill and care should be required through all stages of the
experiment of those who conduct or engage in the experiment.
j. During the course of the experiment the human subject should be at liberty to
bring the experiment to an end if he has reached the physical or mental state where
continuation of the experiment seems to him to be impossible.
k. During the course of the experiment the scientist in charge must be prepared
to terminate the experiment at any stage, if he has probable cause to believe, in the
exercise of the good faith, superior skill and careful judgment required of him that a
continuation of the experiment is likely to result in injury, disability, or death to the
experimental subject.
1. The established policy, which prohibits the use of prisoners of war in human
experimentation, is continued and they will not be used under any circumstances.
3. The Secretaries of the Army, Navy and Air Force are authorized to conduct
experiments in connection with the development of defenses of all types against atomic, biological
and/or chemical warfare agents involving the use of human subjects within the limits prescribed
above.
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Chapter 1
4. In each instance in which an experiment is proposed pursuant to this memorandum,
the nature and purpose of the proposed experiment and the name of the person who will be in
charge of such experiment shall be submitted for approval to the Secretary of the military
department in which the proposed experiment is to be conducted. No such experiment shall be
undertaken until such Secretary has approved in writing the experiment proposed, the person who
will be in charge of conducting it, as well as informing the Secretary of Defense.
5. The addresses will be responsible for insuring compliance with the provisions of this
memorandum within their respective Services.
/signed/
C. E. Wilson
copies furnished:
Joint Chiefs of Staff
Research and Development Board
Downgraded to
UNCLASSIFIED
22 Aug 75
TOP SECRET
On February 26, 1953, Secretary of Defense Wilson signed off on the
AFMPC policy. It was issued in a Top Secret memorandum to the secretaries of
the Army, Navy, and Air Force. The Wilson memorandum reiterates the
principles of the Nuremberg Code, requires written and witnessed informed
consent of research subjects, and prohibits the use of prisoners of war. The policy
was to "govern the use of human volunteers by the Department of Defense in
experimental research in the fields of atomic, biological, and/or chemical warfare
for defensive purposes." 83
The basis for the classification of the 1953 memorandum is not clear.
Since the memorandum dealt with atomic and other unconventional forms of
warfare, its classification may have been routine. There is evidence that the DOD
had a general desire to keep hidden from public view any indication that it was
involved in biological and chemical warfare-related research; the Wilson
memorandum, of course, was just such an indication. In September 1952, the
Joint Chiefs of Staff advised the services to "[e]nsure, insofar as practicable, that
all published articles stemming from BW [biological warfare] and CW [chemical
warfare] research and development programs are disassociated from anything
which might connect them with U.S. military endeavor." 84
In one sense the memorandum is a landmark in its official recognition of
the Nuremberg Code, but in another sense it also generates important questions.
Having determined to recognize international principles of human rights, why, or
how, could the secretary have limited their application to some, but not all, human
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Parti
experiments? Why was the policy directed exclusively to experiments related to
"atomic, biological, and chemical warfare"? Moreover, was the policy intended
to govern such research wherever it was conducted; for example, when it was
performed by private contractors, as well as by intramural researchers? How was
a directive issued in secret implemented?
Communicating the 1953 Wilson Memorandum
That there were problems in the dissemination of Secretary Wilson's Top
Secret memorandum is evidenced in a memorandum containing queries by
officials of the Armed Forces Special Weapons Project (AFSWP), within a year
of the Wilson memorandum's issuance. The AFSWP, now the Defense Nuclear
Agency (DNA), was at the hub of DOD nuclear weapons research. In the course
of a routine review of research reports, an AFSWP official learned that
"volunteers were injured as a consequence of taking part in [a] field experiment"
of flashblindness conducted at an atomic bomb test before the Wilson
memorandum was issued (see chapter 10). The AFSWP reviewer immediately
concluded that a "definite need exists for guidance in the use of human volunteers
as experimental subjects." 85
On further inquiry, the AFSWP reviewer found that a policy already
existed, but had not been disseminated to investigators. A follow-up
memorandum, evidently written in early 1954, records:
In November 53 it was learned that there existed a
T/S [Top Secret] document signed by the Secretary
of Defense which listed various requirements and
criteria which had to be met by individuals
contemplating the use of human volunteers in Bio-
medical or other types of experimentation. ... It
was learned that although this document details
very definite and specific steps which must be taken
before volunteers may be used in experimentation,
no serious attempt has been made to disseminate the
information to those experimenters who have a
definite need-to-know. 86
"The lowest level at which it had been circulated," the AFSWP reviewer
learned, "was that of the three Secretaries of the Services." Efforts by an assistant
secretary to "downgrade" the document had "not been able to obtain
concurrence." The reviewer hoped that "this letter shall point up the need for
some relaxation of the grip in which this document is now held, at least on a
definite need-to-know basis." 87 (The application of the Wilson memorandum to
further experiments conducted at atomic bomb tests is discussed in chapter 10.)
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Chapter 1
Implementation in the Army
The Army did take substantial steps to put into effect the Wilson
memorandum. In June 1953 the Army chief of staff, John C. Oakes, issued a
memorandum implementing the secretary of defense's policy in toto. Referred to
in the Army as CS:385, this memorandum was initially classified Top Secret, but
was declassified the following year. In addition to the provisions of the Wilson
memorandum, the Army document required the prior review and approval of both
the surgeon general and the secretary of the Army. The Army's memorandum
also contained legal analysis that explained the source of the Army's authority to
perform human experiments in the first place and the limits that this authority put
on the selection of subjects. 81 * Even in the midst of the Korean War, the Army
did not view it as self-evident that the DOD could engage in human experiments
or choose any subjects it wished. The memorandum explained that the authority
to experiment on humans came from congressional enactments, including
provisions for research and development. 1 * 9
Interestingly, choice of subjects was to be governed by the Army's ability
to ensure compensation in the case of death or disability. 90 This could be
provided, the lawyers declared, only upon express congressional action. In the
case of military personnel and contractor employees there was such provision.
But there was no such authority in the case of private citizens who offered their
services. The Army lawyers recommended, and the CS:385 policy provided, that
private citizens not employed by Army contractors could not serve as research
subjects. 91
On March 12, 1954, the Army Office of the Surgeon General (OSG)
issued an unclassified statement entitled "Use of Human Volunteers in Medical
Research: Principles, Policies, and Rules." 92 This document too restated the
Nuremberg principles. In contrast with the Wilson and Oakes memorandums, it
was not restricted to research related to atomic, biological, or chemical warfare.
Instead, the OSG statement was directed to "medical research" with human
volunteers generally. 93
Moreover, while CS:385 did not state directly whether it applied to
contract researchers, the 1954 OSG statement was transmitted to at least some
university researchers with the prefatory note, "To be used as far as applicable as
a non-mandatory guide for planning and conducting contract research." 94 There is
evidence that the OSG's requirements were sometimes more than "non-mandatory
guides." For example, in a June 27, 1956, letter to the the Armed Forces
Epidemiological Board, a Tulane University public health researcher agreed that
his vaccine experiments with prisoner subjects would be conducted only after
written consent was obtained from the subjects. 95 The Tulane researcher
indicated that, with respect to his application for funding, "I have held it up since
Dr. Dingle indicated I be familiar with the statement of the Office of the Surgeon
General re the use of human volunteers I have read it and believe that our
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Parti
past and future work have [sic] and will comply with the rules stipulated." 96
Moreover, this researcher provided a written statement to supplement his original
proposal that explained how the OSG requirements would be met. In another
case, a proposal involving measles and normal children, an AFEB official advised
the researcher to "take [the OSG policy] into consideration in writing the
proposal." 97
As discussed earlier, in 1952 the Army obtained congressional authority to
indemnify contract researchers in the event that an experiment caused injury or
death. There is evidence that the Army sought to link the grant of an
indemnification clause (ASPR 7.203.22, "Insurance-Liability to Third Persons")
to contractor acceptance of the principles stated by the Army surgeon general. In
a March 1957 letter to the University of Pittsburgh, which was proposing to use
medical student-volunteers in a (nonradiation) experiment, the Army told
Pittsburgh that the provision of the clause was "contingent upon your adhering to
the following [March 1954 Office of the Surgeon General] principles, policies,
and rules for the use of human volunteers in performing subject medical research
contracts." 98
While the evidence clearly shows that Army officials sought to apply the
Nuremberg Code policy to contractors, it did not meet with complete success, and
the full extent of its efforts remains unclear. As we see in chapter 2, in the early
1960s Harvard successfully resisted the inclusion of the Nuremberg Code
language in its medical research contracts with the Army. As we see in chapter 8,
which discusses DOD funding of research on the effects of total-body irradiation,
the indemnification language was included in at least some contracts in which the
surgeon general's policy was not mentioned. By 1969, however, the policy may
have become standard in Army contracts under the authority of the Medical
Research and Development Command. 99
There are several possible explanations for the seeming absence of
widespread inclusion of the surgeon general's memo as a contractual requirement,
at least where indemnification was provided for. First, as discussed below, it is
possible that the 1954 policy was meant to apply to research with healthy
subjects, and not sick patients. (However, even if that were generally the case,
the provision of indemnification might be expected to have triggered reflection on
this limitation.) Second, as a related matter, the evidence we are reviewing shows
a tension between the government's declaration of a principle and its readiness to
actively insist that the principle be honored within the privacy of the doctor-
patient relationship.
Finally, Army imposition of the surgeon general's principles may also
have depended on the nature of its interest in the research being done. An April
3, 1957, memo distinguished cases where the institution "because of its primary
interest, would conduct the research even without support of the OSG," from
cases where "the study is conducted at the insistence of OSG." In the former case
the strategy would be to seek cost-sharing contracts, in which the institution
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Chapter 1
would "assume all responsibility for any possible effects resulting from the
experimentation." In the latter case, the indemnification clause would be
provided, but the March 1954 policy would also be required and included in the
contract directly or by reference. ino
It is not clear that the 1954 OSG policy on human volunteers was intended
to apply to research with patients. The term volunteer is ambiguous but at the
time was commonly used to refer to healthy subjects. Nonetheless, a 1 962 Army
memorandum that declared that since World War II "by and large research has
been conducted in strict accordance with the Nuremberg Code" mentions
patients. I0 ' The memo reported that a recent survey of contract research found
that the volunteers treated in accord with the Nuremberg Code included "3,000
students, 250 patients, and 300 prisoners." It is not known what kind of research
these 250 patients were involved in, nor is it known what proportion of the
patients who had been subjects of research supported or conducted by the Army
since World War II were represented by these 250.
Unfortunately, the 1962 review's confident declaration that Army research
complied with the Nuremberg Code was too sanguine. In 1975, following public
revelations that the Army and the CIA had conducted LSD experiments on
unwitting subjects, the Army inspector general reviewed the application of the
June 1953 policy to drug testing. The inspector general's review led to the
declassification of the 1953 Wilson memorandum. The inspector general found
that the Army had, with one or two exceptions, used only "volunteers" for its
drug-testing program. However, the "volunteers were not fully informed, as
required, prior to their participation, and the methods of procuring their services
in many cases appeared not to have been in accord with the intent of Department
of the Army policies governing use of volunteers in research." 102
Additional DOD Research Requirements
While the Navy is not known to have taken specific action in response to
the 1953 Wilson memorandum, we have already noted that the Navy had long
since provided for prior review and voluntary participation in some cases. The
1951 Navy "Manual of the Medical Department" required secretarial approval of
human experimentation and the use of volunteers. These requirements applied to
"experimental studies of a medical nature" involving "personnel of the Naval
Establishment (military and civilian)." 103 Participation was to be "on a voluntary
basis only." 104 The manual also mandated prior review for research with patient-
subjects. "Clinical research," including "research projects and therapeutic trials,"
was to be "authorized by" the Bureau of Medicine and Surgery. 105
At least for research with radioisotopes, the requirement for voluntary
participation may have applied to patient-subjects as well as healthy subjects. In
1951 the Navy debated adoption of a permission form for the use of radioisotopes
for patients at naval hospitals. 106 This form, to be signed by either the patient or
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Parti
the responsible next of kin, authorized the use of "tracer-therapeutic" doses
"obtained from the Atomic Energy Commission for research purposes." 107
Although it is not clear that the Army rules implementing the 1953 Wilson
memorandum applied to patient-subjects, there is some evidence that consent
forms that were usually used for surgical procedures were used in patient-related
experimental settings involving radioisotopes. In 1955 an official from the
Letterman Army Hospital in San Francisco asked the Walter Reed Hospital about
the need for written "permission" forms for "test doses" of radioisotopes. 108 In
response, the Army indicated that a standard form used for operations and
anesthesia should also be employed, at the physician's discretion, when
"authorization for administration of radioisotope therapy is desired." 109
In the Air Force, a 1952 regulation on clinical research mandated safety
and administrative procedures for the use of humans in experiments at Air Force
medical facilities." This regulation required prior group review but did not
mention consent provisions or refer to the subjects as volunteers. In 1958 a letter
from the Air Force's Air Research and Development Command describes the
policy for the use of humans in "hazardous research and development tests." This
policy reiterated the requirement for prior review discussed in the 1952
regulation. In this context, however, subjects were to be "volunteers]" who
"understood] the degree of risk involved in the experiment."" 1
What, then, were the operative rules in the Department of Defense for
research involving human subjects in the 1940s and 1950s? By the mid-1950s,
for the entire DOD for research related to atomic, biological, and chemical
warfare, and for all research involving "human volunteers" in the Army, the
formal rules were the ten principles of the Nuremberg Code and the additions
included in the secretary of defense's 1953 policy. According to the 1975
testimony of the surgeon general of the Army before the U.S. Senate and the
internal review conducted by the Army inspector general, these principles were
Army "policy."" 2 At the same time, as the inspector general reported in 1975 and
as we discuss further in chapter 10, these requirements were not always known or
followed. While there were attempts to implement the Army surgeon general's
1954 policy, it is not known how the policy's provisions, including the
requirement to obtain voluntary consent, were interpreted. The Navy's 1951
requirements for prior review and voluntariness applied to all research involving
Navy personnel.
The extent to which research rules applied to patient-subjects in the
clinical setting is less clear. There is some indication that in some cases standard
consent forms, akin to the surgical permits in use at the time, were employed with
patients at military hospitals who were administered "test doses" of radioisotopes.
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Chapter 1
THE NATIONAL INSTITUTES OF HEALTH AND THE
VETERANS ADMINISTRATION
During the late 1940s and 1950s, the AEC and DOD were by no means
the only agencies sponsoring research involving human subjects. The Department
of Health, Education, and Welfare (DHEW), through two of its components, the
Public Health Service and the NIH, was emerging during this period as the
dominant government agency sponsoring human biomedical research. The
Veterans Administration (VA) as well conducted a large medical research
program that involved the use of radioisotopes in numerous human experiments.
In the early 1950s NIH participated in some of the discussions preceding
the issuance of the 1953 secretary of defense memorandum. At the request of a
DOD official for information on NIH's approach to the use of human subjects,
NIH responded with an April 1952 letter that included a draft statement on the
"Ethical Principles Underlying Investigations Involving Human Beings." Among
its other provisions, the April 28, 1952, draft states that
[t]he person who is competent to give consent to an
investigative procedure must do so. He must have legal
capacity to give consent and be able to exercise free choice,
without the intervention of any element of force, fraud,
deceit, duress, constraint or coercion. He must have
sufficient knowledge and comprehension of the nature of
the investigation to enable him to make an understanding
and enlightened decision. He must therefore be told the
nature, duration, and purpose of the experiment; the
method and means by which it is to be conducted; the
inconveniences and hazards reasonably to be expected; and
the effects upon his health or person which can reasonably
be expected to come from his participation in the
investigation. He should understand, furthermore, that by
his participation he becomes a co-investigator with the
physician." 3
Although it is not known what became of this draft statement, around this
time NIH had good reason to develop a policy on the use of human subjects. In
1953 NIH opened the Clinical Center, a state-of-the-science research hospital.
The center adopted a policy requiring "voluntary agreement based on informed
understanding" from all research subjects and written consent from some patient-
subjects involved in research that the physician believed to be unusually
hazardous." 4 Written consent was required from all healthy, "normal" subjects of
research beginning in 1954." 5 Additionally, NIH began a system of group review
of proposed research that became a model for today's institutional review boards
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Part I
(IRBs)." 6 Thus, the NIH policy appears to be the first instance of a single policy
that expressly provides for consent from all subjects, be they healthy or sick.
Even so, the policy was still limited to research at the Clinical Center and did not
apply to the considerable amount of NIH-funded research being undertaken by
grantees (extramural research).
The question of whether "patients," as well as healthy, "normal"
volunteers, should give written consent arose in the development of the NIH
policy. Legal counsel at NIH advised that, "from a legal point of view," there
should be a "written statement . . . indicating the patient's awareness of the nature
of the particular investigation in which he was to participate and acceptance of
any particular inconvenience or risk inherent in his participation."" 7 A signed
form offered the best proof that a "policy" of "informed consent" was followed for
all subjects enrolled in studies at the center.
The NIH attorney wrote that while the Clinical Center's Medical Advisory
Board did not disagree with the principle, it did disagree with the need for a
written statement:
[0]f the members that expressed their views, and
most did so, all rejected such a proposal. The
rejection was due, as I understand it, not to any
particular detail but rather a more basic objection to
written, as opposed to oral, statements. There was
apparently, therefore, no objection to providing the
patient with enough information to permit him to
exercise an informed choice of participation or
refusal as long as not reduced to writing for his
signature." 8
Nonetheless, the principle that all research subjects, including healthy subjects in
the "normal volunteer" program and patient-subjects, should make an informed
choice seems to be acknowledged in the Medical Advisory Board's position.
The NIH Clinical Center approach adopted by the mid-1950s-written
consent from healthy subjects and from only certain patient-subjects— persisted
through the early 1960s and was paralleled in policies of the DOD and the AEC.
The view that written consent from patients might unnecessarily interfere with
doctor-patient relationships prevailed.
Within the NIH, dialogue continued throughout the 1950s, setting the
stage for the leading role DHEW was to take in formulating human research
regulations in the 1960s (see chapter 3)." 9
Although the NIH was by far the dominant agency in research involving
human subjects, a significant amount of radioisotope research occurred at the VA.
The VA research program employing radioisotopes at VA medical centers began
in 1948. 120 This program was limited to VA hospitals affiliated with medical
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Chapter 1
schools. From its inception, this program involved a system of prior group review
by local radioisotope committees, normally composed of non-VA-affiliated
teaching staff of the affiliated medical school. 121 These committees reviewed all
research proposals and approved all research conducted at VA radioisotope units.
In its formative years, the advisers to the new VA program included
Stafford Warren, Shields Warren, and others who were likely to be familiar with
the consent principles articulated by the AEC. Nonetheless, the earliest evidence
of a consent policy at the VA comes in the form of a 1958 general counsel's
opinion on whether the VA could participate in certain research. The general
counsel asserted that
persons who participate [in human subject research]
must voluntarily consent to the experiment on
themselves. Such consent must rest upon an
understanding of the hazards involved. The
volunteer may withdraw from the experiment at any
time. Moreover, before the experiment, steps to
reduce the hazard, as for example, indicated
research on animals, must be made. 122
This opinion was written in response to two proposed research projects, and it is
not known if it was implemented in the projects or applied to others.
CONCLUSION
Records now available show that at the highest reaches of Cold War
bureaucracies officials discussed conditions under which human experimentation
could take place. These discussions took place earlier and in greater, although by
today's standards uncritical and less searching, detail than might have been
assumed. Nonetheless, the stated positions that resulted were often developed in
isolation from one another, were neither uniform nor comprehensive in their
coverage, and were often limited in their effectuation. Several interrelated factors
seem to have been prominent in causing these discussions to take place and in
determining the scope of the requirements that were declared and the efforts that
were undertaken to implement them. We summarize these key factors below.
Administrative and Legal Circumstance
The creation of new programs, or the qualitative expansion of old ones,
impelled officials, lawyers, and researchers to reflect on the rules to govern them.
While these rules were sometimes cast as "legal" or "financial" requirements, they
often included provisions, such as a requirement for written consent, that appear
similar to statements in requirements that govern the conduct of research today.
115
Parti
The language used to describe these rules was often that of law or administration,
such as "waiver" or "release" forms, or it may have had particular meaning to
researchers at the time, such as "clinical testing." As a result, it is often hard to
compare these rules to current requirements, which have benefited from
intervening decades of linguistic and conceptual refinement.
Professional Cultures
Differing professions brought their own tools and perspectives to
discussions of conditions under which human subjects research could proceed.
For example, lawyers were likely to insist on obtaining documented evidence of
patient consent, while medical professionals emphasized the importance of the
trust that underlay the relationship between doctor and patient; they sometimes
objected to the use and implications of written consent forms.
If consent procedures were a source of disagreement, the need to minimize
risk to subjects was not. In creating and administering the AEC's radioisotope
distribution program, physician investigators and other researchers placed a
premium on controlling and minimizing risk in the "human use" of radioisotopes.
This emphasis on the establishment of administrative and educational procedures
to control risk, the details of which are discussed in chapter 6, embodied an
essential principle of ethical research.
The requirement for prior review included in the isotope distribution
program was, as we have seen, also present elsewhere. Even before 1944,
approval of the secretary of the Navy was required for research with human
subjects. The secretary of the Army required prior approval of research related to
atomic, biological, and chemical warfare in 1953. In the Air Force, secretarial
approval of human experiments was codified in 1952. At NIH, prior group
review was employed as a policy from 1953 on. The VA, whose program
developed under the eye of AEC experts and advisers, relied on local isotope
committees.
The Nature of the Subjects
While voluntary consent was acknowledged as a condition of human
research by some government agencies well before 1944, it was not as broadly
applied as it is today. Requirements of voluntary consent were asserted most
clearly and consistently where the subjects were healthy. As a practical matter,
healthy subjects are not likely to participate in experiments without specific
request, and as a legal matter the invasion of a person's body in the absence of a
prior relationship that might justify it has long been unacceptable. Still more
important, the arbitrary use of people in experiments is incompatible with respect
for human dignity.
116
Chapter 1
The use of patients in medical research appeared in a different historical
context from that of healthy subjects, and the agencies appear to have responded
accordingly. From the perspective of the medical profession, the age-old tradition
of the doctor-patient relationship, as we shall see in the next chapter, provided a
justification for research with the potential to benefit patients, but not, of course,
for healthy subjects who were not under medical care. There is little evidence
that the agencies questioned whether research with patients that did not offer a
prospect of benefit warranted a different response. An exception is the position
articulated by the AEC's general manager in 1947, which made the possibility of
benefit to the patient-subject a condition of permissible research, at least where
the research involved "poisonous or harmful" substances. However, there is little
indication that this provision was ever implemented.
The period we reviewed in this chapter led to considerable public disquiet
about the use of healthy subjects and about the use of ill and institutionalized
people in research from which they could not possibly benefit. It was this
disquiet, in the wake of several well-publicized incidents, that formed the basis of
the mid-1960s reforms of federal policy governing research with human subjects
(see chapter 3). The focus on the way that patient-subjects were used in clinical
research that offered some prospect of benefit, and particularly on consent issues,
came much later. The latter discussion is one that continues today, as is evident
from the Advisory Committee's work on current research regulation that is
described in part III.
The Degree of Risk
To the extent that there was discussion in the 1940s and the 1950s of
consent for patient-subjects, it seemed to arise mainly in circumstances in which
those who were ill would be put at unusual risk from the research.
As we have seen, the AEC's radioisotope distribution division concluded
that consent was required where patients were being subjected to "larger doses for
investigative purposes" that apparently posed unusually hazardous or unknown
risks. Similarly, from its establishment at midcentury, the AEC's hospital at Oak
Ridge, which focused on new and potentially risky experimental cancer treatment,
did have routine requirements for consent. Likewise, from its 1953 birth, the
NIH's Clinical Center established a policy that recognized that patient choice was
important for all kinds of research with patients, and written consent was required
when an experiment involved' an unusual hazard.
Formal Policies and Public Morality
It is important not to get lost in the details of the various documents we
have cited in this chapter. What is most significant about the discussions that
took place in federal agencies from the mid- 1940s through the 1950s is the fact
117
Part I
that so many of the ideas and values with which we are familiar were apparent
then. That does not mean that the same words were used or that when they were
used they had the same meaning as they do for us today. But it does mean that
there were certainly more or less rough ideas about voluntary consent and
minimization of risk. As we have seen in this chapter, these ideas were very
much in play in the culture of the time.
118
ENDNOTES
1. The "Common Rule" applies requirements for voluntary consent, prior
review, and risk analysis to all federally sponsored research. This rule is discussed in
chapter 14.
2. David Rothman, Strangers at the Bedside: A History of How Law and
Bioethics Transformed Medical Decision Making (New York: Basic Books, 1991), and
Ruth Faden and Tom Beauchamp, A History and Theoiy of Informed Consent (New
York: Oxford University Press, 1986).
3. George J. Annas and Michael A. Grodin, eds.. The Nazi Doctors and the
Nuremberg Code; Human Rights in Human Experimentation (New York: Oxford
University Press, 1992). 343-345.
4. See Faden and Beauchamp, A Histoiy and Theory of Informed Consent, and
Mark S. Frankel, "Public Policymaking for Biomedical Research: The Case of Human
Experimentation" (Ph.D. diss., George Washington University, 9 May 1976).
5. Stafford L. Warren, Chairman, Interim Medical Advisory Board ("Report of
the 23-24 January 1947 Meeting of the Interim Medical Committee of the United States
Atomic Energy Commission") (ACHRE No. UCLA-1 1 1094-A-26). The report
summarized "specific projects" at twelve institutions. The projects at the University of
Rochester included "Study of the Metabolism of Plutonium, polonium, radium, etc. in
human subjects" (p. 8). In the case of Berkeley, the projects identified to Dr. Stone were
(1 ) Studies in whole-body radiation of human subjects by external and internal
radiation.
(2) Studies on the metabolism of radioactive iodine in animals and man.
(3) Joint studies with Dr. Joseph G. Hamilton to evaluate the therapeutic
applications '
of the fission products and the fissionable elements.
(4) Exploration and therapeutic application of other radioactive elements and
compounds (p. 1 1).
A 14 March 1947 memorandum from Austin Brues, director of the Biology Division of
the Argonne National Laboratory, records that "clinical testing programs" had only been
authorized, at least for the time being, at Berkeley and Rochester. However, Brues urged
that Argonne also be included. On behalf of this request he cited the University of
Chicago's "work using human subjects" with specific reference to a report on plutonium
injections. He further noted that human subject work also included the Argonne project
list provided at the January meeting. A. M. Brues, Director, Biology Division, to N.
Hilberry, Associate Laboratory Director, 14 March 1947 ("Clinical Testing") (ACHRE
No. DOE-050195-B).
6. Stafford Warren, Chairman, Interim Medical Advisory Committee, to Carroll
Wilson, General Manager, AEC, 30 January 1947 ("The opinion on Clinical Testing . . .")
(ACHRE No. DOE-051094-A-439), 1.
19
7. John L. Burling, Deputy General Counsel's Office, AEC, to Edwin
Huddleson, Jr., Deputy General Counsel, AEC, 7 March 1947 ("Clinical Testing")
(ACHRE No. DOE-051094-A-468), 2-3.
8. Ibid., 3.
9. Carroll L. Wilson, General Manager of the AEC, to Stafford Warren, the
University of California at Los Angeles, 30 April 1947 ("This is to inform you that the
Commission is going ahead with its plans . . .") (ACHRE No. DOE-051094-A-439), 2.
10. Ibid.
11. Ibid.
12. Robert J. Buettner, Assistant to Chairman, Interim Medical Advisory
Committee, AEC, to B. M. Brundage, Chief, Medical Division, AEC, 12 May 1947
("Transmitted herewith for your information . . .") (ACHRE No. DOE-05 1 094-A-439),
1.
13. Note in medical chart of Cal-3, dated 18 July 1947 ("Elmer Allen chart")
(ACHRE No. DOE-05 1 094- A-6 1 5). For more information on this case, see chapter 5.
14. Wilson to Warren, 30 April 1947.
15. University of California at San Francisco, February 1995 ("Report of the
UCSF Ad Hoc Fact Finding Committee ") (ACHRE No. UCSF-022495-A-6), 27.
16. J. C. Franklin, Manager, Oak Ridge Operations, to Carroll Wilson, General
Manager, AEC, 26 September 1947 ("Medical Policy") (ACHRE No. DOE-1 13094-B-
3), 2. Although the motivation for Oak Ridge's inquiry is not entirely clear, it seems to
have come in part from concerns of Albert Holland, M.D., who became the acting
medical adviser at Oak Ridge after Major Brundage retired. Holland served on the
committee that oversaw the use of radioisotopes in human research, discussed in chapter
6. In November 1947 Holland wrote, in regard to the isotopes distribution program:
"How far does the AEC's moral responsibility extend in this program?" Albert Holland,
Jr., Medical Adviser, Oak Ridge, to J. C. Franklin, Manager of Oak Ridge Operations, 7
November 1947 ("Medical and Operational Decisions") (ACHRE No. DOE-1 13095-B-
10), 2.
1 7. Unknown author to the Advisory Committee for Biology and Medicine, 8
October 1947 ("It is the desire of the Medical Advisor's Office . . .") (ACHRE No. DOE-
05 1094-A-502).
18. Atomic Energy Commission, Advisory Committee for Biology and
Medicine, minutes of 1 1 October 1947 (ACHRE No. DOE-072694-A-1), 10.
19. Ibid.
20. Ibid.
21 . Carroll Wilson, General Manager, AEC, to Robert Stone, University of
California, 5 November 1947 ("Your letter of September 18 regarding the
declassification of biological and medical papers was read at the October 1 1 meeting of
the Advisory Committee for Biology and Medicine.") (ACHRE No. DOE-052295-A-1).
22. Carroll Wilson, General Manager, AEC, to Alan Gregg, Chairman of the
AEC Advisory Committee for Biology and Medicine, 5 November 1947 ("I want to
thank you for your letter of October 14 concerning the questions raised by Dr. Stone in
his letter to me of September 18 regarding declassification of biological and medical
papers containing information on the experimental use of radioisotopes in human beings
conducted under AEC sponsorship.") (ACHRE No. DOE-052295-A-I).
23. Salgo v. Leland Stanford Jr. University Board of Trustees, 317 P. 2d 170
(1957).
120
24. Joseph Volpe, interview by Gregg Herken, Dan Guttman, and Debra Holland
(ACHRE), transcript of audio recording, 6 October 1994 (ACHRE Research Project
Series, Interview Program Files, Targeted Interview Project), 24-42.
In a May 1995 interview, Volpe agreed that a letter written by the general
manager constituted a "policy." The transcript of the interview records:
Interviewer: . . . today there are regular procedures for getting
something recognized as a policy, including publication
and so forth. In 1947, when the general manager writes
a letter, is that a policy?
Mr. Volpe: Yes, Yes.
Mr. Volpe noted that while the question of the precise authority of the general manager
was not without controversy. Chairman Lilienthal "believed in delegation of authority
and so always took measures to strengthen the general manager's hand on these things."
Joseph Volpe, interview by Barbara Berney, Steve Klaidman, Dan Guttman, Lanny
Keller, Jonathan Moreno, Patrick Fitzgerald, and Gilbert Whittemore (ACHRE),
transcript of audio recording, 18 May 1995 (ACHRE Research Project Series, Interview
Program Files, Targeted Interview Project), 37-38.
25. Leslie M. Redman, Los Alamos Laboratory, to Dr. Alberto F. Thompson,
Chief, Technical Information Service, DBM, 22 January 1951 ("I find myself concerned
in the course of duty with the review of papers relating to human experimentation.")
(ACHRE No. DOE-051094-A-609).
26. Warren did not cite the context for Wilson's discussion of these conditions,
that is, the need for criteria for declassification.
27. Shields Warren, Director, DBM, to Leslie Redman, "D" Division, Los
Alamos National Laboratory, 5 March 1951 (". . . to reply to your letter of January 22,
1951, concerning policies on human experimentation.") (ACHRE No. DOE-051094-A-
603).
28. Everett Idris Evans, M.D., Medical College of Virginia, to John Z. Bowers,
M.D., Assistant to the Director, DBM, AEC, 8 April 1948 ("We have recently obtained
approval from the Isotopes Division for human use of P 32 . . .") (ACHRE No. DOE-
051094-A-64).
29. John Z. Bowers, Assistant to Director, DBM, AEC, to Everett Idris Evans,
M.D., Medical College of Virginia, 27 April 1948 ("Thank you for recent letter
requesting information regarding isotopes.") (ACHRE No. DOE-050194-A-480).
30. Nathan H. Woodruff, Chief Technical Division, Isotopes Division, to Everett
I. Evans, M.D., Medical College of Virginia, 14 May 1948 ("Your letter of April 8 to Dr.
Bowers has been referred to me for answer.") (ACHRE No. NARA-082294-A-10).
3 1 . U.S. Atomic Energy Commission, Advisory Committee for Biology and
Medicine, agenda of 14 February 1948 (ACHRE No. DOE-072694-A), 2.
32. In addition to the document discussed above, there is some indication that
the AEC Isotopes Division was charged with ensuring that consent was obtained. In the
early 1970s, when the AEC conducted an investigation into the plutonium experiments.
Shields Warren told the investigators that his recollection was that ethical issues were
addressed at the time by the issuance of prospective policies. Warren stated:
I think the way it [concern about the plutonium
121
injections] was handled was that Alan Gregg and 1
agreed the best way to do [it] was to see that the rules
were properly drawn up by the . . . Human Applications
Isotope Committee, which had then come into being, so
that use without full safeguards could not occur, and that
we saw no point in bringing this up after the fact as long
as we were sure that nothing of this sort could happen in
the future.
Shields Warren, interview by L. A. Miazga, Sidney Marks, Walter Weyzen (AEC),
transcript of audio recording, 9 April 1974, 10-11 (ACHRE No. DOE-121294-D-14).
33. Unknown author, unpublished draft, 29 March 1948 ("The Experimental
Use of Radioactive Materials in Human Subjects at AEC Establishments") (ACHRE No.
DOE-050194-A-267).
34. Subcommittee on Human Applications, minutes of 22-23 March 1948, as
discussed in the minutes of the 13 March 1949 meeting. S. Allan Lough, Chief,
Radioisotopes Branch, to H. L. Friedell, G. Failla, J. G. Hamilton, and A. H. Holland, 19
July 1949 ("Revised Tentative Minutes of March 13, 1949 Meeting of the Subcommittee
on Human Applications of Committee of U.S. Atomic Energy Commission, AEC
Building, Washington, DC") (ACHRE No. DOE-101 194-A-13), 5.
35. The subcommittee was not definitive about when larger doses were
permitted, however. The policy was to apply in "instances in which the disease from
which a patient is suffering permits the administration of larger doses for investigative
purposes." U.S. Atomic Energy Commission, Isotopes Division, September 1949
("Supplement No. 1 to Catalogue and Price List No. 3, July 1949") (ACHRE No. DOD-
122794-A-l), 3-4.
36. While these statements were perhaps more than was told to patient-subjects
in other institutions, they did not necessarily provide details about the research. In the
application for admission, the applicant agreed to "such operations and biopsies as are
deemed necessary and advisable by the hospital." Oak Ridge Institute of Nuclear
Studies, 1950 ("Application for Admission to the Medical Division Hospital") (ACHRE
No. DOE-121494-C-1), 1.
Upon admission, the applicant was required to sign a "Waiver and Release" that
did not describe the treatment, but included a lengthy release from the patient, the
patient's "heirs, executors, administrators, and assigns," for any "causes of action, claims,
demands, damages, loss, costs, and expenses, whether direct or consequential," associated
with or resulting from the care of the hospital. This form notes that the hospital has
described the "character and kind of treatment." Oak Ridge Institute of Nuclear Studies,
1950 ("Waiver and Release") (ACHRE No. DOE-121494-C-3), 1.
37. Oak Ridge Institute for Nuclear Studies, 1950 ("Waiver and Release")
(ACHRE No. DOE-121494-C-3).
38. Program Committee of the Division of Biological and Medical Research of
the Argonne National Laboratory, minutes of 22 January 1951 (ACHRE No. DOE-
051095-B), 3.
39. Thomas Shipman, M.D., Health Division Leader, Los Alamos Laboratory,
AEC, to Dr. Charles Dunham, Director, DBM, AEC, 18 June 1956 ("Two questions have
recently arisen— one of them specific, the other general— wherein we need an opinion
from you.") (ACHRE No. DOE-091994-B-1).
122
40. Charles Dunham, Director, DBM, AEC, to Thomas Shipman, Health
Division Leader, Los Alamos Laboratory, 5 July 1956 ("This is in response to your letter
of June 18.") (ACHRE No. DOE-091994-B-2). In addition to consent, Dunham indicated
that the research should proceed so long as (a) the doses were small, "true tracer doses";
(b) the proposal was approved by a senior medical officer; and (c) the work was
supervised by a licensed physician.
41. T. L. Shipman, Health Division Leader, Los Alamos Laboratory, to Staff
Distribution, 12 July 1956 ("Administration of Tracer Doses to Humans") (ACHRE No.
DOE-091994-B-3), 1. Also, T. L. Shipman, Health Division Leader, Los Alamos
Laboratory, to "Distribution," 3 September 1963 ("Administration of Tracer Doses to
Humans For Experimental Purposes") (ACHRE No. DOE-091994-B-4), 1.
42. Isotopes Extension, Division of Civilian Application, U.S. AEC, "The
Medical Uses of Radioisotopes, Recommendations and Requirements of the Atomic
Energy Commission" (Oak Ridge, Tenn.: AEC, Februaiy 1956), 15.
43. U.S. Department of the Army, AR 40-210, The Prevention of Communicable
Diseases of Man— General (21 April 1925).
44. Charles W. Shilling, Medical Corps, USN. Retired, undated paper ("History
of the Research Division, Bureau of Medicine and Surgery, USN") (ACHRE No. DOD-
080295-A), 74.
45. The Secretary of the Navy to All Ships and Stations, 7 April 1943
("Unauthorized Medical Experimentation on Service Personnel") (ACHRE No. DOD-
091494-A-2).
46. J. E. Moore, M.D., to Dr. A. N. Richards, excerpt of letter dated 6 October
1942 ("I have recently received an inquiry from Dr. Charles M. Carpenter of the
University of Rochester School of Medicine who believes that he may be able to work
out a human experiment on the chemical prophylaxis of gonorrhea.") (ACHRE No.
NARA-060794-A-1).
47. A. N. Richards to J. E. Moore, 31 October 1942 (" Revision of Dr. Richards'
letter of October 9, 1942") (ACHRE No. NARA-060794-A-1 ). Stafford Warren, the
Manhattan Project medical director, also came from the University of Rochester. It is not
clear how, if at all, the CMR's views on human experiments were accounted for in
Manhattan Project research.
48. Rothman, Strangers at the Bedside, 30-50.
49. The Chief of the Bureau of Medicine and Surgery to the Officer-in-Charge,
Naval Laboratory Research Unit No. 1, University of California, Berkeley, California, 6
March 1943 ("Proposed Clinical Evaluation of Influenza Antiserum, and Messages
concerning Influenza Virus Specimens") (ACHRE No. DOD-062194-C-1).
50. Ibid., 2.
51. Institute of Medicine, National Academy of Sciences, Veterans at Risk: The
Health Effects of Mustard Gas and Lewisite (Washington, D.C.: National Academy
Press, 1993), 66-69.
52. Ibid., 214.
53. Robert S. Stone, unpublished paper, "Irradiation of Human Subjects as a
Medical Experiment," 31 January 1950 (ACHRE No. NARA-070794-A).
54. American Medical Association, Judicial Council, "Supplementary Report of
the Judicial Council," Journal of the American Medical Association 132 (1946): 1090.
55. The Under Secretary of the Navy to the Secretary of Defense, 24 April 1950
("Recommendation that the Armed Service conduct experiments on human subjects to
123
determine effects of radiation exposure") (ACHRE No. NARA-070794-A).
56. Atomic Energy Commission, Advisory Committee for Biology and
Medicine, transcript (partial) of meeting, 10 November 1950 (ACHRE No. DOE-0 12795-
C-l), 28.
57. Ibid., 28-29.
58. J. G. Hamilton, University of California, to Shields Warren, DBM, AEC, 28
November 1950 ("Unfortunately, it will not be possible for me to be at the meeting on
December 8 . . .") (ACHRE No. DOE-072694-B-45), 1.
59. Ibid.
60. Adam J. Rapalski, Administrator, the Armed Forces Epidemiological Board,
DOD, to Chief, Legal Office, 5 January 1952 ("Draft of 'Agreement with Volunteer'")
(ACHRE No. DOD-040895-A).
61. Lieutenant Colonel Robert J. O'Connor, Chief, Legal Officer, JAGD, to
Colonel Frank L. Baier, Army Medical Research and Development, 23 October 1947
("Protection of Research Project Volunteers") (ACHRE No. NARA-012395-A-4).
62. John R. Paul, Director, AEB, DOD, to Dr. Joseph Stokes, Jr., Children's
Hospital, Philadelphia, Pennsylvania, 18 February 1948 ("This is in reply to your hand
written request for a comment [from] me re your letter to Dr. Macleod dated 1 1 February
on the subject of funds for the reimbursement of volunteer prisoners . . .") (ACHRE No.
NARA-012395-A-1).
63. Ibid.
64. Committee Appointed by Governor Dwight H. Green of Illinois, "Ethics
Governing the Service of Prisoners As Subjects In Medical Experiments," Journal of the
American Medical Association 136, no. 7 (1948): 457-458.
65. C. J. Watson, M.D., Commission on Liver Disease, Army Epidemiological
Board, to Colin MacLeod, President of the Board, AEB, 5 April 1948 ("I have given
considerations in the past few weeks to the matter of using volunteers in penal
institutions for experimentation . . .") (ACHRE No. NARA-012395-A-2).
66. Ibid.
67. "Prisoner Dies After Injection in Disease Study," Washington Post, 6 May
1952,3.
68. L. M. Harff, Contract Insurance Branch, to File, 25 April 1952 ("Research
and Development Contracts-Medical Investigations) (ACHRE No. DOD-012295-A).
69. Adam J. Rapalski, Administrator, AEB, to Chief Legal Office, 14 October
1952 ("Applicability of Section 5, Public Law 557-82d Congress") (ACHRE No. NARA-
012395-A).
70. Adam J. Rapalski, Administrator, AEB, to Members of the AEB, undated
memorandum ("Applicability of Section 5, Public Law 557-82nd Congress") (ACHRE
No. NARA-012395-A). In congressional hearings, the activities used to illustrate the
purpose of the indemnification provision included test piloting, damage that might be
caused by cloud modification research, and cataracts caused by the operation of a
cyclotron. In addition, however, biomedical human experimentation was specifically
addressed in the following exchange between Representative Edward Hebert and Colonel
W. S. Triplet, from the Army Research and Development Division:
Mr. Hebert. Colonel, would you expand on the proposal to make
the Government liable for losses and damages? . . .
124
Colonel Triplet. There have been some experiments or types of
research in the past which would have come under section 5 [the
indemnification provision]. There are more coming up in the
future. One of the early cases, long before the time of the bill, I
would cite as an example is Dr. Reed in Cuba in 1900 utilized
the services of 21 volunteers to study yellow fever, an extremely
dangerous experiment. Two of these volunteers died. Eighteen
of the others became seriously ill. As a result a special medal
was awarded these people by Congress. That is an example of
the type of experiment that at the present time is going on in the
medical service.
Subcommittee Hearings on H. R. 1 1 80 to Facilitate the Performance of Research and
Development Work by and on Behalf of the Departments of the Army, the Navy, and the
Air Force, and for Other Purposes; House of Representatives, Committee on Armed
Services, Subcommittee no. 3, 6 June 1952, 621 (ACHRE No. NARA-10495-D).
71. Colonel George V. Underwood, Director, Executive Office, Office of the
Secretary of Defense, to Mr. Kyes, Deputy Secretary of Defense, 5 February 1953 ("Use
of Human Volunteers in Experimental Research") (ACHRE No. DOD-062194-A).
72. Melvin Casberg, Chairman, AFMPC, to the Secretary of Defense, 24
December 1952 ("Human Volunteers in Experimental Research") (ACHRE No. NARA-
101294-A-3).
73. Ibid.
74. Jackson recommended changes to the Nuremberg Code: the elimination of
the Nuremberg Code exception for self-experimentation by physicians and the express
provision that prisoners, but not prisoners of war, could be used. We do not know what
Jackson had "previously submitted." See Stephen Jackson, Assistant General Counsel in
the Office of the Secretary of Defense and Counsel for the AFMPC, to Melvin Casberg,
undated memorandum ("The standards and requirements to be followed in human
experimentation") (ACHRE No. NARA-101294-A-3).
75. Ms. Rosenberg, a high-ranking official in the DOD, was an expert in labor
relations and a New Dealer. Her role was recorded in Stephen Jackson to Melvin
Casberg, Chairman, AFMPC, 22 October 1952 ("I discussed the attached with Mrs.
Rosenberg . . .") (ACHRE No. NARA-101294-A-3).
76. Colonel Adam J. Rapalski, Administrator, Armed Forces Epidemiological
Board, DOD, to Colin MacCleod, President, Armed Forces Epidemiological Board,
DOD, 2 March 1953 ("The attached copy of letter I believe is self-explanatory.")
(ACHRE No. NARA-012395-A-5).
77. F. Lloyd Mussells, Executive Director, Committee on Medical Sciences,
RDB, DOD, to Floyd L. Miller, Vice Chairman, Research and Development Board,
DOD, 12 November 1952 ("Human Experimentation") (ACHRE No. NARA-071 194-A-
2).
78. Ibid.
79. In a 10 November 1952 meeting the Committee on Chemical Warfare was
read a draft of the AFMPC policy. One member remarked to general laughter: "If they
can get any volunteers after that I'm all in favor of it." Committee on Chemical Warfare,
RDB, DOD, transcript of the meeting of 10 November 1952 (ACHRE No. NARA-
102594-A), 128. H. N. Worthley, Executive Director, Committee on Chemical Warfare,
RDB, DOD, to the Director of Administration, Office of the Secretary of Defense, 9
125
December 1952 ("Use of Volunteers in Experimental Research") (ACHRE No. NARA-
101 294- A), 1.
80. This, at least, was the 1994 recollection of Lovett's military assistant.
General Carey Randall, who served in the same role for Lovett's predecessor and
successor. General Carey Randall, interview by Lanny Keller (ACHRE), transcript of
audio recording, 20 September 1994 (ACHRE Research Project Series, Interview
Program File, Targeted Interview Project), 17.
81 . George V. Underwood, Director of the Executive Office of the Secretary of
Defense, to Deputy Secretary of Defense Foster, 4 January 1953 ("I believe that Mr.
Lovett has a considerable awareness of this proposed policy.") (ACHRE No. NARA-
101294-A-l), 1.
82. Melvin A. Casberg, Chairman, Armed Forces Medical Policy Council, DOD,
to the Secretary of Defense, 13 January 1953 ("Digest 'Use of Human Volunteers in
Experimental Research"') (ACHRE No. DOD-042595-A), 1.
83. Secretary of Defense to the Secretary of the Army, Secretary of the Navy,
Secretary of the Air Force, 26 February 1953 ("Use of Human Volunteers in
Experimental Research") (ACHRE No. DOD-082394-A). The second paragraph of the
memorandum stipulates its application to "Armed Services personnel and/or civilians on
duty at installations engaged in such research. . . ." The Advisory Committee takes this
stipulation to be in recognition of the separate authority of the medical services, as
distinct from research and development commands.
84. W. G. Lalor. Secretary, Joint Chiefs of Staff, to Chief of Staff, U.S. Army,
Chief of Naval Operations, Chief of Staff, U.S. Air Force, 3 September 1952 ("Security
Measures on Chemical Warfare and Biological Warfare") (ACHRE No. NARA-0 12495-
A-l).
85. Irving L. Branch, Colonel, USAF, Acting Chief of Staff, to the Assistant
Secretary of Defense (Health and Medicine), 3 March 1954 ("Status of Human
Volunteers in Bio-medical Experimentation") (ACHRE No. DOD-090994-C), 2.
86. Ibid.. 3.
87. Ibid.
88. Brigadier General John C. Oakes, GS, Secretary of the General Staff,
Department of the Army, to the Chief Chemical Officer and the Surgeon General, 30
June 1953 ("CS:385-Use of Volunteers in Research") (ACHRE No. DOD-022295-B-1)
(CS385). This document was originally classified as Top Secret then downgraded to
Confidential and declassified in June 1954. "Research Report Concerning the Use of
Volunteers in Chemical Agent Research." Inspector General and Auditor General, 1975
(Army IG report), 77.
89. Oakes, sec. 3(a).
90. A series of memorandums from the Office of the Judge Advocate General
preceded and shed light on the 30 June 1953 memorandum:
Colonel Robert H. McCaw, JAGC, Chief, Military Affairs Division, to the Chief,
Research and Development, Office of the Chief of Staff, 6 April 1953 ("Volunteers for
Biological Warfare Research") (ACHRE No. DOD-082294-B).
Colonel Robert H. McCaw, JAGC, Chief, Military Affairs Division, to the Chief,
Research and Development, Office of the Chief of Staff, 10 April 1953 ("Volunteers for
Biological Warfare Research") (ACHRE No. DOD-082294-B).
126
Colonel A. W. Betts, GS, Executive for the Chief of Research and Development, to
Mr. J. N. Davis, Office of the Under Secretary of the Army, 15 April 1953 ("Use of
Volunteers in Experimental Research") (ACHRE No. DOD-082294-B).
91. CS:385, sec. 3(d).
92. Army Office of the Surgeon General, 12 March 1954 ("Use of Volunteers in
Medical Research, Principles, Policies, and Rules of the Office of the Surgeon General")
(ACHRE No. DOD-1 20694- A-4).
93. Ibid., 1 . A copy of this document was found in the files of John Enders,
Ph.D., Nobel Laureate in Medicine and Physiology, 1954, Yale University.
94. Ibid.
95. John Fox, M.D., Professor of Epidemiology, Tulane University School of
Medicine, to Captain R. W. Babione, Executive Secretary, AFEB, 27 June 1956 ("Finally
I am able to complete and send to you the application for a research contract to study . . .
") (ACHRE No. NARA-012395-A).
96. Ibid.
97. W. McD. Hammon, M.D., Director, Commission on Viral Infections, AFEB,
to John Enders, Children's Medical Center, 20 November 1958 ("This is to confirm our
telephone call this morning, November 20th, regarding approval of the AFEB for the
protocol of the experiment which you propose to carry out . . .") (ACHRE No. NARA-
032495-B), 1.
98. Max H. Brown, Contracting Officer, to Vice Chancellor, Schools of the
Health Professions, University of Pittsburgh, 12 March 1957 ("This is in reply to letter . .
.") (ACHRE No. DOD NARA-012395-A-6) The DOD has not located the Pittsburgh
contract itself, which may have been long since routinely destroyed; therefore, it cannot
be said for certain that the 1 954 surgeon general provisions were made a contract
requirement.
99. Herbert L. Ley to Colonel Howie, 8 January 1969 ("Review of Department
of the Army Policy on Use of Human Subjects in Research") (ACHRE No. DOD-
063094-A).
100. Max H. Brown to Contracting Officer, OTSG, 5 August 1957 ("The Use of
Human Test Subjects in Medical Research Supported by the Office of the Surgeon
General") (ACHRE No. NARA-012395-A).
101. Donald L. Howie, Assistant Chief, Medical Research, 10 July 1962
("Memorandum for the Record, Use of Volunteers for Army Medical Research")
(ACHRE No. DOD-1 20694- A-3). It is worth noting that prior to this memorandum, in
March 1 962, the Army promulgated its first regulation specifically directed to the
conduct of clinical research. This regulation (AR 70-25, 26 March 1962) specifically
exempted "clinical research," which apparently included research conducted on patients.
See chapter 3.
102. Army IG report, 1975.
103. Department of the Navy, Bureau of Medicine and Surgery, "Manual of the
Medical Department," sec. IV, research article 1-17 (26 September 1951).
104. On the question of written documentation, interestingly, the manual
stipulated: "[Vjolunteers" should not "execute a release for future liability for negligence
attributable to the Navy," but the manual required that a statement be "entered into the
Individual's Health Record" indicating the project number and the physical and
psychological effects, or lack of same, resulting from the investigation. "Manual of the
Medical Department," sec. IV, art. 1-17.
127
105. Ibid.
106. Loren B. Poush, Code 1 1, USN, to Code 74, USN (Bureau of Medicine and
Surgery), 18 October 1951 ("Legal comments relative to proposed means of proper
authorization and safeguard in use of radioisotopes") (ACHRE No. NARA-070794-A-4).
107. Code 74, USN, to Code 1 1, USN, 18 September 1951 ("Proposed Means
of Proper Authorization and Use of Radioisotopes") (ACHRE No. NARA-070794-A-4)
2.
108. Paul O. Wells, Chief, Radiological Service, Letterman Army Hospital, to
Elmer A. Lodmell, Chief, Radiological Service, Walter Reed Army Hospital, 14 January
1955 ("I am writing this letter at the suggestion of General Gillespie after having
discussed with him the matter of requiring patients to sign a permit for radioisotope
therapy.") (ACHRE No. DOD-012295-A).
109. Standard Form 522 (SF-522), "Clinical Record-Authorization for
Administration of Anesthesia and Performance of Operations and Other Procedures," was
proposed for use "in those instances when authorization for administration of
radioisotope therapy is desired." Eugene L. Hamilton, Chief, Medical Statistics Division,
to the Chiefs of the Medical Plans and Operations Division and the Legal Office, 3
August 1955 ("Permit for Radioisotope Therapy") (ACHRE No. DOD-012295-A).
In response to an inquiry from Walter Reed Army Hospital concerning the use of
consent forms for patients, the Medical Statistics Division, recommending the use of SF-
522, indicated that consent should be obtained when a procedure "carries an unusual
risk." Additionally, the Medical Statistics Division recommended that patients should be
"counselled as to the nature, expected results of, and risks involved in procedures."
Eugene L. Hamilton, Chief, Medical Statistics Division, to the Chiefs of the Professional
Division, Medical Plans and Operations Division, and the Legal Office, undated
memorandum (probably November 1956) ("Forms for Authorization of Radiation
Therapy") (ACHRE No. DOD-012295-A).
110. U.S. Air Force, Research and Development, "Clinical Research," AFR 80-
22(11 July 1952).
111. The Deputy Commander for Research and Development of the Air Force
R&D Command to RADC, WADC, APGC, AFCRC, AFSWC, AFMTC, AFMDC,
AFFTC, AFBMD (ARDC), AFOSR, 12 September 1958 ("Conduct of Hazardous
Human Experiments") (ACHRE No. HHS-090794-A).
112. Richard R. Taylor, Surgeon General of the Department of the Army,
testimony before the Subcommittee on Administrative Practice and Procedure of the
Judiciary Committee and the Subcommittee on Health of the Labor and Public Welfare
Committee, U.S. Senate, 94th Cong., 1st Sess., 10 September 1975 (ACHRE No. DOD-
063094-A), 1.
See also, U.S. Army Inspector General, Use of Volunteers in Chemical Agent
Research (Washington D.C.: GPO, 1975), 77.
1 13. Charles V. Kidd, Director, Research and Planning Division, NIH, to Rear
Admiral Winfred Dana, Medical Corps, USN, 30 April 1952 ("In accordance with our
telephone conversation of this afternoon I am enclosing a copy of draft statement which
we have developed.") (ACHRE No. DOD-1 1 1594-A), 2-3. The context of this statement
is not known. Perhaps it was formulated in response to an inquiry from the DOD about
the NIH's research requirements during the discussions that led to the drafting of the
Wilson memorandum.
128
1 14. National Institutes of Health, 17 November 1953 ("Group Consideration of
Clinical Research Procedures Deviating from Accepted Medical Practice or Involving
Unusual Hazard") (ACHRE No. HHS-090794-A), 4.
115. Director, N1H, to Institute Directors, 15 November 1954 ("Participation by
NIH Employees as Normal Controls in Clinical Research Projects") (ACHRE No. HHS-
090794-A), 1. Although this memorandum referred only to NIH employees, Advisory
Committee' staff and NIH staff have concluded it applied to all healthy volunteer subjects.
116. National Institutes of Health, policy statement of 17 November 1953
("Group Consideration of Clinical Research Procedures Deviating From Accepted
Medical Practice Or Involving Unusual Hazard") (ACHRE No. HHS-090794-A).
117. Edward J. Rourke, Legal Adviser, NIH, to Mr. John A. Trautman, Director,
Clinical Center, 5 December 1952 ("At your invitation, I presented to the Medical Board
of the Clinical Center on December 2 a proposal that, in view of several factors in some
degree peculiar to the Clinical Center, it would be advisable from the legal point of view
among others to accept certain procedures relating to patient admission that are more
formal than might otherwise be considered necessary") (ACHRE No. DOD-1 1 1 594- A),
1.
118. Ibid.
119. For a more detailed review of this history see Faden and Beauchamp, A
Histoiy and Theoiy of Informed Consent, and Frankel, "Public Policymaking for
Biomedical Research: The Case of Human Experimentation."
120. George M. Lyon, M.D., Assistant Chief Medical Director for Research and
Education, presentation to the Committee on Veterans Medical Problems, National
Research Council, 8 December 1952 ("Appendix II, Medical Research Programs of the
Veterans Administration") (ACHRE No. VA-052595-A).
121. Ibid., 558.
122. Guy H. Birdsall, General Counsel, Veterans Administration, to Chief
Medical Director, 25 June 1958, ("Op. G.C. 28-58, Legal Aspects of Medical Research")
(ACHRE No. VA-052595-A).
129
Postwar Professional
Standards and Practices for
Human Experiments
In chapter 1, we explored government discussions of research involving
human subjects in the 1940s and 1950s. We found that, at several junctures,
government officials exhibited an awareness of the Nuremberg Code, the product
of an international war crimes tribunal in 1947. If a requirement of voluntary
consent of the subject was endorsed by the Nuremberg judges and was recognized
at the highest reaches of the new Cold War bureaucracy, then how, a citizen
might now ask, could there be any question about the use of this standard to judge
experiments conducted during this time in the United States? And yet precisely
this question has been raised in connection with human radiation experiments.
Did American medical scientists routinely obtain consent from their subjects in
the 1940s and 1950s, including those who were patients, and if not, how did these
scientists square their conduct with the demands of the Nuremberg Code?
This chapter describes the Advisory Committee's efforts to answer these
questions and what we learned. We begin with an examination of what, in fact,
was argued at Nuremberg. We focus particularly on the testimony of Andrew
Ivy, the American Medical Association's (AMA) official consultant to the
Nuremberg prosecutors, and on the AMA's response to the report Dr. Ivy
prepared about the trial for the organization.
We turn next to an analysis of the actual practices of American medical
scientists during this period. In addition to reviewing contemporary
documentation and present-day scholarship, the Advisory Committee conducted
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Chapter 2
interviews with leading medical scientists and physicians who were engaged in
research with human subjects in the 1940s and 1950s. These sources suggest a
different, more nuanced picture of the principles and practices of human research
than that presented at Nuremberg.
Of particular importance in this picture are the practical and moral
distinctions that many researchers made between investigations with healthy
subjects and those with sick patients. Those working with healthy subjects could
cite a tradition of consent that dated, at least, to Walter Reed's turn-of-the-century
experiments; those working with sick patients were in a clinical context that was
conditioned by a tradition of faith in the wisdom and beneficence of physicians, a
tradition that was dominant until at least the 1 970s. Closely related to these
distinctions was the tension between being a scientist and being a physician. This
tension confronted members of a new, and rapidly growing, breed of medical
professionals in the United States working to make careers in clinical research.
The chapter goes on to explore whether these distinctions and tensions were
reflected in the Nuremberg Code and why the trial may not have had much impact
on the treatment of patient-subjects.
The rest of the chapter explores the emerging awareness of the moral
complexities of research at the bedside and the limitations of the Nuremberg Code
to address them. We close with a brief discussion of the Declaration of Helsinki,
the international medical community's attempt to produce a code of conduct
compatible with the realities of medical research.
THE AMERICAN EXPERT, THE AMERICAN MEDICAL
ASSOCIATION, AND THE NUREMBERG MEDICAL TRIAL
In the fall of 1943, the United States, Great Britain, and the Soviet Union
agreed that, once victorious, they would prosecute individuals among the enemy
who might have violated international law during the war. On August 8, 1945--
exactly three months after V.E. Day and two days after the bombing of
Hiroshima-representatives of the American, British, French, and Soviet
governments officially established the International Military Tribunal in
Nuremberg, Germany. An assemblage of Allied prosecutors presented cases
against twenty-four high-ranking German government and military officials,
including Hermann Goering and Rudolph Hess, before this international panel of
judges. Quite early in the course of these initial Nuremberg trials, which ran from
October 1945 to October 1946, "it became apparent," according to the recent
recollections of American prosecutor Telford Taylor, "that the evidence had
disclosed numerous important Nazis, military leaders, and others" who should
also be tried.' In January 1946, President Harry Truman approved a
supplementary series of war crimes trials. These trials were to take place in the
same Nuremberg courtroom, and international law would continue to be the
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Parti
standard by which guilt or innocence would be determined. America's wartime
allies would not, however, participate; responsibility for prosecuting and judging
defendants in the second set of Nuremberg trials was left exclusively to the
United States.
The first of twelve cases that would eventually make up this second series
of trials in Nuremberg is technically called United States v. Karl Brandt et al.
More popularly, this trial is known by a variety of other names such as "The
Doctors' Trial" and "The Medical Case." For the sake of convenience and
consistency we will refer to the trial by another common name: the Nuremberg
Medical Trial. This case began on December 9, 1946, when U.S. Chief of
Counsel for War Crimes Telford Taylor delivered the prosecution's opening
statement against the twenty-three defendants (twenty of whom were physicians).
To one degree or another, Taylor charged the defendants with "murders, tortures,
and other atrocities committed in the name of medical science." The trial ended in
late August 1947 when the judges handed down a ruling that included the so-
called Nuremberg Code and seven death sentences. 2
In the spring of 1946, the American prosecution team preparing for the
Medical Trial, which was made up of lawyers commissioned in the Army, cabled
Secretary of War Robert P. Patterson with a request for a medical expert.
Patterson consulted with Army Surgeon General Norman T. Kirk, who suggested
turning to the American Medical Association. Kirk contacted the AMA, and,
after some internal consultation, the association's Board of Trustees voted in May
1946 to appoint Dr. Andrew C. Ivy as the AMA's official consultant to the
Nuremberg prosecutors. 3 Dr. Ivy was one of America's leading medical
researchers at the time. Early in the war, Ivy was the civilian scientific director of
the Naval Medical Research Institute in Bethesda, Maryland. 4 During the
summer of 1946, he was in the process of moving from a position as head of the
Division of Physiology and Pharmacology at Northwestern University Medical
School to the University of Illinois, where he would serve as a vice president with
responsibility for the university's professional schools in Chicago.
The precise rationale behind Ivy's selection as the AMA's adviser to the
Nuremberg prosecutors remains unclear, but it is likely that the AMA turned to
Ivy for at least two reasons. First, his wartime research interests corresponded in
topic, though not in style, to some of the most shocking experiments that had
taken place in the Nazi concentration camps. Ivy supervised and carried out
experiments in seawater desalination, sometimes using human subjects, with the
intent of developing techniques to aid Allied pilots and sailors lost at sea. He also
conducted some pioneering human experiments in aviation medicine dealing with
the physiological challenges posed by high altitudes. These are two of the areas
in which Nazi researchers had conducted especially gruesome human
experiments. Second, Ivy was well known for his energetic defense of animal
experimentation against American antivivisectionists. For example, he served for
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Chapter 2
eight years as the founding secretary-treasurer of the National Society for Medical
Research, an organization formed by scientists in 1946 to ward off challenges to
medical research posed by antivivisectionists. It seems likely that the AMA
Board of Trustees would have recognized Ivy as someone who possessed an
unusual combination of familiarity with the scientific aspects of experiments
carried out in the concentration camps and broad understanding of the moral
issues at stake in medical research, whether the experimental subjects were
animals or humans. Also, Ivy was almost certainly perceived as someone who
could be trusted to look out for the interests of the American medical research
community during the Nuremberg Medical Trial. The AMA Board of Trustees
probably realized that the entire enterprise of medical research would, to some
degree, be on trial in Germany.
In July or early August of 1946, Ivy went to Germany to meet with the
Nuremberg prosecution team. Ivy offered technical assistance to the lawyers
struggling with the scientific details of the experiments, but he also recognized, as
he put it, that the prosecutors "appeared somewhat confused regarding the ethical
and legal aspects" of human experimentation. 5
After returning from his initial trip to Europe in aid of the Nuremberg
prosecutors, Ivy offered a preliminary oral report to the Board of Trustees of the
American Medical Association at the board's August 1946 meeting. After his
presentation, the trustees asked Ivy to provide a written summary of his findings,
so that the AMA's Judicial Council (a committee of five whose duties included
deliberating on matters of medical ethics) could "make a report as to the manner
in which these [Nazi] experiments [were] infringements of medical ethics." 6
In mid-September, Ivy submitted a written report to the AMA as he had
been directed. 7 At roughly the same time, he also turned over a copy of the
twenty-two-page typescript to the Nuremberg prosecution team. In this piece, Ivy
laid out "the rules" of human experimentation. He stated without equivocation
that these standards had been "well established by custom, social usage and the
ethics of medical conduct." Ivy's rules read as follows:
1 . Consent of the human subject must be obtained.
All subjects must have been volunteers in the
absence of coercion in any form. Before
volunteering the subjects have been informed of the
hazards, if any. (In the U.S.A. during War, accident
insurance against the remote chance of injury,
disability and death was provided. [This was not
true in all cases.])
2. The experiment to be performed must be so
designed and based on the results of animal
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Parti
experimentation and a knowledge of the natural
history of the disease under study that the
anticipated results will justify the performance of
the experiment. That is, the experiment must be
such as to yield results for the good of society
unprocurable by other methods of study and must
not be random and unnecessary in nature.
3. The experiment must be conducted
(a) only by scientifically qualified persons, and
(b) so as to avoid all unnecessary physical and mental
suffering and injury, and
(c) so, that, on the basis of the results of previous
adequate animal experimentation, there is no a priori
reason to believe that death or disabling injury will occur,
except in such experiments as those on Yellow Fever where
the experimenters serve as subjects along with non-
scientific personnel. 8
A comparison of these rules with the Nuremberg Code, which the
Nuremberg Tribunal issued as part of its judgment on August 19, 1947, reveals
that the three judges extracted important elements of clause 1 from Ivy's first rule
and clauses 2, 3, 4, 5, and 8 almost verbatim from the rest of Ivy's formulation.
Significantly, the judges also reiterated Ivy's assertion that these rules were
already widely understood and followed by medical researchers. 9
It is possible that the Nuremberg judges never read Ivy's report directly.
During his testimony at the trial, Ivy essentially read his set of rules into the court
record. 10 Also, the judges could have gained exposure to Ivy's thinking through
two additional indirect sources. First, another medical expert who aided the
prosecution, an American Army psychiatrist named Leo Alexander, submitted on
April 15, 1947, a memorandum to the prosecutors entitled "Ethical and Non-
Ethical Experimentation on Human Beings." In this memorandum, which would
have been passed to the judges, Alexander repeated in very similar language
significant portions of Ivy's rules as outlined in the September 1946 report."
Second, American prosecutor James McHaney closely followed the text of Ivy's
rules when setting before the judges the "prerequisites to a permissible medical
experiment on human beings" during the prosecution's closing statement on July
14, 1947. 12
But Ivy's standards for human experimentation served as even more than
the primary textual foundation for the Nuremberg Code; his set of rules also
undergirded the AMA's first formal statement on human experimentation. As the
Board of Trustees had directed when asking Ivy to prepare his written report, the
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Chapter 2
finished document was immediately forwarded to the AMA Judicial Council.
The board gave the Judicial Council three months to prepare a presentation for the
House of Delegates, the large policy-making body of the AMA that was
scheduled to hold an annual meeting in early December 1946. 13 Unfortunately,
records of the Judicial Council's consideration of Ivy's report have not survived,
but published proceedings of the House of Delegates meeting reveal the results of
the council's deliberations. 14 Dr. E. R. Cunniffe, chair of the Judicial Council,
summarized his panel's response to Ivy's report at an executive session of the
House of Delegates on December 10, 1946 (the day immediately following the
prosecution's opening statement in the Nuremberg Medical Trial). Cunniffe
condemned the Nazi experiments described in Ivy's report as gross violations of
standards that were already inherent in the existing "Principles of Medical Ethics
of the American Medical Association," which had undergone only minor revision
since the AMA adopted them in 1847, the first year of the association's existence.
But in recognition of the fact that guidelines for human experimentation were not
explicitly laid out in these "Principles," the Judicial Council offered the following
distillation of Ivy's rules:
In order to conform to the ethics of the American
Medical Association, three requirements must be
satisfied: (1) the voluntary consent of the person on
whom the experiment is to be performed [must be
obtained]; (2) the danger of each experiment must
be previously investigated by animal
experimentation, and (3) the experiment must be
performed under proper medical protection and
management. 15
These three rules became the official policy of the AMA when the House
of Delegates voted its approval "section by section and as a whole" on the
morning of December 1 1, 1946. The AMA's official governing body also added a
general admonition: "This House of Delegates condemns any other manner of
experimentation on human beings than that mentioned herein." 16 It is worth
noting that in 1946 roughly 70 percent of American physicians belonged to the
AMA. In absolute terms, 126,835 physicians belonged to the association, but it
must be acknowledged that membership in the national association came
automatically with membership in county and state medical societies, which was
often necessary for professional privileges at local hospitals. 17 Each member of
the AMA would have received a regular subscription to the Journal of the
American Medical Association, and all of these subscribers would have had an
opportunity to read the three rules for human experimentation approved by the
House of Delegates. At the same time, however, these rules were not published
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Parti
prominently; they were set in small type along with a variety of other
miscellaneous business items in the lengthy published minutes of the meeting.
Only an exceptionally diligent member, or one with a special interest in medical
ethics, is likely to have located this item.
In mid-June 1947, Ivy took the stand late in the Nuremberg Medical Trial
as a rebuttal witness for the prosecution to counter the claims of the defense that
standards for proper conduct in human experimentation had not been clearly
established before the initiation of the trial. The contents of Ivy's September 1946
report, and the AMA standards that arose from it, played a major role during his
three days of testimony. At one point, prosecution associate counsel Alexander
G. Hardy carefully walked Ivy through a verbatim oral recitation of the rules for
human experimentation contained in Ivy's report and the condensed version of his
rules as approved by the AMA. After a reading of the AMA principles, Hardy
and Ivy had the following exchange:
Q. . . . Now, [do these rules] purport to be the principles
upon which all physicians and scientists guide themselves
before they resort to medical experimentation on human
beings in the United States?
A. Yes, they represent the basic principles approved by the
American Medical Association for the use of human beings
as subjects in medical experiments. 18
Hearing this specific, and obviously important, claim about research with
human subjects in the United States, Judge Harold E. Sebring interjected with a
broad question about the international significance of Ivy's assertion: "How do the
principles which you have just enunciated comport with the principles of the
medical profession over the civilized world generally?" Ivy responded: "They
are identical, according to my information." 19
Later in his testimony, Ivy faced cross-examination by Fritz Sauter,
counsel for two of the German medical defendants. Sauter pushed Ivy to
acknowledge that the AMA guidelines had come into formal existence only as the
Nuremberg Medical Trial was getting under way. In response to this attempt to
diminish the legal force of the AMA standards with the obvious suggestion that
the rules had been made up too recently to be of relevance, Ivy made an explicit
claim in court that the ideas inherent in the AMA standards significantly predated
their official formulation:
Q. You told us that ... an association had made a
compilation regarding the ethics of medical experiments on
human beings. . . . Can you recall what I am referring to?
A. Yes.
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Chapter 2
Q. That was in December 1946, 1 believe.
A. Yes, I remember. . . .
Q. Did that take place in consideration of this trial?
A. Well, that took place as a result of my relations
to the trial, yes.
Q. Before December of 1946 were such instructions
in printed form in existence in America?
A. No. They were understood only as a matter of
common practice. 20
Thus, if Ivy is to be taken literally, the standards he forcefully articulated
during the Nuremberg Medical Trial, which were affirmed by the AMA House of
Delegates as the trial was just beginning and codified by three American judges
as the trial came to an end, were the standards of practice at the time.
