APPLIED

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BIOPHYSICS

Survey of Physical Methods Used in Medicine

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Edited by

o^^r-q DR. N. HOWARD-JONES

^— ^ □ Editor, British Medical Bulletin

1949

CHEMICAL PUBLISHING CO., INC.

BROOKLYN, N. Y.

Copyrighted
1949

CHEMICAL PUBLISHING CO., INC.
Brooklyn n. Y.

PRINTED IN THE U. S. A.

CONTRIBUTING EDITORS

W. Binks, M.Sc, F. Inst. P.

Physics Division, National Physical Laboratory, Teddington,
Middlesex

D. G. Catcheside, M.A., Ph.D.

Lecturer in Botany, University of Cambridge, and Fellozv of Trinity
College

G. E. Donovan, M.Sc, M.B., D.P.H.

Public Health Department, Gorseinon, Swansea

F. Ellis, M.Sc, M.D., F.F.R.

Medical Director, Radiotherapy Department, London Hospital

D. S. Evans, Ph.D.

Clarendon Laboratory, Oxford

A. Glucksmann, M.D.

Strang eways Research Laboratory, Cambridge

L. H. Gray, M. A., Ph.D.

The Mount Vernon Hospital, Northzvood, Middlesex

A. H. S. Holbourn, D.Phil.

Research Physicist, University Laboratory of Physiology and De-
partment of Surgery, Oxford

H. Hurst, B.Sc, Ph.D.

Department of Colloid Science, Cambridge

G. S. Innes, B.Sc, A.M.I.E.E., A. Inst. P.

Physicist and Engineer to the Sassoon Department, St. Bartholo-
mezu's Hospital

D. E. Lea, M.A., Ph.D.

Strangezvays Research Laboratory, Cambridge

W. V. Mayneord, D.Sc

Physics Department, Royal Cancer Hospital (Free) London

• ••

HI

iv Contributing Editors

K. Mendelssohn, D.Phil.

Clarendon Laboratory, Oxford

G. J. Neary, M.A., Ph.D.

Physics Department, Mount Vernon Hospital and the Radium Insti-
tute, Northwood, Middlesex

J. Read, B.Sc, Ph.D.

Physicist, Radiotherapy Department of the London Hospital

S. Russ, C.B.E., D. Sc.

Professor of Physics in the University of London, Physicist to the
Middlesex Hospital

F. G. Spear, M.A., M.D., D.M.R.E.

Strangeways Research Laboratory, Cambridge and Member of the
Scientific Staff, Medical Research Council

FOREWORD

MANY diagnostic and therapeutic procedures in medicine
and surgery are based upon the elementary principles of
physics. We have become so accustomed to accepting and
utilizing these procedures in the everyday pursuit of our voca-
tions that we have oftentimes neglected to pause and give
thought to their origin. The present volume admirably em-
phasizes our obligation to fundamental science.

The radiologist, the radiation biologist, and the physiologist
have of necessity been more closely associated with the physicist
than have many of their colleagues. This association in conjunc-
tion with the biochemist has resulted in the development of the
specialty known as biophysics which has been a major contribu-
tion to the advancement of the medical and biological sciences.
This specialty is rapidly expanding in influence and usefulness.
The biophysicist is frequently a catalytic agent, facilitating the
successful progress of a coordinated research program.

The pile production of large quantities of radioactive isotopes
and their distribution to competent investigators by the Atomic
Energy Commission have stimulated research groups to redouble
their efforts toward the solution of many complex biological
problems. There is a notable tendency to coordinate the talents
of many investigators, each specialized in his particular field,
toward the solution of a specific problem. In such cooperative
work it is particularly important that each worker's specialty be
intelligibly presented for the illumination of his fellow workers
as is done by the present volume.

The biological effects of penetrating radiations have been of
the utmost interest to many investigators and clinicians since
the discovery of X-rays by Roentgen in 1895 ; yet our knowledge
concerning the actual mechanisms of the biological actions re-

V

vi Foreword

suiting from exposure to these radiations is very meager and
little understood. These radiations may be used as a tool for
investigative purposes or in certain instances as a therapeutic
agent. In either case a better understanding of their physical
nature and their biological effects is needed.

The authors of Applied Biophysics are to be congratulated
upon their excellent presentation of a very difficult and complex
subject. The diversity of problems serves to emphasize the
importance of the field and its implications in the broad aspects
of medical science.

Andrew H. Dowdy, m.d.
Rochester, New York

TABLE OF CONTENTS

CHAPTER . PAGE

Foreword to the First American Edition v

1 . Physics in Medicine 1

2. Biophysical Factors in Drug Action 13

3. A Survey of the Applications of Electronics in

JMedicine 34

4. The Clinical Applications of Heat 59

5. The Mechanics of Brain Injuries 74

6. The Biological Effects of Penetrating Radiations 83

7. Comparative Studies of the Biological Effects of

X-rays, Neutrons, and Other Ionizing Radia-
tions 114

8. Genetic Effects of Radiations 138

9. The Actions of Radiations on Viruses and Bacteria 155

10. Quantitative Histological Analysis of Radiation

Effects in Human Carcinomata 162

11. The Measurement of Radiation 175

12. Total Energy Absorption in Radiotherapy 194

13. On Technical Methods in X-ray Therapy 216

14. On Technical Methods in Radium Therapy 234

15. Million-Volt Therapy 241

16. Protective Methods in Radiology 264

Index 283

• ■

Vll

*PHYSICS IN MEDICINE

W. V. MAYNEORD, D.Sc.
Physics Department, Royal Cancer Hospital (Free), London

Introduction

DURING the last fifty years discoveries and developments in
physics have intruded so far into medicine that physical
methods of treatment and diagnosis have become indis-
pensable, yet physics still hovers a little uncertainly on the
fringes of medical research, education, and organization. This
is not surprising when one considers that physics is the most
highly developed and abstract of the fundamental sciences, and
the practice of medicine the most highly developed of the social
arts. Numerical precision, mathematical analysis, and conse-
quent extreme generality and abstraction are the distinguishing
marks or, at least, implied ideals of physics, while in medicine
the individual patient and his often incomprehensible complex-
ities fill the picture, sometimes to the exclusion of general prin-
ciples and more abstract erudition. Yet it is recognized more
and more clearly that physics has now an important part to play
in medical research and even in the daily treatment of the patient.
Correspondingly, physics itself might benefit immensely from
closer contact with the medical and ^biological problems awaiting
solution.

Some Applications of Physics in Medicine

The most striking and perhaps best known of the recent appli-
cations of physics in medicine lie in the sphere of medical radi-

* This book is based on a collection of articles in the British Medical Bulletin.

-1

2 Applied Biophysics

ology, that is, particularly in the applications of radiations to the
problems of medicine. This year marks the fiftieth anniversary
of the discovery of X-rays by Rontgen, an event of outstanding
significance both for pure science and medicine, for it provided
the physicist with a most powerful wxapon of research into the
structure of matter, and the doctor with almost a new sense, and
diagnostic possibilities of the highest order. Later, the rays were
recognized as a lethal agent, whose proper power and scope
against malignant disease are only now being unfolded. The
year 1896 saw the discovery of radioactivity, which again has
furnished, besides the most profound studies of the structure of
matter, a powerful if still largely mysterious agent in the treat-
ment of malignancy. Recently, artificial radioactivity has pro-
vided the experimental physiologist with a means of studying
metabolic processes, while modern nuclear physics seems destined
to influence medicine profoundly as our mastery of atomic tech-
niques develops.

Tt would be easy to show how the classical lines of development
of physical inquiry have been followed in medical radiology, the
sequence first of qualitative observation, then of attempts at
quantitative measurement, disagreement, and final agreement on
units of measurement, subsequent discussion of the significance
of such units, and the gradual development of mathematical gen-
eralization and detailed solution of practical problems. We are
here concerned, however, rather with the need for an expanding
horizon and the insistence that physics has a wider scope and role
in medical thought, research, treatment, and education than so
far usually accorded to it.

This scope of physics in medicine may, for example, be gaged
from an encyclopedia of medical physics recently published in
the United States. Merely to list the headlines would require
many pages, and every branch of medicine and surgery is repre-
sented.

We think, for example, of the many applications of optical
principles in medicine and surgery, ranging from the embodiment
of laws of geometrical optics in spectacle lenses to laryngoscopes,
bronchoscopes, cystoscopes, sometimes of real beauty in design

Physics in Medicine 3

and adaptation. Coupled with the motion-picture camera, the
bronchoscope enables a film to be made during the removal of
an obstruction in a bronchus, and the observer is given a veritable
conducted tour around the lung. Body cavities have become
''accessible" in a new sense. The influence of the rather more
subtle laws of physical optics may be found in instruments for
measuring the average diameters of blood cells by the haloes
they cause around a source of light, instruments descended di-
rectly from the "eriometer," invented by Thomas Young for
measuring the diameters of fine hairs, at the time when this
physician-physicist was laying the foundations of the experi-
mental proofs of the wave theory of light. We might recall the
rather obvious fact that the optical microscope is a physical
weapon, studied and sharpened to a point where this same wave
nature of light is itself the chief and impassible barrier to seeing
the still invisible, and recognize in the substitution of streams of
electric charges for the beam of light in the new electron micro-
scope the next, and perhaps supremely important, contribution
physics has to make to the science of microscopy.

We might similarly range through all the branches of physics
and quote examples of the fundamental nature of the physicist's
contributions, either in technique or in generalizations of wide
and abstract character, which transform the nature of the prob-
lem. The use of specific electronic devices like the cathode-ray
oscillograph with its attendant amplifiers occurs to us immediately.
The science of electronics and electron optics has contributed
and will contribute to many of the problems of neurophysiology.
It may be noted in passing that "magnetism" seems a slightly
disreputable word in medicine, which is unfortunate as it appears
that a study of the magnetic properties, magnetic susceptibility,
for example, of body fluids or tissues, might well yield both useful
and interesting information. The study of sound and of modern
radio-frequency techniques has resulted in great advances in the
applications of acoustics, a subject once more intimately asso-
ciated with Thomas Young. We think, too, of the possible appli-
cations of high-frequency radio science, now making available,
both directly and indirectly, power of a hitherto undreamed of

4 Applied Biophysics

amount at wave lengths of a few centimeters, and applicable to
the heating of the human body.

No physicist turning over the pages of an anatomy textbook
can fail to see before him fascinating problems in mechanics and
the strengths of materials, yet how little we know of the
mechanics of fractures or of the instantaneous stresses and strains
when the human frame suffers some sudden impact or gradually
changing pressure.

It would be, however, tedious and little to the point to attempt
to enumerate the various direct or indirect effects which physi-
cal techniques have had on medicine, for no list can be complete
and the influence is sufficiently obvious.

History of Medical Physios

It would be a fascinating task to trace the history of the connec-
tion between physics and medicine. The interaction might per-
haps be seen as twofold, the two eternal aspects of scientific
progress ; on the one hand the gradual development of specific
techniques and on the other the grasping of great generalizations,
which transform the picture of the world and so, of man's sup-
posed place in it and the significance of his needs.

Most frequently, the repercussions of physical discoveries are
incidental and not at all in the mind of the discoverer. Rontgen
may have been gratified at the medical utility of X-rays, but cer-
tainly no such application was in his mind. This consideration
should be kept continually in view in the development of medical
research programs, where the widest possible latitude is neces-
sary. The point is rather the importance of the closest correla-
tion between pure science and medical practice, and the necessity
for organization to secure the most rapid and efficient develop-
ment of scientific discoveries of medical importance.

If it appears that medicine has a debt to physics, there must
be at least some corresponding recognition of the contributions
made to the fundamental sciences of those whose primary educa-
tion has been medical. Certainly we cannot claim that the physi-
cist interested in medical problems is a new phenomenon or that .

Physics in Medicine 5

medical men have not shown the greatest interest in the use of
physical techniques. The significant development of the present
day is rather the emergence of a group of physicists employed
solely in the study and control of physical agents in their applica-
tions to medicine, and in the recognition that the physicist is now
an indispensable member of any team of specialists using X-rays
or radium in the treatment of malignant diseases, and generally
in the therapeutic use of ionizing radiations. In this development
Britain has played a notable part, and it is probably true to say
that the importance of the physical aspects of medical radiology
are as well recognized here as anywhere in the world.

It is to be hoped that similar development of physical medicine
may occur in the near future, for the crying need in this branch
of medicine is for quantitative information, a great deal of which
can be obtained only by exact physical experiment. It is a curious
thing that the use of heat, one of the oldest medicaments, is from
the physical point of view almost entirely unscientific, and that
only recently have measurements in absolute units been linked
to clinical practice.

It is natural that we find the medical man, a member of one
of the few educated sections of the community, among the first
to make a contribution to "pure" physics. As late as 1600 we
have Gilbert of Colchester, physician to Queen Elizabeth, becom-
ing the father of electrical science, or Borelli seeing in the move-
ments of man and animals applications of the laws of levers.
Even in the beginnings of the modern epoch we find many physi-
cians and surgeons contributing vitally to pure physics.

Thomas Young perhaps stands out as the physician who, in
the early years of the nineteenth century, did most to transform
physics into its present shape. Mayer, the tragic German physi-
cian, so stoutly championed by Tyndall as one of the discoverers
of the great generalization of Conservation of Energy, on the
basis, be it noted, of observations of the blood of the Javanese,
is a notable medical contributor to physics. Tyndall himself,
through his researches in the domain of radiant energy, as well
as his intervention in the controversies around spontaneous gen-
eration and the bacterial origin of disease, is one of the greatest

6 Applied Biophysics

"medical physicists" of the nineteenth century. Again, physics in
medicine certainly found one of its most able exponents in Helm-
holtz, whose mathematical and experimental ability transformed
the science of acoustics, while earlier in the century, a German
physicist, Ritter, seems to have been the discoverer of ultraviolet
radiation, although hotly followed by WoUaston, another medical
physicist.

So from the medical student, Galileo, interested in the swing-
ing of a lamp as a time-keeper to his pulse, to Lawrence and his
giant cyclotron on the hilltop in California, technical advances
in medicine have been linked with physics.

As we have already indicated, physics may influence medicine
very profoundly by its general conceptions of the Universe, as
well as by its detailed techniques. The "recent advances" of
science are bound to excite the more progressive and impatient
medical men of each generation. Again, any adequate account
of these relationships is a task for the medical historian, but it
is tempting to stray a little and recall the influence of the New-
tonian philosophy on the medical practitioner of the early eight-
eenth century. Newton contributed directly to, and indeed in one
sense founded, the science of radiology with his studies of the
visible solar spectrum. In radiation physics his influence is ob-
vious, and no one reading, for example, Herschel's description
of the experiments following his discovery of infrared radiation
in the year 1800, could fail to note the similarity of the train of
thought and experiments with those in Newton's Opticks, pub-
lished about a hundred years earlier. Newton, however, influ-
enced medical thought very profundly in many other ways, as for
example, by his "mechanical" explanation of the Universe, which
gripped the imagination of his contemporaries. It is interesting
to recall that in 1702, one of the most remarkable physicians of
the early eighteenth century, Richard Mead, published A Me-
chanical Account of Poisons, complaining a little that "to unravel
the Springs of the several Motions upon which such Appearances
do depend, and Trace up all the Symptoms to first Causes, re-
quires some Art as well as Labour." Let Mead speak for himself
in his preface :

Physics in Medicine 7

*'My Design in thinking of these Matters was, to try how far I
could carry Mechanical Consideration in Accounting for those
surprising Changes which Poisons make in an Animal Body;
concluding (as I think fairly) that if so abstruse Phaenomena as
these did come under the known Laws of Motion, it might very
well be taken for granted, that the more obvious Appearances in
the same Fabrick are owing to such Causes as are within the
Reach of Geometrical Reasoning."

Again,

"It is very evident, that all other Methods of improving Medicine
have been found Ineffectual, by the Stand It has been at these
Three or Four Thousand Years ; and that since of late Mathe-
maticians have set Themselves to the Study of It, Men do already
begin to Talk so Intelligibly and Comprehensibly, even about
abstruse Matters, that it may be hoped in a short Time, if Those
who are Designed for this Profession, are early, while their Minds
and Bodies are Patient of Labour and Toil, Initiated in the Knowl-
edge of Numbers and Geometry, that Mathematical Learning will
be the Distinguishing Mark of a Physician from a Quack; and
that He who wants this necessary Qualification will be as Ridiculous
as One without Greek or Latin."

So much for those who feel that even if Philosophy and
Physics can agree, Mathematics and Physics cannot. It seems
that mathematics had already invaded medicine, although we
might even now be a little shy at claiming such prerogatives
for it.

It will doubtless be equally interesting to look back in the
year 2200 a.d. and see the influence that the electrical theory
of matter, developed during the first few years of the twentieth
century, had upon medicine.

Physics in Radiotherapy

Advancing techniques in physics applied to medicine bring
problems of organization and human relationships, and it is
perhaps interesting to illustrate some of these problems of daily

8 Applied Biophysics

collaboration of physicist and doctor from the field of medical
radiology, the only one in which the writer could claim firsthand
knowledge. In radiation therapy the closest collaboration be-
tween radiologist and physicist is now recognized to be essential,
yet even to most nonmedical physicists the problems appear
strange and bewildering, and it is scarcely surprising that
medical radiologists find increasing difficulty in following the
detailed mathematical and physical studies of their techniques.

We may -take the view that the medical man has so many
problems of his own that it is quite impossible and undesirable
for him to attempt to follow these details, and similarly the
physicist may find incomprehensible what is to the radiologist
the most elementary anatomy and pathology. Unless the medical
radiologist understands something at least of the power and
limitation of the physical methods, he will certainly not be able
to make the best use of his physical colleagues, who in their
turn will be unable to make relevant suggestions of alteration
in technique, or criticisms of present procedures, unless at least
superfically acquainted with the medical radiologist's mode of
speech.

One of the most efficient ways of bringing together these two
groups of people with such dififerent training and, therefore,
outlook, lies in the regular attendance of the physicist at radio-
logical clinics, where he may see the difference between a neat
diagram of radiation fields and cancer in its anatomical and most
^'unmathematical" forms. The radiologist on his part will find
regular visits to an experimental laboratory stimulating and
chastening experiences. A good deal might be done to relieve
the situation by a more systematic training of the hospital
physicist. Frequently even a change in mathematical approach
to a problem will make collaboration much easier. It will be
found, for example, in studying radiation distributions showing
the dose at various points in the tissues, that the medical radiolo-
gist will visualize results much more clearly if the physicist
avoids formal mathematical analysis and substitutes geometrical
methods. A formula is anathema, but the shape of an ''isodose
surface" is almost anatomy. The physicist is apt to think his

Physics in Medicine . 9

job is done when he states, let us say, "that for a length of 2.7
centimeters the dose in a certain plane does not fall below 90
per cent." Such a statement means little to most medical
radiologists, but expressed in the form that ''the 90 per cent
isodose surface stretches anteriorly from the lower border of
the hyoid bone to the upper border of the cricoid cartilage"
instantly brings a look of relief and gratitude. This method
of approach implies that the hospital physicist should be in-
structed in elementary anatomy, so as to be able to take a more
intelligent interest in the parts of the body he helps to treat,
as well as to be able to transmit his hard-won information in a
more acceptable form to his medical colleagues. The anatomy
taught to him should of necessity be of rather a special variety,
which we might describe as "geometrical anatomy." Size,
shape, and position are of more importance to him than structure
or function, which clearly lie outside his province.

It has usually been thought that too close a reliance on physical
methods leads to rigid techniques and standardized dosage,
that the individuality of the patient is lost, and that all is sub-
ordinated to an inflexible regime. This is a grave error, and
the reverse is more nearly true. There can be no doubt that
variation of size, condition, and sensitivity from patient to
patient is of the utmost importance, but standardization of
technique becomes increasingly indefensible as the detailed physi-
cal studies provide the necessary information to enable adjust-
ment of technique from patient to patient to be made on a
rational basis. Physical studies of sufficient range tend towards
flexibility rather than standardization. This is an important
lesson for both medical man and physicist to learn, and they
are more likely to learn together than separately.