THE "REAL WORLD" OF HUMAN EXPERIMENTATION
It would be historically irresponsible, however, to rely solely on records
related directly to the Nuremberg Medical Trial in evaluating the postwar scene in
American medical research. The panorama of American thought and practice in
human experimentation was considerably more complex than Ivy acknowledged
on the witness stand in Nuremberg. In general, it does seem that most American
medical scientists probably sought to approximate the practices suggested in the
Nuremberg Code and the AMA principles when working with "healthy
volunteers." Indeed, a subtle, yet pervasive, indication of the recognition during
this period that consent should be obtained from healthy subjects was the
widespread use of the term volunteer to describe such research participants. Yet,
as Advisory Committee member Susan Lederer has recently pointed out, the use
of the word volunteer cannot always be taken as an indication that researchers
intended to use subjects who had knowingly and freely agreed to participate in an
experiment; it seems that researchers sometimes used volunteer as a synonym for
research subject, with no special meaning intended regarding the decision of the
participants to join in an experiment. 21
Even with this ambiguity it is, however, quite clear that a strong tradition
of consent has existed in research with healthy subjects, research that generally
offered no prospect of medical benefit to the participant. In the United States
much of this tradition has rested on the well-known example of Walter Reed's
turn-of-the-century experiments, when he employed informed volunteers to
establish the mosquito as the vector of transmission for yellow fever. 22 Indeed, it
seems that a tradition of research with consenting subjects has been particularly
strong among Reed's military descendants in the field of infectious disease
research (which has frequently required the use of healthy subjects). For
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Part I
example, Dr. Theodore Woodward, a physician-researcher commissioned in the
Army, conducted vaccine research during the 1950s with healthy subjects under
the auspices of the Armed Forces Epidemiological Board. In a recent interview
conducted by the Advisory Committee, Woodward recalled that the risks of
exposure to diseases such as typhus were always fully disclosed to potential
healthy subjects and that their consent was obtained. Since some of these studies
were conducted in other countries with non-English-speakers, the disclosure was
given in the volunteer's language. 23 Of his own values during this time,
Woodward stated: "If I gave someone something that could make them sick or kill
them and hadn't told them, I'm a murderer." 24 Similarly, Dr. John Arnold, a
physician who conducted Army-sponsored malaria research on prisoners from the
late 1940s through the mid-1950s, recalled that he always obtained written
permission from his subjects. 25
Not all the evidence on consent and healthy subjects comes from the
military tradition. A particularly compelling general characterization of research
with "normal volunteers" during this period comes from the "Analytic Summary"
of a conference on the "Concept of Consent in Clinical Research," which the
Law-Medicine Research Institute (LMRI) of Boston University convened on
April 29, 1961. At this conference, twenty-one researchers from universities,
hospitals, and pharmaceutical companies across the country were brought
together "to explore problems arising from the legal and ethical requirements of
informed consent of research subjects." 26 The LMRI project was what one might
now call a fact-finding mission; the LMRI staff was attempting "to define and to
analyze the actual patterns of administrative practice governing the conduct of
clinical research in the United States" during the early 1960s. 27 Anne S. Harris,
an LMRI staff member and author of the conference's final report, offered a
simple but significant assessment of the handling of healthy participants in
nontherapeutic research as expressed by the researchers at the meeting, whose
careers included the decade and a half since the end of World War II: "The
conferees indicated that normal subjects are usually fully informed." 28
Even so, researchers who almost certainly knew better sometimes
employed unconsenting healthy subjects in research that offered them no medical
benefits. For example, Dr. Louis Lasagna, who has since become a respected
authority on bioethics, stated in an interview conducted by the Advisory
Committee that between 1952 and 1954, when he was a research fellow at
Harvard Medical School, he helped carry out secret, Army-sponsored experiments
in which hallucinogens were administered to healthy subjects without their full
knowledge or consent:
The idea was that we were supposed to give
hallucinogens or possible hallucinogens to healthy
volunteers and see if we could worm out of them
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secret information. And it went like this: a
volunteer would be told, 'Now we're going to ask
you a lot of questions, but under no circumstances
tell us your mother's maiden name or your social
security number,' I forget what. I refused to
participate in this because it was so mindless that a
psychologist did the interviewing and then we'd
give them a drug and ask them a number of
questions and sure enough, one of the questions was
'What is you mother's maiden name?' Well, it was
laughable in retrospect . . . [The subjects] weren 't
informed about anything [emphasis added]. 29
Lasagna, reflecting "not with pride" on the episode, offered the following
explanation: "It wasn't that we were Nazis and said, 'If we ask for consent we lose
our subjects,' it was just that we were so ethically insensitive that it never
occurred to us that you ought to level with people that they were in an
experiment." 30 This might have been true for Lasagna the young research fellow,
but the explanation is harder to understand for the director of the research project,
Henry Beecher. Beecher was a Harvard anesthesiologist who, as we will see later
in this chapter and in chapter 3, would emerge as an important figure in
biomedical research and ethics during the mid-1960s. 31
If American researchers experimenting on healthy subjects sometimes did
not strive to follow the standards enunciated at Nuremberg, research practices
with sick patients seem even more problematic in retrospect. Advisory
Committee member Jay Katz has recently argued that this type of research still
gives rise to ethical difficulties for physicians engaged in research with patients,
and he has offered an explanation: "In conflating clinical trials and therapy, as
well as patients and subjects, as if both were one and the same, physician-
investigators unwittingly become double agents with conflicting loyalties."
It is likely that such confusion and conflict would have been as
troublesome several decades ago, if not more troublesome, than it is today. The
immediate postwar period was a time of vast expansion and change in American
medical science (see Introduction). Clinical research was emerging as a new and
prestigious career possibility for a growing number of medical school graduates.
Most of these young clinical researchers almost certainly would have absorbed in
their early training a paternalistic approach to medical practice that was not
seriously challenged until the 1970s. This approach encouraged physicians to
take the responsibility for determining what was in the best interest of their
patients and to act accordingly. The general public allowed physicians to act with
great authority in assuming this responsibility because of an implicit trust that
doctors were guided in their actions by a desire to help their patients.
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This paternalistic approach to medical practice can be traced to the
Hippocratic admonition: "to help, or at least do no harm." 33 Another long-
standing medical tradition that can be found in Hippocratic medicine is the belief
that each patient poses a unique medical problem calling for creative solution.
Creativity in the treatment of individuals, which was not commonly thought of as
requiring consent, could be— and often was—called experimentation. This tradition
of medical tinkering without explicit and informed consent from a patient was
intended to achieve proper treatment for an individual's ailments; but it seems also
to have served (often unconsciously) as a justification for some researchers who
engaged in large-scale clinical research projects without particular concern for
consent from patients.
Members of the medical profession and the American public have today
come to better understand the intellectual and institutional distinctions between
organized medical research and standard medical practice. There were significant
differences between research and practice in the 1950s, but these differences were
harder to recognize because they were relatively new. For example, randomized,
controlled, double-blind trials of drugs, which have brought so much benefit to
medical practice by greatly decreasing bias in the testing of new medicines, were
introduced in the 1950s. The postwar period also brought an unprecedented
expansion of universities and research institutes. Many more physicians than ever
before were no longer solely concerned, or even primarily concerned, with aiding
individual patients. These medical scientists instead set their sights on goals they
deemed more important: expanding basic knowledge of the natural world, curing
a dread disease (for the benefit of many, not one), and in some cases, helping to
defend the nation against foreign aggressors. At the same time, this new breed of
clinical researchers was motivated by more pragmatic concerns, such as getting
published and moving up the academic career ladder. But these differences
between medical practice and medical science, which seem relatively clear in
retrospect, were not necessarily easy to recognize at the time. And coming to
terms with these differences was not especially convenient for researchers; using
readily available patients as "clinical material" was an expedient solution to a
need for human subjects.
As difficult and inconvenient as it might have been for researchers in the
boom years of American medical science following World War II to confront the
fundamental differences between therapeutic and nontherapeutic relationships
with other human beings, it was not impossible. Otto E. Guttentag, a physician at
the University of California School of Medicine in San Francisco, directly
addressed these issues in a 1953 Science magazine article. Guttentag's article, and
three others that appeared with it, originated as presentations in a symposium held
in 1951 on "The Problem of Experimentation on Human Beings" at Guttentag's
home institution. Guttentag constructed his paper around a comparison between
the traditional role of the physician as healer and the relatively new role of
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Chapter 2
physician as medical researcher. Guttentag referred to the former as "physician-
friend" and the latter as "physician-experimenter." He explicitly laid out the
manner in which medical research could conflict with the traditional doctor-
patient relationship:
Historically, . . . one human being is in distress, in
need, crying for help; and another fellow human
being is concerned and wants to help and the desire
for it precipitates the relationship. Here both the
healthy and the sick persons are . . . fellow-
companions, partners to conquer a common enemy
who has overwhelmed one of them. . . . Objective
experimentation to confirm or disprove some
doubtful or suggested biological generalization is
foreign to this relationship ... for it would involve
taking advantage of the patient's cry for help, and of
his insecurity. 34
Guttentag worried that a "physician-experimenter" could not resist the
temptation to "tak[e] advantage of the patient's cry for help." 35 To prevent the
experimental exploitation of the sick that he envisioned (or knew about),
Guttentag suggested the following arrangement:
Research and care would not be pursued by the
same doctor for the same person, but would be kept
distinct. The physician-friend and the physician-
experimenter would be two different persons as far
as a single patient is concerned. . . . The
responsibility for the patient as patient would rest,
during the experimental period, with the physician-
friend, unless the patient decided differently.
Retaining his original physician as personal adviser,
the patient would at least be under less conflict than
he is at present when the question of
experimentation arises. 36
Among physicians, Guttentag was nearly unique in medicine in those days
in raising such problems in print. Another example of concern about the moral
issues raised by research at the bedside comes from what might be an unexpected
source: a Catholic theologian writing in 1945. In the course of a general review
of issues in moral theology, John C. Ford, a prominent Jesuit scholar, devoted
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several pages to the matter of experimentation with human subjects. Ford was not
a physician, but his thoughts on this topic-published a year before the beginning
of the Nuremberg Medical Trial-suggest that a thoughtful observer could
recognize, even decades ago, serious problems with conducting medical research
on unconsenting hospital patients:
The point of getting the patient's consent [before
conducting an experiment] is increasingly
important, I believe, because of reports which
occasionally reach me of grave abuses in this
matter. In some cases, especially charity cases,
patients are not provided with a sure, well-tried, and
effective remedy that is at hand, but instead are
subjected to other treatment. The purpose of
delaying the well-tried remedy is, not to cure this
patient, but to discover experimentally what the
effects of the new treatment will be, in the hope, of
course, that a new discovery will benefit later
generations, and that the delay in administering the
well-tried remedy will not harm the patient too
much. . . . This sort of thing is not only immoral,
but unethical from the physician's own standpoint,
and is illegal as well. 37
The transcripts and reports produced in the Law-Medicine Research
Institute's effort during the early 1 960s to gather information on ethical and
administrative practices in research in medical settings suggest that by this time
more researchers had come to recognize the troubling issues associated with using
sick patients as subjects in research that could not benefit them. The body of
evidence from the LMRI project also suggests that problems with this type of
human experimentation had been widespread before the early 1960s and remained
common at that time. The transcript of a May 1, 1961, closed-door meeting of
medical researchers organized by LMRI to explore issues in pediatric research
shows a medical scientist from the University of Iowa offering a revealing
generalization from which none of his colleagues dissented. In order to
understand this transcript excerpt one must know that item "Al" on the meeting
agenda related to research "primarily directed toward the advancement of medical
science" and item "A2" referred to "clinical investigation . . . primarily directed
toward diagnostic, therapeutic and/or prophylactic benefit to patients."
We have done a thousand things with an implied
feeling [of consent]. . . . We wear two hats. Item
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Chapter 2
A2 allows us to do A 1 but we feel uncomfortable
about it. The responsibility of the physician
includes responsibility to advance in knowledge.
Things are different now and this problem of a
secondary role [i.e., to advance knowledge] is
increasingly in front stage [emphasis added]. 38
This researcher acknowledged that many physicians during the period let
themselves slide into nontherapeutic research with patients. He provided the
additional, and significant, assessment that he and his colleagues felt guilty about
this behavior, even though it was quite common.
An even more probing analysis of these issues had taken place two days
earlier at the April 29, 1961, LMRI conference on "The Concept of Consent,"
referred to above in our discussion of research with healthy subjects. The
participants at this meeting recognized that research with sick patients could be
both therapeutic and nontherapeutic. Interestingly, they suggested that patients
employed for research in which "there was the possibility of therapeutic benefit
with minimal or moderate risk" were "usually informed" of the proposed study.
The author of the conference report offered the plausible explanation that
informing subjects in potentially beneficial research "is psychologically more
comfortable for investigators [because] the [therapeutic] expectations of potential
subjects coincide with the purpose and expected results of the experiment." 39 The
conferees identified research in which "patients are used for studies unrelated to
their own disease, or in studies in which therapeutic benefits are unlikely" as the
most problematic. Those at the meeting "indicated that it is most often subjects in
this category to whom disclosure is not made." 40 The conference report outlined
an approach employed by many researchers (including some at the meeting), in
which, rather than seeking consent from patients for research that offers them no
benefit,
[t]he therapeutic illusion is maintained, and the
patient is often not even told he is participating in
research. Instead, he is told he is "just going to
have a test." If the experimental procedure involves
minimal risk, but some discomfort, such as hourly
urine collection, "All you do is tell the patient: 'We
want you to urinate every hour.' We merely let them
assume that it is part of the hospital work that is
being done." 41
Again, it is important to note that the conference participants displayed
some moral discomfort with this pattern of behavior, as can be seen from the
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Part I
following exchange:
Dr. X: There is a matter here of whether the patient
is not informed because the risk is too trivial, or
because it's too serious.
Dr. Y: I think you're getting right at it. There's a
great difference in not telling the patient because
you're afraid he won't participate and not telling him
because you don't think there is a conceivable risk,
and it's so trivial you don't bother to inform him.
Dr. Z: On the question of whether it's [acceptable]
not to tell, we would say that it is not permissible on
the grounds of refusal potential. 42
It is also important to draw out of this transcript excerpt the general point
that most researchers in this period appear not to have had great ethical qualms
about enrolling an uninformed patient in a research project if the risk was deemed
low or nonexistent. Of course, the varying definitions of "low risk" could lead to
problems with this approach. Indeed, the participants at the "Concept of Consent"
conference grappled at length with this very issue without ever reaching
consensus. A minority steadfastly asserted that participants in an experiment
should be asked for consent even if the risk would be extremely low, such as in
only taking a small clipping of hair.
The Advisory Committee's Ethics Oral History Project 43 has provided
extensive additional evidence that medical researchers sometimes (perhaps even
often) took liberties with sick patients during the decades immediately following
World War II. The element of opportunism was recounted in several interviews.
Dr. Lasagna, who was involved in pain-management studies in postoperative
patients at Harvard in the 1950s, explained rather bluntly:
[Mjostly, I'm ashamed to say, it was as if, and I'm
putting this very crudely purposely, as if you'd
ordered a bunch of rats from a laboratory and you
had experimental subjects available to you. They
were never asked by anybody. They might have
guessed they were involved in something because a
young woman would come around every hour and
ask them how they were and quantified their pain.
We never made any efforts to find out if they
guessed that they were part of it. 44
Other researchers told similar tales, with a similar mixture of matter-of-
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Chapter 2
fact reporting and regretful recollection. Dr. Paul Beeson remembered a study he
conducted in the 1940s, while a professor at Emory University, on patients with
bacterial endocarditis, an invariably fatal disease at the time. He recalled that he
thought it would be interesting to use the new technique of cardiac catheterization
to compare the number of bacteria in the blood at different points in circulation:
[This is] something I wouldn't dare do now. It
would do no good for the patient. They had to
come to the lab and lie on a fluoroscopic table for a
couple of hours, a catheter was put into the heart, a
femoral needle was put in so we could get femoral
arterial blood and so on. . . . All I could say at the
end was that these poor people were lying there and
we had nothing to offer them and it might have
given them some comfort that a lot of people were
paying attention to them for this one study. I don't
remember ever asking their permission to do it. I
did go around and see them, of course, and said,
"We want to do a study on you in the X-ray
department, we'll do it tomorrow morning," and
they said yes. There was never any question. Such
a thing as informed consent, that term didn't even
exist at that time. . . . [I]f I were ever on a hospital
ethics committee today, I wouldn't ever pass on that
particular study. 45
Radiologist Leonard Sagan recalled an experiment in which he assisted
during his training on a metabolic unit at Moffett Hospital in San Francisco in
1956-1957.
At the time, the adrenal gland was hot stuff. ACTH
[adrenocorticotropic hormone] had just become
available and it was an important tool for exploring the
function of the adrenal gland. . . . This was the project
I was involved in during that year, the study of adrenal
function in patients with thyroid disease, both hypo-
and hyperthyroid disease. So what did we do? I'd find
some patients in the hospital and I'd add a little ACTH
to their infusion and collect urines and measure output
of urinary corticoids. ... I didn't consider it dangerous.
But I didn't consider it necessary to inform them
either. So far as they were concerned, this was part of
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their treatment. They didn't know, and no one had
asked me to tell them. As far as I know, informed
consent was not practiced anyplace in that hospital at
the time. 46
Sagan viewed the above experiment as conforming not only with the
practices of the particular hospital but also in accord with the high degree of
professional autonomy and respect that was granted to physicians in this era:
In 1945, '50, the doctor . . . was king or queen. It
never occurred to a doctor to ask for consent for
anything. . . . People say, oh, injection with
plutonium, why didn't the doctor tell the patient?
Doctors weren't in the habit of telling the patients
anything. They were in charge and nobody
questioned their authority. Now that seems
egregious. But at the time, that's the way the world
47
was.
Another investigator, Dr. Stuart Finch, who was a professor of medicine at
Yale during the 1950s and 1960s, recalled instances when oncologists there were
overly aggressive in pursuing experimental therapies with terminal patients.
[I]t's very easy to talk a terminal patient into taking
that medication or to try that compound or whatever
the substance is. . . . Sometimes the oncologists
[got] way overenthused using it. It's very easy
when you have a dying patient to say, "Look, you're
going
to die. Why don't you let me try this substance on
you?" I don't think if they have informed consent or
not it makes much difference at that point. 48
Economically disadvantaged patients seem to have been perceived by
some physicians as particularly appropriate subjects for medical experimentation.
Dr. Beeson offered a frank description of a quid pro quo rationale that was
probably quite common in justifying the use of poor patients in medical research:
"We were taking care of them, and felt we had a right to get some return from
them, since it wouldn't be in professional fees and since our taxes were paying
their hospital bills." 49
Another investigator, Dr. Thomas Chalmers, who began his career in
medical research during the 1940s, identified sick patients as the most vulnerable
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Chapter 2
type of experimental subjects-more vulnerable even than prisoners:
One of the real ludicrous aspects of talking about a
prisoner being a captive, and therefore needing
more protection than others, is, there's nobody more
captive than a sick patient. You've got pain. You
feel awful. You've got this one person who's going
to help you. You do anything he says. You're a
captive. You can't, especially if you're sick and
dying, discharge the doctor and get another one
without a great deal of trauma and possible loss of
lifesaving measures. 50
Thus, as compared with prisoners, who are now generally viewed to be
vulnerable to coercion, those who are sick may be even more compromised in
their ability to withstand subtle pressure to be research subjects. Appropriate
protection for the sick who might be candidates for medical research has proved
to be an especially troublesome issue in the era following Nuremberg.
NUREMBERG AND RESEARCH WITH PATIENTS
The record of conducting nontherapeutic research with unconsenting sick
patients during the postwar period discussed above seems to stand in particularly
sharp contrast with the claims about the conduct of research involving human
subjects in the United States that Andrew Ivy made during his testimony in
Nuremberg. We have seen how some observers, even before Nuremberg,
recognized that employing uninformed, vulnerable sick patients solely as a means
to a scientific end was simply wrong. We must, however, also acknowledge that
the particulars of the Nuremberg Medical Trial did not call for careful attention to
the issues surrounding research with sick patients. None of the German
physicians at Nuremberg stood accused of exploiting patients for experimental
purposes.
Nonetheless, it is likely that Andrew Ivy would have argued that consent
was appropriate in virtually all instances of medical research. Dr. Herman
Wigodsky, who worked closely under Ivy at Northwestern in the late 1930s and
early 1940s, explicitly commented during an Ethics Oral History Project
interview that he did not believe that his mentor drew any sort of ethical line
between various types of clinical research: "I don't think he made any distinction
[between research with sick patients and research with healthy subjects].
Research was research. It didn't make any difference." 51
Additional evidence that Ivy would have supported standards of consent
for research with ill as well as with healthy subjects comes from his response to a
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set of rules for human experimentation put forth by the German Ministry of
Interior in 1931, presented to him after he had prepared his written report for the
AM A in the fall of 1946. These rules appear to be considerably more
comprehensive and sophisticated than the Nuremberg Code itself. 52 Most
significantly, the 1931 German standards cover both therapeutic and
nontherapeutic research, calling for consent in both types of medical
investigation. For reasons that are not clear, the prosecution team at Nuremberg
did not choose to place much emphasis on these German standards in constructing
the case. Ivy did, however, attempt (without much help from the prosecution) to
initiate a discussion of the 1931 standards during his testimony. It is clear from
the trial transcript that Ivy saw a rough equivalence between the more detailed and
extensive German rules and those formulated by the AMA, with his assistance.
Shortly after discussing the AMA principles on the witness stand, Ivy had the
following exchange with prosecutor Alexander G. Hardy:
Q. Do you have any further statements to make
concerning rules of medical ethics concerning
experimentation in human beings?
A. Well, I find that since making [my] report to the
American Medical Association that a decree of the
Minister of Public Welfare [Ivy should have said
"the Minister of the Interior"] of Germany in 1931
on the subject of "Regulations for Modern Therapy
for the Performance of Scientific Experiments on
Human Beings" contains all the [AMA] principles
which I have read. 53
Hardy did not take what now seems an obvious opportunity to allow Ivy to
expand further on these rules. However, a few minutes later, Ivy brought up the
German standards again on his own (and again Hardy did not pursue the topic
further). At this point, Ivy stated his general agreement with the German
standards of 1931 even more firmly:
I cited the principles . . . from the Reich Minister of
the Interior dated February 28, 193 1 to indicate that
the ethical principles for the use of human beings as
subjects in medical experiments in Germany in
1931 were similar to these which I have enunciated
and which have been approved by the House of
Delegates of the American Medical Association. 54
Ivy's assertion of "similarity" between the AMA principles and those in the 1931
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Chapter 2
German document may not meet with agreement among those who compare the
two. Though they may be viewed as similar in philosophy and intent, the German
interior ministry document is, far more detailed and comprehensive than that of
theAMA.
Contrary to Ivy's claims at Nuremberg, and the positioning of Ivy by the
prosecution, he cannot in any full sense be taken as the embodiment of the entire
American medical profession in the years immediately following World War II.
Again, Dr. Wigodsky spoke to this point in his recent interview:
Well, I've always felt that that stuff that Ivy wrote
up during the time of the trials was pretty much an
expression of his personal philosophy about
research. And ... it was the kind of understanding
that we had in working with him about how he felt.
Voluntariness being number one--you had to
volunteer and had to be in a situation where you
could volunteer. And consent in the sense that you
didn't do anything to anybody that they didn't know
what you were doing. That you explained to people
what it was you were going to do and why you were
going to do it and that sort of thing [emphasis
added]. 55
Even if it is true that Andrew Ivy would have wholeheartedly endorsed the
notion of obtaining consent from any research subject- whether an experiment
held the possibility of personal benefit or not; whether the subjects were sick or
healthy-it seems likely that the AMA House of Delegates would have been
hesitant to endorse a condensation of Ivy's principles of research ethics if they had
been explicitly extended to cover all categories of clinical investigation.
Obtaining consent from patients within the normal clinical relationship was not a
common practice in late 1946. At that time, and for many years to come, patient
trust and medical beneficence were viewed as the unshakable moral foundations
on which meaningful interactions between professional healers and the sick
should be built. In fact, it was not until 1981 that the AMA's Judicial Council
specifically endorsed "informed consent" as an appropriate part of the therapeutic
doctor-patient relationship. 56
But, in the end, it must be acknowledged that the facts of the Nuremberg
Medical Trial did not force Andrew Ivy, the AMA House of Delegates, the
Nuremberg prosecutors, or the judges to grapple with the distinctions between
research with sick patients and research with healthy subjects, or therapeutic and
nontherapeutic research. The Nuremberg defendants stood accused of ghastly
experimental acts that were absolutely without therapeutic intent, and their
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unfortunate subjects were never under any illusion that they were receiving
medical treatment. To rebut the claims of some of the medical defendants that
obtaining consent from research subjects was not a clearly established principle,
Ivy could, and did, offer a variety of examples on the witness stand from a long
tradition of human experimentation on consenting healthy subjects. 57 Ivy and the
members of the prosecution team were not faced with what might have been a
more troubling process: finding examples of well-organized nontherapeutic
experiments on sick patients in which the subjects had clearly offered consent.
Simply put, the Nuremberg Medical Trial did not demand it.
AMERICAN MEDICAL RESEARCHERS' REACTIONS TO
NEWS OF THE NUREMBERG MEDICAL TRIAL
It is important to have some understanding of the extent to which
American medical scientists paid attention to the events of the Nuremberg
Medical Trial and made connnections with the messages that emanated from the
courtroom in Germany. The Nuremberg Medical Trial received coverage in the
American popular press, but it would almost certainly be an exaggeration to refer
to this attention as exhaustive. Historian David Rothman has provided the
following summary of the trial's coverage in the New York Times:
Over 1945 and 1946 fewer than a dozen articles
appeared in the New York Times on the Nazi
[medical] research; the indictment of forty-two
doctors in the fall of 1946 was a page-five story and
the opening of the trial, a page-nine story. (The
announcement of the guilty verdict in August 1 947
was a front-page story, but the execution of seven
of the defendants a year later was again relegated to
the back pages.) 58
The Advisory Committee's Ethics Oral History Project suggests that
American medical researchers, perhaps like the American public generally, were
not carefully following the daily developments in Nuremberg. For example, Dr.
John Arnold, a researcher who, during the Medical Trial, was involved in malaria
experiments on prisoners at Stateville Prison in Illinois, offered a particularly
vivid (if somewhat anachronistic) recollection of the scant attention paid to the
Nuremberg Medical Trial among American medical scientists: "We were dimly
aware of it. And as you ask me now, I'm astonished that we [were not] hanging
on the TV at the time, watching for each twist and turn of the argument to
develop. But we weren't." 59 It might have been expected that the researchers at
Stateville would have been particularly concerned with the events at Nuremberg
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Chapter 2
because some of the medical defendants claimed during the trial that the wartime
malaria experiments at the Illinois prison were analogous to the experiments
carried out in the Nazi concentration camps.
The strongest statement of awareness came from Dr. Herbert Abrams, a
radiologist who was in his residency at Montefiore Hospital in the Bronx
throughout most of the trial:
[The Nuremberg Medical Trial] was part of the
history of the day. And there was extensive
reportage ... so that the manner of human
experimentation as it had been done by the Nazis
was very much in the news. We were all aware of
it. I think that people experienced this kind of
revulsion about it that you might anticipate. ... It
was surely something, at least in the environment I
was in, we were aware of and that affected the
thinking of everyone who was involved in clinical
investigation. 60
It seems likely, however, that the "environment" this young physician was in
would have caused a heightened awareness of a trial dealing with Nazi medical
professionals. Montefiore is a traditionally Jewish hospital that was home to
many Jewish refugee physicians who had fled the terror and oppression of the
Nazi regime. 61 A trial of German physicians almost certainly would have been of
particular interest in this setting.
Even among American medical researchers who might have been aware of
events at Nuremberg, it seems that many did not perceive specific personal
implications in the Medical Trial. Rothman has enunciated this historical view
most fully. He asserts that "the prevailing view was that [the Nuremberg medical
defendants] were Nazis first and last; by definition nothing they did, and no code
drawn up in response to them, was relevant to the United States." 62 Jay Katz has
offered a similar summation of the immediate response of the medical community
to the Nuremberg Code: "It was a good code for barbarians but an unnecessary
code for ordinary physicians." 63
Several participants in the Ethics Oral History Project affirmed the
interpretations of Rothman and Katz, using similar language. Said one physician:
"There was a disconnect [between the Nuremberg Code and its application to
American researchers]. . . . The interpretation of these codes [by American
physicians] was that they were necessary for barbarians, but [not for] fine
upstanding people." 64 This same physician later acknowledged that, in a sense,
some American researchers did not pay attention to the lessons of the Nuremberg
Medical Trial because it was not convenient to do so:
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The connection between those horrendous acts
[carried out by German medical scientists in the
concentration camps] and our everyday
investigations was not made [by American medical
researchers] for reasons of self-interest, to be
perfectly frank. As I see it now, I'm saddened that
we didn't see the connection, but that's what was
done. . . . It's hard to tell you now . . . how we
rationalized, but the fact is we did/' 5
The popular press mirrored the view that human experimentation as
practiced in the United States was not a morally troubling enterprise—it was as
American as apple pie. Between 1948 and 1960 magazines such as the Saturday
Evening Post, Reader's Digest, and the American Mercury ran "human interest"
stories on "human guinea pigs." These stories generally focused on specific
groups of healthy subjects— prisoners, conscientious objectors, medical students,
soldiers— and described them as "volunteers." The articles explained the ordeals
to which the volunteers had submitted themselves. "Among these men and
women," the New York Times informed its Sunday readership in 1958, "you will
find those who will take shots of the new vaccines, who will swallow radioactive
drugs, who will fly higher than anyone else, who will watch malaria infected
mosquitos feed on their bare arms." 6 ' 1 The articles assured the public that the
volunteers had plausible, often noble, reasons for volunteering for such seemingly
gruesome treatment. The explanations included social redemption (especially in
the case of prisoners), religious or other beliefs (particularly for conscientious
objectors), the advancement of science, service to society, and thrill-seeking. 67 In
sum, most articles in the popular press were uncritical toward experimentation on
humans and assumed that those involved had freely volunteered to participate.
However, a smaller number of press reports in the late 1940s and 1950s
did suggest some tension between the words at Nuremberg and the practices in
America. As early as 1948, for example, Science News reported the Soviet claim
that Americans were using "Nazi methods" in the conduct of prisoner
experiments. 68 Concern also began to be voiced about the dangers to volunteer
"guinea pigs." In October 1954, for another example, the magazine Christian
Century called on the Army to halt, at the first sign of danger, experiments at the
Fitzsimmons Hospital in Denver, where soldiers were called upon to eat foods
exposed to cobalt radiation. 69
It is also possible that press accounts of experiments with patients rather
than healthy subjects were more inclined to be critical, even in the late 1940s. A
Saturday Evening Post article from the January 15, 1949, issue describes how a
VA physician kept quiet about streptomycin trials involving the medical
departments of the Army, Navy, and VA
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Chapter 2
because of the risk of congressional chastisement
from publicity-conscious members of the House and
Senate who might have screamed: 'You can't
experiment on our heroes,' if it had been known that
Army and Navy veterans of former wars were being
used in the medical investigation. This was a real
worry of the doctors who formulated the clinical
program.™
Evidence suggests that some American researchers were genuinely and
deeply concerned with the issues surrounding human experimentation during the
years immediately following World War II. One source of insight into the
thinking of American physicians engaged in clinical research during the 1950s is
found in the ground-breaking work of medical sociologist Renee C. Fox. For two
five-month periods between September 1951 and January 1953, Fox spent long
days "in continuous, direct, and intimate contact with the physicians and patients"
in a metabolic research ward that she pseudonymously called "Ward F-Second."
In 1959 Fox reported with remarkable sensitivity and eloquence on the ethical
dilemmas faced by the physicians conducting research on this ward. She did not
suggest that the scientists under her observation were unaware of the Nuremberg
Code; instead she offered a point-by-point paraphrasing of the Code, which she
identified as "the basic principles governing research on human subjects which
the physicians of the Metabolic Group [her collective term for the researchers
whom she studied] were required to observe." Rather than being unconscious or
contemptuous of a set of principles intended for barbarians, Fox reported that the
researchers on "Ward F-Second" were sometimes troubled by their inability to
apply the high, but essentially unquestioned, standards enunciated at the
Nuremberg Medical Trial:
The physicians of the Metabolic Group were deeply
committed to these principles and conscientiously
tried to live up to them in the research they carried
out on patients. However like most norms, the
"basic principles of human experimentation" are
formulated on such an abstract level that they only
provide general guides to actual behavior. Partly as
a consequence, the physicians of the Metabolic
Group often found it difficult to judge whether or
not a particular experiment in which they were
engaged "kept within the bounds" delineated by
these principles. 71
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Sometimes private discussions among researchers about the ethical
aspects of human experimentation led to public events. A good example from the
early 1950s is the symposium held on October 10, 1951, at the University of
California School of Medicine in San Francisco at which Otto Guttentag made the
presentation discussed earlier. One of Guttentag's colleagues, Dr. Michael B.
Shimkin, organized the symposium in response to some confidential criticism that
he had received for research carried out under his direction with patients at the
University of California's Laboratory of Experimental Oncology. The exact
nature of this criticism is unclear from the records that remain of the episode, but
Shimkin reported in a memoir that "remedial steps" were taken, including
"written protocols for all new departures in clinical research, which we asked the
cancer board of the medical school to review." 72 In his memoirs Shimkin also
recalls that patients were screened carefully before they were admitted to the
Laboratory of Experimental Oncology:
They had to understand the experimental nature of
our work, and every procedure was again explained
to them; the initial release form even included
agreement to an autopsy. The understanding did
not absolve us of negligence, nor deprive patients of
recourse to legal actions, but did set the tone and
nature of our relationships. In all our 5 years of
operations, not a single threat or implied threat of
action against us was voiced. Two patients did
instruct us to terminate our attempts at therapy. 73
The criticism Shimkin experienced also demonstrated to him that a more open
discussion of clinical research might be of benefit to his colleagues. According
to his recollection, "There was an almost visible thawing of attitude by the airing
of the problem" at the symposium. 74
Less than a year after Shimkin's 1 95 1 San Francisco symposium, the
organizers of the "First International Congress of the Histopathology of the
Nervous System," which was held in Rome, were sufficiently concerned with
ethical issues that they invited Pope Pius XII to address "The Moral Limits of
Medical Methods of Research and Treatment." In a speech before 427 medical
researchers from around the world (including 62 Americans), the pope firmly
endorsed the principle of obtaining consent from research subjects— whether sick
or healthy. He also pointed his audience to the relatively recent lessons of the
Nuremberg Medical Trial, which he summed up as teaching that "man should not
exist for the use of society; on the contrary, the community exists for the good of
man." 75 In an interview in 1961, Dr. Thomas Rivers, a prominent American virus
researcher, recalled that the pope's words had been influential among medical
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Chapter 2
scientists working during the 1950s:
[I]n September 1952, Pope Pius XII had given a
speech at the First International Congress on the
Histopathology of the Nervous System in which he
outlined the Roman Catholic Church's position on
the moral limits of human experimentation for
purposes of medical research. That speech had a
very broad impact on medical scientists both here
and abroad. 76
The growing influence of the Nuremberg Medical Trial can be seen by
looking at two editions of the best-known textbook of American medical
jurisprudence in the midtwentieth century. In the 1949 edition of Doctor and
Patient and the Law, Louis J. Regan, a physician and lawyer, offered very little
under the heading "Experimentation," and what he did offer made no reference to
Nuremberg:
The physician must keep abreast of medical
progress, but he is responsible if he goes beyond
usual and standard procedures to the point of
experimentation. If such treatment is considered
indicated, it should not be undertaken until
consultation has been had and until the patient has
signed a paper acknowledging and assuming the
risk. 77
However, in Regan's next edition of the same text, published in 1956, his few
lines on human experimentation had been expanded to three pages. He presented
a lengthy paraphrasing of the Nuremberg Code, and he repeated verbatim
(without quotation marks) the judges' preamble to the Code, stating that "all
agree" about these principles. Regan characterized the standards enunciated by
the judges at Nuremberg as "the most carefully developed set of precepts
specifically drawn to meet the problem of human experimentation." Immediately
following his discussion of Nuremberg, Regan laid out the 1946 standards of the
American Medical Association, which, as he put it, researchers needed to meet
"in order to conform with the ethics of the American Medical Association." 78
NEW TIMES, NEW CODES
In the spring of 1959 the National Society for Medical Research (NSMR),
an organization that Andrew Ivy had helped to found in 1946, sponsored a
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"National Conference on the Legal Environment of Medicine" at the University of
Chicago. Human experimentation was one of the major topics presented for
discussion by the 148 conference participants, primarily medical researchers,
from around the country. The published report of this conference reveals that the
many researchers who gathered in Chicago understood the Nuremberg Code well
enough to use it as a point of departure for discussion. As a group, the conferees
acknowledged that "[t]he ten principles [of the Nuremberg Code] have become
the principal guideposts to the ethics of clinical research in the western world."
Not all those in attendance, however, seemed to have been entirely pleased with
this state of affairs. A "Committee on the Re-Evaluation of the Nuremberg
Experimental Principles" reported general agreement with "the spirit of these
precautions" but discomfort with a number of "particulars." For example, they
suggested that the absolute requirement for consent in the Code's first principle
might be softened by inserting "either explicit or reasonably presumed" before the
word "consent." They also added a clause that would allow for third-party
permission for "those not capable of personal consent." 79
The 1959 NSMR conference strongly suggests that by the late 1950s many
and perhaps even most American medical researchers had come to recognize the
Nuremberg Code as the most authoritative single answer to an important question:
What are the rules for human experimentation? The same conference also
provides compelling evidence that many researchers who were giving the ethical
issues surrounding human experimentation serious attention at this time were not
entirely happy with the prospect of living by the letter of the Code. The sources
of discomfort with the Nuremberg Code can be grouped, retrospectively, into
three broad categories. First, some recognized the discrepancies between what
they had come to know as real practices in research on patient-subjects and what
they read in the lofty, idealized language of the Code. Others simply disagreed
with some elements of the Code. Still others disliked the very idea of a single,
concrete set of standards to guide behavior in such a complex matter as human
experimentation.
Henry Beecher, the Harvard-based medical researcher who was Louis
Lasagna's mentor in the early 1950s, published a paper, "Experimentation in
Man," in the Journal of the American Medical Association only a few months
before the NSMR conference in Chicago. In this lengthy piece, Beecher
addressed a mixture of all three sources of discomfort with the Nuremberg Code.
Beecher offered the assertion that "it is unethical and immoral to carry out
potentially dangerous experiments without the subject's knowledge and consent"
as the "central conclusion" of his paper. 80 But, even with this strong statement, he
was not entirely happy with the first clause of the Code; he viewed the
Nuremberg consent clause as too extreme and not squaring with the realities of
clinical research:
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Chapter 2
It is easy enough to say, as point one [of the
Nuremberg Code] does, that the subject "should
have sufficient knowledge and comprehension of
the elements of the subject matter involved as to
enable him to make an understanding and
enlightened decision." Practically, this is often
quite impossible ... for the complexities of
essential medical research have reached the point
where the full implications and possible hazards
cannot always be known to anyone and are often
communicable only to a few informed investigators
and sometimes not even to them. Certainly the full
implications of work to be done are often not really
communicable to lay subjects. . . . [P]oint one states
a requirement very often impossible of fulfillment
[emphasis added]. 81
Beecher's second form of difficulty with the Code can be found in his
opinion of another Nuremberg clause, which states, in part, that a human
experiment should not be "random and unnecessary in nature." Beecher cited
"anesthesia, x-rays, radium, and penicillin" as important medical breakthroughs
that had resulted from "random" experimentation. He further stated that he
"would not know how to define experiments 'unnecessary in nature. " ,82 Finally,
Beecher expressed skepticism in general that any code could provide effective
moral guidance for researchers working with human subjects. Near the beginning
of his paper he wrote that "the problems of human experimentation do not lend
themselves to a series of rigid rules." 83 Later in the piece, he expanded on this
thought:
[I]t is not my view that many rules can be laid down
to govern experimentation in man. In most cases,
these are more likely to do harm than good. Rules
are not going to curb the unscrupulous. Such abuses
as have occurred are usually due to ignorance and
inexperience. The most effective protection for all
concerned depends upon a recognition and an
understanding of the various aspects of the
problem. 84
Another episode involving Henry Beecher further clarifies the medical
profession's dissatisfaction with the construction of the Nuremberg Code. In the
fall of 1961, Beecher and other members of the Harvard Medical School's
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Administrative Board, the school's governing body, were presented with a set of
"rigid rules" that had begun to appear in Army medical research contracts. The
members of the board quickly recognized the "Principles, Policies and Rules of
the Surgeon General, Department of the Army, Relating to the Use of Human
Volunteers in Medical Research" awarded by the Army as little more than a
restatement of the Nuremberg Code. The Army Office of the Surgeon General's
provisions, as we discussed in chapter 1, originally appeared in 1954. Given what
we have just read of Beecher, it is not surprising that he was uncomfortable with
the prospect of working in strict accordance with the Nuremberg Code if he were
to receive funding from the Army, nor, as we see from the minutes of the
Administrative Board meetings in which this matter came up for discussion, was
Beecher alone in his opposition. At the October 6, 1961, meeting of the board,
when the Army contract insertion was first mentioned, "some members . . . felt
that with the minor changes the regulations were acceptable, while others
described the regulations as vague, ambiguous and, in many instances, impossible
to fulfill."" 5
One of Beecher's fellow board members, Assistant Medical School Dean
Joseph W. Gardella, M.D., produced a thoroughgoing written critique of the
"Principles, Policies, and Rules of the Surgeon General" (and, thus, of the
Nuremberg Code) following the October 1961 meeting for the consideration of
the other board members. Gardella opened his analysis with some general
comments on the intended meaning of the Nuremberg Code:
The Nuremberg Code was conceived in reference to
Nazi atrocities and was written for the specific
purpose of preventing brutal excesses from being
committed or excused in the name of science. The
code, however admirable in its intent, and however
suitable for the purpose for which it was conceived,
is in our opinion not necessarily pertinent to or
adequate for the conduct of medical research in the
United States. 86
After questioning the pertinence of the Nuremberg Medical Trial to American
medical science, Gardella went on to raise a general question about the scope of
the Nuremberg Code; he strongly suggested that the code was not meant to cover
what he perceived as the morally distinct enterprise of conducting potentially
therapeutic research with sick patients:
Does it refer only to healthy volunteers who have
nothing to gain in terms of their health by
participating as research subjects? Or does it
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Chapter 2
include the sick, whose physicians foresee for them
the possibility of personal benefit through their
participation? The distinction is important in that
we believe that it would be difficult and might
prove to be impossible to devise one set of guiding
principles that would apply satisfactorily to both of
these two different categories. 87
Gardella offered a variety of specific objections to the Army surgeon
general's "Principles," but several of these points related directly to the general
questions raised above. The first rule of the Army "Principles" stated (in a clear
example of borrowing from the Nuremberg Code) that "the voluntary consent of
the human subject is absolutely essential." Gardella, like Beecher, did not
question the general spirit of this stricture; he worried about the practical
application of this seemingly simple idea. Some of Gardella's worries arose
specifically in the context of research with sick patients:
The concept of "voluntary consent" is of central
importance in any code relating to experimentation
on humans. . . . And yet the concept of "consent" is
not satisfactorily defined [in the Army
"Principles"]. . . . The quality of the subject's
consent depends . . . upon an interpretation ... of a
factual situation which will frequently be complex.
Could the subject comprehend what he was told?
Did he in fact comprehend? How far was his
consent influenced by his condition or by his trust
in his physician? These questions may be easily
answered in the case of the [healthy] volunteer.
They may be more difficult for the sick [emphasis
added]. 88
Perhaps the most significant addition to the Nuremberg Code found in the
Army "Principles" was the requirement for written consent from research
subjects. Gardella objected to this requirement in research on patients in a firm,
and revealing, fashion:
This condition is . . . inappropriate except in
connection with healthy normal volunteers. The
legal overtones and implications attendant to such a
requirement have no place in [a] patient-physician
relationship based on trust. Here such faith and
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trust serve as the primary basis of the subject's
consent. Moreover being asked to sign a somewhat
formal paper is likely to provoke anxiety in the
subject [i.e., patient] who can but wonder at the
need for so much protocol. 89
Dr. Gardella presented his analysis of the Army "Principles" to the other
members of the Harvard Medical School Administrative Board on March 23,
1962. The minutes of that meeting document that Gardella's views were not
extreme or exceptional among leading medical scientists in the early 1960s, at
least at Harvard University: "The members of the Board were in general
agreement with the objections and criticisms expressed in [Gardella's] critique." 90
At this same meeting, Henry Beecher "agreed, in an expansive moment, to
attempt to capture in a paragraph or so the broad philosophical and moral
principles that underlie the conduct of research on human beings at the Harvard
Medical School." 91 The members of the board hoped that such a statement might
satisfy the Army and that it would allow Harvard, as Gardella put it, "to avert the
catastrophic impact of the Surgeon General's regulation." 92
A few months later, Beecher had completed a two-and-a-half-page
"Statement Outlining the Philosophy and Ethical Principles Governing the
Conduct of Research on Human Beings at Harvard Medical School." At the June
8, 1962, board meeting, Beecher's colleagues "commended" and "reaffirmed" the
views expressed in Beecher's document. 93 In this statement, as in his 1959
published paper, Beecher emphasized the significance of consent, but he also
asserted that "it is folly to overlook the fact that valid, informed consent may be
difficult to the point of impossible to obtain in some cases." More than consent,
Beecher believed in the significance of "a special relationship of trust between
subject or patient and the investigator." In the end, Beecher concluded that the
only reliable foundation for this relationship was a virtuous medical researcher,
with virtuous peers:
It is this writer's point of view that the best
approach [to research with human subjects]
concerns the character, wisdom, experience,
honesty, imaginativeness and sense of responsibility
of the investigator who in all cases of doubt or
where serious consequences might remotely occur,
will call in his peers and get the benefit of their
counsel. Rigid rules will jeopardize the research
establishments of this country where
experimentation in man is essential. 94
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Available evidence suggests that, by offering Henry Beecher's
replacement for the Nuremberg Code, representatives of Harvard Medical School
were able to extract a clarification during a meeting with Army Surgeon General
Leonard D. Heaton, on July 12, 1962, that the "Principles" being inserted into
Harvard's research contracts with the Army were "guidelines" rather than "rigid
rules." 95
While the Harvard Medical School discussion of the Army's "Principles"
took place behind closed doors and involved a policy of limited applicability, the
leaders of the international medical community were simultaneously engaged in a
far more visible and global attempt to bring the standards enunciated in the
Nuremberg Code into line with the realities of medical research. The 1964
statement by the World Medical Association (WMA), commonly known as the
Declaration of Helsinki, created two separate categories in laying out rules for
human experimentation: "Clinical Research Combined with Professional Care"
and "Non-therapeutic Clinical Research." 96 In the former category, physicians
were required to obtain consent from patient-subjects only when "consistent with
patient psychology." In the latter type of research, the consent requirements were
more absolute: "Clinical research on a human being cannot be undertaken
without his free consent, after he has been fully informed." Another noteworthy
deviation from the Nuremberg Code is Helsinki's allowance (in both therapeutic
and nontherapeutic research) for third-party permission from a legal guardian. 97
As one might predict from the similarity between the changes introduced
by the Declaration of Helsinki and the changes to the Nuremberg Code suggested
by the American participants at the NSMR conference in 1959, the WMA
document met with widespread approval among researchers in this country.
Organizations including the American Society for Clinical Investigation, the
American Federation for Clinical Research, and the American Medical
Association offered their quick and enthusiastic endorsements. 98 Compared with
the lofty, idealized language of the Nuremberg Code, the Helsinki Declaration
may have seemed more sensible to many researchers in the early 1 960s because it
offered rules that more closely resembled research practice in the clinical setting.
CONCLUSION
In the late 1940s American medical researchers seldom recognized that
research with patient-subjects ought to follow the same principles as those applied
to healthy subjects. Yet, as we have seen in this chapter, some of those few who
asked themselves hard questions about their research work with patients
concluded that people who are ill are entitled to the same consideration as those
who are not. That some did in fact reach this conclusion is evidence that it was
not beyond the horizon of moral insight at that time. Nevertheless, they were a
minority of the community of physician researchers, and the organized medical
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profession did not exhibit a willingness to reconsider its responsibilities to
patients in the burgeoning world of postwar clinical research.
While a slowly increasing number of investigators reflected on the ethical
treatment of human subjects during the 1950s, it was not until the 1960s and a
series of highly publicized events with names like "Thalidomide,"
"Willowbrook," and "Tuskegee" that it became apparent that a professional code,
whether it originated in Nuremberg or Helsinki, did not provide sufficient
protection against exploitation and abuse of human subjects of research. In the
next chapter we examine how the federal government became intimately,
extensively, and visibly involved in the regulation of research with human
subjects.
162
ENDNOTES
1 . A detailed recounting of the first series of Nuremberg Trials can be found in
Telford Taylor, The Anatomy of the Nuremberg Trials: A Personal Memoir (New York:
Alfred A. Knopf, 1992). Taylor describes the motivation for the second series of
Nuremberg Trials in the introduction to this book (p. xii). He also mentions that he
"hope[s] later to write a description of these subsequent trials" (p. xii). Taylor served as
an assistant to chief American prosecutor Robert H. Jackson at the first series of trials; he
was the chief prosecutor for the second series, which eventually included twelve separate
trials.
2. United States v. Karl Brandt et al, "The Medical Case, Trials of War
Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10"
(Washington, D.C.: U.S. Government Printing Office, 1949). This two-volume set
contains an abridged set of transcripts from the Nuremberg Medical Trial. A general
timeline for the trial can be found on p. 3 of volume 1 ; the quotation of Taylor's charges
can be found in the reproduction of his opening statement in volume 1, p. 27. The
published trial transcripts provide extensive detail on the experiments carried out by
German medical scientists on inmates at Nazi concentration camps. These experiments
included a long list of brutalities carried out in the name of medical science. Some of
these were specifically related to the Nazi war effort. German investigators conducted
high-altitude tolerance tests for the Luftwaffe using a low-pressure chamber. Scientists
forced prisoners to enter the chamber and subjected them to extreme pressure changes
that resulted in excruciating pain and, sometimes, death. Among these experiments were
human twin studies related to genetics and germ warfare. For example, a series of
experiments involved injecting one twin with a potential germ warfare agent to test the
effects of that agent. If the twin injected with the germ died, the other twin was
immediately killed to compare the the organs between the healthy and the sick twin.
Another series of experiments related to downed airman and shipwrecked sailors who
were faced with deprivation of potable water. In these tests, prisoners were divided into
four groups: the first received no water; a second set was forced to drink ordinary
seawater; the third would drink seawater processed to remove the salty taste (but not the
actual salt); and fourth group could drink desalinated seawater. Many of the subjects in
the first three groups died. German researchers also compelled prisoners to engage in a
variety of other cruel experiments, many of which were concerned with infectious
diseases such as malaria, epidemic jaundice, and typhus. More information can be
found on the Nazi prison camp experiments in several sources including Robert Jay
Lifton, The Nazi Doctors: Medical Killing and the Psychology of Genocide (New York:
Basic Books, 1986); Robert N. Proctor, Racial Hygiene: Medicine under the Nazis
(Cambridge, Mass.: Harvard University Press, 1988); and George J. Annas and Michael
A. Grodin, eds., The Nazi Doctors and the Nuremberg Code: Human Rights in Human
Experimentation (New York: Oxford University Press, 1992).
Japanese medical scientists, especially those associated with a biological warfare
(BW) research corps known as Unit 731, also conducted many cruel medical experiments
during the war. Until recently, these experiments were virtually unknown because
American military and medical officials struck a postwar deal with leading Japanese
scientists associated with Unit 73 1 : immunity from war crimes prosecution in exchange
for exclusive American access to the results of the Japanese BW experiments. The
163
Japanese experiments and the American cover-up have recently received coverage in
Sheldon Harris's Factories of Death: Japanese Biological Warfare, 1932-1945, and the
American Cover Up (London/New York: Routledge, 1994). See also Peter Williams and
David Wallace, Unit 731: The Japanese Army's Secret of Secrets (London: Hodder and
Stoughton, 1989); and John W. Powell, Jr., "Japan's Biological Weapons, 1930-1945,"
Bulletin of the Atomic Scientists 37 (October 1981): 44-53.
3. American Medical Association, Board of Trustees, minutes of the May 1946
meeting, AMA Archive, Chicago, Illinois (ACHRE No. IND-072595-A), 156-157.
4. A full-blown biography of Ivy remains to be written, but some biographical
information can be found in the following brief notices: Carl A. Dragstedt, "Andrew
Conway Ivy," Quarterly Bulletin of the Northwestern University Medical School 1 8
(Summer 1944): 139-140; Morton I. Grossman, "Andrew Conway Ivy (1893-1978),"
Physiologist 21 (April 1978): 1 1-12; D. B. Bill, "A. C. Ivy-Reminiscences,"
Physiologist 22 (October 1979): 21-22.
5. The quotation is taken from Andrew C. Ivy, "Nazi War Crimes of a Medical
Nature," Federation Bulletin 33 (May 1947): 133. Ivy first publicly offered this view of
the Nuremberg prosecutors' confusion about the ethics and legality of human
experimentation when he presented this paper at an annual meeting of the Federation of
State Medical Boards of the United States on 10 February 1947-just a few months after
the start of the Medical Trial. In this presentation Ivy said that he traveled to Germany
in August 1946. In a similar description of his experiences with the Nuremberg
prosecution team published a few years later Ivy reiterates a similar story except that the
date of his initial travel is given as July 1946: A. C. Ivy, "Nazi War Crimes of a Medical
Nature," Journal of the American Medical Association 139(15 January 1 949): 131. An
editorial in JAMA confirms some of the essential elements of Ivy's early work with the
Nuremberg prosecutors (his selection by the AMA Board of Trustees at the request of the
federal government and his travel to Germany "a few months" before November 1946):
"The Brutalities of Nazi Physicians," JAMA 132 (23 November 1946): 714. The basic
narrative of Ivy's selection by the Board of Trustees and his travel to Europe can also be
found in R. L. Sensenich, "Supplementary Report of the Board of Trustees," JAMA 132
(21 December 1946): 1006.
6. American Medical Association, Board of Trustees, minutes of the 16 August
1946 meeting, AMA Archive, Chicago, Illinois (ACHRE No. IND-072595-A), 8-9.
7. American Medical Association, Board of Trustees, minutes of the 19
September 1946 meeting, AMA Archive, Chicago, Illinois (ACHRE No. IND-072595-
A), 51-52.
8. A. C. Ivy, "Report on War Crimes of a Medical Nature Committed in
Germany and Elsewhere on German Nationals and the Nationals of Occupied Countries
by the Nazi Regime during World War II," 1946. This report was not published, but it is
available at the National Library of Medicine. A copy also exists in the AMA Archive
(ACHRE No. DOD-063094-A).
9. United States v. Karl Brandt et ah, "The Medical Case, Trials of War
Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10"
(Washington, D.C.: U.S. Government Printing Office, 1949), 2: 181-182. The judges'
preamble to the Code states that "[a]ll agree . . . that certain basic principles must be
observed in order to satisfy the moral, ethical and legal" aspects of human
experimentation.
164
10. Ivy's recitation of his own set of rules does not appear in the published
abridged transcripts of the trial. See the complete transcripts of the trial, which are
available on microfilm at the National Archives (National Archives Microfilm, M887,
reel 9, 13 June 1947, pp. 9141-9142). Throughout this chapter, we cite the abridged
transcripts wherever possible and the full transcripts only if necessary.
11. Leo Alexander later reproduced his 1 5 April 1 947 memo in two
publications: "Limitations in Experimental Research on Human Beings," Lex et Scientia
3 (January-March 1966): 20-22, and "Ethics of Human Experimentation," Psychiatric
Journal of the University of Ottawa 1 (1976): 42-44. In the 1976 article, Alexander made
a seemingly exaggerated claim to be "the original author of the Nuremberg Code" (p. 40).
Side-by-side comparison of Ivy's rules, Alexander's memo, and the Nuremberg Code
does, however, suggest that the judges drew two original contributions from Alexander's
memo: clauses 6 and 7 of the Nuremberg Code are embedded in the 15 April memo (they
do not appear in Ivy's rules).
12. McHaney's closing statement can be found in the complete microfilm
transcripts of the trial available through the National Archives. McHaney's closing
statement and Alexander's memorandum (and Alexander's claim to authorship of the
Code) are also reproduced in Michael A. Grodin's "Historical Origins of the Nuremberg
Code," in The Nazi Doctors and the Nuremberg Code: Human Rights in Human
Experimentation, 134-137.
13. American Medical Association, Board of Trustees, minutes of the 19
September 1946 meeting, AM A Archive, Chicago, Illinois (ACHRE No. IND-072595-
A).
14. The AM A reports that the records of the Judicial Council for all of the 1940s
have been lost. Personal communication between Marilyn Douros, of the AM A
Archives, and Jon M. Harkness (ACHRE), 19 January 1995.
15. "Supplementary Report of the Judicial Council," proceedings of the House
of Delegates Annual Meeting, 9-1 1 December 1946, JAMA 132 (28 December 1946):
1090. The bracketed addition to rule 1 was added in the final version of statement, which
was approved by the House of Delegates on 1 1 December 1946.
16. William A. Coventry, "Report of the Reference Committee on
Miscellaneous Business," proceedings of the House of Delegates Meeting, 9-1 1
December 1946, JAMA 133 (4 January 1947): 35.
17. Robert Williamson, an AMA archivist, reports that in 1942, 65 percent of
American physicians were members of the AMA, and in 1949, 75 percent of American
physicians were members; he did not have percentage figures available for 1946.
Williamson also provided the absolute number of members for 1946. Personal
communication between Jon M. Harkness (ACHRE) and Robert Williamson, 4 January
1995.
1 8. United States v. Karl Brandt et al. , "The Medical Case, Trials of War
Criminals before the Nuremberg Military Tribunal under Control Council Law No. 10,"
voi. 2, 83.
19. Ibid.
20. Complete transcripts of the Nuremberg Medical Trial, National Archives
Microfilm, M887, reel 9, 13 June 1947, pp. 9168-9170.
2 1 . Susan E. Lederer, Subjected to Science: Experimentation in America before
the Second World War (Baltimore: Johns Hopkins University Press, 1995), 105.
165
22. Lederer recounts the historical details of the yellow fever experiment (pp.
19-23) and explores Reed's powerful legacy (pp. 132-134) in Subjected to Science.
23. Theodore Woodward, interview by Gail Javitt and Suzanne White-Junod
(ACHRE), transcript of audio recording, 14 December 1994 (ACHRE Research Project
Series, Interview Program File, Ethics Oral History Project), 6.
24. Interview with Woodward, 14 December 1994, 10.
25. John D. Arnold, interview by Jon M. Harkness (ACHRE), transcript of
audio recording, 6 December 1994 (ACHRE Research Project Series, Interview Program
File, Ethics Oral History Project), 18.
26. The list of participants exists in the extant records of the LMRI project
available at the Center for Law and Health Sciences, School of Law, Boston University.
The quotation explaining the goal of the meeting is taken from the first page of a
summary of the conference prepared for the project's final report, which was not
published: Anne S. Harris, "The Concept of Consent in Clinical Research: Analytic
Summary of a Conference," chapter 6 in A Study of the Legal, Ethical, and
Administrative Aspects of Clinical Research Involving Human Subjects: Final Report of
Administrative Practices in Clinical Research, fNIHJ Research Grant No. 7039 Law-
Medicine Research Institute, Boston University, 1963 (ACHRE No. BU-053194-A).
27. The National Institutes of Health awarded LMRI almost $100,000 on 1
January 1960 to begin this project, which concluded 31 March 1963. The general
statement of the project's purpose appears in LMRI final report, chapter 1 ("Focus of the
Inquiry"), 1.
28. LMRI final report, chapter 6, 48.
29. Louis Lasagna, interview by Jon M. Harkness and Suzanne White-Junod
(ACHRE), transcript of audio recording, 13 December 1994 (ACHRE Research Project
Series, Interview Program File, Ethics Oral History Project), 5.
30. Ibid., 11.
31. Extensive newspaper clippings related to the Nuremberg Medical Trial exist
in Beecher's personal papers in the Special Collections Department, Countway Library,
Harvard University. Beecher's first major publication on research ethics appeared in early
1959: Henry K. Beecher, "Experimentation in Man," JAMA 169 (31 January 1959): 461-
478. Of course, he is best known for a 1966 article: Henry K. Beecher, "Ethics and
Clinical Research," New England Journal of Medicine 274 (16 June 1966): 1354-1360.
Significantly, Beecher acknowledged in a manuscript copy of the original version of the
NEJM paper, which he presented at a conference for science journalists on 22 March
1965, that "in years gone by work in my laboratory could have been criticized." Beecher,
"Ethics and the Explosion of Human Experimentation," 2a, Beecher Papers, Countway
Library (ACHRE No. IND-072595-A).
32. Jay Katz, "Human Experimentation and Human Rights," St. Louis University
Law Journal 38 (1993): 28.
33. Stanley Joel Reiser, Arthur J. Dyck, and William J. Curran, eds., Ethics in
Medicine: Historical Perspectives and Contemporarv Concerns (Cambridge, Mass.: The
MIT Press, 1977), 7.
34. Otto E. Guttentag, "The Physician's Point of View," Science 1 17 (1953):
207-210; the quotation is from 208. Guttentag's article appeared in Science with three
others that had been presented at the 1951 symposium: Michael B. Shimkin, "The
Researcher Worker's Point of View," 205-207; Alexander M. Kidd, "Limits of the Right
166
of a Person to Consent to Experimentation on Himself," 211-212; and W. H. Johnson,
"Civil Rights of Military Personnel Regarding Medical Care and Experimental
Procedures," 212-215.
35. Guttentag, "The Physician's Point of View," 208.
36. Ibid., 210.
37. John C. Ford, "Notes on Moral Theology," Theological Studies 6 (December
1945): 534-535. Ford's discussion of human experimentation arose in a lengthy and
discursive review of issues and ideas in moral theology. For several years, he contributed
a similar review to each volume of Theological Studies.
38. Transcripts of "Social Responsibility in Pediatric Research" conference, 1
May 1961, 7. LMRI records, Center for Law and Health Sciences, School of Law, Boston
University (ACHRE No. BU-053194-A).
39. "LMRI Final Report," chapter 6, 43.
40. Ibid., 43-44.
41. Ibid., 44.
42. Ibid., 46-47.
43. Committee member and historian Susan Lederer took principal
responsibility for organizing the Ethics Oral History Project, with assistance from several
members of the staff including two historians experienced in the techniques of oral
history. The Committee also drew on advice from several outside experts, including
historians and ethicists, to create a list of potential interviewees and to refine the list of
questions that we wanted to explore during interviews. In total, the Committee
conducted twenty-two interviews in the Ethics Oral History Project. Most of the subjects
were medical researchers whose careers began in the late 1940s or early 1950s, but we
also spoke with some research administrators. In general, we chose to interview
researchers who had exhibited some particular interest in research ethics during their
careers. But this does not mean that we held interviews only with researchers who
viewed recent developments in research ethics in a positive fashion. The interviews were
all recorded on audio tape and professionally transcribed. Interview subjects had an
opportunity to review the transcripts. Complete sets of all transcripts can be found in the
archival records of the Advisory Committee.
44. Interview with Lasagna, 13 December 1994, 13.
45. Paul Beeson, interview by Susan E. Lederer (ACHRE), transcript of audio
recording, 20 November 1994 (ACHRE Research Project Series, Interview Program
File, Ethics Oral History Project), 16-17.
46. Leonard Sagan, interview by Gail Javitt, Suzanne White-Junod, Sandra
Thomas, and John Kruger (ACHRE), transcript of audio recording, 17 November 1994
(ACHRE Research Project Series, Interview Program File, Ethics Oral History Project),
13-14.
47. Ibid., 19-20.
48. Stuart Finch, interview by Gail Javitt, Suzanne White-Junod, and Valerie
Hurt (ACHRE), transcript of audio recording, 6 December 1994 (ACHRE Research
Project Series, Interview Program File, Ethics Oral History Project), 52.
49. Interview with Paul Beeson, 20 November 1994, 39.
50. Thomas Chalmers, interview by Jon Harkness (ACHRE), transcript of audio
recording, 9 December 1994 (ACHRE Research Project Series, Interview Program File,
Ethics Oral History Project), 75.
167
5 1 . Herman Wigodsky, interview by Gail Javitt and Suzanne White-Junod
(ACHRE), transcript of audio recording, 17 January 1995 (ACHRE Research Project
Series, Interview Program File, Ethics Oral History Project), 14.
52. For an analysis and translation of the 1931 German rules see Hans-Martin
Sass, "Reichsrundschreiben 1931: Pre-Nuremberg German Regulations Concerning New
Therapy and Human Experimentation," Journal of Medicine and Philosophy 8 ( 1 983):
99-1 1 1 . A similar analysis and translation of the same set of rules appears in Grodin,
"Historical Origins of the Nuremberg Code," 129-132.
53. Full trial transcripts, 9142.
54. Abridged trial transcripts, 83.
55. Interview with Dr. Herman Wigodsky, 17 January 1995, 16-17.
56. Ruth Faden and Tom Beauchamp, A History and Theory of Informed
Consent (New York: Oxford University Press, 1986), 96.
57. Ivy's several examples ranged from Walter Reed's turn-of-the-century
experiments with yellow fever to wartime malaria experiments in American state and
federal prisons. See page 91 19 of the full trial transcripts for Ivy's discussion of the
Reed experiments and pages 9125-9129 for his description of the malaria experiments
that had taken place in the United States during the war.
58. David J. Rothman, Strangers at the Bedside: A Histoiy of How Law and
Bioethics Transformed Medical Decision Making (New York: Basic Books, 1994), 62.
59. Interview with John Arnold, 6 December 1 994, 9- 1 0.
60. Herbert Abrams, interview by Jon Harkness (ACHRE), transcript of audio
recording, 12 January 1995 (ACHRE Research Project Series, Interview Program File,
Ethics Oral History Project), 25.
61. Dorothy Levenson, Montefwre: The Hospital as Social Instrument, 1884-
1984 (New York: Farrar, Straus & Giroux, 1984). For information on the presence of
Jewish refugee physicians at Montefiore, see pages 154-155.
62. Rothman, Strangers at the Bedside, 62-63.
63. Katz, "The Consent Principle of the Nuremberg Code," 228.
64. William Silverman, interview by Gail Javitt (ACHRE), transcript of audio
recording 14 February 1995 (ACHRE Research Project Series, Interview Program File,
Ethics Oral History Project), 61-62.
65. Ibid., 87-88.
66. "Why Human 'Guinea Pigs' Volunteer," New York Times Magazine, 13
April 1958,62.
67. See, for example, John L. O'Hara, "The Most Unforgettable Character I've
Met," Reader's Digest, May 1948, 30-35; Thomas Koritz, "I Was a Human Guinea Pig,"
Saturday Evening Post, 25 July 1953, 27, 79-80, 82; Don Wharton, "A Treasure in the
Heart of Every Man,'" Reader's Digest, December 1954, 49-53 (condensed from
"Prisoners Who Volunteer, Blood, Flesh-and Their Lives," American Mercuiy,
December 1954, 51-55); Howard Simons, "They Volunteer to Suffer," Saturday Evening
Post, 26 March 1960, 33, 87-88.
68. "Experiments on Prisoners," Science Newsletter (also Science News), 2 1
February 1948,53, 117.
69. "C.O.'s Offer Selves for Atomic Experiments," Christian Century, 20
October 1954, 1260.
168
70. Robert D. Potter, "Are We Winning the War Against TB?" Saturday
Evening Post, 15 January 1949. Cited in Marcel C. LaFollette, Making Science Our
Own: Public Images of Science 1910-1955 (Chicago: University of Chicago Press, 1990),
138-140.
71 . Renee C. Fox, Experiment Perilous: Physicians and Patients Facing the
Unknown (Philadelphia: University of Pennsylvania Press, 1974, first published 1959).
Fox describes her long days of observation on page 15; she discusses the Nuremberg
Code at 46-47.
72. Michael B. Shimkin, As Memory Serves: Six Essays on a Personal
Involvement with the National Cancer Institute, 1938-1978 (Bethesda, Md.: U.S.
Department of Health and Human Services, 1983), 127.
73. Ibid., 128.
74. Ibid., 127.
75. The quotation is a translation from the French in which Pius XII delivered
the address: "II faut remarquer que l'homme dans son etre personnel n'est pas ordonne en
fin de compte a l'utilite de la societe, mais au contraire, la communaute est la pour
rhomme." The French text can be found in the Atti del Primo Congresso Internazionale
di Istopatologia del Sistema Nervosa/Proceedings of the First International Congress of
Neuropathology, Rome, 8-13 September 1952. English translations of the pope's address
appear in a variety of publications including The Linacre Quarterly: Official Journal of
the Federation of Catholic Physicians' Guilds 19 (November 1952): 98-107 and The
Irish Ecclesiastical Record 86 (1954): 222-230.
76. Saul Benison, Tom Rivers: Reflections on a Life in Medicine and Science
(Cambridge, Mass.: MIT Press, 1967), 498.
77. Louis J. Regan, Doctor and Patient and the Law, 2d ed. (St. Louis: C. V.
Mosby, 1949), 398.
78. Louis J. Regan, Doctor and Patient and the Law, 3d ed. (St. Louis: C. V.
Mosby, 1956), 370-372.
79. Report on the National Conference on the Legal Environment of
Medicine,27-28 May 1959 (Chicago: National Society for Medical Research, 1959); the
quotations are from pages 91 and 88, respectively.
80. Henry K. Beecher, "Experimentation in Man," Journal of the American
Medical Association 169(1959): 118/470.
81. Ibid., 121/473.
82. Ibid., 122/474.
83. Ibid., 109/461.
84. Ibid., 119/471.
85. Harvard Medical School, Harvard Medical School Administrative Board,
proceedings of the 6 October 1961 meeting (ACHRE No. HAR-062394-A-3).
86. Memorandum to "GPB" [Harvard Medical School Dean Berry] from "JWG"
[Assistant Dean Gardella] ("Criticisms of 'Principles, Policies and Rules of the Surgeon
General, Department of the Army, relating to the use of Human Volunteers in Medical
Research Contracts awarded by the Army'") (ACHRE No. IND-072595-A), 1.
87. Ibid., 2.
88. Ibid.
89. Ibid., 3.
169
90. Harvard Medical School, Harvard Medical School Administrative Board,
proceedings of 23 March 1962 (ACHRE No. HAR-062394-A-3).
91. Joseph W. Gardella, Assistant Dean, Harvard Medical School to Henry K.
Beecher, Massachusetts General Hospital, 27 March 1962 ("I write to confirm my
impression . . .") (ACHRE No. HAR-062394-A-4).
92. Ibid.
93. Harvard Medical School, Harvard Medical School Administrative Board,
proceedings of 8 June 1962 (ACHRE No. HAR-062394-A-3).
94. Henry Beecher, undated ("Statement Outlining the Philosophy and Ethical
Principles Governing the Conduct of Research on Human Beings at the Harvard Medical
School") (ACHRE No. IND-072595-A).
95. Henry K. Beecher to Lieutenant General Leonard D. Heaton, 12 July 1962
("I have just returned to Boston . . .") (ACHRE No. HAR-062394-A-2).
96. World Medical Association, "Declaration of Helsinki: Recommendations
Guiding Medical Doctors in Biomedical Research Involving Human Subjects," adopted
by the Eighteenth World Medical Assembly, Helsinki, Finland, 1964.
97. "Draft Code of Ethics on Human Experimentation," British Medical Journal
2 (1962): 1119; "Human Experimentation: Code of Ethics of the World Medical
Association," British Medical Journal 2 (1964): 177.
98. Faden and Beauchamp, A History and Theory of Informed Consent, 1 56- 1 57,
and Paul M. McNeill, The Ethics and Politics of Human Experimentation (Cambridge,
U.K.: Press Syndicate of the University of Cambridge, 1993), 44-47. For a more detailed
comparison between the Nuremberg Code and the Declaration of Helsinki, see Jay Katz,
"The Consent Principle of the Nuremberg Code," 231-234.
170
Government Standards for
Human Experiments:
The 1960s and 1970s
1 he year 1974 marks the upper bound for the period of the Advisory
Committee's historical investigation. That year two landmark events in the
history of government policy on research involving human subjects took place:
the promulgation by the Department of Health, Education, and Welfare (DHEW)
of comprehensive regulations for oversight of human subject research and
passage by Congress of the National Research Act. The DHEW regulations set
rules for oversight of human subject research supported by the single largest
funding source for such research, and the National Research Act authorized the
establishment of the National Commission for the Protection of Human Subjects
of Biomedical and Behavioral Research (also known as the National
Commission), which was charged with examining the conduct of research
involving human subjects. In the years following 1974, many of the rules
promulgated by DHEW were subsequently adopted by various other government
agencies, culminating in governmentwide regulations under the Common Rule in
1991.'
In the first part of this chapter, we trace the developments in the 1960s and
early 1970s that influenced and led up to the DHEW regulations and the National
Research Act. These developments included congressional hearings on the
practices of the drug industry and the thalidomide tragedy, critical scholarly
writings, interim policies at DHEW, public outcry over controversial cases of
medical research, and the congressional hearings these cases occasioned. People
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Parti
were surprised and shocked to learn about practices and behaviors they knew to
be wrong. While the ethical principles such practices violated may not have been
well articulated specific to the enterprise of human research, they were part of
individuals' moral consciousness. The history of these events has been well told
before, and we only summarize it here, drawing heavily on the previous work of
other authors. 2
The 1974 regulations were promulgated by DHEW and applied only to
that agency. Likewise, the National Research Act authorized the establishment of
the National Commission and directed it to make recommendations to the
secretary of DHEW. In the latter part of this chapter, we review developments in
policies governing human research during this period in agencies other than
DHEW. This is a history that has received comparatively little scholarly
attention.
In the 1970s, just as DHEW was moving ahead with broad new
regulations, scandal rocked the Department of Defense and the CIA. It was
revealed that, with cooperation from university researchers, these agencies had
engaged in secret experimentation on military and civilian subjects without their
knowledge, sometimes with tragic results. 3 The discovery of the existence of
these secret programs led to further congressional investigations and to a 1975
Department of the Army review of the effectiveness of the 1953 Secretary of
Defense Wilson memorandum adopting the Nuremberg Code. This Army review
led to the eventual declassification of the Wilson memorandum, which had been
Top Secret upon its issuance and remained classified until 1975. It also led, much
later, to litigation in which justices of the U.S. Supreme Court for the first time
commented on the applicability of the Nuremberg Code to actions undertaken by
the U.S. government. 4 The chapter concludes with a discussion of these
important events.
THE DEVELOPMENT OF HUMAN SUBJECT RESEARCH
POLICY AT DHEW
As the largest funding source in the federal government for human subject
research, DHEW led the way in developing regulations aimed at protecting the
rights and welfare of subjects. The evolution of the regulations, which would
eventually be adopted on a government wide basis, was influenced by revelations
of unethical research, congressional reaction to the revelations, and concern over
public perception of such research. That regulations were eventually adopted at
all by DHEW was influenced by the political realities of the time and the lack of
congressional support for a standing regulatory body to oversee human subject
research, as had been recommended by an influential federally appointed panel,
the Tuskegee Syphilis Study Ad Hoc Panel. In a trade-off that would have major
influence on the future of human subject research oversight, the proposed bill
creating the standing regulatory body was withdrawn in exchange for the National
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Chapter 3
Research Act, establishing the National Commission, and an understanding that
DHEW would promulgate the aforementioned regulations. This historical
backdrop is outlined in the rerhainder of this chapter.
The Thalidomide Tragedy and the Congressional Requirement for Patient
Consent
In 1959 a Senate subcommittee chaired by Senator Estes Kefauver of
Tennessee began hearings into the conduct of pharmaceutical companies.
Testimony revealed that it was common practice for drug companies to provide
samples of experimental drugs, whose safety and efficacy had not been
established, to physicians, who were then paid to collect data on their patients
taking these drugs. Physicians throughout the country prescribed these drugs to
patients without their knowledge or consent as part of this loosely controlled
research. These practices and others prompted calls by Kefauver and other
senators for an amendment to the Food, Drug, and Cosmetic Act of 1938 to
address the injuriousness and ineffectiveness of certain drugs. In 1961 the
dangers of new drug uses were vividly exemplified by the thalidomide disaster in
Europe, Canada, and to a lesser degree, the United States. 5 Starting in late 1957,
the sedative thalidomide was given to countless pregnant women and caused
thousands of birth defects in newborn infants (most commonly, missing or
deformed limbs). The thalidomide disaster was widely covered by the television
networks, and the visual impact of these babies stunned viewers and caused
Americans to question the protections afforded those receiving investigational
agents.
It is in large measure because of the thalidomide episode that the 1962
Kefauver-Harris amendments to the Food, Drug, and Cosmetic Act were passed, 6
requiring that informed consent be obtained in the testing of investigational
drugs. 7 While such testing occurred mainly with patients, Congress carefully
avoided interfering in the doctor-patient relationship and in the process severely
reduced the effectiveness of the requirement. Consent was not required when it
was "not feasible" or was deemed not to be in the best interests of the patient—
both judgments made "according to the best judgment of the doctors involved." 8
Despite their being limited in scope, the Kefauver-Harris amendments were
influential in advancing considerations of protections of research subjects first
within the DHEW and later throughout the rest of the government.
NIH and PHS Develop a Uniform Policy to Protect Human Subjects
In late 1963, concerns were raised within NIH by Director James Shannon
after disturbing revelations about two research projects funded in part by the
Public Health Service and NIH. One was the unsuccessful transplantation of a
chimpanzee kidney into a human being at Tulane University, a procedure that
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promised neither benefit to the recipient nor new scientific information. The
transplant was reportedly done with the consent of the patient, but without
consultation or review by anyone other than the medical team involved."
The second was research undertaken in mid- 1963 at the Brooklyn Jewish
Chronic Disease Hospital. There, investigators (the chief investigator, Dr.
Chester M. Southam was a physician at the Sloan-Kettering Cancer Research
Institute, and he received permission to proceed with the work from the hospital's
medical director, Dr. Emmanuel E. Mandel) had undertaken a research project in
which they injected live cancer cells into indigent elderly patients without their
consent. The research went forward without review by the hospital's research
committee and over the objections of three physicians consulted, who argued that
the proposed subjects were incapable of giving adequate consent to participate. 10
The disclosure of the experiment served to make both PHS officials like Shannon
and the Board of Regents of the University of the State of New York, which had
jurisdiction over licensure of physicians, aware of the shortcomings of procedures
in place to protect human subjects. They were further concerned over the public's
reaction to disclosure of the research and the impact it would have on research
generally and the institutions in particular. After a review, the Board of Regents
censured the researchers. They suspended the licenses of Drs. Mandel and
Southam, but subsequently stayed the suspension and placed the physicians on
probation for one year." There were no immediate repercussions for the hospital,
Sloan-Kettering, the university, or PHS, but the case nonetheless profoundly
affected the subsequent development of federal guidelines to protect research
subjects.
To add to the ferment, NIH officials had closely followed the work of the
Law-Medicine Research Institute at Boston University, which issued survey
findings in 1 962 showing that few institutions had procedural guidelines covering
clinical research. 12 And in the year after both the above-mentioned cases came to
light, the World Medical Association issued its Declaration of Helsinki, which set
standards for clinical research and required that subjects give informed consent
prior to enrolling in an experiment. 13 Thus national and world opinion on matters
related to the ethics of human subject research created a climate ripe for changes
in policies and approaches toward research ethics.
Concern over disturbing cases and the growing attention paid to research
ethics prompted NIH director James Shannon to create a committee in late 1 963
under the direction of the NIH associate chief for program development, Robert
B. Livingston, whose office supported centers at which NIH-funded research took
place. The internal committee was charged with studying problems of inadequate
consent and the standards of self-scrutiny involving research protocols and
procedures. The committee was also to recommend a suitable set of controls for
the protection of human subjects in NIH-sponsored research. The Livingston
Committee recognized that ethically questionable research—exemplified by the
research at the Jewish Chronic Disease Hospitals-could wreak havoc on public
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Chapter 3
perception, increase the likelihood of liability, and inhibit research. 14 These
problems made it worthwhile to reconsider central oversight~or lack thereof-for
research contracted out. However, the committee expressed concern over NIH
taking too authoritarian a posture toward research oversight and so argued that it
would be difficult for the agency to assume responsibility for ethics and research
practices. When it issued its report in late 1964, the committee did not
recommend any changes in the current NIH policies and, moreover, cautioned
that "whatever NIH might do by way of designating a code or stipulating
standards for acceptable clinical research would be likely to inhibit, delay, or
distort the carrying out of clinical research. . . ."' 5 In deference to physician
autonomy and traditional regard for the sanctity of the doctor-patient relationship,
the report concluded that NIH was "not in a position to shape the educational
foundations of medical ethics. . . ." 16
Director Shannon did not think the conclusions of the Livingston
Committee went far enough, feeling as he did that NIH should take a position of
increased responsibility for research ethics. 17 Especially in light of the Jewish
Chronic Disease Hospital case and its implications for the NIH, both internally
and in terms of public perception, he felt that a stronger reaction was needed.
Thus, despite the committee's limited conclusions, Shannon and Surgeon General
Luther Terry together decided in 1965 to propose to the National Advisory Health
Council (NAHC), an advisory committee to the surgeon general of the Public
Health Service, 1S that in light of recent problems, the NIH should assume
responsibility for formal controls on individual investigators. 19 At the NAHC
meeting, Shannon argued for impartial prior peer review of the risks research
posed to subjects and questioned the adequacy of the protections of the rights of
subjects. 20
The council's members mostly agreed with Shannon's concerns and three
months later issued a "resolution concerning research on humans" following
Shannon's broad recommendations and endorsing the importance of obtaining
informed consent from subjects:
Be it resolved that the National Advisory Health
Council believes that Public Health Service support
of clinical research and investigation involving
human beings should be provided only if the
judgment of the investigator is subject to prior
review by his institutional associates to assure an
independent determination of the protection of the
rights and welfare of the individual or individuals
involved, of the appropriateness of the methods
used to secure informed consent, and of the risks
and potential medical benefits of the investigation. 21
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What this statement did not do, however, was explain what would count as
informed consent. The NAHC recommendations were accepted by the new
surgeon general, William H. Stewart, and in February 1966 he issued a policy
statement requiring PHS grantee institutions to address three topics by committee
prior review for all proposed research involving human subjects:
This review should assure an independent
determination (1) of the rights and welfare of the
individual or individuals involved, (2) of the
appropriateness of the methods used to secure
informed consent, and (3) of the risks and potential
medical benefits of the investigation. 22
The 1966 PHS policy required that institutions give the funding agency a
written "assurance" of compliance, but like the NAHC recommendations, the
policy spoke strictly to the procedural aspects of informed consent and not to its
meaning and criteria. Substantive informed consent criteria were established for
research at the NIH Clinical Center shortly after the PHS policy was issued, but
this new policy applied only to intramural research, that is, to research undertaken
at the Clinical Center. The Clinical Center policy was important as the first
federal research policy with a specific definition of what constituted informed
consent requirements in the research context. The inclusion of specific consent
requirements in policies applying to extramural research would not occur,
however, until the mid-1970s.
The 1966 PHS policy is significant both for its recognition that patient-
subjects, like healthy subjects, should be included in the consent provisions for
federally sponsored human experimentation and for its attempt to strike a balance
between federal regulation and local control, which continues to this day. Such a
balancing continued the work begun by the AEC, in its provision for local human
use committees as a condition for the use of AEC-supplied isotopes, and the
DOD, in the provision for high-level review of proposed experimentation.
Although a landmark in the government regulation of biomedical research, the
1966 policy was to be revised and changed throughout the decade as biomedical
research drew greater attention and informed consent grew in importance.
While, from the outset, the PHS policy was revised periodically, 23 site
visits by PHS employees to randomly selected institutions revealed a wide range
of compliance. 24 These site visits found widespread confusion about how to
assess risks and benefits, refusal by some researchers to cooperate with the policy,
and in many cases, indifference by those charged with administering research and
its rules at local institutions. Complaints of overworked review committees and
requests for clarification and guidance came from research institutions all over the
country. 25
In response to continued questions about the scope and meaning of the
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Chapter 3
policy, DHEW in 1971 produced The Institutional Guide to DHEW Policy on
Protection of Human Subjects. 2 * Better known as the "Yellow Book" because of
its cover's color, this substantial guide contained both the requirements and
commentary on how the requirements were to be understood and implemented.
The guide provided that informed consent was to be obtained from anyone who
"may be at risk as a consequence of participation" in research-including both
patients and healthy volunteers. 27
As the 1960s progressed, increased discussion of research practices
appeared in both professional literature and the popular press. One person who
advanced the debate in both arenas was Henry Beecher of Harvard Medical
School.
Henry Beecher: The Medical Insider Speaks Out
Henry Beecher, as noted in chapter 2, was an active participant in
professional discussions of ethics in research during the late 1950s and early
1960s. In March 1965, Beecher focused attention on the issues at a conference
for science journalists sponsored by the Upjohn pharmaceutical company. There
Beecher presented a paper discussing twenty-two examples of potentially serious
ethical violations in experiments that he had found in recent issues of medical
journals. 28 (Among them was the Brooklyn Jewish Chronic Disease Hospital
study.) He explained this research had not taken place "in a remote corner, but
[in] . . . leading medical schools, university hospitals, top governmental military
departments, governmental institutes and industry." 29 He also acknowledged that
his own conscience was not entirely clear: "Lest I seem to stand aside from these
matters I am obliged to say that in years gone by work in my laboratory could
have been criticized." 30 Beecher also explained the consciousness-raising purpose
of these revelations with stark clarity: "It is hoped that blunt presentation of these
examples will attract the attention of the uninformed or the thoughtless and
careless, the great majority of offenders." 31
In making this presentation to a group of journalists, Beecher was clearly
breaking with a professional expectation that such matters should be addressed
within the biomedical community. After some reservations on the part of medical
journals, the March 1965 paper having been rejected by at least the Journal of the
American Medical Association (JAMA), Beecher published a revised version in
the New England Journal of Medicine in June 1966. 32 That article, like his
presentation at the conference, indicted the entire biomedical research community
and the journals that published biomedical research results.
Beecher's efforts to focus professional, press, and therefore public
awareness on the conduct of research involving human subjects met with some
success. A July 1965 article in the New York Times Magazine was headlined
"Doctors Must Experiment on Humans~But What Are the Patient's Rights?" 33 In
February 1966, as the PHS issued its first uniform policy for biomedical research,
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more headlines, this time in the Saturday Review, asked, "Do We Need New
Rules for Experimentation on People?" 34 In July 1966, following Beecher's
article in the New England Journal of Medicine and an editorial in JAMA, 35
another article declared "Experiments on People— The Growing Debate." 36 Thus,
by the mid- to late 1960s, professional, governmental, and public attention was all
being drawn to issues of research on human subjects. Revelations of purportedly
unethical treatment of research subjects would not be over by this time, but
changes in policy largely driven by attention from so many corners were
beginning to move toward a more comprehensive approach to research oversight.
Public Attention Is Galvanized: Willowbrook and Tuskegee
From 1956 to 1972 Dr. Saul Krugman of New York University led a study
team at the Willowbrook State School for the Retarded, on Staten Island, New
York. The study was not secret or hidden. (It was one of the twenty-two projects
Beecher discussed as ethically troublesome in his 1966 article.) The
Willowbrook study was discovered by the media beginning in the late 1 960s 37 and
was the subject of further discussion of the case in separate places by Beecher, 38
theologian Paul Ramsey, 39 and physician Stephen Goldby. 40 Noting the high
incidence of hepatitis among the residents of the school, nearly all of whom were
profoundly mentally impaired children and adolescents, Krugman and his
colleagues injected some of them with a mild form of hepatitis serum. The
researchers justified their work on the grounds that the subjects probably would
have become infected anyway, and they hoped to find a prophylaxis for the virus
by studying it from the earliest stages of infection. Before beginning the work,
Krugman discussed it with many physician colleagues and sought approval from
the Armed Forces Epidemiological Board, which approved and funded the
research, 41 and the executive faculty of the New York University School of
Medicine, who approved the research. A review committee for human
experimentation did not exist in 1955, 42 but later, when such a committee was
formed, it too approved the research.
According to Krugman, the parents of each subject signed a consent form
after receiving a detailed explanation of the research, without any pressure to
enroll their child. 43 Some critics argued that the content of the consent form was
itself deceiving, since it seemed to say that children were to receive a vaccine
against the virus. Moreover, charges of coercion arose. It is alleged that parents
who enrolled their children in the study were initially offered more rapid
admission to the school through the hepatitis unit and later found, due to
overcrowding, that the only route for admission of new patients was through the
hepatitis unit. 44 Commentators further argued that the fault in the doctors' study
lay in their deliberate attempt to infect the children, with or without parental
consent, as opposed to studying the course of disease in children who naturally
became sick.
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Chapter 3
Soon after Willowbrook, another research project, the Tuskegee syphilis
study, provoked widespread public outcry when it was revealed the study had
exposed people to unnecessary and serious harm with no prospect of direct
benefit to them. Beginning in 1 932, PHS physicians sought to trace the natural
history of syphilis by observing some 400 African- American men affected by the
disease and another group of approximately 200 African- American men without
syphilis serving as controls. All the subjects lived in or around Tuskegee,
Alabama. Originally designed to be a short-term study in the range of six to eight
months, some investigators successfully argued that the potential scientific value
of longer-term study was so great that the research ought to go on indefinitely.
The subjects were enticed into the study with offers of free medical examinations.
Many of those who came from around the area to be tested by "government
doctors" had never had a blood test before and had no idea what one was. 45 Once
selected to be subjects in the study, the men were not informed as to the nature of
their disease or of the fact that the research held no therapeutic benefit for them.
Subjects were asked to appear for "special free treatments," which included
purely diagnostic procedures such as lumbar punctures. 46
By the mid- 1940s it was becoming clear that the death rate for the infected
men in the study was twice as high as for those in the control group. This was the
period in which penicillin was discovered and soon after began to be used to treat
syphilis, at least in its primary stage. The study was reviewed by PHS officials
and medical societies and reported by a number of journals from the early 1930s
to 1970. In the 1960s a growing number of criticisms began to appear, although
the study was not stopped until 1973.
Thus, men with a confirmed disease were not told of their diagnosis and
were deceived into participating in the study under the guise of its being
therapeutic for unspecified maladies. In addition to exposing the subjects to the
additional harms of participation in the study, the false belief that treatment was
being administered prevented subjects from otherwise seeking medical care for
their disease. As at Willowbrook, a justification given after the fact for the
research was that the disease had appeared in a way that was natural and
inevitable and that the study would be of immense benefit to future patients. 47
Over this forty-year history, at least 28 participants died and approximately 100
more suffered blindness and insanity from untreated syphilis before the study was
stopped.
In 1972, an account of the study was published on the front page of the
New York Times. 4 * In response, DHEW appointed the Tuskegee Syphilis Study
Ad Hoc Panel to review the Tuskegee study as well as the department's policies
and procedures for the protection of human subjects. The work of the ad hoc
panel-which consisted of physicians, a university president, a theologian, an
attorney, and a labor representative-contributed in large measure to the passage
of the first comprehensive regulations for federally sponsored human subjects
research. One member of the ad hoc panel who is also a member of the Advisory
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Committee, Jay Katz, expressed his dismay over the unwillingness or incapacity
of society to mobilize the necessary resources for "treatment" at the beginning of
the study and the deliberate efforts of the investigators to "obstruct the
opportunity for treatment." 49
Despite the fact that the PHS Policy for the Protection of Human Subjects
had been in place for six years by the time the Tuskegee study was revealed, it
was exposed by a journalist rather than by a review committee. Although an
institutional committee had allegedly reviewed the Tuskegee study, the study was
not discontinued until after the recommendation of the ad hoc panel. 50 The human
rights abuses of the Tuskegee study demonstrated the need for both prior and
ongoing review, in that the study was undertaken before prior review
requirements were in place, and the prevailing review policies during the period
of the study were so flawed that the study was allowed to continue.
As a result of their deliberations, the ad hoc panel found that neither
DHEW nor any other agency in the government had adequate policies for
oversight of human subjects research. The panel recommended that the Tuskegee
study be stopped immediately and that remaining subjects be given necessary
medical care resulting from their participation. 51 The panel also recommended
that Congress establish "a permanent body with the authority to regulate at least
all federally supported research involving human subjects." 52 In summary, the
panel concluded that despite the lessons of Nuremberg, the Jewish Chronic
Disease Hospital case, and the Declaration of Helsinki, human subject research
oversight and mechanisms to ensure informed consent were still inadequate and
new approaches were needed to adequately protect the rights and welfare of
human subjects.
Congressional Response to Abuses of Human Subjects: The National
Research Act
Public attention to abuses such as those inflicted on the subjects of the
Tuskegee study increased during the late 1960s and early 1970s. Following the
initial revelations about the Tuskegee syphilis study, several bills were introduced
in Congress to regulate the conduct of human experimentation. In February 1973
Senator Edward Kennedy held hearings on these bills; 53 the Tuskegee study;
experimentation with prisoners, children, and poor women; and a variety of other
issues related to biomedical research and the need for a national body to consider
the ethics of research and advancing medical technology. 54 After the hearings,
Senator Kennedy introduced an unsuccessful bill to create a National Human
Experimentation Board, as recommended by the Tuskegee Syphilis Study Ad Hoc
Panel. When it became clear, however, that the bill would not be successful,
Senator Kennedy introduced the bill that would become the National Research
Act, endorsing the regulations about to be promulgated by DHEW and
establishing the National Commission for the Protection of Human Subjects of
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Chapter 3
Biomedical and Behavioral Research, in return for DHEW's issuance of human
subject research regulations. 55 The trade-off was clear: no national regulatory
body in return for regulations applying to the research funded or performed by the
government agency responsible for the greatest proportion of human subject
research. This meant that the goal of oversight of all federally funded research
would not be achieved and that whatever oversight did exist was left to the
funding agencies rather than an independent body.
On May 30, 1974, DHEW published regulations for the use of human
subjects in the Federal Register. 5 " These regulations required that each grantee
institution form a committee (what became known as an institutional review
board, or IRB) to approve all research proposals before they were passed to
DHEW for funding consideration. These committees were charged with
reviewing the safety of the proposals brought to them as well as the adequacy of
the informed consent obtained from each subject prior to participation in the
research. Additionally, the regulations defined not only the procedure for
obtaining informed consent but substantive criteria for it as well. Shortly after the
announcement of the DHEW regulations, in July 1974, the National Research Act
was passed, and with it came the establishment of the National Commission. 57
The National Commission-charged with advising the secretary of DHEW
(though the National Research Act did not require the secretary to follow the
commission's recommendations)--existed over the next four years and published
seventeen reports and appendix volumes. During its tenure, the commission did
pioneering work as it addressed issues of autonomy, informed consent, and third-
party permission, particularly in relation to research involving vulnerable subjects
such as prisoners, children, and people with cognitive disabilities. It was also
charged with examining the IRB system and procedures for informed consent, as
background for proposing guidelines that would ensure that basic ethical
principles were instituted in the research oversight system and in research
involving vulnerable populations.
In the course of its deliberations, the commission identified three general
moral principles-respect for persons, beneficence, and justice-as the appropriate
framework for guiding the ethics of research involving human subjects. These
three are known as the Belmont principles because they appeared in The Belmont
Report, one of the commission's major publications. 58
The National Commission was required to examine the "nature and
definition" of informed consent as well as the "adequacy" of current practices. In
its reports, the commission decisively argued that the basic justification for
obligations to obtain informed consent is the moral principle of respect for
persons. This emphasis on respect for persons meant a great premium was put on
autonomous decision making by the research subject, an emphasis that continues
to the current day.
While it may not have been the intent of those who sponsored it, the
National Research Act-because it was limited to DHEW-funded research-did
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not ensure that all federally sponsored research would be subject to requirements
for informed consent and prior review. Nonetheless, by this time, as described
below, published policies within the DOD, the AEC, the VA, and NASA did meet
these requirements.
The passage of the National Research Act and the promulgation of
DHEW's regulations were important milestones in the development of federal
standards for the protection of human subjects of research. They represented the
first national recognition of the need to protect human subjects. Moreover, they
attempted to provide for that protection through the IRB requirement and
establishment of the National Commission. The Advisory Committee's charter
requires that it examine the standards for research between 1944 and 1974. These
two landmark events in 1974 ushered in a new era in which the conduct and
oversight of biomedical experimentation with humans remained a topic of
national scrutiny and debate. Eventually, the approaches required by the 1974
DHEW regulations would be applied to nearly all federally sponsored human
research, as described in chapter 14.
THE DEVELOPMENT OF REQUIREMENTS FOR HUMAN
SUBJECT RESEARCH IN OTHER FEDERAL AGENCIES
The history and evolution of human subject research policy in the federal
government is well documented for DHEW. However, many other agencies,
most notably the military services, have important but less well-documented and
less well-studied histories. Some of this history is described in chapter 1 of this
report. Here we continue with a brief treatment of that history in the context of
the evolution of human subject research policy.
Army Policy
In 1962 the Army, for the first time, issued as a formal regulation, Army
Regulation (AR) 70-25, the 1953 policy embodied in the Wilson memorandum.
The regulation made explicit, as the 1953 DOD and Army policies had only left
implicit, basic issues about the scope of the DOD's rules. Unlike the Wilson
memorandum, the new regulation applied to all types of research, not simply that
related to atomic, biological, and chemical warfare. However, the regulation
specifically excluded clinical research, that is, the research likely to be performed
with patients at the Army's many hospitals. In 1963, an ad hoc committee of
Army and civilian personnel concluded that the rule applied where research was
done by contractors; however, tracer research (which arguably posed minimal
risk) was excluded. 59 Despite the committee's recommendations, no immediate
changes were made to the regulation. In 1963, however, the Army issued a
regulation for radioisotope use that required local institutions to convene review
committees and obtain approval from the secretary of the Army pursuant to AR
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Chapter 3
70-25 when radioisotopes were to be used with "volunteer" experimental
subjects. 60
The regulatory void apparently persisted until 1973, when another rule
(AR 40-38, "Medical Services-Clinical Investigation Program") closed the gap.
That rule clearly applied to "any person who may be at risk because of
participation . . . [in] clinical investigation," including "patients" and "normal
individuals." 61 It required that subjects of research be given an explanation of the
proposal in understandable language and sign a "volunteer agreement." 62
Moreover, clinical research with patients, as well as healthy people, was to be
reviewed by a "Human Use Committee." 63
Navy Policy
As we saw in chapter 1 , the Navy had required oral consent from research
volunteers since at least 195 1. Some evidence suggests that written consent was
required in the mid-1960s; in a 1964 proposal to study the effects of hypoxia on
service personnel it is indicated that a "signed Consent to Voluntarily Participate
in Research Experiment (NMRI Form 3)" would be used. 64 In 1967 a clear
requirement for written consent appeared in the Navy's Medical Department
manual. 65 It is unclear whether the policy drew a distinction between research on
patients and research on healthy subjects. In 1969, in any event, the secretary of
the Navy issued a comprehensive policy requiring written informed consent of
research subjects, which appeared to cover both groups. 66
Air Force Policy
In 1965 the Air Force promulgated AFR 169-8, "Medical Education and
Research— Use of Volunteers in Aerospace Research," which required voluntary
and written informed consent from all subjects in any "research, development,
test, and evaluation" that may involve "distress, pain, damage to health, physical
injury, or death." 67 As such, it seems inclusive of both healthy and patient-
subjects. 68 Updating the language of the Nuremberg Code's first principle, the
policy was based on the idea that the "voluntary informed consent of the human
subject is absolutely essential." 69 Additionally, the regulation provided for the
appointment of a committee to review all human research proposals at each
originating facility.
NASA Policy
The National Aeronautics and Space Administration (NASA), created in
1958, inherited staff and research expertise from the DOD and other federal
agencies. Before 1968, local centers at which research using radioisotopes was
conducted-notably the Ames Research Center and the Manned Spacecraft Center
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Part I
(MSC)-were essentially autonomous. Each center established medical use
subcommittees, as required by AEC rules.™ Reorganization within NASA in
1 968 combined the medical operations functions and the medical research
functions at MSC into one medical research and operations directorate headed by
Dr. Charles A. Berry.
By 1968, Ames had a policy requiring informed consent. 71 By definition,
of course, the work of astronauts is frequently risky and experimental. The
question of the proper boundary between experimental and occupational activities
was one that could not be drawn easily. Consequently, the policy authorized the
director of Ames to waive the consent requirement in several instances, including
when obtaining consent would seriously hamper the research or when test pilots
or astronauts were involved. 72
Between 1968 and 1970, prior review for risk and subject consent was
adopted at Ames in the form of the Human Research Experiments Review Board
and indirectly at the MSC in accordance with the AEC requirements for a medical
use committee. 73 In 1972 the prior review provisions and consent requirements of
Ames and the MSC were reformulated in a NASA-wide policy. 74 This policy
required voluntary and written informed consent from subjects prior to
participation. The policy continued to provide waivers for "exceptional cases," as
in the Ames policy, and did not apply to research conducted by NASA contractors
or grantees.
The development of NASA's polices, like those at the PHS, NIH, and the
DOD, appeared at a time when the public was becoming increasingly interested in
biomedical research. In contrast with the 1940s and 1950s, bureaucratic
developments during the 1960s and 1970s were mirrored by growing public
debate about the adequacy of protections for human subjects.
SUPREME COURT DISSENTS INVOKE THE NUREMBERG
CODE: CIA AND DOD HUMAN SUBJECTS RESEARCH
SCANDALS
As we have seen, the development of federal legislation for government-
sponsored research with human subjects arose in part because of institutional and
governmental concern and public reaction to perceived abuses and failures by the
government. Around the same time that the 1974 National Research Act was
enacted, a scandal arose surrounding the discovery of secret Cold War chemical
experiments conducted by the CIA and DOD. The review of these experiments
led to the rediscovery of the previously secret 1953 Wilson memorandum and
later to the first Supreme Court decision in which comment was made, in dissent,
on the application of the Nuremberg Code to the conduct of the U.S. government.
In December 1974, the New York Times reported that the CIA had
conducted illegal domestic activities, including experiments on U.S. citizens,
during the 1 960s. That report prompted investigations by both Congress (in the
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Chapter 3
form of the Church Committee) and a presidential commission (known as the
Rockefeller Commission) into the domestic activities of the CIA, the FBI, and
intelligence-related agencies of the military. In the summer of 1975,
congressional hearings and the Rockefeller Commission report revealed to the
public for the first time that the CIA and the DOD had conducted experiments on
both cognizant and unwitting human subjects as part of an extensive program to
influence and control human behavior through the use of psychoactive drugs
(such as LSD and mescaline) and other chemical, biological, and psychological
means. They also revealed that at least one subject had died after administration
of LSD. Frank Olson, an Army scientist, was given LSD without his knowledge
or consent in 1953 as part of a CIA experiment and apparently committed suicide
a week later. 75 Subsequent reports would show that another person, Harold
Blauer, a professional tennis player in New York City, died as a result of a secret
Army experiment involving mescaline. 76
The CIA program, known principally by the codename MKULTRA,
began in 1950 and was motivated largely in response to alleged Soviet, Chinese,
and North Korean uses of mind-control techniques on U.S. prisoners of war in
Korea. Because most of the MKULTRA records were deliberately destroyed in
1973 by order of then-Director of Central Intelligence Richard Helms, it is
impossible to have a complete understanding of the more than 150 individually
funded research projects sponsored by MKULTRA and the related CIA
programs. 77 Central Intelligence Agency documents suggest that radiation was
part of the MKULTRA program and that the agency considered and explored uses
of radiation for these purposes. 78 However, the documents that remain from
MKULTRA, at least as currently brought to light, do not show that the CIA itself
carried out any of these proposals on human subjects.
The congressional committee investigating the CIA research, chaired by
Senator Frank Church, concluded that "[p]rior consent was obviously not
obtained from any of the subjects." 7 " The committee noted that the "experiments
sponsored by these researchers . . . call into question the decision by the agencies
not to fix guidelines for experiments." 80 (Documents show that the CIA
participated in at least two of the DOD committees whose discussions, in 1952,
led up to the issuance of the Wilson memorandum.) Following the
recommendations of the Church Committee, President Gerald Ford in 1976 issued
the first Executive Order on Intelligence Activities, which, among other things,
prohibited "experimentation with drugs on human subjects, except with the
informed consent, in writing and witnessed by a disinterested party, of each such
human subject" and in accordance with the guidelines issued by the National
Commission. 81 Subsequent orders by Presidents Carter and Reagan expanded the
directive to apply to any human experimentation. 82
Following on the heels of the revelations about CIA experiments were
similar stories about the Army. In response, in 1975 the secretary of the Army
instructed the Army inspector general to conduct an investigation. 83 Among the
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Part I
findings of the inspector general was the existence of the then-still-classified 1953
Secretary of Defense Wilson memorandum. In response to the inspector general's
investigation, the Wilson memorandum was declassified in August 1975. The
inspector general also found that the requirements of the 1953 memorandum had.
at least in regard to Army drug testing, been essentially followed as written. The
Army used only "volunteers" for its drug-testing program, with one or two
exceptions." 4 However, the inspector general concluded that the "volunteers were
not fully informed, as required, prior to their participation; and the methods of
procuring their services, in many cases, appeared not to have been in accord with
the intent of Department of the Army policies governing use of volunteers in
research." 85 The inspector general also noted that "the evidence clearly reflected
that every possible medical consideration was observed by the professional
investigators at the Medical Research Laboratories." 86 This conclusion, if
accurate, is in striking contrast to what took place at the CIA.
The revelations about the CIA and the Army prompted a number of
subjects or their survivors to file lawsuits against the federal government for
conducting illegal experiments. Although the government aggressively, and
sometimes successfully, sought to avoid legal liability, several plaintiffs did
receive compensation through court order, out-of-court settlement, or acts of
Congress. Previously, the CIA and the Army had actively, and successfully,
sought to withhold incriminating information, even as they secretly provided
compensation to the families. 87 One subject of Army drug experimentation,
James Stanley, an Army sergeant, brought an important, albeit unsuccessful, suit.
The government argued that Stanley was barred from suing it under a legal
doctrine—known as the Feres doctrine, after a 1950 Supreme Court case, Feres v.
United States—that prohibits members of the Armed Forces from suing the
government for any harms that were inflicted "incident to service." 88
In 1987, the Supreme Court affirmed this defense in a 5-4 decision that
dismissed Stanley's case. 89 The majority argued that "a test for liability that
depends on the extent to which particular suits would call into question military
discipline and decision making would itself require judicial inquiry into, and
hence intrusion upon, military matters." 90 In dissent, Justice William Brennan
argued that the need to preserve military discipline should not protect the
government from liability and punishment for serious violations of constitutional
rights:
The medical trials at Nuremberg in 1947 deeply
impressed upon the world that experimentation with
unknowing human subjects is morally and legally
unacceptable. The United States Military Tribunal
established the Nuremberg Code as a standard
against which to judge German scientists who
experimented with human subjects. . . . [I]n
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Chapter 3
defiance of this principle, military intelligence
officials . . . began surreptitiously testing chemical
and biological materials, including LSD. 91
Justice Sandra Day O'Connor, writing a separate dissent, stated:
No judicially crafted rule should insulate from
liability the involuntary and unknowing human
experimentation alleged to have occurred in this
case. Indeed, as Justice Brennan observes, the
United States played an instrumental role in the
criminal prosecution of Nazi officials who
experimented with human subjects during the
Second World War, and the standards that the
Nuremberg Military Tribunals developed to judge
the behavior of the defendants stated that the
'voluntary consent of the human subject is
absolutely essential ... to satisfy moral, ethical, and
legal concepts.' If this principle is violated, the very
least that society can do is to see that the victims are
compensated, as best they can be, by the
perpetrators. 92
This is the only Supreme Court case to address the application of the
Nuremberg Code to experimentation sponsored by the U.S. government. 93 And
while the suit was unsuccessful, dissenting opinions put the Army-and by
association the entire government-on notice that use of individuals without their
consent is unacceptable. The limited application of the Nuremberg Code in U.S.
courts does not detract from the power of the principles it espouses, especially in
light of stories of failure to follow these principles that appeared in the media and
professional literature during the 1960s and 1970s and the policies eventually
adopted in the mid-1970s.
CONCLUSION
The 1960s and early 1970s witnessed an extraordinary growth in
government, institutional, and public awareness of issues in the use of human
subjects, fueled by scandals and an increasing emphasis on individual expression.
The branches of the military had articulated policies during this period, in spite of
numerous problems in implementation. By 1974 the DHEW had established a set
of regulations and a system of local review, and Congress had established a
commission to issue recommendations for further change to the DHEW.
Together, these advances created a model and laid the groundwork for human
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Parti
subjects protections for all federal agencies.
Many conditions coalesced into the framework for the regulation of the
use of human subjects in federally funded research that is the basis for today's
system. Described further in chapter 14, this framework is undergirded by the
three Belmont principles that were identified by the National Commission as
governing the ethics of research with human subjects: respect for persons,
beneficence, and justice. The federal regulations and the conceptual framework
built on the Belmont principles became so widely adopted and cited that it might
be argued that their establishment marked the end of serious shortcomings in
federal research ethics policies. Whether this position is well supported is
evaluated in light of the Advisory Committee's contemporary studies in part III.
By 1974, DHEW had extensive policies to protect human subjects within
its purview. Policies were more variable among other government agencies. By
1975, the branches of the military set about developing their own more
comprehensive policies for human subject research, and the CIA was required by
executive order to comply with consent requirements in human subject research in
light of scandalous practices in the past. In order to evaluate the adequacy of the
efforts taken to protect people before these policies were established, we must
take into account both the government's policies and rules and the norms and
practices of medicine reviewed in chapters 1 through 3. The Advisory
Committee's framework for the consideration of these factors is presented in the
next chapter.
188
ENDNOTES
1 For a discussion of the development of the Common Rule, see chapter 1 4.
2 We relied particularly on Ruth R. Faden and Tom L. Beauchamp, A History
and Theory of Informed Consent (New York: Oxford University Press, 1986). Other
excellent sources include Jay Katz, Experimentation with Human Beings (New York:
Russell Sage Foundation, 1972), and Robert Levine, Ethics and Regulation of Clinical
Research (Baltimore: Urban and Schwarzenberg, 1981).
3 U S. Congress, The Select Committee to Study Governmental Operations
with Respect to Intelligence Activities, Foreign and Military Intelligence [Church
Committee report], report no. 94-755, 94th Cong., 2d Sess. (Washington, D.C.: GPO,
1976). Also, U.S. Army Inspector General, Use of Volunteers in Chemical Agent
Research [Army IG report] (Washington, D.C.: 1975).
4 In dissenting opinions, four justices of the U.S. Supreme Court (Brennan,
Marshall, Stevens, and O'Connor) cited the Nuremberg Code. United States et al. v.
Stanley, 483 U.S. 669, 687, 710 (1987). u ,,-^ t t tW
" 5. Thalidomide was only available in clinical trials in the United States at that
time but was approved for use in a number of other countries.
6 Louis Lasagna, interview by Susan White-Junod and Jon Harkness
(ACHRE) transcript of audio recording, 13 December 1994 (ACHRE Research Project
Series Interview Program Files, Ethics Oral History Project), 37-38. See also, Louis
Lasagna "1938-1968: The FDA, the Drug Industry, the Medical Profession, and the
Public," in Safeguarding the Public: Historical Aspects of Medicinal Drug Control, ed.
John B. Blake (Baltimore: The Johns Hopkins Press, 1970), 173.
7 Food Drug and Cosmetic Act amendments, 21 U.S.C. § 355 (1962).
8* Congressional Record, 87th Cong, 2d Sess., 22042, as cited in an attached
memorandum, C. Joseph Stetler, Pharmaceutical Manufacturers Association, to James L.
Goddard M.D., Commissioner of Food and Drugs, DHEW, 1 1 October 1966
("Regarding Statement Appearing in August 30, 1966 Federal Register Concerning
Clinical Investigation of Drugs") (ACHRE No. HHS-090794-A).
9 Keith Reemtsma et al., "Reversal of Early Graft Rejection after Renal
Heterotransplantation in Man," Journal of the American Medical Association 1 87
(1964): 691-696.
1 This research, conducted by Dr. Chester Southam of Sloan-Kettenng
Institute and Dr. Emmanuel Mandel of the Jewish Chronic Disease Hospital in 1963 and
funded by the U.S. Public Health Service and the American Cancer Society, raised
concern within PHS and brought about an investigation by the hospital. Drs. Mandel and
Southam were subject to a disciplinary hearing before the Board of Regents of the
University of the State of New York. The hospital's internal review and a suit against
the hospital prompted concern and debate at the NIH. Edward J. Rourke, Assistant
General Counsel, NIH, to Dr. Luther L. Terry, Surgeon General, 16 September 1965
("Research Grants-Clinical-PHS responsibility-Fin* v. Jewish Chronic Disease
Hospital [New York Supreme Court, Kings County]") (ACHRE No. HHS-090794-A).
For a more thorough discussion of this case, see Katz, Experimentation with
Human Beings, 9-65.
11. In 1967 Dr. Southam was elected vice president of the American
Association for Cancer Research and became president the following year. Katz,
189
Experimentation with Human Beings, 63 and 65.
12. For a fuller discussion of the Law-Medicine Research Institute, see chapter
2.
13. The development of the Declaration of Helsinki is discussed briefly in
chapter 2.
14. Robert B. Livingston, Associate Chief for Program Development,
Memorandum to the Director, NIH, 4 November 1964 ("Progress Report on Survey of
Moral and Ethical Aspects of Clinical Investigation" [the Livingston report]) (ACHRE
No. HHS-090795-A), 3.
15. Ibid., 7.
16. Ibid.
17. Mark S. Frankel, "Public Policymaking for Biomedical Research: The Case
of Human Experimentation" (Ph.D. diss., George Washington University, 9 May 1976),
50-51.
1 8. The NAHC discussed the "general question of the ethical, moral, and legal
aspects of clinical investigation" at its meetings of September and December 1965.
Terry's interest in this was motivated in part by the concern of Senator Jacob K. Javits
that the informed consent provisions of the 1962 Drug Amendments were not applicable
to nondrug-related research. See (a) draft letter to Senator Javits from the Surgeon
General, 15 October 1965; (b) Senator Javits to Luther L. Terry, Surgeon General, 15
June 1965; and (c) Edward J. Rourke, Assistant General Counsel, to William H. Stewart,
Surgeon General, 26 October 1965. All in ACHRE No. HHS-090794-A.
19. Transcript of the NAHC meeting, Washington, D.C., 28 September 1965.
See Faden and Beauchamp, A History and Theory of Informed Consent, 208.
20. Ibid.
21 . Dr. S. John Reisman, the Executive Secretary, NAHC, to Dr. James A.
Shannon, 6 December 1965 ("Resolution of Council") (ACHRE No. HHS-090794-A).
22. Surgeon General, Public Health Service to the Heads of the Institutions
Conducting Research with Public Health Service Grants, 8 February 1966 ("Clinical
research and investigation involving human beings") (ACHRE No. HHS-090794-A).
This policy was distributed through Bureau of Medical Services Circular no. 38, 23 June
1966 ("Clinical Investigations Using Human Beings As Subjects") (ACHRE No. HHS-
090794-A).
23. In December 1966 the policy was expanded to include behavioral as well
as medical research. William H. Stewart, Surgeon General, Public Health Service, to
Heads of Institutions Receiving Public Health Service Grants, 12 December 1966
("Clarification of procedure on clinical research and investigation involving human
subjects") (ACHRE No. HHS-072894-B), 2.
In 1967 the Public Health Service required that intramural research, including
that conducted at NIH, abide by similar requirements. William H. Stewart, Surgeon
General of the Public Health Service, to List, 30 October 1967 ("PHS policy for
intramural programs and for contracts when investigations involving human subjects are
included") (ACHRE No. HHS-072894-B), 2.
24. Frankel, "Public Policymaking for Biomedical Research: The Case of
Human Experimentation," 161.
25. Ibid., 161-162.
26. U.S. Department of Health, Education, and Welfare, The Institutional
Guide to DHEW Policy on Protection of Human Subjects (Washington, D.C.: GPO,
190
1971) (ACHRE No. HHS-090794-A).
27. Ibid., 1-2.
28. Beecher's criticism involved many aspects of the research, including the
risk assessment, usefulness of the research, and the question of informed consent. On
this last point, Beecher argued that while consent was important, he disputed the belief
that it was easily obtainable. In his talk at Brook Lodge, Beecher questioned the "naive
assumption implicit in the Nuremberg Code," that consent was readily obtainable.
Beecher indicated the difficulty of obtaining truly informed consent may have led many
researchers to treat the provision cavalierly and often to ignore it. Henry K. Beecher,
"Ethics and the Explosion of Human Experimentation," unpublished manuscript of paper
presented 22 March 1965, "a," Beecher Papers, Countway Library (ACHRE No. IND-
072595-A).
29. lbid.,"a" and "b."
30. Ibid., 2a.
31. Ibid., 2.
32. H. K. Beecher, "Ethics and Clinical Research," New England Journal of
Medicine 274(1966): 3354-1360.
33. W. Goodman, "Doctors Must Experiment on Humans~But What are
Patients Rights?" New York Times Magazine, 2 July 1965, 12-13, 29-33, as cited in
Faden and Beauchamp, A History and Theory of Informed Consent, 1 88.
34. J. Lear, "Do We Need New Rules for Experimentation on People?"
Saturday Review, 5 February 1966, 61-70.
35. Henry K. Beecher, "Consent in Clinical Experimentation: Myth and
Reality," Journal of the American Medical Association 1 95 ( 1 966): 34-35.
36. J. Lear, "Experiments on People-The Growing Debate," Saturday Review,
2 July 1966,41-43.
37. Both the New York Times and the Wall Street Journal ran stories on 24
March 1971. See Medical World News, 15 October 1971, "Was Dr. Krugman Justified
in Giving Children Hepatitis?"
38. Beecher, Research and the Individual: Human Studies (Boston: Little,
Brown, and Company, 1970), 122-127.
39. Paul Ramsey, The Patient as Person: Explorations in Medical Ethics (New
Haven: Yale University Press, 1970), 51-55.
40. In a letter to the Lancet, Dr. Stephen Goldby called the work "unjustifiable"
and asked, "Is it right to perform an experiment on a normal or mentally retarded child
when no benefit can result to the individual?" (S. Goldby, "Letters to the Editor," Lancet
7702 [1971]: 749). The Lancet editors agreed with Goldby. On this side of the Atlantic,
however, the editors of NEJM and JAMA, among others, defended Krugman's work.
41. Armed Forces Epidemiological Board, minutes of 24 May 1957 (ACHRE
No. NARA-032495-B).
42. S. Krugman, "Ethical Practices in Human Experimentation," text of lecture
presented at the Fifth Annual Midwest Student Medical Research Forum, 1 March 1974
(ACHRE No. IND-072895-A).
43. Ibid., 3-4.
44. Louis Goldman, "The Willowbrook Debate," World Medicine (September
1971 and November 1971): 23, 25.
45. James H. Jones, Bad Blood (New York: Free Press, 1993 edition), 1 14.
191
46. Jones, Bad Blood (1981), 69-7 1 ; Levine, Ethics and Regulation of Clinical
Research, 70.
47. Charles J. McDonald, "The Contribution of the Tuskegee Study to Medical
Knowledge," Journal of the National Medical Association (January 1 974): 1 - 1 1 , as cited
in Faden and Beauchamp, A History and Theory of Informed Consent, 194-195.
48. Jean Heller, "Syphilis Victims in U.S. Study Went Untreated for 40
Years," New York Times (26 July 1972) 1, 8, as cited in Faden and Beauchamp, A
History and Theory of Informed Consent, 195.
49. U.S. Department of Health, Education, and Welfare, Final Report of the
Tuskegee Syphilis Study Ad Hoc Panel (Washington, D.C.: GPO, 1 973), Jay Katz
Concurring Opinion, 14.
50. Ibid.
51. Ibid., 21-32.
52. Ibid., 23.
53. Senator Jacob Javits introduced legislation that would have made the
DHEW policy a regulation backed by federal law. S. 878 and S. 974, 93d Cong., 1st
Sess. (1973).
Senator Hubert Humphrey introduced a bill to create a National Human
Experimentation Standards Board~a separate federal agency with authority over research
similar to the Security and Exchange Commission's authority over securities transactions.
S. 934, 93d Cong., 1 st Sess. ( 1 973).
Also, Senator Walter Mondale introduced a resolution to provide for a "study
and evaluation of the ethical, social, and legal" aspects of biomedical research. S.J. Res.
71, 93d Cong., 1st Sess. (1973).
54. It is worth noting here that Senator Kennedy had convened similar hearings
two years previously, in 1971, to consider the establishment of a national commission to
examine "ethical, social, and legal implications of advances in biomedical research."
Among the topics mentioned in this hearing was the total-body irradiation research
sponsored by the Department of Defense at the University of Cincinnati, which we
discuss in chapter 8.
55. Jay Katz, "Human Experimentation: A Personal Odyssey," IRB 9, no. 1
(January/February 1987): 1-6.
56. Protection of Human Subjects, 39 Fed. Reg. 105, 18914-1 8920 (1974) (to
be codified at 45 C.F.R. §46).
57. National Research Act of 1974. P.L. 348, 93d Cong., 2d Sess. (12 July
1974).
58. U.S. Department of Health, Education, and Welfare, Office for Protection
from Research Risks, 18 April 1979, OPPR Reports [The Belmont Report] (ACHRE No.
HHS-011795-A-2), 4-20.
59. Interestingly, this committee included Henry Beecher, who, as was
discussed in part I, chapter 3, had objected to the imposition of these requirements to
contract research in 1961 . Beecher's presence on the committee testifies to the common
relationship between military and private research during this time. Like many of the
AFEB members and commissioners, many of the members of the ad hoc panel were
nonmilitary consultants to the DOD.
60. Department of the Army, Army Regulation 40-37, 12 August 1963
("Radioisotope License Program [Human Use]").
192
61. Department of the Army, AR 40-38, 23 February 1973 ("Medical Services-
Clinical Investigation Program").
62. Ibid.
63. Ibid.
64. Commanding Officer, Naval Medical Research Institute, National Naval
Medical Center, to Secretary of the Navy, 30 November 1964 ("Authorization to use
human volunteers as subjects for study of effects of hypoxia on the visual field; request
for") (ACHRE No. DOD-091494-A), 2.
65. Department of the Navy, "Manual of the Medical Department," 20-8,
Change 36, 7 March 1967 ("Use of Volunteers in Medical or Other Hazardous
Experiments") (ACHRE No. DOD-091494-A).
66. Department of the Navy, SecNav Instruction 3900.39, 28 April 1969 ("Use
of volunteers as subjects of research, development, tests, and evaluation").
67. Department of the Air Force, AFR 169-8, 8 October 1965 ("Medical
Education and Research—Use of Volunteers in Aerospace Research").
68. Ibid.
69. Ibid.
70. National Aeronautics and Space Administration, Manned Spacecraft
Center, MSCI 1860.2, 12 May 1966 ("Establishment of MSC Radiological Control
Manual and Radiological Control Committee") (ACHRE No. NASA-022895-A), 3.
National Aeronautics and Space Administration, "Ames Management Manual
7170-1," 15 January 1968 ("Human Research Planning and Approval") (ACHRE No.
NASA- 120894- A), 3.
71 . Ames required the voluntary, written informed consent of the subject and
stipulated that consent be informed by an
explanation to the subject in language understandable to
him . . . [including] the nature, duration, and purpose of
the human research; the manner in which it will be
conducted; and all foreseeable risks, inconveniences and
discomforts.
"Ames Management Manual 7170-1," 15 January 1968, 3.
72. The Ames director was authorized to waive the consent requirements (a)
when the requirements would "not be necessary to protect the subject"; (b) when the
research uses "classes of trained persons who knowingly follow a specialized calling or
occupation which is generally recognized as hazardous," including "test pilots and
astronauts"; and (c) when the research "would be seriously hampered" by compliance.
"Ames Management Manual 7170-1," 15 January 1968, 3.
73. For example, one review from this group recommended changes in a
consent form to include
[T]he part of the procedure you are consenting to which
principally benefits the research program and is not part
of your treatment is known as arterial puncture. . . .
These risks will be explained to you in detail if you so
desire. The entire procedure, including the diagnostic
radioscan, takes about an hour.
193
Although this proposed consent form does not delineate the medical risks posed by the
procedure, its statement that the patient's participation is incidental to treatment may
provide a greater opportunity for the patient to make an informed decision about
participation. George A. Rathert, Jr., Chairman, Human Research Experiments Review
Board, ARC, to Director, 20 January 1969 ("Proposed Investigation entitled
'Measurement of Cerebral Blood Flow in Man by an Isotopic Technique Employing
External Counting,' by Dr. Leo Sapierstein, Stanford University") (ACHRE No. NASA-
022895-A), 4.
At MSC, the instruction establishing the Medical Uses Subcommittee was
rescinded in 1968. In 1969, formal combination of the medical operations and medical
research functions at MSC led to the reestablishment of the instruction as the Medical
Isotopes Subcommittee at MSC. No evidence suggests what factors, other than risk,
were considered in this form of prior review is available currently. National Aeronautics
and Space Administration, Manned Spacecraft Center, MSCI 1860.2, 12 May 1966
("Establishment of MSC Radiological Control Manual and Radiological Control
Committee"); and National Aeronautics and Space Administration, NMI 1 156.19, 28
August 1969 ("Medical Isotopes Subcommittee of the MSC Radiation Safety
Committee") (ACHRE No. NASA-022895-A).
74. National Aeronautics and Space Administration, NMI 71008.9, 2 February
1972 ("Human Research Policy and Procedures") (ACHRE No. NASA-022895-A). See
also, National Aeronautics and Space Administration, NMI 7100.9 ("Power and
Authority - To Authorize Human Research and to Grant Certain Related Exceptions and
Waivers") (ACHRE No. NASA-022895-A).
75. Commission on CIA Activities within the United States, Report to the
President, (Washington, D.C.: GPO, 1975).
76. U.S. Congress, The Select Committee to Study Governmental Operations
with Respect to Intelligence Activities, Foreign and Military Intelligence [Church
Committee report], report no. 94-755, 94th Cong., 2d Sess. (Washington, D.C.: GPO,
1976), 394.
77. For general information on the CIA program, see the Church Committee
report, 385-422, and J. Marks, The Search for the "Manchurian Candidate": The CIA
and Mind Control (New York: Times Books, 1978).
78. Church Committee report, book 1, 389.
79. Church Committee report, book 1, 400, 402. In 1963 the CIA inspector
general (IG) recommended that unwitting testing be terminated, but Deputy Director for
Plans Richard Helms (who later became director of Central Intelligence) continued to
advocate covert testing on the ground that "positive operational capability to use drugs is
diminishing, owing to a lack of realistic testing. With increasing knowledge of the state
of the art, we are less capable of staying up with the Soviet advances in this field." The
Church Committee noted that "Helms attributed the cessation of the unwitting testing to
the high risk of embarrassment to the Agency as well as the 'moral problem.' He noted
that no better covert situation had been devised than that which had been used, and that
'we have no answer to the moral issue.'"
80. Ibid., 402.
8 1 . Executive Order 11905(19 February 1 976).
82. Executive Order 12036, section 2-301 (26 January 1978) and Executive
Order 12333, section 2.10 (4 December 1981).
194
83. U.S. Army Inspector General, Use of Volunteers in Chemical Agent
Research [Army IG report] (Washington, D.C.: GPO, 1975), 2.
84. One noted exception involved using LSD as an interrogation devise on ten
foreign intelligence agents, and one U.S. citizen suspected of stealing classified
documents. Army IG report, 143.
85. Army IG report, 87.
86. Ibid.
87. The CIA paid death benefits to the Olson family after Frank Olson's death,
and the Army secretly paid half of an $18,000 settlement that the Blauer family
negotiated with the state of New York in 1955. The state ran the psychiatric institute
that administered the drugs, but which never disclosed the Army's involvement. Both
agencies feared that the resulting embarrassment and adverse publicity might undermine
their ability to continue their secret research programs. Barrett v. United States, 6660 F.
Supp. 1291 (E. D. N.Y., 1987).
88. Feres v. United States, 340 U.S. 1 46 ( 1 950).
89. United States v. Stanley, 483 U.S. 669 ( 1 987).
90. 483 U.S. 669, 682.
91. 483 U.S. 669, 687-88.
92. 483 U.S. 669, 709-10.
93. George Annas, a scholar of human experimentation and biomedical ethics,
has traced the history of the Nuremberg Code in the U.S. courts. The first express
reference in a majority opinion, Annas found, was in a 1973 decision in the Circuit Court
in Wayne County, Michigan. The decisions in which the Code has since been cited,
Annas concluded, reflect the proposition that the Nuremberg Code is a "document
fundamentally about nontherapeutic experimentation." Thus, the "types of experiments
that U.S. judges have found the Nuremberg Code useful for setting standards have
involved nontherapeutic experiments often conducted without consent. . . . Many of
these experiments were justified by national security considerations and the cold war."
George J. Annas, "The Nuremberg Code in U.S. Courts: Ethics versus Expediency," in
George J. Annas and Michael A. Grodin, eds.. The Nazi Doctors and the Nuremberg
Code: Human Rights in Human Experimentation (New York: Oxford University Press,
1992), 218.
195
4
Ethics Standards
in Retrospect
/\ccording to the mission set out in our charter, the Advisory Committee
is in essence a national ethics commission. In this capacity we were obliged to
develop an ethical framework forjudging the human radiation experiments. This
proved to be one of our most difficult tasks, for we were not only dealing with
complex events that occurred decades ago, but also with some of the most
controversial issues in moral philosophy. This chapter sets out the standards that
we believe are appropriate for evaluating human radiation experiments and offers
reasons for relying on them. It then applies these standards to the results of the
historical research we have conducted and draws ethical conclusions.*
Fulfilling our charge to "determine the ethical and scientific standards and
criteria" to evaluate human radiation experiments that took place between 1 944
and 1974 requires consideration of a complex question: Is it correct to evaluate
the events, policies, and practices of the past, and the agents responsible for them,
against ethical standards and values that we accept as valid today but that may not
"Some of the features of the moral framework presented in this chapter pertain to
biomedical experiments only and not to intentional releases. A moral analysis of
intentional releases involves somewhat different elements than a moral analysis of
biomedical experiments, because they engage different ethical issues. For example, a
requirement of individual informed consent is not applicable to the intentional releases,
and the concepts of risk and benefit and national security have different implications for
them. Ethical and policy issues specific to intentional releases are discussed in chapter
11.
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Chapter 4
have been widely accepted then? Or must we limit our ethical evaluation of the
past to those standards and values that were widely accepted at the time? This is
the problem of retrospective moral judgment.
Quite apart from the issue of the validity of projecting current standards
onto the past, there is another question that this chapter must address: In a
pluralistic society such as ours, is there at present a sufficiently broad consensus
on ethical standards to make possible a public evaluation that is not simply the
arbitrary imposition of one particular moral point of view among several or even
many? This is the problem of value pluralism. The ethical framework the
Advisory Committee employs takes both these issues into account.
This chapter is divided into two parts. In the first part we present and
defend the ethical framework adopted by the Committee for the evaluation of
human radiation experiments conducted from 1944 to 1974 and the agents
responsible for them. We begin by identifying the types of moral judgments with
which the Committee is concerned and the different kinds of ethical standards
against which these judgments can be made. We next address two challenges to
the position that the Advisory Committee can use these, or any other, standards to
make valid ethical judgments. These challenges are (1) that the diversity of views
about ethics in American society invalidates any effort by a public body such as
the Advisory Committee to make moral judgments and (2) that the diversity of
views about ethics across time similarly invalidates our making defensible moral
judgments about the past. Although the Committee does not accept these
challenges as definitive, we discuss these as well as other factors that influence or
limit ethical evaluation. We include here a discussion of an issue of particular
relevance to our charge: what role, if any, considerations of national security
should play in the Committee's ethical framework. We also consider factors that
can mitigate the blame we would otherwise place on agents (whether individuals
or collective entities) for having conducted morally wrong actions.
In the second part of the chapter, we explore how the Committee's ethical
framework can be used to evaluate both experiments conducted in the past and the
people and institutions that sponsored and conducted them. Drawing on the
history presented in chapters 1 through 3, we illustrate how, when applied, the
framework is specified by context and detail. This specification of the framework
continues in part II of the report, when the framework is used to evaluate specific
cases.
AN ETHICAL FRAMEWORK
Two Types of Moral Judgment
For purposes of the Committee's charge, there are two main types of moral
judgment: judgments about the moral quality of actions, policies, practices,
institutions, and organizations; and judgments about the praiseworthiness or
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Parti
blameworthiness of individual agents and in some cases entities such as
professions and governments (insofar as these can be viewed as collective agents
with powers and responsibilities). The first type contains several kinds of
judgments. Actions may be judged to be obligatory, wrong, or permissible.
Institutions, policies, and practices can be characterized as just or unjust,
equitable or inequitable, humane or inhumane. Organizations can be said to be
responsible or negligent, fair-dealing or exploitative.
The second type of judgment about the praiseworthiness or
blameworthiness of agents also contains a diversity of determinations. Agents,
whether individual or collective, can be judged to be culpable or praiseworthy for
this or that action or policy, to be generous or mean-spirited, responsible or
negligent, to respect the moral equality of people or to discriminate against
certain individuals or groups, and so on.
Three Kinds of Ethical Standards
A recognized way to make moral judgments is to evaluate the facts of a
case in the context of ethical standards. The Committee identified three kinds of
ethical standards as relevant to the evaluation of the human radiation
experiments: 1
1 . Basic ethical principles that are widely accepted and generally
regarded as so fundamental as to be applicable to the past as
well as the present;
2. The policies of government departments and agencies at the
time; and
3. Rules of professional ethics that were widely accepted at the
time.
Basic Ethical Principles
Basic ethical principles are general standards or rules that all morally
serious individuals accept. The Advisory Committee has identified six basic
ethical principles as particularly relevant to our work: "One ought not to treat
people as mere means to the ends of others"; "One ought not to deceive others";
"One ought not to inflict harm or risk of harm"; "One ought to promote welfare
and prevent harm": "One ought to treat people fairly and with equal respect"; and
"One ought to respect the self-determination of others." These principles state
moral requirements; they are principles of obligation telling us what we ought to
do. 2
Every principle on this list has exceptions, because all moral principles
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Chapter 4
can justifiably be overridden by other basic principles in circumstances when they
conflict. To give priority to one principle over another is not a moral mistake; it
is a reality of moral judgment. The justifiability of such judgments depends on
many factors in the circumstance; it is not possible to assign priorities to these
principles in the abstract.
Far more social consensus exists about the acceptability of these basic
principles than exists about any philosophical, religious, or political theory of
ethics. This is not surprising, given the central social importance of morality and
the fact that its precepts are embraced in some form by virtually all major ethical
theories and traditions. These principles are at the deepest level of any person's
commitment to a moral way of life.
It is important to emphasize that the validity of these basic principles is
not typically thought of as limited by time: we commonly judge agents in the past
by these standards. For example, the passing of fifty years in no way changes the
fact that Hitler's extermination of millions of people was wrong, nor does it erase
or even diminish his culpability. Nor would the passing of a hundred years or a
thousand do so.
This is not to deny that it might be inappropriate to apply to the distant
past some ethical principles to which we now subscribe. It is only to note that
there are some principles so basic that we ordinarily assume, with good reason,
that they are applicable to the past as well as the present (and will be applicable in
the future as well). We regard these principles as basic because any minimally
acceptable ethical standpoint must include them.
Policies of Government Departments and Agencies
The policies of departments and agencies of the government can be
understood as statements of commitment on the part of those governmental
organizations, and hence of individuals in them, to conduct their affairs according
to the rules and procedures that constitute those policies. In this sense, policies
create ethical obligations. When a department or agency adopts a particular
policy, it in effect promises to make reasonable efforts to abide by it. 3
At least where participation in the organization is voluntary, and where the
organization's defining purpose is morally legitimate (it is not, for example, a
criminal organization), to assume a role in the organization is to assume the
obligations that attach to that role. Depending upon their roles in the
organization, particular individuals may have a greater or lesser responsibility for
helping to ensure that the policy commitments of the organization are honored.
For example, high-level managers who formulate organizational policies have an
obligation to take reasonable steps to ensure that these policies are effectively
implemented. If they fail to discharge these obligations, they have done wrong
and are blameworthy, unless some extenuating circumstance absolves them of
responsibility. One sort of extenuating circumstance is that the policy in question
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Parti
is unethical. In that case, we would hold an individual blameless for not
attempting to implement it (at least if the individual did so because of a
recognition that the policy was unethical). Moreover, we might praise the
individual for attempting an institutional reform at some professional or personal
risk.
Different types of organizations have different defining purposes, and
these differences determine the character of the department's or agency's role-
derived obligations. All government organizations have special responsibilities to
act impartially and to fairly protect all citizens, including the most vulnerable
ones. These special obligations constitute a standard for evaluating the conduct
of government officials.
Rules of Professional Ethics
Professions traditionally assume responsibilities for self-regulation,
including the promulgation of certain standards to which all members are
supposed to adhere. These standards are of two kinds: technical standards that
establish the minimum conditions for competent practice, and ethical principles
that are intended to govern the conduct of members in their practice. In exchange
for exercising this responsibility, society implicitly grants professions a degree of
autonomy. The privilege of this autonomy in turn creates certain special
obligations for the profession's members.
These obligations function as constraints on professionals to reduce the
risk that they will use their special power and knowledge to the detriment of those
whom they are supposed to serve. Thus, physicians, whose special knowledge
gives them opportunities for exploiting patients or breaching confidentiality, are
obligated to act in the patient's best interest in general and to follow various
prescriptions for minimizing conflicts of interest.
Unlike basic ethical principles that speak to the whole of moral life, rules
of professional ethics are particularized to the practices, social functions, and
relationships that characterize a profession. Rules of professional ethics are often
justified by appeal to basic ethical principles. For example, as we discuss later in
this chapter, the obligation to obtain informed consent, which is a rule of research
and medical ethics, is grounded in principles of respect for self-determination, the
promotion of others' welfare, and the noninfliction of harm.
In one respect, rules of professional ethics are like the policies of
institutions and organizations: they express commitments to which their members
may be rightly held by others. That is, rules of professional ethics express the
obligations that collective entities impose on their members and constitute a
commitment to the public that the members will abide by them. Absent some
special justification, failure to honor the commitment to fulfill these obligations
constitutes a wrong. To the extent that the profession as a collective entity has
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Chapter 4
obligations of self-regulation, failure to fulfill these obligations can lead to
judgments of collective blame.
Ethical Pluralism and the Convergence of Moral Positions
Although we have argued that there is broad agreement about and
acceptance of basic ethical principles in the United States, such as principles that
enjoin us to promote the welfare of others and to respect self-determination,
people nevertheless disagree about the relative priority or importance of these
principles in the moral life. For example, although any minimally acceptable
ethical standpoint must include both these principles, some approaches to
morality emphasize the importance of respecting self-determination while others
place a higher priority on duties to promote welfare. These differences in
approaches to morality pose a problem for public moral discourse. How can a
public body, such as the Advisory Committee, purport to speak on behalf of
society as a whole and at the same time respect this diversity of views about
ethics? The key to understanding how this is possible is to appreciate that
different ethical approaches can and often do converge on the same ethical
conclusions. People can agree about what ought to be done without necessarily
appealing to the same moral arguments to defend their common position.
This phenomenon of convergence has been observed in the work of other
public bodies whose charge was to make ethical evaluations on research
involving human subjects, including the National Commission for the Protection
of Human Subjects of Biomedical and Behavioral Research and the President's
Commission for the Study of Ethical Problems in Medicine and Biomedical and
Behavioral Research. 4 For example, both those who take the viewpoint that
emphasizes obligations to promote welfare and to refrain from inflicting harm and
those who accord priority to self-determination can agree that law and medical
and research practice should recognize a right to informed consent for competent
individuals. The argument for a requirement of informed consent based on
promoting welfare and refraining from inflicting harm assumes that individuals
are generally most interested in and knowledgeable about their own well-being.
Individuals are thus in the best position to discern what will promote their welfare
when deciding about participation in research or medical care. Allowing
physicians or others to decide for them runs too great a risk of harm or loss of
benefits. By contrast, an approach based on self-determination assumes that, at
least for competent individuals, being able to make important decisions
concerning one's own life and health is intrinsically valuable, independent of its
contribution to promoting one's well-being. The most compelling case for
recognizing a right of informed consent for competent subjects and patients draws
upon both lines of justification, emphasizing that this requirement is necessary
from the perspective of self-determination considered as valuable in itself and
from the standpoint of promoting welfare and refraining from doing harm.
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Part I
Therefore, although people may have different approaches to the moral
life, which reflect different priorities among basic moral principles, these
differences need not result in a lack of consensus on social policy or even on
particular moral rules such as the rule that competent individuals ought to be
allowed to accept or refuse participation in experiments. On the contrary, the fact
that the same moral rules or social policies can be grounded in different basic
moral principles and points of view greatly strengthens the case for their public
endorsement by official bodies charged to speak for society as a whole.
The three kinds of ethical standards upon which the Committee relies for
our ethical evaluations-the basic moral principles, government policies, and rules
of professional ethics—also enjoy a broad consensus. They are not idiosyncratic
to a particular ethical value system. Thus it would be a mistake to think that in
order to fulfill our charge of ethical evaluation, the Advisory Committee must
assume that there is only one uniquely correct ethical standpoint. A broad range
of views can acknowledge that the medical profession should be held accountable
for moral rules it publicly professes and that individual physicians can be held
responsible for abiding by these rules of professional ethics. Likewise, regardless
of whether one believes that the ultimate justification for government policies is
the goal of promoting welfare and minimizing harms or respect for self-
determination, one can agree that policies represent commitments to action and
hence generate obligations. Moreover, any plausible ethical viewpoint will
recognize that when individuals assume roles in organizations they thereby
undertake role-derived obligations.
We have already argued that the basic ethical principles that we employ in
evaluating experiments are widely accepted and command significant allegiance
not only from our contemporaries but also from reflective and morally sensitive
individuals and ethical traditions in the past. It would be very implausible to
construe any of them as parochial or controversial.
Retrospective Moral Judgment and the Challenge of Relativism
Some may still have reservations about the project of evaluating the ethics
of decisions and actions that occurred several decades ago. The worry is that it is
somehow inappropriate, if not muddled, to apply currently accepted standards to
earlier periods when they were not accepted, recognized, or viewed as matters of
obligation. This is an important worry, though one that does not apply to our
framework.
The position that the values and principles of today cannot be validly
applied to past situations in which they may not have been accepted is called
historical ethical relativism. This is the thesis that moral judgments across time
are invalid because moral judgments can be justified only by reference to a set of
shared values, and the values of a society change over time. According to this
view, one historical period differs from another by virtue of lacking the relevant
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values contained in the other historical period, namely, those that support or
justify the particular moral judgments in question. Understood in this way,
historical ethical relativism, if true, would explain why some retrospective moral
judgments are invalid, namely, where the past society about which the judgments
are made lacked the values that, in our time, support our judgments. In other
words, the claim is that moral judgments made about actions and agents in one
period of history cannot be made from the perspective of the values of another
historical period.
The question of whether historical ethical relativism limits the validity of
retrospective moral judgment is not a mere theoretical puzzle for moral
philosophers. It is an eminently practical question, since how we answer it has
direct and profound implications for what we ought to do now. Most obviously,
the position we adopt on the validity of retrospective moral judgment will
determine whether we should honor claims that people now make for remedies for
historical injustices allegedly perpetrated against themselves or their ancestors.
Similarly, we must know whether there is any special circumstance resulting from
the historical context in which the responsible parties acted that mitigates
whatever blame would be appropriate. We return to this question later in the
chapter.
In addition, something even more fundamental is at stake in the debate
over retrospective moral judgment: the possibility of moral progress. The idea of
moral progress makes sense only if it is possible to make moral judgments about
the past and to make them by appealing to some of the same moral standards that
we apply to the present. Unless we can apply the same moral yardstick to the past
and the present, we cannot meaningfully say either that there has been moral
progress or that there has not. For example, unless some retrospective moral
judgments are valid, we cannot say that the abolition of slavery is a case of moral
progress, moral regression, or either one. More specifically, unless we can say
that slavery was wrong, we cannot say that the abolition of slavery was a moral
improvement.
For these and other reasons, the acceptance of historical ethical relativism
has troubling implications. But even if we were to accept historical ethical
relativism as the correct position, it would not follow from this alone that there is
anything improper about making judgments about radiation experiments
conducted decades ago based on the three kinds of ethical standards the
Committee has identified. Two of these kinds of standards-government policies
and rules of professional ethics-are standards used at the time the experiments
were conducted. Neither of these kinds of standards involves projecting current
cultural values onto a different cultural milieu.