Only the closest personal collaboration of radiologist and
physicist, only the daily discussion of common problems, and
the realization that the medical man has the final responsibility
but the physicist an indispensable interest, can solve the problem
of one of the most important applications of science in medicine.
The physicist must realize that however fascinating and im-
portant his more academic problems, his primary responsibility

10 Applied Biophysics

in this respect is to be useful, while on the part of the medical
radiologist we ask for a more enHghtened understanding of the
importance of the physicist, not only in solving the technical
day-to-day problems, but also as a spearhead of the attack on
the fundamental biophysical problems of the structure of living
material and its interaction with radiation. As new fields of
medical physics develop, doubtless similar problems of coopera-
tion will arise, but the principles of cooperative study and
education are universal.

Developing Influence of Physics in Biology and Medicine

It is certain that the materials of the living organism are
much more complex than any hitherto subjected to physical
inquiry, but that advances in knowledge of the structure of
these living materials, both normal and pathological, might
bring about revolutionary changes in medicine no one could
deny. The use of modern physical weapons like the X-ray
spectrograph, the electron microscope with its possibilities of
electron diffraction, or the radioactive tracers, offers nothing
less. A great deal of the knowledge may not at first be new,
but both physics and biology seem to have reached a stage
where the techniques and perhaps the "ideology" of physics
are becoming vital to biological progress. The cyclotron pro-
ducing its wealth of artificial radioactive products, and the
electron microscope lowering the limits of visible size over
a critical region covering the viruses and colloidal particles,
make possible an attack on the wealth of organization lying
between the small molecule and the visible speck of living
matter. These and other weapons hold out promise of rich
rewards in a field in which hitherto physics has hardly dared
to venture. \\ hether there will develop a reasonably well-
defined science of biophysics analogous to biochemistry it is
difficult to foretell. Physics is such a vigorous parent that
its lusty children tend to early maturity and independence.

It will not be easy to combine the distinctive features of
physics and biology. The conceptions of physics tend towards

Physics in Medicine 11

the static and universal ; those of biology towards the dynamic
and individual. The physicist learns to deal with effects accom-
plished and finished with fairly clear comprehension of the
chain of events between. The study of living organisms necessi-
tates intrusion into a delicately-poised working mechanism which
may react in unsuspected and disconcerting ways. There is
apt to be a great gap of ignorance between the original stimulus
and the resulting effect, with a consequent belief that the
mechanism is much simpler and more amenable to mathematical
analysis than is in fact the case. The physicist is prepared to
admit variability, but has a feeling that proper statistical methods
will lead to unerring conclusions. The biological experimenter
(and good clinician) has to make many inspired guesses on
most insufficient evidence, and sometimes needs a good deal
of convincing as to its inadequacy.

Again the only solution seems to be the closest possible col-
laboration between experimental biologists, cytologists, bio-
chemists, and many others with the physicist, each knowing
enough of the other aspects to visualize the -outline of the
picture even if the sketch is a little misty.

These considerations inevitably raise the question of educa-
tion. It is an unfortunate fact that most physicists learn ex-
tremely little or no biology and conversely, that the biologist
is usually quite innocent of physics and has an alleged dislike
of mathematics. It is most important that opportunities be
available for members of both groups to be educated in the two
fields. The medical undergraduate, again, presents special prob-
lems in this respect, for physics will not be applied in medical
practice and so make its proper co^ntribution to medicine unless
the doctor of tomorrow has at least some grasp of its scope and
potentialities. This is not easy, for the truth is that the funda-
mentals of physics are often most clearly exemplified with
simple nonmedical examples, \\hile the branches of physics
which are of most direct application in medicine are complex,
difficult, and often regarded as "unsuitable for children."

Moreover, those teaching physics in the ordinary way have
little if any contact with the medical profession and courses

12 Applied Biophysics

are better adapted to the needs of engineers. There can be no
doubt that a medical school in the closest possible contact with
a large general hospital is the best training ground in medical
physics, for even at the most elementary stage it is very doubtful
if the teaching of physics in medicine can be adequately dealt
with away from the hospital and patient. Certainly, here will
occur the best opportunity of making physics a real part of
medical education, particularly if the courses are constructed
so as to bring vividly and continuously before the mind of the
student examples of the applications of physical principles and
instruments in daily practice. Without such education it seems
improbable that the applications of physics to medicine will be
made as rapidly or as completely as is desirable.

To sum up then, physics seems destined to assume an in-
creasing importance in medicine, by the introduction both of
specific techniques and of general ideas. Its influence has already
a fascinating historical background, but the interest at the
moment lies rather in the organization and training of physicists
devoted solely to discovery and application in medicine. There
arise many questions of education and cooperation for both
medical man and physicist, and these problems can best be
solved by the development of mutual understanding while work-
ing together. It seems that we must provide education in both
the biological and physical sciences to the hospital physicist of
the future, for the developments of biophysics are likely to play
an increasing part in medical practice.

*^^rv5

BIOPHYSICAL FACTORS IN DRUG ACTION

H. HURST, B.Sc, Ph.D.
Department of Colloid Science, Cambridge

Introduction

THE rapid advances which have been made within the past
few years in our knowledge of tissue ultrastructure and
cell chemistry have introduced new perspectives into the
possibilities of a better understanding of the various modes of
drug action, by closer collaboration between the biologist and
the chemist. Perhaps one of our chief difficulties in seeking a
rational explanation of the biological activities of drugs in terms
of simple physicochemical or biophysical factors is the apparent
simplicity of the relationships which may readily be deduced by
analogy w^th artificial model systems. The justification for the
use of such models has frequently been based on the assumption
that the living system is so complex that the gross properties
of a particular structure are often embodied in a simplified re-
constructed system.

But the physiologist is now inclined to enquire a little further
into the intermediary factors which influence the production of
a biological response to a drug. The morphologist is becoming
increasingly interested in the dynamic significance of the struc-
tures he examines, and he is better acquainted with the uses
of the ultraviolet and electron microscopes in detecting struc-
tures which cannot be resolved with the ordinary light micro-
scope. Moreover he is able to interpret the molecular arrange-
ments in these structures with the polarization microscope and
the methods of X-ray difi"raction analysis.

13

14 , Applied Biophysics

The Analytical Approach to the Study of Drug Action

The aim of the hiochemist has primarily been the isolation and
analysis of the purihed components of the living cell, and consid-
erable information is now available concerning the structural
components, which are essentially lipids and proteins, and the
vital enzvme svstems which are intimateh' associated with these
components. In this connection, the physical chemist has been
able to offer valuable cooperation, for the organization of living
matter frequently takes the form of discrete celkilar fabrics or
membranes, and, apart from the permeability of such membranes,
the uptake of a drug is also influenced by the asymmetrical forces
resident at their surfaces of separation. Schulman and Rideal ^^
have shown how it is possible to study the nature of the inter-
actions of drugs with the biological components of membranes
by means of the Adam-Langmuir trough. Lipids and proteins
can be spread on suitable substrates as two-dimensional films,
or monolayers consisting of a single layer of molecules. The
changes in the physical state, surface pressure, and surface poten-
tial of the monolayers gives an accurate measure of the associat-
ing forces between the biological components and the drugs which
are introduced into the underlying substrates.

The ''Receptor Theory

99

Yet despite these ordered advances in what we might term
the analytical approach to the nature of drug action, the bulk
of existing pharmacological data can be interpreted only by
assuming that drugs combine with hypothetical "receptors" in the
living organism to produce similar or antagonistic responses.
When this occurs it is supposed that the drugs compete for the
same receptors in the surface or tissue which is the site of drug
action. For example, the bacteriostatic action of sulphonamide
drugs is neutralized by the presence of /J-aminobenzoic acid, an
essential metabolite which is utilized by the bacteria. Woods '*-
has advanced the view that the antisulphonamide activity of

Biophysical Factors in Drug Action 15

/j-aminobenzoic acid is due to the similarity in structure between
the drugs and the metabolite, and that owing to this similarity
there is a displacement of metabolite from the bacterial enzyme
receptors by the competitive action of the drug. This reduction
in available substrate results in an inhibition of bacterial growth.

Tlie "Lipoid Theory" of Narcotic Action

It is less easy to apply the structural relationships of the re-
ceptor theory to the mode of action of depressants or narcotics,
where activity appears to depend mainly on the physical proper-
ties of the drug molecules rather than on special molecular con-
figurations. Here the drugs have a characteristic reversible ac-
tion. The numerous relationships between the intensity of a
depressant action and the changes in the physical properties of
narcotics in homologous series of drugs suggest that there is a
physical equilibrium between the drug and some component of
the living cell which is narcotic sensitive. If we assume that
narcotic action depends on the uptake of the drug by the cell
lipids, we can collect a great deal of experimental evidence which
supports the coincidence between narcotic action and simple drug
chstribution in model systems containing a mixture of oil and
water. This relationship forms the basis of the well-known
"lipoid theory" of narcosis which was advanced towards the close
of the last century by Overton 2^' ^^' -^' ^^ and Meyer.-^ A later
generalization by Traube ^^' ^^' ^^ seeks to correlate narcotic ac-
tion with the adsorption of drugs at cell surfaces or interfaces.
This ''adsorption theory" depends on the parallelism between
narcotic activity and the surface activity of drugs, and it is sup-
posed that the cell lipids are not ne"cessarily the dominant bio-
logical substrates or receptors involved in drug uptake.

The literature abounds with numerous discussions and criti-
cisms of the Overton-Meyer and Traube concepts. These prin-
ciples have the outstanding merit of simplicity, and their attrac-
tion rests in the abundant evidence that has since accumulated
and which lends added support to either theory. An adequate
survey of the extensions and modifications of these early gen-

16 Applied Biophysics

eralizations is beyond the scope of the present article, and many
comprehensive reviews on the subject are already in existence.
But the central problem is to elucidate the mechanism by means
of which we can relate narcosis with the depression of the oxi-
dative events of the living cell and also with the association of
the drugs with the structural fabric of the cell. We can demon-
strate the inhibition of enzymic activity in isolated enzyme sys-
tems. We can also detect changes in the molecular orientations
of the structural fabrics which form the natural environment of
these enzyme systems, but we have been quite unable so far to
link these changes in the living system.

Reconciliation of "Rival" Theories

In view of the uncertainty which exists as to the nature of the
drug receptors, it may be more constructive at this stage to
assume that the "rival" theories which have been proposed from
time to time are not necessarily divergent, but are rather expres-
sions of experimentally observed regularities in the relationships
of drugs with particular systems. The justification for this as-
sumption will become apparent when we search for common
physicochemical factors in some of the diverse structural arrange-
ments in membrane organization which are consistent with
pharmacological action, and it will be of interest to notice that
the anomalous systems often provide more information than those
which show more regular coincidence with simple model systems.

The early work of Overton stressed the importance of the
lipids in cell organization and membrane permeability, and the
parallelism between the uptake of substances by cells and differ-
ential oil-water solubility indicated the preponderance of fatty
material in the cell membrane. More recently Osterhout and
coworkers -^ have studied the permeability of homogeneous arti-
ficial membranes consisting of organic solvents, such as guaiacol,
and have related the passage of substances through such oil
films with the permeability of the protoplasmic surfaces of large
multinucleate plant cells, such as Valonia, Halicystis, and Nitella.
In these systems the cell membrane appears to behave as an

Biophysical Factors in Drug Action \7

oily liquid of low dielectric constant. CoUander ^' ^ was in gen-
eral agreement with the view that the penetration of nonelectro-
lytes through the plasma membrane takes place through the
membrane lipids, but he found that small molecules penetrate
into the cells of the alga Chara fragilis more rapidly than would
be expected from considerations of oil solubility alone. He
concluded that the cell membrane acts as a molecular sieve in
which the specialized channels become a dominant factor in
drug access when the molecular size of the penetrating molecules
decreases to a critical value. Nathansohn ^^ was similarly led
to conclude that the cell membrane is heterogeneous, but his
concept differed from that of CoUander in assuming that the
specially differentiated patches are much larger than molecular
sieves, and that the penetration of substances depends on their
chemical properties rather than on their molecular size. If we
accept the view that the cell membrane is heterogeneous and
consists of a mosaic arrangement of relatively hydrated patches
distributed in a lipophilic framework, we must also suppose that
interfaces exist in the membrane structure, which may, however,
approximate to a homogeneous lipid layer in certain types of
cells. In this way, some measure of agreement is found which
relates the Overton-Meyer and Traube principles in terms of
structural membrane relationships, rather than the relationships
which exist in model systems.

Investigations on the Erythrocyte Envelope

The erythrocyte has been the favored object of much investiga-
tion. Despite the convergent attack which has been made on
the nature of the structural organization of the erythrocyte
envelope, a considerable degree of uncertainty still exists as to
its precise structure. Here, also, the biological complexities in
the system are so marked that many new concepts of cell struc-
ture have been based on analogy with simple models. For ex-
ample, by means of the analytical leptoscope, Waugh and
Schmitt ^^ have estimated that the total thickness of the erythro-
cyte envelope is about 200 A. of which up to 100 A. may consist

18 Applied Biophysics

of lipid. This instrument has only recently been developed, and
the essential principle involved consists in the comparison of the
relative intensities of light reflected from the cells and built-up
step films of barium stearate of known thickness deposited on a
similar substrate to that used for the erythrocytes, which are
examined in the form of the dried hemolyzed "ghosts."

Gorter and Grendel ^"'* reported that the fat-soluble lipid is
sufficient to form a bimolecular layer, 50 A. in thickness, cover-
ing the surface of the envelope. Danielli and Davson ^^ and
Danielli and Harvey ^- have proposed a more stable form of
membrane which consists of a lipid layer several molecules in
thickness stabilized by the adsorption of protein on the internal
and external surfaces which are in contact with the more aqueous
environment. It cannot be denied that this "paucimolecular
theory," ^^ which is a modification of Overton's concept of a
homogeneous lipid layer, serves to rationalize a large body of
existing permeability data.

Rather critical evidence has been presented recently by Par-
part and Dziemian ^^ which suggests that a considerable propor-
tion of the lipids in the erythrocyte envelope is firmly bound to
the structural fabric of the ghost in the form of fat-insoluble
lipo-protein "complexes." The molecular ratio of the fat-soluble
fractions, comprising the phospholipids, cephalin and lecithin,
and the sterol, cholesterol, is more related to permeability than
the total lipid contents of the erythrocytes in different mammals.
The cephalin fraction is relatively uniform in the different cells,
but there is a much greater divergence between the molecular
ratios of lecithin and cholesterol. These results have some bear-
ing on the structural features of the envelope, for the perme-
ability to fat-soluble substances shows little variation in the
species examined, but a higher proportion of lecithin and
cholesterol is present in the cells which are more permeable
to lipid-insoluble substances. It would appear that the cephalin
has a structural role in the organization of the erythrocyte
membrane, while lecithin and cholesterol are involved in the
more labile diffusion processes. In support of this, we may cite
the evidence offered by Chargaflf and coworkers,*- ^' ^' ^ who

Biophysical Factors in Drug Action 19

found that cephalin forms a salt-like lipo-protein with salniine,
which is a basic protein, over a pH range of 2-11 ; lecithin forms
an analogous complex only at />H 10-11. The complex formed
between cephalin and salmine has rubberlike physical proper-
ties. The dried precipitates swell in water and organic solvents,
and they may be recrystallized from ethyl alcohol. Other basic
proteins, such as histone, also form complexes.

X-ray Diffraction Analysis

From X-ray diffraction analysis of such complexes, Schmitt
and Palmer,^^ in collaboration with Chargaff, assumed the
existence of a single layer of protein between each bimolecular
double layer of cephalin. According to Schmitt and Palmer,
the positive polar groups of the extended protein molecules are
attached to the negative polar groups of the cephalin molecules
on both sides of the protein, and this association results in a
decrease in the solvation or hydration of the system. Analogous
bimolecular lipid leaflets were detected in emulsions prepared
from mixed brain lipids, but the diffraction spacings between
the leaflets were much larger than those which occur in the
dried lipoprotein complexes. This shows that even in highly
solvated systems, the lipid molecules retain their relative orienta-
tion to the interlayer aqueous phase. The spacing between the
lipid layers in the mixed lipid emulsions is greatly reduced
by the presence of divalent cations such as calcium, and this
may be related to the conduction of the nerve impulse, for
Scott ^^ has reported that the bulk of the calcium in a nerve
fiber is located in the myelin sheath.

Boehm ^ and Handovsky ^^ have described the results of
X-ray diffraction analysis on surviving nerves. The association
of narcotics with the lipids results in a dispersant action on the
packing or orientation of the layers, which become wider and
more diffuse. Using similar methods, supplemented by bire-
fringence studies in polarized light, Reynolds, Corrigan, and
Hayden ^^ were led to believe that orientated lipid associations
occur in the human brain, but the degree of orientation varies

20 Applied Biophysics

and Is apparently more marked in nerve trunks than in white
matter.

The Pattern of Lipid-Proteiii-Enzyme Relationship

These diverse observations stress the close relationship be-
tween the lipids and proteins in organized tissues. We may
imagine that the lipids exert a protective action on the protein
structural components of membranes. Baker, Harrison, Miller,
and W^exler ^ have found that the action of synthetic detergents
on bacteria is inhibited by the presence of phospholipids, and
it is supposed that the denaturation of the proteins of the bac-
terial membrane is prevented by the lipids. Perhaps a similar
protective action may account for the resistance of the cell
membrane or ghost to the digestive action of pepsin and trypsin,
but Ballentine and Parpart '" point out that this may depend on
the resistant nature of the protein itself, and have suggested
that the structural proteins of the erythrocytes are sclero-
proteins, possibly of the albuminoid type.

It is permissible to conclude from these examples that,
although we have not yet obtained a coherent pattern of the way
in which lipids, proteins, and enzymes are organized in living
systems, the shape of this pattern is gradually being resolved.
The biologist holds the initiative in this respect, for, as he
extends the range of his biological systems and his technical
resources for examining these systems, he can select model
systems to assist in the elucidations of the complexities of mem-
brane structure, instead of selecting his biological systems to
elucidate complexities in model systems which are of uncertain
biological significance. ^Vhat may we profitably look for when
we encounter a natural membrane which we have not examined ?
We can visualize a structural framework or fabric composed of
a relatively resistant lipo-protein complex in which the com-
ponents swell in fat solvents or water but are not readily dis-
solved in these media. Incorporated functionally in this frame-
work are labile lipids and proteins or lipo-proteins, and possibly
enzymes which can be more readily displaced or removed from

Biophysical Factors in Drug Action 21

the membrane lattice. The membrane is heterogeneous or mosaic
in structure, but the preponderance of Hpids may confer upon
the membrane the properties of a homogeneous oil layer. More-
over, the membrane may have a lamellar structure, which
possesses peculiar significance according to the particular physio-
logical function of the membrane.

Insect Cuticle as Test Material

The author ^^' ^^' -^ has found that the study of the uptake
of drugs by insects is facilitated by the fact that the cuticle
can be readily removed from the insect and studied as a separate
physicochemical system. The insect cuticle consists of an outer
lipoidal layer which covers a much thicker inner more hydro-
philic layer. The outer layer, which is only a few |.i in thickness,
contains lipids incorporated in a lipo-protein framework. A
proportion of the lipids can be removed by the action of fat
solvents. This outer layer, or epicuticle, confers on the cuticle
framework its physiological function as a water-impermeable
membrane. The inner layer, or endocuticle, may be more than
100 |i in thickness, and consists of hydrated protein closely
associated with chitin,^'* together with a smaller proportion of
lipids. This layer serves a mechanical supporting or exoskeletal
function in relation to the internal tissues and body fluids. The
cuticle has a pronounced lamellar structure, and the positive
form birefringence indicates the presence of orientated lipids in
the lamellae, while the extension of the molecules of protein
parallel to the cuticle surface is supported by the X-ray diffrac-
tion studies of Fraenkel and Rudall,^"* and by the fact that the
cuticle can be mechanically separated into component layers.

Effects of Mixed Drug Systems on Insect Cuticle

The soft cuticles of blowfly larvae, or ''maggots," are very
suitable for experimental manipulation, and they can be attached
to small tubes in the form of osmometers. Some very interesting
results have been obtained from the study of mixed drug svs-

22 Applied BiopJiysics

terns. Owing to the high resistance of the cuticle, drugs may
be appHed to the insect at concentrations which would be rapidly
toxic to less resistant organisms. When an aqueous solution
(10%) of ethyl alcohol is injected into the blood of the blowfly
larva, Calliphora crythroccphala, the insect is rapidly paralyzed,
but will remain active in pure alcohol for more than an hour
when this is applied externally. It is clear that the alcohol
cannot penetrate through the cuticle into the tissues of the
insect. If the alcohol is now diluted (1:1) with a fat solvent,
such as kerosene, whicli is by itself nontoxic, the insect is killed
in less than a minute, starts to swell owing to the rapid penetra-
tion of alcohol into the tissues, and bursts explosively in about
4 minutes, during which time the body weight has increased by
some 50% (figure la). If the insect is transferred from the
alcohol-kerosene mixture to pure alcohol when the body weight

'$. 50

V. 40

<u
u.
o

C 30

bo

C

(U

u
u

20

10

/i 4-

if-

I .'

F

•«■= 1 1 1 1 \ \ 1 1 I

10

Period of immersion (minutes)

FIG. 1. Uptake of Ethyl Alcohol by Blowfly Larvae (Calliphora

crythroccphala).
a Continuous immersion in alcohol -|- kerosene mixture.
b Alternate immersion in alcohol + kerosene mixture and pure alcohol.
X Bursting point of insects.

= alcohol + kerosene.

=■ alcohol.

Biophysical Factors in Drug Action 23

has increased by 10%, the rate of swelling slows down and stops,
but increases again rapidly when the insect is returned to the
mixture (figure lb). These effects can be repeated in smaller
increments, and are not dependent on vital transfer processes,
for they can be reproduced with the isolated cuticle attached
to a small osmometer filled with water.

The penetration of the alcohol through the cuticle is clearly
dependent on the presence of kerosene in the cuticle framework.
This must be a very labile association, as the kerosene is readily
eluted from the cuticle when the insect is transferred from the
mixture into the pure alcohol. The penetration of alcohol which
is induced by kerosene is accompanied by a simultaneous increase
in the exosmosis of water from the cuticle. This can be observed
in the cloudy swirling zone near the surface of the cuticle indi-
cating that kerosene is thrown out of solution in this region.
The insect is not dehydrated when immersed in pure alcohol.

Similar results can be obtained with methyl or propyl alcohol,
and with fat solvents such as ether, benzene, or chloroform
instead of kerosene. The synergistic action is also shown in
mixtures which contain structurally related components, such
as ethyl and octyl alcohol. Here, apart from its own toxicity,
the octyl alcohol increases the permeability of the cuticle to ethyl
alcohol, resulting in a progressive swelling of the insect which
does not occur in octyl alcohol alone.

The problem which arises is to decide how fat solvents, which
are only slightly soluble in water, increase the permeability of
the cuticle to water-soluble fat solvents and also to water. Ex-
periments with isolated layers of the cuticles attached to os-
mometers show that the site of the increase in cuticle perme-
ability is in the outer lipophylic epicuticle. The inner thicker
endocuticle layer is very permeable to water, and exosmosis
of water takes place very rapidly when this layer is in contact
with ethyl alcohol or with alcohol-kerosene mixtures. We are
led to consider the possibility that the uptake of kerosene by
the epicuticle lipids does not involve only a simple swelling or
disorientation of this phase in situ, but also a displacement of
lipid from the more hydrated protein or lipo-protein components.

24 Applied Biophysics

But the effects of induced penetration of alcohol also occurs when
the fat-soluble lipid has been removed from the cuticle, so we
must study the structural organization of the cuticle for a further
clue to the nature of the spatial relationships of the lipids and
proteins in the epicuticle. For this purpose, the epicuticle is
stained red with acid fuchsin and the underlying endocuticle is
counter-stained with iron hematoxylin.

Structure of Insect Cuticle

In a transverse section, through the cuticle of the blowfly
larva, Sarcophaga falculata, the heavily-stained epicuticle is
apparently homogeneous, but in a tangential section, the
heterogeneous or mosaic structure of this layer can be clearly
seen (figures 2a, 2b). There is a closely packed network of

I /PAL I

FIG. 2. a Transverse section through cuticle of blowfly larva, Sarcophaga
fatciilata, showing densely stained outer epicuticle and portion of inner lamellar
endocuticle.

b Tangential section through epicuticle, showing mosaic lipophilic network (dark
strands), and transitional zone between epicuticle and endocuticle.

Biophysical Factors in Drug Action 25

lipophilic aggregates which have a somewhat fibrous appearance
and are generally radially disposed across the epicuticle frame-
work. The network is interlaced with more hydrated processes
from the underlying endocuticle. Lamellation cannot be seen
in the epicuticle although it is marked in the endocuticle. This
may be due to the more heavily staining outer layer, and as both
layers are secreted by the same layer of epidermal cells, it is
probable that a lamellar fabric exists also in the epicuticle. The
spacing between the layers is relatively wide in the endocuticle
and it is possible that a more minute form of structure may be
revealed by X-ray diffraction analysis. If we assume the exist-
ence of a microscopic lamellar fabric in the epicuticle, and sup-
pose that the visible mosaic network is incorporated in the
membrane, the gross relationships of the structural components
become more apparent (figure 4a).

99

Effect of Permeability on "Tanning

We can explain the action of fat solvents in increasing the
permeability of the cuticle to other fat solvents such as ethyl
alcohol, by assuming that the solvents swell the more lipophilic
radially disposed strands of the mosaic network which extends
across the epicuticle. But we still have to account for the asso-
ciated increase in the permeability to water, and this makes it
necessary to depart somewhat from the usual classical concepts
in which the heterogeneity in a membrane is supposed to consist
of pores or channels. Any increase in the permeability of the
cuticle to water will probably involve the displacement of protec-
tive lipid from the more hydrated protein or lipoprotein struc-
tures. But if we "tan" the cuticle by"" means of a protein reagent
such as />-benzoquinone, the protected protein zones will tan
more slowly than those in which access of /'-benzoquinone is
restricted by the competitive action of the lipid for the amino
groups of the protein.

As with ethyl alcohol, the access of /'-benzoquinone through
the cuticle takes place more rapidly in kerosene than in alcohol
or water, and this can be measured by the darkening of the

26

Applied BiopJiysics

cuticle and by the lethal symptoms which are coincident with
the first visible signs of a reddish-brown tinge in the cuticle.
The tanning action of the quinone monomer is also accompanied
by the deposition of the colored polymerized oxidation products,
and these can be observed in optical sections of the cuticle outer
layers. The mosaic structure of the epicuticle in the housefly
larva, Miisca domestica, is now shown up clearly 1)y the differ-
entiation of the tanned zones from the untanned zones where the
lipid is more strongly attached to the protein. The extension of
the dimensions of the tanned regions which takes place under
the progressive action of chloroform sensitization or kerosene
sensitization results in a reduction in the more lipophilic zones,
corresponding to the mosaic shown in figure 2b. We may con-
clude that the lipid between the discrete aggregates of the mosaic
is also more readily displaced from the apparent network in
which the lipophilic mosaic is embedded (figures 3a, 3/?, 3c).

I /OM I

FIG. 3. Artificial Tanning and Hardening of Insect Cuticle

(Mitsca domestica).
a, h, c Optical section of epicuticle layer, showing progressive tanning by p-henzo-
quinone in mosaic network where lipid is displaced by fat-solvent action (dark
regions) (nonenzymic).

d, e, f Similar progressive tanning by catechol (enzymic),

Biophysical Factors in Drug Action 27

The fact that the whole cuticle becomes eventually deeply tanned
and hardened by prolonged treatment with />-benzoquinone
indicates the general lipo-protein character of the cuticle struc-
ture. We may conclude that the spatial changes produced by a
fat solvent or narcotic in the mosaic organization are as shown
in figures 4a, 4h. There is a general swelling and increase in
phase volume of the lipophilic radially arranged aggregates,
resulting in an increase in the permeability of this phase to fat
solvents which have less lipid-dispersant properties, such as
ethyl alcohol. At the same time there is a disorientation and
displacement of lipid, probably from the general lamellar fabric
of the epicuticle, and this results in an increase in the hydration
of the lipid and the protein from which the displacement occurs.
In this way, the permeability of the cuticle to water and
/j-benzoquinone is increased.

Permeability and Enzyme Activity

Finally, we can now consider the interesting question of the
relation of these changes in membrane permeability to the
activity of enzymes which are protected by the environmental
influence of the membrane framework. A lipid-free gelatin
membrane immersed in a /'-benzoquinone substrate becomes
rapidly tanned, but if we now substitute a catechol substrate for
the p-benzoquinone, tanning of the membrane does not occur.
Wagreich and Nelson ^^ have shown that the enzymic oxidation
of catechol results in the production of an intermediary o-quinone.
This quinone has tanning properties similar to those of /^-benzo-
quinone, and it is readily produced by the action of an enzyme
known as peroxidase which can be Extracted from horseradish
roots.-^ Catechol is very rapidly oxidized in an aqueous substrate
containing peroxidase and hydrogen peroxide, and gelatin
membranes in this substrate become rapidly tanned by the
diffusible o-quinone. Similarly, we can prepare gelatin mem-
branes which contain peroxidase. These also become tanned
when in contact with catechol and hydrogen peroxide, but here
the reactive o-quinone is formed within the membrane frame-
work. Insect cuticle behaves as a membrane of this type, for it

Bound lipid Labile lipid

Protein-enzyme
complex

w

3

o
-o

c

W

I

"'•i'r «'v • • • ■ * . % AJ*

r

$

V

•.

•:
•J

I

l.

<%«;^v=v^\1^S'^v^^vi« iA v^W,>iWAv5iv?^8^?V^i-»^

V

a

FIG. 4A. Mechanism of Sensitizing Action of Fat Solvents on Insect Cuticle.
Mosaic arrangement of bound and labile lipid in lipoprotein framework of cuticle
of blowfly larvae. A lamellar distribution of labile lipid is shown in the epicuticle
and endocuticle.

28

SUBSTRATE

Sensitizing ^
Fat solvent ^

O

Protein-enzyme
complex

v-^w.wCV

• .V *: '

.»

■J.

•V •

FIG. 4B. Mechanism of Sensitizing Action of Fat Solvents on Insect Cuticle.
The uptake of a fat solvent, such as chloroform, results in a swelling of the
bound-lipid mosaic network. There is a simultaneous displacement of labile lipid,
resulting in an increase in cuticle permeability to fat-soluble and water-soluble
substances.

29

30 Applied Biophysics

contains an enzyme system which oxidizes catechol very rapidly
in the presence of hydrogen peroxide. This enzyme system is
involved in the natural hardening of insect cuticle. Both the
enzyme and natural polyphenol substrate are secreted into the
cuticle by specialized epidermal cells. The rate of natural tan-
ning is increased by abrading the outer layer of the cuticle and
impregnating the abraded layer with a concentrated aqueous
horseradish-peroxidase extract. Alternatively, the penetration
of catechol into the cuticle is increased by treating the cuticle
with a fat solvent and then immersing the insect in an aqueous
catechol substrate containing hydrogen peroxide. The catechol
is oxidized to the o-quinone inside the cuticle framework, but
the diffusion of the quinone within the membrane framework
does not take place uniformly owing to the mosaic structure,
and in this respect the insect cuticle differs from the simpler
homogeneous gelatin membrane.

However, when we examine the pattern of enzymic tanning
which has been induced in the cuticle (figures 3d, 3e, 3/), we see
that it is similar to that induced by the nonenzymic tanning
with /'-benzoquinone (figures 3a, 3b, 3c). We note further,
that there is a general parallelism between the degree of induced
enzymic cuticle tanning produced by sensitizing the cuticle with
fat solvents such as hexane, heptane, benzene, ether, or chloro-
form, and the degree of nonenzymic tanning by /'-benzoquinone
induced by the action of these fat solvents on the protective
lipids in the cuticle framework. We conclude that access of
catechol to the cuticle enzyme receptors is similarly influenced
by a permeability factor or by competitive action of protective
. lipid on the structural protein-enzyme complex.

Analogy between Insect Cuticle and Cell Membrane

It may well be argued that the insect cuticle is a highly
specialized membrane which has little in common with the
more complex and submicroscopic cell membrane. But when
intact isolated insect tissues are treated with a fat solvent such
as chloroform, there is a large increase in tissue-peroxidase
activity, suggesting a similar sensitization of the bounding mem-

Biophysical Factors in Drug Action 31

branes of the component cells. Using appropriate substrates,
analogous results can be demonstrated with the phenoloxidase
systems, catechol oxidase and tyrosinase, which are also present
in the cuticle and internal tissues.

These results can be most logically explained by postulating
a lipoprotein mosaic structure in the cell membranes of the
tissues, in which the availabilities of the enzvmes are influenced
by the labile lipids present in the structural frameworks. Sim-
ilar increases in the availability of these enzymes can be
induced in the intact insect by two different kinds of physical
stimuli : ( 1 ) heat, which increases cuticle permeability and
phenoloxidase activity in the internal tissues, and (2) mechani-
cal damage of the cuticle and tissues which exposes the available
enzymes. If the posterior segments of an insect such as meal-
worm larvae, Tenebrio molitor, are subjected to the action of
{a) chloroform, {h) heat (40-45° C), and (c) mechanical dam-
age by squeezing, the insects first become paralyzed, and this
stage is followed by a similar local blackening in the posterior
segments owing to an increase in the availability of tissue
tyrosinase in these regions, a change which is associated with
an increase in oxygen uptake.

These results are in accord with Henderson^s suggestion that
narcosis and oxidative processes are separable phenomena.^''
Although fat-solvent narcotics appear to exert a physical action
on the cell lipids, the secondary changes which cause a disturb-
ance in oxidative metabolism may be much more complex. In
insects, the increase in tissue-phenoloxidase activity results in
the accumulation of reactive o-quinones in the blood and tissues.
Richter ^"^ has shown that these oxidation products act as power-
ful inhibitors of catechol-oxidase activity ; it is likely that they
would exert a general toxic action on the vital processes within
the insect.

Conclusions

It is doubtful whether this selective environmental influence
of the structural tissue components on enzymic activity can be
simulated specifically in reconstructed enzyme systems, where

32 Applied Biophysics

we study the nature of the reactions, but not their dynamic
aspects in relation to the Hving system. The so-called "law of
homologous series/' which expresses the regularity with which
pharmacological activity increases with the length of hydro-
carbon chain, is possibly due to the close association of the
lipids and enzyme receptors at the site of drug action. The
primary role of the structural lipids may be the storage and
presentation of drug to the active groups in the enzyme system.
The characteristic rise and fall in activity as a series of
homologous drugs is ascended, for example, with the maximum
pressor activity in the aliphatic primary amines ; antiseptic ac-
tivity of the alkyl phenols, ^^ resorcinols -"^ ; and bactericidal and
fungicidal activities of alkyl derivatives of o- and /^-chlorphenols
investigated by Klarman, Shternov, and Gates,^- may simply
be due to some optimal association of the drugs with the struc-
tural lipids or lipoproteins, which is consistent with maximum
access or presentation of the drugs to the associated enzyme
complex. This concept would also explain how the maximum
activity in a homologous series of drugs may vary in different
tissues and organisms.

References

1 Baker, Z., R. W. Harrison, B. F. Miller and G. Wexler (1941)

/. Exp. Med. 74, 621.
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35.

6 Chargaff, E., IM. Ziff and D. Rittenburg (1941) .J. Biol. Chcm. 138,

439.

7 Chargaff, E., M. Ziff and D. Rittenburg (1942) ./. Biol. Chem. 144,

343.
sCoIlander, R. (1937) Trans. Faraday Soc. 33, 985.
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lOCoulthard, C. E., J. Marshall and E. L. Pyman (1930) J. Chem.

Soc. 280.
11 Danielli, J. F. and H. Davson (1934) /. Cell. Comp. Physiol. 5, 495.

Biophysical factors in Drug Action 33

12 Danielli, J. F. and E. N. Harvey (1935) /. Cell. Conip. Physiol. 5, 483.

13 Davson, H, and J. F. Danielli (1943) The Permeability of Natural

Membranes, Cambridge.

14 Fraenkel, G. and K. M. Rudall (1940) Proc. Roy. Sac. B. 129, 1.
i5Gorter, E. and F. Grendel (1925) .T. Exp. Med. 41, 439.
i^Handovsky, H. (1933) Kolloid-Z. 62, 21.

1'^ Henderson, V. E. (1930) Physiol. Rev. 10, 171.

18 Hurst, H. (1940) Nature, Lond. 145, 462.

19 Hurst, H. (1943a) Ahiture, Lond. 152, 292.

20 Hurst, H. (1943b) Trans. Faraday Soc. 39, 390.

21 Keilin, D. and T. Mann (1937) Proc. Roy. Soc. B. 122, 119.
22Klarman, E., V. A. Shternov and L. W. Gates (1934) /. Lab. Clin.

Med. 20, 40.

23 Leonard, V. (1924) /. Amer. Med. Ass. 83, 2005.

24 Meyer, H. H. (1899) Arch. exp. Path. Pharmak. 42, 109.

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Quant. Biol. 8, 17.

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Roentgenol. 43, 81.
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Quant. Biol. 8, 94.

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4iWaugh, D. F. and F. O. Schmitt (1940) Cold Spring Harbor Symp.

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A SURVEY OF THE APPLICATIONS OF ELECTRONICS

IN MEDICINE

G. E. DONOVAN, M.Sc, M.B., D.P.H.
Public Health Department^ Gorseinon^ Swansea

Introduction

ELECTRONICS in medicine covers such a large field that,
in this article, only some of the more important and interest-
ing aspects of the subject can be dealt with. There is hardly
a branch of medicine which cannot benefit from the application
of electronics.

The phenomena with which a physician has to deal — sound,
pressure, heat, etc. — can easily be transformed into electrical
equivalents which can be amplified by thermionic-valve ampli-
fiers, and graphically recorded. Bioelectric quantities, such as
the electrical variations of the heart, lend themselves readily to
valve-amplifier technique and registration. The extent of ampli-
fication of the signal is governed by the amplification given by
the valves in the various stages, and is modified by the attenua-
tion which occurs as a result of the relationship of signal fre-
quency to the resistance-capacity values used for coupling. This
relationship is the frequency response characteristic of the
amplifier.

The amount of useful amplification really depends on the
"resolving power" of the amplifier, i.e., the smallest potential
change that can be detected, and this in turn is mainly dependent
on the working of the first stage of the amplifier. At present
we can detect an input change of one microvolt in a circuit of
high resistance, like a small nerve trunk, but it is difficult to
deal with anything less than this because of fluctuations intro-
duced by the resistors, valves, etc.

34

Applications of Electronics in Medicine 35

Nerve Action Potentials

Nerve fiber is a tissue in which some of the properties of Hving
matter, especially conductivity and excitability, have become de-
veloped to an exceptional extent. The electrical stimulus is the
common one employed experimentally, but chemical or mechani-
cal stimuli are also effective. A nerve impulse travelling along
a nerve fiber is accompanied by a characteristic electrical change,
which is a diphasic potential wave. Once the impulse has been
initiated in a nerve, it is "all or none." If a nerve fiber is
stimulated electrically, the rate of travel and magnitude are
independent of the strength of the stimulus, and depend only
on the state of the nerve at the point under consideration. In
any particular fiber, stronger stimulation causes only an increase
in the frequency of the potential waves. A nerve trunk may
contain thousands of fibers of varying types and sizes, and
records may show a complex series of transients. In the human
body, the waves have a peak potential of about 1.0 millivolt
(which is only a fraction of that developed by the nerve owing
to the shunting effect of the inactive adjacent fibers in the nerve
trunk), and last about 1.0 milliseconds.