We have already argued that basic ethical principles, the third kind of
standard adopted by the Committee, are not temporally limited. Although there
have been changes in ethical values in the United States between the mid- 1940s
and the present, it is implausible that these changes involved the rejection or
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affirmation of principles so basic as that it is wrong to treat people as mere means,
wrong to inflict harm, or wrong to deceive people. Thus, the Advisory
Committee's evaluations of the human radiation experiments in light of these
basic principles is based on a simple and we think reasonable assumption that,
even fifty years ago, these principles were pervasive features of moral life in the
United States that were widely recognized and accepted, much as we recognize
and accept them today. 5
Factors That Influence or Limit Ethical Evaluation
Several considerations influence and can limit the ability to reach ethical
conclusions about Tightness and wrongness and praise and blame. Some of these
may be more likely to be present in efforts to evaluate the past, but all can arise
when attempts are made to evaluate contemporary events as well. The most
important such limitations relevant to the Advisory Committee's evaluations are
these:
( 1 ) Lack of evidence as to whether ethical
standards were followed or violated and if so,
by whom, and
(2) The presence of conflicting obligations.
The three kinds of ethical standards adopted by the Committee can yield
the conclusion that an individual or collective agent had or has a particular
obligation. But this conclusion is not by itself sufficient to determine in any
particular case whether anything wrong was done or whether any individual or
collective agent deserves blame.
Lack of Evidence
Sound evaluations cannot be made without sufficient evidence.
Sometimes it cannot be determined if anything wrong was done because key facts
about a case are missing or unclear. Other times there may be sufficient evidence
that a wrong was done, but insufficient evidence to determine who performed the
action that was wrong or who authorized the policy that was wrong or who was
responsible for a practice that was wrong. This is why the Advisory Committee
strove during our tenure to reconstruct the details of the circumstances under
which the human radiation experiments themselves took place. However, these
records are incomplete, and even the copious documentation we have gathered
does not tell as complete a story as sometimes was needed to make ethical
evaluations.
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Conflicting Obligations
Because we all have more than one obligation, because they can conflict
with one another, and because some obligations are weightier than others, a
particular obligation that is otherwise morally binding may not be binding in a
particular circumstance, all things considered. For example, a government
official might be obligated to follow certain routine procedures, but in a time of
dire emergency he or she might have a weightier obligation to avert great harm to
many people by taking direct action that disregards the procedures. Similarly, a
physician is obligated to keep his patient's condition confidential, but in some
cases it is permissible and even obligatory to breach this confidence (for example,
in order to prevent the spread of deadly infectious diseases). In such cases, the
agent has done nothing wrong in failing to do what he or she would ordinarily be
morally obligated to do; that obligation has been validly overridden by what is in
the particular circumstances a weightier obligation.
The presence of conflicting obligations may limit our ability to make
moral judgments when, for example, it is difficult to determine, in a particular
case, which obligation should take precedence. At the same time, however, if it
can be determined which obligation is weightier, then the presence of this factor
does not serve as an impediment to evaluation; rather, it can lead to the
conclusion that nothing morally wrong was done and that no one should be
blamed.
An example of a potentially overriding obligation that is especially
important for the Advisory Committee's work is the possibility that, during the
period of the radiation experiments, obligations to protect national security were
sometimes more morally weighty than obligations to comply with standards for
human subjects research. If the threat were great enough, considerations of
national security grounded in the basic ethical principle that one ought to promote
welfare and prevent harm could justifiably override the basic ethical principle of
not using people as mere means to the ends of others, as well as the more specific
rule of research ethics requiring the voluntary consent of human subjects. Had
such an overriding obligation to protect national security existed during the period
we studied, it also would have relieved responsible individuals of any blame
otherwise attributable to them for using individuals in experiments that were
crucial to the national defense.
Especially during the late 1940s and early 1950s, and then again in the
first years of the early 1960s, our country was engaged in an intense competition
with the Soviet Union. A high premium was placed upon military superiority, not
only in "conventional" warfare but also in atomic, biological, and chemical
warfare. The DOD's Wilson memorandum, when originally promulgated in 1953,
declared that it was directed toward the need to pursue atomic, biological, and
chemical warfare experiments "for defensive purposes" in these fields.
It would not be surprising, therefore, to discover that, in the government's
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policies and rules for human subject research, provisions had been made for the
possibility that obligations to protect national security might conflict with and
take priority over obligations to protect human subjects, and thus that such
policies would have included exceptions for national security needs. The moral
justification would also not be surprising: that, in order to preserve the American
way of life with its precious freedoms, some sacrifices of individual rights and
interests would have to be made for the greater good. The very phrase Cold War
expressed the conviction that we already were engaged in a life-or-death struggle
and that in war actions may be permissible that would be impermissible in
peacetime. Survival in the treacherous and heavily armed post-World War II era
might demand no less, repugnant as those actions otherwise might be to many
Americans.
The Advisory Committee did not undertake an inquiry to determine
whether during either World War II or the Cold War there were ever
circumstances in which considerations of national security might have justified
infringements of the rights and protections that would otherwise be enjoyed by
American citizens in the context of human experimentation. Our sources for
answering this question were limited to materials pertinent to specific human
radiation experiments and declassified defense-related memorandums and
transcripts. With regard to the experiments, particular cases are reviewed in part
II of this report. In those experiments that took place under circumstances most
closely tied to national security considerations, such as the plutonium injections
(see chapter 5), it does not appear that such considerations would have barred
satisfying the basic elements of voluntary consent. Thus, for instance, although
the word plutonium was classified until the end of World War II, subjects could
still have been asked their permission after having been told that subjects in the
experiment would be injected with a radioactive substance with which medical
science had had little experience and which might be dangerous and that would
not help them personally, but that the experiment was important to protecting the
health of people involved in the war effort or safeguarding the national defense.
With regard to defense-related documents, in none of the memorandums
or transcripts of various agencies did we encounter a. formal national security
exception to conditions under which human subjects may be used. In none of
these materials does any official, military or civilian, argue for the position that
individual rights may be justifiably overridden owing to the needs of the nation in
the Cold War. In none of them is an official position expressed that the
Nuremberg Code or other conventions concerning human subjects could be
overridden because of national security needs.
Some government officials, military and civilian, may have personally
advocated the view that obligations to protect national security were more
important than obligations to protect the rights and interests of human subjects.
It is, of course, possible that the priority placed on national security was so great
in some circles of government that the ability of security interests to override
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other national interests was implicitly assumed, rather than explicitly articulated.
It is a matter of historical record that some initiatives undertaken by government
officials at some agencies during this period adopted the view that greater
national purposes justified the exploitation of individuals. Notorious examples
are the CIA's MKULTRA project and the Army's psychochemical experiments,
which subjected unsuspecting people to experiments with LSD and other
substances (see chapter 3). A However, even the internal investigation of the
Department of Defense into these incidents in the 1970s concluded that these
incidents were violations of government policy, not recognized legitimate
exceptions to it. 7
During the era of the Manhattan Project, the United States and its allies
were engaged in a declared and just war against the Axis powers. Regarding the
possibility of a wartime exception, it is well documented that during World War II
the Committee on Medical Research (CMR) of the Executive Office of the
President funded research on various problems confronting U.S. troops in the
field, including dysentery, malaria, and influenza. This research involved the use
of many subjects whose capacity to consent to be a volunteer was questionable at
best, including children, the mentally retarded, and prisoners. K However, when
the CMR considered proposed gonorrhea experiments that would have involved
deliberately exposing prisoners to infection, the resulting discussion about the
ethics of research exhibited a cautious attitude. The conclusion was that only
"volunteers" could be used and that they had to be carefully informed about the
risks and benefits of participation. In these and other classified conversations, the
CMR took the position that care is to be taken with human subjects, including
conscientious objectors and military personnel. 9
It is difficult to reconcile these deliberations with the fact that many
subjects of CMR-funded research were not true volunteers. Whether the CMR
believed that the needs of a country at war justified the use of people who could
not be true volunteers as research subjects is not known.
It would, however, be an error to conclude that, even in contexts where
important national security interests are at stake, such as during wartime, a
conflict between obligations to protect national defense and obligations to protect
human subjects ought always to be resolved in favor of national security. The
question of whether any and all means are morally acceptable for the sake of
national security and the national defense is a complex one. Even in the case of a
representative democracy that is not an aggressor, it would be wrong to assume
that there are no moral constraints in time of war. All of the major religious and
secular traditions concerning the morality of warfare recognize that there are
substantial limitations upon the manner in which even a just war is conducted. 10
The issue of the morality of "total warfare" for a just cause, including the use of
medical science, was beyond the scope of the Advisory Committee's charter,
deliberations, and expertise.
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Distinguishing Between the Wrongness of Actions and Policies and the
Blameworthiness of Agents
Factors That Influence or Limit Judgments About Blame
The factors we have just discussed—lack of evidence and the presence of
conflicting obligations-place limits on our ability to make judgments about both
the Tightness and wrongness of actions and the blameworthiness of the agents
responsible for them. Some factors, however, place limits only on our ability to
make judgments about the blameworthiness of agents. Even in cases where
actions or policies are clearly morally wrong, it may be uncertain how
blameworthy the agents who conducted or promulgated them are, or in fact,
whether they are blameworthy at all. Some factors make it difficult to affix
blame; other factors can mitigate or lessen the blame actors deserve. Four such
factors are of particular concern to the Committee: ' '
(1) Factual ignorance;
(2) Culturally induced ignorance about relevant moral considerations;
(3) Evolution in the interpretations and specification of moral principles;
and
(4) Indeterminacy in an organization's division of labor, with the result
that it is unclear who has responsibility for implementing the
commitments of the organization.
Factual Ignorance
Factual ignorance refers to circumstances in which some information
relevant to the moral assessment of a situation is not available to the agent. There
are many reasons that this may be so, including that the information in question is
beyond the scope of human knowledge at the time or that there was no good
reason to think that a particular item of information was relevant or significant.
However, just because an agent's ignorance of morally relevant information leads
him or her to commit a morally wrong act, it does not follow that the person is not
blameworthy for that act. The agent is blameworthy if a reasonably prudent
person in that agent's position should have been aware that some information was
required prior to action, and the information could have been obtained without
undue effort or cost on his or her part. Some people are in positions that obligate
them to make special efforts to acquire knowledge, such as those who are directly
responsible for the well-being of others. Determinations of culpable and
nonculpable factual ignorance often turn on whether the competent person in the
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field at that time had that knowledge or had the means to acquire it without undue
burdens.
Culturally Induced Moral Ignorance
Sometimes cultural factors can prevent individuals from discerning what
they are morally required to do and can therefore mitigate the blame we would
otherwise place on individuals for failing to do what they ought to do. In some
cases these factors may have been at work in the past but are no longer operative
in the present, because of changes in culture over time.
An individual may, like other members of the culture, be morally
ignorant. Because of features of his or her deeply enculturated beliefs, the
individual may be unable to recognize, for example, that certain people (such as
members of another race) deserve equal respect or even that they are people with
rights. Moral ignorance can impair moral judgment and hence may result in a
failure to act morally.
In extreme cases, a culture may instill a moral ignorance so profound that
we may speak of cultural moral blindness. In some societies the dominant culture
may recognize that it is wrong to exploit people but fail to recognize certain
classes of individuals as being people. Some of those committed to the ideology
of slavery may have been morally blind in just this way, and their culture may
have induced this blindness.
Here it is crucial to distinguish between culpable and nonculpable moral
ignorance. The fact that one's moral ignorance is instilled by one's culture does
not by itself mean that one is not responsible for being ignorant; nor does it
necessarily render one blameless for actions or omissions that result from that
ignorance. What matters is not whether the erroneous belief that constitutes the
moral ignorance was instilled by one's culture. What matters is the extent to
which the individual can be held responsible for maintaining this belief, as
opposed to correcting it. Where opportunities for remedying culturally induced
moral ignorance are available, a person may rightly be held responsible for
remaining in ignorance and for the wrongful behavior that issues from his or her
mistaken beliefs.
People who maintain their culturally induced moral ignorance in the face
of repeated opportunities for correction typically do so by indulging in
unjustifiable rationalizations, such as those associated with racist attitudes. They
show an excessive partiality to their own opinions and interests, a willful rejection
of facts that they find inconvenient or disturbing, an inflated sense of their own
self-worth relative to others, a lack of sensitivity to the predicament of others, and
the like. These moral failings are widely recognized as such across a broad
spectrum of cultural values and ethical traditions, both religious and secular.
Only if an agent could not be reasonably expected to remedy his or her
culturally induced moral ignorance would such ignorance exculpate his conduct.
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But even in cases in which the individual could not be blamed for persisting in
ignorance, this would do nothing to show that the actions or omissions resulting
from his or her ignorance were not wrong. Nonculpable moral ignorance only
exculpates the agent; it does not make wrong acts right.
Evolution in Interpretations of Ethical Principles
There is another respect in which the dependence of our perceptions of
right and wrong on our cultural context has a bearing on the Advisory
Committee's evaluations. While basic ethical principles do not change,
interpretations and applications of basic ethical principles as they are expressed in
more specific rules of conduct do evolve over time through processes of cultural
change.
Recognizing that more specific moral rules do change has implications for
how we judge the past. For example, the current requirement of informed consent
is the result of evolution. Acceptance of the simple idea that medical treatment
requires the consent of the patient (at least in the case of competent adults) seems
to have preceded by a considerable interval the more complex notion that
informed consent is required. 12 Furthermore, the notion of informed consent itself
has undergone refinement and development through common law rulings, through
analyses and explanations of these rulings in the scholarly legal literature, through
philosophical treatments of the key concepts emerging from legal analyses, and
through guidelines in reports by government and professional bodies. 13 For
example, as early as 1914, the duty to obtain consent to medical treatment was
established in American law: "Every human being of adult years and sound mind
has a right to determine what shall be done with his own body; and a surgeon who
performs an operation without his patient's consent commits an assault." 14
However, it was not until 1957 that the courts decreed that consent must be
informed, 15 and this 1957 ruling was only the beginning of a long debate about
what it means for a consent to be informed. Thus it is probably fair to say that the
current understanding of informed consent is more sophisticated, and what is
required of physicians and scientists more demanding, than both the preceding
requirement of consent and earlier interpretations of what counts as informed
consent. As the content of the concept has evolved, so has the scope of the
corresponding obligation on the part of these professionals. For this reason it
would be inappropriate to blame clinicians or researchers of the 1940s and 1950s
for not adhering to the details of a standard that emerged through a complex
process of cultural change that was to span decades. At the same time, however,
it remains appropriate to hold them to the general requirements of the basic moral
principles that underlie informed consent—not treating others as mere means,
promoting the welfare of others, and respecting self-determination.
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Inferring Bureaucratic Responsibilities
It is often unclear in complex organizations such as government agencies
who has responsibility for implementing the organization's policies and rules.
This is particularly common in new and changing organizations, where it is more
likely than in stable organizations that there will be interconnecting lines of
authority among employees and officials, and job descriptions that are not explicit
with respect to responsibility for implementation of policies and initiatives. When
policies are not properly implemented in organizations that fit this description, it
often is difficult to assign blame to particular individuals. An employee or
official of an agency cannot fairly be blamed for a failed or poorly executed
policy unless it can be determined with confidence that the person had
responsibility for implementing that policy and should have known that he or she
had this responsibility.
The Importance of Distinguishing Wrongdoing from
Blameworthiness
Judgments of wrongdoing and judgments of blameworthiness have very
different implications. Even where a wrong was done, it does not follow that
anyone should be blamed for the wrong. This is because there are factors,
including the four we have just described, that can lessen or remove blame from
an agent for a morally wrong act but that cannot in any way make the wrong act
right. If experiments violated basic ethical principles, institutional or
organizational policies, or rules of professional ethics, then they were and will
always be wrong. Whether and how much anyone should be blamed for these
wrongs are separate questions. 16
The distinction between the moral status of experiments and that of the
individuals who were involved with conducting, funding, or sponsoring them also
has important implications for our own time. For a society to make moral
progress, individuals must be able to exercise moral judgment about their actions.
It is important for social actors to be critical about their activities, even those in
which they have been engaged for some time. It is important for them to be able
to step back and analyze their actions as right or wrong. If we did not distinguish
between actions and agents, then people may feel that, once they have perceived
their moral error, it is "too late" for them to change their ways, to object to the
ongoing activity, and to try to rally others in support of reform.
For any generation to initiate morally indicated reforms, it must be able to
take this critical stance. As we see in part III of this report, even now there are
aspects of our society's use of human subjects that should be critically examined.
The actions we ourselves have performed do not condemn us as moral agents
unless we refuse to open ourselves to the possibility that we have in some ways
been in error. As we have said, even if we are exculpated by our own culturally
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induced moral ignorance, that does not make our wrong acts right. Even if we
must accept a measure of blame for our actions, we are free to achieve a critical
assessment and to initiate and participate in needed change.
The Significance of Judgments About Blameworthiness
The Committee believes that its first task is to evaluate the Tightness or
wrongness of the actions, practices, and policies involved in the human radiation
experiments that occurred from 1944 to 1974. However, it is also important to
consider whether judgments ascribing blame to individuals or groups or
organizations can responsibly be made and whether they ought to be made.
There are three main reasons forjudging culpability as well as wrongness..
First, a crucial part of the Committee's task is to make recommendations that will
reduce the risk of errors and abuses in human experimentation in the future, on
the basis of its diagnoses of what went wrong in the past. A complete and
accurate diagnosis requires not only stating what wrongs were done, but also
explaining who was responsible for the wrongs occurring. To do this is likely to
yield the judgment that some individuals were morally blameworthy. Second,
unless judgments of culpability are made about particular individuals, one
important means of deterring future wrongs will be precluded. People
contemplating unethical behavior will presumably be more likely to refrain from
it, other things being equal, if they believe that they, as individuals, may be held
accountable for wrongdoing than if they can assure themselves that at most their
government or their particular government agency or their profession may be
subject to blame. Third, ethical evaluation generally involves both evaluation of
the Tightness or wrongness of actions and the praiseworthiness or
blameworthiness of agents. In the absence of any explicit exemption of the latter
sorts of judgment in our mandate, the Committee believes it would be arbitrary to
exclude them.
Having made a case for judgments of culpability as well as wrongness, the
Committee believes it is very important to distinguish carefully between judging
that an individual was culpable for a particular action and judging that he or she is
a person of bad moral character. Justifiable judgments of character must be based
on accurate information about long-standing and stable patterns of action in a
number of areas of a person's life, under a variety of different situations. Such
patterns cannot usually be inferred from information about a few isolated actions
a person performs in one particular department of his or her life, unless the
actions are so extreme as to be on the order of heinous crimes.
APPLYING THE ETHICAL FRAMEWORK
The three kinds of standards presented in this chapter provide a general
framework for evaluating the ethics of human radiation experiments. In this
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section of the chapter, we revisit those standards in the specific context of human
radiation experiments conducted between 1944 and 1974 and what we have
learned about the policies and practices involving human subjects during that
period.
Basic Ethical Principles
Earlier in this chapter we identified six basic ethical principles as
particularly relevant to our work: "One ought not to treat people as mere means to
the ends of others"; "One ought not to deceive others"; "One ought not to inflict
harm or risk of harm"; "One ought to promote welfare and prevent harm"; "One
ought to treat people fairly and with equal respect"; and "One ought to respect the
self-determination of others."
These principles are central to our analysis of the cases we present in part
II of the report, although not every case we evaluate engages every principle.
Two of the principles, however, recur repeatedly as we consider the ethics of past
experiments. These are "One ought not to treat people as mere means to the ends
of others" and "One ought not to inflict harm or risk of harm." Whether an
experiment involving human subjects violates the principle not to use people as
mere means generally depends on two factors-consent and therapeutic intent. An
individual may give his or her consent to being treated as a means to the ends of
others. If a person freely consents, then he or she is no longer being used as a
mere means, that is, as a means only. Thus, if a person is used as a subject in an
experiment from which the person cannot possibly benefit directly, but the
person's consent to that use is obtained, the person is not being used as a mere
means to the ends of others. By contrast, if a person is used as a subject in such
an experiment but the person's consent is not obtained for that use, the person is
being used as a mere means to the ends of the investigator conducting the
experiment and the institutions funding or sponsoring the experiment.
If an action that involves the use of a person is undertaken in whole or in
part for that person's benefit, then the person is not being used as a mere means
toward the ends of others. Thus, if a person is used as a subject in an experiment
that is intended to offer the subject a prospect of direct benefit, then, even if the
subject's consent has not been obtained, the subject is not being used as a mere
means to the ends of others. This is because the experiment is intended to serve
the subject's interests as well as the interests of the investigator and funding
agency. It may be wrong not to obtain the subject's consent in this case, but the
wrong does not stem from a violation of the principle not to use people as mere
means. Instead, the wrong reflects the violation of other basic principles such as
the principles enjoining us to respect self-determination and to promote welfare
and prevent harm.
These two factors-the obtaining of consent and an intention to benefit-
also can transform the moral quality of an act that involves the imposition of harm
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or risk of harm. One important way to make the imposition of a risk of harm
justifiable is to obtain the person's permission for the imposition. The imposition
of risk on a person also is more justifiable when the risk is imposed to secure a
benefit for that person, although even in the presence of a prospect of offsetting
benefit, the imposition of risk on another without that person's consent is morally
questionable because it appears to violate the principle of respect for self-
determination. 17
Consider the following example of how the factors of therapeutic intent
and consent can transform a morally questionable action into a morally acceptable
one. Patients are enrolled in an experiment in which they are given a new drug
that is unproven in humans, induces substantial discomfort or even suffering, and
may produce irreversible damage to vital organs. There is, however, no effective
treatment for the condition from which these patient-subjects suffer, and the
condition is life threatening. The drug is theoretically promising compared with
related drugs used in similar diseases, and it has proven effective in animals.
Further, the opportunity to participate in the experiment is offered to patients
while they are lucid, comfortable, and at ease. Under these circumstances the
imposition of harm may be transformed into a caring and respectful act.
Policies of Government Agencies
Where agencies of the government had policies on the conduct of research
involving human subjects, and where these policies included requirements or
rules that are morally sound, these policies constitute standards against which the
conduct of the agencies and the people who worked there, as well as the
experiments the agencies sponsored or conducted, can be evaluated. Government
agencies must be held responsible for failures to implement their own policies.
To do otherwise is to break faith with the American people, who have a
reasonable expectation that an agency will conduct its affairs in accord with the
agency's stated policies. As we noted in chapter 1 , it is not always clear,
however, whether statements made in letters or memorandums constitute agency
policy. When there is little evidence that a statement by a government official
was ever implemented, it is often difficult to determine whether this was an
instance of an agency failing to implement its own policies or an instance where a
statement by a government official was not perceived as agency policy in the first
place.
Among the general conclusions that can be drawn from the discussions
about policies during the late 1940s and early 1950s is that the AEC, DOD, and
NIH required investigators to obtain the consent of the healthy or "normal"
subject, and prior group review was required for risk in research using
radioisotopes for all private and publicly financed research (and, in the NIH, for
all hazardous procedures). Also, in 1953, the Department of Defense adopted the
Nuremberg Code as the policy for research related to atomic, biological, and
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chemical warfare, and the NIH Clinical Center articulated a consent requirement
for patient-subjects in intramural research (see chapter 1).
Two questions that arise at this juncture are whether an experiment was
wrong if it violated one of these policies but took place at another government
agency, and whether an experiment was wrong if it took place under the auspices
of an agency before it promulgated the policy. The answer to both questions is
the same: Even if such an experiment was not wrong according to the policy of
the agency sponsoring the experiment at the time, the experiment may
nevertheless have been unethical based on one or more basic ethical principles or
rules of professional ethics.
As is the case today, decades ago government officials had obligations to
take reasonable steps to see that policies were adequately implemented. 18 Policies
constitute organizational commitments, and organizational commitments generate
obligations on the part of the organization and its members. In some cases,
however, it is not clear that conditions stated by individual officials rise to a level
that all would be comfortable calling "policies." Accordingly, it is not clear
whether corresponding obligations to implement can be inferred. The two letters
signed by AEC General Manager Carroll Wilson in April and November 1947 are
the best examples of this problem. Nevertheless, if it is correct to say that high
officials have an obligation to exert due efforts to implement and communicate
the rules they are empowered to establish, then they may reasonably be blamed
for failures in this regard. Further, if they do not even attempt to articulate rules
that are indicated by basic ethical principles and that are clearly relevant to
organizational activities that fall under their authority, they are also subject to
moral blame.
The mitigating condition of culturally induced moral ignorance does not
apply to government officials who failed to exercise their responsibilities to
implement or communicate requirements that clearly fell within the ambit of their
office and of which they were aware. The very fact that these requirements were
articulated by the agencies in which they worked is evidence that officials could
not have been morally ignorant of them.
We have observed, however, that, especially with regard to research
involving patients, policies were frequently unclear. When this research offered
patient-subjects a chance to benefit medically, the widespread discretion granted
physicians to make decisions on behalf of their patients is a mitigating factor in
judging the blameworthiness of government officials for failing to impose consent
requirements on physician-investigators. This failure could be attributed to a
cultural moral ignorance concerning the proper limits to the authority of
physicians over their patients.
The same cannot be said of government officials for failing to impose
consent requirements on physician-investigators who used patient-subjects in
research from which the patients could not benefit medically. This use of human
subjects took place outside of the therapeutic context that defines the doctor-
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Parti
patient relationship and therefore also was outside of the authority then ceded to
physicians. In this case responsible agency officials had a ready analogy to
healthy subjects for whom there was a lengthy tradition of policies and rules
requiring the use of "volunteers" and the obtaining of consent. Government
officials could and should have perceived the morally identical nature of these
cases— that, without consent, both cases involved violation of the principle not to
use people as mere means to the ends of others. Those who were ill should have
been granted the same protections as those who were well.
In contrast to requirements for consent, requirements intended to ensure
that risks to experimental subjects were acceptable were far more clearly stated.
Government officials are blameworthy if they permitted research to continue that
was known to entail unusual risks to the subjects, in direct violation of agency
policy.
Finally, some lessons that can be drawn from the experience of the human
radiation experiments we considered speak to the conduct of government itself as
a collective agent, rather than simply to individual government officials. In too
many instances, as we saw in chapter 1, we found a lack of clarity about the status
within an agency of specific declarations by responsible officials. Particularly
when agencies are engaged in activities that may compromise the rights or
interests of citizens, it is critically important that agencies be clear about their
commitments and policies and that they not remain passive in the face of
questionable practices for which they may bear some responsibility. In chapter 3
we saw an effective response to such a situation in the 1960s by the PHS. This
example attests to the fact that institutional clarity and active reform measures can
succeed and that when they do they can be great forward strides.
Rules of Professional Ethics
Even if the federal government had adopted no formal human research
ethics policy whatsoever, the medical profession and its members would still have
moral obligations to those who entrust themselves to their care. The successes of
modern medical research, regardless of its funding source, are ultimately due to
the efforts of talented and dedicated medical scientists. These investigators bear a
profound ethical burden in their work with human subjects. Society entrusts them
with the privilege of using other human beings to advance their important work.
Although society must not discourage them from the pursuit of new information,
it also must diligently pursue signs that medical scientists have not exercised their
ethical responsibility with the care and sensitivity that society has good reason to
expect from them.
Without reference to the policies adopted by federal agencies, what rules
of professional ethics were seen by the medical profession during the 1944-1974
period as relevant to the conduct of its members engaged in human subjects
research? The answer to this question depends upon which kind of experimental
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Chapter 4
situation is under discussion: an experiment on a healthy subject; an experiment
on a patient-subject without a scientific or clinical basis for an expectation of
benefit to the patient-subject; or an experiment on a patient-subject with a
scientific or clinical basis for an expectation of benefit to the patient-subject.
Experiments on Healthy Subjects: By the mid- 1 940s it was common to
obtain the voluntary consent of healthy subjects who were to participate in
biomedical experiments that offered no prospect of medical benefit to them.
Sophisticated philosophical analysis is not required to reach the conclusion that
using a human being in a medical experiment that offers the person no prospect of
personal benefits without that person's consent is wrong. As we have already
noted, such conduct violates the basic ethical principle that one ought not use
people as mere means to the ends of others.
Experiments on Patient-Subjects Without a Scientific or Clinical Basis for
an Expectation of Benefit to the Patient-Subject: The Hippocratic tradition of
medical ethics inherited by physicians in the 1940s holds that, unless the
physician is reasonably sure that his or her treatment is, on balance, likely to do
the patient more good than harm, the treatment should not be introduced. The
heart of the Hippocratic ethic is the physician's commitment to putting the
interests of the patient first. Subjecting one's patient to experimentation that
offers no prospect of benefit to the patient without his or her consent is a direct
repudiation of this commitment. (If the patient consents to this use, the moral
warrant for proceeding with the experiment comes from the patient's permission,
not from the Hippocratic ethic.)
Experiments on Patient-Subjects with a Scientific or Clinical Basis for an
Expectation of Benefit to the Patient-Subject: Even in Hippocratic medicine it is
recognized that physicians should attempt to use unproven or experimental
methods to benefit the patient, whether through efforts at cure or palliation, but
only so long as there is no efficacious standard therapy available and innovative
measures are compatible with the obligation to avoid doing harm without the
prospect of offsetting benefit. Interventions in this category should be based on
scientific reasoning and conservative clinical judgment. Arguably, so long as
these conditions prevailed, it was not thought morally necessary within the
medical profession to obtain the patient's consent to such experimentation prior to
the 1960s. But the physician assumed a corresponding obligation to base his or
her deviation from standard practice on the reasonable likelihood of patient
benefit, sufficient to outweigh the risks associated with being in the experiment.
This type of reasoning, too, has been available to and accepted by physicians for
many years, even though the ability to assess and calculate risks has developed
greatly.
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Part I
Although the professional ethics of the period thus had relevant moral
rules for each of these three experimental situations, compliance with these rules
is a separate matter. There may be many reasons for specific failures by
physicians to adhere to the requirements of their ethical tradition, some of which
may render them nonculpable, and there are various limitations on our ability to
assign blame for particular cases of a physician's failure to adhere to professional
ethics. However, any use of human subjects that did not proceed in accordance
with these rules of professional ethics was wrong in the sense that it was a
violation of sound professional ethical standards. Moreover, even if there was
then or is now a lack of clarity about the rules of professional ethics, recognition
by morally serious individuals of basic ethical principles is enough to identify
certain sorts of human experiments as morally unacceptable.
The special moral responsibilities of the medical profession as a whole,
whether decades ago or in our own time, deserve careful consideration, especially
insofar as previous experience can help formulate lessons for the future. Like the
government, the medical profession as a whole must be held to a higher standard
than individuals in society. Confidence in the medical profession is important
because individuals put their very lives, and the lives of their loved ones, in the
hands of those whom the profession has certified as competent to practice.
Unlike government officials, members of the medical profession are explicitly
bound to a moral tradition in their professional relations, based on which society
grants the medical profession the privilege of largely policing itself. This
authority is part of what constitutes the medical profession as a profession, but the
authority is granted by society on the condition that the profession will adhere to
the high moral rules it professes and that, if necessary, the medical profession will
reform or encourage the reform of relevant institutions to ensure that those rules
will be honored in practice.
Moreover, many of the privileges that devolve on the medical profession
are granted on the condition that it is sufficiently well organized to police itself,
with minimal intervention by the government and the legal system. Therefore,
members of the medical profession are further legitimately expected to engage in
organizational conduct that constitutes sound moral practices. Implicit in this
arrangement is also the assumption that it will be self-critical even about its
relatively well-entrenched attitudes and beliefs, so that it will be prepared to
undertake reforms. Without this commitment to self-criticism, self-regulation
cannot be effective and the public's trust in the professional's ability to self-
regulate would be unwarranted.
Today we regard subjects of biomedical research whose consent was not
obtained to have been wronged; under conditions of significant risk, the wrong is
greater, and in the absence of the potential for offsetting medical benefit, greater
still. The historical silence of the medical profession with respect to
nontherapeutic experiments was perhaps based on the rationale that those who are
ill and perhaps dying may be used in experiments because they will not be
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Chapter 4
harmed even though they will not benefit. But this rationale overlooks both the
principle that people should never be used as mere means and the principle of
respect for self-determination; it may also provide insufficient protection against
harm, given the position of conflict of interest in which the physician-researcher
may find him-or herself. Nevertheless, until the mid-1960s medical conventions
were silent on experiments with patient-subjects that offered no direct benefit but
which physicians believed to pose acceptable risk. This silence was a failure of
the profession.
One defense of the profession in this regard is that it was as subject to the
phenomenon we have called cultural moral ignorance as any other group in
society at the time, including the arguably excessive deference to physician
authority on the part of the government and possibly the public at large.
However, the medical profession was in a wholly different position from the
others, in several respects. First, it insisted upon and was given the privilege of
policing its own behavior. Second, the profession was the direct beneficiary of
the deference paid to it. Third, there were already examples of experiments that
had involved subject consent that could have served as models of reform. Under
these conditions the profession had an obligation to be self-critical concerning the
norms and rules it thought appropriate to govern its members' conduct.
The medical profession could and should have seen that healthy subjects
and patient-subjects in nontherapeutic experiments were in similar moral
positions—neither was expected to benefit medically. Just as physicians had no
moral license to determine an "acceptable risk" for healthy subjects without their
voluntary consent, they had no moral license to do so in the case of other subjects
who also could not benefit from being in research, even if they were patients. The
prevailing standards for healthy subject groups could easily have been applied to
patient-subjects for whom there was no expectation of medical benefit. The moral
equivalence of the use of healthy people and ill people as subjects of experiments
from which no subject could possibly benefit directly was perceptible at the time.
This moral equivalence would have made it clear that no one, well or sick,
should be used as a mere means to advance medical science without voluntary
consent. Thus, this moral ignorance could have and should have been remedied at
the time. Indeed, it is arguably the case that physicians could and should have
seen that using patients in this way was morally worse than using healthy people,
for in so doing one was violating not only the basic ethical principle not to use
people as a mere means but also the basic ethical principle to treat people fairly
and with equal respect.
American physicians are members of a society that places a high value on
these basic moral principles, still more vital than the advancement of medical
science. These principles are as easily known to physicians as to anyone else, and
it is unacceptable to single oneself out as an exception to these principles simply
because one is a member of an esteemed profession. Someone who is ill deserves
to be treated with the same respect as someone who is well. Accordingly, a
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Parti
physician who failed to tell a patient that what was proposed was an experiment
with no therapeutic intent was and is blameworthy. To the extent that the
experiment entailed significant risk, the physician is more blameworthy; where it
was reasonable to assume that the experiment imposed no risk or minimal risk or
inconvenience, the blame is less.
We argue here that the use of patients in nontherapeutic experiments
without their consent was not only a violation of these basic moral principles but
also a violation of the Hippocratic principle that was the cornerstone of
professional medical ethics at that time. That principle enjoins physicians to act
in the best interests of their patients and thus would seem to prohibit subjecting
patients to experiments from which they could not benefit. It might be argued
that a widespread practice that is not in conformity with a principle of
professional ethics invalidates the principle, since the practice shows that the
profession was not really committed to the principle in the first place. This is a
misunderstanding, however, of what it means for a profession to adopt and
espouse a moral principle. Even if many or most physicians sometimes fail or
even often fail to comply with the principle, it is still coherent to say that the
principle is accepted by the profession, if the principle has been publicly
pronounced and affirmed by the profession, as was clearly the case with respect to
the Hippocratic ethic.
To characterize a great profession as having engaged over many years in
unethical conduct-years in which massive progress was being made in curbing
some of mankind's greatest ills-may strike some as arrogant and unreasonable.
However, fair assessment indicates that the circumstance was one of those times
in history in which wrongs were committed by very decent people who were in a
position to know that a specific aspect of their interactions with others should be
improved. Wrongs are not less egregious because they were committed by a
member of a certain profession or by people who are very decent in their
relationships with other parties. It is common for us to look back at such conduct
in amazement that so many otherwise good and decent people could have
engaged in it without a high level of self-awareness. Moral consistency requires
the Advisory Committee to conclude that, if the use of healthy subjects without
consent was understood to be wrong at the time, then the use of patients without
consent in nontherapeutic experiments should also have been discerned as wrong
at the time, no matter how widespread the practice.
It should be emphasized, however, that often these nontherapeutic
experiments on unconsenting patients constituted only minor wrongs. Often there
was little or no risk to patient-subjects and no inconvenience. Although it is
always morally offensive to use a person as a means only, as the burden on the
patient-subject decreased, so too did the seriousness of the wrong.
Much the same can be said of experiments that were conducted on
patient-subjects without their consent but that offered a prospect of medical
benefit. To the extent that such experiments were conducted within the moral
220
environment of the doctor-patient relationship, that is, based on the physician's
considered and informed judgment that it was in the patient's best interests to be
enrolled in the research, then the less blameworthy the physician was for failing
to obtain consent. However, where the risks were great or where there were
viable alternatives to participation in research, then the physician was more
blameworthy for failing to obtain consent.
It is often difficult to establish standards and make judgments about right
and wrong, and about blame and exculpation. Our charge was all the more
difficult because the context of the actions and agents we were asked to evaluate
differs from our own. In arriving at this moral framework for evaluating human
radiation experiments, we have tried to be fair to history, to considerations of
ethics, and above all, to the people affected by our analysis-former subjects,
physician-investigators, and government officials.
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ENDNOTES
1 . International declarations of human rights that would otherwise be relevant
to an evaluation of human experimentation, such as the Covenant on Civil and Political
Rights (1966), were articulated after the human radiation experiments with which we are
mainly concerned, with the significant exception of the Nuremberg Code, as discussed in
chapter 2.
2. The Advisory Committee is aware that questions such as precisely what
ethical principles should be considered "basic," how they are related to those less basic,
and how the basic ethical principles are known are among the most controversial and
difficult in moral philosophy. For the Advisory Committee's limited purposes, a
comprehensive and systematic moral theory is not required and is, in any case, far
beyond the scope of this report. We have rather settled on a list of immediately
recognizable and widely accepted ethical principles that are not usually thought to
require justification themselves and that should be included in any adequate moral
theory.
3. Some view promise keeping as a basic ethical principle on a par with the
prohibition against deception. It may also be seen as grounded in one or more of the
basic ethical principles on our list of six, such as those concerning deception and treating
people as mere means.
4. The President's Commission functioned from 1978 to 1983, under the Carter
and Reagan administrations, and produced a number of influential reports and
recommendations concerning medical ethics and health care policy.
5. It may be argued that historical ethical relativism reduces to cultural ethical
relativism. On this position, the notion that even basic ethical principles vary by era is
part of a more general claim that what is really at stake is different "world views," and
these different world views may exist at the same time but in cultures that are different
from one another in certain crucial respects. On this analysis, in other words, the
temporal factor is not the essential one. However, some find it easier to reject historical
ethical relativism than cultural ethical relativism, for they find it plausible that essentially
the same values operative in, say, the United States in the 1990s were operative in the
1950s, but not that essentially the same values that are operative in the United States in
the 1990s are also operative in China in the 1990s.
6. In its report on the CIA and Army psychochemical experiments, the U.S.
Senate found that
[i]n the Army's tests, as with those of the CIA, individual
rights were . . . subordinated to national security
considerations; informed consent and follow-up
examinations of subjects were neglected in efforts to
maintain the secrecy of the tests.
U.S. Congress, The Select Committee to Study Governmental Operations with Respect
to Intelligence Activities, Foreign and Military Intelligence [Church Committee report],
report no. 94-755, 94th Cong., 2d Sess. (Washington, D.C.: GPO, 1976), book 1,4111.
However, even in the light of the Army's own analysis of its LSD experiments, presented
in a 1959 staff study by the U.S. Army Intelligence Corps (USAINTC), the operative
legal principles should not have permitted the resulting practices to take place:
222
It was always a tenet of Army intelligence that the basic
American principle of dignity and welfare of the
individual will not be violated ... In intelligence, the
stakes involved and the interests of national security
may permit a more tolerant interpretation of moral-
ethical values, but not legal limits, through necessity . . .
[emphasis added].
USAINTC Staff Study, Material Testing Program EA 1 729 ( 1 5 October, 1959), 26. The
staff study's distinction between the flexibility of "moral-ethical values" and "legal
limits" is puzzling.
7. U.S. Army Inspector General, Use of Volunteers in Chemical Agent Research
(Army IG report) (Washington D.C.: GPO, 1975).
8. David J. Rothman, Strangers at the Bedside: A History of How Law and
Bioethics Transformed Medical Decision Making (New York: Basic Books, 1991), 32-
9. Rothman writes of the CMR's deliberations on the gonorrhea proposal: It
[the CMR] conducted a remarkably thorough and sensitive discussion of the ethics of
research and adopted procedures that satisfied the principles of voluntary and informed
consent. Indeed, the gonorrhea protocols contradict blanket assertions that in the 1940s
and 1950s investigators were working in an ethical vacuum." Ibid., 42-43.
10. Michael Walzer, Just and Unjust Wars (New York: Basic Books, 1977).
11. Another factor often important in assessments of blame is duress. All
systems of ethics recognize that people cannot be blamed for actions that violate basic
ethical principles if they acted under duress. Duress includes manipulation, blackmail,
or threats of physical harm. There is no evidence that any particular individual involved
in the human radiation experiments functioned under conditions of duress.
12. Ruth Faden and Tom Beauchamp, A History and Theory of Informed
Consent (New York: Oxford University Press, 1986).
13. For example, the National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research published ten reports. Many of these
recommendations were enacted into federal regulation. U.S. Congress, Office of
Technology Assessment, Biomedical Ethics in U.S. Public Policy-Background Paper,
OTA-BP-BBS-105 (Washington, D.C.: GPO, June 1993), 10.
14. Scholendorffv. Society of New York Hospital, 2 1 1 N.Y. 2d ( 1 9 1 4).
1 5. Salgo v. Leland Stanford, Jr., University Board of Trustees. 3 1 7 P.2d 1 70
(1957).
1 6. In each case we assume that the principles or policies in question were
morally sound; if not, anyone who refused to take part in unethical experiments
performed in accordance with them acted, in retrospect, in a praiseworthy manner.
1 7. Again, with regard to the elements of an ethical framework suited to the
intentional releases, we note that different justifications are used to evaluate the risks to
collectives or communities as against those used to evaluate risks to individuals.
18. Note, however, that the intended scope of the policy was not always clear.
Also, if the government or an agency had no policy at all concerning the use of human
subjects but did conduct such research, then the absence of a policy would itself be
objectionable.
223
PART II
CASE STUDIES
Part II
Overview
W hen we began our work, the Advisory Committee was aware of
several dozen human radiation experiments and the thirteen intentional releases in
our charter. Soon, however, we found that these represented a fraction of the
several thousand government-sponsored human radiation experiments and
hundreds of intentional releases conducted from 1944 to 1974.
It was clear that the Committee would have to decide how to proceed in
examining the experiments. Our ability to review all of the experiments and
releases in detail was limited not only by time and resources, but even more so by
the information available. For the majority of experiments identified, only the
barest descriptions remained. It appeared that the vast majority of experiments
involved trace amounts of radioisotopes, as are routinely used today for the study
of bodily processes and the diagnosis of disease. However, where reports or other
data were available, they did not routinely provide information needed to assess
the precise risks to which subjects were exposed. These reports were even less
likely to identify what kinds of people were chosen as subjects and why and how
they were selected.
Since the Committee could not review all experiments, we decided to
prepare a series of case studies focused on groups of experiments. We quickly
found that there was no one right way to organize the experiments for purpose of
case study. For example, the case studies could have been defined by the type of
radiation to which subjects were exposed. This would likely have yielded
groupings of experiments with differing purposes, differing populations, and
differing risks and benefits. Likewise, grouping all experiments according to the
characteristics of the people who were the subjects of the research would have
lumped together experiments with differing purposes, risks, and scientific
procedures.
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Part II
The ACHRE Experiments Database
By Cabinet directive on January 19, 1994, federal agencies were ordered to "establish
forthwith an initial procedure for locating records of human radiation experiments conducted by
the Agency or under a contract or grant of the Agency." The agencies most closely associated
with these activities-the DOD, DOE, DHHS, NASA, CIA, and VA (and later the NRC)--in
cooperation with Advisory Committee staff, identified record collections of importance and
provided ACHRE with copies of documents potentially containing information on human radiation
experiments. The documents were analyzed to identify individual experiments, which were then
described according to a protocol developed by ACHRE members and staff, given unique
identifiers, and recorded in an electronic database. Experiments were also identified by Advisory
Committee staff in the published literature, discovered through a search of the National Library of
Medicine databases and bibliographies, and documented by individuals who came forward with
information for the Advisory Committee.
The database contains records for approximately 4,000 human radiation experiments.
Information was collected, to the extent it was available, on the identity of the experiment
(including investigators, location, dates, title, and documentation); funding, program approval and
classification; the type and dose of radiation used; various characteristics of the experimental
subjects; and the nature of the consent obtained. The experiments were in addition categorized by
various themes and characteristics developed by Advisory Committee members and staff to reflect
ACHRE research interests.
Documentation for individual experiments varies widely, sometimes including significant
primary protocol documentation, often including only a journal article or abstract and, for the
greatest number, just an investigator's name, a location, a date, and a title. As a result, although
the database and the records it abstracts constitute an impressive and unique collection of
information on human radiation experiments, that collection is not a comprehensive information
resource on human radiation experiments but really just the best place to start to look for
information.
The supplemental volume titled Sources and Documentation contains a more extensive
and detailed description of the database and its sources.
After extensive deliberation, the Committee settled on eight case studies,
which together address the charges to and priorities of the Committee. For
example, we were charged to consider both intentional releases of radiation into
the environment and the question of whether any former subjects of human
radiation experiments would benefit medically from notification of their
involvement. In addition, the Committee saw a responsibility to address those
experiments that had received significant public attention at the time of the
Committee's creation as well as those brought to our attention by members of the
public. These experiments either offered no prospect of medical benefit to
subjects or they involved interventions alleged to be controversial at the time. We
228
Overview
also, however, recognized the importance of considering the far larger group of
experiments that received no such attention but that also may have involved no
prospect of benefit to subjects. We also placed a priority on experiments that
were conducted on behalf of secret programs and for national security reasons;
experiments that posed the greatest risk of harm; and experiments in which the
subjects selected for experimentation were particularly powerless to resist or
exercise independent judgment about participation. Together, these
considerations formed the basis for the selection of the case studies.
In chapter 5, we look at the Manhattan Project plutonium-injection
experiments and related experimentation. Sick patients were used in sometimes
secret experimentation to develop data needed to protect the health and safety of
nuclear weapons workers. The experiments raise questions of the use of sick
patients for purposes that are not of benefit to them, the role of national security
in permitting conduct that might not otherwise be justified, and the use of secrecy
for the purpose of protecting the government from embarrassment and potential
liability.
In contrast to the plutonium injections, the vast majority of human
radiation experiments were not conducted in secret. Indeed, the use of
radioisotopes in biomedical research was publicly and actively promoted by the
Atomic Energy Commission. Among the several thousand experiments about
which little information is currently available, most fall into this category. The
Committee adopted a two-pronged strategy to study this phenomenon. In chapter
6, we describe the system the AEC developed for the distribution of isotopes to be
used in human research. This system was the primary provider of the source
material for human experimentation in the postwar period. In studying the
operation of the radioisotope distribution system, and the related "human use"
committees at local institutions, we sought to learn the ground rules that governed
the conduct of the majority of human radiation experiments, most of which have
received little or no public attention. Also in this chapter we review how research
with radioisotopes has contributed to advances in medicine.
The Committee then selected for particular consideration, in chapter 7,
radioisotope research that used children as subjects. We determined to focus on
children for several reasons. First, at low levels of radiation exposure, children
are at greater risk of harm than adults. Second, children were the most
appropriate group in which to pursue the Committee's mandate with respect to
notification of former subjects for medical reasons. They are the group most
likely to have been harmed by their participation in research, and they are more
likely than other former subjects still to be alive. Third, when the Committee
considered how best to study subject populations that were most likely to be
exploited because of their relative dependency or powerlessness, children were
the only subjects who could readily be identified in the meager documentation
available. By contrast, characteristics such as gender, ethnicity, and social class
were rarely noted in research reports of the day.
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Part II
Moving from case studies focused on the injection or ingestion of
radioisotopes, chapter 8 shifts to experimentation in which sick patients were
subjected to externally administered total-body irradiation (TBI). The Committee
discovered that the highly publicized TBI experiments conducted at the
University of Cincinnati were only the last of a series in which the government
sought to use data from patients undergoing TBI treatment to gain information for
nuclear weapons development and use. This experimentation spanned the period
from World War II to the early 1970s, during which the ethics of experimentation
became increasingly subject to public debate and government regulation. In
contrast with the experiments that flowed from the AEC's radioisotope program,
the use of external radiation such as TBI did not in its earlier years involve a
government requirement of prior review for risk. The TBI experimentation raises
basic questions about the responsibility of the government when it seeks to gather
research data in conjunction with medical interventions of debatable benefit to
sick patients.
In chapter 9 we examine experimentation on healthy subjects, specifically
prisoners, for the purpose of learning the effects of external irradiation on the
testes, such as might be experienced by astronauts in space. The prisoner
experiments were studied because they received significant public attention and
because a literally captive population was chosen to bear risks to which no other
group of experimental subjects had been exposed or has been exposed since. This
research took place during a period in which the once-commonly accepted
practice of nontherapeutic experimentation on prisoners was increasingly subject
to public criticism and moral outrage.
Chapter 10 also explores research involving healthy subjects: human
experimentation conducted in conjunction with atomic bomb tests. More than
200,000 service personnel—now known as atomic veterans— participated at atomic
bomb test sites, mostly for training and test-management purposes. A small
number also were used as subjects of experimentation. The Committee heard
from many atomic veterans and their family members who were concerned about
both the long-term health effects of these exposures and the government's
conduct. This case study provided the opportunity to examine the meaning of
human experimentation in an occupational setting where risk is the norm.
In chapter 1 1 we address the thirteen intentional releases of radiation into
the environment specified in the Committee's charter, as well as additional
releases identified during the life of the Committee. In contrast with biomedical
experimentation, individuals and communities were not typically the subject of
study in these intentional releases. Rather, the releases were to test intelligence
equipment, the potential of radiological warfare, and the mechanism of the atomic
bomb. While the risk posed by intentional releases was relatively small, the
releases often took place in secret and remained secret for years.
The final case study, in chapter 1 2, looks at two groups that were put at
risk by nuclear weapons development and testing programs and as a consequence
230
Overview
became the subjects of observational research: workers who mined uranium for
the Atomic Energy Commission in the western United States from the 1 940s to
1960s and residents of the Marshall Islands, whose Pacific homeland was
irradiated as a consequence of a hydrogen bomb test in 1954. While these
observational studies do not fit the classic definition of an experiment, in which
the investigator controls the variable under study (in this case radiation exposure),
they are instances of research involving human subjects. The Committee elected
to examine the experiences of the uranium miners and Marshallese because they
raise important issues in the ethics of human research not illustrated in the
previous case studies and because numerous public witnesses impressed on the
Committee the significance of the lessons to be learned from their histories.
Part II concludes with an exploration of an important theme common to
many of the case studies-openness and secrecy in the government's conduct
concerning human radiation research and intentional releases. In chapter 13 we
step back and look at what rules governed what the public was told about the
topics under the Committee's purview, whether these rules were publicly known,
and whether they were followed.
231
Experiments with Plutonium,
Uranium, and Polonium
In August 1944, at the secret Los Alamos Laboratory in New Mexico, a
twenty-three-year-old chemist was trying to learn what he could about the
properties of a radioactive metal. One year later, the new "product"-one of
several code words for this three-year-old element with a classified name-would
power the bomb dropped on Nagasaki. That day the young scientist, Don
Mastick, was working with the entire Los Alamos supply of the material, 10
milligrams. It was sealed in a glass vial several inches long and about a quarter
inch in diameter. Unknown to Mastick, a chemical reaction was causing pressure
to build up inside the vial. Suddenly it burst, firing an acidic solution against the
wall from where it splattered into Mastick's face, some of it entering his mouth.'
Realizing the importance to the war effort of the plutonium he had just
ingested, Mastick hurried directly to the office of Louis Hempelmann, the health
director at Los Alamos. Hempelmann pumped Mastick's stomach and instructed
the young scientist to retrieve the plutonium from the expelled contents.
Hempelmann expressed a concern related to worker safety: there was no way
available to determine how much plutonium remained in Mastick's body. He
immediately pressed the lab's director, J. Robert Oppenheimer, for authorization
to conduct studies to develop ways of detecting plutonium in the lungs, and in
urine and feces, and of estimating the level of plutonium in the body from the
amount found in excreta. 2
Looming over Mastick's accident was the well-known tragedy of the
radium dial workers more than a decade earlier. Like Mastick, they had ingested
radioactive material through their mouths, as they licked the brushes they used to
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Part II
apply radium paint to watch dials. As time passed, many suffered from a
gruesome bone disease localized in the jaw, and some bone cancers developed.
Could plutonium cause a similar tragedy? If so, how much plutonium needed to
be ingested before harmful effects might arise? How could one tell how much
plutonium a person had already ingested? The answers to these questions were
crucial, not only in the case of accidents such as Mastick's, but also, in the long
run, to establish occupational health standards for the hundreds of workers who
would soon be mass-producing plutonium for atomic bombs. Several pounds of
radium, handled without recognition of the dangers, had led to dozens of deaths;
what might plutonium cause?
A starting point was to examine the available data on radium poisoning,
compare the characteristics of the radiation emitted by radium and plutonium, and
try to extrapolate from radium to plutonium. However, plutonium had already
revealed unexpected physical properties, which were posing problems for the
bomb designers. Could plutonium also have unexpected biochemical properties?
Extrapolation from radium was a good starting point, but could never be as
reliable as data on plutonium itself.
Oppenheimer agreed that this research was critical. In an August 16,
1944, memorandum to Hempelmann, Oppenheimer authorized separate programs
to develop methods to detect plutonium in the excreta and in the lung. With
respect to biological studies, which Oppenheimer speculated might involve
human experimentation, he wrote: "I feel that it is desirable if these can in any
way be handled elsewhere not to undertake them here." 3 The reason
Oppenheimer did not want these experiments conducted at Los Alamos remains
obscure. Nine days later, Hempelmann met with Colonel Stafford L. Warren,
medical director of the Manhattan Project, and others. They agreed to conduct a
research program using both animal and human subjects. 4
Mastick, who reported no ill effects from the accident when Advisory
Committee staff interviewed him in 1995, 5 was not the first alert to the potential
hazards of plutonium. Human experiments to study the metabolism and retention
of plutonium in the body had been contemplated from the earliest days of the
Manhattan Project. On January 5, 1944, Glenn Seaborg, who in 1941 was the
first to recognize that plutonium had been created in the cyclotron at the
University of California at Berkeley, wrote to Dr. Robert Stone, health director of
the Metallurgical Laboratory in Chicago (a Manhattan Project contractor) and a
central figure in efforts to understand the health effects of plutonium:
It has occurred to me that the physiological hazards
of working with plutonium and its compounds may
be very great. Due to its alpha radiation and long
life it may be that the permanent location in the
body of even very small amounts, say one
milligram or less, may be very harmful. The
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ingestion of such extraordinarily small amounts as
some few tens of micrograms might be unpleasant,
if it locates itself in a permanent position. 6
Seaborg urged that a safety program be set up. In addition, "I would like
to suggest that a program to trace the course of plutonium in the body be initiated
as soon as possible. In my opinion such a program should have the very highest
priority." 7 Stone reassured Seaborg that human tracer studies "have long since
been planned. . . . although never mentioned in official descriptions of the
program." 8 The work began at Berkeley with studies on rats conducted by Dr.
Joseph Hamilton. 9
Even as these studies on the biological effects of plutonium were
beginning, the amount of plutonium being produced was dramatically increasing.
Most of the effort at Oak Ridge was devoted to the separation of isotopes of
uranium. However, the X- 10 plant at Oak Ridge was a larger version of the very
small plutonium-producing reactor developed at the University of Chicago. The
X-10 plant began operating on November 4, 1943, and by the summer of 1944
was sending small amounts of plutonium to Los Alamos. 10 By December 1944
large-scale production of plutonium began at the Hanford, Washington, reactor
complex. ' '
By late 1944, in the wake of the Mastick accident, the need to devise a
means of estimating the amount of plutonium in the body became acute. It
seemed that the only way to estimate how much plutonium remained in a worker's
body would be to measure over time the amount excreted after a known dose and,
from this, estimate the relationship between the amount excreted and the amount
retained in the body. 12
Maximum Permissible Body Burden (MPBB) for Plutonium
The plutonium injections were part of a larger research project intended to provide data
for an occupational safety program riddled with uncertainty. Not only was there a need for ways to
monitor the exposure of personnel-the driving force behind the plutonium injections-but the
maximum permissible body burden (MPBB) for plutonium, the maximum amount of plutonium
that would be permitted in the bodies of workers, was still under debate.
The concept of "maximum permissible body burden" had begun to develop before the
war in light of the known hazards of radium. Just prior to the war, primarily at the request of the
Navy, a committee of experts was formed to establish occupational health standards for the
factories producing dials illuminated by radium paint. After examining the data on radium dial
painters, this committee agreed that 0. 1 microgram fixed in the body should be the "tolerance
level" for radium: an amount that, in the words of the committee chairman, Robley Evans, would
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Part II
be "at such a level that we would feel comfortable if our own wife or daughter were the subject." 8
After the war the term maximum permissible body burden was adopted and defined more precisely
as the amount of a radioisotope that, when continuously present inside the body, would produce a
dose equivalent to the allowable occupational exposure (the maximum permissible dose). For
radioisotopes that, like radium, primarily reside in bone, biological data and mathematical models
were used to determine how much of another bone seeker would produce the same dose as the
original 0. 1 -microgram radium standard.
Between 1943 and the spring of 1945, based on the body burden for radium and
preliminary results of animal experiments, a tentative MPBB for plutonium of 5 micrograms was
adopted by the Manhattan District. b This level was derived by direct comparison of the relative
energies of plutonium and radium.
By the spring of 1945, differences between the deposition of radium and plutonium in the
body were becoming clearer. Animal data indicated that plutonium deposited in what was called at
the time the "organic matrix" of the bone-the part of the bone most associated with bone growth.
This was different from radium, which seemed to deposit instead in the mineralized bone. Wright
Langham wrote to Hymer Friedell supporting the choice of 1 microgram as an operating limit in
lieu of a more formal policy. Langham wrote that with the adoption of this lower limit "the
medico-legal aspect will have been taken care of and of still greater importance, we will have
taken a relatively small chance of poisoning someone in case the material proves to be more toxic
than one would normally expect."" This level was adopted and held until the Tripartite Permissible
Dose Conference at Chalk River, Canada, in September 1 949.
At this conference, representatives from the United States, United Kingdom, and Canada
agreed on tolerance doses for many radioactive isotopes, including a maximum body burden of 0. 1
microgram for plutonium. This reduced by a factor of 10 the value under which Los Alamos
production had been operating. This reduction was based on the results of acute toxicological
experiments with animals, which indicated that plutonium was as much as fifteen times more toxic
than radium.
On January 20, 1950, Wright Langham wrote to Shields Warren, then the director of the
AEC's Division of Biology and Medicine, alerting him to the problems caused by the Chalk River
Conference's new "extremely conservative tolerances [which] may have a drastic effect on the
efficiency and productivity of the Los Alamos Laboratory. Their official adoption will
undoubtedly force major alteration in both present and future laboratory facilities and may add
millions of dollars to the cost of construction of the permanent building program now in the
a. Robley Evans, "Inception of Standards for Internal Emitters, Radon and Radium," Health
Physics 41 (September 1981): 437-448.
b. W. H. Langham et al., "The Los Alamos Scientific Laboratory's Experience with Plutonium in
Man," Health Physics 8 (1962): 753.
C. Wright Langham, Los Alamos Scientific Laboratory Health Division, to Hymer Friedell, 21
May 1945 ("Since the Chicago Meeting, 1 am somewhat lost as to what our program should be in the
future . . .") (ACHRE No. DOE-1 13094-B-7), 1.
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Chapter 5
planning phases.'" 1 Langham continued with reasons for regarding the Chalk River value of 0.1
micrograms of plutonium as "unnecessarily low." He cited, among other things, differences
between acute and chronic toxicity and new analysis of data from the radium watch dial painters.
On January 24, 1950, Shields Warren, Austin Brues of Argonne National Laboratory,
Robley Evans, Karl Morgan, and Wright Langham met in Washington. Langham wrote later: "As
a result of this meeting, Dr. Shields Warren of the Division of Biology and Medicine authorized
0.5 ug (0.033 uc) of Pu 2 " as the AEC's official operating maximum permissible body burden."
There were no minutes or transcripts taken of this meeting. The calculation of this level was again
based on the body burden for radium, this time modified by the 1/15 toxicity factor (since
experiments had indicated that plutonium was up to fifteen times more toxic than radium), by the
relative retention of plutonium and radium in rodents, and by the energy ratios modified by radon
retention.
Thus far, the entire debate had occurred behind the closed doors of the AEC.
Consideration of all the complex issues applied in setting a permissible body burden had been
within a small circle of scientists and administrators. While the MPBB for plutonium accepted at
the January 1950 meeting has held until today, its derivation has changed over the years.
By March 1945, there was disturbing news that urine samples from Los
Alamos workers were indicating, based on models developed from animal
experimentation, that some might be approaching or had exceeded a body burden
of 1 microgram. 13 A March 25 meeting led to Hempelmann's recommendation
that the Project "help make arrangements for a human tracer experiment to
determine the percentage of plutonium excreted daily in the urine and feces. It is
suggested that a hospital patient at either Rochester or Chicago be chosen for
injection of from one to ten micrograms of material and that the excreta be sent to
the laboratory for analysis." 14 The overall program, as it was envisioned by Dr.
Hymer Friedell, deputy medical director of the Manhattan Engineer District,
Oppenheimer, and Hempelmann, consisted of three parts: improvement of
methods to protect personnel from exposure to plutonium; development of
methods for diagnosing overexposure of personnel; and study of methods of
treatment for overexposed personnel. On March 29, Oppenheimer forwarded the
recommendation to Stafford Warren, with his "personal endorsement." 15
d. The letter went on to say that "operations of the Los Alamos Laboratory would be curtailed or
stopped if such action were necessary to the reasonable and sensible protection of the personnel. The
seriousness of this action, however, seems to be adequate reason for requesting that official adoption of the
tolerances by the AEC be postponed until they have been carefully reviewed in order to make certain that the
values are not unnecessarily conservative." Wright Langham, Los Alamos Laboratory Health Division, to
Shields Warren, Director of AEC Division of Biology and Medicine, 20 January 1950 ("Radiation
Tolerances Proposed by the Chalk River Permissible Dose Conference of September 29-30, 1949") (ACHRE
No. DOE-020795-D-6), 1.
e. W. H. Langham et al„ "The Los Alamos Scientific Laboratory's Experience with Plutonium in
Man," Health Physics 8 (1962): 754.
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Part II
The accident at Los Alamos was part of the prelude to experiments
conducted between 1945 and 1947 in which eighteen hospital patients were
injected with plutonium to determine how excreta (urine and feces) could be used
to estimate the amount of plutonium that remained in an exposed worker's body.
One patient was injected at Oak Ridge Hospital in Oak Ridge, Tennessee; eleven
were injected at the University of Rochester, three at the University of Chicago,
and three at the University of California.
The results of these experiments contributed to the development of a
monitoring method that, with small changes, is still used today. The experimental
data were used to develop a model relating body burden to short-term excretion
rate. Known as the "Langham model," it was based on short-term excretion data,
long-term excretion data that were collected in 1950 from two injection subjects,
and worker excretion data. This model has been used almost universally to
monitor plutonium workers since 1950, although it has been modified over the
years as longer-term and more extensive data were accumulated. While now, fifty
years later, not every question concerning the quality of the science or the basis
for estimating risk can be answered with precision, there is general agreement
among radiation scientists that the experiments were useful.
Although this would be the first time that plutonium would be injected
into human beings, the plutonium experiments were not viewed at the time as
being extremely risky, and for good reason. Based on experience with other
bone-seeking radioisotopes such as radium, the investigators had firm basis for
believing, even in the 1940s, that the amount of material to be injected was likely
too small to produce any immediate side effects or reactions. No one was
expected to feel ill or have any negative reaction to the injection, and apparently
no one did. Because acute effects were not expected, the plutonium injections
were viewed as posing no short-term risks to human subjects. There was concern,
however, about long-term risk. A draft report, written by one of the primary
investigators within a few years of the injections, records that "acute toxic effects
from the small dose of pu [plutonium] administered were neither expected nor
observed." The document also recognized that "with regard to ultimate effects, it
is too early to predict what may occur." 16 Based largely on the experience of the
radium dial painters, it was recognized that exposure to plutonium could result,
perhaps ten or twenty years later, in the development of cancer in a human
subject. This was viewed as a significant risk but also as a risk that could be
minimized by the use of small doses and wholly avoided if the subjects were
expected to die well before a cancer had a chance to materialize.
Even if the plutonium injections had been entirely risk free, an
impossibility in human experimentation, they could still be morally problematic.
As we discussed in chapter 2, it was not uncommon in the 1940s for physicians
to use patients as subjects in experiments without their knowledge or consent.
This occurred frequently in research involving potential new therapies, where
there was at least a chance that the patient-subjects might benefit medically from
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Chapter 5
being in an experiment. But it also occurred even in experiments-like the
plutonium injections- where there was never any expectation and no chance that
the experiment might be of benefit to the subjects.
The conduct of the plutonium experiments raises a number of difficult
ethics and policy questions: Who should have been the subjects of an experiment
designed to protect workers vital to bomb production in wartime? What should
the subjects have been told about the risks of the secret substance with which they
were being injected? What should they have been told about the purpose of the
experiment? What were the subjects told? Did they know they were part of an
experiment in which there was no expectation that they would benefit medically?
An inquiry initiated by the AEC commissioners in 1974 investigated some
of these questions. That inquiry focused on whether consent was obtained from
the subjects, either at the time of the plutonium injections or during 1973 follow-
up studies funded by the AEC's Argonne National Laboratory in Chicago,
designed to determine the long-term effects of the injections. Sixteen patient
charts were examined for evidence of consent at the time of injection; the other
two charts had been either lost or destroyed. Of the sixteen charts examined, only
one chart-that of the only subject injected after the April 1947 directive of AEC
General Manager Carroll Wilson (discussed in chapter 1) that required
documented consent-contained evidence of some form of consent. The other
fifteen contained no record of consent. 17 According to AEC investigators, oral
testimony pointed to failure to obtain consent in the case of the Oak Ridge
injection and to some form of disclosure to patients for the California and
Chicago experiments. The AEC concluded that testimony was inconclusive for
the Rochester experiments. 11 * With regard to the follow-up studies conducted with
three surviving subjects in 1973, the investigation concluded that two subjects had
deliberately not been informed of the purpose of the follow-up and that one
subject had actually been misled about the purpose. 19
As we will see later in this chapter, the AEC's conclusion that consent was
not obtained from the surviving subjects for the 1973 follow-up studies was
correct. Moreover, additional documentary evidence and testimony suggests that
patient-subjects at the Universities of Rochester and California were never told
that the injections were part of a medical experiment for which there was no
expectation that they would benefit, and they never consented to this use of their
bodies.
The rest of this chapter provides a chronological account of the plutonium
injection experiments and follow-up studies conducted over the course of many
years, assesses the influence of secrecy on the conduct of the experiments, and
examines the motivating factors behind the prolonged secrecy of the experiments
and the continued deception of surviving subjects. We also consider the conduct
of experimentation with uranium and polonium. Finally, we render judgments
where we can about the ethical conduct of these experiments.
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Part II
THE MANHATTAN DISTRICT EXPERIMENTS
The First Injection
A few days after Hempelmann's March 26, 1945, recommendation that a
hospital patient be injected with plutonium, Wright Langham, of the Los Alamos
Laboratory's Health Division, sent 5 micrograms of plutonium to Dr. Friedell,
with instructions for their use on a human subject. 20 The subject, as it turned out,
was already in the Oak Ridge Army hospital, a victim of an auto accident that had
occurred on March 24, 1945. 2I He was a fifty-three-year-old "colored male" 22
named Ebb Cade, 23 who was employed by an Oak Ridge construction company as
a cement mixer. The subject had serious fractures in his arm and leg, but was
otherwise "well developed [and] well nourished." 24 The patient was able to tell
his doctors that he had always been in good health. 25
Mr. Cade had been hospitalized since his accident, but the plutonium
injection did not take place until April 10. On this date, "HP- 12" (the code name
HP— "human product" 26 --was later assigned to this patient and to patients at the
University of Rochester) was reportedly injected with 4.7 micrograms of
plutonium. (It is important here to distinguish between administered dose and
retained dose; not all of the injected dose would remain fixed in the body. It was
not known with certainty, however, how much of the 4.7 micrograms of
plutonium would remain in his body.)
The small amount of material injected into Mr. Cade would not be
expected to produce any acute effects, and there is no indication that any were
experienced. However, except for his fractures, Mr. Cade was apparently in good
health and at age fifty-three could reasonably have been expected to live for
another ten to twenty years. Thus, in Mr. Cade's case, the risk of a plutonium-
induced cancer could not be ruled out.
Dr. Joseph Howland, an Army doctor stationed at Oak Ridge, told AEC
investigators in 1974 that he had administered the injection. There was, he
recalled, no consent from the patient. He acted, he testified, only after his
objections were met with a written order to proceed from his superior, Dr.
Friedell. 27 Dr. Friedell told Advisory Committee staff in an interview that he did
not order the injection and that it was administered by a physician named Dwight
Clark, not Dr. Howland. 28 The Committee has not been able to resolve this
contradiction.
Measurements were to be taken from samples of Mr. Cade's blood after
four hours, his bone tissue after ninety-six hours, and his bodily excretions for
forty to sixty days thereafter. 29 His broken bones were not set until April 1 5— five
days after the injection~when bone samples were taken in a biopsy. 30 Although
this was several weeks after his injury, during this era when antibiotics were only
beginning to become available, it was common practice to delay surgery if there
was any sign of possible infection. One document records that Mr. Cade had
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Chapter 5
"marked" tooth decay and gum inflammation/ 1 and fifteen of his teeth were
extracted and sampled for plutonium. The Committee has not been able to
determine whether the teeth were extracted primarily for medical reasons or for
the purpose of sampling for plutonium. In a September 1945 letter, Captain
David Goldring at Oak Ridge informed Langham that "more bone specimens and
extracted teeth will be shipped to you very soon for analysis." 32 It remains
unclear whether these additional bone specimens were extracted at the time of the
April 15 operation or later.
According to one account, Mr. Cade departed suddenly from the hospital
on his own initiative; one morning the nurse opened his door, and he was gone."
Later it was learned that he moved out of state and died of heart failure on April
13, 1953, in Greensboro, North Carolina. 34
The experiment at Oak Ridge did not proceed as planned. "Before" and
"after" urine samples were mistakenly commingled, so no baseline data on kidney
function was available. 35 Thus, the subject's kidney function would be difficult to
assess. In May 1945, 36 Dr. Stone convened a "Conference on Plutonium" in
Chicago to discuss health issues related to plutonium, including the relationship
between dose and excretion rate, the permissible body burden, and potential
therapy and protective measures. 37 Wright Langham spoke about the Oak Ridge
injection at the conference, carefully qualifying the reliability of the excretion
data obtained from Mr. Cade. Langham observed that "the patient might not have
been an ideal subject in that his kidney function may not have been completely
normal at the time of injection" 38 as indicated by protein tests of his urine.
The Chicago Experiments
On April 1 1, the day after the Oak Ridge injection, Hymer Friedell
transmitted the protocol describing the experiment on Mr. Cade to Louis
Hempelmann at Los Alamos. "Everything went very smoothly," he wrote, "and I
think that we will have some very valuable information for you." 39 He then went
on to discuss the injection of more patients: "I think that we will have access to
considerable clinical material here, and we hope to do a number of subjects. At
such time as we line up several patients I think we will make an effort to have Mr.
Langham here to review our setup." 40
Subsequently, between late April and late December of 1945, three cancer
patients, code-named CHI-1, 2, and 3, were injected with plutonium. At least two
and possibly all three were injected at the Billings Hospital of the University of
Chicago. The doses to subjects CHI-2 and CHI-3 were the highest doses
administered to any of the eighteen injection subjects-approximately 95
micrograms. 41 However, the amount of material injected was still below what
would be expected to produce acute effects. Moreover, unlike Mr. Cade, all three
of these patients were seriously ill and at least two of them died within ten months
of receiving the injection. That the selection of seriously ill patients was an
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intentional strategy to contain risk is indicated in a 1946 report on CHI-1 and
CHI-2: "Some human studies were needed to see how to apply the animal data to
the human problems. Hence, two people were selected whose life expectancy
was such that they could not be endangered by injections of plutonium." 42 It
remains a mystery why CHI-3 was not included in this report.