The early work on nerve action potentials was handicapped
by the fact that the majority of recording instruments which
were sensitive enough for the purpose, for instance, the capillary
electrometer and the string galvanometer, required appreciable
power to work them, besides suffering from inertia. Pioneer
work was done by Adrian,^ using a capillary electrometer, and
Forbes and Thacher -^ with a string galvanometer. Gasser and
Erlanger -^ used the cathode-ray Oscillograph as the recording
device. Adrian - in his monograph on The Mechanism of Nerv-
ous Action, gives a review of the work done in this field to that
date.

Wever and Bray ^^ had the courage to connect the auditory
nerve with an amplifier and telephone. They found that any
sound reaching the ear was reproduced in the telephone ; speech
could be understood, and the speaker identified by his voice.

36 Applied Biophysics

These nerve action potentials can be demonstrated visually by
means of the cathode-ray oscillograph.

A suitable amplifier for the demonstration of the electrical
changes in sensory nerves consists of a four-stage resistance-
capacity coupled amplifier employing MH4 thermionic triode
valves. The plate of the first valve is fed through a resistance
of 50,000 ohms, 20,000 ohms of which is used for decoupling
through a 4 mfd condenser. The second valve is fed through
a similar resistance, 10,000 ohms of which is used for decoupling
through a 4 mfd condenser. The third valve is fed through a
similar resistance, and the decoupling is the same as in the
preceding valve. The output valve is fed through all ,000 ohms
resistance, 1,000 ohms of which is employed for decoupling
through a 4 mfd condenser. The anode of this stage is fed via
a 2 mfd condenser, and the earth line to the Y plates of a
cathode-ray oscillograph. The intercoupling condenser of each
stage is 1 mfd, and the grid-bias resistor is 0.25 meg ohms,
giving for each stage a time constant of 0.25 seconds.

Various specialized amplifiers and general purpose biological
amplifiers have been developed for this type of work. Other
recording devices besides the cathode-ray oscillograph, such as
the mirror oscillograph, have been used.

Muscle Action Potentials

The action potentials of muscle fibers are similar in shape
to those of nerve fibers, but are larger and slower.

Wedensky ^- used the telephone as an indicator to study the
rate of electrical changes in voluntary muscular contraction.
Piper ^^ used the string galvanometer in recording the electro-
myogram. Adrian and Bronk ^ demonstrated that the action
potentials from voluntary muscle can be recorded by means of
a concentric needle electrode. Denny-Brown and Pennybacker ^^
showed that the recording of action potentials from voluntary
muscle in certain pathological conditions gave useful information
concerning the nature and position of the underlying patho-
logical process. Weddell, Feinstein, and Pattle ^^ point out that

Applications of Electronics in Medicine 37

the activity of normally contracting motor units and of fibrillation
can be easily distinguished, and it is consequently possible to
decide whether a muscle is innervated normally, partially, or
not at all. For the exploration of the whole muscle, about six
punctures of the needle electrode may be required, but this is
rarely necessary and gives only trifling discomfort. Elliott ^'^
made electromyographic studies of tender muscles in sciatica.
He demonstrated that the tender spots in the muscles are, as a
rule, the seat of a localized increase of irritability and a con-
tinuous discharge of action potentials, which lasts as long as
the needle remains in the muscle.

A technique commonly employed in electromyography is to
insert a concentric electrode, made of fine wire running through
the center of a fine-gage hypodermic needle, into the belly of
the muscle. The needle's barrel acts as an earthed shield, and
the minute wire electrode picks up the electrical activity of units
within a radius of 1 millimeter. The electrical potentials are
amplified by a standard amplifier, and records can be observed
and photographed on a cathode-ray tube. Weddell, Feinstein,
and Pattle '^^ employ a special all-mains-operated amplifier.
Cathode-ray oscilloscope tracings are used for permanent records,
for practical purposes, however, only the sounds emitted from
an output loudspeaker are noted ; the detection of small differ-
ences in duration and frequency are more easily assessed by
auditory than by visual methods.

Chronaxie Meters and Electronic Stimulators

The effectiveness of a stimulus depends not only on its
strength, but also on the time duTing which it is allowed to
flow through the tissues. Chronaxie is defined as the time during
which a current, twice as great as the rheobase, must flow through
a tissue to set up activity. It is a measure of the excitability of
a tissue.

Brian Denny ^ developed, from the original circuits of
Bauwens, an apparatus which aims at providing the means of
determining, accurately, the response to electrical stimulation of

38 Applied Biophysics

muscle and nerve and of applying electrical treatment of known
character and dosage.

Ritchie ^^ has described a simple variable "square-wave"
stimulator for biological work. The instrument uses two stand-
ard triode valves to produce impulses independently variable
in intensity, duration, and frequency over the wide ranges used
in the excitation of nerve and muscle.

Electrocardiography

The electrical variations produced by the heart during con-
traction are distributed through the body, and can be led ofif
from the moist skin surface of such areas as the arms and legs,
and recorded.

Kolliker and Miiller -^ showed, by physiological experiments,
that an electrical change accompanies the beat of the isolated
frog's heart. \\^aller ^^ demonstrated similar changes occurring
in the human heart, when electrodes are applied to the limbs.
He used Lippman's capillary electrometer, and his experiments
remained of academic interest only. Einthoven ^^ introduced
the string galvanometer which made electrocardiography, in its
modern form, a clinical science. Some of the disadvantages of
the string-galvanometer type of electrocardiograph are : the
fragility of the string, the necessity of skin-current compensation,
and the use of nonpolarizable electrodes.

Because of the extremely low voltage generated by the action
of the heart, instruments for its measurement in the past have
necessarily been extremely sensitive, and the recorders of these
have, therefore, been very delicate. The introduction of thermi-
onic-valve amplifiers, and the substitution of robust oscillagraphs
changed all this. The usual form of recorder employed with
thermionic-valve amplifiers was the mirror galvanometer of
comparatively low sensitivity. Examples of such instruments
are the \^ictor electrocardiograph and the Matthews electro-
cardiograph.

The Both electrocardiograph works on the thermionic-valve
amplifier principle, but feeds a small cutting stylus which indents

Applications of Electronics in Medicine 39

a specially prepared surface. The resultant electrocardio-
gram is -FrT of standard size, and must be viewed through a

microscope for direct visual observation. If a permanent
standard-record-size electrocardiogram is desired, the original
record must be sent to the agents for enlarging.

The ink-writing electrocardiograph uses a valve amplifier and
an ink-writing oscillograph. The record is made on inexpensive
paper tape. It is immediately visible, and requires no process
of developing or fixing. The upper-frequency response of the
instnmient is limited, due mainly to the friction between the
writing pen and the recording paper.

For exact reproduction of the wave shape of the electrocardio-
gram, it is essential to use an oscillographic recording element
which will respond to the highest-frequency components. Such
a device is the cathode-ray oscillograph. The cathode-ray tube
is essentially an oscillographic indicator characterized by two
striking and valual^le properties : first, the almost complete
absence of inertia in the recorder, and, secondly, the two-dimen-
sional recording field. The tube, itself, is essentially a compli-
cated thermionic valve. It contains, at one end, an electrode
structure, called the "electron gun," and, at the other end, the
fluorescent screen. The "electron gun" possesses a filament, a
cathode, a grid, and an anode. The electrons emitted by the
heated cathode are accelerated by the high positive potential
of the anode, and are caused to pass down the length of the
tube in the form of a narrow beam. These high- velocity electrons
impinge on a fluorescent screen, and there give rise to a spot
of light. The direction of motion of the electrons, forming the
electron beam, is affected by electric or magnetic fields. At any
point between the accelerating system (or "electron gun") and
the screen, the beam may be deflected by the electric or magnetic
field ; the resulting displacement of the spot is a measure of the
strength of that field. In the most usual arrangement, the
cathode-ray tube is fitted with two pairs of deflecting plates
mutually at right angles, and the deflection of the spot along
an axis is closely proportional to the voltage difference between

40 Applied Biophysics

opposite plates. In the gas-focused type of tube, the combined
action of a small amount of gas within the tube, and of the nega-
tive grid potential, causes the beam to be focused to a fine spot.
A modern high-vacuum type incorporates several refinements.
Instead of a simple plate for the anode, two or more cylinders
are used ; focusing is brought about by electrical optical means.
The pair of deflecting plates in the vertical plane are called the
Y plates, and those in the horizontal plane are called the X
plates. The deflectional sensitivity of the cathode-ray tube is
insufficient to produce a record when the heart potentials are
applied directly to it. A high-gain amplifier is therefore neces-
sary to magnify these potentials sufficiently to give a trace on
the screen of the tube. The output of this amplifier is connected
to the pair of Y plates, and thus gives a vertical trace. If re-
quired, the vertical movements can be photographically recorded
on moving film. If it is desired to view the wave form of the
electrical variations of the heart on the screen of the cathode-ray
tube, it is necessary for the beam to move slowly across the
whole of the screen of the cathode-ray oscilloscope in the hori-
zontal, or X axis, from left to right. This movement is given
by a time-base circuit. For the direct visual observation of the
electrocardiogram, the fluorescent-screen material used in the
tube is chosen to have a very long afterglow, so that the trace
of the spot, when seen in a darkened enclosure, is visible for
several seconds after the spot has gone by.

Rijlant,'*^ Schmitz ^"^ and Matthews ^^ were among the first
who adapted the cathode-ray tube to electrocardiography. They
used the cathode-ray tube merely as a recording device, and
not as an oscilloscope. Robertson ^"^ introduced a new electro-
cardiograph employing the cathode-ray tube as an oscilloscope
and fitted with a screen having a long afterglow, which permitted
direct visual observation of the electrocardiogram. Brokes-
Smith ® devised a similar apparatus, but without any device
to obviate origin distortion. Asher and Hoecker "^ mention in
their paper that Wilson has adapted the afterglow cathode-ray
oscilloscope to electrocardiography.

The cathode-ray tube has been adapted to vectorcardiography

Applications of Electronics in Medicine 41

by Hollmann and HoUmann,-^ Wilson and Johnston,^"* and
others.

HoflF, Kramer, DuBois and Patten -^ have employed valve-
amplifier technique for recording the electrocardiogram of the
embryonic heart of the developing chick. Mann and Bernstein ,-^-
Ward and Kennedy "'^ and others have used electroencephalo-
graphic technique for the registration of the electrical variations
of the human foetal heart.

The Phoiioelectrocardioscope

The phonoelectrocardioscope ^^' ^-' ^'^' ^-^ incorporates a double-
beam cathode-ray oscilloscope fitted with a long afterglow screen,
which permits the simultaneous and constant, viewing of a pair
of phenomena such as the phonocardiogram and electrocardio-
gram at the patient's bedside, while the heart sounds can be
heard at the same time through an electrical amplifying stetho-
scope or a loud-speaker. The double-beam cathode-ray oscillo-
scope has also many uses in biology and medicine.^ ^

1^ ^tv^ VT'".

FIG. 1. The Phonoelectrocardioscope.

42 Applied Biophysics

Figure 1 shows a photograph of the apparatus, and figure 2
a schematic diagram. The heart sounds are picked up by a
piezoelectric microphone, which converts them into electrical
pulsations. These are amplified by a thermionic-valve amplifier
which has special variable electrical frequency controls incor-
porated in it. An electrical stethoscope reconverts the amplified
electrical pulsations into sound waves. The phonocardiogram
can be directly observed on the long afterglow screen of the
double-beam cathode-ray oscilloscope. The electrical variations
of the heart can be simultaneously amplified by the second
channel, and directly observed as the second trace on the screen.

The following are some of the uses of the phonoelectrocardio-
scope in cardiology :

1. Simultaneous direct visual observation of the phonocardio-
gram and electrocardiogram, plus amplified auscultation.

3. Simultaneous direct visual observation of the phonocardio-
gram and sphygmogram, plus amplified auscultation.

3. Simultaneous direct visual observation of the electrocardio-

gram and pneumocardiogram, plus amplified ausculta-
tion.

4. Simultaneous direct visual observation of a logarithmic

phonocardiogram, and stethoscopic phonocardiogram, or
any one of the foregoing with a linear phonocardiogram,
plus amplified auscultation.

5. Simultaneous direct visual observation of the phonocardio-

gram of one area with that of another, plus amplified
auscultation.

6. Simultaneous direct visual observation of any pair of

electrocardiogram leads, such as leads I and III.

7. Photographic registration.

8. Murmurs or desired sounds can be accentuated and un-

desirable ones muted by filter controls.

Figure 3 shows a peculiarity of the double-beam cathode-ray
tube. It will be noted that the bottom logarithmic phono-
cardiogram is apparently 180 degrees out of phase compared
with the similar trace on the top. This can be rectified by

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43

Applied Biophysics

FIG. 3. The same apical phonocardiogram has been recorded by both beams on
moving film. It will be noted that they are apparently 180° out of phase, and that
there is no "fogging." Illustrative tracing taken with the author's phonoelectro-
cardioscope.

reversing the input leads for the bottom trace. The pair of
traces have been recorded on moving fihn, and, despite the
long afterglow screen, there is no trace of "fogging." Figure
4 shows a logarithmic phonocardiogram and electrocardiogram,

FIG. 4. Logarithmic apical phonocardiogram. Electrocardiogram, lead II. Re-
corded on moving film. Illustrative tracing taken with the author's phonoelectro-
cardioscope.

lead II, recorded on moving film. The precaution mentioned
above has been adopted, and the electrocardiogram shows the
right way up.

Figure 5 shows how a pair of traces look on the screen when
viewed directly. The top trace is electrocardiogram, lead II,
and the bottom trace is the jugular-pulse sphygmogram. They
have been photographed by focusing a camera on the fluorescent
screen of the double-beam cathode-ray oscilloscope, and taking
one traverse of the pair of spots as they appear for visual ob-

Applications of Electronics in Medicine

45

FIG. 5. Electrocardiogram, lead II. Electrical jugular pulse tracing. The
traverse of the pair of spots was photographed as they appeared for visual observation
- — opening the shutter at the beginning and closing it at the end of the traverse of
the spots. Illustrative tracing taken with the author's phonoelect;ocardioscope.

servation — opening the camera shutter at the beginning, and
closing it at the end of the traverse of the spots. Figure 6 is
similar to Figure 5, but shows electrocardiogram, lead II, and
a stethoscopic phonocardiogram, taken over the mitral area of
a case of rheumatic endocarditis.

FIG. 6. Electrocardiogram, lead II. Apical phonocardiogram of a case of rheu-
matic mitral endocarditis. The traverse of the pair of spots was photographed as
they appeared for visual observation — opening the shutter at the beginning and
closing it at the end of the traverse of the spots. Illustrative tracing taken with
the author's phonoelectrocardioscope.

46 Applied Biophysics

The loudness of the heart sounds as heard in the amplifying
stethoscope is governed by a tone-compensated gain control,
which helps to correct certain deficiencies in the human ear
in which the auditory sensation produced by complex sounds
may be decidedly different in character as well as intensity
when the stimulating level is increased or decreased. Such a
device permits greater latitude in varying the intensity levels at
which the heart sounds are heard.

It is easy to pick up the jugular sphygmogram by shunting
the microphone with a 1 mfd condenser. The shunted-condenser
microphone method is also used for recording the pneumo-
cardiogram. It is an obvious advantage to have an all-electric
method of recording these traces.

The phonoelectrocardioscope is of value in teaching, research
and clinical medicine.

Electroencephalography

The technique of electroencephalography is analogous to that
of electrocardiography, viz., amplification and registration of
the electrical potentials from the brain as picked up from the
surface of the body. The upper limit of size of the brain poten-
tials as led off from the scalp approaches that of the electro-
cardiogram, i.e., about 1 millivolt. Potentials even greater than
this are obtained when leads are placed directly on the exposed
cortex. Discharges of this magnitude are rare, and only found
in abnormal conditions.

The electrical variations generated by the brain fall into
certain patterns. The alpha waves, normally present in most
people, have frequencies in the neighborhood of 10 cycles per
second and amplitude of 10-50 microvolts. The beta waves have
a frequency of 30-40 cycles per second, but are of lower voltage.
Low-frequency waves, below ?> cycles per second, are called
delta waves, and are often of larger amplitude than either the
alpha or beta waves. The patterns are frequently superimposed.
Walter and Dovey ^^ suggest that rhythms at about 6 cycles
per second should be termed "theta" rhythms, and that such

Applications of Electronics in Medicine

47

FIG. 7. The Marconi encephalograph. (Courtesy of Marconi Instruments, Ltd.)

rhythms are characteristic of the resting, immature, or isolated
parietotemporal cortex. Single rounded waves, alternate with
sharp spikes, are found during epileptic seizures, sometimes not
perceptible through other symptoms. Williams has dealt with
the clinical application of electroencephalography in a recent
number of the British Medical Bulletin.

The cathode-ray tul)e suggests itself as the most convenient
form of recording apparatus in electroencephalography, but its
use in this field is by no means universal. It is being replaced,
for routine work, by the ink-writing recorder. The mirror
oscillograph is still used by some workers.

48 Applied Biophysics

Parr and Walter ^^ describe the technical methods, and give
circuit diagrams of amplifiers suitable for electroencephalographic
recording. Traugott '*'"' discusses electroencephalograph design
and publishes the circuit of his amplifier. The Technical Sub-
committee of the Electroencephalographic Society has drawn uj)
recommendations for recording apparatus.

The Marconi four-channel electroencephalograph (see figure
7), particulars of which, as far as the author is aware, have
not yet been published, consists of two double-channel amplifiers,
and a four-pen ink-recorder, with a variable-speed paper drive.
Each pen is actuated by a moving iron armature, the signal
w^inding being stationary (a permanent magnet field system is
used). Provision is made for the attachment of auxiliary equip-
ment, such as a cathode-ray oscilloscope, or a frequency analyzer.
Power supply units for operation from alternating cur-
rent supply mains are incorporated. The final smoothing of
the high-tension supplies is accomplished electronically and,
where necessary, electronic regulation is also employed to take
care of mains voltage fluctuations. Each amplifier channel has
a differential input and uses a common-cathode push-pull circuit
throughout. The time constant is controllable in four steps
between 1 second and 0.01 second, and the limit of high-
frequency response is variable between 15 cycles per second and
4,000 cycles per second. The upper limit of response with ink-
recording is 75 cycles per second. The overall sensitivity is
such that, at maximum gain, a 20 microvolt peak-peak input
produces a 20 millimeter peak-peak deflection of the recorder.
Inputs up to 100 millivolts peak-peak are accommodated. The
amplifier noise with the input short circuited and earthed does
not exceed 2 microvolts root mean square.

Beevers and Furth •''• ^ devised the encephalophone which
converts the electrical-potential changes into sound waves.
Basically, this apparatus is a form of heterodyne oscillator,
where the brain rhythm varies the frequency of the heterodyne
beat note. The "alpha" and "beta" rhythms give characteristic
trills, while "delta" waves produce slow sweeps of tone.

Various ways of supplementing primary inspection of the

Applications of Electronics in Medicine 49

electoencephalogram have been devised, such as that by Grass
and Gibbs.-^ Walter ^" introduced a device to overcome the diffi-
culties of the foregoing method. Briefly, Walter's method is as
follows : A series of tuned reeds are energized by the output of
the electroencephalograph. These reeds act as frequency split-
ters, since each is tuned to a frequency in the band to be studied.
Each reed is provided with a fine steel contact wire, which dips
in and out of a mercury cup when the reed vibrates, but is just
out of the mercury when the reed is at rest. A high resistance,
a source of electromotive force, and a condenser are in series
with this mercury reed-contact. The condenser is charged
up to a potential which is a function of the total dura-
tion of the contact time, and, therefore, of the amount of energy
at the reed frequency during the specified time. An amplifier
is connected to each condenser in turn by a motor-driven rotary
switch, and this amplifier works a wide-arc recording-pen
across the recording paper on which the original electro-
encephalogram is at the same time being traced. The summation
epoch is chosen to be 10 seconds, so that each 10-second stretch
of record has traced over it a histogram of its spectrum. The
analysis is performed automatically every 10 seconds. The de-
tails of design are fairly intricate and the adjustment is critical.
Electroencephalographic amplifiers can be modified for use
in electromyography, cardiography, and as general purpose
biological amplifiers.