On April 26, 1945, CHI-1, a sixty-eight-year-old man who had been
admitted to Billings Hospital in March, was injected with 6.5 micrograms of
plutonium. At the time of injection he was suffering from cancer of the mouth
and lung. The patient reportedly "remained in fair condition until August 1945,
when he complained of pain in the chest." 4 ' 1 His lung cancer had apparently
spread, and he died on October 3, 1945. 44
The next injection took place eight months later. CHI-2 was a fifty-five-
year-old woman with breast cancer who had been admitted to Billings Hospital in
December 1945 after the cancer had already spread throughout her body. The
1 946 report recorded that "the patient's general condition was poor at the time of
admission and deteriorated steadily throughout the period of hospitalization." 45
She was injected with 95 micrograms of plutonium on December 27 and died on
January 13, 1946. 46
There is little known about the condition of CHI-3, the other subject who
was injected with approximately 95 micrograms. He was a young man suffering
from Hodgkin's disease, reportedly injected on the same date as CHI-2. 47 His
condition at the time of injection remains unknown, as does his date of death.
There is some question whether he was injected at Billings hospital or at another
hospital in the Chicago area. 4 *
There was no discussion of consent in the original reports on the Chicago
experiments. However, a draft report on an interview conducted with E. R.
Russell for the 1974 AEC investigation into the experiments (Russell was
coauthor of the 1946 report on the Chicago experiments) summarized Russell's
description of consent as follows: "[H]e prepared the plutonium solutions for
injection and acted together with a nurse as witness to the fact that the patient was
or had been informed that a radioactive substance was going to be injected. The
administration of this substance, according to what was said in obtaining consent,
was not necessarily for the benefit of the patients but might help other people." 49
To say that the injection was "not necessarily" for the benefit of the patient
implies that there was some chance these patients might benefit; in fact, there was
no expectation that this would occur.
Russell's account was obtained in the context of an official inquiry into his
conduct and the conduct of the other investigators and officials involved in the
plutonium injections, an inquiry that focused on whether consent was obtained
from the subjects. We have no way of corroborating this account or of assessing
what Dr. Russell's motivations were in explaining the plutonium injections to the
subjects in the way claimed.
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Chapter 5
The Rochester Experiments
By the time the war began, the University of Rochester, which had a
cyclotron, had assembled a group of first-rate physicists and medical researchers
who were pioneering the new radiation research. Following the selection of the
university's Stafford Warren to head its medical division, the Manhattan Project
turned to Rochester for an increasing share of its biomedical research-including,
in particular, research needed to set standards for worker safety. 50
The university's metabolism ward, at what is now the Strong Memorial
Hospital, became the central Manhattan District site for the administration of
isotopes to human subjects. The two-bed ward, headed by Dr. Samuel Bassett,
was part of the Manhattan District's "Special Problems Division," which worked
on the health monitoring of production plants, the development of monitoring
instruments, and research on the metabolism and toxicology of long-lived
radioactive elements. 51 An experimental plan called for fifty subjects altogether,
in five groups often subjects each. Each group would receive plutonium, radium,
polonium, uranium, or lead. 52 Although the exact number of subjects remains
unknown, at least twenty-two patients were administered long-lived isotopes in
experiments with plutonium (eleven subjects), polonium (five subjects), and
uranium (six subjects).
At the time the experiment was being designed, the main selection
criterion for the subjects chosen at Rochester for the plutonium experiment was
that they have a metabolism similar to healthy Manhattan Engineer District
workers. In a work plan for the plutonium study based on a September 1 945
meeting with a representative of Colonel Warren's office and the Rochester
doctors, Langham wrote:
The selection of subjects is entirely up to the
Rochester group. At the meeting it seemed to be
more or less agreed that the subjects might be
chronic arthritics [patients with serious collagen
vascular diseases, such as scleroderma] or
carcinoma patients without primary involvement of
bone, liver, blood or kidneys.
It is of primary importance that the subjects have
relatively normal kidney and liver function, as it is
desirable to obtain a metabolic picture comparable
to that of an active worker.
Undoubtedly the selection of subjects will be
greatly influenced by what is available. The above
points, however, should be kept in mind. 53
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Although this protocol specifies cancer patients as potential subjects,
evidently the deliberate choice was made later by the experimenters to select
patients without malignant diseases in the hope of ensuring normal metabolism. 54
Thus no cancer patients were included among the plutonium subjects at
Rochester. Preference appears to have been given to patients the doctors believed
would benefit from additional time in the hospital. 55
An additional perspective on the selection of subjects for the plutonium
experiments is provided in three retrospective reports written by Wright
Langham. In a 1950 report on the plutonium project, including the experiments
conducted at Rochester, Langham wrote that "as a rule, the subjects chosen were
past forty- five years of age and suffering from chronic disorders such that
survival for ten years was highly improbable." 56 In subsequent reports, Langham
refers to the plutonium subjects as having been "hopelessly sick" 57 and
"terminal." 58
Documents retrieved for the Advisory Committee show that all but one of
the plutonium subjects at Rochester suffered from chronic disorders such as
severe hemorrhaging secondary to duodenal ulcers, heart disease, Addison's
disease, cirrhosis, and scleroderma. 59 One subject, Eda Schultz Charlton, did not
have any such condition. According to the draft of the 1950 report, she was
misdiagnosed: "a woman aged 49 years may have a greater life expectancy than
originally anticipated due to an error in the provisional diagnosis." 60
Most of the subjects at Rochester were not terminally ill, and at least some
of them had the potential to live more than ten years. Three of the Rochester
subjects were known to still be living at the time of the 1974 AEC investigation
into the plutonium experiments. Whether the inclusion of subjects at Rochester
with the potential to live more than ten years is an indication that the investigators
were not using Langham's criterion to select subjects or that they erred in their
predictions is unclear. Judgments about the life expectancy of the chronically ill
are difficult to make and often in error, even today.
The likelihood that long-term risks can be altogether eliminated does
exist, however, if the subject is in the terminal stages of an illness and death is
imminent. This was recognized by the plutonium investigators, and it led to the
observation that the use of a terminal patient permitted a larger dose, which would
make analysis easier. The first terminal patient at Rochester was injected toward
the end of that series, and the possibility of further injections into terminal
patients was discussed explicitly. In a March 1946 letter, Wright Langham wrote
to Dr. Bassett, the primary physician-investigator at Rochester:
In case you should decide to do another terminal
case, I suggest you do 50 micrograms instead of 5.
This would permit the analysis of much smaller
samples and would make my work considerably
easier. ... I feel reasonably certain there would be
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Chapter 5
no harm in using larger amounts of material if you
are sure the case is a terminal one [as was done in
two of the three Chicago injections]. 61
As was the case at Oak Ridge and Chicago, there was no expectation that
the patient-subjects at Rochester would benefit medically from the plutonium
injections. The Advisory Committee found no documents that bear directly on
what, if anything, the subjects were told about the injections and whether they
consented. The recollections of at least some of those intimately involved have
survived, however, and these recollections all suggest that the patients did not
know they had been injected with radioactive material or even that they were
subjects of an experiment.
Milton Stadt, the son of a Rochester subject, told the Advisory Committee
the following at a meeting in Santa Fe, New Mexico, on January 30, 1995:
My mother, Jan Stadt, had a number, HP-8. She
was injected with plutonium on March 9th, 1946.
She was forty-one years old, and I was eleven years
old at the time. My mother and father were never
told or asked for any kind of consent to have this
done to them.
My mother went in [to the hospital] for scleroderma
. . . and a duodenal ulcer, and somehow she got
pushed over into this lab where these monsters
were.
Dr. Hempelmann, in an interview for the 1974 AEC investigation, said he
believed that the patients injected with plutonium were deliberately not informed
about the contents of the injections. 62 Dr. Patricia Durbin, a University of
California researcher who in 1968 undertook a scientific reanalysis of the
experiments, reported on a visit with Dr. Christine Waterhouse in 1971 . Dr.
Waterhouse was a medical resident at Rochester at the time of the plutonium
injections. Durbin wrote the following regarding the Rochester subjects who
were still alive:
She [Dr. Waterhouse] believes that all three persons
would be agreeable to providing excretion samples
and perhaps blood samples, but they are all quite
old~in their middle or late 70's and cannot travel
far. More important, they do not know that they
received any radioactive material. 63
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In notes on a 1971 telephone conversation with Wright Langham, Dr.
Durbin wrote: "He is, I believe, distressed by . . . the fact that the injected people
in the HP series were unaware that they were the subjects of an experiment." 64
This recollection is even more troubling than the recollections of Drs. Waterhouse
and Hempelmann, as it indicates not only that the subjects did not know that they
were being injected with plutonium or a radioactive substance, but also that they
did not know even that they were subjects of an experiment.
Even the doctors in charge of some of the injections at Rochester may not
have known what they were injecting into patients. In 1974, Dr. Hempelmann
suggested that the physician who actually injected the solution quite possibly did
not know of its contents. 65
Further evidence suggesting that the patient-subjects were never told what
was done to them comes from 1 950 correspondence between Langham and the
physicians at Rochester. These physician-investigators were looking for signs of
long-term skeletal effects in follow-up studies with two of the subjects at
Rochester. Langham wrote to Rochester that he was "very glad to hear that you
will manage to get follow-ups on the two subjects. The x-rays seem to be the all-
important thing, but please get them in a completely routine manner. Do not
make the examination look unusual in any way." 66
Moreover, a letter from Langham to Dr. Bassett discussed the
undesirability of recording plutonium data in the Rochester subjects' hospital
records:
I talked to Col. [Stafford] Warren on the phone
yesterday and he recommended that I send copies of
all my data to Dr. [Andrew] Dowdy where it would
be available to you and Dr. [Robert M.] Fink to
observe. He thought it best that I not send it to you
because he wanted it to remain in the Manhattan
Project files, instead of taking a chance on it finding
its way into the hospital records. I think this is
probably a sensible suggestion.
67
Uranium Injections at Rochester
Under the Manhattan Engineer District program, physicians at the
Rochester metabolism ward also injected six patients with uranium (in the form of
uranyl nitrate enriched in the isotopes uranium 234 and uranium 235) to establish
the minimum dose that would produce detectable kidney damage due to the
chemical toxicity of uranium metal, and to measure the rate at which uranium was
excreted from the body. To achieve the first objective, the experimenters used a
higher dose with each new subject until the first sign of minimal kidney damage
occurred. Damage occurred in the sixth and last subject (at a calculated amount
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Chapter 5
of radioactivity of 0.03 microcuries), indicated by protein tests of his urine.
Unlike the plutonium injections, this was an experiment that evidently was
designed not only to obtain excretion data but to cause actual physical harm,
however minimal. Thus, although the investigators could reasonably view the
plutonium injections as an experiment that was extremely unlikely to produce
acute effects, this was not true of the uranium experiment, which was intended to
produce acute effects. As with the plutonium injections, the uranium injections
also posed a long-term risk of the development of cancer. The Committee does
not know in this case how long subjects survived after injection; there is no
documentation of follow-up with these subjects as there is for some of the
subjects of the plutonium injections.
The subjects of this experiment, like some of the plutonium-injection
subjects, were not at risk of imminent death, but did suffer from chronic medical
conditions such as rheumatoid arthritis, alcoholism, malnutrition, cirrhosis, and
tuberculosis. According to Dr. Bassett, again the primary investigator, the
subjects "were chosen from a large group of hospital patients. Criteria of
importance in making the selection were reasonably good kidney function with
urine free from protein and with a normal sediment on clinical examination. The
probability that the patient would benefit from continued hospitalization and
medical care was also a factor in the choice." 68
The 1948 report on the experiment did not discuss the question of consent.
We were not able to locate any documents that bear on what, if anything, the
subjects were told about the uranium injections, nor have any relevant
recollections about the experiment survived. Two 1946 documents, however,
discussing whether Dr. Bassett should be permitted to give a departmental
seminar on the excretion rate of uranium in humans, illustrate the secrecy that
surrounded these injections and suggest that the subjects were not informed of the
experiment. By the time of this correspondence, the uranium research with
animals at Rochester had been declassified. The first document, a letter written by
Andrew Dowdy, the director of the Manhattan Department at the University of
Rochester, to a Manhattan District Area engineer requesting permission for
Bassett to give the seminar, included the following: "I feel that there is no reason
why he should not discuss this matter, and I believe that the fact that this
information was actually obtained on his own patients is of more concern to
himself than to the District." 69 In the second document, an intraoffice
memorandum, the area engineer discussed this point, and more:
Dr. Dowdy states that the patients were Dr.
Bassett's, but it should be borne in mind that all the
work performed by Dr. Bassett was performed at
the request of the Manhattan District Medical
Section. This seminar is to be conducted for persons
who are all Doctors of Medicine and it is doubtful if
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Part II
this information would get out to any of the families
of the patients or the patients on whom the
experiments were performed. . . .
At the time these experiments were started, this
office was given strict orders that the information
should not be released to any but authorized
persons. Almost all the correspondence and result
of experiments were exchanged between Dr. Wright
Langham at Santa Fe and Dr. Bassett of the
University of Rochester. This rule is still in effect
on some of the material that Dr. Bassett is using and
knowledge of the experiments is kept from
personnel at the Rochester Area. 70
Polonium Injections at Rochester
In addition to the subjects injected with plutonium and uranium at
Rochester, five subjects were chosen for an experiment with polonium. The
purpose of the experiment was to determine the excretion rate of polonium after a
known dose, as well as to analyze the uptake of polonium in various tissues. The
primary investigator for these experiments was Dr. Robert M. Fink, assistant
professor of radiology and biophysics at the University of Rochester. Four
patients were injected with the element, and one ingested it. 71 All five patients
selected for this study were suffering from terminal forms of cancer:
lymphosarcoma, acute lymphatic leukemia, or chronic myeloid leukemia. It is
unclear why patients with malignant diseases were chosen as subjects in this
experiment but excluded from the subject pools for the plutonium and uranium
experiments. There is no discussion in the 1950 final report on the polonium
experiments of the possibility that patients with malignant diseases might have
abnormal metabolism, and the excretion data were employed right away in the
establishment of occupational safety standards. 72
The final report, unlike other reports on the Manhattan District
metabolism studies, briefly discusses the question of consent: "the general
problem was outlined to a number of hospital patients with no previous or
probable future contact with polonium. Of the group that volunteered as subjects,
four men and one woman were selected for the excretion studies outlined
below." 73 This statement leaves no clear impression of what the subjects actually
were told; like the experiments with plutonium and uranium, the human polonium
experiment was a classified component of the metabolism program. Still, this
report provides a contrast to the contemporaneous reports on the Manhattan
District plutonium and uranium experiments, which make no mention of consent
and which do not refer to the patient-subjects as "volunteers."
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Chapter 5
The California Experiments
While the University of Rochester had been conducting experiments for
the Manhattan Engineer District, a related effort was under way at the University
of California at Berkeley. 74 Before the war, Drs. Joseph Hamilton and Robert
Stone had been exploring medical applications of radioisotopes with the aid of the
University of California's cyclotron. Hamilton and his colleagues had pioneered
in using radioisotopes to treat cancer, in particular iodine 131 in the 1930s. At the
time the United States entered the war, they were investigating another isotope for
cancer therapy, strontium 89. Indeed, it was this area of Hamilton's expertise that
attracted the : interest of the Manhattan Project. While Stone moved to the Chicago
Metallurgical Laboratory during the war, Hamilton remained at the University of
California's Radiation Laboratory, or "Rad Lab," at Berkeley. A colleague of both
men, Dr. Earl Miller, a radiologist at the University of California, reported
regularly to Stone on the progress of the Berkeley plutonium project.
Under the Manhattan District contract, Hamilton's studies originally had
involved exposing rats to plutonium in an effort to determine its metabolic fate
and thereby project the risk to workers at atomic plants. Toward the end of the
war, Hamilton began to conduct plutonium studies on humans for the
government. 75 Experiments with humans could be handled expeditiously,
Hamilton wrote, because of the close relationship between the Rad Lab and the
medical school at the University of California at San Francisco. 76 In January
1945, Hamilton confirmed to the Manhattan District that he planned "to
undertake, on a limited scale, a series of metabolic studies with [plutonium] using
human subjects." 77 The purpose of this work, Hamilton wrote, "was to evaluate
the possible hazards ... to humans who might be exposed to them, either in the
course of the operation of the [Chicago] pile, or in the event of possible enemy
action against the military and civilian population." 78
Subsequently, three subjects, two adults and one child (known as CAL-1,
2, and 3), were injected with plutonium. In addition, in April 1947 a teenage boy
(CAL-A) was injected with americium, and in January 1948 a fifty-five-year-old
female cancer patient (CAL-Z) was injected with zirconium. 79
On May 10, 1945, Hamilton reported he was awaiting "a suitable patient"
for the plutonium experiment. 80 Four days later, fifty-eight-year-old Albert
Stevens, designated CAL-1, was injected with plutonium, becoming the first
human subject in the California portion of the project. 81 Albert Stevens was
chosen in the belief that he was suffering from advanced stomach cancer. 82
Shortly after the injection, however, a biopsy revealed a benign gastric ulcer
instead of the suspected cancer. The researchers collected excreta daily for almost
one year, analyzing them for plutonium content. 83 Evidently, by two months after
the injection, Mr. Stevens was considering moving out of the Berkeley area; this
would have prevented further collection of excretion specimens. Dr. Hamilton
proposed to Drs. Stone and Stafford Warren that he be permitted to "pay the man
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Part II
fifty dollars per month" in order to keep Mr. Stevens in the area. Hamilton
recognized, however, that there were "possible legal and security situations which
may present insurmountable obstacles." 84 In response to this request, Dr. Joe
Howland (who was reportedly involved with the Oak Ridge plutonium injection)
wrote the following to the California area engineer:
Possible solutions to this problem could be:
a. Pay for his care in a hospital or nursing home as
a service.
b. Place this individual on Dr. Hamilton's payroll in
some minor capacity without release of any
classified information.
It is not recommended that he be paid as an
experimental subject only." 5
According to a 1979 oral history of Kenneth Scott, an investigator at
Berkeley who evidently was responsible for the analysis of Mr. Stevens's
excretion specimens, the patient was paid some amount each month to keep him
in the area. However, Dr. Scott also recalled that he never told Mr. Stevens what
had happened to him: "His sister was a nurse and she was very suspicious of me.
But to my knowledge he never found out." 86
In addition, an April 1946 report on the experiment records that "several
highly important tissue samples were secured including bone." 87 It appears that
these tissue specimens, which included specimens of rib and spleen, were
removed four days after the injection in an operation for the patient's suspected
stomach cancer. 88
Four months after Mr. Stevens was injected, Dr. Hamilton told the
Manhattan District that the next subject would be injected "along with Pu238
[plutonium], small quantities of radio-yttrium, radio-strontium, and radio-
cerium." The purpose of this experiment was to "compare in man the behavior of
these three representative long-lived Fission Products with their metabolic
properties in the rat, and second, a comparison can be made of the differences in
their behavior from that of Plutonium." 89 This research would provide data to
improve extrapolation from higher-dose animal experiments.
Despite Hamilton's hope to have a second patient by the fall, CAL-2 was
not selected until April 1946. Simeon Shaw was a four-year-old Australian boy
suffering from osteogenic sarcoma, a rare form of bone cancer, who was flown
from Australia to the University of California for treatment. According to
newspaper articles at the time, Simeon's family had been advised by an Australian
physician to seek treatment at the University of California. 90 Arrangements then
were made by the Red Cross and the U.S. Army for Simeon and his mother to fly
by Army aircraft to San Francisco. Within days, he had been injected with a
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Chapter 5
solution containing plutonium, yttrium, and cerium by physicians at the
university. 91
Following his discharge on May 25, about a month after his injection, the
boy returned to Australia, and no follow-up was conducted. He died in January
1947. In February 1995 an ad hoc committee at the University of California at
San Francisco (UCSF) concluded that probably at least part of the motivation for
this experiment was to gather scientific data on the disposition of bone-seeking
radionuclides with bone cancers. 92
One piece of evidence indicating that there was a secondary research
purpose for the injection of CAL-2 was a handwritten note in the boy's medical
record saying that the surgeons removed a section of the bone tumor for
pathology and for "studies to determine the rate of uptake of radioactive materials
that had been injected prior to surgery, in comparison to normal tissues." 93
It is likely that the CAL-2 experiment was designed both to acquire data
for the Manhattan District and also to further the physicians' own search for
radioisotopes that might treat cancer in future patients. The California researchers
themselves noted the dual purpose of their research at the time. Hamilton wrote in
a report to the Army in the fall of 1945 that there were "military considerations
which can be significantly aided by the results of properly planned tracer
research." 94
As the February 1995 UCSF report on the experiments concluded,
however, the "injections of plutonium were not expected to be, nor were they,
therapeutic or of medical benefit to the patients." 95 This corresponds with the
evidence of a letter, written by Hamilton in July 1946, three months after the
injection of CAL-2, to the author of an article on the peacetime implications of
wartime medical discoveries:
To date no fission products, aside from radioactive
iodine, have been employed for any therapeutic
purposes. There is a possibility that one or more of
the long list of radioactive elements produced by
uranium fission may be of practical therapeutic
value. At the present time, however, we can do no
more than speculate. 96
Documentary evidence suggests that consent for the injections likely was
not obtained from at least some of the subjects at the University of California. A
1946 letter from T. S. Chapman, with the Manhattan District's Research Division,
said the following regarding preparations for injections:
. . . preparations were being made for injection in
humans by Drs. [Robert] Stone and [Earl] Miller.
These doctors state that the injections would
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Part II
probably be made without the knowledge of the
patient and that the physicians assumed full
responsibility. Such injections were not divergent
from the normal experimental method in the
hospital and the patient signed no release. A release
was held to be invalid.
The Medical Division of the District Office has
referred "P" reports for project 48A to Colonel
Cooney for review and approval is withheld
pending his opinion. 97
Chapman does not specify whether the "injections" referred to in this letter
were injections of plutonium or of some other substance. It is unclear whether "'P'
reports" refers to Hamilton's overall progress reports on his tracer research, which
had reported mostly on research with plutonium (but also on research with cerium
and yttrium), or whether "P" referred specifically to reports on work with
plutonium. As we noted at the outset of this chapter, Chapman's claim that it was
commonplace at the time to use patients in experiments without their knowledge
and without asking them to sign a "release" is correct.
In the case of Albert Stevens (CAL-1), no documentary evidence that
bears on disclosure or consent has been found. Simeon Shaw's (CAL-2's) medical
file contains a standard form "Consent for Operation and/or Administration of
Anaesthetic." This form, however, was signed by a witness attesting to consent of
Simeon's mother one week after the injection and therefore probably applies to a
biopsy done a week after the injection, not to the injection itself. 98
On December 24, 1946, at the prompting of Major Birchard M. Brundage,
who was chief of the Manhattan District's Medical Division, Colonel K. D.
Nichols, commander of the Manhattan District, ordered a halt to injections of
"certain radioactive substances'' into human subjects at the University of
California. 99 "Such work," Nichols wrote, "does not come under the scope of the
Manhattan District Programs and should not be made a part of its research plan. It
is therefore deemed advisable by this office not only to recommend against work
on human subjects but also to deny authority for such work under the terms of the
Manhattan contract." The following week, the civilian AEC took over
responsibility for all Manhattan District research and temporarily reaffirmed the
Manhattan District's suspension of human experimentation at the University of
California. 100 It is unclear why this action was taken.
THE AEC'S REACTION: PRESERVING SECRECY WHILE
REQUIRING DISCLOSURE
When the civilian Atomic Energy Commission took over for the
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Manhattan District on January 1, 1947, the plutonium injections provoked a
strong reaction at the highest levels. One immediate result was the decision to
keep information on the plutonium injections secret, evidently for reasons not
directly related to national security, but because of public relations and legal
liability concerns. The other immediate result, as we saw in chapter 1, was the
issuing of requirements for future human subjects research as articulated in letters
by the AEC's general manager, Carroll Wilson.
In December 1946, as the civilian AEC was about to open its doors,
Hymer Friedell, who had been deputy medical director of the Manhattan Engineer
District, recommended the declassification of one of the plutonium reports, "CH
[Chicago]-3607--The Distribution and Excretion of Plutonium in Two Human
Subjects." The report, Friedell argued, "will not in my opinion result in the release
of information beyond that authorized for disclosure by the current
Declassification Guide." 101
Friedell's recommendation was soon reversed. Officials with the new AEC
had learned of the human injection experiments, and on February 28, 1947, an
AEC declassification officer concluded that declassification was out of the
question. The reasons are revealed in a previously classified document recently
found at Oak Ridge:
The document [CH-3607] appears to be the most
dangerous since it describes experiments performed
on human subjects, including the actual injection of
the metal plutonium into the body. The locations of
these experiments are given and the results, even to
the autopsy findings in the two cases. It is unlikely
that these tests were made without the consent of
the subjects, but no statement is made to that effect
and the coldly scientific manner in which the results
are tabulated and discussed would have a very poor
effect on the public. Unless, of course, the legal
aspects were covered by the necessary documents,
the experimenters and the employing agencies,
including the U.S., have been laid open to a
devastating lawsuit which would, through its
attendant publicity, have far reaching results. 102
It is not clear to the Advisory Committee on what basis the
declassification officer who wrote this comment concluded that it was unlikely
that consent was not obtained from the Chicago subjects. This statement could be
read as careful bureaucratic language, intended to leave an appropriate paper trail
in the event of subsequent legal problems. On the other hand, the statement does
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support the claim, noted earlier, made by one of the Chicago doctors in 1974 that
some form of oral consent for the injections had been obtained from the Chicago
subjects. It is clear that there was no documentation of disclosure or consent on
which the AEC could rely. As a consequence, secrecy was to be maintained, not
as a defense against foreign powers, but to avoid a "devastating lawsuit" and
"attendant publicity." Upon further review the report was "reclassified
'Restricted' on 3/31/47." 103 In a March 19, 1947, memorandum, Major Brundage,
by that time chief of the AEC's Medical Division, explained:
The Medical Division also agrees with Public
Relations that it would be unwise to release the
paper 'Distribution and Excretion of Plutonium'
primarily because of medical legal aspects in the
use of plutonium in human beings and secondly
because of the objections of Dr. Warren and
Colonel Cooney that plutonium is not available for
extra Commission experimental work, and thus this
paper's distribution is not essential to off Project 104
experimental procedures. 105
In July 1947, Argonne National Laboratory's declassification officer,
Hoylande D. Young, inquired about possible declassification of this report as well
as Hamilton's report on the CAL-1 injection. She stated that the directors of
Argonne's Biology and Health Divisions (including J. J. Nickson, one of the
authors of the Chicago report on the injections) believed that declassification of
these reports would not be "prejudicial to the national interests." 106 The AEC
continued to withhold declassification of these reports, however, on the grounds
that they involved "experimentation on human subjects where the material was
not given for therapeutic reasons." 107 Thus, there was clearly no expectation at
the time that the plutonium injections would benefit the patient-subjects but some
expectation that the general public might be disturbed by human experimentation
in the absence of a prospect of offsetting benefit.
In 1950, Wright Langham and the Rochester doctors undertook to prepare
a "Plutonium Report" 101 * that would be "the last word on the plutonium
situation." 109 It would be the "last word" to only a select few. In 1947, Rochester's
Andrew Dowdy had urged Los Alamos to give advance notice of declassification
of the Rochester part of the experiment "because of possible unfavorable public
relations and in an attempt to protect Dr. [Samuel] Bassett from any possible legal
entanglements." 110 This is likely a reference to the same concern raised in the
discussion of Dr. Bassett's seminar about his having experimented upon his own
patients, except in this case the context is the plutonium rather than the uranium
injections. "We think," Langham wrote to Stafford Warren, "the classification will
be 'Secret,' and the circulation limited, depending on Dr. Shields Warren's [the
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head of AEC's Division of Biology and Medicine] wishes."" 1 In August, Shields
Warren approved the report for "CONFIDENTIAL classification and limited
circulation as [Dr. Langham] requested."" 2
Even though its data and analysis were the basis for widespread plutonium
safety procedures, the report remained unavailable to the public until 1971 when,
at the urging of Dr. Patricia Durbin, it was downgraded to "Official Use Only."" 3
(This categorization means that while the document was not likely to be released
to the public absent specific request, it could be disclosed.)
What was it that was so potentially embarrassing about the plutonium
experiments? The answer appears to lie in the 1947 letters from General Manager
Wilson, discussed in detail in chapter 1 . These letters state rules for both the
conduct of human experiments and the declassification of previously conducted
secret experiments." 4
In his April 1947 letter, Wilson stated the requirements that there be
expectation that research "may have therapeutic effect" and that at least two
doctors "certify in writing (made part of an official record) to the patient's
understanding state of mind, to the explanation furnished him, and to his
willingness to accept the treatment."""' In his November 1947 letter, Wilson
reiterated these terms for human experiments, again calling for "reasonable
hope . . . that the administration of such a substance will improve the condition of
patient" and this time calling for "informed consent in writing" by the patient." 6
All of the seventeen plutonium injections conducted prior to the letters violated
both these terms. As a consequence, they would have to stay secret. The only
secret experiments that could be declassified were those that satisfied these
requirements; to do otherwise was to risk adverse public reaction. Thus, the
decision to keep the plutonium reports secret was itself an example of the way in
which the AEC's assertion of conditions for human experimentation was coupled
with the decision to keep secret those experiments that evidently did not adhere to
these conditions (see chapter 13).
HUMAN EXPERIMENTATION CONTINUES
In March 1947, just as he was declaring that "public relations" required
the reclassification of plutonium data. Medical Division chief Major Brundage
approved a 1947-48 "Research Program and Budget" for Rochester that provided
for metabolism studies with polonium, plutonium, uranium, thorium, radiolead,
and radium." 7 The program was put on hold by the AEC soon after." 8
The future of the metabolism work at Rochester apparently was decided
when Shields Warren was named the first chief of the AEC's Division of Biology
and Medicine in fall 1947. In his private diary for December 30, 1947, Warren
tersely noted: "Ordered abandonment of human isotope program at Rochester.""'
The program at the University of California at Berkeley, however, continued. On
December 4, 1947, Shields Warren had met with Hamilton and Stone; 120 the
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Part II
decision to allow the program to continue clearly was not a hasty one. A 1 974
recollection of Shields Warren indicates that his decision to allow the program to
continue may have been due to Hamilton's assertion in December 1947 that it had
been the University of California's practice to obtain some form of
(undocumented) consent. 121
According to Warren, Hamilton had said that subjects were told "they
would receive an injection of a new substance that was too new to say what it
might do but that it had some properties like other substances that had been used
to control growth processes in patients, or something of that general sort." 122
Warren went on to observe that "you could not call it informed consent because
they did not know what it was, but they knew that it was a new and to them
unknown substance." 123 Warren's observation does not go far enough, however. If
Warren's secondhand account is accurate and this is indeed what the patient-
subjects at the University of California were told, then they were more misled
than informed. Analogizing plutonium to substances that "control growth
processes in patients," even in prospect, might reasonably lead patients to believe
that they would be receiving a substance with some hope of treating their cancer.
Certainly such a remark would not communicate to patients that the experiment to
be performed was not for their own benefit. It would have been appropriate that
these patients be told that their participation might benefit future patients with the
same conditions. It would have been crucial to distinguish, however, between
this legitimate explanation of potential benefit to future cancer patients and
misleading the patient into believing the experiment might benefit him or her.
Human Experimentation Continues at the University of California
By the summer of 1947, human experimentation had resumed at the
University of California under AEC contract. In June, "CAL-A," a teenage Asian-
American bone cancer patient at Chinese Hospital in San Francisco, was injected
with americium. An instruction in the patient's file by one of Hamilton's assistants
specifies that "we will use the same procedure as with Mr. S,"' 24 evidently a
reference to Albert Stevens. Dr. Durbin, Hamilton's associate, believes that CAL-
A's guardian was informed of the procedure followed in that case. 125 The
Advisory Committee received incomplete records for CAL-A that contained no
evidence of disclosure or consent; UCSF has told the Committee that records at
Chinese Hospital from the 1950s and earlier have been destroyed. I2(1
A thirty-six-year-old African-American railroad porter named Elmer
Allen, code-named CAL-3, was believed to be suffering from bone cancer and
was injected with plutonium at the University of California in July 1947. His left
leg was amputated shortly thereafter. There is a note in his medical chart signed
by two physicians, stating that the experimental nature was "explained to the
patient, who agreed to the procedure" and that "the patient was in fully oriented
and in sane mind." 127 It is likely that this note was intended to fulfill one of the
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April 1947 conditions for human experimentation, which allowed for such a
procedure as documentation of having obtained the patient-subject's consent. It is
not clear from the note, however, whether in explaining about the experimental
nature of the procedure the physicians told the patient about the potential effects
of the injection, as required by the Wilson letter, or that the injection was not
intended to be of medical benefit to the patient. On this second point, the
injection was in violation of the Wilson letter, which also required that there be an
"expectation that it may have therapeutic effect." 128 As acknowledged by the
February 1995 UCSF report, there was never any expectation on the part of the
experimenters that the injection would be of therapeutic benefit to Mr. Allen.
Mr. Allen lived until 1991. According to UCSF's 1995 review of patient-
subjects' medical charts, upon biopsy of his tumor a pathologic diagnosis was
made of chondrosarcoma, a type of malignant bone tumor. UCSF reported that
patients with this type of tumor "frequently surviv[e] many years beyond
diagnosis if there is complete excision of the primary tumor."' 29 This pathology
finding suggests that Mr. Allen was a long-term cancer survivor. A note in his
patient chart recorded that the tumor was "malignant but slow growing and late to
metastasize. Prognosis therefore moderately good." 130
On March 15, 1995, Elmerine Whitfield Bell, the daughter of Elmer Allen,
told the Advisory Committee in Washington, D.C., that she
continue[s] to be appalled by the apparent attempts
at cover-ups, the inferences that the nature of the
times, the 1940s, allowed scientists to conduct
experiments without getting a patient's consent or
without mentioning risks. We contend that my
father was not an informed participant in the
plutonium experiment.
He was asked to sign his name several times while a
patient at the University of California hospital in
San Francisco. Why was he not asked to sign his
name permitting scientists to inject him with
plutonium? Why was his wife, who was college
trained, not consulted in this matter?
On January 5, 1948, a fifty-five-year-old woman with cancer was injected
with zirconium at the University of California. '■" The patient record for this case
has not yet been located, nor have any other documents that might bear on
whether this experiment was conducted in compliance with the consent
requirements of the Wilson letters. We do know that the injection of zirconium
was not expected to benefit the subject herself. 132
A secret report on the zirconium injection was reviewed by the AEC in
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light of public relations and liability concerns. In August of that year, the report
was denied declassification with the approval of Shields Warren, who wrote,
"This document should not be declassified for general medical publication [and] it
would be very difficult to rewrite it in an acceptable manner." 113 Warren was
responding to a memorandum from Albert H. Holland, Jr., medical adviser at Oak
Ridge, which specified that the concern about rewriting had to do with public
relations and the fact that the report "specifically involves experimental human
therapeutics." 134
Follow-up of the Patient-Subjects at Rochester
The investigators at Rochester and the AEC were interested in obtaining
long-term data from surviving subjects on excretion levels and the distribution of
plutonium in various tissues. Follow-up studies at Rochester continued at least
through 1953 with two of the subjects in the HP series, Eda Charlton and John
Mousso. We have already noted Wright Langham's 1950 instruction to the
physicians at Rochester suggesting that they were not to give these patients any
indication of the true purpose of the follow-up studies. 135 In addition, Langham
sought help in early 1950 to locate Ebb Cade (the man injected at Oak Ridge
Hospital) for follow-up excretion studies. Langham asked Dr. Albert Holland at
Oak Ridge to try to locate Mr. Cade and to keep his "eyes open for a possible
autopsy." 136 It is unclear to the Committee whether follow-up of any kind was
ever done with Mr. Cade.
On June 8, 1953, Eda Charlton's rib was removed during exploratory
surgery for cancer and analyzed for plutonium. Louis Hempelmann, who by that
time had moved from Los Alamos to Strong Memorial Hospital at Rochester,
wrote to Charles Dunham of the AEC's Division of Biology and Medicine in
advance of the procedure:
The patient in question was brought in for a skeletal
survey, and turned out to have a 'coin-like' lesion
inside the chest wall. ... It is undoubtedly an
incidental finding, but she must be explored by the
chest surgeon here at Strong. In the course of the
operation, he will remove a rib which we can
analyze. Her films show the same type of minimal
indefinite change in the bone that the others have
had. 137
It was standard practice at the time to remove a section of rib incidental to
lung surgery. It is clear that the patient was still being followed for long-term
effects of plutonium and that some subclinical bone changes of unclear
significance had already been observed by this time. Therefore, the examination
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of this rib segment would have included special tests to determine whether
plutonium was present.
On August 31, 1950, an internal DBM memorandum recorded the
understanding of some AEC officials that Wright Langham and Rochester doctors
were engaged in follow-up studies. 13 " In a 1974 interview, however, Shields
Warren recalled that he had no knowledge that the patients were the subjects of
follow-up studies: "I did not learn of this continuing contact while I was in office
at AEC I had assumed because I had been told that they were incurable
patients that they all had died by the time we talked." 139
Additional Follow-up Studies and the Argonne Exhumation Project
In 1968 Dr. Patricia Durbin undertook an investigation of the plutonium-
injection subjects, which included a reevaluation of the original plutonium data.
Her goal was to pursue "some elusive information on Pu in man and the
information or assumptions about physiology needed to create a believable Pu
model for man." She "decided to look at all the old Pu patients as individuals
rather than in a lump " 14 ° Durbin was surprised to find in her search for the
original experimental data that the University of California data were drawn from
three subjects who received plutonium and one who received americium; the data
from only one plutonium subject from California had previously been reported in
the open scientific literature. 141 Durbin asked the original researchers why these
data had not been analyzed. She wrote: "I understand from Wright Langham that
this problem has been discussed before and discarded as too messy." 14
In 1972, after the classified report on the experiments had been
downgraded to "Official Use Only," she went on to publish "Plutonium in Man:
A New Look at the Old Data," a landmark paper in the plutonium story. 143 This
was the first review in the open literature to analyze Langham's results in light of
the actual medical conditions of the patient-subjects. Because of the prolonged
secrecy surrounding the experiments, it was generally not known that two of the
three University of California cases had been omitted from the 1950 analysis.
The report also revealed in retrospect that all the patients were not hopelessly or
terminally ill, as had been suggested in Langham's later public references, that
some were still alive, and that some had been misdiagnosed.
In December 1972, Argonne National Laboratory's Center for Human
Radiobiology (CHR), to whom Durbin had provided the names of surviving
subjects, began a review of the data from all eighteen people who were injected
with plutonium between 1945 and 1947. CHR was the national center designated
by the AEC to do long-term follow-up of individuals with internally deposited
radionuclides, primarily the radium dial painters. Argonne's follow-up plan for the
plutonium experiments was to uncover the postinjection medical histories of all
the subjects, obtain biological material from those still living, and exhume and
study the bodies of those deceased in order to "provide data on the organ contents
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at long times after acquisition of plutonium." 144
In 1973, three patients--Eda Charlton, John Mousso, and Elmer Allen-
were admitted to the University of Rochester's metabolic ward for more excretion
studies paid for by CHR. Elmer Allen had first been brought to Argonne, where
an unsuccessful attempt had been made to detect plutonium by external counting
techniques. In the course of his examination, however, CHR found subclinical
bone "changes" that an Argonne radiologist characterized as "suggestive of
damage due to radiation." 145
Again there was no disclosure to the subjects that they were now being
followed because they had been subjects of an experiment that had been unrelated
to their medical care, an experiment in which there was continuing scientific
interest. The 1974 AEC investigation concluded that, in the case of the surviving
Rochester subjects, Dr. Waterhouse, who conducted the follow-up studies with
these patients for Argonne, had not told them the purpose of the studies in 1973
because she believed "that disclosure might be harmful to them in view of their
advanced age and ill health." 146 This suggests that Dr. Waterhouse had well-
intentioned motivations for not being straightforward with the Rochester subjects.
It also suggests that these subjects had not been told the truth about the
experiments at the time the injections occurred, or that they had forgotten.
According to Dr. Waterhouse, the studies were feasible without the subjects'
knowledge of the true purpose of the research since these two patients "were
accustomed to participating in clinical studies, unrelated to this matter, involving
the collection of excretion specimens." 147 Elmer Allen's physician was told by
CHR that the purpose of bringing Mr. Allen to Argonne's CHR and the University
of Rochester for follow-up was interest in the treatment he received at the
University of California in 1947 for his cancer. 148 This use of the term treatment
in the information provided Mr. Allen's physician, which he presumably relayed
to Mr. Allen and his family, was deceptive and manipulative; it implied that the
injection Mr. Allen received had been given as therapy for his benefit.
The second component of this follow-up study was research on the
exhumed bodies of deceased subjects. The 1974 AEC investigation concluded
that the families were not informed that plutonium had been injected. Instead,
they were told that "the purpose of exhumation was to examine the remains in
order to determine the microscopic distribution of residual radioactivity from past
medical treatment" and that the subjects had received an "unknown" mixture of
radioactive isotopes. 149 The investigation concluded that such disclosure "could be
judged misleading in that the radioactive isotopes were represented as having
been injected as an experimental treatment for the patient's disease." 150 Thus, the
families of the deceased subjects as well as those subjects still surviving were
deceived by officials of the AEC.
A December 1972 intralaboratory memorandum, written by an Argonne
investigator, instructs that "outside of CHR we will never use the word plutonium
in regard to these cases. 'These individuals are of interest to us because they may
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have received a radioactive material at some time' is the kind of statement to be
made, if we need to say anything at all." 151 Robert E. Rowland, the author of this
memorandum, told Advisory Committee staff in 1995 that he had written this
after he had been instructed earlier that month by Dr. James Liverman, director of
the AEC's Division of Biomedical and Environmental Research, that "I could not
tell the individuals that they were given plutonium. I protested that they must be
given a reason for our interest in them, and I was told to tell them that they had
received an unknown mixture of radioisotopes in the past, and that we wanted to
determine if it was still in their bodies. Further, we were not to divulge the names
of the institutions where they received this unknown mixture." 152 Dr. Rowland
said he had received these instructions during a trip to Washington, D.C., to
obtain approval and funding for the study. 153 Dr. Liverman told Advisory
Committee staff that he has "no recollection of discussions with anyone in which
some stricture would have been placed on what could be discussed with the
patients. That is a medical ethics issue which would have been left to the
physicians." 154
This study was not brought to the attention of the Argonne Human Use
Committee until November 1973, even though it had been established in January
1973. (See chapter 6 for a discussion of human use committees.) In a briefing for
the 1974 AEC investigation, Dr. Liverman attributed this failure to bring the
study before the Human Use Committee to the following factors: "( 1 ) [Argonne's]
opinion that the studies came under the scope of a protocol approved by that
Committee in 1971. (2) The nature of the studies was to be suppressed to avoid
embarrassing publicity for AEC." 155
In 1974 the AEC informed at least two of the four living subjects— Eda
Charlton and John Mousso— of the plutonium injections and had them sign
documents to this effect. These documents did not provide any information on
possible effects of the injections, although they did describe the purpose as having
been "to determine how plutonium, a man-made radioactive material, is deposited
and excreted in the human body." 156 One living patient, Jan Stadt, was not told,
because it was her attending physician's opinion that her condition was precarious
and that disclosure in this case would be "medically indefensible." 157 This
judgment, like that of Dr. Waterhouse's, exemplifies how physicians of the time
commonly managed the information they shared with their patients. Physicians
typically told patients only what they thought it was helpful for them to know; if
in the physician's judgment information might cause the patient to become upset
or distressed, this was often considered reason enough to withhold it. 15X The
judgment also suggests that Ms. Stadt, like Ms. Charlton and Mr. Mousso, had not
been told the truth about the experiments at the time the injections occurred or
that she had forgotten.
The AEC recommended that exhumations continue, but only with full
disclosure to the subjects' next of kin.
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The Boston Project Uranium Injections
Human experiments conducted to measure the excretion and distribution
of atomic weapons materials did not stop with the last of the injections at the
University of California. The Boston Project human uranium-injection
experiments were conducted from 1953 to 1957 at Massachusetts General
Hospital (MGH) as part of a cooperative project between the hospital and the
Health Physics Division of Oak Ridge National Laboratory. Eleven patients with
terminal conditions were injected with uranium, although data obtained from
three of these subjects were never published. 159 The ORNL and the AEC
undertook the Boston Project to obtain better data for the development of worker
safety standards. One of the investigators wrote that the Boston Project would
provide "a wonderful opportunity to secure 'human data' for the analysis and
interpretation of industrial exposures." 160 The occupational standards for uranium
at the time were based on animal data and on the experiment conducted at
Rochester in the 1940s. No autopsy data were obtained from this earlier
experiment at Rochester, however, since none of the patients had terminal
diseases. Thus, wrote a Boston Project investigator, "the uncertainty, in so far as
the distribution of uranium was concerned, was not reduced [by the Rochester
experiment] or could not even be determined." 161
The Boston Project involved a second purpose—the search for a
radioisotope that would localize in a certain type of brain tumor—called
glioblastomas— and destroy them when activated by a beam of neutrons. This had
long been the research interest of Dr. William Sweet at MGH; at the time, these
tumors were clearly diagnosable and 100 percent fatal, and there was no effective
treatment. This research involved many radioisotopes over the years, most
notably isotopes of boron and phosphorus. It is unclear whether Dr. Sweet would
have tested uranium without ORNL's involvement— or whether it would have been
made available to him by the AEC. Dr. Sweet has indicated to the Committee that
he was interested in the potential of uranium as a therapeutic agent prior to being
approached by the AEC about the possibility of conducting a joint project. 162
The Boston Project produced data on the distribution of uranium in the
human body that the earlier Manhattan District uranium studies had not provided.
The data obtained indicated that uranium, at least at the dose levels used in the
Boston Project, localized in the human kidney at higher concentrations than small
animal data had predicted and that therefore the maximum permissible levels for
uranium in water and air might be unsafe. Recommendations made by the
investigators of the Boston Project for more conservative occupational standards
were apparently not heeded, however. The accepted occupational levels for
uranium became less rather than more conservative over the years, despite the
findings of the Boston Project. 163
Hopes that uranium would localize sufficiently in brain tumors to be of
potential therapeutic use were unfulfilled. In a 1979 interview, Robert Bernard,
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one of the health physicists at ORNL most intimately involved with the study,
was asked if during the experiment uranium was showing any promise as a
treatment. "No, it concentrated in the kidney just like Rochester said back in the
'40's. . . . They got brain tumor samples. There was very little uranium present,
but Sweet was still wondering: maybe [it was] not a high enough dose." 164
In a 1995 interview, Karl Morgan, head of the Health Physics Division of
ORNL at the time of the Boston Project, indicated that the project was ultimately
discontinued in 1957 165 because of the concerns of an ORNL health physicist:
He felt that the patients were given very large doses
of uranium which our data had indicated— that is,
the data we collected [at ORNL] in setting
permissible doses—would be very harmful. ... I
immediately cancelled our participation in the
program. Apparently, they were given doses that
were many times the . . . permissible body
burden. 166
In their application to their radioisotope committee, MGH investigators clearly
recorded that the proposed dose of 2.12 rem per week "exceeds maximum
permissible exposure rate of 0.3 rem/week but [patients] are terminal." 16
At least one of the subjects was selected for the distribution part of the
study only. Reports describe the patients as "virtually all" having malignant brain
tumors; newly available documents indicate that at least one patient injected with
uranium did not have a brain tumor at all. An unidentified male, identity and age
still unknown at the time of his death, became Boston Project subject VI when he
"was brought to the Emergency Ward after being found unconscious. ... No other
information was obtainable." I6X According to his autopsy report, this patient was
suffering from a subdural hematoma~a severe hemorrhage— on his brain. There
was clearly no benefit intended for this patient from the injection of uranium, but
there is evidence of harm attributable to the injection. His autopsy report records
clinical evidence of mild kidney failure 169 and pathological evidence of kidney
nephrosis (damage to the kidney tubules) from the chemical toxicity of uranium
metal. 170 The report also records that "the liver, spleen, kidneys and bone marrow
showed evidence of radiation." 171
Even for the patient-subjects with brain cancer, there was no expectation
on the part of investigators that the experiment would benefit the subjects
themselves. The object of the experiment was to test whether uranium would
localize sufficiently in brain tumors to be of therapeutic value in the future. In
order for uranium to have had therapeutic potential for patient-subjects, exposure
to a reactor's neutron beam would have been necessary to then activate the
uranium, if it had localized sufficiently in the tumors, which it did not. There was,
however, no plan to expose these particular patient-subjects to a neutron beam;
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the goal was to see whether the concentration would justify further research that
would involve exposure to a neutron beam. Most of the subjects were already
comatose and "in the terminal phase of severe irreversible central nervous system
disease." 172
The doses used in the Boston Project were high; the lowest dose was
comparable to the highest used in the earlier Rochester uranium experiment— a
dose that had caused detectable kidney damage in one of the Rochester subjects.
One document records that at least two Boston Project subjects, in addition to
subject VI, had kidney damage at the time of death, although this document does
not directly link this damage to the uranium injections.' 73
There is no discussion of consent in any of the Boston Project reports. It
appears that ORNL left such considerations to Dr. Sweet and MGH. In an interim
report, ORNL discusses the division of responsibility in the experiment: "It was
agreed that the Y-12 Health Physics Department [at Oak Ridge] would prepare
injection solutions and perform the analytical work associated with this joint
effort. Massachusetts General Hospital agreed to select the patients, perform the
injections, and care for the patients during the period of study." 174
Dr. Sweet told the Advisory Committee in 1995 that it was his practice to
obtain consent from patients or from their families and "scrupulously to give a
patient all the information we had ourselves." 175 The Committee has not been
able to locate any documents that bear on questions of disclosure or consent for
this experiment. I7A The case of the Boston Project subject who was brought into
the hospital after being found unconscious, and who, according to his autopsy
report, was never identified and never regained consciousness, indicates that this
rule was not applied universally.
CONCLUSION
From 1945 through 1947 Manhattan Project researchers injected eighteen
human subjects with plutonium, five human subjects with polonium, and six
human subjects with uranium to obtain metabolic data related to the safety of
those working on the production of nuclear weapons. All of these subjects were
patients hospitalized at facilities affiliated with the Universities of Rochester,
California, and Chicago or at Oak Ridge. Another set of experiments took place
between 1953 and 1957 at Massachusetts General Hospital, in which human
subjects were injected with uranium. In no case was there any expectation that
these patient-subjects would benefit medically from the injections.
At fifty years' remove, it is in some respects remarkable that so much
information has survived that bears on the question of what the patient-subjects
and their families were told. Particularly for the Manhattan Project plutonium
experiments information is available, in large part because of the 1974 AEC
inquiry in which interviews with principals of these experiments were conducted
and records of these interviews maintained. At the same time, however, there are
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significant gaps in the record for all the experiments. Particularly where the
evidence is skimpy, it is possible that some of the patient-subjects agreed to be
used in nontherapeutic experiments., But the picture that emerges suggests
otherwise. This picture is bolstered by the historical context. As we discussed in
chapter 2, it was not uncommon in the 1940s and 1950s for physician-
investigators to experiment on patients without their knowledge or consent, even
where the patients could not benefit medically from the experimental procedures.
This context is referenced in a 1946 letter about the University of California
injections: "These doctors state that the injections would probably be made
without the knowledge of the patient Such injections were not divergent from
the normal experimental method in the hospital. . . ."' 77
Here we present our conclusions about the ethics of these experiments,
first for the set of experiments conducted between 1945 and 1947 and then for the
experiment conducted from 1953 to 1957. Because the facts appear to be
different in the different institutions at which these experiments took place, we
summarize what we have learned about risk, disclosure, and consent at each
location. We also analyze the ethical issues the experiments raise in common. In
our analysis, we focus on whether the subjects consented to being used in
experiments from which they could not benefit medically, and the extent to which
the subjects were exposed to risk of harm. We also focus on the particular ethical
considerations raised when research is conducted on patients at the end of their
lives. All but one member of the Advisory Committee believe that what follows
is the most plausible interpretation of the available evidence in light of the
historical context.
With one exception, the historical record suggests that these patients-
subjects were not told that they were to be used in experiments for which there
was no expectation they would benefit medically, and as a consequence, it is
unlikely they consented to this use of their person.
In the case of the plutonium experiments, there was no reason to think that
the injections would cause any acute effects in the subjects. This was not true,
however, in the case of the Rochester uranium experiments. Both the plutonium
and the Rochester uranium experiments put the subjects at risk of developing
cancer in ten or twenty years' time. In some cases, this risk was eliminated by the
selection of subjects who were likely to die in the near future. The selection of
subjects with chronic illnesses was also an apparent strategy to contain this long-
term risk of cancer. However, some of these subjects lived for far longer than ten
years, and some were misdiagnosed altogether. On the basis of available
evidence, we could not conclude that any individual was or was not physically
harmed as a result of the plutonium injections. There is some evidence that there
were observable, subclinical bone changes of unclear significance in at least two
surviving subjects who were followed up in 1953 and 1973 and in one deceased
subject who was exhumed in 1973. The uranium injections at Rochester were
designed to produce minimal detectable harm-that was the endpoint of the
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experiment. Such minimal damage is reported to have occurred in the sixth
patient of the series.
In the case of Mr. Cade at Oak Ridge, a physician claiming to have
injected Mr. Cade reported that his consent was not obtained. An apparently
healthy man in his early fifties, Mr. Cade was put at some (probably small) risk of
cancer by the plutonium injection.
At the University of Chicago, the only evidence that bears on disclosure
and consent comes from an interview with a Chicago investigator conducted as
part of the AEC's 1974 inquiry. The investigator was recorded as saying that in
obtaining consent patients were told that the radioactive substance to be injected
"was not necessarily for the benefit of the patients but might help other people." 178
This statement is misleading. It suggests that there was some chance these
patient-subjects might benefit when there was no such expectation. At the same
time, however, this statement suggests that the subjects at Chicago were told
something. These subjects also were all apparently terminally ill and thus at no
risk of developing plutonium-induced cancer; at least two of the three were
known to have died within one year of the injection.
Misleading language was purportedly also used with subjects at the
University of California, where a secondhand account suggests that subjects were
told they were to be injected with a new substance that "had some properties like
other substances that had been used to control growth processes in patients." 179
Language in a 1946 letter suggests that at least some of the injections at the
University of California may have occurred altogether without the knowledge of
the patients. In the case of Mr. Allen, one of the California subjects, two
physicians attested that the experimental nature of the procedure had been
explained to Mr. Allen and that he had consented. And yet Mr. Allen's physician
was subsequently informed that the follow-up studies were in relation to
treatment Mr. Allen had received at the University of California. This suggests
that, while Mr. Allen may have been told the procedure was experimental, it is
not likely that he was told that the procedure was part of an experiment in which
there was no expectation that he would benefit medically. Both Mr. Allen and
Mr. Stevens survived long enough after injection to be at risk of plutonium-
induced cancer.
All the available evidence suggests that none of the subjects injected with
either plutonium or uranium at Rochester knew or consented to their being used
as subjects in experiments from which they could not benefit. This evidence
comes from recollections of some of the individuals who were involved with the
plutonium injections, as well as documents about seminars and follow-up studies
in the early 1950s suggesting that information about the experiments should be
concealed from the subjects. Most of the subjects at Rochester had serious
chronic illnesses. It is unclear how likely it was at the time that these patients
would not survive more than ten years. A few of these subjects were still alive
more than twenty years after the injections. None of the plutonium subjects but all
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of the uranium subjects were put at risk of acute effects from the experiment.
The purpose of the 1973 follow-up studies was withheld from two
surviving subjects. Also, both Elmer Allen's physician and family members of
deceased subjects were misled by AEC officials about the purpose of the follow-
up studies. They were told that the follow-up was in relation to past medical
treatment, which was not true.
It is unlikely that AEC officials would have lied about or otherwise
attempted to conceal the purpose of the follow-up studies if at the outset the
subjects had known and agreed to their being used as subjects in nontherapeutic
experiments. It is also relevant that when the Atomic Energy Commission
succeeded the Manhattan Project on January 1, 1947, officials decided to keep the
plutonium injections secret. It appears that this decision was based on concerns
about legal liability and adverse public reaction, not national security. The
documents show that the AEC responded to the possibility that consent was not
obtained in the plutonium experiments, as well as their lack of therapeutic benefit,
by stating requirements for informed consent and therapeutic benefit for future
research, while still keeping the experiments secret. As a result of the decision to
keep the injections secret, the subjects and their families, as well as the general
public, were denied information about these experiments until the 1970s.
The one likely exception to this picture of patients not knowing that they
were used as subjects in experiments that would not benefit them is the polonium
experiment conducted at Rochester. This is the one instance in which the patient-
subjects are said to have volunteered after being told about "the general problem."
Although there is no direct evidence that these subjects were told that the
experiment was not for their benefit, the language of volunteering suggests a more
forthright disclosure was made, more in keeping with the conventions in
nontherapeutic research with healthy subjects than in research with patients (see
chapter 2). We cannot reconcile the account of the polonium experiment with the
historical record on the other injections.
The Advisory Committee is persuaded that these experiments were
motivated by a concern for national security and worker safety and that,
particularly in the case of the plutonium injections, they produced results that
continue to benefit workers in the nuclear industry today. 180 However, with the
possible exception of the polonium experiments, we believe that these
experiments were unethical. In the conduct of these experiments, two basic moral
principles were violated-that one ought not to use people as a mere means to the
ends of others and that one ought not to deceive others-in the absence of any
morally acceptable justification for such conduct. National security
considerations may have required keeping secret the names of classified
substances, but they would not have required using people as subjects in
experiments without their knowledge or giving people the false impression that
they or their family members had been given treatment when instead they had
been given a substance that was not intended to be of benefit.
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The egregiousness of the disrespectful way in which the subjects of the
injection experiments and their families were treated is heightened by the fact that
the subjects were hospitalized patients. Their being ill and institutionalized left
them vulnerable to exploitation. As patients, it would have been reasonable for
them to assume that their physicians were acting in their best interests, even if
they were being given "experimental" interventions. Instead, the physicians
violated their fiduciary responsibilities by giving the patients substances from
which there was no expectation they would benefit and whose effects were
uncertain. This is clearest at Rochester where at least the uranium subjects, and
perhaps the plutonium subjects, were apparently the personal patients of the
principal investigator.
Concern for minimizing risk of harm to subjects is evident in several of
the planning documents relating to the experiments, an obligation that many of
those involved apparently took seriously. At Chicago, for example, where the
highest doses of plutonium were used, care was taken to ensure that all the
subjects had terminal illnesses. In those cases where this concern for risk was
less evident and subjects were exposed to more troubling risks, the moral wrong
done in the experiments was greater. Where it was not reasonable to assume that
subjects would be dead before a cancer risk had a chance to materialize, or in the
case of the uranium injections at Rochester where acute effects were sought, the
experiments are more morally offensive.
Consideration for the basic moral principle that people not be put at risk of
harm is apparently what animated the decision to give higher doses to only
"terminal" patients who could not survive long enough for harms to materialize.
A person who is dying may have fewer interests in the future than a person who is
not. This does not mean, however, that a dying person is owed less respect and
may be used, like an object, as a mere means to the ends of others. There are
many moral questions about research on patients who are dying; the desperation
of their circumstances leaves them vulnerable to exploitation. At a minimum,
nontherapeutic research on a dying patient without the patient's consent or the
authorization of an appropriate family member is clearly unethical.
Uranium was also injected in eleven patients with terminal conditions at
Massachusetts General Hospital in an experiment conducted jointly by the
hospital and Oak Ridge National Laboratory from 1953 to 1957. ORNL's purpose
was to obtain data for setting nuclear worker safety standards. A second purpose
was to identify a radioisotope that would localize in brain tumors and destroy
them when activated by a neutron beam. Although all but one of the patient-
subjects had brain cancer, the limited purpose of the experiment— to establish
whether uranium would localize sufficiently—meant that there was no expectation
that patient-subjects might benefit medically from the uranium injections.
The uranium doses in the Boston experiment were comparable to or higher
than the one that caused measurable physical harm in the Rochester subject.
Boston subjects were apparently subjected to brain biopsies, presumably solely
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for scientific purposes. At least three Boston subjects showed kidney damage at
the time of death. In one of these cases, a trauma victim who was found
unconscious, the autopsy report recorded clinical evidence of some amount of
kidney failure and pathological evidence of kidney damage due to the chemical
toxicity of uranium.
The only evidence available about what the Boston subjects were told
comes from 1995 testimony of one of the investigators, Dr. William Sweet, who
said it was his practice to "give a patient all the information we had ourselves."
Presumably this would have included that the injections had no prospect of
benefiting the patient. The Boston Project was an instance in which high doses
were given to dying patients. Some of these patients were comatose or otherwise
suffering from severe, irreversible central nervous system disease. Unless these
patients, or the families of comatose or incompetent patients, understood that the
injections were not for their benefit and still agreed to the injections, this
experiment also was unethical. There was no justification for using dying
patients as mere means to the ends of the investigators and the AEC. In at least
one case, this disrespectful treatment clearly occurred. The trauma victim who
arrived at the hospital unconscious was used as a subject despite the fact that his
identity was never known. Presumably he was not accompanied by any family or
friends who might have authorized such a use of his body.
Only extraordinary circumstances can justify deception and the use of
people as mere means by government officials and physicians in the conduct of
research involving human subjects. In the case of the injection experiments, we
see no reason that the laudable goals of the research could not have been pursued
in a morally acceptable fashion. There is no reason to think that people would not
have been willing to serve as subjects of radiation research for altruistic reasons,
and indeed there is evidence of people writing to the AEC to volunteer
themselves for just such efforts (see chapter 13).
That people are not likely to live long enough to be harmed does not
justify failing to respect them as people. Concerns about adverse public relations
and legal liability do not justify deceiving subjects, their families, and the public.
Insofar as basic moral principles were violated in the conduct of the injection
experiments, the Manhattan Engineer District, the AEC, the responsible officials
of these agencies, and the medical professionals responsible for the injections are
accountable for the moral wrongs that were done.
269
ENDNOTES
1. Don Mastick, telephone interview with Steve Klaidman (ACHRE), 23 July 1995
(ACHRENo. IND-072395-F), 1.
2. L. H. Hempelmann, Los Alamos Laboratory Health Division Leader, to J. R.
Oppenheimer, Director, Los Alamos Laboratory, 16 August 1944 ("Health Hazards
Related to Plutonium") (ACHRE No. DOE-051094-A-17), 1.
3. J. R. Oppenheimer, Director, Los Alamos Laboratory, to L. H. Hempelmann,
Los Alamos Laboratory Health Division Leader, 16 August 1944 ("Your memorandum
of August 16, 1944") (ACHRE No. DOE-051094-A-17), 1.
4. L. H. Hempelmann, Los Alamos Laboratory Health Division Leader, to J. R.
Oppenheimer, Director of the Los Alamos Laboratory, 29 August 1944 ("Medical
Research Program") (ACHRE No. DOE-051094-A-17), 1.
5. Interview with Mastick, 23 July 1995, 1.
6. Glenn Seaborg, head of Chemistry Section C-l of the Metallurgical
Laboratory, to Robert Stone, Health Director of the Metallurgical Laboratory, 5 January
1944 ("Physiological Hazards of Working with Plutonium") (ACHRE No. DOE-070194-
A-3), 1.
7. Ibid.
8. Robert Stone, Health Director of the Metallurgical Laboratory, to Glenn
Seaborg, Head of the Chemistry Section C-l of the Metallurgical Laboratory, 8 January
1944 ("Hazards of Working with Plutonium") (ACHRE No. DOE-070194-A-4), 1.
9. Seaborg suggested that several milligrams of the first shipment of plutonium
from Oak Ridge be sent on to Dr. Hamilton at Berkeley. A minute amount of plutonium
was sent to Hamilton, who began his studies on rats in February 1944. Next came more
animal work at Chicago, focusing on the toxic effects of plutonium, as well as its
distribution in various tissues. These studies showed that plutonium, like radium, was a
"bone-seeking" element, the potential deadly consequences of which radium had already
demonstrated. Furthermore, these studies demonstrated that in rats, plutonium distributed
itself in bone in a potentially more hazardous way than radium. J. Newell Stannard,
Radioactivity and Health: A History (Oak Ridge, Tenn.: Office of Scientific and
Technical Information, 1988), 1424.
10. Richard Rhodes, The Making of the Atomic Bomb (New York: Simon and
Schuster, 1986), 547-548.
11. Ibid., 560.
12. The most likely route of worker exposure to plutonium would be inhalation.
Hempelmann and others wrote to Oppenheimer in March 1945 that "the very important
and difficult problem of detection of alpha active material in the lungs has been studied
only at this project and here only on a very limited scale. This problem should be given
much higher priority here and at other projects." L. H. Hempelmann, Los Alamos
Laboratory Health Division Leader et al., to J. R. Oppenheimer, Director of the Los
Alamos Laboratory, 15 March 1945 ("Medical Research of Manhattan District concerned
with Plutonium") (ACHRE No. DOE-051094-A-17), 1. Inhalation experiments with
rodents were undertaken, starting in 1944, at the University of California's Radiation
Laboratory and the University of Chicago's Metallurgical Laboratory, although these
studies did not result in extensive analysis of data until the latter half of the 1940s. W. H.
270
Langham and J. W. Healy, "Maximum Permissible Body Burdens and Concentrations of
Plutonium: Biological Basis and History of Development," in Uranium - Plutonium -
Transplutonic Elements, eds. H. C. Hodge et al. (New York: Springer- Verlag, 1973),
576. Wright Langham wrote in 1945 that "if a limited amount of human tracer data are to
form the basis of a method of diagnosing internal body contamination," it would be
necessary "to assume that [plutonium] is metabolized in the same way regardless of the
route of absorption or administration." Wright Langham, Los Alamos Laboratory Health
Division, 28 July 1945 ("Report of Conference on Plutonium-May 14th and 15th")
(ACHRE No. DOE-05 1 094-A-427), 29. Since the time of the experiments, it has become
clearer that the deposition of plutonium in the body can differ in cases of chronic
inhalation exposure versus other types of exposures.
13. Langham and Healy, "Maximum Permissible Body Burdens and
Concentrations of Plutonium," 576.
14. L. H. Hempelmann, Los Alamos Laboratory Health Division Leader, to J.
R. Oppenheimer, Director of the Los Alamos National Laboratory, 26 March 1945
("Meeting of Chemistry Division and Medical Group") (ACHRE No. DOE-05 1094-A-
17), 1.
15. J. R. Oppenheimer, Director, Los Alamos Laboratory, to Colonel S. L.
Warren, 29 March 1945 ("We are enclosing a record of discussions . . .") (ACHRE No.
DOE-05 1094-A- 17), 1.
16. Samuel Bassett [attr.], undated ("Excretion of Plutonium Administered
Intravenously to Man. Rate of Excretion in Urine and Feces with Two Observations of
Distribution in Tissues") (ACHRE No. DOE-121294-D-10), 29.
17. Division of Biomedical and Environmental Research and Division of
Inspection, AEC, 13 August 1974 ("Disclosure to Patients Injected with Plutonium")
(ACHRE No. DOE-05 1094-A-586), 11.
18. Ibid.
19. Ibid., 10.
20. Wright Langham, Los Alamos Laboratory Health Division, to Hymer
Friedell, Executive Officer of the Manhattan District's Medical Section, 6 April 1945
("Although we sent you directions for the 49 experiment along with the material . . .")
(ACHRE No. DOE-120894-E-1), 1.
2 1 . Wilson O. Edmonds, AEC Resident Investigator, to Jon D. Anderson,
Director, Division of Inspection, 15 July 1974 ("Division of Biomedical and
Environmental Research, Headquarters-Request to Locate Mr. Ebb Cade") (ACHRE
No. DOE-05 1 094- A-6 11), 2.
22. Undated document ("Experiment I on P. 49+4") (ACHRE No. DOE-
113094-B-5), 1.
23. The Committee uses names of subjects in this chapter only where the names
were already a matter of public record.
24. "Experiment I on P. 49+4," 1.
25. Ibid.
26. Hannah E. Silberstein, University of Rochester, to Wright Langham, Los
Alamos Laboratory Health Division, 25 October 1945 ("This letter is to report the
injection on the second human product subject, HP-2 . . .") (ACHRE No. DOE-121294-
D-19), 1.
271
27. W. H. Weyzen, 25 April 1974 ("Visit with Dr. Joe Howland, Chapel Hill
Holiday Inn, April 24, 1974") (ACHRE No. DOE-121294-D-18), 1.
28. Hymer Friedell, interviewed by Steve Klaidman and Ron Neumann
(ACHRE), transcript of audio recording, 23 August 1994 (ACHRE Research Project
Series, Interview Program File, Targeted Interview Project), 49-50.
29. "Experiment I on P. 49+4," 3.
30. Ibid.
31. Ibid., 2.
32. Captain David Goldring, Medical Corps, to Wright Langham, Los Alamos
Laboratory Health Division, 19 September 1945 ("Enclosed is a brief resume of E. C.'s
medical history . . .") (ACHRE No. NARA-082294-A-47), 1.
33. Karl Morgan, interviewed by Gil Whittemore and Miriam Bowling
(ACHRE), transcript of audio recording, 6 January 1995 (ACHRE Research Project
Series, Interview Program File, Targeted Interview Project), 147.
34. Edmonds to Anderson, 15 July 1974, 3.
35. "Experiment I on p. 49+4," 3.
36. On 7 May 1945 Germany had surrendered to the Allied forces. The
Manhattan Engineer District continued on with the building and testing of the first
atomic bomb (the first test was scheduled for July of that year).
37. Robert Stone, Health Director of the Metallurgical Laboratory, to Stafford
Warren, Hymer Friedell et al., undated ("On Monday, May 14th, we plan to have an all
day meeting dealing with plutonium . . .") (ACHRE No. N ARA-082294-A-5 1 ), 1 .
38. Wright Langham, Los Alamos Laboratory Health Division, 28 July 1945
("Report of Conference on Plutonium-May 14th and 15th") (ACHRE No. DOE-051094-
A-427), 29.
39. Colonel Hymer Friedell, Executive Officer of the Manhattan District's
Medical Section, to L. H. Hempelmann, 1 1 April 1945 ("Enclosed is a protocol of the
clinical experiment as we intend to carry it out . . .") (ACHRE No. DOE-121294-D-1), 1.
40. Ibid.
41. J. J. Nickson to R. S. Stone, 23 January 1946 ("Abstract of Monthly Report
for January, 1946") (ACHRE No. DOE-051094-A), 1.
42. E. R. Russell and J. J. Nickson, 2 October 1946 ("The Distribution and
Excretion of Plutonium in Two Human Subjects") (ACHRE No. DOE-051094-A-370),
1.
43. Ibid.
44. Ibid.
45. Ibid., 2.
46. Ibid.
47. Nickson to Stone, 23 January 1946, 1.
48. Sidney Marks, 3 May 1974 ("Interview with Dr. Leon Jacobson ... by
Marks and Miazga at about 1:30 p.m. on 4/16/74") (ACHRE No. DOE-121294-D-15), 2.
49. W. H. Weyzen, 25 April 1974 ("Visit with Edwin R. Russell, Savannah
River Plant, April 23, 1974") (ACHRE No. 121294-D-17), 1.
50. Andrew H. Dowdy, Director of AEC Rochester Project ("Proposed Research
Program and Budget: July 1, 1947 - July 1, 1948") (ACHRE No. DOE-061794-B-16).
272
51. William F. Bale, Head of Special Problems Division, undated
("Contributions of the Division of Special Problems to the Manhattan Project") (ACHRE
No. DOE-113094-B), 1.
52. L. H. Hempelmann and Wright H. Langham, undated ("Detailed Plan of
'Product' Part of Rochester Experiment") (ACHRE No. 121294-D-2), 5.
53. W. H. Langham. undated ("Revised Plan of 'Product' Part of Rochester
Experiment") (ACHRE No. DOE-121294-D-3), 2.
54. The choice not to use subjects suffering from malignant conditions is
discussed retrospectively in a partial draft version of the 1950 report (probably written
by Dr. Bassett). This discussion was not included in the final version of the report:
The individuals chosen as subjects for the experiment
were a miscellaneous group of male and female hospital
patients for the most part with well established
diagnoses. Preference was given to those who might
reasonably gain from continued residence in the hospital
for a month or more. . . . Patients with malignant disease
were also omitted from the group on the grounds that
their metabolism might be affected in an unknown
manner.
Bassett, "Excretion of Plutonium Administered Intravenously to Man," 2.
55. Ibid.
56. Wright Langham et al., 20 September 1950 ("Distribution and Excretion of
Plutonium Administered Intravenously to Man") (ACHRE No. DOE-070194-A-18). 10.
57. Wright Langham. 27 September 1957 ("Proceedings of the Second Annual
Meeting on Bio- Assay and Analytical Chemistry: October 1 1 and 12, 1956 ~ Panel
Discussion of Plutonium") (ACHRE No. DOE-120894-C-1), 80.
58. W. H. Langham et al.. "The Los Alamos Scientific Laboratory's Experience
with Plutonium in Man," Health Physics 8 (1962): 755.