Sound

An audiometer is an apparatus for the measurement of hearing
loss. Many of these devices have been introduced. A popular
model of such an instrument comprises a tone source (a ther-
mionic-valve oscillator working on the heterodyne principle)
which has a frequency range of 100-10,000 cycles per second
continuously variable. The output of the tone source is fed to a
high-fidelity moving-coil ear piece via an attenuator calibrated
to read in hearing loss or gain. An auxiliary control auto-
matically corrects the reading for the variation of the threshold

50 Applied Biophysics

of hearing with frequency. A piezoelectric microphone may be
switched into circuit to facihtate speaking to a partially deaf
person undergoing test. They are valuable in the diagnosis
of deafness and the accurate prescription of hearing aids. Many
a physician who prides himself on his skill with his stethoscope
would be surprised at his audiogram if he were tested with an
audiometer.

Hearing aids employing modern small piezoelectric micro-
phones, miniature valves and batteries, and compensating tone
circuits, can be of great value to the deaf. Tone-compensated
and automatic volume controls have increased the usefulness of
these instruments. Lately there has been a tendency for
wireless specialists to "fit" deaf persons with hearing aids ; this
is a dangerous practice. One must remember that many deaf
persons will not benefit at all by the use of these aids.

There are many types of amplifying stethoscopes working on
the thermionic-valve amplifier principle. Instruments have been
introduced for the graphic registration of the heart sounds, which
incorporate such devices. Olson ^^ introduced a new acoustic
stethoscope which transmits all frequencies over the range
from 40-4,000 cycles per second without discrimination or ap-
preciable attentuation, whereas an ordinary stethoscope has an
effective range of only 200-1,500 cycles per second. There is a
marked falling off in the frequency response of an orthodox
acoustic stethoscope below 200 cycles per second. A filter
control is incorporated in the instrument described by Olson.
The arrangement used for comparing the response characteris-
tics of this stethoscope with others is as follows : Sound vibra-
tions were developed in the human body by means of a sub-
aqueous loudspeaker fed by an audioamplifier and audiosignal
generator. An artificial ear was first held directly against the
opposite side of the body to secure a reference characteristic,
and different stethoscopes in turn were then ihtroduced between
the artificial ear and the body.

The recording and reproduction of sound is of interest to
the physician. Such records are of value foi; teaching and re-
search purposes, Henriques -^ described an apparatus for record-

Applications of Electronics in Medicine 51

ing the heart sounds on gramophone records. Sound can be
recorded on discs, steel wire, and photographic film. It may also
be recorded by embossing a track with a needle on film or plain
cellophane strip.

Reynolds '^^ has experimented on the problem of synchronizing
the electrocardiogram, as recorded by a cathode-ray type electro-
cardiograph, with a cinematographic film of the heart cycle.
The writer suggests that, theoretically, it should be possible to
develop this technique so that a cinematographic film of the
cardiac cycle could be produced, which has a sound track of
the heart sounds. If necessary, a simultaneous jugular sphygmo-
gram, phonocardiogram, etc., could also be shown on the film.

Synthetic sound is a term applied to sound produced by
methods like those devised by Rudolf Pfenniger who painted
by hand the desired wave forms, afterwards photographing
them onto a sound track for conversion into sound.

Electronic pH Meters

The estimation of the hydrogen-ion concentration of fluids
such as the blood in clinical practice is, in the main, confined
to the tintometer method. A number of pathological depart-
ments and bacteriological research institutions are now using pH
meters employing thermionic-valve circuits. The results ob-
tained with these devices are more accurate than those obtained
with other methods. Serum electrodes have been devised which
are capable of dealing with very small quantities of fluid —
0.2-0.3 milliliters. In clinical bacteriology, the growth of cul-
tures can be retarded, advanced, or even the manner of growth
can be directed by proper pH control.

Thermostromuhr Apparatus

Rein ^^ introduced the thermostromuhr method for measuring
blood flow through a blood vessel. A small insulator clip is
placed around the blood vessel. Two small plates which pass a
radio-frequency current through the blood stream are fixed in

52 Applied Biophysics

the central portion of the dip on opposite sides of the vessel.
At each end of the clip, there is a thermocouple differentially
connected. These make contact with the vessel wall. The pass-
age of the radio-frequency current through the blood stream
warms it slightly. The temperature difiference, which varies
inversely with the blood flow rate, is read electrically with a
sensitive galvanometer. Calibration of the instrument is done
by measuring the radio-frequency current used and adjusting
a comparison resistance to take the same current, thus permitting
the dissipated wattage to be estimated. The constants of the
blood vessel clips are readily fixed by the application of a simple
formula. A graph is obtained which permits this nondestructive
instrument to be used almost as easily as a direct-reading
mechanical flow meter. This method has been improved upon
by Essex, Herrick, Baldes, and Mann ^'^ and applied even to
the coronary circulation.

Photocells

Light-sensitive devices have been responsible for some of
the more recent developments of control engineering, as well as
of sound reproduction and optical determination. There are
three main types of photocell, the photoconductive, the photo-
electric and the photovoltaic.

Photoelectric colorimeters are being used in many laboratories.
They can be applied to practically every colorimetric problem,
from the simple evaluation of intrinsic color at selected portions
of the visible spectrum, to the more complex requirements of
the analytical chemist.

A fall in hemoglobin level is one readily detected sign of
incipient malnutrition. Another use for a rapid hemoglobin-
ometer would be in assessing minor degrees of anemia among
blood donors. The photoelectric hemoglobinometer is more ac-
curate than the visual method. In these, as green light is
absorbed by a red solution (of oxyhemoglobin), a constant
source of light is used together with an appropriate green filter

Applications of Electronics in Medicine 53

to pass a green light through the oxyhemoglobin solution ; the
amount of light able to pass is measured by a photoelectric
cell. The amount of light absorbed is proportional to the con-
centration of oxyhemoglobin, and thus it is possible to construct
a scale from which the percentage of hemoglobin can be rapidly
and accurately determined. Bell and Guthmann/ among others,
have devised a simple photoelectric hemoglobinometer.

Photoelectric colorimeters can be used for turbidimetric de-
terminations just as readily as for colorimetric procedures. The
basis for the calibration of these methods, which depend on the
development of a uniform turbidity rather than a color, is a
solution of standard turbidity. Readings and results are obtained
just as with colored solutions. There are many applications
of photoelectric turbidimetric methods, but only their use in
penicillin assay will be mentioned here. Joslyn ^^ and Mc-
Mahan,^^ among others, used such methods. Rantz and Kirby ^^
studied the action of penicillin on staphylococci by such a device.

Nygaard ^^ studied the kinetics and phases of blood coagula-
tion by means of a photoelectric device. His method depends
on recording the amount of light transmitted through clotting
blood to a photoelectric cell. A continuous photographic record
of the diminution of the transmitted lisfht can be taken.

•fc>'

Photoelectric Plethysmography

The basic principle of Leibel's method ^^ of measuring
peripheral blood flow is that the light intensity passing through
a finger or toe on which a beam of light is directed will vary
with the blood volume within the part, and will thus be an index
of the circulation through it. The^ emergent beam falls on a
photoelectric cell which changes any variation in the intensity
of the light into a corresponding variation in an electric circuit.
These electrical changes are amplified and then recorded with an
electrocardiograph. Two practical applications of this method
are the measurement of the pulse velocity by superimposing the
electrocardiogram on the tissue-circulation record, and the other

54 Applied Biophysics

is the demonstration in senile gangrene of increased blood flow
in the affected toe for some hours after the application of a
Parvex glass boot.

Hertzman and Dillon -^ have applied photoelectric plethys-
mography to the vascular reactions, such as Raynaud's disease,
or in evaluating the completeness of sympathetic denervation
of the skin, etc.

Radio-frequency Oscillators

The main uses of these devices in medicine are diathermy
and short wave therapy. These are so well known that it is
not necessary to deal with them here.

Radio-frequency probe. Farmer and Osborn ^^ describe an
apparatus for indicating the approximate position of metallic
substances. Theoretically, the instrument should be of value
in conjunction with X-ray examination. The principle is as
follows : A radio-frequency oscillator works on a frequency of the
order of 10*^ or 10^ cycles per second and the whole of the turning
inductance of this oscillator is in the form of a search coil capable
of being moved about near the patient. If the search coil ap-
proaches a metallic substance — such as a splinter in the operation
area — the inductance of the coil will change, and hence, the
frequency of the oscillator. The change of frequency can be
made audible by heterodyning these oscillations with those of a
second oscillator working on a slightly different frequency.
A beat note can be detected which can be heard through a
loudspeaker or headphones.

The Electron Microscope

The resolving power of a microscope is limited by the wave
length of light used. Moving electrons act as if they were asso-
ciated with a wave length. By using electron waves, 10~® of
the wave length of visible light, much greater resolution can be
got than with the optical microscope.

The electron microscope is classified as follows : the magnetic

Applications of Electronics in Medicine 55

electron microscope, the electrostatic electron microscope, the
scanning microscope, and the shadow electron microscope.

The electron microscope is of value in the study of viruses,
bacteriophages, the combination of antibodies with flagellar and
somatic antigens, the structure of bacteria, organic chemistry, etc.

The Cyclotron and Betatron

Rutherford, twenty-six years ago, performed the first mutation
of one element into another, viz., nitrogen into oxygen, and
directed attention to the means of energizing particles to such
a degree as would enable them to penetrate the nuclear barrier
of the atom. J. H. Lawrence experimented with lower voltages
tuned to give the particles a series of pushes. Thus, the cyclotron
was brought into being — an instrument in which the particle is
kept moving in a circular path by a magnetic field, and inter-
mittently accelerated by an electrical field. These particles move
inside two hollow semicircular electrodes placed between the
poles of an electromagnet, and are accelerated by an oscillating
potential applied to the electrodes every time they cross the
central gap between them. The angular velocity of the particle
caused by the magnetic field is constant, but the successive
acceleration of its linear velocity, caused by the electrical field,
makes it move in an ever widening flat spiral. The ultimate
energy of the particle is limited only by the diameter of the
hollow electrodes. Experimenters in nuclear physics, in the last
ten years, had energies extending up to 16 million electron
volts available in the form of high-speed positive ions from the
cyclotron.

The three major fields of biological study developed about
the cyclotron are : the use of a radioactive element to trace the
absorption, utilization, and excretion of its stable isotope by the
body in both health and disease ; the therapeutic effect of the
radiations emitted by radioactive substances internally admin-
istered ; and beams of both fast and slow neutrons are being
used in the treatment of cancer in a manner similar to X-rays
and y-rays in external therapy.

56 Applied Biophysics

The cyclotron did not provide high-energy electrons as well
as positive ions, because the lightweight electron behaves rela-
tivistically when its kinetic energy is still very small. Kerst -^
gives details of the construction of an improved induction accel-
erator which gives electrons 20 million electron-volts energy.
The accelerator has a 19-inch [about 58 centimeters] diameter
pole face and weighs approximately 33^ tons [about 3,050
kilograms]. The X-ray output, as measured in a thick-wall
ionization chamber, is 16 revolutions per minute at one meter.
The most important improvement incorporated in this accelerator
is the electromagnetic expansion of the equilibrium orbit, which
can be timed to send the electrons against the target at any
desired energy up to 20 million electron-volts.

The high-energy X-rays and electrons which are made avail-
able by the betatron can be employed for both physical experi-
ments and practical purposes. It is probable that all the elements
in the periodic table can be disrupted with the 20 million
electron-volts now available by a photonuclear process. The
energy of the X-rays or y-rays is used, generally, in ejecting
a neutron from the parent nucleus. The electrons of 20 million
volts energy are capable of penetrating at least 10 centimeters
into the human body. It has been suggested that they could be
used therapeutically instead of X-rays, and that they would
have the advantage that the ionization produced by them would
stop rather abruptly at about the middle of the body, and do
no damage beyond. The betatron produces X-rays which have
intensities comparable with those produced by commercial
machines. The maximum ionization caused by these X-rays
occurs at about 4 centimeters beneath the surface, which makes
it possible to administer a large dose to the interior of the body
without harming the surface.

In conclusion. I wish to thank Mr. C. Home, of Marconi
Instruments ; Metropolitan Vickers of England ; Mr. G. Parr,
editor of Electronic Engineering ; Mr. T. J. Shields, librarian
of the British Medical Association ; and Mr. G. F. Home,
librarian of the Royal Society of Medicine.

Applications of Electronics in Medicine 57

References

1 Adrian, E. D. (1926) /. Physiol. 62, 33.

2 Adrian, E. D. (1932) The Mechanism of Nervous Action, London.

3 Adrian, E. D. and D. W. Bronk (1929) /. Physiol 67, 119.

4 Asher, G. and F. Hoecker (1938) Amer. Heart J. 16, 51.

5 Beevers, C. A. and R. Furth (1943a) Electronic Engng. 15, 419.
« Beevers, C. A. and R. Furth (1943b) Nature, Lond. 151, 110.

7 Bell, G. H. and E. Guthmann (1943) /. Sci. Instrum. 20, 145.

8 Brookes-Smith, C. H. W. (1935) Elect. Commun. 13, 235.

9 Denny, B. (1944) Electronic Engng. 17, 26.

10 Denny-Brown, D. and J. Pennybacker (1938) Brain, 61, 311.

11 Donovan, G. E. (1943a) /. Instn. Elec. Engrs. 90, 38.

12 Donovan, G. E. (1943b) Irish J. Med. Sci., 583.

13 Donovan, G. E. (1943c) Med. Pr. 209, 298.

14 Donovan, G. E. (1943d) Proc. Roy. Soc. Med. 36, 603.

15 Donovan, G. E. (1944) Lancet, 1, 500.

16 Einthoven, W. (1903) Ann. Phys., Lps. 12, 1059 [and succeeding

volumes].

17 ElHott, F. A. (1944) Lancet, 1, 47.

18 Essex, H. E., J. F. Herrick, E. S. Baldes and F. C. Mann (1936)

Amer. J. Physiol. 117, 271.

19 Farmer, F. T. and S. B. Osborn (1941) Lancet, 2, 517.

20 Forbes, A. and C. Thacher (1920) Amer. J. Physiol. 52, 409.
2iGasser, H. S. and J. Erlanger (1922) Amer. J. Physiol. 62, 496.

22 Grass, A. M. and F. A. Gibbs (1938) /. Neurophysiol. 1, 521.

23 Henriques, C. V. (1937) Lancet, 1, 686.

24 Hertzman, A. B. and J. B. Dillon (1940) Amer. Heart J. 20, 650.
25Hoff, E. C., T. C. Kramer, D. Du Bois and B. M. Patten (1939)

Amer. Heart J. 17, 470.
26Hollmann, W. and H. E. Hollmann (1937) Z. Krehsforsch. 29, 546.
27 Joslyn, D. A. (1944) Science, 99, 21.
28Kerst. D. W. (1942) Rev. Sci. Instrum. 13, 387.
29K611iker, A. and H. Miiller (1855) Verh. phys.-med. Ges. Wiirzhurg,

6, 528.
30Leibel, B. (1940) Brit. Heart I. 2, 141.

31 McMahan, J. R. (1944) I. Biol Chcm. 153, 249.

32 Mann, H. and P. Bernstein (1941) Amer. Heart J. 22, 390.

33 Matthews, B. H. C. (1933) /. Physiol 78, 21.

34 Nygaard, K. K. (1941) Hemorrhagic Diseases; Photoelectric Study

of Blood Coagulability, St. Louis.

35 Olson, H. F. (1943) Electronics, 16, 185.

36 Parr, G. and W. G. Walter (1943) Electronic Engng. 15, 462.

58 Applied Biophysics

37 Piper, H. (1912) Elektrophysiologic menschlicher Muskchi. Berlin,

3s Rantz. L. A. and W. M. M. Kirby (1944) /. Immunol 48, 335.

3« Rein, H. (1928) Z. Biol. 87, 394.

4<' Reynolds. R. J. (1936) /. Instn. Elect. Engnrs. 79, 478.

•tiRijlant, P. (1932) Compt. rend. sac. bioL. Paris, 111, 246.

42 Ritchie, A. E. (1944) /. Sci. lustrum. 12, 64.

43 Robertson, D. (1934) Proc. Roy. Soc. Med. 27, 1541.

44 Schmitz. W. (1933) Pfliigers Arch. ges. Physiol. 232, 1.
45Traugott, P. (1943) Electronics, 16, 132.

46 Waller, A. D. (1887) /. Physiol. 8, 229.

47 Walter, W. G. (1943) Electronic Eng. 16, 9 & 236.

48 Walter, W. G. and V. J. Dovey (1944) /. Neurol. Neurosurg. Psychiat.

7, 57.

49 Ward, J. W. and A. Kennedy (1942) Amer. Heart J. 23, 64.
soWeddell, G., B. Feinstein and R. E. Pattle (1943) Lancet, 1, 236.
51 Weddell. G., B. Feinstein and R. E. Pattle (1944) Brain, 67, 178.
52Wedensky, X. (1883) Arch. Anat. Physiol., Leipzig, Physiol. Abt.,

p. 316.

53 Wever, E. G. and C. W. Bray (1930) Science, 71, 215.

54 Wilson, F. N. and F. D. Johnston (1938) Amer. Heart J. 16, 14.

THE CLINICAL APPLICATION OF HEAT

D. S. EVANS, Ph.D. & K. MENDELSSOHN, D.Phil.
Clarendon Laboratory^ Oxford

Introduction

IN VIEW of the fundamentally important part which heat
energy plays in the life of the human being, and the prom-
inence of the physiological processes regulating the body
temperature, it is remarkable that so very little is known about
the quantitative administration of heat in clinical practice. In
most cases, the recommendation of heat treatment goes no further
than the ancient prescription "Keep the patient warm." Coupled
with our ignorance of quantitative administration, there is also
a remarkable lack of information about the exact therapeutic
effects produced by heat. While it is generally true that by
the application of heat energy the production of heat by the
body can be supplemented to the advantage of the patient, we
have to face the fact that, for instance, the application of a hot-
water bottle produces an increase in body heat greater than the
amount actually transmitted from the bottle. Clinicians are also
aware of therapeutic effects produced by radiant heat at depths
in the tissues quite out of the reach of the radiation employed.

Physical Basis of Heat Therapy

However, before all these questions can be discussed, we must
first establish a basis for the dosage of heat treatment and, since
the methods of administration of heat are governed by the laws
of physics, our first concern must be to establish a sound physical
basis for clinical heat treatment. Normally the body disposes of
about 100 kilogram calories of heat per hour, and it is therefore

59

60 Applied Biophysics

likely that therapeutic effects will be obtained only if the amount
of heat administered to the body, or to part of it, approaches the
total metabolic heat, or the proportion of this normally allocated
to the part of the body in question. It is thus clear that, in
contrast to X-ray or ultraviolet therapy which relies on a selec-
tive action of the radiation, in the case of heat application
therapeutic effects wnll require the application of considerable
energy. As in every other kind of therapy, the chief danger to be
guarded against is overdosage. From what has been said, two
different kinds of overdosage can be foreseen. In the first place
the tolerable concentration of heat input over a restricted area
may be exceeded. When heat is applied to one square centimeter
of the skin its temperature is raised, and the degree to which
this happens depends on the strength of the energy flow pro-
vided by the heat source, and on the capacity of the tissues to
remove the local heating. With increasing heat flow, removal
processes are stimulated, but they will break down eventually
and a serious local over-heating of the tissues will be the result ;
in other words a burn will be produced. The limiting tempera-
ture above which the skin tissues must not be heated has been
determined by Mendelssohn and Rossiter,^ and has been found
to be 45-50° C.

The other danger lies in the general application of heat. If
the amount of heat applied becomes of the same order as the
total metabolic heat, and especially if, in addition, normal
methods of heat excretion (radiation and perspiration) are
restricted, then the total heat balance of the body may be upset,
and the patient may develop heatstroke.

Methods of Heat Transfer

The physical distinction between methods of heat transfer is
usually made as between convection, conduction, and radiation.
However, in the methods employed by the clinician, this clear
distinction can rarely be drawn, for usually several modes of
heat transfer are operative simultaneously. Pure convection is
met with, for example, only in the case of a hot-air cabinet,

The Clinical Application of Heat 61

and even here it may be necessary to consider also conduction
through the air, and radiation from the heated walls of the
cabinet. Methods relying mainly on conduction are met with
more frequently, examples being hot baths, electric blankets,
and hot-water bottles. All these methods of conveying heat to
the patient are admittedly convenient, but they present consid-
erable difficulties from the point of view of quantitative control
of administration. It is extremely difficult to discover how much
heat the patient actually receives, for example, from a hot bath.
The increase in body temperature produced can serve only as
a very rough indication of the amount of heat received, for it
must be remembered that as soon as heat is administered, the
processes of heat removal are also speeded up. In addition, the
ability to excrete heat may differ very considerably from patient
to patient, and even in one and the same patient there may be
changes according to the state of health.

A further difficulty in the application of electric blankets
and heating pads arises from the time factor. As has been
pointed out by Brown and Mendelssohn,- it takes more than
an hour for an electric blanket to deliver heat at full strength.

Heat Transfer by Radiation

The administration of heat by radiation has proved to lend
itself better than either convection or conduction to accurate
measurement and quantitative dosage. It is for this reason
that attention has been turned to this method of clinical heat
application.

X-rays, ultraviolet rays, visible light, and infrared rays are all
of a similar nature, and can all be classified under the heading
of electromagnetic radiation. All represent a transport of energy,
and when any of these rays is absorbed in a perfectly absorbing
or "black" body, this energy appears as heat. The difference
between these various types of radiation is solely that of differ-
ence in wave length : the wave length of X-rays is from several
thousand to several hundred times shorter than that of visible
yellow light ; ultraviolet rays are intermediate in wave length

62 Applied BiopJiysics

between X-rays and Ansible light. Deep-blue light with a wave
length of OAS[i represents the shortest wave length visible to
the eye, while red light with a wave length of from 0.63[i to
0.70u represents the longest visible wave length. Infrared
radiation describes wave lengths from 0.70[i to 20|.i or more,
and these merge imperceptibly into the short electric or radio
waves. The wave lengths used in radiant heat treatment are
from the visible red up to, say, 20[.i.

In addition to the generalized heating produced when electro-
magnetic radiation is absorbed, specific efifects may be produced,
and these have been explained by the quantum theory. This
theory states that radiation is not to be considered as a con-
tinuous flow of energy but as a shower of minute energy parcels
or quanta, each representing an energy contribution of a definite
amount. Emission and absorption of radiation can only take
place in whole or multiple quanta, never in fractions of a quan-
tum. The energy contribution of each quantum in radiation
of a given wave length is inversely proportional to the wave
length, i.e., the energy parcels of X-rays are larger than those
of ultraviolet rays, and these in turn are larger than those of
visible light or infrared radiation. The production of certain
intramolecular changes, for example, those leading to the pro-
duction of vitamin D in the tissues, requires the action of quanta
of a certain minimum size peculiar to this particular change,
that is, this change can be produced only by light of a wave
length sufficiently short to give quanta of the necessary size.
The application of radiation of longer wave length will not pro-
duce the same efifect, even if large amounts of energy are
supplied, simply because this longer wave radiation contains
no quantum of the necessary size. The efiicacy of X-ray and
ultraviolet therapy depends on this fact. They are administered
in small doses — only 10 gram calories or less at a treatment —
and produce specific chemical changes in the tissues. They also,
of course, produce heating of the tissues, but this is so slight as
to be masked completely by the specific changes, even though
the latter are caused by only a small proportion of the total
incident energy.

The Clinical Application of Heat 63

The visible range of electromagnetic waves represents roughly
the size of quanta below which no specific action is produced in
the body tissues. In other words, the action of infrared radia-
tion is distinguished by the fact that it produces no specific reac-
tions at all, and its absorption merely causes a rise of temperature
in the tissues. The short wave radiations, such as X-rays or
ultraviolet rays, are limited in their application by the harmful
efifects which are produced by an excess of the specific changes
for which they are responsible. Infrared radiation, on the other
hand, can be applied at a strength which is limited only by the
capacity of the tissues to withstand heating. It is for this reason
that infrared radiation has become known under the name of
''radiant heat" for, in contrast to the shorter wave length radia-
tions, it offers a safe method of pumping heat energy into the
body.

To produce any sensible effect with infrared, large doses, in
some cases as much as 200,000 gram calories at a treatment, are
used, but this infrared radiation must not be accompanied by
more than a minute proportion of ultraviolet radiation, which, in
this case, would produce unwanted specific effects, and would
severely limit the total energy which could be pumped into
the patient without injury.

\\' hen a body is heated it emits electromagnetic radiation, and
the total quantity of energy emitted from one square centimeter
of its surface, as well as the wave lengths in which this energy
is emitted, depend on the temperature of the body. A body at
2000° K * emits 256 times as much energy from each square
centimeter of its surface as a similar body at 500° K. For the
first, the greatest intensity of radiation is in a wave length of
about 2[{ ; for the second, the wave length of maximum intensity
is four times as great. . Even a body at 4000° K, which is sixteen
times as efficient an emitter of radiation as one of 2000° K, emits
the greater part of its energy in the infrared, but now there

* It is convenient to give temperatures in degrees Kelvin or "absolute," which
means the centigrade temperature plus 273°. The total energy radiated from a
blaclv surface is proportional to the fourth power of the absolute temperature, and
other characteristics of the radiation are all most simply expressed in this tem-
perature scale.

64 Applied Biophysics

is an appreciable contamination with ultraviolet radiation.

In practice, the hot bodies used as sources of radiation are
all at fairly low temperatures, and so provide radiation which
is all in the infrared with a little visible red light. An excep-
tional case is provided by the arc lamp, where the hottest part
of the carbon rods may be at a temperature as high as 3500° C
(3730° K) and gives a considerable proportion of ultraviolet
radiation, even though the greatest part of the energy emitted
is in the infrared. Even an ordinary incandescent filament lamp
actually emits a small proportion of ultraviolet radiation, but this
is all absorbed in the glass of the lamp bulb.

At all temperatures, therefore, which may be acquired by the
dull emitter heating elements, or the metal shields and reflectors
of radiant heat apparatus, the radiation emitted is in the infrared,
and, because of absorption by glass, the actual radiation which
reaches the patient from an incandescent filament lamp is also
infrared, accompanied by a small proportion of energy in the
visible region.

On the other hand, low-temperature sources are relatively
inefficient, and thus, if we wish to secure a large total emission
of radiation from the source, we must use extended sources,
such as heated metal sheets, or groups of point sources. To
illustrate this point, the example of a heated metal sheet radiating
to surroundings at room temperature may be quoted. At a
temperature of 100° C this emits only one calorie per minute
from each square centimeter of surface.

Calculation of Dosage

The X-ray worker always has to deal with a point source
of radiation, so that the radiation comes to his patient as a
beam. For him it is a comparatively simple matter to calculate
the dosage received by the patient from the strength of the
source, the distance of the patient, the area irradiated, and
similar data. In radiant-heat therapy with extended sources,
such as, for example, radiant-heat cradles, there is no single
beam of radiation, and each part of the patient's skin receives

The Clinical Application of Heat 65

energy from all directions. It is possible to calculate the energy
received on the skin from the strengths, temperatures, and
positions of the various parts of the source,^ but it is a somewhat
severe mathematical problem, and is clearly an impossible method
for ordinary clinical use. Reliance must be placed on direct
measurement, and what is needed is some simple method of
measuring the energy actually received on the patient's skin.

In X-ray work, with beam therapy, a suitable standard of
measurement would be the energy falling in one minute on a
surface of one square centimeter placed normal to the beam.
That was suggested by IMayneord and TuUey ^ as suitable also
for infrared work, but, in fact, a slight amplification of their
definition is necessary. A more suitable specification would be
the total energy coming from all directions which impinges in one
minute on a surface of one square centimeter placed in the
position to be occupied by the skin of the patient. For a unit
incident energy flux of one gram calorie per minute, we have
suggested the name pyron}

This unit specifies the total incident energy without regard
to wave length (color, quality), but as the effect of all wave
lengths of infrared radiation is simply to heat the tissues, the
consideration of the range of wave lengths used in any given
circumstance is of an importance secondary to the consideration
of the total energy received in all wave lengths. There are, of
course, problems connected with the difference in penetrating
power of different wave lengths, but the first task is to provide
convenient methods of determining the total flux.

Special Problems of Measurement

Before discussing practical methods of measurement we must
first consider a theoretical point. As explained above, all hot
bodies radiate energy, and cease to do so only if cooled to the
absolute zero of temperature (zero on the absolute scale, see
footnote, page 63. Thus, all our surroundings continually
radiate energy, and energy is being continually radiated from
our skins to our surroundings. What we must measure, there-

66 Applied Biophysics

fore, as being of clinical importance, is not the absolute amount
of radiation energy received from a clinical source, but the excess
of radiant energy received on the skin, over that which would
normally arrive from the surroundings. That is, we must com-
pare the incident flux with that from surroundings at normal
room temperature.

The fundamental physical method of measuring radiation flux
is to absorb all the incident radiation on the blackened surface
of known area of, say* a block of metal, and to determine the
energy received from the rise in temperature of the receiver.
Corrections must be applied for the cooling of the receiver
which will lose heat by ^ radiation and by conduction to the sur-
rounding air. To eliminate the latter and to secure a rapid
reading, the receiver is made of small heat capacity, is placed
inside an evacuated glass envelope, and its temperature is
measured by thermoelectric methods. Estimates of intensity of
infrared radiation made with a vacuum thermopile are, however,
liable to be very misleading in clinical practice, because the glass
envelope absorbs all radiation beyond about 3.5u, and we have
found,"^ that in certain clinically important cases, two-thirds of
the incident flux may be beyond this limit.

The Thernioradionieter

We have developed an instrument for the clinical measure-
ment of radiation flux (thermoradiometer) which dispenses
with such an envelope. It consists of two receiver plates
which are blackened and carry a pair of thermo junctions on
their reverse faces. The upper one receives the radiation
flux to be measured, while the lower one receives radiation
from a surface maintained by water cooling at room tem-
])erature, and which, therefore emits the radiation characteristic
of our normal temperature surroundings. The two receiver
})lates are screened from one another by a small metal block,
which has the efl"ect of smoothing out random fluctuations of
temperature. On the other hand, the two plates are very close
together, and, therefore, the air temperature for each of them

The Clinical Application of Heat

67

FIG. 1. The complete thermoradiometer, consisting of receiver unit (to be placed
in the position of the skin area to be irradiated) and millivoltmeter calibrated in
pyrons (gram-calories per minute passing through a square centimeter). In addition
to the current leads, tubes for water-cooling are attached.

is likely to be very nearly the same, so that the losses of heat
by air conduction are practically the same for the two discs.
Since the quantity which is actually measured in this arrange-
ment is the fairly small temperature difference between the two
discs, all temperature effects due to air conduction are cancelled.
The lower, or reference, disc is screened from stray radiation
which would falsify the readings, but a small air gap is left
between the screen and the main part of the instrument through
which a slow convection of air takes place. Without this air
gap, layers of hot air might be trapped in the concavity of the
water jacket and would falsify the readings. We find that such
an instrument registers a final reading in 30-40 seconds, and that
it is accurate, certainly within 5%. It should be pointed out

FIG. 2. Close view of the receiver unit. The circular plate in the center is the
actual receiver plate which, like a similar plate facing the water-cooled background,
is suspended on the screening block.

68 Applied Biophysics

here that this accuracy is probably better than is needed in
clinical work. What is needed is an instrument which, under
varied conditions of use, will always indicate within a few per
cent the total incident radiation. A vacuum thermocouple is
more accurate in the sense that it measures a certain quantity
very precisely, but as we shall see, under certain not unusual
clinical conditions, the quantity which it does measure is very
different from the quantity which the clinician needs for con-
trolling his treatment. Our instrument must, of course, be cali-
brated against known radiation sources, or by other methods,
but when this is done it is found to have a linear response, and
the millivoltmeter or other instrument used to measure the
thermoelectric current may then be calibrated with a linear scale
of pyrons. Typical examples of determinations of total flux
under various clinical radiation sources are shown in the figures
on pages 69 and 70.

When this instrument is used to measure the incident flux
under various types of clinical radiation source, it is usually
found that the flux increases with time. This is due to the
fact that the glass envelopes of the electric lamps, metal re-
flectors, and other parts of the source, become heated in course
of time, and these in their turn become sources of radiant energy.
The temperatures attained by these parts of the source are low,
but in many cases they are of considerable area, so that they
may eventually come to provide the major part of the flux
received by the patient. On the other hand, the radiation which
they do provide is all low-temperature, long-wave radiation
which is absorbed by glass. Therefore, a glass-enclosed instru-
ment will show little or no increase even under circumstances
when, in the course of an hour, this instrument will show a
three-fold increase of flux. We have pointed this out in a dis-
cussion of radiant-heat cradles,*'^ where we found that the flux
at the center of the cradle increased from 0.4 pyrons to 1.2
pyrons in an hour. The patient, of course, will respond to this
change in ways which may be unpleasant, but for the reasons
given, a glass-enclosed thermocouple will not respond to it. This
time factor is thus of peculiar importance in estimating radiant-

The Clinical Application of Heat 69

heat dosage ; its effects cannot be detected with a glass-enclosed
instrument, but, if it is neglected, serious overdosage and injury
to the patient may ensue.

10

20

«o

FIG. 3A. Isophotes (curves of equal radiation flux) from a bright-emitter treat-
ment lamp of 1000 watts determined with the thermoradiometer (receiver plate normal
to the axis of the lamp).

t toctns .

FIG. 3B. Isophotes (curves of equal radiation flux) from a dull-emitter treat-
ment lamp determined with the thermoradiometer (receiver plate normal to the axis
of the lamp).

70

The Clinical Application of Heat

71

Quality of Radiation: Transmission by Textiles

The study of the quaHty, or dominant wave length, of infra-
red radiation under conditions of chnical treatment is a difficult
one, and little progress has heen made. Some advance can be
made by comparing different types of source, such as, for

18 20

r

(wave length)

FIG. 4. Wave length distribution of radiant energy from a heat cradle. The area
(1) represents the energy from the bulbs, which is all the energy emitted in the first
minutes of treatment. The area (2) is radiation from the cradle background after one
hour of use; the total energy emitted after one hour from switching on the cradle
is represented by the sum of (1) and (2). The figure shows not only that the energy
transmitted to the patient increases greatly with time, but also that the additional
radiation from the background will escape detection if a glass-enclosed thermocouple
is used. The wave length beyond which glass will cut off all radiation is marked by
the dotted line.

72 Applied Biophysics

example, an electric lamp (giving a radiation maximum at
^ l.Sji) with an electric fire (giving a radiation maximum
at '^ 3\i). Mayneord and Tulley ^ have approached this prob-
lem by studying the al)sorption of radiation of different tempera-
tures in various thicknesses of celluloid. However, as they point
out, care must be taken in the interpretation of the results be-
cause of the scatter of radiation in this medium. This difficulty
is, of course, aggravated in the case of infrared radiation which
is not administered in a beam. Secondary radiation from the
filter may also cause falsification of results.

We have made preliminary ex])eriments on the transmission
by various types of textile materials (blankets, towels, cotton
and linen sheets, lint, etc. ) and find that, in general, materials
transmit 20-30% of the long-wave incident radiation, and 30-
40% of the short-wave. However, if a patient is covered by a
blanket, it must not be assumed that he will only receive, say
25%, of the energy incident on the upper surface of the blanket.
In addition, the blanket will gradually warm up to a temperature
depending on the particular circumstances, and will transmit
energy, not only by secondary radiation, but also by conduction,
both by direct contact and across air pockets trapped between
the blanket and the skin.

What is of importance is the total heat supplied to the patient
by all mechanisms, and we have been able to evaluate the dif-
ferent contributions in one case. Before an open electric fire we
found that a layer of lint transmitted 27.5% of the incident
radiation, and that conduction was responsible for transmitting
an amount of heat equal to 32% of the incident radiation. In
this case the covering was not enclosed, and so the lint did not
acquire a high temperature, and did not in consequence provide
any appreciable amount of reradiation. The total energy received
on a calorimeter placed behind the lint was. in this case, 60%
of the incident radiation.

The Clinical Application of Heat 73

Conclusion

Thus, although some progress has been made during the
past few years in the assessment of the physical factors govern-
ing the clinical application of radiant heat, and in its quantitative
measurement, very much remains to be done. In particular, the
physical details and clinical significance of the absorption proc-
esses of various wave lengths in the tissues needs careful study.
However, the most important problem of the clinical application
of heat in general is the determination of limits of tolerance,
together with the study of the relative therapeutic value of heat
dosages of different magnitude. It is likely that, in this field of
quantitative dosage, radiant heat will be found to be the method
of administration for which quantitative control can most easily
be achieved.

The work described in this paper on the physical factors
governing the clinical application of heat constitutes a part of a
general investigation of methods of administration, and of the
effects of heat treatment carried out in the Nuffield department
of clinical medicine, Oxford University, and it is a pleasant
duty to thank the director of this department,. Professor L. J.
Witts, for his interest and help at all stages of the work.

References

1 Brown, G. M., D. S. Evans and K. Mendelssohn (1943) Brit. Med.

J. 1, 66.

2 Brown, G. M. and K. Mendelssohn (1944) Brif. Med. J. 1, 391.

3 Evans, D. S. and K. Mendelssohn (1944) Brit. Med. /. 2, 811.

4 Evans, D. S. and K. Mendelssohn (f945) Proc. Roy. Soc. Med. 38

[in press].
SMayneord, W. V. and T. J. Tulley (1943) Proc. Roy. Soc. Med. 36,

411.
« Mendelssohn, K. and R. J. Rossiter (1944) Quart. .J. Exp. Pliysiol.

32, 301.

THE MFXHANICS OF BRAIN INJURIES

A. H. S. HOLBOURN, D.Phil.

Research Physicist^ University Laboratory of PhysioUtgy and
Department of Surgery, Oxford

Introduction

THERl^ is some truth in almost all the theories of the
mechanisms of brain injuries due to violence,^- ^^' ^^ but in
the writer's view '■ "^ only skull bending, fracture, and
rotation ^ of the head are important. The physicist would
attribute the comparative failure of most of the theorists to their
wrong method of approaching the problem, in that they began
by fastening their attention on a particular mechanism (e.g.,
coup and contrecoup, or production of cerebral anemia). The
physicist's initial assumption is that damage to the brain is a
consequence, direct or indirect, of the movements, forces, and
deformations at each point in the brain. The movements, forces,
and deformations are not independent ; so that it is sufficient
to express everything in terms of deformations. These are
worked out with strict adherence to Newton's laws of motion,
but with approximations to the constitution and shape of skull
and brain. Hence further advances can come only from making
better approximations.

Tlie Forces to be Considered

As a consequence of the principle of superposition, it is
reasonal)ly correct to assume, in this particular problem, that
each cause produces its own independent injury. These causes
may be regarded as (a) forces on the brain resulting from bend-
ing of the skull, (b) forces resulting from fracture of the skull

74

The Mechanics of Brain Injuries 75

or separation of sutures, (c) forces resulting from movement
of the head as a whole and which would exist even if the skull
were undeformable. (c) may be subdivided into (ci) linear
acceleration forces, (C2) rotational acceleration forces, (C3) cen-
trifugal forces, (C4) Coriolis forces. Of these (ca) and (C4) are
clearly negligible.

Now it is allowable to analyze the deformations of each
infinitesimal element due to (a, b, ci, Co) into two and only two
types (a) change of shape, or distortion, without change of
volume (this is analyzed by physicists into a set of shear strains)
and (P) a change in volume without distortion, (a) is extremely
liable to injure animate^ or inanimate objects. (P) is of two
kinds (Pi) decrease in volume due to increase of hydrostatic
pressure and (Pi.) increase in volume due to decrease in hydro-
static pressure. Common sense suggests that (Pi) is harmless
provided it does not cause prolonged occlusion of blood vessels.
Its harmlessness has been verified for peripheral nerves.^ (P2)
is also harmless unless the decrease in pressure is sufficient to
cause cavitation, i.e., liberation of bubbles of vapor or dissolved
gases.