59. Addison's disease is an endocrine disease produced by adrenal gland failure.
Today this disease is treated with steroid therapy that was developed in the 1940s and
that was extremely expensive at the time of the experiments. HP-6, diagnosed with
Addison's, was given steroid treatment as part of his care at the University of Rochester;
he lived until 1984.
Scleroderma is a collagen-vascular disease that can produce extreme pain,
especially in the hands; can affect eating and swallowing if the esophagus is involved;
and eventually leads to organ failure and death. Steroids are the treatment of choice
today, but if this disease is not well controlled it can still be fatal. HP-8, who was
diagnosed with scleroderma, lived until 1975.
60. Bassett, "Excretion of Plutonium Administered Intravenously to Man," 2.
Her provisional diagnosis according to this report was mild hepatitis and malnutrition.
Ibid, 18. Her medical records indicate, however, that she had symptoms related to
nutritional deficiencies, which appear to have been alleviated with proper diet and rest.
Strong Memorial Hospital, 20 December 1945 ("Discharge Summary Form") (ACHRE
No. DOE-051094-A-612), 1.
61 . Wright Langham, Los Alamos Laboratory Health Division, to Samuel
Bassett, Head of Metabolism Ward of Strong Memorial Hospital, 13 March 1946 ("Your
273
letter of February 27 regarding Hp 1 1 was startling, to say the least . . .") (ACHRE No.
DOE-121294-D-4), 1.
62. Document dated 17 April 1974 ("Comments on Meeting with Dr.
Hempelmann on April 17, 1974") (ACHRE No. DOE-121294-D-16), 1.
A 1955 letter from Dr. Hempelmann to the AEC's Division of Biology and
Medicine (discussed in more detail in chapter 13) indicates Hempelmann's belief that, in
general, patients could be easily deceived about the true research purpose of a medical
intervention. In this letter, Hempelmann (who was by then professor of experimental
radiology at Rochester) is proposing that researchers present themselves as life insurance
agents to AEC workers as a ruse, in order to conceal the true purpose of follow-up
medical examinations. He observes that it would be more difficult to deceive workers
than it would be to mislead patients in a hospital:
If you feel that the physical examinations are vital to the
survey, then, perhaps, you could offer to pay the people
to compensate them for the time and effort that they will
spend on the part of your alleged survey for the
insurance company. They would think they were getting
something for nothing and might not feel that you were
worried or they were seriously ill. I don't know if these
ideas are helpful at all. It is more difficult to find an
excuse for these individual workers than it is in the case
of patients who were treated for something or other at a
hospital.
Louis Hempelmann, University of Rochester, to Charles Dunham, Director, AEC
Division of Biology and Medicine, 2 June 1955 ("I did not have an opportunity . . ." )
(ACHRE No. DOE-092694-A), 1.
63. Patricia Durbin, 9 December 1971 ("Report on Visit to Rochester")
(ACHRE No. DOE-121294-D-I2), 1.
64. Patricia Durbin, 10 December 1971 ("Dr. Wright Langham, of the Los
Alamos Scientific Laboratory, was the biochemist who performed the Pu analyses . . .")
(ACHRE No. DOE-121294-D-13), 1.
65. "Comments on Meeting with Dr. Hempelmann on April 17, 1974," 1.
66. Langham further instructed Rochester to look for the following longer-term
"symptoms" in the examination of the patients: "Judging from the recent observations
that Robley Evans has made, a generalized osteitis with rarefaction of the bones of the
feet, the jaw and the heads of the long bones with coarsening of the trabeculae are the
most likely symptoms." Wright Langham, Los Alamos Health Division, to Dr. Joe
Howland, Chief of University of Rochester's Division of Medical Services, 2 October
1950 ("I am very glad to hear that you will manage to get follow-ups on the two subjects
. . .") (ACHRE No. DOE- 1 2 1 294-D- 1 1 ), 1 .
67. Wright Langham, Los Alamos Laboratory Health Division, to Samuel
Bassett, Head of Metabolism Ward of Strong Memorial Hospital, 25 October 1946 ("I
just received a shipment of samples which I am sure are the ones you collected on HP-3 .
. .") (ACHRE No. DOE-121294-D-5), 1.
68. Samuel Bassett et al., 19 July 1948 ("The Excretion of Hexavalent Uranium
Following Intravenous Administration II. Studies on Human Subjects") (ACHRE No.
CON-030795-A-1), 8.
274
69. Andrew H. Dowdy, Director, Manhattan Department, University of
Rochester, to the Area Engineer, Rochester Area, 22 October 1946 ("Clearance of
Material for Seminar") (ACHRE No. DOE-120994-A-4), 1.
70. Madison Square Area Engineer, 24 October 1946 ("Uranium Studies in
Humans") (ACHRE No. DOE 120994-A-4), 1.
71. Robert M. Fink ("Biological Studies with Polonium, Radium, and
Plutonium") (ACHRE No. CON-030795-A-2), 122.
72. K. Z. Morgan, Oak Ridge National Laboratory Health Physics Division, to
R. S. Stone, Health Director of the Metallurgical Laboratory, 5 May 1945 ("Tolerance
Values for Polonium Used at Clinton Laboratories") (ACHRE No. DOE-1 13094-B-6), 2.
73. Fink, "Biological Studies with Polonium, Radium, and Plutonium," 122.
74. A supplemental volume contains a chapter on the development of human
subject research at the University of California at Berkeley and San Francisco.
75. Hamilton's work with plutonium had begun in 1 942 with support from the
Office of Scientific Research and Development; it was later supported by the Manhattan
Engineer District.
76. Joseph Hamilton, Radiation Laboratory of University of California at
Berkeley, to Colonel E. B. Kelly, 28 August 1946 ("Summary of Research Program for
Contract #W-7405-eng-48-A") (ACHRE No. DOE-1 13094-B-8), 2.
77. Joseph Hamilton, 1 1 January 1945 ("Proposed Biochemical Program at
University of California") (ACHRE No. IND-071395-A-14), 2.
78. Ibid.
79. At least eleven patients were injected with columbium (later renamed
niobium) or zirconium between 1 948 and 1 950. These experiments appear to have been
outside the federal effort.
80. Joseph Hamilton, 10 May 1945 ("Progress Report for Month of May 1945")
(ACHRE No. DOE-072694-B-65), 4.
81. Joseph Hamilton, 14 June 1945 ("Progress Report for Month of June 1945")
(ACHRE No. DOE-072694-B-66), 4.
82. Ibid.
83. Joseph G. Hamilton, Radiation Laboratory, University of California,
Berkeley, to Captain Joe W. Howland, 23 April 1946 ("The problems of the research
program . . .") (ACHRE No. DOE-120894-E-40), 2.
84. Joseph G. Hamilton, Radiation Laboratory, University of California,
Berkeley, to Robert Stone, Metallurgical Laboratory, 7 July 1945 ("I am writing
concerning our experimental subject . . .") (ACHRE No. IND-071395-A), 1.
85. Joe W. Howland, First Lieutenant. Medical Corps, to the Area Engineer,
California Area, 12 July 1945 ("Status of Experimental Subject") (ACHRE No. IND-
071395-A), 1.
86. Kenneth Scott, interviewed by Sally Hughes (University of California Oral
History Project), transcript of audio recording, 17 December 1979, 49-50.
87. Ibid.
88. Hamilton, "Progress Report for Month of June 1945," 4.
89. Joseph Hamilton, 14 September 1945 ("Progress Report for Month of
September 1945") (ACHRE No. DOE-072694-B-67), 5.
275
90. "Mercy Flight Brings Aussie Boy Here: Suffering From Rare Bone Ailment,
He Seeks U.S. Treatment," San Francisco Examiner, 16 April 1946, 1.
91. In addition to this injection, which was not performed for his benefit, the
child also received superficial external radiation (five doses of 250 rad over five days)
for palliation of his pain. A 1995 report written by an ad hoc committee at the University
of California at San Francisco (UCSF) described the child's prognosis as having been
"grave with palliation the only option." With that in mind, superficial irradiation was
performed to reduce the patient's pain, not to destroy the sarcoma of the right leg.
University of California at San Francisco, February 1995 ("Report of the USCF Ad Hoc
Fact Finding Committee on World War II Human Radiation Experiments, February 1995,
Appendix 19: Summary of the medical record of CAL-2") (ACHRE No. UCSF-022495-
A-6), 3.
92. UCSF, "Report of the USCF Ad Hoc Fact Finding Committee," 27.
93. Loren J. Larson, Assistant in Orthopedic Surgery, University of California
Hospital, 1 1 June 1946 ("To Whom It May Concern . . .") (ACHRE No. DOE-05I094-A-
605), 2.
94. Joseph Hamilton, Radiation Laboratory of the University of California at
Berkeley, to Samuel K. Allison, 1 1 September 1945 ("Plans for Future Biological
Research") (ACHRE No. IND-071395-A-2), 3.
95. UCSF, "Report of the USCF Ad Hoc Fact Finding Committee," 27.
96. Joseph Hamilton, Radiation Laboratory of the University of California at
Berkeley, to John Fulton, Historical Library, Yale University Medical Center, 19 July
1946 ("Inasmuch as both the Lawrence brothers are away at the moment, I thought it
best that I answer your letter of July 16, 1946, to John . . .") (ACHRE No. DOE-122294-
A-3), 1.
97. T. S. Chapman, Chief of Operations Branch, Research Division, to Area
Engineer, Berkeley Area, 30 December 1946 ("Human Experiments") (ACHRE No.
DOE-112194-D-3), 1.
98. Form dated 2 May 1946 ("Consent for Operation and/or Administration of
Anaesthetic") (ACHRE No. DOE-051094-A-604), 1.
99. Colonel K. D. Nichols, Corps of Engineers, to the Area Engineer, California
Area, 24 December 1946 ("Administration of Radioactive Substances to Human
Subjects") (ACHRE No. DOE-1 I3094-B-2), 1. This order followed a renewed request to
the Army by Hamilton for additional plutonium, "to be used for certain human studies,"
and a further progress report on the injection of Albert Stevens.
100. John L. Burling, AEC Legal Division, to Edwin E. Huddleson, AEC
Deputy General Counsel, 7 March 1947 ("Clinical Testing.") (ACHRE No. DOE-
051094-A-468), 1.
101. Undated document ("CH-3607 . . . Excerpts from statements of reviewers")
(ACHRE No. 113094-B-9), I.
102. Ibid.
103. Ibid. For discussion of classification levels, see chapter 13.
104. "Off Project" probably refers to work not sponsored by the AEC.
105. Major B. M. Brundage, Chief, Medical Division, to Declassification
Section, 19 March 1947 ("Clearance of Technical Documents") (ACHRE No. DOE-
113094-B-4), 1.
276
106. Hoylande D. Young, Argonne National Laboratory, to Charles A. Keller,
25 July 1947 ("Declassification has been refused for the following reports . . .") (ACHRE
No. NARA-050995-A-6), 1.
107. Carroll Wilson, AEC General Manager, to Robert Stone, University of
California Medical Center, 12 August 1947 ("Declassification of Biological and Medical
Papers") (ACHRE No. DOE-061394-A-1 11), 1.
108. Wright Langham, Los Alamos Laboratory Health Division, to Stafford
Warren, University of California, 1 July 1950 ("Dr. Bassett has been here and helped me
finish the semi-final draft of the Plutonium Report . . .") (ACHRE No. DOE-082294-B-
72), 1.
109. Wright Langham, Los Alamos Laboratory Health Division, to Joe W.
Howland, Chief, Division of Medical Services, University of Rochester School of
Medicine and Dentistry, 15 April 1950 ("1 am curious to hear your reaction to the names
that I sent you . . .") (ACHRE No. DOE-082294-B-73), 1 .
1 10. Andrew H. Dowdy, Director of the Manhattan Department, University of
Rochester, to Norris E. Bradbarry [sic], Director of the Los Alamos Laboratory, 18
February 1947 ("Dr. Wright Langham and Dr. Samuel Bassett were discussing with me
today the technical details relative to writing the report . . .") (ACHRE No. DOE-121294-
D-6), 1.
111. Langham to Warren, 1 July 1950, 1.
112. Walter D. Claus, Acting Chief, Biophysics Branch, AEC Division of
Biology and Medicine, to Wright Langham, Los Alamos Laboratory Health Division, 30
August 1950 ("You will be pleased to learn that Dr. Shields Warren has approved your
report for CONFIDENTIAL classification . . .") (ACHRE No. DOE-082294-B-2), 1 .
113. It is not clear when CH-3607, the report Dr. Friedell recommended for
declassification in December 1946, was declassified. The copy retrieved by the
Committee bears a 31 December 1946 declassification date and no indication of
subsequent reclassification. Russell and Nickson, "The Distribution and Excretion of
Plutonium in Two Human Subjects," 1 . In 1956 Dr. Langham made a brief reference to
fifteen experimental subjects at an unclassified technical conference. Langham,
"Proceedings of the Second Annual Meeting on Bio-Assay and Analytical Chemistry,"
80. In 1951, a report, based on Metallurgical Laboratory Memorandum MUC-ERR-209
("Distribution and Excretion of Plutonium") appeared in a volume of the public
Manhattan District research history.
1 14. While the Wilson letters do not expressly reference the plutonium
experiments, the context seems to leave little question that the policies stated in the
letters were arrived at with the plutonium experiments in mind. In 1974, when asked
what steps had been taken when the plutonium injections had been brought to the
attention of the AEC, Shields Warren, who became director of the AEC's Division of
Biology and Medicine in late 1947, said that it had been decided "that the rules [should
be] properly drawn up by the ... Human Applications Isotope Committee ... so that
use without full safeguards could not occur, and that . . . nothing of the sort could
happen in the future." Shields Warren, interviewed by L. A. Miazga, Sidney Marks, and
Walter Weyzen (AEC), transcript of audio recording, 9 April 1974 (ACHRE No. DOE-
121294-D-14), 10.
115. Carroll Wilson, AEC General Manager, to Stafford Warren, University of
California, 30 April 1947 ("This is to inform you that the Commission is going ahead
277
with its plans to extend the medical research contracts . . .") (ACHRE No. DOE-051094-
A-439), 2.
1 16. Carroll Wilson, AEC General Manager, to Robert Stone, University of
California Medical School, 5 November 1947 ("Your letter of September 18 regarding
the declassification of biological and medical papers was read . . .") (ACHRE No. DOE-
061395-A-112), 1.
1 17. Dowdy, "Proposed Research Program and Budget: July 1, 1947-July 1,
1948," 25.
1 18. A December 1947 memorandum from Dr. Bassett recorded:
In the autumn of 1 945 the Section on Human
Metabolism was activated under your direction at the
request of the Manhattan Engineer District to carry out
certain tracer studies with long-lived isotopes. As you
know, this program was discontinued in the spring of
1 947 under a directive from the Atomic Energy
Commission although we were instructed to keep the
personnel of the section intact. When this directive was
received, it was anticipated that follow-up studies on the
several subjects of the original investigation would
provide occupation for the employees of the section.
Samuel H. Bassett, Section on Human Metabolism, University of Rochester, to William
F. Bale, Head of Special Problems Division, University of Rochester, 2 December 1947
("Proposal of Work for Metabolism Section") (ACHRE No. DOE-121294-D-7), 1.
Dr. Bassett proposed an interim activity for the employees of the section— a
study of certain aspects of radiation injury. This was approved by Bale until "the project
research program of the Metabolism Section . . . with regard to tracer studies with heavy
elements is clarified." William F. Bale, Head of Special Problems Division, University
of Rochester, to Andrew H. Dowdy, Director of AEC's Rochester Project, 3 December
1947 ("Program of Work for Metabolism Section") (ACHRE No. DOE-121294-D-8), 1.
1 19. Gilbert Whittemore, 3 March 1995 ("Shields Warren Papers: A Cumulative
Update of Excerpts") (ACHRE No. BU-030395-A-1), 3.
120. Ibid.
121. Interview with Warren, 9 April 1 974, 1 1 .
122. Ibid.
123. Ibid. According to Dr. Durbin, it is likely that the "other substances"
referred to were probably phophorus 32 and strontium 89, which were used at the
University of California between 1941 and 1944 as experimental tracers or for palliation
of pain. Dr. Patricia Durbin, telephone interview with Miriam Bowling (ACHRE), 2
August 1995 (ACHRE No. ACHRE-081095-A), 1.
124. Undated note in medical record of CAL-A from "K..G.S." (Ken G. Scott
[attr.]) ("The day after solution is injected . . .") (ACHRE No. UCLA-1 1 1094-A-l), 1.
125. Telephone interview with Durbin, 2 August 1995, 1.
126. Lori Hefner; telephone interview by John Kruger (ACHRE), 6 July 1995
(ACHRE No. IND-070695-A), 1.
127. Note in medical record of CAL-3 dated 1 8 July 1 947 ("Elmer Allen
Chart") (ACHRE No. DOE-051094-A-615), 2.
278
128. Wilson to Warren, 30 April 1947, 2.
129. UCSF, "Report of the USCF Ad Hoc Fact Finding Committee, Appendix
20: Summaries of the medical record of CAL-3," 3-4.
130. Ibid., 4. If the diagnosis was correct, surgical amputation would have been
appropriate treatment at the time to completely excise the tumor.
131. B. V. Low Beer et al., Radiation Laboratory, University of California,
Berkeley, 15 March 1948 ("Comparative Deposition of Zr-95 in a Reticulo-Endothelial
Tumor to Normal Tissues in a Human Patient") (ACHRE No. DOE- 101 194-B-4), 4.
1 32. Ibid. The test dose was administered to the patient just twenty-four hours
prior to the midthigh amputation of her leg for cancer.
133. Shields Warren, Director of AEC's Division of Biology and Medicine, to
Albert H. Holland, Jr., AEC Medical Adviser, 19 August 1948 ("Review of Document")
(ACHRE No. DOE-101494-B), 1.
134. Albert H. Holland, Jr., AEC Medical Adviser, to Shields Warren, Director
of AEC's Division of Biology and Medicine, 9 August 1948 ("Review of Document")
(ACHRE No. DOE-051094-A), I.
135. Langham to Howland, 2 October 1950, 1.
136. Wright Langham, Los Alamos Laboratory Health Division, to Albert H.
Holland, AEC Director of Research and Medicine, 20 March 1950 ("It seems that I
really fouled up regarding my promise to you at the Washington meeting . . .") (ACHRE
No. NARA-082294-A-155), 1.
137. L. H. Hempelmann. University of Rochester, to Charles Dunham, AEC
Division of Biology and Medicine, 23 May 1953 ("There are several things on my mind
that I would like to bring to your attention . . .") (ACHRE No. DOE-041495-A-1), 1.
138. Walter D. Claus, Acting Chief of the Biophysics Branch, AEC Division of
Biology and Medicine, to Charles L. Dunham, Chief, Medical Branch, 31 August 1950
("Physical Examinations at Rochester") (ACHRE No. DOE-051094-A-471), 1.
139. Interview with Warren, 9 April 1974, 8.
140. Patricia W. Durbin, University of California, to William E. Lotz, AEC
Division of Biology and Medicine, 13 September 1968 ("You will never guess what I
found today . . .") (ACHRE No. DOE-051094-A-606), 1.
141. Ibid.
142. Ibid.
143. Patricia Durbin, 1 972 ("Plutonium in Man: A New Look at the Old Data")
(ACHRE No. DOE-051094-A-160), 469.
144. R. E. Rowland, Argonne National Laboratory's Center for Human
Radiobiology, 8 November 1973 ("Plutonium Studies at the Center for Human
Radiobiology [CHR]") (ACHRE No. DOE-051094-A-608), 4.
145. I. E. Kirch, Radiological and Environmental Research Division, Argonne
National Laboratory, 13 June 1973 ("Center for Human Radiobiology: Radiologist's
Report") (ACHRE No. DOE-051094-A-616), 1. The report records: "In the proximal
portions of both humeri as well as in the adjacent acromions, there are some changes in
the trabeculae which are consistent with findings in early radium deposition, but not yet
completely specific. The mandible shows abnormal trabeculae, suggestive of damage
due to radiation."
Subclinical bone changes were also observed in a deceased subject who was
exhumed for the Argonne study. The same radiologist summarized that an "abnormality
279
is present, namely, that there are very many very small very dense deposits on the
surfaces of a number of the bones, and other such deposits in the soft tissues very close
to the bone surfaces. This abnormality is attributed to the plutonium which has been
administered during the subject's life. The radiographic pattern is unique." I. E. Kirch,
Radiological and Environmental Research Division, Argonne National Laboratory, 15
November 1974 ("Center for Human Radiobiology: Radiologist's Report") (ACHRE No.
DOE-051094-A-618), 1.
146. AEC Division of Biomedical and Environmental Research and Division of
Inspection, 13 August 1974 ("Disclosure to Patients Injected With Plutonium") (ACHRE
No. DOE-051094-A-586), 10.
147. Ibid.
148. Ibid.
149. Ibid.
150. Ibid.
151. Robert E. Rowland, Argonne National Laboratory, to H. A. Schultz, 21.
December 1972 ("Plutonium Cases") (ACHRE No. DOE-080795-A), 1.
152. Robert E. Rowland to Miriam Bowling (ACHRE Staff), 7 August 1995
("Attached is the memo of December 2 1 , 1972 . . .") (ACHRE No. DOE-080795-A), 1.
153. Ibid.
154. James L. Liverman to Miriam Bowling (ACHRE Staff), 20 August 1995
("With your fax of August 9 was included . . .") (ACHRE No. IND-082095-A), 1.
155. James L. Liverman, 29 April 1974 ("Briefing on Plutonium Project by Dr.
James L. Liverman on April 29, 1974") (ACHRE No. DOE-051094-A-I96), 8. The 1971
protocol referred to in this briefing had covered a follow-up project involving the radium
dial painters. Although the procedures for the two follow-up studies were similar, the
original conditions of exposure were quite different. The radium dial painters, unlike the
plutonium-injection subjects, had not been chosen as subjects in a carefully planned
medical experiment organized by the government. They had been exposed either
occupationally as dial painters or therapeutically as patients receiving one of a variety of
prewar radium treatments.
156. Signed form dated 28 August 1974 ("Acknowledgement of Disclosure")
(ACHRE No. DOE-051094-A-619), 1.
157. Document dated 24 May 1974 ("Patients Injected with Plutonium [Draft
Report of 5-24-74]") (ACHRE No. DOE-051094-A-607), 1.
158. There is some evidence suggesting that at least one subject had a serious
emotional reaction to the news, many years after the fact, that she had been injected with
plutonium. This suggests that physicians involved in the follow-up had cause to be
concerned about how at least some patients might respond to knowledge of the injections.
159. K. F. Eckerman to Barry A. Berven, 7 January 1994 ("The Boston-Oak
Ridge Uranium Study") (ACHRE No. DOE-051094-A-425), 1.
160. John C. Gallimore, Associate Health Physicist, to Dr. W. H. Sweet,
Massachusetts General Hospital, 22 March 1954 ("First Results of Uranium Distribution
and Excretion Study") (ACHRE No. NARA-082294-A-35), 1.
161. S. R. Bernard, "Maximum Permissible Amounts of Natural Uranium in the
Body, Air and Drinking Water Based on Human Experimental Data," Health Physics 1
(1958): 288-305.
280
162. According to the 1957 interim report on the study, it was Harold Hodge of
the University of Rochester's Atomic Energy Project, who had been involved with the
MED metabolism work at Rochester, who ultimately coordinated the beginning of the
joint research. S. R. Bernard and E. G. Struxness, 4 June 1957 ("A Study of the
Distribution and Excretion of Uranium in Man: An Interim Report") (ACHRE No. DOE-
051094-A-369), 3.
163. Bernard, "Maximum Permissible Amounts of Natural Uranium in the
Body, Air and Drinking Water Based on Human Experimental Data," 296-298; Standards
for Protection Against Radiation, 9 C.F.R. 20 (1958-1994).
1 64. Robert Bernard, interviewed by J. Newell Stannard, transcript of audio
recording, 17 April 1979 (ACHRE No. DOE-061794-A), 8.
1 65. A continuation of the study at lower doses was proposed by the ORNL in
1958; it is unclear whether this project went forward. Karl Morgan, Director of ORNL's
Health Physics Division, to William Sweet, Massachusetts General Hospital, 16 July
1958 ("Your help in our cooperative study on the distribution and excretion of uranium
in man has been of great value to us . . .") (ACHRE No. DOE-021695-A-1 ), 1. A study
similar to the one proposed by the ORNL in 1958 may have taken place during the mid-
1960s at Argonne Cancer Research Hospital. K. Z. Morgan to W. H. Jordan, 3
September 1963 ("Proposed Study of Distribution and Excretion of Enriched Uranium
Administered to Man") (ACHRE No. DOE-051094-A-620), 1.
166. Interview with Morgan, 6 January 1995, 118-119.
1 67. Form dated 3 November 1 953 ("Application for Approval of Radioactive
Isotopes: Massachusetts General Hospital") (ACHRE No. MGH-030395-A-1), 4.
1 68. Leonard Atkins, M.D., 26 June 1 954 ("Necropsy No. : June 26, 1 954 at
12:30 p.m.") (ACHRE No. DOE-050895-D-1), 6.
169. Ibid., 1.
170. Ibid. The "Anatomic Diagnoses" include "Uranium nephrosis, acute."
171. Ibid., 5.
172. Bernard and Struxness, "A Study of the Distribution and Excretion of
Uranium in Man: An Interim Report," 6.
173. Undated document ("#l Cloudy swelling of the epithelium of proximal
and distal convoluted tubules . . .") (ACHRE No. DOE-050895-D-2), 1. The document
records a diagnosis for the two additional patients as "acute nephrosis," and for subject
VI, as "severe subacute nephrosis."
174. Bernard and Struxness, "A Study of the Distribution and Excretion of
Uranium in Man: An Interim Report," 4.
175. William Sweet, interviewed by Gil Whittemore (ACHRE), transcript of
audio recording, 8 April 1995 (ACHRE Research Project Series, Interview Program File,
Targeted Interview Project), 46.
176. By the end of the Committee's deliberations, MGH had not yet completed
its search for the patient records of the Boston Project subjects.
177. Chapman to Area Engineer, Berkeley Area, 30 December 1946, 1 .
178. Weyzen, "Visit with Edwin R. Russell, Savannah River Plant, April 23,
1974," 1.
179. Interview with Warren, 9 April 1974, 1 1 .
180. The relatively small population that has been exposed to substantial levels
of plutonium precludes definitive conclusions about risks to humans, but the available
281
evidence clearly suggests that an epidemic of cancer of the magnitude that afflicted the
radium dial painters from an earlier era has not occurred in plutonium workers. In the
case of the radium dial painters, the unprotected handling of only a few pounds of
radium led to hundreds of deaths; in contrast, studies of plutonium workers suggest that
to date there is no definite excess mortality in this population. A forty-two-year follow-
up of twenty-six Manhattan Project workers who worked with plutonium found a total of
seven deaths, including three cancers (two lung and one osteogenic sarcoma), a
substantially lower mortality rate than expected based on the U.S. population. The
authors concluded that "the diseases and physical changes noted in these persons are
characteristic of a male population in their 60s." G. L. Voelz and J. N. Lawrence, "A 42-
year Medical Follow-up of Manhattan Project Plutonium Workers," Health Physics 61
(1991): 181-190. A larger study of 15,727 LANL workers followed through 1990, some
of whom had plutonium exposures, found no cause of death significantly elevated among
the plutonium-exposed workers compared with unexposed workers, although there was a
nonsignificant 78 percent elevation in lung cancer (a site that is directly exposed) and a
single osteogenic sarcoma, a rare cancer that has been associated with plutonium
exposure in animal studies. L. D. Wiggs, E. R. Johnson, C. A. Cox-DeVore and G. L.
Voelz, "Mortality Through 1990 Among White Male Workers at the Los Alamos
National Laboratory: Considering Exposures to Plutonium and Ionizing Radiation,"
Health Physics 67 (1994): 577-588. Another study of 5,413 workers at the Rocky Flats
Nuclear Weapons Plant found elevated risks for various cancers comparing workers with
body burdens of 2 nanocuries (nCi) or greater, but with wide uncertainties; no excesses
were seen for bone or liver cancers. . The authors concluded that "these findings suggest
that increased risks for several types of cancers cannot be ruled out at this time for
individuals with plutonium body burdens of > 2 nCi. Plutonium-burdened individuals
should continue to be studied in future years." G. S. Wilkinson et al., "Mortality Among
Plutonium and Other Radiation Workers at a Plutonium Weapons Facility," American
Journal of Epidemiology 125 (1987): 231-250.
282
6
The AEC Program of
Radioisotope Distribution
At the dawn of the atomic age, many people hoped for dramatic
advances in medicine, akin to the new miracle drug penicillin. Many of these
hopes have been fulfilled. Radioisotopes have become remarkable tools in three
areas. First, as their travels within the body are "traced," radioisotopes provide a
map of the body's normal metabolic functions. Second, building on tracer
research, diagnostic techniques distinguish between normal and abnormal
functioning. Finally, radioisotopes, carried by the body's own processes to
abnormal or cancerous cells, can deliver a lethal dose of radiation to those
undesirable cells. By supplying radioisotopes and supporting their use, the
Atomic Energy Commission (AEC) actively promoted the research needed to
achieve this progress.
The growth in the applications of radioisotopes involved thousands of
experiments using radioisotopes. No feasible method was found to review in
detail the vast number of individual radioisotope experiments in the Advisory
Committee's database. This was due not only to the large number of experiments,
but also to the scarcity of information about many of the individual experiments.
Both consent and exact dose levels were often not discussed in published work;
no federal repository was found that had collected records documenting these
aspects of experiments. Given the decentralized structure of American medicine,
it is not surprising that the Committee found that records on consent and exact
dose, if they exist, would still be held at the local institutions conducting research
or perhaps even in the private papers of physicians and scientists. Even when
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records were found at the local level, there was little documentation about
consent.
Thus, for the largest group of human radiation experiments, little
documentation remains, and a meaningful examination of all such experiments
was not possible. The Committee instead chose to focus its energies in two
directions: examining the overall system of oversight created by the federal
government and examining small subsets of radioisotope experiments that posed
significant ethical issues. The first effort led to this chapter, an overview of the
system created by the federal government to monitor radioisotope experiments.
The second effort led to the case study on experiments involving children (chapter
7) since those raised questions of both additional biological risk and justification
for doing nontherapeutic research on minors.
The AEC's isotope distribution program was faced with three essential
ethical questions. The most immediate question concerned the allocation of a
scarce resource. Given the likelihood that demand for radioisotopes would exceed
supply, how should priorities be set? The question involved not simply the choice
among competing proposals for "human uses" (including experimentation,
treatment of disease, and diagnosis), but between human uses and other kinds of
uses (for example, basic scientific research or industrial uses).
Another immediate question was the safety with which this new material
would be used. Since the government was actively promoting the use of
radioactive isotopes, it had an obligation to ensure their safe use. Harm to
patients, physicians, and others involved could arise from inexperienced and
untrained users of radioisotopes. When properly used in trace amounts,
radioisotopes posed risks well below those deemed acceptable in occupational
settings. Balancing risks versus benefits—and seeking means to decrease risks and
increase benefits as the field developed— was a major ethical obligation.
Finally, there was the question of the relationship between researcher and
subject— more precisely, the question of the authorization for use in humans and
the process of disclosure and consent, if any, to be followed. These uses can be
divided into (1) therapeutic/diagnostic uses, (2) therapeutic/diagnostic research,
and (3) nontherapeutic research.
As we shall see, great attention was paid initially to the question of
resource allocation; but supply soon proved far greater than expected, and the
need for this attention evaporated. The control of the risk posed by the use of
AEC-provided radioisotopes was also a source of intense focus from the outset
and remained so as the program grew. By contrast, notwithstanding the 1947
declarations by AEC General Manager Carroll Wilson on the importance of
consent, the matter of consent received only limited attention in the early years of
the program.
284
Chapter 6
ORIGINS OF THE AEC RADIOISOTOPE DISTRIBUTION
PROGRAM IN THE MANHATTAN PROJECT
The medical importance of radioisotopes was recognized before World
War II but distribution was unregulated by government. The postwar program
for distributing radioisotopes grew out of the part of the Manhattan Project that
had developed the greatest technical expertise during the war: the Isotopes
Division of the Research Division at Oak Ridge. 1 Production of useful
radioisotopes required extensive planning for both their physical creation and
their chemical separation from other materials. Plans to distribute radioisotopes
to medical researchers outside the Manhattan Project were developed in the final
year of the Project.
In June 1946, the Manhattan Project publicly announced its program tor
distributing radioactive isotopes. The new world of radioisotope research was to
be shared with all. Most research would be unclassified. 2 An enthusiastic Science
magazine reported: "Production of tracer and therapeutic radioisotopes has been
heralded as one of the great peacetime contributions of the uranium
chain-reacting pile. This use of the pile will unquestionably be rich in scientific,
medical, and technological applications." 3 An article in the New York Times
Magazine told readers that "properly chosen atoms can become a powerful and
highly selective weapon for the destruction of certain types of cancer." Until
now "the doctors and biologists have had to plea for samples of isotope material
from their brothers in the cyclotron laboratories. ... Now the picture has changed
in a revolutionary way. The Government has adapted one of the Oak Ridge
uranium piles to the mass production of radioactive 'by-product material."'
Extensive planning led up to this public announcement. Although the
initial expectations were that basic research would precede extensive medical
applications, from the very beginning officials planned for "clinical investigation
with humans. In doing so, they recognized that the "administration to humans
places extreme demands, both moral and legal, upon the specifications and timing
of the radioisotope material supplied." 6 The recognition of special moral and
legal aspects of human experimentation and reliance on the professional
competency of those administering radioisotopes formed the cornerstones of the
radioisotope distribution system's oversight of experiments. Significantly,
however, the system was not designed to oversee consent from subjects prior to
the administration of radioisotopes.
Radioisotopes could not simply be ordered from the Manhattan Engineer
District; each purchase had to be reviewed and approved. For human applications,
each application was reviewed by a special group of experts: the Advisory
Subcommittee on Human Applications of the Interim Advisory Committee on
Isotope Distribution Policy of the Manhattan Project. According to one of the
initial planners, "The chief reason for setting this group up as a separate entity
from the Research group [another subcommittee] is that of medico-legal
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Part II
responsibility involved in the use or treatment of humans, experimentally or
otherwise." 7 (When the AEC began its work, this subcommittee continued but
was renamed the "Subcommittee on Human Applications of the Committee on
Isotope Distribution of the AEC." In 1959 it was absorbed into the "Advisory
Committee on Medical Uses of Isotopes." 8 In 1974, the AEC's responsibilities
were transferred to the Nuclear Regulatory Commission.) Coupled with this
review was a requirement that those wishing to purchase radioisotopes
demonstrate the special competence required for working with radioactive
materials. This mechanism for centralized, nationwide review was unusual at the
time it was begun.
The breadth of the subcommittee's purview can be seen in the range of
proposals examined. Although the Advisory Committee is concerned primarily
with medical research, the AEC subcommittee review extended well beyond this
realm. Apparently, the subcommittee reviewed all proposed uses for
radioisotopes that might result in the exposure of humans to radiation. These
included, for example, using cobalt 60 in nails in wooden survey stakes (probably
to assist in later locating them), sulfur 35 in firing underground coal mines, and
yttrium 90 as a tracer in gasoline in simulated airplane crashes. 9 (Its jurisdiction
was limited to by-product material, however, and did not extend to fissionable
materials such as plutonium and uranium.)
Soon after the Manhattan Project's public announcement, both the
radioisotope distribution system and its oversight structure began operation. On
June 28, 1946, the Subcommittee on Human Applications held its first meeting.
Attending as members were Dr. Andrew Dowdy, chairman, and biophysicist
Gioacchino Failla. Dowdy was director of the University of Rochester's
Manhattan Project division, while Failla was a professor at Columbia University
and consultant to the Metallurgical Laboratory in Chicago. Not attending was the
third member of the subcommittee, Dr. Hymer Friedell, executive officer of the
Manhattan Project's Medical Section. Attending as nonvoting secretary was Paul
Aebersold, in charge of the production of radioisotopes at Oak Ridge (later to
head the AEC's Isotopes Division). His efforts to promote the use of
radioisotopes later earned him the nickname "Mr. Isotope." Also attending as
advisers from Oak Ridge were W. E. Cohn, the author of the original
memorandum proposing a system for distributing radioisotopes, and Karl
Morgan, director of Health Physics at Oak Ridge, who would, over the years,
become a leading figure in the establishment of occupational exposure limits for
radioisotopes. 10
Although the primary task of the subcommittee was to oversee safety, at
the time, many expected a shortage of radioisotopes. Thus, much of this first
meeting was taken up with a discussion of priorities for allocation." (As it
happened, supply exceeded demand within one year.) It was in the context of this
discussion of allocation, not a discussion of safety or ethics, that a system of
local committees was suggested. Each local committee (also called "local isotope
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Chapter 6
committee" at this meeting) would include "(a) a physician well versed in the
physiology and pathology of the blood forming organs; (b) a physician well
versed in metabolism and metabolic disorders; (c) a competent biophysicist,
radiologist, or radiation physiologist qualified in the techniques of
radioisotopes."' 2 The main advantages of a system of local committees were ^
administrative efficiency and delegation of prioritization for scarce isotopes.
The primary functions of each local isotope committee were coordination,
allocation, and safety. Evidently no mention was made of overseeing subject
consent. .
At this first meeting, the subcommittee had before it no actual requests to
evaluate. Even so, members did agree on the general principles on which they
would deny a request:
a. The requestors are not sufficiently qualified to
guarantee a safe and trustworthy investigation.
b. Insufficient knowledge exists to permit a safe
application of the material in the proposed human
14
cases.
There was no elaboration of crucial terms such as qualified, safe and trustworthy,
insufficient knowledge, and safe application. Although no standards of adequate
consent were mentioned, this degree of oversight was unusual in medical research
during this time and even later.
Although it had no specific requests before it, the subcommittee did
consider the anticipated uses of some isotopes. The uses of some isotopes were
apparently rejected, not only because of the hazards of radiation, but also because
of chemical toxicity and the availability of less-hazardous alternatives. For
others, specific limits were set. For example, the subcommittee was especially
cautious concerning isotopes of strontium because it concentrated in bone, as did
radium, which was known to be hazardous from the prewar experience of the dial
painters. The subcommittee set a specific exposure limit: "the Sr 90 (and Y 90
daughter) should not contribute in excess of 1% to the total rate of beta
disintegration." 16 . •
Such general guidelines have little effect unless a procedure is established
for their implementation. At its first meeting, the subcommittee set out in detail
the mechanism for its own future operation. What the subcommittee would be
reviewing were requests to purchase isotopes for any use in human beings. Only
after the subcommittee approved a request would the isotope be sold and shipped
to the researcher. The need for speed in responding to requests for human uses
was recognized. 17
Details of the procedure for purchasing isotopes were disseminated to
potential users through a brochure issued in October 1946 by the Isotopes Branch
at Oak Ridge. 18 Most of the brochure concerned the paperwork, which, among
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Part II
other things, ensured that the Subcommittee on Human Applications would
actually be notified of all applications for human use.
The last stage of the purchase procedure indicates the underlying concern
with legal liability. Although Manhattan Project approval was required, the
actual purchase was from the private contractor-operator of the Clinton
Laboratories (later designated the Oak Ridge National Laboratory) in Oak Ridge,
at that time Monsanto Chemical Company. The final purchase agreement
contained a clause relieving both the government and the private contractor from
any responsibility for "injury to persons or other living material or for any
damage to property in the handling or application of this material. . . ."' 9 The
Manhattan Project also required the purchaser to file with the Isotopes Office a
statement required by section 505(i) of the Federal Food, Drug, and Cosmetic
Act. However, the Advisory Committee found no evidence of direct involvement
by the FDA at that time in the planning or operation of the radioisotope
distribution program. 20
By October 1 946, the distribution program was well under way: 2 1 7
requests had been received. Of these, 21 1 had been approved. Human use requests
totaled 94, of which 90 had been approved. 21
THE AEC ASSUMES RESPONSIBILITY FOR
RADIOISOTOPE DISTRIBUTION
When the AEC took over responsibility for the program on January 1,
1947, the structure of the radioisotopes distribution system remained intact. The
Subcommittee on Allocation and the Subcommittee on Human Applications
remained as standing subcommittees of the Interim Committee on Isotopes
Distribution Policy, which became known as the Advisory Committee on Isotope
Distribution Policy. The forms developed by the Manhattan Project were reissued
as AEC forms without substantial revision. The system of application from
private users, review, purchase, and distribution continued to operate.
At first, there appears to have been some confusion over the responsibility
of the AEC for its own research program and for its program to distribute
radioisotopes to private researchers. As discussed in chapter 1, two 1947 letters
from AEC General Manager Carroll Wilson describe strong consent
requirements. The April letter to Stafford Warren was expressly directed to the
terms on which research conducted by AEC contractors (including universities)
would be approved. The November letter was sent to Robert Stone. As we have
discussed, those clear statements to contract researchers do not seem to have been
made to those applying for radioisotopes. This confusion about the relationship
between contract research and isotope distribution is discussed in a September 26,
1947, memorandum from J. C. Franklin, manager of Oak Ridge Operations, to
Carroll Wilson. 22 Other correspondence also indicates confusion over whether the
AEC's own labs (which were themselves often operated by contractors) were to
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Chapter 6
follow the procedures for the radioisotope distribution program, which would
have placed their human use requests before the Subcommittee on Human
Applications.
Initially, requests for by-product materials from within the AEC used a
form that did not specify whether the radioisotope was to be used on humans. 23
By August 1949, Shields Warren, director of the AEC's Division of Biology and
Medicine, had directed that human use by AEC laboratories be subject to review
by the Subcommittee on Human Applications. 24 However, when regulations
governing radioisotope distribution were first promulgated, AEC-owned facilities
were specifically exempted from all such regulations. 25 Warren's goal was
achieved instead by a memorandum from Carroll Wilson in July 1950. This
memorandum discontinued use of the earlier form and directed that all requests
use the same form used by outside purchasers, which directed human use requests
to the Subcommittee on Human Applications. 26
The AEC Subcommittee on Human Applications
At the heart of overseeing the expansion of the use of radioisotopes was
the Subcommittee on Human Applications of the AEC's Advisory Committee on
Isotope Distribution. Applications had to have been approved by a local isotope
committee before even being considered by the subcommittee. 27 The
subcommittee itself conducted most of its reviews by mail. Unfortunately, only
fragmentary records of this correspondence have been found.
The subcommittee formally met only once a year to discuss general issues.
By its second meeting, in March 1948, membership had grown to four. Dowdy
was no longer on the subcommittee; Joseph Hamilton and A. H. Holland had been
added. Hamilton was, as described in chapter 5, a physician-investigator with the
University of California's Radiation Laboratory in Berkeley. Holland was a
physician-investigator who became medical director at the AEC's Oak Ridge
Operations in late 1947. (As we shall see in chapter 13, he played a central role
in the question of the declassification of secret experiments.) As the
subcommittee continued to "examine each case on its own merits" it began to
generate principles for "general guidance." In doing so, it began to categorize
experiments, apparently according to the degree of hazard posed.
One category was tracer studies in "normal adult humans" using beta and
gamma emitters with half-lives of twenty days or fewer. Applications needed to
include information on biodistribution and biological half-life of the radioisotope,
based on either animal studies or references to the literature. 28
A second category was studies in "normal children." In 1948 the
subcommittee did not issue detailed guidelines, but instead simply stated that such
applications "would be given special scrutiny by the Subcommittee on Human
Applications." 29 In 1949 it issued more detailed guidelines, which indicate that
the concern was with minimizing risk, not requiring or overseeing consent:
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Part II
In general the use of radioisotopes in normal
children should be discouraged. However, the
Subcommittee will consider proposals for use in
important researches, provided the problem cannot
be studied properly by other methods and provided
the radiation dosage level in any tissue is low
enough to be considered harmless. It should be
noted that in general the amount of radioactive
material per kilogram of body weight must be
smaller in children than that required for similar
studies in adults. 30
Coupled with the children's category in 1 949 were studies on pregnant women:
"The use of radioactive materials in all normal pregnancies should be directly
discouraged where no therapeutic benefit is to be derived." 31 Although not
specifically mentioned in the minutes, such a policy may, like research in "normal
children," have been waived for "important researches" that could not otherwise
be undertaken.
One recurring difficulty was the problem of deciding when an application
could be considered "safe." There was no simple, mechanical process for making
such a judgment. This can be seen in the subcommittee's detailed consideration of
an application for phosphorus 32 to be used in a blood volume study of children.
The amount of radioactivity proposed ranged from 1/4 to 1 microcurie per
kilogram of body weight. Initially, three of the four members approved the
application and the allocation was made. However, the fourth member, replying
late, reopened the question. Following reconsideration by the entire
subcommittee, three of the four members concluded the original application for
use on children should be turned down and the investigator asked to revise the
application to "state the importance of making the study in children" and to keep
the amount of activity less than 1/2 microcurie per kilogram. 32 The reduction in
allowable amount of activity illustrates both the diligence with which the
subcommittee pursued its task and the inherent difficulties in making judgments
about what constituted "safe" practices in a rapidly developing field of research.
The subcommittee's task was made a bit easier when considering
applications with adults, where it could draw upon occupational guidelines.
Requests for "long-lived radioisotopes" were placed in a third category, defined
as those with a biological half-life greater than twenty days. In contrast with
experiments on children, here the subcommittee was willing to set a general dose
limit: "The dosage in the critical tissue should be such as to conform to the
limitations stated by the National Committee on Radiation Protection." 33 (The
NCRP, now the National Council on Radiation Protection and Measurements, is
an independent organization that publishes occupational radiation protection
guidelines based on expert reviews of contemporary scientific knowledge.) As
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with children, such applications "must be reviewed separately." The
subcommittee did not wish this limit to be ironclad: "In special cases, however,
the Subcommittee on Human Applications may permit the use of radioisotopes in
higher dosages." 34 At this point the subcommittee appears to have been
establishing general principles; no specific radioisotopes or particular research
proposals are mentioned.
A final category was applications using radioisotopes with long half-lives
in patients with short life expectancies. The term moribund was used in
correspondence by Paul Aebersold prior to the second meeting of the
subcommittee in March 1948. He wrote to the subcommittee members explaining
that the item was on the agenda because requests for such work had been
received. He referred to a written request from a physician at Massachusetts
General Hospital to use calcium 45 and an oral request from a staff member at
Presbyterian Hospital in Chicago to use testosterone labeled with carbon 14.
Aebersold did not provide any details as to the purposes of the proposed research.
The issue was what policy to adopt when the patients were predicted not to live
long enough for long-term hazards to develop. Aebersold told the subcommittee
that "this office feels that such requests should be allowed if a satisfactory
mechanism for determining the 'moribundness' of the patients in question is
established. We believe that this question should be decided by a group of doctors
and written evidence signed by the group filed with the Isotopes Division prior to
use of the material." 35
The subcommittee had no objection to the basic principle of applying
larger doses to patients with short life expectancies, but its language was more
oblique than Aebersold's letter: "It is recognized that there may be instances in
which the disease from which the patient is suffering permits the administration
of larger doses for investigative purposes." 36 Safeguards were to be provided by
reliance on the judgment of local physicians, not a precise definition of moribund.
Indeed, the subcommittee did not even use the term. Applications would be
approved providing:
1. Full responsibility for conduct of the work is
assumed by a special committee of at least three
competent physicians in the institutions in which
the work is to be done. This will not necessarily be
the local Radioisotope Committee.
2. The subject has given his consent to the
procedure.
3. There is no reasonable likelihood of producing
manifest injury by the radioisotope to be
employed. 37
No further explanation was given of how the second requirement, giving consent,
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would be fulfilled by a "moribund" patient, nor was additional guidance provided
to clarify the third criterion.
One instance in which this policy was applied took place at the Walter E.
Fernald State School in Massachusetts (see chapter 7). Correspondence between
the researchers and the AEC indicates that the AEC allowed the administration of
50 microcuries of calcium 45 (fifty times the amount the AEC allowed the
researchers to administer to other subjects in the study) to a ten-year-old patient
with a life expectancy of a few months, suffering from Hurler-Hunter syndrome
(a degenerative disease of the nervous system). In applying for the radioisotope,
Dr. Clemens Benda, the researcher, noted that "permission for the use of higher
doses administered to moribund patients has been granted by you to other
investigators . . . ." 38 This subject was part of a study of calcium metabolism
approved by the superintendent of the school. Students had been described as
"voluntarily participating" in a letter sent earlier to the parents asking if they
objected, but that did not mention the use of radioactive tracers. Lack of response
from a parent was presumed to be approval. 39 The subject with Hurler-Hunter
syndrome was found to have abnormal calcium metabolism, but died before the
study could be completed. 40
Even as it developed procedures for unusual cases, the subcommittee
recognized that some existing uses were becoming routine and did not need to be
continuously reviewed by the subcommittee itself. The subcommittee delegated
the review of such requests to the Isotopes Division, setting out the criteria to be
applied:
Such applications should be justified by:
a) A commensurate increase in patient load.
b) An expanded research program.
c) Provision of adequate storage and handling facilities.
d) Assurance that personnel protection and supervision are
adequate for the larger amounts requested. 41
An additional simplification occurred with the introduction in 1951 of "general
authorizations," which delegated more authority to the local radioisotope
committees of approved institutions. 42 These authorizations enabled research
institutions to obtain some radioisotopes for approved purposes after filing a
single application each year, therefore eliminating the need to file a separate
application for each radioisotope order. As such, they also reduced the oversight
of the AEC's Subcommittee on Human Applications, as each order was no longer
reviewed individually. However, at first the general authorizations did not apply
to human use, and when they were expanded to human use in 1952, they were
limited to certain radioisotopes for clinical use and excluded radioisotopes in
cancer research, therapy, and diagnosis. 43
Both the AEC and the subcommittee reacted strongly when proper
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bureaucratic procedures were not followed. One example was a private industrial
lab that used iodine 131 for a human study that had not been properly reviewed.
Even though no one was harmed, the AEC threatened to suspend shipments of all
radioisotopes, not just iodine 131; such action would have put the company out of
business. 44 Aebersold, at the direction of the subcommittee, notified the company
president that while the incident "did not lead to any unfortunate results from the
standpoint of radiation hazard ... a recurrence of this type of violation should
result in cessation of all shipment of radioactive materials to Tracerlab, Inc." 45
For his part, the company president reacted by notifying employees that such
action would be grounds for automatic dismissal. 46
Thus, as it proceeded in its work of evaluating individual applications, the
subcommittee developed more general principles such as categories of human
uses based upon risk and updating of criteria based upon developing knowledge.
The goal, as the AEC's director of research, K. S. Pitzer, stated in 1950, was "to
make radioisotopes as nearly as possible ordinary items of commerce in the
technical world." 47 For example, cancer researchers initially received
radioisotopes at no charge. 48 This free program was changed to an 80 percent
discount program in 1952 49 and ended in July 1961. 50
AEC Regulations and Published Guidelines
An important step toward making the use of radioisotopes a component of
medical practice routine was formally enacting regulations governing the use of
isotopes. The first regulations were enacted in 1951. 5 ' These early regulations
essentially promulgated facility and personnel requirements without establishing
dose limits or mentioning the consent requirement established in 1949 for
administering larger doses to very sick patients. Throughout the 1950s, changes in
the regulations dealt with administrative procedures. Other concerns about
radioisotope use, such as consent requirements, were disseminated through
circulars, brochures, and guides of the Isotopes Division. In 1948 the circular
describing medical applications was only three pages long; by 1956 it had been
replaced by a twenty-four-page guide that provided detailed requirements for
many different applications of isotopes. 52
This greater precision can be seen, for example, in the guidelines for
terminal patients. By the time of the 1956 guide, the use of radioisotopes with
half-lives greater than thirty days ordinarily would not be permitted without prior
animal studies establishing metabolic properties, unless patients had a short life
expectancy. The judgment of local physicians was now to be guided by a more
exact definition: exceptions would be "limited to patients suffering from diseased
conditions of such a nature (life expectancy of one year or less) that there is no
reasonable probability of the radioactivity employed producing manifest injury." 53
However, while a more precise definition of terminal was now provided, there
was no longer explicit mention of a specific requirement for consent from these
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patient subjects, as had been made earlier.
Consent was required, though, in the section of the 1956 guide on the "use
of radioisotopes in normal subjects for experimental purposes." (Presumably,
"normal" here means "healthy.") This section included the earlier provisions that
the tracer dose not exceed the permissible body burden and that such experiments
not normally be conducted on infants or pregnant women. It also, however,
included a new provision that such experiments were to be limited to "volunteers
to whom the intent of the study and the effects of radiation have been outlined." 54
The term volunteer would seem to imply a requirement that consent be obtained
following a disclosure of information to potential subjects. The disclosure
requirement dops not include, however, all of the elements of information that
today are included in duties to obtain informed consent.
This 1956 consent requirement now governed all radioisotope
experiments in normal subjects, a substantial expansion of the earlier requirement
of consent only from terminal patients receiving larger-than-usual doses. It also
explicitly required that both the purpose and effects of radiation be explained. It
is unclear whether the failure to mention consent in the section on terminal
patients was an oversight in drafting or a deliberate distinction between patients
and "normal" subjects. The Advisory Committee has not found documents
revealing the history of this provision, nor any explanation of the choice to limit
the broad consent requirement to "normal" subjects. 55
This broad requirement continued over the next decade as part of AEC
policy. In 1965, the AEC published the "Guide for the Preparation of Applications
for the Medical Use of Radioisotopes." The guide described the application
process and specific policies for the "Non-Routine Medical Uses of Byproduct
Material." This policy statement reiterated the exclusion of pregnant women and
required that subject characteristics and selection criteria be clearly delineated in
the application. Another requirement stated that applications should include
"confirmation that consent of human subjects, or their representatives, will be
obtained to participate in the investigation except where this is not feasible or in
the investigator's professional judgment, is contrary to the best interests of the
subjects." 56
During the 1960s, the entire system of oversight of radioisotope research
began to change as the Food and Drug Administration began developing a more
active role in supervising the development of radiopharmaceuticals. 57 The
regulatory history of this shift in authority is complex and beyond the scope of
this report. Suffice it to say that by the mid-1960s the regulation of radioisotope
research was beginning to merge with the regulation of pharmaceutical research
in general.
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LOCAL OVERSIGHT: RADIOISOTOPE COMMITTEES
From its inception, the AEC distribution system required each local
institution to establish a "local radioisotope committee," later termed a "medical
isotopes committee." Initially, the primary purpose was to simplify the allocation
process by having local institutions establish their own priorities before applying
to the AEC. 5X Soon after the program began, supply increased and no dramatic
new uses developed, so allocation was no longer a major issue. These local
committees also took on responsibilities for physical safety, usually working
closely with radiation safety offices. By October 1949 this requirement also
applied to the AEC's national labs. 59 When "general authorizations" were issued
in 1951, granting broader discretion to qualifying local institutions, local isotope
committees assumed greater responsibility. 60
By 1956, the functions of the local radioisotope committees included
reviewing applications, prescribing any special precautions, reviewing reports
from their radiological safety officers, recommending remedial action when
safety rules were not observed, and keeping records of their own activities. The
basic focus on radiological safety remained, although in reviewing applications a
local medical isotopes committee could also consider "other factors which the
[local medical isotopes] Committee may wish to establish for medical use of these
materials." 61 Exactly what these "other factors" might be was not specified.
These local committees together reviewed thousands of applications over
the next decades. Although not federal agencies, they were required by the AEC,
and their proper functioning was an important part of the oversight system
envisioned by the AEC. To fully assess whether this system fulfilled its goals
would be an enormous task, requiring the retrieval and examination of thousands
of local records. However, to make a preliminary assessment of whether the
system as a whole generally appeared to function as planned, the Advisory
Committee did examine the records of several public and private institutions: the
Veterans Administration (VA), the University of Chicago, the University of
Michigan, and Massachusetts General Hospital (MGH). 62 Doing so provided us
with an understanding of the techniques of risk management used at the local
level on a day-to-day basis. We specifically examined whether local radioisotope
committees in fact were established as directed and what techniques they
developed to monitor consent and ensure safety.
Establishment of Local Isotope Committees
Overall, the federal requirement seems to have been an effective means of
instituting a reasonably uniform structure across the nation for local radioisotope
committees. The AEC's requirements for local committees were followed in all
the institutions studied, and there is no reason for believing they were exceptional.
One local radioisotope committee, that of Massachusetts General Hospital, was
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established in May 1946, prior to the AEC requirement. 63 The other institutions
established a local radioisotope committee when required to do so by the AEC.
Local committees also could have broader tasks than those required by the
AEC. For example, the Radiation Policy Committee at the University of Michigan
regulated all radioactive substances used on campus, not just those purchased
from the AEC. These included reactor products, transuranic elements, and
external sources of radiation. 64
The Veterans Administration added another level of oversight in the form
of a systemwide Central Advisory Committee. 65 In 1947 the VA embarked on a
radioisotope research program that would take place within newly established
radiation units in the hospitals that would be the recipients of AEC-supplied
isotopes. 66 Among early research projects were the treatment of toxic goiter and
hyperthyroidism with iodine 131 and treatment of polycythemia rubra vera
(overproduction of red blood cells) with phosphorus 32 at Los Angeles,
radioactive iron tracers of erythrocytes at Framingham, and sodium 24 circulatory
tracers in Minneapolis. 67 By the end of 1948, radioisotope units had been
established in eight VA hospitals. 68 Each of the eight was asked to establish a
radioisotope committee (as required by the AEC) to be appointed by the Dean's
Committee of each hospital, while representatives from affiliated universities
agreed to serve as consultants in the various units.
Local Monitoring of Consent
Generally, although local institutions created clear procedures to monitor
safety, these local radioisotope committees did not establish procedures to
monitor or require consent. 69 (See part I for discussion of the broader historical
context of consent in medical research.) The standard application form to the
Massachusetts General Hospital committee, as of 1953, had no place to describe
an informed consent procedure. This does not, of course, resolve the question of
whether consent was given. According to one prominent neurosurgeon
interviewed by the Advisory Committee staff, William Sweet, at that time, in the
case of brain tumor patients, oral consent was obtained from both the patient and,
since mental competency could later be an issue, the next of kin. 70
Similarly, no mention of the 1947 AEC requirements stated in General
Manager Wilson's letters is contained in the advice Shields Warren gave in 1948
to the VA, even though Warren, as director of the AEC's Division of Biology and
Medicine, must have known of discussions about consent requirements. An issue
that arose before the VA Central Advisory Committee was whether patient-
subjects should sign release slips. This issue posed the question of whether the
radioisotope units in the VA hospitals were treatment wards or clinical research
laboratories. If wards, patients need not sign consent forms, for they were simply
being treated in the normal course of an illness. Shields Warren agreed with this
presumption and felt that there was no need for the patients to sign release slips:
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"The proper use of radioisotopes in medical practice is encompassed in the
normal responsibilities of the individual and of the institution or hospital." 71 In
addition, he felt that the practice would draw "undue and unwholesome attention
to the use of radioisotopes." 72
Movement toward more formal consent requirements gradually arose at
the local level. In 1956 the University of Michigan's own Human Use
Subcommittee directed that in an experiment using sodium 22 and potassium 42,
each "volunteer would be required to sign a release indicating that he has full
knowledge of his being subjected to a radiation exposure." Since the local
committee was concerned about what it termed "unnecessary" radiation, the
volunteers presumably were healthy subjects not otherwise receiving radiation for
treatment or diagnosis. The committee appended a recommended "release" form
to its minutes:
I, the undersigned, hereby assert that I am
voluntarily taking an injection of at a dose
level which I understand to be considered within
accepted permissible dose limits by the University
of Michigan Radio-isotope Human Use Sub-
Committee. 73
By 1967, the Michigan subcommittee also required that the subject
explain the experiment to the researcher to clarify any doubts or
misunderstandings. The following statement was incorporated into all
applications to the university's Human Use Subcommittee:
The opinion of the Committee is that INFORMED
CONSENT is the legal way of describing a
"meeting of the minds" in a contract. In this
situation it means that the subject clearly
understands what the experiment is, what the
potential risks are, and has agreed, and without
pressure of any kind, elected to participate. The best
way to ascertain that the consent is informed, is to
have the subject explain back fully to the
interviewer, exactly what he thinks he is submitting
to and what he believes the risks might be. This
facilitates clarification of any doubts, spoken or
unspoken. The content of this discussion will be
recorded in detail below. 74
During the 1960s, as explained in chapter 3, concern was growing over the
adequacy of consent from subjects. Although not intended by the AEC to
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monitor the obtaining of consent from subjects, over the years the local
radioisotope committees may have come to take on this task. By requiring such
local committees, the AEC had, probably unwittingly, provided an institutional
structure that allowed later concern for informed consent to be implemented at the
local level.
Local Monitoring of Risk
This local and informal approach to consent is in sharp contrast to the
detail and documentation with which risk was assessed. As discussed earlier,
monitoring risk was the major task of the AEC's Subcommittee on Human
Applications. The local committees mirrored this task, examining in detail the
various experiments presented to them. As with the AEC subcommittee, local
committees developed a variety of methods, none especially surprising, to ensure
what they believed was adequate safety. 75
The basic dilemma facing local committees was to allow exploration of
new territory while attempting to guard against hazards that, precisely because
new territory was being explored, were not totally predictable. This dilemma was
apparent at the local level, as well as at the level of the AEC's Subcommittee on
Human Applications. For example, in the minutes of the Massachusetts General
Hospital local radioisotope committee in 1955, during a discussion of new and
experimental radiotherapies for patients, one member of the committee declared
that the safety of the patient was of "paramount importance." 76 Yet, other
members suggested that a risk-benefit analysis needed to be an integral
component of such a policy decision. The committee as a whole concluded
merely that it was a complicated issue and that "it is not wise in any way to inhibit
investigators with ideas, and yet the safety of the patient must come first." 77
Requiring prior animal studies was a basic method of assessing risk. For
example, the twenty-two studies reviewed by the University of Chicago's local
committee in 1953 included multiple therapeutic and tracer studies involving
brain tumors, the thyroid gland, metastatic masses, and tissue differentiation.
Those the Chicago committee viewed as involving any risk to the patient were
preceded by extensive animal studies. 78
Animal studies were usually tailored to each project and also raised the
question of the differences between how humans and animals might respond to a
particular radioisotope. A more uniform standard directly applicable to humans
was the system of dose limits established by the National Committee on Radiation
Protection for occupational purposes: the maximum permissible dose for each
isotope. In addition, although no national system existed for reporting their
decisions, local committees drew upon their knowledge of what had been
approved at other institutions. 79 At least one local committee issued its own dose
limits. The Massachusetts General Hospital local committee in 1949 issued a
seven-point policy on human use of beta- and gamma-emitting radioisotopes. 80
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By 1956, the Michigan committee provided explicit limits for exposure of
volunteers/ 1
At other times, the condition of subjects who were patients was accepted
as justification for higher doses. For example, in 1953 the Chicago committee
approved a tracer study using mercury 203 "to study uptake by malignant renal
tissue." Although admitted to be unusual, it was approved as potentially
efficacious in patients suffering hypernephroma (a kidney cancer). Total dose
would not exceed 10 milligrams of ionic mercury, a high dose for most tracer
studies, which was approved as reasonable given the illness of the patients. 82
Similarly, the Harvard Medical School committee in 1956 stipulated that "the risk
of incurring any type of deleterious effect due to the radiation received should be
comparable to the normal everyday risks of accidental injury." For seriously ill
patients receiving experimental treatment, however, the committee stated, "the
estimated deleterious effect from radiation should be offset by the expected
beneficial effects of the procedure." 83
In addition to setting limits, local committees encouraged the use of
technical methods to reduce risk. Use of different detection techniques could
reduce the dose required. In 1955, for example, the Michigan committee
considered an application to administer to normal volunteers up to 30 microcuries
of sodium 22 and up to 350 microcuries of potassium 42, resulting in internal
radiation doses of up to 300 millirem per week. (The purpose was to study
sodium-potassium exchanges.) The committee asked itself: "Is it justifiable to
subject the volunteers to an exposure in excess of the maximum permissible?
This Committee did not resolve this question but came forward with the
suggestion that more-sensitive counting techniques might permit this
investigation at lower dose levels." 84
Another method of reducing risk was to restrict the type of subjects to
those whose life expectancy was too short for long-term effects to appear. This
has already been seen regarding terminal patients. Another variation of the same
technique was to restrict the use of volunteers to those over a certain age. At
Michigan, age restrictions on who would be acceptable as a volunteer began
appearing in the 1960s. 85
When a worthwhile experiment also involved novel risks, another method
to control risk was to require additional monitoring by the local committee as the
experiment proceeded. At times, the Michigan committee required preliminary
reports before allowing experiments to proceed further. 86 In another instance, the
Michigan committee required the researcher to obtain long-term excretion data
because of concern that "the usual biologic half-life data might not be
sufficient." 87 Similar additional oversight was required at the University of
Chicago in 1953. A proposal was made to use tritium-labeled cholesterol to study
steroid-estrogen metabolism in women. The question of the distribution of
estrogenic hormones in humans was unexplored at the time and deemed worthy of
research. While the risk appeared low, the committee ultimately approved the
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study for the first round of the experiment only for nonpregnant women who were
sterile or pregnant women who planned to be sterilized postabortion. If data from
the first round suggested minimal risk to the women and the fetuses, the program
could be expanded. 88
Thus, in establishing a system of local radioisotope committees, the AEC
effectively increased the detail with which each proposed experiment was
reviewed. Often, it appears, experimental protocols were revised at the local level
before being approved and sent on to the AEC. Thus, the system created by the
AEC did some of its most effective risk management out of sight of direct federal
oversight.
GENERAL BENEFITS OF RADIOISOTOPE RESEARCH
The system for distribution of radioisotopes worked well and encouraged
researchers to explore new applications. There are two striking aspects of the
application of radioisotopes to medicine since World War II: rapid expansion and
complexity. Practices that at the end of the war were limited to fewer than four
dozen practitioners have now become mainstays of modern medicine. 89 The
second major aspect of the field is its complexity. Just as nature at times is best
regarded as a seamless web, not unconnected scientific fields, knowledge
nurtured in one field often provides unexpected benefits in another. A few
examples can illustrate how some of the hopes at the dawn of the atomic age have
actually been realized. 90
Improved Instrumentation to Detect Radiation
Improved instruments, the basic tools for all biological research using
radioisotopes, were developed through the interaction of biology and medicine
with physics and engineering. Improvements not only provide greater precision,
they also allow the same amount of information to be gathered with lower doses
of radiation, thereby reducing the risk.
Perhaps the best-known example is the application of the "whole-body
counter" to biological problems. The device was originally developed as a tool
for physics, enabling measurements of minute amounts of radiation by combining
sensitive detectors with extensive shielding to eliminate extraneous radiation.
The result was similar to placing a sensitive microphone in a sound-proofed room,
allowing lower levels of radioactivity to be detected than was previously possible.
For some research, no radioisotope at all was administered; the counters could
measure naturally occurring radioisotopes. Whole-body counters also greatly
simplified metabolic studies. In some studies, subjects who previously would
have had to reside continuously in a metabolic ward could now schedule visits to
the whole-body counter for their natural radioactivity to be measured on an
outpatient basis. 91 This device was later adapted for whole-body counting after
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administration of tracer amounts of radioisotopes and is the basis for a number of
fundamental nuclear medicine tests.
In the early 1 970s, computerized tomographic scanning (CT) was
introduced. This technique was first applied to x-ray imaging by taking multiple
x-ray "slices" through a region of the body, then programming a computer to
construct a three-dimensional image from the information. Thus, internal
structures of the body may be imaged noninvasively. Newer types of
tomographic scanning include positron emission tomography (PET), in which
various metabolites or drugs are labeled with a very short half-life positron-
emitting radioisotope, such as fluorine 18, and the passage of the labeled material
is tracked throughout the body by taking multiple images over several minutes or
hours.
Diagnostic Procedures
The first medical application of any radiation was the use of x rays for
diagnostic purposes, such as locating broken bones inside the patient.
Radioisotopes later opened another window into the body. The natural tendency
of certain organs to preferentially absorb specific radioisotopes, coupled with
ever-improving detection techniques, allowed radioisotopes to be used to increase
the contrast between different parts of the body. X rays could distinguish
between hard and soft tissues because of their different densities. Radioisotopes
could go one step further and distinguish different kinds of tissues from one
another based upon their metabolic function, not merely their physical density.
Radioisotopes also could go beyond detecting different types of tissues.
Since they were distributed throughout the body by the body's own metabolism,
their location provided a picture not only of structure, but also of processes.
Tracing radioisotopes was a means of observing the body in action. The earliest
success was using radioiodine to measure the activity of the thyroid. The gland
cannot distinguish between radioactive and nonradioactive forms of iodine and
therefore preferentially absorbs all isotopes of iodine. Thus, the activity of the
gland can be assessed by observing its absorption of radioiodine. Largely as a
result of these advances, the thyroid gland is arguably the best understood of all
human endocrine organs, and its hormones the best understood of all endocrine
secretions. Since the incidence of thyroid disease is second only to diabetes
mellitus among human endocrine diseases, this understanding is basic to therapy
in large numbers of patients. 92
Because the brain is a crucial and delicate organ, techniques for
diagnosing brain tumors without surgery were vital. In 1948 radioactive isotopes
were applied to this task. Using radiotagged substances that were preferentially
absorbed by brain tumors, physicians could more accurately detect and locate
brain tumors, allowing better diagnosis and more precise surgery. Similar
"scanning" techniques were later developed for the liver, spleen, gastrointestinal
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system, gall bladder, lymphomas, and bone.
As mentioned, a recently developed technique is PET scanning, which is
especially helpful in studying the human brain in action. Glucose is the primary
food for the brain; by tagging a glucose analog with fluorine 18, investigators can
identify the actively metabolizing portions of the brain and relate that to function.
This technique, has opened a new era of studies of the brain. Outwardly
observable functions, such as language, object recognition, and fine motor
coordination can now be linked with increased activities in specific areas of the
brain.
Radioisotopes allow investigators to increase the sensitivity for analyzing
biological samples, such as tissue and blood components, especially when
separating out the material of interest using chemical processes would be difficult.
Because instruments to measure radioactivity are so sensitive, radioisotopes are
frequently used in tests to detect particular hormones, drugs, vitamins, enzymes,
proteins, or viruses.
Therapeutic Techniques
Radioisotopes are energy sources that emit one or more types of radiation
as they decay. If radioisotopes are deposited in body tissues, the radiation they
emit can kill cells within their range. This may be harmful to the individual if the
exposed cells are healthy. However, this same process may be beneficial if the
exposed cells are abnormal (cancer cells, for example).
The potential for radiation to treat cancer had been recognized in the early
days of work with radiation, but after World War II the effort to develop radiation
therapy for cancer increased. Iodine 1 3 1 treatment for thyroid cancer was
recognized as an effective alternative to surgery, both at the primary and
metastatic sites. Cancer is not the only malady susceptible to therapy using
radioisotopes. The use of radioiodine to treat hyperthyroidism is perhaps the
most widespread example. It illustrates the progression from using a radioisotope
to measure a process (thyroid activity) to actually correcting an abnormal process
(hyperthyroidism). 93
Not all experimental applications of radioisotopes are successful. Some
experiments end in blind alleys, an important result because this prevents
widespread application of useless or even harmful treatments. Negative results
also help researchers to redirect their efforts to more promising areas. The
importance of negative results is sometimes not appreciated because they do not
lead to effective treatments. Negative results may range from simply not
obtaining an anticipated beneficial effect to the development of severe side
effects. Such side effects may or may not have been anticipated; they may occur
simultaneously with beneficial effects, such as the killing of cancer cells.
Occasionally negative results include earlier-than-anticipated deaths of severely
ill subjects. An example is the experimental use of gallium 72 in the early 1950s
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on patients diagnosed with malignant bone tumors. 94
Another radioisotope, cobalt 60, has been used successfully to irradiate
malignant tumors, but in this case the radioisotope is not administered internally
to the patient; rather, the cobalt 60 forms the core of an external irradiator, and the
gamma radiation emanating from the radioisotope source is focused on the
patient's tumor. Although cobalt 60 irradiators have been largely replaced by
linear accelerators, they were developed under AEC sponsorship and were
responsible for many advances in radiation therapy.
Recent efforts to utilize radioisotopes in cancer diagnosis and treatment
are based on the ability of antibodies to recognize and bind to specific molecules
on the surface of cancer cells and the ability of biomedical scientists to custom-
design and manufacture antibodies, thus improving their specificity. These fields
are now contributing to a hybrid technique: cloning antibodies and tagging them
with radioactive isotopes. As the antibody selectively binds to its target on the
surface of the cancer cell, the radioactive isotopes attached to the antibody can
either tag the cell for detection and diagnosis or deliver a fatal dose of radiation to
the cancer cell. The Food and Drug Administration recently approved the first
radiolabeled antibody, to be used to diagnose colorectal and ovarian cancers. 95
Even in the case of widespread metastases where cure is no longer
possible, radiation treatments will often produce tumor regression and ease the
pain caused by cancer. Phosphorus 32 has been used to ease (palliate) the bone
pain caused by metastatic prostate and breast cancers. Recently, the FDA
approved the use of strontium 89 for similar uses. 9 ''
Metabolic Studies
Studies of the basic processes within the body may not have any
immediate application in diagnosis or therapy, but they can indirectly lead to
practical applications. One example is in the study of the metabolism of iron in
the body. Iron is an important part of hemoglobin, which carries oxygen from the
lungs to all cells in the body. Studies using radioactive iron established the
pathway iron takes, from its ingestion in food to its use in the blood's hemoglobin
and its eventual elimination from the body; these studies had practical
applications in blood disease, nutrition, and the importance of iron metabolism
during pregnancy.
Radioisotopes have also been used to study how the weightlessness of
space travel affects the human body. Radioisotopes have allowed more precise
observation of effects of space travel on blood plasma volume, total body water,
extracellular fluid, red cell mass, red cell half-life, and bone and muscle tissue
turnover rates.
Other uses of radioisotopes are in studies of the transport and metabolism
of drugs through the body. New drugs for any clinical application, whether
diagnostic or therapeutic, must be understood in detail before the FDA will
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approve them for general use. One method for readily determining how a drug
moves through the blood to various tissues, and is metabolically changed in
structure, is to incorporate a radioactive isotope into the structure of the drug.
Unexpected results from an experiment can at times have widespread
consequences. An example is how the work of Rosalyn Yalow and Solomon
Berson of the Bronx VA Medical Center opened up the field of
radioimmunoassay. In the early 1950s, it was discovered that adult diabetics had
both pancreatic and circulating insulin. This appeared odd; previously, it had
been believed that all diabetics lacked insulin. To explain the presence of
diabetes in people with pancreatic insulin, Yalow and Berson decided to study
how rapidly insulin disappeared from the blood of diabetics. To do this, they
synthesized radioiodine-labeled insulin. This would act as a radioactive tag,
making it much easier to measure the presence of insulin in blood. To their
surprise, they found that insulin disappeared more slowly from diabetic patients
than from nondiabetic people. 97
Their work had an impact beyond the study of diabetes, however. In the
process of studying the plasma of patients who had been injected with insulin,
they discovered that the radioactively tagged insulin was bound to an antibody, a
defensive molecule that had been produced by the patient's body and custom-
designed to attach itself to the foreign insulin molecule. This was a surprise, since
prevalent doctrine held that the body did not produce antibodies to attack small
molecules such as insulin. To study the maximum binding capacity of the
antibodies, they did saturation tests, using fixed amounts of radiolabeled insulin
and of antibody to measure graded concentrations of insulin. With this technique
Yalow and Berson realized they could measure with great precision the quantities
of insulin in unknown samples. They thus developed the first
radioimmunoassay. This technique, for which Rosalyn Yalow was awarded the
Nobel Prize in Medicine in 1977, has become a basic tool in many areas of
research. Radioimmunoassay revolutionized the ability of scientists to detect and
quantify minute levels of tissue components, such as hormones, enzymes, or
serum proteins, by measuring the component's ability to bind to an antibody or
other protein in competition with a standard amount of the same component that
had been radioactively tagged in the laboratory. This technique has permitted the
diagnosis of many human conditions without directly exposing patients to
radioactivity.
No discussion of the impact of radioisotopes on biomedical science would
be complete without a recognition of their fundamental importance in basic
biological investigations. The ability of radioisotopically labeled metabolites to
act like, and therefore trace, their nonradioactive counterparts has allowed
scientists to follow virtually every aspect of metabolism in cells of bacteria,
yeasts, insects, plants, and animals, including human cells. Among the benefits of
such studies are (a) an understanding of the similarities in metabolism of
organisms throughout the evolutionary scale, (b) identification of sometimes
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subtle differences in cell structure and function between organisms and thus the
ability of drugs to kill bacteria, fungi, or insects without harming humans, and (c)
elucidation of the fundamental properties of genetic material (DNA), The last of
these examples has important implications today, as the human genes controlling
many important bodily functions are being identified and cloned and gene therapy
is just beginning to find its way into clinical application. Many benefits of
understanding the human genetic code have already been realized, and others will
likely accrue in the next few years. These benefits are the result of fundamental
advances in genetics and molecular biology of the past half century, which in turn
depended heavily on studies with lower organisms and with radioisotopically
labeled materials. Thus, human health is benefiting from both human and
nonhuman research with radioisotopes.
The grandest dream of the early pioneers—a simple and complete cure for
cancer-remains unfulfilled. Promising paths at times proved to be dead ends.
However, the AEC's widespread provision of radioisotopes, coupled with support
for new techniques to apply them, laid the foundation stones for much of modern
medicine and biology. This section has only skimmed the field of nuclear
medicine, with its vast array of diagnostic and therapeutic techniques, and the use
of radioisotopes in many areas of basic research.
An Example of Hopes Unfulfilled: The Gallium 72 Experiments
Human experiments with gallium 72, as discussed in the section titled "General Benefits
of Radioisotope Research," were conducted at the Oak Ridge Institute of Nuclear Studies in the
early 1950s. The experiments used gallium 72 because of its short half-life (14.3 hours) and
because an earlier animal study indicated it concentrated in new bone, making it useful as a tumor
marker and possibly for therapy." The 1953 published report stated that the purpose of the study
was "to investigate the therapeutic possibilities in human tumors involving the skeletal system. " b
In 1995 one of the original researchers stated to Advisory Committee staff a somewhat broader
purpose: "to exploit to the fullest possible extent any possible use of this isotope as a bone seeking
element rather than to seek a cure for a specific malignant bone tumor, such as osteogenic
sarcoma. . . . While the GalIium-72 studies did include osteogenic sarcomas, they only represented
a. Herbert D. Herman. M.D., FACR, to Dan Guttman, Executive Director, Advisory Committee
on Human Radiation Experiments, 19 May 1995 ("It has come to my attention . . ."), 2. Dr. Kerman cites as
the preceding study: H. C. Dudley and G. E. Maddox, "Deposition of radiogallium (Ga-72) in skeletal
tissues," Journal of Pharmacology,' and Experimental Therapeutics 96 (July 1949): 224-227.
b. Gould A. Andrews, M.D., Samuel W. Root, M.D.. and Herbert D. Kerman, M.D.. "Clinical
Studies with Gallium-72," 570, in Marshall Brucer, M.D. (ed.), Gould Andrews, M.D., and H. D. Bruner,
M.D., "Clinical Studies with Gallium-72," Radiology 66 (1953): 534-613.
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less than half (9/21 ), 43%, of all the other primary and metastatic skeletal malignancies studied.'"
Patients were chosen who had been diagnosed with "ultimately fatal neoplasms not
amenable to curative surgery or radiotherapy.'" 1 The diagnosis later proved to be accurate in all but
one of the fifty-five subjects. In one part of the study, thirty-four patients were given trace
amounts of gallium. Both external radiation measurements and a variety of excreta, blood, and
tissue samples were analyzed to determine the localization of gallium. In another part of the study,
twenty-one other patients were given doses that the researchers hoped would be in the therapeutic
range. Total doses ranged from 50 to 777 microcuries. 1 The gallium was administered in
fractionated doses biweekly. According to the medical investigators, these patients "were, in
general, in a more advanced stage of disease and were completely beyond even palliation from
conventional forms of therapy." 6 For these patients, "doses which were believed to be moderate
were given and gradually increased to toxic level. " h The conclusion of the report notes that "most
of the patients in whom gallium therapy was attempted were given maximum amounts of the
isotope. Only the hopelessness of their prognoses justified a trial of doses so damaging to the
hematopoietic tissues.'"
A major difficulty was lack of knowledge about both the chemical toxicity of stable (that
is, nonradioactive) gallium and the radiation toxicity of gallium 72. Calculations and small animal
studies indicated that dosimetry techniques used for other radioisotopes would "be of little value." 1
During the study, close monitoring was done of many bodily functions to observe toxic effects as
soon as they began to appear. Blood tests revealed changes that "were prominent and were usually
of primary importance in determining when the treatments should be discontinued. " k Other effects
included drowsiness, then anorexia, nausea, vomiting, and skin rash.
One problem was determining whether these effects were due to chemical toxicity,
radiation toxicity, or a combination. Due to technical difficulties in separating out pure gallium
c. Kerman to Guttman, 19 May 1995, 2. Dr. Kennan presumably was referring to the twenty-one
subjects who received doses in the therapeutic range, not the thirty-four who received trace doses.
d. Andrews, Root, and Kerman, "Clinical Studies with Gallium-72," 570.
e. A patient was diagnosed with osteogenic sarcoma in his leg, which was amputated. X rays also
revealed dense nodules in his lung, which were diagnosed as inoperable but typical pulmonary metastases.
He was discharged after the gallium study. When he later returned to the hospital, an operation revealed that
the nodules were not typical metastases, but unidentifiable lesions "not characteristic of any specific lesion."
This could not have been known prior to the study, when only x rays were available for diagnosis. Ibid., 585.
f. The researchers reported that these doses were equivalent to 8.5-89.2 mg/kg of body weight.
Ibid., 574-577.
g. Ibid., 570.
h. Ibid., 571.
i. Ibid., 587.
j. The investigators wrote that "[njormal tissue and whole-body tolerances for amounts of
radiogallium necessary to produce a significant effect upon malignant tissues were unknown. Preliminary
calculations and small animal experiments had indicated that accepted radiation dosimetry as applied to other
isotopes would be of little value in calculating radiation dosage to tissues. It was therefore necessary to
utilize the hematologic picture to assess the damaging effects of whole-body irradiation, and clinical and
roentgenographic experience in evaluating a therapeutic response." Ibid., 571.
k. Ibid., 573.
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72. the radioactive gallium was injected with larger amounts of stable gallium, so both chemical
and radiation effects could be present. To distinguish them, one patient was administered an
amount of stable gallium equal to a therapeutic dose, but with only an insignificant amount of
radioactive tracer (to determine localization). Observed toxic effects in this patient did not include
bone marrow depression. The researchers concluded, therefore, that the "profound bone marrow
depression is characteristic of radiation damage and is probably chiefly caused by radiation,
though an element of stable metal toxicity may also be contributory." 1
Bone marrow depression gradually ended after gallium injections were stopped. While it
lasted, bone marrow depression led to greater susceptibility to infection and bleeding. Two
subjects died sooner than anticipated, one from infection and bleeding and the other from
infection, while their bone marrow was still depressed. "These two patients died in spite of
antibiotics, blood transfusions, and toluidine-blue therapy.'"" The researchers reported that "in two
patients our estimates of safe dosage limits were in error and radiogallium is believed to have
hastened death."" One researcher, writing in 1995, stated that "since 'safe dosage' levels were only
estimates and seven other patients had survived with even higher dosages, our choice of language
[citing the preceding quotation] was unfortunate. It must be emphasized that this portion of the
study must be likened to a current clinical Phase I trial where in a limited fashion [a] broad range
of toxicity levels may at best be only estimated."
The major conclusion of the experiment was that hopes for gallium therapy were
unfulfilled. Even though the maximum tolerated doses had been administered, the researchers
reported that "we were impressed with the almost complete lack of any clinical improvement
following gallium treatment, even in patients who showed evidence of striking differential
localization of gallium in tumor tissue."
Concerning patient consent, the published study says nothing, which was normal for
scientific articles at that time. Near the end of the Advisory Committee's deliberations, ORINS
reportedly found consent forms signed by subjects in the gallium study. 4 One of the researchers in
1995 did offer his recollections regarding consent to the Committee:
Forty-five years ago all of our patients and their families were
given a booklet of information explaining how radioisotopes
were used in medicine and more specific information about
I. Ibid., 575.
m. Ibid., 573. Neither had suffered from osteogenic sarcoma; one had suffered from
adenocarcinoma of the kidney with lytic bone metastases and another from cancer of the prostate with
metastatic skeletal involvement, Kerman to Guttman, 19 May 1995, 3.
n. Andrews, Root, and Kerman, "Clinical Studies with Gallium-72," 571.
o. Ibid.
p. Ibid., 587. Researchers reported evidence of concentration in tumors as being one of the
following: "no data," "none." "little," "moderate," or "pronounced." Ibid., 574.
q. Dr. Shirley Fry, telephone interview with Dan Guttman (ACHRE), 30 August 1995, I. The
Advisory Committee did not have enough time to review the forms and related file materials once they were
identified, which, because ORINS deemed them privacy-protected material, would have required review at
Oak Ridge.
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their own involvement including the possible known risks.
Signed applications for admission and waiver and release
forms were demanded for all patients. When, as in the ongoing
gallium studies, toxicity or enhanced risks were encountered,
these were immediately made clear to the patients and their
families if they were known in that time frame. Very often
toxicity is only apparent after review of the clinical data. In the
gallium studies, when on review of the data it was determined
that no therapeutic benefit had occurred, the study was
immediately terminated/
CONCLUSION
At the end of World War II, radioisotopes were regarded as the most
promising peacetime application of our new knowledge of the atom. Venturing
into new fields carried with it substantial risks: risks due to our ignorance of what
lay ahead, and risks due to the lack of training of many would-be explorers. The
AEC consistently accepted and acted upon its responsibility to manage this risk.
An extensive administrative system was created to oversee the safety of human
radiation experiments that used radioisotopes supplied by the AEC. At the heart
of the system was the AEC's Subcommittee on Human Applications of the
Advisory Committee on Isotopes Distribution Policy. This system regulated the
types of uses allowed according to their hazard and the extent of our knowledge
of the risks. It required and provided training of those who would use
radioisotopes. It required the establishment of local radioisotope committees,
which not only reviewed proposals but suggested changes at the local level in
experimental design to reduce risk.
While extensive measures were taken to minimize risk, few measures
were taken to ensure that all the explorers, subjects as well as researchers, were
fully informed and willing members of the expedition. No evidence has yet been
found that the standards for documented consent, articulated by AEC General
Manager Carroll Wilson in 1947, were applied by the AEC Isotopes Distribution
Division. A limited consent requirement was instituted only for the administration
of larger-than-usual doses to very sick patients. Only in the late 1950s did a
consent requirement for normal volunteers appear in the AEC guidelines.
Based on the records examined by the Advisory Committee, the adjunct
r. Kerman to Guttman, 19 May 1995, 3. The booklet, "ORINS Patient Information Booklet"
(circa May 1950). is discussed in chapter 1 . ORINS hospital was known to be dedicated to experimental
work with radiation and radioisotopes. Patients were admitted to the hospital only if they were willing to be
experimental subjects. It is not as clear, however, whether the details of any particular experiment were
always explained adequately to patients.
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system of local radioisotope committees appears to have functioned as planned.
The records of local institutions indicate that they established their own local
radioisotope committees, as required by the AEC, and that these local committees
closely assessed the risks of experiments. At times, this system went beyond
what the AEC had planned. Some local committees had jurisdictions that
extended to all radiation-related work, not merely to radioisotopes supplied by the
AEC. The local committees also provided, probably unintentionally, a ready-
made vehicle for administering greater oversight of consent practices, as concern
developed in the 1960s. Requirements for consent on a federal level changed only
in the late 1960s, as part of a governmentwide concern.
309
ENDNOTES
1. The first complete proposal for radioisotope distribution is contained in a
memo dated 3 January 1946. Radioisotope Committee of Clinton Laboratories (Oak
Ridge, Tennessee) to Colonel S. L. Warren, Medical Director of the Manhattan Project,
3 January 1946 ("Specific Proposals for the National Distribution of Radioisotopes
Produced by the Manhattan Engineer District") (ACHRE No. NARA-082294-A-31).
This memo, in turn, was derived from a more extensive document prepared by Waldo
Cohn, a member of the lab staff. W. E. Cohn, 3 January 1946 ("The National
Distribution of Radioisotopes from the Manhattan Engineer District") (ACHRE No.
DOE-051094-A-317).
2. The press release announcing the program noted that, in addition to technical
qualifications of researchers, "An additional qualification will require all groups using
the isotopes for fundamental research or applied science to publish or otherwise make
available their findings, thereby promoting further applications and scientific advances."
Headquarters, Manhattan District (Oak Ridge, Tennessee), 14 June 1946 ("For Release
in Newspapers Dated June 14, 1946") (ACHRE No. NARA-082294-A-31), 1.
3. "Availability of Radioactive Isotopes: Announcement from Headquarters,
Manhattan Project, Washington, D.C.," Science 103 (14 June 1946): 697-705.
4. Harry H. Davis, New York Times Magazine (typescript), 22 September 1946
("The Atom Goes to Work for Medicine") (ACHRE No. DOE-051094-A-408), 2.
5. Ibid., 6.
6. Cohn, 3 January 1946, 10.
7. Ibid., 14.
8. R. E. Cunningham, 20 February 1971 ("Historical Summary of the
Subcommittee on Human Applications") (ACHRE No. NRC-012695-A), 6.
9. AEC Subcommittee on Human Applications of the Committee on Isotope
Distribution, 13 March 1949 ("Revised Tentative Minutes of March 13, 1949, Meeting
of Subcommittee on Human Application of the Committee on Isotope Distribution of
U.S. Atomic Energy Commission: AEC Building, Washington, D.C.") (ACHRE No.
NARA-082294-A-62), 7.
10. Advisory Subcommittee on Human Applications of the Interim Advisory
Committee on Isotope Distribution Policy, 1 1 July 1946 ("Minutes of Initial Meeting-
Held June 28, 1946; Oak Ridge, Tennessee") (ACHRE No. NARA-082294-A-84), 1.
11. Ibid., 2-8.
12. Ibid., 5.
13. Ibid., 6.
14. Ibid., 10.
15. For example, proposals to study possible therapeutic uses of UX1/ UX2, a
"naturally radioactive pair [that] behaves chemically as UX1, a thorium isotope
(Th 234). . . . Aside from the danger of bone damage, the material would have to be used
with much caution because of likely kidney damage. No advantage could be seen in the
use of radiothorium over the use of certain other beta ray emitting radioisotopes which
deposit in bone." Ibid., 9.
16. Ibid.
17. "In general, there is more of a need for speed in handling requests for human
applications than for others because: (1) therapeutic action may be needed urgently, (2)
310
the case may be an exceptionally good one for some purpose and may only be available
for study immediately (for example, the chance to obtain tracer samples resulting from a
special operation)." Ibid., 10.
18. Isotopes Branch, Research Division, Manhattan District, Oak Ridge,
Tennessee, 3 October 1946 ("Details of Isotope Procurement") (ACHRE No.
NARA-082294-A-31).
19. Isotopes Branch, Research Division, Manhattan District, Oak Ridge,
Tennessee, 3 October 1946 ("Agreement and Conditions for Order and Receipt of
Radioactive Materials") (ACHRE No. NARA-082294-A-31), 2.
20. The statement read:
This is to certify that the undersigned has adequate facilities for the
investigation to be conducted by him as proposed in the 'Interim
Period Request for Radioelement, Form 313,' Serial Number ,
and that such drug will be used solely by him or under his direction
for the investigation, unless and until an application becomes
effective with respect to such drug under section 505 of the Federal
Food, Drug and Cosmetic Act, Isotopes Branch, Research Division,
Manhattan District, Oak Ridge, Tenn.
Isotopes Branch, Research Division, Manhattan District, Oak Ridge, Tennessee, 3
October 1946 ("Certificate . . . EIDM Form 465") (ACHRE No. NARA-082294-A-31),
1.
21. Isotopes Branch, Research Division, Manhattan District ("Report of
Requests Received to July 31,1 946," "2nd Report of Request Received August 1 to 3 1 ,
1946," "3rd Report of Request Received September 1 to 30, 1946," "4th Report of
Requests Received October 1 to 31, 1946") (ACHRE No. NARA-082294-A-31).
22. Franklin asked:
What is the relationship of the Atomic Energy Commission Medical
Division to the Isotopes Branch and the medical and biological aspects
of the isotope distribution program?
(1) Will allocations for human administration be subject to medical
review and what control will be exercised?
(2) What responsibilities does the Atomic Energy Commission bear
for the human administration of isotopes (a) by private physicians and
medical institutions outside of the Project, and (b) by physicians within
the Project? This latter category includes contractor personnel
employing Atomic Energy Commission funds (indirectly) to perform
tracer research, some of which is of no immediate therapeutic value to
the patient. What are the criteria for future human tracer research?
(3) What responsibilities does the Atomic Energy Commission bear
for the safe handling by the recipient of the more hazardous
radioisotopes?
(4) What responsibilities does the Atomic Energy Commission bear
for radioactive waste disposal outside the Project?
J. C. Franklin, Manager, Oak Ridge Operations, to Carroll Wilson, AEC General
Manager, 26 September 1947 ("Medical Policy") (ACHRE No. DOE-1 13094-B-3), 2.
311
23. Research Division, Manhattan District, 3 October 1946 ("Isotope Request,
For Manhattan Project Use Only . . . EIDM Form 558") (ACHRE No. NARA-082294-A-
31), 1.
24. In a 5 October 1949 memorandum to Carroll Tyler, Manager of Los Alamos,
Paul Aebersold, Chief of the Isotopes Division, noted that "Dr. [Shields] Warren
instructed that such allocations would be made by the Isotopes Division only after
review and approval by the Subcommittee on Human Applications of the Commission's
Committee on Isotope Distribution. It should be emphasized that the instruction applies
even though the radiomaterial is produced in the laboratory where it is to be used.
"Since this procedure has not been uniformly followed in the past, we are
writing to acquaint you with the appropriate details." Paul Aebersold, Chief, Isotopes
Division, to Carroll Tyler, Manager, Los Alamos, 5 October 1949 ("Use of Radioisotopes
in Human Subjects") (ACHRE No. DOE-021095-B-4), 1 . An identical memo was also
sent to the manager of the AEC's New York office regarding requirements for
Brookhaven National Laboratory. Paul Aebersold, Chief, Isotopes Division, to W. E.
Kelley, Manager, New York, 5 October 1949 ("Use of Radioisotopes in Human
Subjects") (ACHRE No. DOE-012795B).
25. Presumably codifying existing practice, 10 C.F.R. 30.10 (1951 supplement
to 1949 edition) states:
The regulations in this part do not apply to persons to
the extent that such persons operate Commission-owned
facilities in carrying out programs on behalf of the
Commission. In such cases, the acquisition, transfer,
use, and disposal of radioisotopes are governed by the
contracts between such persons and the Commission,
and internal bulletins, instructions and directives issued
by the Commission.
26. Carroll L. Wilson, AEC General Manager, to Principal Staff, Washington,
and Managers of Operations, 7 June 1950 ("Bulletin GM-161, Procedure for Securing
Isotopic Materials and Irradiation Services") (ACHRE No. NARA-122994-B), 1.
27. Subcommittee on Human Applications, 13 March 1949, 1.
28. Ibid., 3.
29. Ibid. These minutes include a review of the minutes of the 22-23 March
1948, meeting.
30. Ibid., 10-11.
31. Ibid., 10.
32. Ibid., 12-13.
33. Ibid., 4.
34. Ibid.
35. Paul Aebersold, Chief, Isotopes Division, Oak Ridge Operations, to Hymer
Friedell, G. Failla, Joseph G. Hamilton, and A. H. Holland, Jr., 9 March 1948 ("Meeting
of Subcommittee on Human Applications in Washington, March 22 and 23") (ACHRE
No. NARA-082294-A-17), 2.
36. Subcommittee on Human Applications, 13 March 1949, 5-6.
37. Ibid.
38. Clemens Benda, Director of Research and Clinical Psychiatry, to AEC
Subcommittee on Human Applications, 29 September 1953 ("This letter is written in
312
order to elicit your permission to administer a dose of 50 uc Ca45 to a moribund gargoyle
patient now hospitalized in our institution . . ."), 1 . Reproduced at appendix B-27, Task
Force on Human Subject Research, to Philip Campbell, Commissioner, Commonwealth
of Massachusetts Executive Office of Health and Human Services, Department of Mental
Retardation, April 1994 ("A Report on the Use of Radioactive Materials in Human
Subject Research that Involved Residents of State-Operated Facilities within the
Commonwealth of Massachusetts from 1943 to 1973") (ACHRE No. MASS-072194-A).
39. Clemens Benda, Clinical Director, to "Parent," 28 May 1953 ("In previous
years we have done some examinations in connection with the nutritional department of
the Massachusetts Institute of Technology . . ."), 1. Reproduced at appendix B-23, Task
Force on Human Subject Research, to Philip Campbell, April 1994.
40. Task Force on Human Subject Research, to Philip Campbell, April 1994, 16.
41. Subcommittee on Human Applications, 13 March 1949, 8.
42. AEC Isotopes Division, "General Authorizations for Procurement of
Radioisotopes," Isotopics: Announcements of the Isotopes Division 1 (April 1951): 1-3.
43. AEC Isotopes Division. "General Authorizations for Clinical Use of
Radioisotopes," Isotopics: Announcements of the Isotopes Division 2 (April 1952): 1-2.
44. Subcommittee on Human Applications, 13 March 1949, 1 1.
45. Paul C. Aebersold, Chief, AEC Isotopes Division, to William E. Barbour,
Jr., President, Tracerlab, Inc., 1 1 April 1949 ("Violation of 'Acceptance of Terms and
Conditions for Order and Receipt of Byproduct Materials [Radioisotopes]'") (ACHRE
No. NARA-082294-A-4), 1.
46. William Barbour, President, Tracerlab, Inc., to Employees, April 1949
("Violation of AEC Regulations") (ACHRE No. NARA-082294-A-4), 1 . Barbour stated
that a recurrence would
mean cessation of all radiochemical operations of the
Company. In turn this would jeopardize the investments
of several thousand new stockholders who have placed
great faith in the integrity and ability of the management.
A violation of a specific agreement with the AEC would
be a breach of that faith and could only result in the
automatic dismissal of anyone contributing to such a
violation.
47. AEC Isotopes Division, 23 March 1950 ("Meeting of the Advisory
Committee on Isotope Distribution, March 23 and 24, 1950, Washington, D.C.,
Minutes") (ACHRE No. NARA- 1 22994-B- 1 ), 4.
48. AEC Isotopes Division, September 1949 ("Supplement No. 1 to Catalogue
and Price List No. 3") (ACHRE No. DOD-122794-A-1), 1.
49. Paul C. Aebersold, Director, Isotopes Division, to T. H. Johnson, Director,
Division of Research, 2 November 1954 ("Providing Radioisotopes at Reduced Prices
for Medical, Biological, or Other Research Uses") (ACHRE No. TEX-101294-A-4), 1 .
50. 10 C.F.R. 37(1961).
51. A conscious decision was made not to include detailed standards in the
regulations. The discussion is summarized in Advisory Committee on Isotope
Distribution, 23 March 1950, 7-8. The regulations were first promulgated in 10 C.F.R.
30.50(1951 supplement to 1949 edition).
313
52. AEC Isotopes Division, 6 December 1948 ("Isotopes Division Circular D-4:
Radioisotopes for Use in Medicine") (ACHRE No. DOE-101 194-A-5); Isotopes
Division, "Supplement No. 1," September 1949; Isotopes Extension, Division of Civilian
Application, U.S. Atomic Energy Commission, "The Medical Use of Radioisotopes:
Recommendations and Requirements by the Atomic Energy Commission," RC- 1 2
(February 1956).
53. Isotopes Extension, February 1956, 14.
54. Ibid., 15.
55. R. E. Cunningham, "Historical Summary," 5.
56. AEC Division of Materials Licensing, "Non-Routine Medical Uses of
Byproduct Material," A Guide for the Preparation of Applications for the Medical Use of
Radioisotopes (November 1965), 47-48.
57. See, for example, Bryant L. Jones, Division of Oncology and
Radiopharmaceuticals, Bureau of Medicine, Food and Drug Administration, 1 8 May
1967 ("FDA Responsibility in Radiopharmaceutical Research") (ACHRE No. DOE-
051094-A-236).
58. Advisory Subcommittee on Human Applications, 1 1 July 1946, 6.
59. This requirement is stated in Aebersold's memo of 5 October 1949, quoted
earlier in endnote 24, which notified AEC labs that their applications for human use
would now be reviewed by the Subcommittee on Human Applications of the AEC's
Committee on Isotope Distribution. Concerning local isotope committees, the memo
states: "It should be emphasized that each application should be accompanied by a
formal, written endorsement, signed by the Chairman of the local "Isotopes Committee,"
the recommended membership of which is outlined on pages 30 and 31 of the catalog."
Paul Aebersold, Chief, Isotopes Division, to Carroll Tyler, Manager, Los Alamos, 5
October 1949 ("Use of Radioisotopes in Human Subjects") (ACHRE No. DOE-021095-
B-4); Paul Aebersold, Chief, Isotopes Division, to W. E. Kelley, Manager, New York, 5
October 1949 ("Use of Radioisotopes in Human Subjects") (ACHRE No. DOE-0 12795-
B).
60. AEC Isotopes Division, Isotopics 1,1.
61. Isotopes Extension, February 1956, 7. The full description of the functions
of the Medical Isotope Committee is:
1. Formation of a Medical Isotopes Committee. The
Medical Isotope Committee shall include at least three
members. Membership should include physicians expert
in internal medicine (or hematology), pathology, or
therapeutic radiology and a person experienced in assay
of radioisotopes and protection against ionizing
radiations. It is often appropriate that a qualified
physicist be available to the Committee, at least in
consulting capacity. It is recognized that the
composition of local isotope committees may vary from
institution to institution depending upon the individual
interests of a particular medical facility.
2. Duties of the Medical Isotopes Committee
314
Generally, the Committee should have the following
responsibilities:
a. Review and grant permission for, or disapprove, the
use of radioisotopes within the institution from the
standpoint of radiological health safety and other factors
which the Committee may wish to establish for medical
use of these materials.
b. Prescribe special conditions which may be necessary,
such as physical examinations, additional training,
designation of limited area or location of use, disposal
methods, etc.
c. Review records and receive reports from its
radiological safety officer or other individual responsible
for health-safety practices.
d. Recommend remedial action when a person fails to
observe safety recommendations and rules.
e. Keep a record of actions taken by the Committee.
62. The Advisory Committee also reviewed materials from the AEC's Oak
Ridge, Los Alamos, Argonne, and Brookhaven laboratories, the Air Force School of
Aviation Medicine, and the University of California. The development of research at the
University of California at Berkeley and San Francisco is the subject of a case study
appearing in a companion volume to this report.
63. N. W. Faxon, Director, Massachusetts General Hospital, to Drs. Aub,
Moore, Shulz, and Rawson, 3 May 1946 ("At the meeting of the General Executive
Committee held on May 1, 1946, consideration of the use of radioactive isotopes was
discussed . . .") (ACHRE No. H AR- 100394- A- 1), 1.
64. "It should be emphasized that the University Radiation Policy Committee
was established to deal with all types of radiation problems at the University and was not
limited to the scope of 'radioisotope committees' suggested by the AEC for radioisotope
procurement. In fact this Committee predated the earliest suggestions of the AEC by
almost a year." W. W. Meinke, Chairman, University of Michigan Radiation Policy
Committee, to I. Lampe, 27 February 1956 ("On October 13, 1950, the President of the
University of Michigan established the Radiation Policy Committee . . .") (ACHRE No.
MIC-010495-A-2), 1.
65. Consisting of Hugh Morgan (Vanderbilt University), Stafford Warren
(University of California at Los Angeles), Hymer Friedell (Case Western Reserve
University ), Shields Warren (AEC Division of Biology and Medicine), and Perrin Long
(Johns Hopkins University).
66. There was some debate at the beginning as to the name of the units. With
"radioactive" still a charged word for much of the population, an early memo suggested
that "it could to advantage be called a Metabolism Ward." Veterans Administration, 15
September 1948 ("Minutes of the Meeting, Central Advisory Committee on
Radioisotopes, U.S. Veterans Administration") (ACHRE No. UCLA- 100794- A), 23.
67. The chairman listed the already-achieved benefits to thyroid gland research
and blood volume diagnosis, and claimed, "It is not an overstatement to say that progress
can be expected to be rapid and on a wide front as greater use is made in medical and
biological research when this new tool is applied in attempts to solve such problems."
315
Ibid., 3.
68. Framingham, Massachusetts; Bronx, New York; Cleveland, Ohio; Hines,
Illinois; Minneapolis, Minnesota; Van Nuys, California; Los Angeles, California; and
Dallas, Texas.
69. Joseph C. Aub et. a!., to the Executive Committee, Massachusetts General
Hospital, 17 June 1946 ("The Radioactive Isotope Committee had its first meeting on
June 15th . . .") (ACHRE No. HAR-100394-A-2), 1-2.
70. William Sweet, interviewed by Gilbert Whittemore (ACHRE), transcript of
audio recording, 8 April 1995 (ACHRE Research Project Series, Interview Program File,
Targeted Interview Project), 20.
7 1 . VA Central Advisory Committee on Radioisotopes, 1 5 September 1 948, 26.
72. Ibid.
73. University of Michigan Subcommittee on Human Use of Isotopes, 10
December 1956 ("Minutes, Meeting of the Subcommittee on Human Use of Isotopes")
(ACHRE No. MIC-010495-A-3), 1.
74. William H. Beierwaltes to Edward A. Carr, Chairman, University of
Michigan Subcommittee on Human Use of Radioisotopes, 20 May 1968 ("Enclosed are
our calculations to date on our first two patients studied in the Clinical Research Unit . .
.") (ACHRE No. MIC-010495-A-6), 3. The form includes space for a signature by a
witness as well as the patient.
75. In an effort to develop an overall assessment of the possible harm from
radioisotope experiments conducted in the past, the Advisory Committee extracted dose
data from our Experiment Database, whenever available, in order to perform risk
analyses using contemporary standards. Unfortunately, most of the data recovered by the
Committee was fragmentary and did not provide a sufficient basis for an analysis of
possible harm in most cases.
76. Massachusetts General Hospital Radioactive Isotope Committee, 15 March
1955 ("Meeting of the Massachusetts General Hospital Radioactive Isotope Committee")
(ACHRE No. HAR-100394-A-4), 1.
77. Ibid.
78. One proposal, for example, involved saturating gelfoam with silver 1 1 1 or
yttrium 90, and then implanting the gelfoam into the tumor. Preliminary work had been
done on animals in the previous year on normal brain tissue. After extensive animal
testing, the procedure was to be attempted on those humans who already suffered brain
cancer and had undergone surgery. Theodore Rasmussen, 29 May 1952 ("Local
Application of Beta Ray Isotopes to Brain Tumors") (ACHRE No. DOE-122194-A).
79. For example, in 1 953 the Chicago committee approved a proposal to use
tritium and C-14-labeled acetate to trace the development of adrenal cholesterol in
advanced cancer patients as well as a control group. The committee noted that the doses
"are smaller than have been used in human studies at other institutions and in no case
involve amounts which will produce internal radiation in excess of maximum permissible
dose." George V. LeRoy, Chairman, Radioisotope Committee, 24 February 1953
("Minutes of the Radioisotope Committee Meeting") (ACHRE No. DOE- 122 1 94- A), 1.
80. This included recommendations for using the minimum amounts of isotopes
possible, a limitation of 1 rep [roentgen equivalent physical] for tracers, mandatory blood
tests before administration and forty-eight hours after, and a listing of dose
recommendations. The policy on patients and children was specific: "Adult humans who
are ill and who are expected to receive benefit from the procedure, shall not receive tracer
316
doses of radioactive material giving off radiation in excess of a total of 4 rep. Children
(all patients below 15 years of age) shall not receive more than a total of 0.8 rep." J. C.
Aub, A. K. Solomon, and Shields Warren, Harvard Medical School, 7 May 1949 ("Tracer
Doses of Radioactive Isotopes in Man") (ACHRE No. HAR-100394-A-3), 1.
81 . The committee stated that all volunteers receiving Na-22 and K-42 should
be subjected to doses no more than 100 millirads for the whole body, nor more than one-
third the maximum permissible values to a specific organ. University of Michigan
Subcommittee on Human Use of Isotopes, 10 December 1956, 1.
82. W. F. to University of Chicago Radioisotope Committee, 28 September
1953 ("Permission is requested to administer intravenously 500 microcuries, or less, of
radio-mercury to a patient . . .") (ACHRE No. DOE-122194-A-2), 1 .
83. Harvard Medical School Committee on Medical Research in Biophysics,
August 1957 ("Tracer Doses of Radioactive Isotopes in Man") (ACHRE No. HAR-
100394-A-5), 2.
84. University of Michigan Subcommittee on Human Use of Isotopes, 27
September 1955 ("Minutes of Human Use Committee Meeting") (ACHRE No. MIC-
010495-A), 2.
85. A 1963 memorandum indicates the committee's unwillingness to allow a
procedure involving selenium 75-labeled methionine for parathyroid scanning limited to
use in patients over forty years old, while in a 1 966 letter Carr stated that he was
"strongly inclined to refuse to permit the use of radioisotopes in all volunteers below the
age of 21, unless there are special mitigating circumstances approved by the whole
subcommittee." Ronald C. Bishop, Acting Chairman, Subcommittee on Human Use, 13
August 1963 ("Dr. E. A. Carr has asked me to act as chairman of the Subcommittee on
Human Use in his absence . . .") (ACHRE No. MIC-010495-A-4), 1; Edward A. Carr to
Dr. Bishop, 3 September 1966 ("To Members of the Subcommittee on Human Use of
Radioisotopes") (ACHRE No. MIC-010495-A-5), 1.
86. In 1 968 the committee approved a proposal for an experiment that involved
doses of NM-125 labeled with 1-131 or 1-125 for patients with melanomas or a reasonable
clinical suspicion of melanoma for thirty patients, and then wished to see results before
approving of further administration. Likewise, the committee gave approval to a closely
related experiment involving use of the same substances in patients with lung cancer. For
that regime, the committee demanded feedback after fifteen patients. For a further
related matter involving the same substances in patients with pulmonary carcinoma, the
committee limited the work to five patients. In each case the dose was to exceed 2
millicuries per patient. Edward A. Carr, Chairman, Subcommittee on Human Use, to
William H. Beierwaltes, Director, Nuclear Medicine, 27 September 1968 ("This is to
inform you that the Sub-committee on Human Use of Radioisotopes, at its meeting of
September 26, 1968, approved the use of a single dose of NM-1 13 . . .") (ACHRE No.
M1C-010495-A-6), 1.
87. A researcher had applied to use sodium 22 in a tracer procedure with several
patients. The committee was concerned that "a small but significant fraction of one of
the radioisotopes might remain localized in the body for a long period of time . . ."
Edward A. Carr, 3 June 1968 ("Sub-committee on Human Use of Radioisotopes, Minutes
of the Meeting of June 3, 1968") (ACHRE No. MIC-010495-A-7), 1 .
88. George V. LeRoy, 3 November 1953 ("Minutes of the Radioisotope
Committee Meeting") (ACHRE No. DOE-122194-A-3), 1.
317
89. Paul C. Aebersold, Chief, Isotopes Division, to John Z. Bowers, Assistant to
Director, Division of Biology and Medicine, 18 March 1948 ("Investigation of Patients
Who Have Received Radioactive Isotopes") (ACHRE No. DOE-061395-E-1), 1.
90. A comprehensive history of the application of radioisotopes is well beyond
the scope of this chapter and would needlessly duplicate substantial histories already
written. See, for example, J. Newell Stannard, Radioactivity and Health: A History
(Springfield, Va.: Office of Scientific and Technical Information, 1988).
91. An example is Konstantin N. Pavlou, William P. Steffee, Robert H. Lerman,
and Belton A. Burrows, "Effects of Dieting and Exercise on Lean Body Mass, Oxygen
Uptake, and Strength," Medicine and Science in Sports and Exercise 17(1 985): 466-47 1 .
The study was conducted at the Boston University Medical School and the Boston VA
Medical Center.
92. There is a vast literature on radioiodine and the thyroid. Government studies
specifically noted by the Veterans Administration as significant are the following: H. C.
Allen, R. A. Libby, and B. Cassen, "The Scintillation Counter in Clinical Studies of
Human Thyroid Physiology Using 1-131," Journal of Clinical Endocrinology and
Metabolism 1 1 (1951): 492-51 1; B. A. Burrows and J. A. Ross, "The Thyroid Uptake of
Stable Iodine Compared with the Serum Concentration of Protein-Bound Iodine in
Normal Patients and in Patients with Thyroid Disease," Journal of Clinical
Endocrinology and Metabolism 13 (1953): 1358-1368; S. A. Berson and R. S. Yalow,
"Quantitative Aspects of Iodine Metabolism: The Exchangeable Organic Iodine Pool,
and the Rates of Thyroidal Secretion, Peripheral Degradation and Fecal Excretion of
Endogenously Synthesized Organically Bound Iodine," Journal of Clinical Investigation
33 (1954): 1533-1552; M. A. Greer and L. J. DeGroot, "The Effect of Stable Iodide on
Thyroidal Secretion in Man," Metabolism 5 (1956): 682-696; K. Sterling, J. C. Lashof,
and E. B. Man, "Disappearance from Serum of 1-131 Labeled I-Thyroxine and 1-
Triiodothyronine in Euthyroid Subjects," Journal of Clinical Investigation 33 (1954):
1031; K. Sterling and R. B. Chodos, "Radiothyroxine Turnover Studies in Myxosema,
Thyrotoxicosis, and Hypermetabolism Without Endocrine Disease," Journal of Clinical
Investigation 35 (1956): 806-813.
93. See, for example, J. F. Ross, "Cooperative Study of Radioiodine Therapy for
Hyperthyroidism," Bulletin of the Committee on Veterans Medical Problems (National
Academy of Sciences) (1952): 576-578.
94. Gould A. Andrews, M.D., Samuel W. Root, M.D., and Herbert D. Kerman,
M.D., "Clinical Studies with Gallium-72," 570-588 in Marshall Brucer, M.D. (ed.),
Gould Andrews, M.D., and H.D. Bruner, M.D., "Clinical Studies with Gallium-72,"
Radiology 66 (1953): 534-613.
95. OncoScint, developed by Cytogen, was approved by the FDA for diagnosis
of colorectal and ovarian cancers on 29 December 1992, Product License Application no.
89-0601, with Amendment no. 90-0278. The use of monoclonal antibodies to treat cancer
is discussed in Oliver W. Press, M.D., Ph.D., et al., "Radiolabeled-Antibody Therapy of
B-Cell Lymphoma with Autologous Bone Marrow Support," New England Journal of
Medicine 329 (21 October 1993): 1219-1224. Progress in the field is reviewed in an
accompanying editorial, Robert C. Bast, Jr., M.D., "Progress in Radioimmunotherapy,"
New England Journal of Medicine 329(21 October 1993): 1266-1268.
96. Strontium 89, commercially available as Metastron from Amersham-
Mediphysics, was approved on 18 June 1993, New Drug Application no. 20134. One of
its therapeutic uses is described in an article by Arthur T. Porter. M.D., and Lawrence P.
318
Davis, M.D., "Systemic Radionuclide Therapy of Bone Metastases with Strontium-89,"
Oncology 8 (February 1994): 93-96.
97. R. S. Yalow and S. A. Berson, "Assay of Plasma Insulin in Human Subjects
by Immunological Methods," Nature 184 (1959): 1648.
319
nontherapeutic research on
Children
In the late 1940s and again in the early 1950s, Massachusetts Institute of
Technology scientists conducting research fed breakfast food containing minute
amounts of radioactive iron and calcium to a number of students at the Walter E.
Fernald School, a Massachusetts institution for "mentally retarded" children. 1
The National Institutes of Health, the Atomic Energy Commission, and the
Quaker Oats Company funded the research, which was designed to determine
how the body absorbed iron, calcium, and other minerals from dietary sources and
to explore the effect of various compounds in cereal on mineral absorption.
In 1961, researchers from Harvard Medical School, Massachusetts
General Hospital, and Boston University School of Medicine administered small
amounts of radioactive iodine to seventy children at the Wrentham State School,
another Massachusetts facility for mentally retarded children. With funding from
the Division of Radiologic Health of the U.S. Public Health Service, the scientists
conducting this experiment used Wrentham students to test a proposed
countermeasure to nuclear fallout. Specifically, the study was meant to determine
the amount of nonradioactive iodine that would effectively block the uptake of
radioactive iodine that would be released in a nuclear explosion.
Recently, these two studies have received considerable media attention,
and an official Massachusetts state task force has reported on both episodes in
some detail. 2 Although they represent special cases because they involve
institutionalized children, the Fernald and Wrentham experiments nonetheless are
the most widely known examples of a category of research that raises particular
concerns for the Committee: nontherapeutic experimentation on children.
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Chapter 7
Experiments involving children are important to the Committee for two
reasons. First, children are more susceptible than adults to harm from low levels
of radiation, and thus as a group they are more likely than adults to have been
harmed as a consequence of their having been subjects of human radiation
experiments. Second, an evaluation of research with children is critical to
determining whether any former subjects of radiation experiments should be
notified in order to protect their health, one of our specific charges. 3 Subjects
who were children at the time of their exposure are more likely than adults to be
candidates for such notification, both because of their increased biological
sensitivity and because they are more likely to still be alive. (See chapter 18 for
the Committee's recommendations with respect to notification and follow-up.)
We elected to focus on pediatric research that offered subjects no prospect
of medical benefit, so-called nontherapeutic research, because it is this kind of
research that has generated the most public concern and is the most ethically
problematic. This is not to say, however, that experiments on children in which
the children stand to benefit medically never raise ethical issues; such research
certainly can and does. But in deciding how to allocate our limited resources, we
chose to concentrate where the issues are mostly sharply drawn. Also, because
most nontherapeutic research with children involved tracer doses of radioisotopes,
focusing on this work allowed us a window into radioisotope research generally.
We begin the chapter by setting the context for nontherapeutic radiation
experiments on children. We review those factors that make nontherapeutic
research on children ethically problematic and how such research has been
viewed historically. We next consider what the practices and standards were for
research on children in the 1940s, 1950s, and 1960s. This is a continuation of the
discussion in chapter 2, which focused on professional standards and practices for
human research.
The next three sections address human radiation experiments in terms of
the central ethical issues raised by nontherapeutic research involving children-
level of risk, authorization for the involvement of children, and selection of
subjects. To address the question of risk, we analyzed twenty-one nontherapeutic
radiation experiments with children conducted during the 1944-1974 period. The
focus of this analysis is whether it is likely that any of the subjects of these
experiments was harmed or remains at risk of harm attributable to research
exposures. A table summarizing these experiments and our risk estimates can be
found at the end of this chapter. The twenty-one experiments were selected from
eighty-one pediatric radiation research projects identified by the Committee from
government documents and the medical literature. Although these eighty-one by
no means constitute all the pediatric radiation research conducted during this
time, they include what are likely fairly typical examples of such research. Of the
eighty-one, thirty-seven studies were judged to be nontherapeutic, and twenty-one
of these were conducted or funded by the federal government and thus fell under
the charge of the Committee. Included within these twenty-one studies were the
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Part II
two nutrition experiments conducted at the Fernald School and one fallout-related
study conducted at the Wrentham School discussed in the introduction to this
chapter. All twenty-one studies employed radioisotopes to explore human
physiology and pathology.
We turn next to a consideration of how authorization for the inclusion of
the children in these experiments was obtained and who these children were.
Unfortunately, for most of these experiments, little is known about either of these
issues. The last section of the chapter focuses specifically on the experiments at
the Fernald School where, thanks to the work of the Massachusetts Task Force on
Human Subject Research, relevant information is available. Throughout the
chapter, we focus only on research in which children could not have benefited
medically. The Committee did not have the resources to pursue two related areas
of research—nontherapeutic research on pregnant women and therapeutic research
on children. We include two capsule descriptions of examples of these types of
research at the end of this chapter.
THE CONTEXT FOR NONTHERAPEUTIC RESEARCH WITH
CHILDREN
Children as Mere Means
In both law and medical ethics, it has long been recognized that children
may not authorize medical treatment for themselves, except in special
circumstances. 4 Instead, authorization must be sought from the parent.
Historically, the source of this respect for parental authority rested upon the view
that children were the property of their parents, and thus parents had the right to
determine how their "property" Was to be treated. Today, we still speak of
parental rights, although the justification for these rights no longer rests on an
analysis of children as property. Instead, respect for the rights of parents is
viewed as a mechanism for valuing and fostering the institution of the family and
the freedom of adults to perpetuate family traditions and commitments. Another
important line of justification for respecting the authority of parents relies not on
a recognition of parental rights but on the view that the interests of the child are
generally best served by ceding decisional authority to the parent. The parent is
thought not only to be in the best position to determine what is in the interests of
the child but is also thought to be generally motivated to act in the child's best
interests. 5
When research involving children offers a prospect of medical benefit to
the child-subject, the application of the above analysis is straightforward. Parents
are generally thought to have the authority to determine whether their children
should be made subjects of such research. Certainly today, any use of a child in
research would not be ethically acceptable or legally permissible without the
parent's permission/' Where the research does not offer any prospect of benefit to
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Chapter 7
the child, however, the legitimacy of the parent as authorizer is less clear.
Respect for the authority of parents to make decisions for their children
and otherwise control their children's lives is not without bounds. The law
recognizes several exceptions, designed primarily to protect the child from what
society at large considers to be unacceptable or unjustifiable harm or risk of
harm. 7 Laws against the physical abuse of children are perhaps the most obvious
example of such limitations on parental authority. In the context of research, the
question arises of whether a parent has the authority to permit a child to be put at
risk of harm in an experiment from which the child could not possibly benefit
medically. In this case, the child is to be used as a means to the ends of others.
Children are not in a position to determine for themselves whether they wish to
agree to such a use and thus cannot themselves render the use morally acceptable.
Should parents have such authority? Should anyone?
This question was resolved as a matter of public policy in the 1970s
through the work of the National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research and the subsequent adoption, in
1983, of federal regulations governing research involving children that were
guided by the recommendations of the National Commission. 8 These regulations
state that children can participate in federally funded research that poses greater
than minimal risks to the subject if a local review committee (an institutional
review board, or IRB) finds that the potential risk is "justified by the anticipated
benefit to the subjects"; "the relation of the anticipated benefit to the risk is at
least as favorable to the subjects as that presented by available alternative
approaches"; and "adequate provisions are made for soliciting the assent of the
children and permission of their parents or guardians." 9 The word consent is
purposely avoided in these regulations to distinguish parental permission and
minor assent from the autonomous, legally valid consent of a competent adult.
Federal regulations do allow nontherapeutic research on children if an IRB
determines that the research presents "no greater than minimal risk" to the
children who would serve as subjects, although no clear definition of what
constitutes minimal risk is provided. 10 As with therapeutic pediatric research,
parents or guardians must grant "permission" and children who are deemed
capable must offer "assent."
The regulations also allow for nontherapeutic research with children that
does present more than minimal risk, again with parental permission and assent of
the child (as appropriate), but only if 'the risk represents a minor increase over
minimal risk, the procedures involved are commensurate with the general life
experiences of subjects, and the research is likely to yield knowledge of "vital
importance" about the subjects' disorder or condition." Research with children
that is not otherwise approvable may be permitted, but only under special, and
presumably rare, circumstances. In addition to local IRB review, such research
must withstand the special scrutiny of the secretary of the agency sponsoring the
research, who is to be advised by a special IRB. 12 The secretary must also allow
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Part II
the opportunity for "public review and comment" on a proposed nontherapeutic
research project that is not otherwise approvable.
The regulations thus draw a sharp distinction between therapeutic and
nontherapeutic research. Nontherapeutic research, while severely restricted, is
not banned. The decision to permit parents to authorize the use of their children in
nontherapeutic research reflects both the recognition that some important
advances in pediatrics could come only from research with children that was of no
benefit to them and the recognition that we all—as parents, as potential future
parents, and as members of society— share in the interest of advancing the health
of the young. At the same time, however, parental authority to permit such use of
a child is generally restricted to research judged to pose little risk; as important as
it is to promote the welfare of children (as a class), this interest justifies only
minor infringements of the principle not to use people as mere means to the ends
of others.
These 1983 regulations, and the reasoning behind them, were the
culmination of considerable public debate and scholarly analysis, much of which
occurred in the 1970s. To situate properly the experiments of interest to the
Committee, it is necessary to examine the social and professional roots of the
issues and arguments that ultimately led to the federal regulations.
Public Attitudes, Professional Practices
Attitudes and Practices Prior to 1944
There was significant research interest in infants and children as early as
the eighteenth century, as scientists began to experiment with vaccines and
immunization. Children were particularly valuable subjects for this type of
research because in general, they were less likely than adults to have been
exposed to the disease being studied. 13 A child's response to immunizations was
also of great interest because most immunizations are performed during
childhood.
During the nineteenth century, the Industrial Revolution greatly increased
the number of child laborers, and the public began to acknowledge the need for
laws to protect children from abuse. 14 Physicians started to specialize in
pediatrics, studying specifically the health problems and diseases that afflicted
children. Simultaneously, as social reformers were creating a wide range of
institutions for children, such as orphanages, schools, foundling homes, and
hospitals, scientists recognized the value of research conducted in these types of
institutions. In the late nineteenth and early twentieth centuries, Alfred F. Hess,
the medical director of the Hebrew Infant Asylum in New York City, conducted
pertussis vaccine trials and undertook extensive studies of the anatomy and
physiology of digestion in infants at the asylum. According to Advisory
Committee member and historian Susan Lederer, Hess sought to take advantage
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Chapter 7
of the conditions in the asylum as they approximated those "conditions which are
insisted on in considering the course of experimental infection among laboratory
animals, but which can rarely be controlled in a study of infestation in man." 15
Although many shared Hess's laudable goal of improving the health of
asylum children, many people drew the line at the pediatrician's investigations of
scurvy and rickets. In order to study the disease, Hess and his colleagues
withheld orange juice from infants at the asylum until they developed lesions
characteristic of scurvy. Responding to the public discussion of the ethics of
using children in such nontherapeutic experiments, the editors of one American
medical journal insisted that such investigations gave the children an opportunity
to repay their debt to society, even as they conceded that experimentation on
human beings should be limited to "children as may be utilized with parental
consent." 16
Hess's work was not the only case in which experiments involving
children attracted negative public opinion. In 1896, for example, American
antivivisectionists attacked a Boston pediatrician, Arthur Wentworth, who
performed lumbar punctures on infants and children in order to establish the
safety and utility of the procedure. The antivivisectionists were particularly
alarmed because this procedure, which caused pain and discomfort, did not confer
any benefits to the subjects. John B. Roberts, a physician from Philadelphia,
labeled Wentworth's procedures "human vivisection," saying that "using the
children in the hospital without explaining his plan to their mothers or gaining
their permission intensified public fear of hospitals." 17
The twentieth century brought new drugs and advanced technologies,
which allowed for increased research on children. The conduct of this
experimentation, however, was largely left to the individual investigator. When
his experimental gelatin injections provoked "alarming symptoms of prostration
and collapse in three normal children (including a 'feeble-minded' four-year-old
girl), the physician Isaac Abt stopped his pediatric experiments and began
experimenting on rabbits." 18 Meanwhile, legislation was being proposed
throughout the country to protect children and pregnant women from
experimenting physicians. Two proposals were introduced in the U.S. Senate in
1900 and 1902; proposals '"to prohibit such terrible experiments on children,
insane persons and pregnant women . . . ,' and to ensure 'that no experiment
should be performed on any other human being without his intelligent written
consent' were introduced in the Illinois legislature" in 1905 and 1907; in 1914 and
1923, the New York legislature considered bills that prohibited exoerimentation
with children. 19 Although these bills did not become law, it is clear that some
unease concerning nontherapeutic research on children existed among the public
and elected officials.
Reaction to the polio vaccine trials conducted during the 1930s further
demonstrated the growing discomfort over pediatric experimentation as thousands
of American children were involved in what some considered at the time to be
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Part II
premature human trials of the polio vaccine. Although it appears that parental
consent was obtained for a number of these studies, the controversy over these
trials stalled polio vaccine research for almost two decades and generally made
investigators ambivalent about the use of human subjects. 20
Although there are no legal cases that bear directly on nontherapeutic
research with children during this period, an appellate court ruling in 1941,
Bonner v. Moran, involving the performance of a nontherapeutic medical
procedure on a child without parental consent, suggests how such a case might
have been decided. 21 John Bonner, a fifteen-year-old African-American boy from
Washington, D.C., had undergone an experimental skin graft for the benefit of
Clara Howard, a cousin suffering from severe burns. When he discovered that
John Bonner had the same blood type as the burn victim, Howard's plastic
surgeon, Robert Moran, persuaded Bonner to allow him to fashion "a tube of
flesh" by cutting from the boy's "arm pit to his waist line." 22 This procedure,
however, was conducted without the consent of a parent, as "his mother, with
whom he lived, was ill at the time and knew nothing about the arrangement." 23
Moran then attached the free end of Bonner's flesh tube to Clara Howard, hoping
that the flesh-and-blood link would bring benefit to the burned girl. Due to poor
circulation in the tube, the procedure did not help the burn patient and put the
healthy boy, who was required to stay in the hospital for two months, at
significant risk (and left him with permanent scars). Bonner's mother brought suit
against Moran for assault and battery.
The appellate court based its ruling against Moran on what it perceived as
a disturbing combination of a lack of direct benefit for John Bonner and a lack of
permission from the boy's mother:
[H]ere we have a case of a surgical operation not
for the benefit of the person operated on but for
another. . . . We are constrained, therefore, to feel
. . . that the consent of the parent was necessary. 24
The court did not refer to the episode as an instance of experimentation, but the
parallels between this novel procedure performed for the benefit of another and a
nontherapeutic medical experiment are quite powerful. 25
Attitudes and Practices 1944-1974
As best the Committee can establish, there were no written rules of
professional ethics for the conduct of research on children prior to 1964. Taken
literally, the Nuremberg Code, which requires that all subjects of research "have
legal capacity to give consent," precludes all research with children. 26 There is no
reason to believe, however, that the judges at Nuremberg meant to impose such a
prohibition, and the Nuremberg Code did not result in a ban on research with
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Chapter 7
children.
Pediatric research flourished after World War II, as did biomedical
research in general. What is less clear is how this research was conducted, and on
whom. One source of evidence about legal thinking on pediatric research, if not
actual practice, is the writings of Irving Ladimer, a lawyer who, in 1958, was
completing a doctoral degree in juridical science at the same time he was
employed as an administrator at the National Institutes of Health. Ladimer
concluded his doctoral dissertation, "Legal and Ethical Implications of Medical
Research on Human Beings," with an appendix devoted to the issues surrounding
"Experimentation on Persons Not Competent to Provide Personal Consent,"
whom he defined broadly as minors and mental incompetents. 27 Ladimer argued
that it was "permissible to employ minors and incompetents as subjects of
medical investigations . . . where there is informed consent by a parent or
guardian (including the state) for procedures which also significantly benefit or
may be expected to benefit the individual. " 2X Ladimer was less sanguine,
however, about nontherapeutic research with these populations. He expressed
particular concern about the use of institutionalized children— even with proxy
permission—in research that did not hold the possibility of personal benefit:
"Permission given by parents or the state to utilize institutionalized children,
without any suggestion of benefit to the children, may well be beyond the ambit
of parental or guardianship rights." 29
Ladimer did, however, leave open a window for the use of legally
incompetent subjects in nontherapeutic research, but he clearly harbored great
discomfort with his own suggestion:
[T]he availability of certain persons, not able to
consent personally, may constitute a strategic
resource in terms of time or location not otherwise
obtainable. It must be remembered, however, that
the Nazis hid behind this rationalization in
explaining certain highly questionable or
clandestine medical experiments. Such justification
should not even be considered except in dire
circumstances. If ever employed, it should not be
assimilated into the concept of personal benefit, else
there may be no legal or ethical control for the
protection of both prospective subject and
investigator and their individual integrity. 30
As part of the Committee's Ethics Oral History Project, we interviewed
two pediatricians who were beginning their careers in academic medicine in the
late 1940s. One of these respondents, Dr. Henry Seidel, had some research
experience with institutionalized children. He noted that "we got access [to the
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Part II
children] very easily," and although his research was merely observational, it was
"not hard to imagine" that experimental research with these children could have
been conducted. 31 When asked about the studies conducted by Dr. Saul Krugman
on institutionalized children at the Willowbrook State School (discussed later in
this chapter), Seidel observed, "I didn't have any problem imagining that
possibility. In retrospect, I'm sure it could happen, you know. There was
something about those reports that rang true. . . ." 32 William Silverman, the other
pediatrician interviewed, had clear recollections of how research was conducted
in pediatrics at that time. He recalled that, in the 1950s, many pediatricians,
including himself, believed that it was not necessary to obtain the permission of
parents before using a pediatric patient as a subject in research-even if the
research was nontherapeutic (he has since become a strong proponent of the
parental permission requirement in pediatric research). 33 He also asserted that
performing nontherapeutic experiments on children without authorization from
parents was part of a broader "ethos of the time" in which "everyone was a
draftee" in a national war on disease. 34 Dr. Silverman's account squares with the
picture that emerged in chapter 2 of practices in research with adults, in which it
was not uncommon to use adult patients as subjects of research without their
knowledge or consent.
Silverman was among the researchers invited by Boston University's Law-
Medicine Research Institute (LMRI) to participate in a conference on "Social
Responsibility in Pediatric Research" held in May 1961. 35 This meeting was one
in a series of closed-door conferences organized by LMRI to investigate actual
practices among clinical researchers. The transcripts of the conference provide an
important window onto practices and attitudes of the time; in large measure, they
confirm Silverman's recollection of his own position some thirty-five years ago.
Early in the meeting, Silverman asserted that "there is an unwritten consent by
being a living person at this time to participate in this kind of advancement of
knowledge [that is, nontherapeutic pediatric research]." 3 ' 1 Some of the other
participants employed the same analogy to the military draft that Silverman
recently used to relate his recollections.
However, there was by no means unanimity about the appropriateness of
this view:
Dr. A: [Dr. B] says that this [research without
consent] is like military conscription.
Dr. C: Not comparable. We voted to do military
conscription. 37
The proceedings of the conference suggest that while it may not have been
uncommon for pediatric patients to be used as subjects of nontherapeutic research
without the permission of their parents, at least some physician-investigators,
including investigators who followed this practice, thought it was morally wrong
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Chapter 7
to do so. Consider, for example, a story relayed by one pediatrician-investigator
at the conference who seemed to embrace with particular earnestness the desire of
the conference organizers to learn the unvarnished reality of clinical research. In
the opening minutes of the meeting, this researcher reminded his colleagues that
"the question for us to discuss here today is how we operate on a daily basis." 38
He offered for discussion a provocative case from his personal experience in
which he and his associates "wanted [to do] lumbar punctures on newborns. " 39
He explicitly noted that "this study [was] not of benefit to the individual; it was an
attempt to learn about normal physiology." 40 One of the other conferees asked,
"Did you ask [parental] permission?" The researcher responded, "No. We were
afraid we would not get volunteers." 41 The case prompted a great deal of
discussion at the conference, but perhaps most tellingly this researcher frankly
acknowledged toward the end of the discussion— in a meeting that had begun with
an assurance of confidentiality from the organizers—that he had "sinned" in
carrying out these lumbar punctures in "normal infants" without parental
permission. 42
The proceedings of the conference also suggest that at least some
pediatrician investigators routinely obtained the permission of parents before
embarking on research with their children. It is perhaps significant that the
pediatric researcher who articulated this position at the conference was from
Canada— and the conference transcript seems to suggest that he was providing a
general characterization of practices in his country:
Dr. A: Let's ask [Dr. B] from Canada.
Dr. B: We have been quite sticky on consent. If we
want a biopsy or a radioactive exposure and the
parent says "no" then we don't do it. . . . The
question of morals is too valuable. 43
If this statement represents the sensitivity of Canadian pediatrician-investigators
to issues of parental permission (which this single quotation does not prove),
there is no obvious explanation as to why many of their colleagues in the United
States behaved differently.
The LMRI conference is noteworthy not only for what it reveals about the
range of views and practices concerning parental permission for nontherapeutic
research, but also for the unanimity expressed about the importance of obligations
to prevent or minimize harm to pediatric subjects of research. Minimizing risk
was recognized by those at the conference as the most important (and, for some
participants, the only) moral duty of pediatric investigators. 44
Three years after the LMRI conference, in the summer of 1964, the World
Medical Association ratified a code of ethics for human experimentation at a
meeting in Helsinki. Unlike the Nuremberg Code, this statement, known as the
Declaration of Helsinki, recognizes that research may be conducted on people
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Part II
with "legal incapacity to consent." 45 The Declaration distinguishes between two
kinds of research: "Clinical Research Combined with Professional Care" and
"Non-therapeutic Clinical Research." 46 It permits the use of people with legal
incapacity to consent as subjects in both kinds of research, provided that the
consent of the subject's legal guardian is procured.
Subjects of the first kind of research are referred to as patients; disclosure
to and consent from patient-subjects are required by the Declaration, "consistent
with patient psychology." 47 The Declaration does not specify whether
considerations of "patient psychology" also could justify not obtaining the
consent of the guardian where the subject does not have the legal capacity to
consent.
The subjects of "non-therapeutic clinical research" are not referred to as
patients but as human beings who must be "fully informed" and whose "free
consent" must be obtained. 48 The Declaration also requires that nontherapeutic
research be discontinued if in the judgment of the investigators to proceed would
"be harmful to the individual." 49 Thus, although the Declaration permits parents
to authorize the use of their children as subjects in nontherapeutic research, such
research is not intended to be "harmful" to the subjects.
The language and reasoning of the Declaration was unclear and confusing
with regard to clinical research, both therapeutic and nontherapeutic, on legally
incapacitated individuals. It was revised in 1 975, at a time when the ethics of
research with human subjects was receiving considerable public attention in the
United States (see chapter 3).
Both in the 1960s and early 1970s, public controversies erupted about
several cases of research involving human subjects, controversies that led to the
establishment of the National Commission and publication of the federal
regulations (see chapter 3). One of the most well known of these cases involved
research on institutionalized children. During the 1950s and 1960s, Dr. Saul
Krugman of New York University conducted studies of hepatitis at the
Willowbrook State School, an institution for the severely mentally retarded. 50 To
study the natural history, effects, and progression of the disease, Krugman and his
staff systematically infected newly arrived children with strains of the virus.
Although the investigators did obtain the permission of the parents to involve
their children in the research, critics of the Willowbrook experiments maintained
that the parents were manipulated into consenting because, at least in the later
years of the research, the institution was overcrowded and the long waits for
admittance were allegedly shorter for children who were entering the research
unit. Henry Beecher, a Harvard anesthesiologist whose impact on the history of
research ethics is detailed in chapter 3, condemned Krugman and his staff for not
properly informing the parents about the risks involved in the experiment. 51
Beecher also challenged the legal status of parental consent when no therapeutic
benefit for the child was anticipated. A New York state senator, Seymour R.
Thaler, criticized the Willowbrook research on the pages of the New York Times
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Chapter 7
in 1967, only to come to its defense later in 1971. Also in the early 1970s
Willowbrook became the subject of a heated debate in the medical literature. 52
Interestingly, Dr. Krugman was one of the participants at the LMRI
"Social Responsibility in Pediatric Research" conference where he expressed
pride that he routinely obtained permission from the parents of the children in his
studies. In that group in 1961, Krugman was thus among those pediatric
investigators most sympathetic to the position that children could not be used as
mere means to the ends of the researcher without the authorization of the parent.
AEC Requirements for Radiation Research With Children
Although in the 1940s and 1950s there were apparently no written rules of
professional ethics for pediatric research in general, there were guidelines for the
investigational use of radioisotopes in children. In 1949, the Subcommittee on
Human Applications of the Atomic Energy Commission's Isotope Division
established a set of rules to judge proposals submitted by researchers for the use
of radioisotopes in medical experiments with human subjects, including "normal
children."" These standards appeared in the fall 1949 supplement to the AEC's
isotope catalogue and price list. Under the heading "Normal Children" the
isotope catalogue offered the following statement:
In general the use of radioisotopes in normal
children is discouraged. However, the
Subcommittee on Human Applications will
consider proposals for such use in important
researches, provided the problem cannot be studied
properly by other methods and provided the
radiation dosage level in any tissue is low enough to
be considered harmless. It should be noted that in
general the amount of radioactive material per
kilogram of body weight must be smaller in
children than that required for similar studies in the
adult. 54
These guidelines did not mention consent--of parents, guardians, or
children. 55 Instead, this statement simply discouraged nontherapeutic experiments
with children. The guidelines did not, however, suggest that the practice was
completely inappropriate; the subcommittee asserted that "important" research
using "harmless" levels of radiation dosage with children was acceptable. The
crucial terms important and harmless were left undefined.
It seems reasonable to expect that "important" pediatric research would
address a significant medical problem affecting children or would explore key
aspects of normal human physiology-relevant to health promotion or disease
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Part II
prevention— for which research on children is indispensable. By these standards,
the twenty-one nontherapeutic radiation experiments with children whose risks
we review in the next section of this chapter could all be said to address important
questions relevant to pediatric health care. This judgment is not based on a
determination of whether a given study proved important in the subsequent
development of a particular field. Such retrospective analysis would place an
unreasonable burden on investigators of the past, as research is an inherently
speculative enterprise. Many experiments that prove to be of little value in the
advance of medical knowledge are, at the time they are implemented, well
designed and appropriate attempts to address important research questions.
It is easier to infer what the members of the AEC Subcommittee on
Human Applications would have considered "important" research than what the
subcommittee would have considered "harmless" radioisotope research. Acute
toxicity is not seen following administration of nontherapeutic (tracer) doses of
radioisotopes. Thus, the principal potential harm from radiation exposure at
lower doses is the subsequent development of cancer. In the 1940s and 1950s,
some in the field apparently discounted the risk, while others were wary of a
prevailing uncertainty. Dr. John Lawrence, an early radioisotope researcher at the
University of California, described how some researchers conducted public
demonstrations of tracers, using an "unsuspecting physician out of the audience to
act as the guinea pig," presumably to reassure the audience that tracers were
innocuous. 56 By contrast, other investigators focused on the tragedy of the radium
dial painters, concerned that this might be repeated with man-made radionuclides.
Evidence of how well the AEC enforced its 1949 guidelines with respect
to research on children is elusive (see chapter 6). AEC correspondence with
researchers at the Fernald School suggests that in at least one case there was
oversight of research in which children were administered radioisotopes. 57
RISK OF HARM AND NONTHERAPEUTIC RESEARCH
WITH CHILDREN
The Twenty-One Case Examples
During the 1944-1974 period, there was an explosion of interest in the use
of radioisotopes in clinical medicine and medical research, including pediatrics.
The twenty-one research projects we review here include only a small number of
all those that were likely conducted. These twenty-one do include, however,
every nontherapeutic study that was funded by the federal government and fell
into our original group of eighty-one pediatric radiation experiments. The table
that appears at the end of the chapter provides information about the number of
children involved in each of the experiments, the radioisotopes used, and risk
estimates for cancer incidence. These twenty-one represent a subset of eighty-one
studies identified in documents of the Atomic Energy Commission and a review
332
Chapter 7
of the medical literature that met the criteria described above."
All twenty-one projects analyzed in detail involve the administration of
radioisotopes to children in order to better understand child physiology or to
develop better diagnostic tools for pediatric disease. In this respect, the studies
supported by the federal government do not differ from those reviewed that had
other funding sources. With the exception of the study at the Wrentham school to
evaluate protective measures for fallout, none of the twenty-one experiments
reviewed was related to national defense concerns. Seventeen of the twenty-one
experiments involved the use of iodine 131 for the evaluation of thyroid function.
Three examples of research reviewed by the Committee will help illustrate
the nature of the experiments and the risks posed to children. In the first example
investigators at Johns Hopkins in 1953 injected iodine 131 into thirty-four
children from ages two months to fifteen years with hypothyroidism and an
unknown number of healthy "control" children in order to better understand the
cause of this disease. 59 Iodine is normally taken up and used by the thyroid gland
for hormone production. In this experiment, a radiation detector was placed over
the thyroid to detect the amount of iodine 1 3 1 taken up. Most children with
hypothyroidism have an underdeveloped thyroid gland, in which case only very
low levels of iodine 131 uptake will occur. Indeed, this is what the investigators
found in this experiment, which was one of the first projects to use iodine 131
uptake as a measure of thyroid function in children. Hypothyroidism is a
relatively common condition (1 per 4,000 births) that can cause profound mental
retardation if untreated. Today, better diagnostic tests for thyroid function
including radioimmunoassay and effective thyroid hormone replacement have
virtually eliminated hypothyroidism as a cause of mental retardation in the
developed world.