Changes in Volume

Unfortunately the terms "increase in volume" and especially
''decrease in volume'' are imprecise. Decrease in volume of a
particular region might be brought about by a true hydrostatic
pressure acting equally in solid tissues, blood, and tissue fluids,
and not allowing anything to pass out of the given region. Under
such conditions the ratio of the volume decrease of a cubic
centimeter of brain to the pressure increase is the true com-
pressibility, and is the same as that of water, 5 X 10'^^ dyne"^
square centimeter. Alternatively, the pressure causing the de-
crease in volume might act only on the solid tissue and might
allow blood, or blood and certain tissue fluids, to escape from
the region considered. Under such conditions one would obtain
a pseudocompressibility, whose value would depend on many
things. A value of 2 X 10 *" dyne"^ square centimeter was found

76 Applied Biophysics

by Flexner, Clark, and Weed.* It can be shown, however, that
in any ordinary sort of accident very Httle blood or other fluid
is forced out of the brain, and most of it will return when the
blow is over. Therefore, exsanguination is not the cause of
immediate loss of consciousness, and the brain during an accident
may be assumed to be nearly as incompressible as water. The
medical man may, perhaps, be more easily convinced of the
unimportance of immediate exsanguination by the observation
that it is clearly not responsible for such things as massive
hemorrhages into the temporal lobes, and that in slow crushing
injuries, where exsanguination is greatest, there is no concus-
sion.^ Of course, long after the blow is over, anemia may occur
owing to various pathological processes; but this is outside the
scope of the present article.

Comparative Effects of the Forces : Linear and
Rotational Acceleration

To recapitulate, therefore, 4:he forces (a, b, Ci, C2) are im-
portant only in so far as they give rise to (a), distortion (or
shear strain) or (P2) decrease in pressure sufficient to cause
cavitation.

On these assumptions, bending of the skull (a) produces,
owing to distortion, superficial bruising of the brain near the
spot hit, combined with injury (usually negligible) where tissue
is squeezed out of a foramen or defect; (c) causes distortion
injury to brain and blood vessels near the fracture; (ci) can be
neglected because, as the brain is nearly uniform macrascopically
in density, it causes almost entirely increases of (|3i) or de-
creases of (P2) in pressure at every point. ((3i), as explained,
is harmless. ((3^) would be injurious only if the pressure fell by,
say, 5 X 10'*^ dyne per square centimeter. Now, in the average
accident, the pressure fall due to linear acceleration is accom-
panied by a shear stress in the brain due to rotational acceleration
of about equal order of magnitude when expressed in dyne per
square centimeter. But 5 X 10^ dyne per square centimeter of
shear stress would cause utter destruction of brain. Therefore,

FIG. 1. Absolute movement in space of the skull and brain when the skull experi-
ences a linear acceleration. Arrows mark the actual paths in space of particles of
skull and brain. The brain participates completely in the motion, each bit being
pushed forward the requisite amount to keep step with the skull owing to the brain's
extreme incompressibility. No part of the brain moves appreciably relative to the
skull. Thus, the brain suffers no distortion and therefore no injury.

FIG. 2. Absolute movement in space of a skull and hypothetical brain, supposed
completely incompressible and completely rigid, when the skull is rotated about o.
Arrows mark actual paths in space. The skull and brain move as a single rigid unit
and the brain is not distorted.

77

78

Applied Biophysics

in almost every accident, the linear acceleration, (ci), can be
neglected in comparison with the rotational acceleration, (co).
There is an essential difference between linear and rotational
movement. When the skull is moved in a straight line, it is the
brain's incompressibility which prevents it from being left behind.
This being very high, none of it lags behind, so that it moves as
a whole, and there is no appreciable distortion ( figure 1 ) . On the
other hand, when the skull is rotated, the brain has to depend
on its rigidity to avoid being left behind. But its rigidity is small,
so that parts of it do get left behind to a considerable degree.
It is therefore distorted (figures 3 and 4).

\

FIG. 3. Absolute movement in space of a skull and real brain of small rigidity
when the skull is rotated about o. Arrows as in figures 1 and 2. Skull and brain
do not rotate together as a single rigid unit. The brain moves relative to the skull
and is therefore distorted and injured.

The Mechanics of Brain Injuries

79

FIG. 4. Relative movement of the brain with respect to the skull when the skull
is rotated as in figure 3. In other words, this is a diagram of the lag of the brain
behind the skull. The tail end of an arrow marks the starting position of a particle
of. brain relative to the skull and the point the final position, e.g., a sulcus moves
in relation to the skull from the dotted position A to the full line position B. It is
seen that the brain makes the only lagging movement open to an incompressible sub-
s.tance in an enclosed space, viz., a whirling movement. The amount of the rotation
and rotational acceleration is completely independent of the position of the point o
in figure 3. Neither this figure nor figure 3 are quantitatively accurate.

Distribution of Damage from Rotation

As rotation is theoretically so important, it is of interest to
find the distribution of damage produced by it. This is done
easily, though approximately, by making a model of a section of
the brain out of gelatin, and giving it a rotational jerk in a cir-
cular polariscope which renders the shear strains in the gelatin
visible. Figure 5 shows a system of shear strains obtained in
this way. The good agreement with the findings at necropsy is
to some extent fortuitous, as the following approximations have
been made. There are no fissures or sulci in the model. The
elasticity of the gelatin is uniform throughout the model, whereas
white matter, for example, is stiffer than gray matter. This
nonuniformity would tend to cause specially large strains near
the junction between white and gray matter.^ There is a two-
dimensional strain system in the model, but a three-dimensional
strain system in the brain. The brain has different rheological
properties from gelatin, which nearly obeys Hook's law. On
the other hand, differences in stiffness between gelatin and brain
do not matter; in fact exactly the same strain diagram would

80

Applied Biophysics

FIG. 5. The shear strains (= distortion) which arise when a gelatin model is
rotated as in figure 3, or in the reverse direction. The darker the shading the greater
the distortion. Note the comparative absence of distortion in the lateral cerebellar
lobe and high distortion at tip of the temporal lobe.

hold for glass or metal. Figure 5 refers only to blows of long
duration.

Rotation causes the so-called contrecoup injuries, and presum-
ably (as the effects of fracture and skull bending are purely
local) concussion. It follows that if the head can only rotate
slowly, e.g., in the case of crushing between railway buffers,
or is fixed, there is no concussion. The latter result agrees with
that of Denny-Brown and Russell,^ but not with that of Scott. ^^
From a well-known theorem in kinematics, it makes absolutely
no difference to the rotational component of injury whether the
rotation is one about an axis through the "center" of the brain,
or is an equal one about a parallel axis through the atlas or
through Timbuktoo. But since the last case would involve a
linear acceleration up to millions of miles per hour, the rotational
component of injury would be comparatively unimportant. The
rotational injury is ai)proximately the same whether the head
rotates forward from a blow on the occiput, or backward from

The Mechanics of Brain Injuries 81

a blow on the forehead. In both of these cases, the damage is
clearly symmetrical with respect to the midplane ; but it is also
approximately symmetrical with respect to the midplane when-
ever the head is hit at any point whatsoever by a blow whose
direction is exactly perpendicular to the midplane. Such a blow
causes a rotation about an axis lying in the midplane or parallel
to it.

If the distribution in any region is sufficiently great, every-
thing in that region that can be injured will be injured — blood
vessels will be torn, axons torn, synapses disrupted, etc. The
injury due to lesser amounts of distortion will depend on the
degree of distortion, on the nature of the distorted region, and
on the directions of the shear strains relative to fiber directions.
But, in general, it must take less distortion to produce a quickly
reversible effect in a cell body or axon than it takes to produce
an actual tear in them or in a blood vessel. The small distor-
tions in a peripheral nerve produced by a falling drop of mercury
or a jet of air are known to excite it without causing injury.^
It is reasonable to suppose that there is some similar sort of effect
in the brain, and thus, that blows so small that they produce no
anatomical injury nevertheless momentarily upset the existing
activity in the brain. Possibly momentary amnesia or the splash
of light which often accompanies a blow are due to this effect.
The shear strains which arise as a result of squeezing a peripheral
nerve can cause it to fail to conduct impulses, and if the strains
have not been too severe the nerve will recover spontaneously
after some minutes, even in the absence of a blood supply. Once
again, one would expect a similar effect in the brain. Amnesia
lasting only a few minutes might be the result of such a mech-
anism.

Although the whole brain is distorted by rotation, some parts
are much more distorted than others. Thus, so far as the physics
of the problem is concerned, loss of consciousness might be due
to a diffuse neuronal injury, or to injury to a particular region,
or both, or sometimes one, sometimes the other,

82 Applied Biophysics

Concliision

To sum up the position as it appears to a physicist : in the
vast majority of accidents to human beings, only skull bending,
fracture, and rotation are of any importance ; but, with sufficient
experimental ingenuity, it would obviously be possible to produce
injuries by other mechanisms: some of the experimenters who
report results due to the other mechanisms may have had this
ingenuity ; others may be misinterpreting their experiments.

The treatment given here needs modification in the case of
injury by high velocity missiles.

Postscript. After this article had gone to press, a film showing the
surface of the brain as seen through a transparent window 12 was
exhibited in England. It shows that in the case of a nonpenetrating blow,
the surface of the brain slides several millimeters along the under-surface
of the skull, no gap appearing between the two. Hence the brain is
executing a swirling movement like that in figure 4. Of course, there
is no proof that all the damage is due to the swirling, but no reasonable
person who has seen the film can doubt its importance.

References

lAnzelius, A. (1943) Acta Path. Microbiol. Scand. Suppl. 48, 153.

2 Blair, H. A. (1935-36) Amer. J. Physiol. 114, 586.

3 Denny-Brown, D. and W. R. Russell (1941) Brain, 64, 93.

4 Flexner, L. B., J. H. Clark and L. H. Weed (1932) Amer. .J. Physiol.

101, 292.
^ Goggio, A. F. (1941) /. Neurol. Psychiaf. 4, 11.
«Grundfest, H. (1936) Cold Spring Harbor Symp. Quant. Biol. 4, 179.

7 Holbourn, A. H. S. (1943) Lancet, 2, 438.

8 Holbourn, A. H. S. (1944a) Lancet, 1, 483.

9 Holbourn, A. H. S. (1944b) /. Netirosurg. 1, 190.

10 Jakob, A. (1912) Llistol. histopath. Arb. 5, 182.

11 Scott, W. W. (1940) Arch. Neurol. Psychiaf., Chicago, 43, 270.

12 Shelden, C. H., R. H. Pudenz, J. S. Restarski and W. M. Craig (1944)

/. Netirosurg. 1, 67.

13 Sj5vall, H. (1943) Acta Path. Microbiol. Scand. Suppl. 48, 1.

THE BIOLOGICAL EFFECTS OF PENETRATING

RADIATIONS

F. G. SPEAR, M.A., M.D., D.M.R.E.

Straii^eways Research Laboratory, Cambridge, and Member of the
Scientific Staff, Medical Research Council

Introduclion

WHIL.E Planck was putting forward his theory of energy
quanta, Becquerel, by accident, and Curie and Asch-
kinass, by design, made experiments upon themselves
and, with others, demonstrated the destructive action of radium
and X-rays on Hving tissues. As a consequence, the biological
effects of penetrating radiations became widely studied, in part
to satisfy a natural curiosity, but also to determine how the rays
might be usefully employed in medicine. The fiftieth anniversary
of the discovery (in November 1895) of X-rays seems a fitting
time to review the trends and some of the achievements in this
now vast field of experimental radiobiology, which was born
so soon after Rontgen's momentous announcement.

For roughly 25 years, biological observations were mainly
qualitative and were concerned with the changes, seen in a
great variety of biological material, after exposure to arbitrarily
chosen and crudely measured doses, of radiation. By this seem-
ingly haphazard method, however, many facts of fundamental
importance were learned. For example, the selective action of
radiation was recognized in the discovery that the cells of some
tissues were more affected by a given dose of radiation than the
cells of other tissues exposed to the same dose under identical
conditions. It was also found that the same dose produced a
different result according to whether it was given at a high
intensity for a short time or a low intensity for a longer time. It

83

84 Applied Biophysics

was noted that proliferating tissues showed a more marked re-
action to radiation than those without dividing cells and that
a latent period, which varied for different types of response,
elapsed between exposure and the appearance of radiation effects.

From about 1920, biological response was, in the laboratory
at least, much more frequently measured quantitatively, though
all tissues were not equally convenient for experiments of this
kind. Some observers chose what was alreadv familiar to them,
and others what was most conveniently available. Meanwhile,
work on the physical measurement of dose made progress, cul-
minating in the international unit of measurement for X-rays,
now applicable to gamma radiation as w^ell.

Experimental radiobiology has thus grown to a science in
which physical dose and biological response can be measured with
reasonable accuracy. Its development has been greatly influenced
by its relation to medicine and, while attempts are sometimes
made to distinguish those investigations which have obvious
application to medical practice ("applied radiology") from those
which have not ("pure research"), opinion would often be
divided as to which category any particular investigation should
be assigned. At least one major effort has been made to review
the literature not immediately concerned with practical radio-
therapy.^*^ The vast mass of literature which has accumu-
lated on the other side has been the subject of many re-
views.-^' ^^' -^' ^^' '^^' ^^-' ^^^- ^-^ The purpose of this paper will,
however, best be served by ignoring this somewhat arbitrary
division and giving a brief summary of each of the main branches
into which the subject has, through circumstance or convenience,
become divided.

Background Theory

The most conspicuous advances in experimental radiobiology
have been made when physicist and biologist have worked in
harmonious collaboration, an achievement which in practice is
too seldom realized. This is mainly due, perhaps, to a difference
in training and outlook which needs to be remedied by reeduca-
tion on both sides.*^

Biological Effects of Penetrating Radiations 85

The effects produced by radiations in their passage through
Hving matter may be studied in two ways. The investigation
may be concerned with the mechanism of the action of radiation
by means of specially designed experiments on selected materials,
usually of the simplest kind. This is often referred to as
* 'fundamental research," and is a long-term program of research
in which much detailed information is gradually collected for a
particular material, but it does not necessarily follow that what
is observed for one tissue applies to other kinds of tissue after
similar doses of irradiation. The other, or short-term method,
involves a study not of the exact mechanism of the biological
action of radiations, but of their histological effects under given
physical conditions. Much of this work forms the background
of medical radiotherapy, and its results are no less fundamental
than those obtained by the other approach ; they are sometimes
of great practical use.

It was natural, perhaps, that the physicists should be attracted
to problems concerned with the mechanism of action of radiation
on living cells, while the biologists, in the main, devoted their
energies to recording changes in behavior of irradiated tissues
under a variety of experimental conditions. This division of
labor has, however, had an unfortunate tendency to sharpen
the difference between the physical and biological approach to
radiological problems. The result has been the elaboration of
theories of action of radiation with, at best, only a limited scope,
which have generated a great deal of controversy, not always to
the advancement of the science. Theories of action start from
the law of Grotthus and Draper that only absorbed radiation
is effective. The physical unit for absorption is the atom. The
biological unit is the cell, made up of some 10^^ molecules in
active motion, within which effective radiation energy must be
absorbed. Absorption of X-rays in matter produces secondary
electrons, and it was suggested by Dessauer^'^ that these electronic
energies are nonspecifically degraded on colliding with protein
molecules, and that the energy is transformed into the basic
process of heat at isolated points.

According to Holthusen,^-- ^'' on the other hand, the energy
required for the radiation effects originates from the state of

86 Applied Biophysics

excitation (Bohr) of protein molecules, following the absorption
of quanta of radiation, making the molecules capable of new
reactions. For example, an increase in intracellular osmotic pres-
sure may result from the formation of substances with smaller
molecular weights than the original substance. If the surrounding
fluids are not changed to the same extent, this would cause
swelling of cells. An increase in cell size after irradiation is
known to occur in certain instances,"'^* ^^' ^^•^' ^^"^ but is by no
means common to all cells affected by radiation. A suggestion
that radiation caused a rearrangement of colloid charges,^" which
was at first regarded as an alternative mechanism of action, can
now be fitted into Holthusen's photochemical theory by regard-
ing the change of charge as a photochemical process.

Ionization rather than excitation became generally regarded
as the link between energy absorption and biological response,
and a hypothesis which has attracted a great deal of attention
was put forward, ^■*' ^"' ^^' ''*'• '- according to which there exists
in the cell a specially sensitive volume within which ionizations
are biologically effective, and these account for the changes sub-
sequently observed. More than one ionization may be required
to produce a biological effect, but any ionization which occurs
within the cell, but outside the sensitive volume, is ineffective.
This view of the mode of action of radiation has come to be
known as the target or "quantum hit" theory, and among its
supporters are many physicists. Differences in sensitivity to
radiation are explained by the chance distribution of ionizations
in the vital volume of the cell. Those who oppose the idea have,
perhaps, less well-defined views on radiation action, and are
united mainly in their opposition to the theory. As an alterna-
tive hypothesis they suggest that a chemical or metabolic change
is produced in the cell by irradiation, and they argue that the
biological results of physical as well as chemical agents can be
explained on the assumption that individual cells differ in their
reactions to the changes produced : the weakest succumb first,
then the less weak, and the strongest last of all. A great deal
of time and effort has been spent in attempts to prove and dis-
prove one or other theory, and most lively controversies have

Biological Effects of Penetrating Radiations 87

taken place between the contending parties. ^-^ The idea of a
compromise has come late, but the results of at least one in-
vestigation ^•'- were shown by the author to be equally well
explained either by the quantum hit theory or by that of variation
in individual sensitivity.

That the target theory holds for particular cases now seems
indisputable. It is true in certain instances where the criterion
of effect is a lethal action, or a type of injury is produced from
which there is no recovery.*^^' ^^ But it cannot be made to fit
all types of biological response to radiation, since by definition
it makes no allowance for adaptability in living organisms to
changes of environment, including those brought about by radia-
tion. The cell is not inert until it is dead, and so long as it is
alive it is capable of a change of behavior, and with that change,
an alteration in its susceptibility to radiation, which cannot be
predicted. The types of response must be learned from observa-
tion under different biological conditions. For example, the same
cell differs in its susceptibility to radiation, among other things,
according to its state of dryness, its metabolic activity, its stage
of growth, and its age.'*^^' ^^' ^'^' ^^^' ^^^ There is a danger in at-
tempting too much simplification by physical explanations when
dealing with such complex biological material.

Physical Dose and Biological Response

The need for a quantitative measure for radiations was ap-
parent as soon as their biological effects had been recognized,
and one equally suited to experimental and clinical use was
desirable. The question of a biological or a physical basis for
radiation dosimetry has been debated for many years. As early
as 1918 it was suggested by Russ ^^^ that the amount of radiation
necessary to kill mouse cancer cells might be used as a standard
for which he suggested the name "rad." Since then, many similar
methods of dosage have been devised and will be considered
under Biological Indicators.

The most practical and useful method of dosimetry, however,
is that based upon the ionization produced in air by radiation,

88 Applied Biophysics

originally suggested in 1908, and now developed into the inter-
national rontgen (r) of X- and gamma-ray measurement.'*"
Much research has been done to discover under what conditions
the ionization in air may be taken as a measure of the dose in
living tissues. '^^^ ^'^^

Assuming that ionization in the tissue is responsible for the
biological changes produced, the rontgen should be a useful unit
for linking physical dose with biological response, since an
accurate measure of any well-recognized biological response in
terms of the rontgen would enable the experimental conditions
to be repeated anywhere by any competent person. The first
and most obvious biological response to be recognized was the
erythema produced in human skin, and since the tolerance of
the skin to radiation is a limiting factor in many radiotherapeutic
procedures, the determination of the "skin erythema dose"
(SED) in rontgens has been the subject of much careful in-
vestigation.^^^' ^^^ The difficulties of such an apparently simple
procedure are, however, considerable. The dose received by the
skin is due not only to the incident radiation, but also to
scattered radiation which may constitute half the total dose,
and which varies with the quality of radiation, the size of the
irradiated area, and the particular part of the body (depending
on the relative amount of bone, muscle and fluid) being ir-
radiated.^^' ®'^' ^^^' ^^^' ^^^ On the biological side, the accuracy
of the determination is vitiated, partly owing to individual varia-
tion in the response to irradiation, and partly to difTerence of
opinion of various observers as to what constitutes the proper
erythema reaction. Taking the results obtained from the majority
of observations made, it is possible to compile tables of the
approximate value of the SED for different quality radiations
falling on a field of given area ^^^' ^^^ or volume of given size.^^^
In any one series of observations made under constant conditions
by the same observer, the doses are likely to be comparable with
each other, but where different series of experiments are con-
sidered a comparison of doses must be made with caution.