A second example of research reviewed by the Committee is an
experiment by investigators at the University of Minnesota in 1951 in which four
children with nephrotic syndrome were injected with an amino acid labeled with
sulfur 35, along with two "control" children hospitalized for other conditions. 60
Nephrotic syndrome is a serious pediatric condition in which protein is excreted
by the kidneys in large quantities. There was controversy at the time over
whether children with nephrotic syndrome have low blood protein levels solely
because of renal losses or whether they also have impaired protein production
This experiment looked at the incorporation of the radioisotope-labeled amino
acid into protein, and the results suggested that the protein production in children
with nephrotic syndrome is normal.
A third example of research reviewed by the Committee is a study of
iodine 125 and iodine 131 uptake by eight healthy children performed at the Los
Alamos Laboratory in 1963. 61 The purpose of the study was to evaluate the use of
radioisotopes in very small doses (nanocurie levels) as a measure of thyroid
function. The study demonstrated that the technique was scientifically valid and
exposed the children to smaller radiation doses than earlier methods
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Part II
Estimating Risk
How can the risks posed to children in these types of experiments be
estimated? The primary risk posed by the administration of radioisotopes is the
potential development of cancer years, even decades, after the exposure. As will
be discussed further, the risk of cancer following external radiation exposure was
not well documented until the late 1950s and the early 1960s. Thus, the published
reports of research projects prior to that time rarely discuss the issue of long-term
risks.
The principles of risk assessment for radioisotopes are laid out in "The
Basics of Radiation Science" at the end of "Introduction: The Atomic Century." 62
To review: the increased risk of cancer is generally assumed to be proportional to
the dose of radiation delivered to the various organs of the body. This dose
depends upon a number of factors, including the amount of radioactivity
administered, its chemical form (which determines which organs will be
exposed), and how long it stays in the body, which in turn depends upon the
radioactive decay rate and the body's normal excretion rate for that substance.
For many radioisotopes, the overall personal dose can be derived by the
"effective-dose method," in which the doses to the ten most sensitive organs are
computed and added together, weighting the various organs in proportion to their
radiosensitivity. Thus, this effective dose can be thought of as producing the
same excess risk of cancer (all sites combined) as if the whole body had received
that amount as a uniform dose. This risk is then computed by multiplying the
effective dose by established risk estimates per unit dose for various ages. For
this chapter, the Advisory Committee has adopted the effective doses and risk
estimates tabulated by the International Commission on Radiation Protection and
the National Council on Radiation Protection. 63 The lifetime-risk estimate used in
this chapter is 1/1,000 excess cancers per rem of effective dose for children and
fetuses exposed to slowly delivered radiation doses, like those from radioactive
tracers.
The risks of thyroid cancer following exposure to radioactive iodine
(generally 1-131) represent a special case for three reasons. First, use of the
effective-dose method is inappropriate because the dose is much greater to the
thyroid than for other organs, and the lifetime risk is therefore dominated by the
thyroid cancer risk. Therefore, risk is best calculated using only the thyroid dose
and its associated risk. Second, the thyroid cancer risk varies even more by age
than for other cancers. Third, the risk for iodine 1 3 1 has not been measured
directly, but several lines of evidence suggest that it may be substantially lower
than for external radiation. For this chapter, the Advisory Committee has adopted
estimates provided by three follow-up studies of external irradiation of the thyroid
by x rays or gamma rays in childhood: 2,600 children who received x-ray
treatment for enlarged thymus glands in the first year of life; 64 1 1,000 children
who were treated by x rays in Israel for ringworm under age ten; 65 and Japanese
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Chapter 7
atomic bomb survivors under age twenty. 66 The risk estimates from these studies
were divided by three to convert them to internal iodine 131 exposures. 67 The
estimates from these studies are for cancer incidence; for mortality we have
divided them by 10, since 90 percent of thyroid cancers are curable. The resulting
estimates are summarized in table 1 . These are the same estimates used by the
Massachusetts Task Force, which investigated the Fernald and Wrentham
experiments. 68
We can use data from the previously described Johns Hopkins iodine 1 3 1
study as an example. In this study, the amount of radioactivity administered was
1.75 microcuries per kilogram body weight; equivalent to 44 microcuries in a
seven-year-old child weighing 25 kilograms. Based on interpolation of the tables
in ICRP 53, and assuming a 13 percent thyroid uptake, this would produce a
thyroid dose of 1 15 rem to a child aged seven. In this age range (5-9), the lifetime
risk of developing thyroid cancer would be calculated by multiplying this dose by
20 per million person rems to produce an estimate of 2.3 cases per 1,000 exposed
individuals, or 0.23 percent for a particular child. The risk of dying of thyroid
cancer would be one-tenth of this, or 0.023 percent.
The twenty-one experiments subjected to the Committee's detailed risk
analysis included approximately 800 children. Eleven of the studies produced
estimates of average risk of cancer incidence within the range of 1 and 0.1
percent; eight studies ranged within 0.09 and 0.01 percent, and the remaining two
studies produced average risk estimates of 0.001 percent. The maximum potential
risk estimate was 2.3 percent in a few children aged one to two years at the time
of exposure. The average risk of cancer incidence for the Fernald radioiron and
radiocalcium studies were 0.03 percent and 0.001 percent respectively, and for the
Wrentham fallout (iodine 131) study, 0. 10 percent. All of the highest-risk
experiments involved iodine 131, and hence the risks of dying of cancer would be
about ten times smaller. (See table 2 at the end of this chapter for further details.)
Based on the average risk estimate for each of the twenty-one
experiments, we would estimate an excess cancer incidence of 1 .4 cases for the
entire group of 792 subjects. However, given the uncertainties built into the risk
analysis, it is also possible that no excess cases resulted. Furthermore, since most
of that excess would have been thyroid cancer, it is particularly unlikely that any
cancer deaths would have been caused. Finally, as thyroid cancer does occur in
the general population, it would be difficult to attribute these cases to an
individual's involvement in research. In addition, any cases of thyroid cancer
among former subjects attributable to their participation in research conducted in
the 1940s and 1950s are likely to have occurred already, although there is little
long-term follow-up data to know for certain what the ultimate lifetime risk might
be.
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Part II
Table 1. Summary of Risk Estimates for Thyroid Cancer
from Iodine 131
EXPOSURE AT VARIOUS AGES
Age
0-4*
5-9 +
10-14*
15-19 §
Lifetime risk" of cancer incidence per million exposed per rem
Males
27
13
6.7
1.9
Females
53
27
13
3.7
Both
40
20
10
2.8
Lifetime risk of cancer mortality per million exposed per rem
Males
2.7
1.3
0.7
0.2
Females
5.3
2.7
1.3
0.4
Both
4.0
2.0
1.0
0.3
* From R. E. Shore et al., "Thyroid Tumors Following Thymus Irradiation,"
Journal of the National Cancer Institute 74 ( 1 985): 1 1 77- 1 1 84, based on 2.9 cases per
million person-year-rem.
t From E. Ron and B. Modon, "Thyroid and Other Neoplasms Following
Childhood Scalp Irradiation," in J. D. Boice, Jr., and J. F. Fraumeni, Jr., eds., Radiation
Carcinogenesis: Epidemiology and Biological Significance (New York: Raven, 1984),
139-151, based on the risk in this age group being half that in the 0-4 age group.
\ From R. L. Prentice et al., "Radiation Exposure and Thyroid Cancer Incidence
Among Hiroshima and Nagasaki Residents," National Cancer Institute Monographs 62
(1982): 207-212, based on the risk in this age group being one-third of that in the 0-9 age
group.
§ Ibid., based on 0.21 per million person-year-rem.
I Based on an assumed forty-year period at risk from five to forty-five years
after exposure and assuming females have twice the excess risk of males.
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Chapter 7
How do these risk figures compare with what is acceptable in
nontherapeutic research today? As noted earlier in this chapter, the contemporary
regulatory standard permits children to be involved in nontherapeutic research if
the research poses no more than "minimal risk" to the subjects. "Minimal risk" is
defined by analogy only: "A risk is minimal where the probability and magnitude
of harm or discomfort anticipated in the proposed research are not greater, in and
of themselves, than those ordinarily encountered in daily life or during the
performance of routine physical or psychological tests. "^ The regulations also
allow for nontherapeutic research with children that does present more than
minimal risk, but only //"the risk represents a minor increase over minimal risk,
the procedures involved are commensurate with the general life experiences of
subjects, and the research is likely to yield knowledge of "vital importance" about
the subjects' disorder or condition. 70 The regulations do not specify what would
count as a minor increase over minimal risk. With this general guidance, it is the
obligation of individual institutional review boards (IRBs) to determine whether a
nontherapeutic study involving children is acceptable. 71 It is likely that a cancer
risk of greater than 1 per 1 ,000 subjects would be considered by most, if not all
IRBs to be unacceptable by a minimal-risk standard, even for nonfatal cancers. It
is less clear whether this risk would be considered unacceptable by the "minor
increase over minimal risk" standard (assuming the research satisfied the "vital
importance" condition). The difficulty of establishing an acceptable level of risk
in nontherapeutic radiation research with children is currently being debated in
the medical literature, 72 a debate that will likely continue at least until federal
guidelines become more specific.
What Was Known at the Time About Risk in Children
Assuming that any study that posed risks of greater than 1 excess case of
cancer per 1,000 subjects would be judged to be more than minimal risk, eleven
of the twenty-one research projects reviewed by the Committee exposed children
to higher risk than is acceptable today for nontherapeutic experiments. From a
moral perspective, a crucial question is whether investigators at the time could or
should have known that they were putting their pediatric subjects at greater than
minimal risk. If they could have known, then, arguably, these investigators were
not conforming to the AEC's requirement permitting nontherapeutic research in
children provided that "the radiation dosage level in any tissue is low enough to
be considered harmless."
It is clear that the medical community's understanding of the nature and
magnitude of risks posed to children by radiation exposure is not what it is today.
Researchers did not positively associate prior exposure to external radiation with
an increased risk of cancer until the mid to late 1950s. In 1950, Duffy and
Fitzgerald raised the question as to whether there might be cause to investigate a
possible association between therapeutic thymic irradiation during childhood and
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Part II
subsequent development of thyroid or thymic cancers:
To pose a cause and effect relationship between
thymic irradiation and the development of cancer
would be quite unjustified on the basis of data at
hand when one considers the large number of
children who have had irradiation of an "enlarged
thymus." However, the potential carcinogenic
effects of irradiation are becoming increasingly
apparent, and such relationships as those of thymic
irradiation in early life and the subsequent
development of thyroid or thymic tumors might be
profitably explored. 73
By 1959, several studies had reported an association between radiation
exposure and the subsequent development of leukemia. 74 Saenger et al.
performed an epidemiologic study of several thousand children in 1960 to
evaluate the association between radiation exposure and cancer. 75 They stated:
The question of whether or not radiation can be
indicted as the principal causative factor in the
induction of neoplasia following radiation exposure
for either diagnostic or therapeutic purposes has
been of increased interest over the past several
years. 76
In completing their analysis, they concluded: "It remains a fact, indisputable in
all respects, that the rate of thyroid cancers in the irradiated group is
disproportionately high." 77
In 196U Beach and Dolphin prepared a detailed analysis of the literature
on the relationship between radiation and thyroid cancer in children. 78 They
reported:
The thyroid has always been considered to be an
organ comparatively radio-resistant to alteration
and subsequent tumor development. Although no
definite development of radiogenic tumor has been
reported in adults after therapeutic administration of
iodine-131, Jelliffe and Jones (1960) discuss a total
of 10 cases of thyroid cancer reported in the
literature in persons treated early in life by x-ray
irradiation in the neck region. [T]he total of
malignant thyroid tumors which develop in children
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Chapter 7
given a dose of x-radiation to the thyroid that is of
the same order of magnitude as the incidence
estimated for other tumors if a linear dose-response
relationship is assumed. No biologic significance is
attached to this point, apart from noting the fact that
the child's thyroid appears to be more radio-
sensitive than an adult's but not more sensitive than
some adult tissues. 79
This lack of appreciation for the potential long-term effects of radiation in
children is further reflected in institutional policy development for use of
radioisotopes at the time. The Massachusetts General Hospital developed
standards for tracer doses of radioisotopes in May 1949. Dr. Shields Warren
director of the AEC Division of Biology and Medicine, assisted in the
development of the MGH standard:
Tracer doses in humans will always be kept to the
absolute minimum required to make the
observation.
Adult humans who are ill and who are expected to
benefit from the procedure, shall not receive tracer
doses of radioactive material giving off radiation in
excess of a total of 4 rep. Children (all patients
below 15 years of age) shall not receive more than a
total of 0.8 rep. sn
In any other cases, tracer doses will be limited to
radioactive material giving off radiation in an
amount less than a total of 1 rep.
In the case of iodine, the thyroid, which retains
most of the radioactivity, is radioresistant. In this
case, the permitted dosage may be increased by a
factor of 100. 81
Despite the cautious tone of this document, the policy illustrates the
complete lack of understanding of the true radiosensitivity of the thyroid gland
especially in the pediatric population. Further allowances must be made with '
regard to what was known about the distribution of radioisotopes in children at
the time. It is evident that investigators using radioisotopes in children were not
employing available information on organ weights in children to calculate tissue
exposures at least until the mid-1960s. When "standard man" assumptions were
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Part II
used to calculate pediatric exposures before pediatric standards were developed,
investigators may have significantly and systematically underestimated effective
tissue dosages in children. It is notable that the highest levels of risk posed in the
experiments reviewed were to infants administered iodine 131.
Iodine 131 was routinely used for diagnostic procedures in the pediatric
population until the 1980s, when it was replaced by 1-123, a newly available
radioisotope with a significantly shorter half-life, which reduced the thyroid dose
markedly. The Wrentham fallout study, performed in 1 96 1 , employed doses of
iodine 131 that resulted in an average dose of 44 rad to the gland, slightly less
than the dose that would have been received for a diagnostic thyroid scan during
this time. ,
Although the doses of radioisotopes subsequently declined during these
years for both therapeutic medicine and nontherapeutic research, these guidelines
were not based on long-term outcome studies of exposed individuals but rather
on conservative extrapolations from high-dose studies and on the dosages
necessary to enable detection with the available equipment.
The debate over the potential risks of low-dose exposure continues today,
as epidemiological studies of thyroid cancer incidence subsequent to iodine 131
administration in both the diagnostic as well as therapeutic dose range have been
largely negative. Risks as a result of iodine 131 exposure are still unclear, and
risk analyses for exposure to radioisotopes are thus based on extrapolations from
studies involving external irradiation.
In summary, during the period in which children were exposed to the
highest levels of risk from nontherapeutic research involving radioisotopes,
investigators had a limited understanding of the potential long-term risks of low-
dose radiation and of methods to accurately calculate the tissue doses in children.
Today, we cautiously assume that any exposure to radiation likely produces some
small increase in cancer risk, so that no exposure is absolutely harmless. Instead,
the concept of minimal or acceptable risk is commonly used, as discussed earlier.
Some of the studies during this period involved risks that would be judged as
minimal even today, whereas others would be clearly viewed as unacceptable
today. Should the investigators then have viewed any of these studies as
harmless? Though an understanding of the association between exposure to
external radiation and subsequent development of cancer was emerging during
this time, a similar association had not been made for exposure to low dose levels
of radioisotopes. In addition, the relative radiosensitivity of many pediatric
tissues, including thyroid, had not been established, and most researchers during
this period subscribed to the "threshold" theory of risk, which assumed that
sufficiently low doses were probably harmless. In the face of such widespread
factual ignorance, it is difficult to hold these investigators culpable for imposing
risks on their subjects that were not appreciated at the time.
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BEYOND RISK: OTHER DIMENSIONS OF THE ETHICS OF
NONTHERAPEUTIC RESEARCH ON CHILDREN
The level of risk to which children are exposed is critical in evaluating the
ethics of nontherapeutic research on children. Also important, however, is
whether and how the authorization of parents was solicited, and also which
children were selected to be so used. For nineteen of the twenty-one studies
reviewed by the Committee, we know almost nothing about whether the
permission of parents was sought or what the parents were told about their
children's involvement. Two of the studies conducted at the Fernald School were
the exceptions, as a result of extensive historical and archival research by the
Massachusetts Task Force on Human Subjects Research.
There is a reference to parents in the published literature on only one of
the remaining nineteen studies, a 1954 iodine uptake experiment at the University
of Tennessee. This paper included the following line: "The procedure was
described to the mothers of the infants studied, and the mothers gave consent for
the study before the tests were made."* 2 (The inclusion of this line is noteworthy
for it suggests that at least some investigators thought parental permission was
worth mentioning in published reports of their research.)
If the Committee had devoted extensive investigatory resources to these
nineteen studies, it is likely we would have learned more about whether or how
parental authorization was obtained in at least some cases. It is also almost
certain that even the deepest archival digging would have produced no useful
information about parental authorization for some of these experiments. The
recent experience of the Massachusetts Task Force demonstrates the possibility of
both outcomes: for some of the experiments conducted at the Fernald School, the
task force's diligent historical research uncovered a variety of documents that
shed important light on what both parents and children were told; for the
experiments at Wrentham, similar efforts did not produce any significant
information on questions of parental authorization.
Again with the exception of the experiments conducted at Fernald and
Wrentham, we know almost nothing about who the children were who served as
subjects in these experiments. The journal articles on these remaining studies do
not describe the sociodemographic characteristics of the subjects. They do
sometimes mention whether the subjects had relevant medical conditions and
usually that the children, including the "control" subjects, were hospitalized
patients. In some of the experiments reviewed by the Committee, the scientific
research questions of interest could have been pursued only in children who were
ill and hospitalized. In other instances, however, the hospitalized children were
likely samples of convenience. This is particularly plausible in the case of control
subjects, when a sample of healthy, nonhospitalized children might have made a
better control group from a scientific perspective. As we saw in chapter 2,
hospitalized patients were often viewed by physician-investigators as a
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convenient source of research subjects.
Because so little is known, the Committee cannot draw conclusions about
the ethics of most of the nontherapeutic studies involving children we reviewed,
apart from the important issue of risk of harm to the children involved. We turn
now to an analysis of the studies where relevant information about parental
authorization, disclosure, and subject selection is available: the studies conducted
at the Fernald School.
THE STUDIES AT THE FERNALD SCHOOL
Researchers from the Massachusetts Institute of Technology, working in
cooperation with senior members of the Fernald staff, carried out nontherapeutic
nutritional studies with radioisotopes at the state school in the late 1940s and
early 1950s. The subjects of these nutritional research studies were young male
residents of Fernald, who were members of the school's "science club." In 1946,
one study exposed seventeen subjects to radioactive iron. The second study,
which involved a series of seventeen related subexperiments, exposed fifty-seven
subjects to radioactive calcium between 1950 and 1953. It is clear that the doses
involved were low and that it is extremely unlikely that any of the children who
were used as subjects were harmed as a consequence. These studies remain
morally troubling, however, for several reasons. First, although parents or
guardians were asked for their permission to have their children involved in the
research, the available evidence suggests that the information provided was, at
best, incomplete. Second, there is the question of the fairness of selecting
institutionalized children at all, children whose life circumstances were by any
standard already heavily burdened.
Parental Authorization
The Massachusetts Task Force found two letters sent to parents describing
the nutrition studies and seeking their permission. The first letter, a form letter
signed by the superintendent of the school, is dated November 1949." The letter
refers to a project in which children at the school will receive a special diet "rich"
in various cereals, iron, and vitamins and for which "it will be necessary to make
some blood tests at stated intervals, similar to those to which our patients are
already accustomed, and which will cause no discomfort or change in their
physical condition other than possibly improvement." The letter makes no
mention of any risks or the use of a radioisotope. Parents or guardians are asked
to indicate that they have no objection to their son's participation in the project by
signing an enclosed form. 84
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The second letter, dated May 1953, we quote in its entirety:
Dear Parent:
In previous years we have done some
examinations in connection with the nutritional
department of the Massachusetts Institute of
Technology, with the purposes of helping to
improve the nutrition of our children and to help
them in general more efficiently than before.
For the checking up of the children, we
occasionally need to take some blood samples,
which are then analyzed. The blood samples are
taken after one test meal which consists of a special
breakfast meal containing a certain amount of
calcium. We have asked for volunteers to give a
sample of blood once a month for three months, and
your son has agreed to volunteer because the boys
who belong to the Science Club have many
additional privileges. They get a quart of milk daily
during that time, and are taken to a baseball game,
to the beach and to some outside dinners and they
enjoy it greatly.
I hope that you have no objection that your
son is voluntarily participating in this study. The
first study will start on Monday, June 8th, and if
you have not expressed any objections we will
assume that your son may participate.
Sincerely yours,
Clemens E. Benda, M.D.
[Fernald] Clinical Director
Approved:.
Malcom J. Farrell, M.D.
[Fernald] Superintendent 85
Again, there is no mention of any risks or the use of a radioisotope. It was
believed then that the risks were minimal, as indeed they appear to have been, and
as a consequence, school administrators and the investigators may have thought it
unnecessary to raise the issue of risks with the parents. There was no basis,
however, for the implication in both letters that the project was intended for the
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children's benefit or improvement. This was simply not true.* 6
The conclusion of the Massachusetts Task Force was that these
experiments were conducted in violation of the fundamental human rights of the
subjects. This conclusion is based in part on the task force's assessment of these
letters. Specifically, the task force found that
1 [t]he researchers failed to satisfactorily inform the
subjects and their families that the nutritional
research studies were non-therapeutic; that is, that
the research studies were never intended to benefit
the human subjects as individuals but were intended
to enhance the body of scientific knowledge
concerning nutrition.
The letter in which consent from family members
was requested, which was drafted by the former
Fernald superintendent, failed to provide
information that was reasonably necessary for an
informed decision to be made. 87
Fairness and the Use of Institutionalized Children
The Fernald experiments also raise quite starkly the particular ethical
difficulties associated with conducting research on members of institutionalized
populations-especially where some of the residents have mental impairments.
Living conditions in most of these institutions (including Fernald and Wrentham)
have improved considerably in recent years, and sensitivity toward people with
cognitive impairments has likewise increased. As Fred Boyce, a subject in one of
these experiments has put it, "Fernald is a much better place today, and in no way
does it operate like it did then. That's very important to know that." ss
The Massachusetts Task Force describes conditions in state-operated
facilities like Fernald, particularly as they bear on human experimentation, as
follows:
Until the 1970s, the buildings were dirty and in
disrepair, staff shortages were constant, brutality
was often accepted, and programs were inadequate
or nonexistent. There were no human rights
committees or institutional review boards. If the
Superintendent (in those days required to be a
medical doctor) "cooperated" in an experiment and
allowed residents to be subjects, few knew and no
one protested. If nothing concerning the
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experiments appeared in the residents' medical
records, if "request for consent" letters were less
than forthright, or if no consent was obtained there
was no one in a position of authority to halt or
challenge such procedures. 89
Although public attitudes toward people who are institutionalized are
admittedly different today than they were fifty years ago, it is likely that this state
of affairs would have been troubling to most Americans even then. Historian
Susan Lederer has revealed several episodes of experimentation with
institutionalized children in America that caused considerable public outcry even
before 1940, presaging the concern generated by Willowbrook when this research
became a public issue in the 1960s. 90
The LMRI staff reported in the early 1960s that the pediatric researchers
whom they had gathered agreed in principle that the convenience of conducting
research on institutionalized children did not outweigh the moral problems
associated with this practice:
Several investigators spoke about the practical
advantages of using institutionalized children who
are already assembled in one location and living
within a standard, controlled environment. But the
conferees agreed that there should be no differential
recruitment of ward patients rather than private
patients, of institutionalized children rather than
children living in private homes, or of handicapped
rather than healthy children. 91
A particularly poignant dimension of the unfairness of using
institutionalized children as subjects of research is that it permits investigators to
secure cooperation by offering as special treats what other, noninstitutionalized
children would find far less exceptional. The extra attention of a "science club," a
quart of milk, and an occasional outing were for the boys at Fernald extraordinary
opportunities. As Mr. Boyce put it:
I won't tell you now about the severe physical and
mental abuse, but I can assure you, it was no Boys'
Town. The idea of getting consent for experiments
under these conditions was not only cruel but
hypocritical. They bribed us by offering us special
privileges, knowing that we had so little that we
would do practically anything for attention; and to
say, I quote, "This is their debt to society," end
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quote, as if we were worth no more than laboratory
mice, is unforgivable. 92
Even when a child was able to resist the offers of special attention and
refused to participate in the experiment, the investigators seem to have been
unwilling to respect the child's decision. One MIT researcher, Robert S. Harris,
explicitly noted that "it seemed to [him] that the three subjects who objected to
being included in the study [could] be induced to change their minds." 93 Harris
believed that the recalcitrant children could be "induced" to join in the study by
emphasizing "the Fernald Science Club angle of our work." 94
From the perspective of the science, it was considered important to
conduct the research in an environment in which the diet of the children-subjects
could be easily controlled. From this standpoint, the institutional setting of
Fernald was ideal. The institutional settings of the boarding schools in the
Boston area, however, would have offered much the same opportunity. Although
the risks were small, the "children of the elite" were rarely if ever selected for
such research. It is not likely that these children would have been willing to
submit to blood tests for extra milk or the chance to go to the beach.
The question of what is ethical in the context of unfair background
conditions is always difficult. Perhaps the investigators, who were not
responsible for the poor conditions at Fernald, believed that the opportunities
provided to the members of the Science Club brightened the lives of these
children, if only briefly. Reasoning of this sort, however, can all too easily lead to
unjustifiable disregard of the equal worth of all people and to unfair treatment.
Today, fifty years after the Fernald experiments, there are still no federal
regulations protecting institutionalized children from unfair treatment in research
involving human subjects. 95 The Committee strongly urges the federal
government to fill this policy void by providing additional protections for
institutionalized children. 96
CONCLUSION
If an ethical evaluation of human experiments depended solely upon an
assessment of the risks to subjects as they could reasonably be anticipated at the
time, the radiation experiments conducted on children reviewed in this chapter
would be relatively unproblematic. 97 During this time, the association between
radiation exposure and the subsequent development of cancer was not well
understood, and in particular, little was known about iodine 131 and the risk of
thyroid cancer. Both researchers and policymakers appear to have been alert to
considerations of harm and concerned about exposing children to an unacceptable
level of risk.
At the same time, however, the scientific community's experience with
radionuclides in humans was limited, and this approach to medical investigation
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was new. Although the available data about human risk were encouraging and
the biological susceptibility of children to the effects of radiation was not
appreciated, we are left with the lingering question of whether investigators and
agency officials were sufficiently cautious as they began their work with children.
This is a difficult judgment to make at any point in the development of a field of
human research; it is particularly difficult to make at forty or fifty years' remove.
Investigators and officials had to make decisions under conditions of considerable
uncertainty; this is commonplace in science and in medicine. Although the
biological susceptibility of children was not then known, investigators and
officials held the view that children should be accorded extra protection in the
conduct of human research, and they made what they thought were appropriate
adjustments when using children as subjects. If human research never proceeded
in the face of uncertainty, there would be no such experiments. How little
uncertainty is acceptable in research involving children is a question that remains
unresolved. Today, we continue to debate what constitutes minimal risk to
children, in radiation and in other areas of research. The regulations governing
research on children offer little in the way of guidance, either with respect to
conditions of uncertainty about risk or when risks are known.
As best as we can determine, in eleven of the twenty-one experiments we
reviewed, the risks were in a range that would today likely be considered as more
than minimal, and thus as unacceptable in nontherapeutic research with children
according to current federal regulations. It is possible, however, that four of the
eleven might be considered acceptable by the "minor increase over minimal risk"
standard. 98 In these four experiments, the average risk estimates were between
one and two per thousand, the studies were directed at the subjects' medical
conditions, and they may well have had the potential to obtain information of
"vital importance."
Physical risk to subjects is not the only ethically relevant consideration in
evaluating human experiments. With the exception of the studies at Fernald, we
know almost nothing about whether or how parental authorization for the
remaining nineteen experiments we reviewed was obtained. And with the
exception of the Fernald studies and the experiment at Wrentham, we know very
little about the children who were selected to be the subjects of this research.
Therefore, we cannot comment on the general ethics of these other experiments.
The experiments at Fernald and at the Wrentham School unfairly burdened
children who were already disadvantaged, children whose interests were less well
protected than those children living with their parents or children who were
socially privileged. At the Fernald School, where more is known, there was some
attempt to solicit the permission of parents, but the information provided was
incomplete and misleading. The investigators successfully secured the
cooperation of the children with offers of extra milk and an occasional outing-
incentives that would not likely have induced children who were less starved for
attention to willingly submit to repeated blood tests.
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One researcher speaking almost thirty-five years ago set out the
fundamental moral issue with particular frankness and clarity:
... we are talking here about first and second class
citizens. This is a concept none of our consciences
will allow us to live with. . . . The thing we must all
avoid is two types of citizenry."
It might have been common for researchers to take advantage of the convenience
of experimenting on institutionalized children, but the Committee does not
believe that convenience offsets the moral problems associated with employing
these vulnerable children as research subjects~now or decades ago.
The Vanderbilt Study
In an exceptionally large study" at Vanderbilt University in the 1940s, approximately 820
poor, pregnant Caucasian women were administered tracer doses of radioactive iron. Vanderbilt
worked with the Tennessee State Department of Health, and the research was partly funded by the
Public Health Service. 11 Today, most women take iron supplements during pregnancy. This
experiment provided the scientific data needed to determine the nutritional requirements for iron
during pregnancy.
The radioiron portion of the nutrition study, directed by Dr. Paul Hahn, was designed to
study iron absorption during pregnancy.' The women, who were anywhere from less than ten
weeks to more than thirty-five weeks pregnant, were administered a single oral dose of radioactive
a. Most of the other tracer studies involving pregnant women and offering no prospect of benefit
that were reviewed by the Committee involved fewer than twenty women as subjects.
b. William J. Darby, Director of the Tennessee-Vanderbilt Project et al., Summary Report. Section
B. Tennessee-Vanderbilt Nutrition Project. July 1. 1946 to December 31. 1946 (ACHRE No. CORP-020395-
A), 97-1 10. This nutrition study summary report notes, "Considerable expansion of the program of study of
maternal and infant nutrition has been made possible by a grant of $9,000 per year which was made by the
U.S. Public Health Service. These funds were available beginning November 1, 1946." Ibid., 99. The
summary observes that the grant was to be used for additional personnel, including the appointment of Dr.
Richard Cannon, an obstetrics resident, to the staff of the Division of Nutrition beginning 1 January 1947.
Dr. Cannon's name subsequently appears as an investigator in the medical report discussing the radioiron
portion of the study, along with Dr. Paul Hahn's and others.
c. P. Hahn et al., "Iron Metabolism in Human Pregnancy as Studied with the Radioactive Isotope,
Fe-59," American Journal of Obstetrics and Gynecology 61 (March 1951): 477-486. The exact years of the
radioiron portion of the nutrition study are uncertain. Minutes from a meeting of the nutrition study
investigators indicate the study was to begin in September 1945. Tennessee-Vanderbilt Nutrition Project,
Nutrition in Pregnancy Study, "Minutes of Meeting for Discussion of Nutrition in Pregnancy Study, August
17, 1945" (ACHRE No. CORP-020395-A). 17A-C. The radioiron study probably began at approximately
that time and appears to have continued until sometime in 1947, based on a review of periodic study
summaries.
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Chapter 7
iron, Fe-59, during their second prenatal visit, before receiving their routine dose of therapeutic
iron.' 1 On their third prenatal visit, blood was drawn and tests performed to determine the
percentage of iron absorbed by the mother. The infants' blood was then examined at birth to
determine the percentage of radioiron absorbed by the fetus. The doses to the women were
estimated in the study article, using crude dose-estimation methods available at the time, to be
from 200,000 to 1,000,000 countable counts per minute." Although the investigators did not
estimate doses to the fetuses in the original study. Dr. Hahn later estimated fetal doses to be
between 5 and 15 rad. This estimate, however, has been questioned. 1
There is at least some indication that the women neither gave their consent nor were
aware they were participating in an experiment. Vanderbilt study subjects, expressing bitterness at
the way they believed they had been treated, testified at an Advisory Committee meeting that the
proffered drink, called a "cocktail" by the investigators, was offered with no mention of its
contents. "1 remember taking a cocktail," one woman said simply. "I don't remember what it was,
and I was not told what it was." B Although it is not clear what, if anything, the subjects were told,
information about the Vanderbilt experiment was available to the general public. In late 1946
news reports appeared in the Nashville press. 1 '
The actual risk to the fetuses in the Vanderbilt experiment has long been a matter of
study. In 1963-1964, a group of researchers at Vanderbilt found no significant differences in
malignancy rates between the exposed and nonexposed mothers. 1 However, they did identify a
higher number of malignancies among the exposed offspring (four cases in the exposed group:
acute lymphatic leukemia, synovial sarcoma, lymphosarcoma, and primary liver carcinoma, which
was discounted as a rare, familial form of cancer). No cases were found in a control group of
similar size, and approximately 0.65 cases would have been expected on Tennessee state rates,
compared to which the three observed cases is a marginally significant excess. This led the
researchers to conclude that the data suggested a causal relationship between the prenatal exposure
to Fe-59 and the cancer. The investigators also concluded that Dr. Hahn's estimate of fetal
d. The Advisory Committee has not been able to determine whether Dr. Hahn got the radioactive
iron used in the study from a private or government source, or both.
e. Counts per minute is a measure of the radioactivity detected by a specific counting instrument.
The sensitivities of counting instruments vary; a specific instrument may not "see" and count all the radiation
coming from a particular substance. Thus, the total amount of radiation emitted by a substance may be
calculated by considering the sensitivity of the counter.
f. Contemporary estimates of the fetal doses by the Committee and others suggest that the fetal
effective dose was a few hundred millirems.
g. Wilton McClure, transcript of audio testimony before the Advisory Committee on Human
Radiation Experiments, Small Panel Meeting, Knoxville, Tennessee, 2 March 1995, 182.
h. "Iron Doses with Radioactive Isotopes Aid to Pregnancy, Experiment Shows," Nashville
Banner, 13 December 1946; "VU to Report on Isotopes," The Nashville Tennessean, 14 December 1946
(ACHRE No. CORP-020395-A).
i. The investigators identified the hospital records of 751 exposed mothers and 771 unexposed
controls, as well as 719 exposed offspring and 734 unexposed offspring, and mailed them questionnaires. Of
the exposed mothers, 90.4 percent responded, as did 91.45 percent of the unexposed mothers, 88.2 percent
of the exposed offspring, and 89.2 percent of the unexposed. Ruth M. Hagstrom et al.,"Long Term Effects
of Radioactive Iron Administered During Human Pregnancy," American Journal of Epidemiology 90 ( 1 969):
1-8.
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exposure was an underestimation of the fetal-absorbed dose.
A 1969 study, funded by the AEC and conducted by one of the investigators from the
1963-1964 study, attempted to reconstruct the doses of Fe-59 to the fetuses in the original
Vanderbilt study . J The investigators observed that the one case of leukemia might have been due
to radiation damage, but that the doses in the other two cases were low; therefore, the relationship
between the radiation exposure and the cancer in those cases might not have been causal.
However, the researchers also noted that due to incomplete data, they could not estimate the dose
absorbed by the fetus with confidence and that no definitive conclusions could be drawn from this
study as to whether these exposures resulted in damage to the fetus. k
The Vanderbilt study raises many of the same ethical issues as the experiments reviewed
in this chapter. Like these experiments, the Vanderbilt study offered no prospect of medical
benefit to the pregnant women or their offspring, raising the question of the conditions under
which it is acceptable to put children at risk for the benefit of others, whether before or after birth.
What could the investigators reasonably have been expected to know about the risks to which they
put their subjects? Did they exercise appropriate caution in exposing fetuses to radiation? What
were the pregnant women told, if anything, and was their permission sought? Who were these
women, and how were they positioned relative to pregnant women, generally?
The Committee did not have the resources to pursue these questions in both research in
which children were the subjects and research in which children were exposed as fetuses. We did
establish that the Vanderbilt study was not the only experiment during this period to expose
fetuses in research that offered no prospect of medical benefit to them or their mothers. While the
Committee did not conduct an exhaustive review of the scientific literature, we did find twenty-
seven human radiation studies that included pregnant or nursing women as subjects between 1944
and 1974.' Of these studies, eight were considered therapeutic, and nineteen offered no prospect of
benefit to the subject. Most of the nineteen were tracer experiments.
These studies were performed in order to examine human physiology during pregnancy
or to study the uptake of radioactive substances by fetuses or nursing infants." 1 They generally
j. Norman C. Dyer and A. Bertrand Brill, "Fetal Radiation Dose from Maternally Administered
Fe-59 and 1-131," in Radiation Biology of the Fetal and Juvenile Mammal: Proceedings of the Ninth Annual
Hanford Biology Symposium at Richland. Washington. May 5-8. 1969, eds. Melvin R. Sikov and D. Dennis
Mahlum (Washington, D.C.: GPO, December 1969), 78-88. This study was reviewed in detail by the
Committee. The study also investigated fetal absorption of radioiodine because that isotope was and is
commonly used in diagnosis and therapy, including in pregnant women.
k. Ibid., 85.
1. All of the nineteen studies reviewed in detail by the Committee were conducted or at least
partially funded by the federal government or were supplied with radioisotopes by the AEC. For the earlier
years, the Committee relied on the ACHRE experiments database, AEC isotope distribution lists provided by
DOE, and relevant biographies. The Committee also consulted relevant medical indexes and computer
databases; the isotope distribution lists provided by DOE did not cover these years. While the computer
search would have located nontherapeutic tracer experiments for this period as well, very few were
identified.
m. Of the nineteen tracer experiments (funded by the government) involving pregnant or nursing
women identified by the Committee, only three administered tracer doses to nursing women that offered no
prospect of benefit; in at least one of the studies the infants were exposed. In one case, six nursing women
were given radioiodine to determine excretion in breast milk, the infants were not given the exposed milk. In
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addressed valid scientific questions that could not be investigated in other populations.
Knowledge of fetal exposure to radioiodine. for example, was relevant to issues such as potential
harm to the fetus from maternal uptake of radioiodine in diagnostic tests or to estimate the
potential effects of environmental exposure to radioiodine on the human fetus. In other studies,
radioactive iron was administered to better understand the physiology of maternal and fetal intake
of iron during pregnancy.
another case, two infants were intentionally exposed to the breast milk of their mothers, who were given I-
131. An I- 1 3 1 tracer study on the general population, incidentally included two nursing women. The report
indicates that both had been nursing their children, and since there is no indication that the mothers were
warned to avoid breastfeeding after the exposure, it is quite probable that the infants were exposed.
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Nasopharyngeal Irradiation
Nasopharyngeal irradiation," introduced by S. J. Crowe and J. W. Baylor of the
Otological Research Laboratory at the Johns Hopkins University, was employed from 1924 on as
a means of shrinking lymphoid tissue at the entrance to the eustachian tubes to treat middle ear
obstructions, infections, and deafness. For this treatment, intranasal radium applicators (sealed
ampules containing radium salt) were inserted (at least three insertions per treatment cycle) into
the nasopharyngeal area for twelve-minute periods. 11 The therapeutic effect of the treatments
resulted from the penetrating radiation emitted from the radium source (gamma and beta rays), not
a. Nasopharyngeal irradiation was studied in adults as well as children. In the early 1940s, 732
submariners were subjects of a controlled experiment designed to test whether nasopharyngeal radium
treatments could be used to shrink lymphoid tissue surrounding the eustachian tubes, thereby preventing and
treating aerotitis media in submariners by equalizing external and middle ear pressure. This treatment was
successful in 90 percent of the cases. H. L. Haines and J. D. Harris, "Aerotitis Media in Submariners,"
Annals of Otology. Rlrinology. and Laryngology 55 ( 1 946): 347-37 1 . In a 1 945 journal article, it was noted
that a controlled study was considered by the Army Air Forces, but rejected because of the urgent need to
treat fliers immediately and keep them flying. However, the published report describes differences between
various dose groups, implying an uncontrolled experimental comparison was made. Captain John E.
Hendricks et al., "The Use of Radium in the Aerotitis Control Program of the Army Air Forces: A Combined
Report by the Officers Participating," Annals of Otology, Rlrinology. and Laryngology' 54 ( 1 945 ): 650-724.
Tens of thousands of servicemen were subsequently given this nasopharyngeal radium treatment.
Relying on the risk estimate developed in the Sandler study, Stewart Farber, a radiation-monitoring
specialist with a background in public health, has projected 5 1 .4 excess brain cancers over a fifty-year
period in the 7,613 servicemen irradiated in the Navy and Army Air Forces studies noted above. Stewart
Farber, Consulting Scientist of the Public Health Sciences, to Stephen Klaidman, ACHRE Staff. 8 March
1995 ("Nasopharyngeal Radium Irradiation-Initial Radiation Experiments Performed by DODon 7,613
Navy and Army Air Force Military Personnel during 1944-45"). Alan Ducatman, M.D.. of the University of
West Virginia School of Medicine, who coauthored a letter with Farber to the New England Journal of
Medicine regarding the radium exposure of military personnel, wrote that he found "no convincing evidence
of excess cancer in the exposed population." He added, however, "there is also no good evidence for the null
hypothesis." Alan Ducatman, West Virginia University School of Medicine, to Duncan Thomas, Member of
the Advisory Committee on Human Radiation Experiments, 22 February 1995 ("I'm sorry I could not
respond . . .") (ACHRE No. WVU-02 1 795-A).
Han K. Rang, with the Environmental Epidemiology Service of the Veterans Health
Administration, is currently conducting a study to assess the feasibility of an epidemiologic study of Navy
veterans who received radium treatments. Han K. Rang. Environmental Epidemiology Service, Veterans
Health Administration, "Feasibility of an Epidemiologic Study of a Cohort of Submariners Who Received
Radium Irradiation Treatment," 23 August 1994. It is not clear, however, that sufficient numbers of
treatment-documented personnel can be identified, as a group representing submariners has apparently been
able to identify only six former Navy personnel from of a pool of twenty-seven whose records indicate they
received radium treatment. (It is not clear whether the data being collected by the VFW with the support of
Senator Joesph Lieberman of Connecticut will be from a representative sample of respondents. If, in fact,
these data are from a highly nonrepresentative sample, the study may not be considered scientifically valid.)
However, the Veterans of Foreign Wars organization apparently is now processing hundreds of surveys filled
out by veterans who say they underwent nasopharyngeal radium treatment. Once this task is completed.
Senator Lieberman plans to present the data to the Department of Veterans Affairs with a recommendation
that an epidemiologic study be conducted.
b. Samuel J. Crowe, "Irradiation of the Nasopharynx," Annals of Otology, Rhinology and
Laryngology 55 (\9Ad): 31.
352
Chapter 7
from the internal deposition of radium itself. Crowe and his colleagues reported that "under this
treatment, the lymphoid tissue around the tubal orifices gradually disappeared, marked
improvement or complete return of the hearing followed, and in many the bluish discoloration of
the tympanic membrane also disappeared."" This method was used for more than a quarter century
as a prophylaxis against deafness, for relieving children with recurrent adenoid tissue following
tonsillectomy and adenoidectomy, and for children with chronic ear infections. Asthmatic
children with frequent upper respiratory infections were also often considered for this type of
irradiation.
An average of 1 50 patients a month, mostly children, were given the treatment at the
Johns Hopkins clinic over a period of several years.' 1 Many children received the treatment more
than once as recurrent lymphoid tissue Was considered an indication for treatment.
Crowe and his colleagues reported that the results following irradiation of the
nasopharynx alone were not only as good as, but often better than, those following removal of
tonsils and adenoids." In review articles, they noted that approximately 85 percent of treated
patients responded with decreased numbers of infections and/or improved hearing when treated at
young ages. They also concluded that "it is effective, safe, painless, inexpensive and has proved
particularly valuable for prevention of certain ear, sinus and bronchial condition in children." 1
Although early articles by Crowe and colleagues indicate that nasopharyngeal radium treatments
were accepted as standard procedure for the prevention of childhood deafness, these treatments,
like most standard interventions in medicine, had not been subjected to formal scientific
evaluation. A controlled study was conducted from 1948 to 1953 by Crowe and his colleagues to
determine "the feasibility of irradiation of the nasopharynx as a method for controlling hearing
impairment in large groups of children associated with lymphoid hyperplasia in the nasopharynx;
to draw conclusions concerning the per capita cost of such an undertaking as a public health
measure." 6 Crowe et al. wrote in an NIH "Notice of Research" that "the procedure of treatment is
not new, as an individual measure; this is the first adequately controlled experiment of sufficient
size for accurate statistical analysis."' 1
This work was funded by NIH for the entire period of study. As recorded in an NIH grant
application, the study involved approximately 7,000 children screened for hearing impairment.' Of
those screened, approximately 50 percent were selected for further study based on the chosen
criteria for hearing loss. Half of this study group was irradiated with radium, while the other half
served as a control group. Crowe and colleagues reportedly concluded from this study (published
in 1955) that the radium treatments did shrink swelling of lymphoid tissue and improve hearing. 1
This type of therapy was ultimately discontinued because of newly available antibiotics and the
c. Ibid.. 30.
d. Ibid., 33.; Dale P. Sandler et al., "Neoplasms Following Childhood Radium Irradiation of the
Nasopharynx," Journal of the National Cancer Institute 68 ( 1982): 3-8.
e. Ibid., 33.
f. Ibid.
g. S. J. Crowe et al.. The Johns Hopkins University School of Medicine and School of Hygiene
and Public Health, to Federal Security Agency, Public Health Service, National Institutes of Health, July
1948 ("The Efficiency of Nasopharyngeal Irradiation In the Prevention Of Deafness in Children, Notice of
Research Project, Grant No. B-19") (ACHRE No. HHS No. 092694-A).
h. Ibid,
i. Ibid.
j. Ibid.
353
Part II
use of transtympanic drainage tubes, as well as awareness of the potential risks of radiation
treatment.
In addition to the targeted lymphoid tissue, the brain and other tissues in the head and
neck region, including the paranasal sinuses, salivary glands, thyroid, and parathyroid glands are
also exposed to significant doses of radiation during the radium treatments, prompting concern that
these treated individuals might have been placed at increased risk for radiation-induced cancers at
these sites. Dale P. Sandler et al., in their 1982 study of the effects of nasopharyngeal irradiation
on excess cancer risk for children treated at the Johns Hopkins clinic, found "a statistically
significant overall excess of malignant neoplasms of the head and neck among exposed subjects,"
based however on only four cases in comparison with 0.57 expected. 1 This excess was accounted
for mainly by three brain tumors that occurred in the irradiation subjects. One other malignant
tumor, a cancer of the soft palate, was also reported. The Department of Epidemiology at the
Johns Hopkins University has undertaken a further follow-up study of the Crowe et al. cohort of
children irradiated there, previously studied by Sandler et al. 1 Verduijn et al., in their 1989 study
of cancer mortality risk for those individuals (mostly children) treated by nasopharyngeal
irradiation with radium 226 in the Netherlands, reported that "the present study has found no
excess of cancer mortality at any site associated with radium exposure by the Crowe and Baylor
therapy. Specifically,
the finding of Sandler et al. of an excess of head and neck cancer was not found in this study
group.""'
Among the Japanese atomic bomb survivors, no excess of brain tumors was found.
However, several studies have noted an increased risk of both benign and malignant brain tumors
following therapeutic doses of radiation to the head and neck region during childhood." From the
Committee's own limited risk analysis of these experiments, we concluded that the brain and
surrounding head and neck tissues would be put at highest risk and estimated the lifetime risk at
approximately 4.35 per 1,000 and an increased relative risk of 62 percent."
k. For the combination of benign and malignant neoplasms, there were 23 cases, for a relative risk
of 2.08 with a 95 percent confidence interval of 1.12 to 3.91. Sandler, "Neoplasms Following Childhood
Radium Irradiation," 5.
I. Jessica Yeh and Genevieve Matanowski, fax to Anna Mastroianni (ACHRE), 7 July 1995
("Nasopharyngeal Power Analysis"), 1-3.
in. Verduijn et al., "Mortality after Nasopharyngeal Irradiation," Annals of Otology. Rhinology,
and Laiyngolog}- 98 ( 1 989): 843.
n. S. Jablon and H. Kato, "Childhood Cancer in Relation to Prenatal Exposure to Atomic-Bomb
Radiation," The Lancet, ii (1970): 1000-1003.; M. Colman, M. Kirsch, and M. Creditor, "Radiation Induced
Tumors," in Late Biological Effects of Ionizing Radiation. Vol. I (Vienna: International Atomic Energy
Agency, 1978), 167-180; R. E. Shore, R. E. Albert, and B. S. Pasternak, "Follow-up Study of Patients
Treated by X ray Epilation for Tinea Capitis: Resurvey of Post-Treatment Illness and Mortality Experience,"
Archives of Environmental Health 31(1 976): 1 7-24; and C. E. Land.Xarcinogenic Effects of Radiation on
the Human Digestive Tract and Other Organs." in Radiation Carcinogenesis, eds. A. C. Upton et al. (New
York: Elsevier, 1986), 347-378.
o. The radiation dose estimate to the head and neck region was calculated according to the
following assumptions: ( I ) Source description: 50 ing of radium, active length 1 .5 cm, filtered by 0.3 mm of
Monel metal. (2) Average treatment: 60 mg/hrs; based on three 12-minute treatments (radium applicators
inserted through both nostrils)= ( 12x3x50x2 )/60 mins per hour= 60 mg-hrs. (3) Dose rate at points in a
central orthogonal plane surrounding the source: for distances up to 5 centimeters dose estimated using
published data (Quimby Tables, Otto Glasser et al.. Physical Foundations of Radiology, 3d ed. [New York:
Paul Hoeber, Inc., 1961]) for linear radium sources with dose increased by 50% to allow for the reduced
354
Chapter 7
The Hopkins nasopharyngeal study raises different ethical issues than those posed by the
other experiments reviewed in this chapter, all of which offered no prospect of medical benefit to
the children who served as subjects. By contrast, the nasopharyngeal irradiation experiment was
designed to determine whether children at risk for hearing loss would be better off receiving
radiation treatments or not receiving such treatments. A central issue here was whether it was
permissible to withhold this intervention from "at risk" children. The application of radium was at
this point a common, but scientifically unproven, treatment for children at risk of hearing loss; the
risks of the treatment were not well characterized. If it was really unknown which was better for
children-receiving radium or no intervention-then the medical interests of the children were best
served by being subjects in the research because, as a consequence, they would have a 50 percent
chance of receiving the better approach. The nasopharyngeal experiment thus belongs to a class of
research the Committee did not investigate-therapeutic research with children.
filtration provided by the applicator wall and converting roentgen to rad by a multiplication factor of 0.93.
For distances greater than 5 centimeters, the dose rate is reduced in accordance with the inverse square law,
with a proportionality constant of 690 rad-cnr. There was no dose correction for attenuation of the gamma
rays by tissue absorbtion, which has been calculated to be about 2%/cm (yielding a dose reduction of about
20% at 10 cm).
The local gamma dose to the head and neck region was assumed to be distributed according to an
inverse square law d(r) = 690/r rad. The Committee approximated the exposed region of the body by a
sphere with radius 10 centimeters. This was felt to be a conservative assumption, because although the dose
does not go to zero at the base of the neck, a 10-centimeter sphere would also extend outside the skull.
Averaging this dose distribution over the exposed sphere, the average dose to the head was found to be 20.7
rad. The exposed volume is about 4189 cm', or 29 percent of the total body, so the average whole body dose
is about 6.0 rad. Multiplying this by the BEIR V risk coefficient for children exposed at age five. 1.4/1,000
person-rad, produces a lifetime risk of about 8.4/1,000. This calculation assumes that the brain and other
head tissues have average radiosensitivity. BEIR V also gives absolute-risk coefficients for brain cancer
ranging from 1 to 9 per million person-year-rad, with 3 being a reasonable average. Applying this figure to
an average head dose of 20.7 rad, the Committee estimates a lifetime risk of about 4.35/1,000. The
corresponding relative risk coefficients average about 3 percent per rad, so this dose would correspond to an
excess relative risk of 62 percent.
355
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ENDNOTES
1 . As noted in the report of the Massachusetts Task Force, "many of the people
who became residents of the Walter E. Fernald School . . . were not admitted with a
diagnosis of mental retardation. Societal and cultural norms of the day permitted persons
to be admitted to state-operated institutions for a number of reasons. All were labeled
mentally retarded just by virtue of having lived within the facility." Task Force on
Human Subject Research, to Philip Campbell, Commissioner, Commonwealth of
Massachusetts Executive Office of Health and Human Services, Department of Mental
Retardation, April 1994, "A Report on the Use of Radioactive Materials in Human
Subject Research that Involved Residents of State-Operated Facilities within the
Commonwealth of Massachusetts from 1943 to 1973" (ACHRE No. MASS-072194-A),
1.
2. Task Force on Human Subject Research, April 1994 ("A Report on the Use
of Radioactive Materials in Human Subject Research that Involved Residents of State-
Operated Facilities within the Commonwealth of Massachusetts from 1943 to 1973");
and the Working Group on Human Subject Research to Philip Campbell, June 1994
("The Thyroid Studies: A Follow-up Report on the Use of Radioactive Materials in
Human Subject Research that Involved Residents of State-Operated Facilities within the
Commonwealth of Massachusetts from 1943 through 1973") (ACHRE No. MASS-
072194-B).
3. Unfortunately, the published reports of the twenty-one research projects we
review in this chapter often provide little or no information that could be used to identify
the individual children. Many published reports provide information only about the
child's age, weight, and diagnosis. Other reports provide only the child's initials and
diagnosis. In either case, it would be difficult or impossible to identify specific
individuals from this limited information. An existing chart may or may not confirm a
child's involvement in a research project. If the investigators maintained records, those
could serve as a key to identify the individuals. Even if the hospital records do exist,
however, records for a period of several years prior to publication of the research would
have to be reviewed in order to match a set of initials with a diagnosis. However, it is
unlikely that research records have been maintained for many of these projects for the
past three to five decades. Finally, the identification of an individual would be only the
first step in tracking him to his current location.
Many of the children at the Wrentham and Fernald Schools have been located
through extensive local efforts. The existence of the research records, as well as the
records of these long-term residential institutions, have made these identifications
possible.
4. There are a few exceptions to the usual involvement of parents in decisions
concerning their minor children. Children who are considered either "emancipated
minors" or "mature minors" are generally able to receive routine medical care without
any need for parental involvement. Emancipated minors are minor children who have
taken on adult responsibilities, such as maintaining financial independence and/or living
away from the parents' home. A mature minor, on the other hand, is considered to be
decisionally capable under special circumstances because he or she has demonstrated the
maturity and ability to decide treatment decisions for himself or herself. Adolescents can
be considered emancipated or mature minors and are thereby exempted from parental
consent. In addition, if a minor is close to the age of majority (at least fifteen), the
treatment clearly benefits the minor and is medically necessary, there is good justification
for not obtaining parental consent, and if the procedure is not extraordinary or one
358
involving substantial risk to the child, then practitioners are usually able to deliver
medical care without parental permission. A number of states permit minors to give
consent to the diagnosis or treatment of venereal disease, drug addiction, alcoholism,
pregnancy, or for purposes of giving blood. For more information on this subject, please
see: A. R. Holder, Legal Issues in Pediatrics and Adolescent Medicine (New Haven, Yale
University Press, 1985), 123; and Robert H. Mnookin and D. Kelly Weisberg, Child,
Family, and State: Problems and Materials on Children and the Law (Little Brown and
Company, New York, 1995).
5. Mnookin and Weisburg, Child, Family, and State, 536. In addition, parents
are considered to be "legally responsible for the care and support of their children," and
"the parental consent requirement protects parents from having to pay for unwanted or
unnecessary medical care and from the possible financial consequences of supporting the
child if unwanted treatment is unsuccessful."
6. In addition to the exceptions given in endnote 4, there are other standard
common law and statutory limitations and exceptions to the general parental consent
requirement. "These relate to mandatory immunizations and screening procedures
(applicable to all children), the neglect limitation (where a court may override a parental
decision for an individual child), the emergency treatment of children (where no parental
consent is required if the parent is unavailable)." Ibid.
7. "Some medical procedures are required of all children and in this sense
represent generally applicable limitations on parental prerogatives. The Supreme Court
has held, for example, that a state could impose a compulsory smallpox vaccination law
as a 'reasonable and proper exercise of police power.' Jacobsen v. Massachusetts, 197
U.S. 1 1, 35 (1905) quoting Viemeister v. White, 72 N.E. 97 (1904). A vaccination
requirement may act to protect society from various public health hazards created by
communicable diseases where a parental decision may endanger not only a particular
child but society at large." Mnookin and Weisburg, Child, Family, and State, 55 1 .
8. The National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research, Research Involving Children: Report and
Recommendations (Washington, D.C.: GPO, 1977), and Protection of Human Subjects,
45 C.F.R. § 46, subpart D.
9. Protection of Human Subjects, 45 C.F.R. § 46.408.
10. Ibid., § 46.404.
11. Ibid., § 46.406.
12. Ibid., § 46.407.
13. Susan E. Lederer and Michael A. Grodin. "Historical Overview: Pediatric
Experimentation," in Children as Research Subjects: Science, Ethics, and Law, eds.
Michael A. Grodin and Leonard H. Glantz (New York: Oxford University Press, 1994),
4.
14. Ibid., 5.
15. Ibid., 6.
16. "Orphans and Dietetics," American Medicine 27 (1921): 394-396.
1 7. Lederer and Grodin, Children as Research Subjects, 11-12.
18. Ibid., 14.
19. Ibid., 12.
20. Ibid., 15.
2 1 . This ruling is summarized in Jay Katz, Experimentation with Human
Beings, the Authority of the Investigator, Subject, Professions, and State in the Human
Experimentation Process (New York: Russell Sage Foundation, 1972), 972-974.
22. Ibid.
23. Ibid.
359
24. Ibid.
25. This case is also discussed in "Use of Fifteen Year Old Boy as Skin Donor
Without Consent of Parents as Constituting Assault and Battery: Bureau of Legal
Medicine and Legislation Society Proceedings," Journal of the American Medical
Association 1 20 ( 1 7 October 1942): 562-563.
26. For more information on the Nuremberg Code, please see United States v.
Karl Brandt, et ai, "The Medical Case," Trials of War Criminals before the Nuremberg
Military Tribunals under Control Council Law No. 10 (Washington, D.C.: GPO, 1949),
2; Jay Katz, "Human Experimentation and Human Rights," St. Louis University Law-
Journal 38 (1993); and George J. Annas and Michael A. Grodin, eds., The Nazi Doctors
and the Nuremberg Code: Human Rights in Human Experimentation (New York:
Oxford University Press, 1992).
27. Irving Ladimer, "Legal and Ethical Implications of Medical Research on
Human Beings," (S.J.D. diss., George Washington University, 1958), appendix II, 202-
208.
28. Ibid., 207.
29. Ibid., 206.
30. Ibid., 208.
3 1 . Henry Seidel, interview by Gail Javitt ( ACHRE), transcript of audio
recording, 20 March 1995 (Research Project Series, Oral History Project), 67-68.
32. Ibid.
33. William Silverman, interview by Gail Javitt (ACHRE), transcript of audio
recording, 14 February 1995 (Research Project Series, Oral History Project), 26.
34. Ibid.
35. Boston University, Law-Medicine Research Institute, 1 May 1961
("Conference on Social Responsibility in Pediatric Research")(ACHRE No. BU-062394-
A). This was part of a larger LMRI project (which was funded by NIH) to investigate
actual practices in clinical research. The project began in early 1960 and continued until
1963, resulting in a lengthy final report, which was never published.
36. Ibid., 5. In this document, speakers are identified by initials. A list of
participants found in these same records generally makes identifying particular speakers
in the transcripts quite straightforward. In this case, however, a complexity arises
because the speaker is identified as "WF." The list of participants reveals no one with
these initials, and "WF" appears only once in the transcripts. It is almost certain that
"WF" is a typographical error, and given the flow of the transcripts, it is also almost
certain that "WF" should have been "WS"--William Silverman.
37. Ibid., 7.
38. Ibid,, 3.
39. Ibid.
40. Ibid., 2.
41. Ibid., 6.
42. Ibid., 17.
43. Ibid., 15.
44. Ibid.
45. The Declaration of Helsinki can be found in many sources, but its earliest
published appearance was perhaps "Human Experimentation: Code of Ethics of the
World Medical Association," British Medical Journal 2 (1964): 177.
46. Ibid.
47. Ibid.
48. Ibid.
49. Ibid.
360
50. Much has been written on the Willowbrook studies; for a short summary of
this episode see Ruth R. Faden and Tom L. Beauchamp, A Histoiy and Theoiy of
Informed Consent (New York: Oxford University Press, 1986), 5, 163-164.
5 1 . Henry Beecher, Research and the Individual: Human Studies (Boston:
Little, Brown, and Company, 1970), 122-127.
52. There were many exchanges in the medical literature over the hepatitis
studies conducted by Saul Krugman at the Willowbrook State School. Stephen Goldby
wrote an editorial to The Lancet, expressing his outrage over The Lancet's position on
Krugman's research, saying that the research was "quite unjustifiable, whatever the aims,
and however academically or therapeutically important are the results. ... Is it right to
perform an experiment on a normal or mentally retarded child when no benefit can result
to that individual?" The editors of The Lancet responded to Goldby's letter, expressing
agreement with his position, stating, "The Willowbrook experiments have always carried
a hope that hepatitis might one day be prevented there and in other situations where
infection seems almost inevitable; but that could not justify the giving of infected
material to children who would not directly benefit." Krugman responded to these
editorials by arguing,
Our proposal to expose a small number of newly
admitted children to the Willowbrook strains of hepatitis
virus was justified in our opinion for the following
reasons: 1 ) they were bound to be exposed to the same
strains under the natural conditions existing in the
institution, 2) they would be admitted to a special, well-
staffed unit where they would be isolated from exposure
to other infectious diseases which were prevalent in the
institution. . . . Thus, their exposure in the hepatitis unit
would be associated with less risk than the type of
institutional exposure where multiple infections could
occur; 3) they were likely to have a subclinical infection
followed by immunity to the particular hepatitis virus;
and 4) only children with parents who gave informed
consent would be included.
The debate over these experiments continued, as evidenced by editorials by Geoffrey
Edsall, Edward Willey, and Benjamin Pasamanick in The Lancet and through an editorial
in JAMA as well. Jay Katz, Experimentation with Human Beings, 1007-1010; Geoffrey
Edsall, "Experiments at Willowbrook," The Lancet ( 1 July 1971): 95; Edward N. Willey
and Benjamin Pasamanick, "Experiments at Willowbrook," The Lancet (22 May 1971):
1 078- 1 079; and "A Shedding of Light," Journal of the American Medical Association
212(11 May 1970): 1057-1058.
53. S. Allan Lough, Chief of the Radioisotopes Branch, AEC Isotopes Division,
to Drs. Hymer L. Friedell, G. Failla, Joesph G. Hamilton, A. H. Holland, Members of
AEC Subcommittee on Human Applications, 19 July 1949 ("Revised Tentative Minutes
of March 13, 1949 Meeting of Subcommittee on Human Applications of Committee on
Isotope Distribution of U.S. Atomic Energy Commission, AEC Building, Washington,
D.C.") (ACHRE No. NARA-082294-A-24). For price list and isotope catalogue, see
AEC Isotopes Division, Supplement No. 1 to Catalogue and Price List No. 3, September
1949 (ACHRE No. DOD-122794-A), 3-4.
54. S. Allan Lough, 19 July 1949 ("Revised Tentative Minutes of March 13,
1949 Meeting..."), 10.
361
55. AEC General Manager Carroll Wilson's two 1947 letters that address the
consent issue (see chapter 1) did not specifically mention children. The second letter,
dated November 1947, required that "the patient give his complete and informed consent
in writing, and (c) that the responsible nearest of kin give in writing a similarly complete
and informed consent. . . ." It is not clear, however, that Wilson's phrase, "responsible
nearest of kin," was written out of concern for children and other patients not capable of
giving "complete and informed consent," as opposed, for example, to adult patients who
were too sick to give such consent. Moreover, it is not even clear whether the letter was
intended to apply to experiments with healthy subjects, as opposed to sick patients, or to
experiments using tracer amounts of radioactive substances. The second letter is
specifically focused on "substances known to be, or suspected of being, poisonous or
harmful." It is plausible, for example, that tracer amounts of radionuclides were
considered "harmless," especially since the Wilson letter expressly prohibited the
administration of "harmful" substances unless there was a reasonable hope that "such a
substance will improve the condition of the patient." Carroll L. Wilson, General Manager
of the AEC, to Stafford Warren, the University of California, Los Angeles, 30 April 1947
("This is to inform you that the Commission is going ahead with its plans . . .") (ACHRE
No. DOE-051094-A-439), 1. Also C. Wilson, General Manager, AEC, to Robert Stone,
University of California, 5 November 1947 ("Your letter of September 1 8 regarding the
declassification of biological and medical papers was read at the October 1 1 meeting of
the Advisory Committee on Biology and Medicine.") (ACHRE No. DOE-052295-A).
56. J. H. Lawrence, "Early Experiences in Nuclear Medicine," The Journal of
Nuclear Medicine 20 (1979): 561 . (Publication of speech given in 1955). Dr. Lawrence
concludes, however, that "as a matter of fact, in the 20 years since we first used
artificially produced radioisotopes in humans, we have not run into delayed effects or
complications as some of the skeptics predicted we would." Ibid., 562.
57. This correspondence can be found in Task Force on Human Subject
Research, A Report on the Use of Radioactive Materials, appendix B, documents 16-18.
58. Citations for the studies for which the Committee performed detailed risk
analysis can be found in the supplemental volumes.
59. S. H. Silverman and L. Wilkins, "Radioiodine Uptake in the Study of
Different Types of Hypothyroidism in Childhood," Pediatrics 12 (1953): 288-299.
60. V. C. Kelley et al., "Labeled Methionine as an Indicator of Protein
Formation in Children with Lipoid Nephrosis," Proceedings of the Society for
Experimental Biology and Medicine 76 ( 1 950): 1 53- 1 55.
61 . M. A. Van Dilla and M. J. Fulwyler, "Thyroid Metabolism in Children and
Adults Using Very Small (Nanocurie) Doses of Iodine- 125 and Iodine- 131," Health
Physics 9 (\963): 1325-1331.
62. For more information, please see the "Introduction: The Atomic Century,"
sections entitled "How Do We Measure the Biological Effects of Internal Emitters?" and
"How Do Scientists Determine the Long-Term Risks From Radiation?"
63. International Commission on Radiological Protection, Publication 53: Data
for Protection Against Ionizing Radiation from External Sources (New York: Pergamon
Press, 1973); see also National Council on Radiation Protection and Measurements,
Report 80: Induction of Thyroid Cancer by Ionizing Radiation— Recommendations of the
National Council on Radiation Protection and Measurements (New York: The Council,
1985).
64. R. E. Shore et al., "Thyroid Tumors Following Thymus Irradiation," Journal
of the National Cancer Institute 74 ( 1 985): 1 1 77- 1 1 84.
65. E. Ron and B. Modan, "Thyroid and Other Neoplasms Following Childhood
Scalp Irradiation," in J. D. Boice, Jr., and J. F. Fraumeni, Jr., eds., Radiation
362
Carcinogenesis: Epidemiology and Biological Significance (New York: Raven, 1 984),
139-151.
66. R. L. Prentice et al., "Radiation Exposure and Thyroid Cancer Incidence
among Hiroshima and Nagasaki Residents," National Cancer Institute Monographs 62
(1982): 207-212.
67. National Council on Radiation Protection and Measurements, Report 80:
Induction of Thyroid Cancer by Ionizing Radiation. The BIER V report recommends a
figure of 0.66 but with a broad confidence interval of (0.14-3.15). National Research
Council, Board on Radiation Effects Research, Committee on the Biological Effects of
Ionizing Radiation, Health Effects of Exposure to Low Levels of Ionizing Radiation:
BIER V{ Washington, D.C.: National Academy Press, 1990), 5, 298.
68. Task Force on Human Subject Research, "A Report on the Use of
Radioactive Materials in Human Subject Research that Involved Residents of State-
Operated Facilities within the Commonwealth of Massachusetts from 1943 to 1973."
69. Protection of Human Subjects, 45 C.F.R. § 46. 1 02.
70. Ibid., § 46.406.
71 . F. P. Castronovo, "An Attempt to Standardize the Radiodiagnostic Risk
Statement in an Institutional Review Board Consent Form," Investigative Radiology 28
(1993): 533-538.
72. W. L. Freeman, "Research with Radiation and Healthy Children: Greater
than Minimal Risk," IRB: A Review of Human Subjects Research 5, no. 16 (1994): 1-5.
73. B. J. Duffy and P. J. Fitzgerald, "Thyroid Cancer in Childhood and
Adolescence: A Report of Twenty-eight Cases," Cancer 3 (November 1950): 1018-1032.
74. R. Murray, P. Heckel, and L. H. Hempelmann, "Leukemia in Children
Exposed to Ionizing Radiation," New England Journal of Medicine 261(1 959): 585-597.
75. Eugene L. Saenger et al., " Neoplasia Following Therapeutic Irradiation for
Benign Conditions in Childhood," Radiology 74 (1960): 889-904. For more information
on the work of Eugene Saenger, please see chapter 8, "Total-Body Irradiation: Problems
When Research and Treatment Are Intertwined."
76. Ibid., 889.
77. Ibid., 901.
78. S. A. Beach and G. W. Dolphin, "A Study of the Relationship Between X-
Ray Dose Delivered to the Thyroids of Children and the Subsequent Development of
Malignant Tumors," Physics in Medicine and Biology 6 ( 1 962): 583-598.
79. Ibid., 583.'
80. One rep (roentgen equivalent physical), a unit that is no longer used, is
approximately equivalent to one rem (roentgen equivalent man).
81. J. C. Aub, A. K. Solomon, and Shields Warren, Harvard Medical School, 7
May 1949 ("Tracer Doses of Radioactive Isotopes in Man") (ACHRE No. HAR- 100395-
A). It appears that at least one physician-researcher of the time determined to avoid an
unknown risk by not administering radioisotopes in studies with pregnant women and
children. In his recent autobiography, Dr. Francis Moore, an eminent Boston-based
surgeon, recalled that "in pregnancy, even very small doses of radiation are dangerous to
the unborn child, so we did not use radioactive isotopes in studying the body composition
in pregnant women or in young children." Presumably Dr. Moore is referring to the
1940s when he began his pioneering research employing radioisotopes to determine the
composition of the body, although this is not clear. Whether Dr. Moore's view was
informed by dialogue with the relevant pediatric perspectives reviewed here also is
unclear. Francis D. Moore, M.D., A Miracle and a Privilege: Recounting a Half Century
of Surgical Advance (Washington, D.C.: Joseph Henry Press, 1995), 109, 111.
363
82. L. Van Middlesworth, "Radioactive Iodide Uptake of Normal Newborn
Infants," American Journal of Diseases of Children 88(1 954): 44 1 .
83. Malcom J. Farrell, Superintendent, Walter E. Fernald State School, to
Parent, 2 November 1949 ("The Massachusetts Institute of Technology and this
institution are very much interested . . ."), as cited in the Task Force for Human Subject
Research, "A Report on the Use of Radioactive Materials," appendix B, document 19.
84. This form states,
To the Superintendent of the Walter E. Fernald State
School:
This is to state that I give my permission for the
participation of in the project mentioned in your
letter of
Witnessed by:
Signature
Date:
Relationship
Permission form from Parent to the Superintendent of the Walter E. Fernald State School,
2 November 1949 ("This is to state that I give my permission . . ."), as cited by the Task
Force on Human Subject Research, in "A Report on the Use of Radioactive Materials,"
appendix B, document 19.
85. Clemens E. Benda, Director of Research, the Walter E. Fernald State
School, to Parent, 28 May 1953, as cited by the Task Force on Human Subject Research,
in "A Report on the Use of Radioactive Materials," appendix B, document 23.
86. As stated in the Massachusetts Task Force report, the purpose of the
nutritional research studies was to "understand how the body obtained the minerals iron
and calcium from dietary sources and to find out whether compounds in cereals affected
their absorption ... the immediate goal of the research was to understand if either of
these cereals was preferable from a nutritional point of view." Ibid., 16.
87. Ibid., 43.
88. Fred Boyce, transcript of audio testimony before the Advisory Committee
on Human Radiation Experiments, 16 December 1994, 38.
89. Task Force on Human Subject Research, in "A Report on the Use of
Radioactive Materials," 33.
90. Susan E. Lederer and Michael A. Grodin, "Historical Overview: Pediatric
Experimentation," 12-13.
91. Boston University, Law-Medicine Research Institute, 1 January 1960 to 31
March, 1963, /J Study of the Legal, Ethical, and Administrative Aspects of Clinical
Research Involving Human Subjects: Final Report of Administrative Practices in Clinical
Research, Research Grant No. 7039 (ACHRE No. BU-053194-A), 34.
92 
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