The determination of the SED for different quality radia-
tions has shown a rise in the skin tolerance as the wave length

Biological Effects of Penetrating Radiations 89

of the radiation shortens. Large doses of highly penetrating
radiations can now be given to a deep-seated tumor with
comparative safety to the skin. But with this decrease in
absorption of radiation on the skin, there is an increase in the
energy absorbed in the deeper parts of the body, and this, in
turn, indirectly affects the "treated area" by the production of
adverse constitutional disturbances. This question of body dose
was raised in 1938, when the constitutional effects of teleradium
therapy were under consideration at the Radium Beam Therapy
Research, London. ^^'^ It has been systematically developed by
Mayneord in a series of publications. For measuring this radia-
tion he suggests a unit to be called the "gram-rontgen," which
may be defined as the energy absorbed in 1 gram of tissue irradi-
ated with one rontgen.®'^

TABLE I

Illustrating Biological Response to a Variety of Radiation Dosiis

No. Dose in r Biological Response

1 10"^ "Safety" limit of exposure for radiographers, etc.,

per second ^

2 0.175 Dose received per day by attendants using a 4-

gram radium unit ^

3 0.25 "Safety" limit of exposure per day (7-hour day)-^

4 0.5-1.0 Front of fluorescent screen during examination

of patient ^2

5 '1.0 Palpating hand of operator using fluorescent

screen every 10 min.^^
"Safety" limit of exposure per day (5-day week) 5
Threshold for mitotic effect in grasshopper '^
Received by diagnostician making complete radio-
graphic study of gastro-intestinal tract (see
No. 13)68
9 15 To either gamete produces developmental abnor-

malities in 5% of individuals (frog) (see No.
18)57

10 34 Threshold for mitotic effect in chick fibroblasts

(cf. No. 7)1^9

11 40 Alteration in ultraviolet absorption in cell-cyto-

plasm

6

1.25

7

8.0

8

9-70

90

Applied Biophysics

No.
12

13

17

18

23

24

Dose in r
50

50-100

14

170

15

290

16

350

400

500

19

800

20

1,000

21

1,039

22

1,200

Biological Response

30% inactivation of enzyme in dilute solution
icf. No. 28)21

Tube-side of fluorescent screen during examina-
tion of patient (see No. 8)^2

Temporary sterilization of ovary in women ^^^

Cessation of ovulation ^6

Increases by 1% sex-linked lethal mutation in
Drosopiiila (maximum yield 15% with 5,150 r,
above which dose sperm degenerates) 1^5

Initial injury to ovarian follicles and germinal
epithelium of domestic fowl ^"*

Developmental abnormalities nearly 100% in frog
(see No. 9)5"^

Follicular disintegration in domestic fowl 34

Mean lethal dose for Ascaris eggs ^^

Average skin-erythema dose for gamma rays 108

Total destruction of male gonads of domestic
fowl 34

Total destruction of female gonads of domestic
fowl 34

Prevents "take" when inoculating benzpyrene-
induced sarcoma in rat ^^

Inhibits regeneration in worm-segments ^32, 140

Delays cleavage in sea-urchin egg ^^*

Causes complete inactivation of frog-sperm ^"^

30% inactivation of enzyme in concentrated solu-
tion (X 345 that of No. 12) 21

Immediate death of chick-fibroblast cultures ^23

Mean lethal dose B. mesentericus spores "^^

Mean lethal dose Colpidiuni colpoda 14, 15

Inactivation of plant viruses ^^

These considerations illustrate some of the complexities of the
irradiation problem where organized body tissues are concerned.
Great technical advances have been made on the physical side
in delivering a given dose to a selected volume of tissue, but a
stage has been reached when it is easier to deliver a given dose
of radiation than to know precisely what biological changes that
irradiation produces in the tissue irradiated. It is time now
for corresponding advances on the biological side.

2,000

7,000

25

9.000-20,000

26

30,000

27

40.000

28

100,000

29

117,000

30

200.000

31

330.000

Z2

1,000,000

Biological Effects of Penetrating Radiations 91

Radiochemistry

In studying the effects of radiation on biological material use-
ful information may be obtained from experiments on nonliving
matter. A recent survey by Allsopp - of the chemical action of
radiations has shown how developments in the field of radio-
chemistry can be related to the study of the biological effects of
radiation. Until quite recently, enormous doses of radiation
were required to produce measurable chemical changes in vitro,
and it w^as suggested that chemical processes could not be in-
volved in therapeutic radiation at any rate, since recognizable
changes could be obtained only with doses far above the max-
imum human tolerance dose.^^

Recent work by Dale,^^' -^' ^^ however, has shown the fallacy
of the conclusion. Dale arranged his experimental procedure so
that the chemical changes produced by irradiating purified
enzymes in aqueous solution were magnified many times by the
accompanying changes in biological activity. Dale's results show
quite clearly that a constant amount of solute is inactiviated for
a given amount of radiation energy absorbed in the whole solu-
tion, irrespective of the concentration of the solution. The
simplest explanation of these results is that the initial process
consists in "activation" of solvent molecules by absorption of
radiation, followed by the transfer of energy to the solute by

inelastic collision, without the term "activation" being precisely
defined.40. 112

It may be recalled here, however, that in the initiation of
radiochemical reactions in gaseous systems, excitation of mole-
cules is apparently more important'than ionization, since radio-
chemical reactions in the gas phase in general follow the same
course as the corresponding photochemical reactions. ^^' ^^' ^--
There is no reason to suppose that radiochemical reactions in
aqueous solutions are not similarly initiated by energy-carrying
solvent molecules.^ The experimental evidence is consistent with
the hypothesis that the energy carrier is a free hydroxyl radical. ^^^

Since the number of solute molecules decomposed by a given

92 Applied Biophysics

radiation dose depends on the concentration of activated solvent
produced (not on the concentration of the sokite) and will,
therefore, be relatively small, the concentrations of solute em-
ployed must be the smallest consistent with chemical analysis,
in order that changes in them may be relatively large. It was
the widespread failure to recognize this which led to the supposi-
tion that significant chemical changes could not be produced
ill vitro by doses within the therapeutic range. For the simplest
case, i.e., only one substance in solution, the activation theory
would seem a reasonable interpretation of observed facts.

Dale has recently described some striking experiments in which
an apparent loss of radiosensitivity occurs when enzymes are
irradiated in the presence of varios protein and other substrates
which share the available energy between them and thus "screen"
the original solute.-- This work on the protection of one solute
by another is a valuable contribution to the interpretation of the
chemical effects of radiation in vivo. If the indirect-action theory
is applicable under these conditions, then a new light may be
thrown on the mechanism of action of radiations. From the
point of view of a solute, e.g., an enzyme, its inactivation by
energy carriers derived from molecules of aqueous solvent could
be regarded as the target theory in reverse ! The possibility of
this mechanism operating in vivo, if only under certain condi-
tions of dilution, is a further caution against making any gen-
eralization prematurely.

Whether "activated water" is also connected with such physico-
chemical effects as the precipitation of positively charged colloids,
viscosity changes, and change of electrokinetic potentials remains
to be seen.^^ It seems more likely that the physicochemical effects
are produced by simple ions.^

Biological Indicators

From time to time, investigators have sought for a simpler
biological material with a more definite and convenient reaction
than the skin erythema to serve as a biological dose unit. When
the irradiated tissue is very small, such as the egg of an insect,

Biological Effects of Penetrating Radiations 93

and is suspended in air so that scattered radiation reaching it
is at a minimum, the absorption of energy is uniform throughout
the object irradiated and is directly proportional to the intensity
of the radiation beam. For example, if a large number of Droso-
pliila eggs is exposed to an X-ray beam of unknown intensity
for 10 minutes and if, as a result, half the individuals fail to
hatch, then 180 rontgen units have been delivered at the rate of
18 r/min.^^ The constancy with which such quantitative experi-
ments yield the same result is perhaps one of the most striking
features of this type of investigation. With Drosophila eggs the
error is not more than 3%,^^^- ^*^^ and this order of accuracy is
obtained with other types of biological material under laboratory
conditions.

A great variety of organisms has now been used as biological
indicators of radiation action by many observers, and each ma-
terial has its advantages and its limitations. The most important
consideration is that the experimenter shall be familiar with the
material chosen for experiment, and be able to distinguish with
certainty the changes produced by radiation and those uncon-
nected with it.

These indicators are of particular use where the biological
effects of two different types of radiation, with no physical unit
of measurement in common, are being compared ; for example, a
comparison of the biological effects of X-rays and neutrons.*^- ^^"^
If the biological response can be matched, then a useful com-
parison of the physical conditions of irradiation is obtained.
Biological indicators are also useful to establish the relationship
between injury produced by radiation and other types of injury,
e.g., to determine whether the effects of two agents are additive,
equal, unrelated, or whether one is capable of potentiating the
other. ^^*-^ The indicators should be small in size, easily available
in large numbers at all times, they must show only a small and
definite amount of normal variation, and the reaction to radia-
tion must be sharp and easily measured.^'' Some investigations
may be simplified by using a response which is independent of
the time factor. Since radiosensitivity varies enormously with
stage of development, it is essential that the greatest care is taken

94 Applied Biophysics

to insure constancy in age and temperature of the biological
indicator selected. ^-^

Among the materials used in this way, the following may be
mentioned, although not all conform to Holthusen's specification
for the ideal test-object : Eggs of the sea-urchin, Ascaris, Droso-
phila, silkworm, grasshopper, frog and axolotl, viruses, bacteria,
yeast, pollen grains, protozoa, vegetable root-tips, and tissue
cultures. ^^' ^'^' ^^' ^^"^ Germ cells and somatic cells of higher ani-
mals, blood cells, skin, and even whole animals have also served
as indicators in special cases. ''^-

Such material has been used for demonstrating the wide dif-
ference in sensitivity which exists among biological objects.
This is illustrated, for the lethal efifect, in Table II, taken from
data given by Packard ^^^ and by Crowther.^^ The reason for
these great differences is quite unknown.

TABLE II

Dose in Rontgens Necessary to Kill 50% of the

Samples of Organisms Irradiated or to Reduce

Their Growth to Half That of Controls

Organism Dose in r

Eggs of CaUiphora 40

Eggs of Axolotl 50

Eggs of Drosophila 190

Eggs of Ascaris 1,000

Larva of Drosophila 1,300

Escherichia colt 5,100

Mesotaenium 9,000

Saccharo)iiyces 42,000

Imago of Drosophila 95,000

B. mesentericus 200,000

Colpidium colpoda 330,000

Biological indicators have also been extensively used in studies
of the efifect of wave length on biological response, in genetics,
and in testing the validity of various theories of action of radia-
tion and the significance of alterations in the physical conditions
of irradiation.

The results, although usually consistent for a given material,

Biological Effects of Penetrating Radiations 95

are often at variance when the response of one material is com-
pared with that of another. Each result has to be considered by
itself. The contrast is most marked when the results of irradiat-
ing independent biological units, such as bacteria or insect eggs,
are compared with those of an organized colony of cells which
make up a body tissue. This is hardly surprising, since in the
one case radiation acts on single units without any biological
spread of effect to adjacent units, and in the other it acts upon
cells capable of being further influenced by changes brought a])out
in adjacent cells. However nearly the radiosensitivity of the
indicator approaches that of the body cells (one of Holthusen's
stipulations for the ideal test object) it is unlikely to give the
same information as would be obtained from direct observations
on the body cell. This is the limitation which restricts the use-
fulness of most of the indicators listed above. Tissue cultures
constitute a special case, since the technique enables samples
to be taken from the body (before or after radiation), and obser-
vations or experiments to be made under the relatively simple
conditions of growth in vitro for direct comparison with changes
seen in similar tissue in vivo after similar irradiation treat-
ment.^-* An intermediate step is thus provided between the
simplicity which is the essence of laboratory experiment, and the
complexity of irradiation of organized tissues in vivo, which is
a very useful guide in comparative investigations.

Genetic Effects of Radiation

The demonstration by Muller ^^' ^- and shortly after by Stad-
ler ^^^ that X-rays could produce ^ene mutations in Drosophila
and barley excited geneticists throughout the world to take the
keenest interest in this property of radiation ; X-rays immediately
became their most important tool for producing mutations. An
extensive literature bears witness to the enthusiasm aroused by
this discovery, which has opened up a new and large field of
research.^' i^' ^^' '^•* The sterilizing effects of X-rays were dis-
covered nearly a generation earlier,^ and much fundamental work
on the results of irradiating genetical material was completed

96 Applied Biophysics

before any observations on mutation production by radiation
diverted attention in this direction. These early observations
were somewhat restricted and rarely extended to the offspring
of irradiated organisms. The effects of radiation were judged
by abnormalities in development after irradiating sperm or ova,
or by alterations in the chromosome configuration of dividing
cells. It was later found that radiation may cause an abnormal
distribution of hereditary material without change in its com-
position. Then, as cytological technique advanced, it was realized
that the alterations in the chromosomes themselves were of at
least two kinds : ( 1 ) changes in the linear arrangement of the
chromosome threads, resulting from single or double breakage
and recombination in new alignments, with or without loss of
chromosome fragments; and (2) changes in the composition of
the unit hereditary particles or genes, without disturbance of
their position on the chromosome thread (gene mutation).

Chromosome abnormality offers a verv convenient method for
making a quantitative measure of radiation effect. The scoring
of abnormalities is tedious, but can be made with fair accuracy.
Some breaks in the chromosome thread rejoin immediately, but
for the rest, the injury, once made, is permanent, so that the
result is not complicated by gradual recovery processes. A great
variety of structural change is seen after suitable radiation dos-
age, and this may be classified according to whether one or more
chromosomes have been involved and how the broken ends have
reconnected.^^' ''^ The material is almost ideal for statistical pur-
poses, because the chromosomes act as targets which mark the
hits by breaks in continuity of the thread which can be seen
and counted. The tangle in which the broken threads in some
cases become involved may cause the breaking up of the cell,
or the production of nonviable daughter cells owing to the un-
equal distribution of the hereditary material. In this respect,
chromosome abnormalities are more detrimental than gene
mutations (which may not exert their effects for several genera-
tions) since they cause marked infertility in the first-generation
offspring.

Structural changes in chromosomes are most easily investi-

Biological Effects of Penetrating Radiations 97

gated in insects and plant cells which have a small number of
chromosomes of large size, and they are most easily recognized
in the metaphase and anaphase of division, at whatever point
in the life cycle of the cell the irradiation is given. The practice
of scoring abnormal anaphases as a measure of radiation ef-
fect ^^' ^^ has the limitation, however, that cells irradiated in
premitotic or early mitotic stages may break down altogether in
late prophase or early metaphase. Such cells are, therefore,
missed in the anaphase count.

The total number of breaks produced is proportional to the
dose and independent of intensity, but neutrons are more efficient
in producing breaks than are X-rays.^-- "^^^ ^^^ These observa-
tions can be explained on the hypothesis that a chromosome is
broken by the passage through it of a single ionizing particle,
but that it is necessary for the ionizing particle to be sufficiently
densely ionizing for several ionizations to be produced within
(or very near) the chromosome. A proton (from neutron ir-
radiation) is sufficient; only the "tail" of a fast electron track
gives a sufficient number of ionizations in the given volume.
On this hypothesis, X-rays of long wave length should be more
efifective than those of short wave length, and this has been
found to be the case with an optimum at 4A." Longer wave
length X-rays produce too short an electron track to span a
chromosome, and so their efficiency is diminished.

Changes in the composition of hereditary particles which lead
to gene mutations occur in germ cells of all types, but have been
studied most extensively in the case of the fruit-fly, Droso-
phila}^' '^^' "'^^ ^^ A dose of 3,000r of X-rays produces a mutation
rate of about 12%. This is about one hundred times the natural
mutation rate, but qualitatively is indistinguishable from spon-
taneously-occurring mutations. The yield of radiation-produced
mutations is proportional to dose, independent of intensity, and
diminishes for equal doses of different radiations in the order :
X-rays, neutrons, alpha rays. It is considered that a mutation
in Drosophila is the result of a single ionization.

All cells are not equally susceptible to the mutational effects
of radiation, and other factors, e.g., temperature, anesthesia,

98 Applied Biophysics

state of nutrition, and degree of germination, affect the muta-
tion rate.^^ Most gene mutations are recessive, i.e., able to pro-
duce their characteristic effect only when paired with another
mutated gene of the same kind. Only a minority produce any
conspicuous morphological abnormality. Occasionally a change
in the gene occurs which initiates new developmental processes,'**^
A mutation caused by one irradiation may be reversed by a subse-
quent exposure. ^'^^ This is exceptional, however, and in nearly
every case the mutation effect is exactly proportional to the
amount of energy received, and exactly cumulative over an
indefinitely long period even in successive generations. It is
unknown to what extent these observations are applicable to
man.

Thus, radiation can be regarded as a useful tool in purely
genetic investigations on such problems as the properties of
genes and chromosomes, the size and number of genes and their
mutational potentialities. Investigations on the genetic effects
of radiations provide valuable data on one of the ways in which
biological material responds to radiation, but, as rightly empha-
sized by one of the foremost genetical investigators, "Not all
the effects of radiation in killing organisms or disturbing their
development are referable to changes either of the class of gene-
mutations or chromosome re-arrangements." ^^

Injurious and Lethal Effects of Radiation

In previous sections some account has been given of the in-
juries caused to small organisms (biological indicators) and to
particular organs within cells (chromosome effects) by penetrat-
ing radiations. There still remains to be considered the largest
field of inquiry within the domain of experimental radiology,
namely, studies of the effects of radiation upon complex tissues
both in health and disease and after experimental injury.

Innumerable observations have been made of the effects of
radiation, under the greatest variety of physical conditions, upon
embryological development, the various systems of the body at
different stages of growth, individual organs and on the body

Biological Effects of Penetrating Radiations 99

as a whole. Such studies on the response of normal tissues to
radiation are not only of interest and importance in themselves,
but also because of the information they give concerning the
amount of radiation that the healthy body or organ can tolerate.
Unless healthy tissue were able to tolerate a greater quantity
of radiation energy than diseased tissue, penetrating rays would
be of little use in radiotherapy.

In general, biological indicators show a response which is
independent of the wave length of radiation but dependent on
the intensity, while the mutation effect, though dependent on the
wave length, is independent of the intensity. The biological
effects now to be considered vary with alteration in both the
intensity and the wave length of the irradiation to which they
are exposed.

Radiation affects any given cell of a complex tissue in at least
two ways, first by a direct action on the cell, and secondly by
injuring neighboring tissues upon the health functioning of
which the cell depends.

The term "indirect effect of radiation" conveniently describes
all the effects of radiation except its direct action on the cell,
but it has by custom come to be restricted to those effects
produced as a result of injury to the blood supply. This quite
arbitrary and rather unfortunate limitation of a useful term
requires another to describe the consequences of the action of
radiation upon remote tissues and body fluids. For this the term
''constitutional effects of radiation" is now reserved.

When blood supply is restricted or inhibited by radiation the
results are so conspicuous ^- that it is not surprising, perhaps,
that they should at one time have practically monopolized atten-
tion. It has even been suggested that all the radiation effects on
a complex tissue are the results of the action on the circulation.
This view is easily refuted, however, by reducing the radiation
dose below the level which affects the blood supply, when the
direct effects of the radiation can be seen, unmasked by injuries
caused from lack of blood. Alternatively, the role of the blood
supply can be demonstrated by irradiating embryos in ova before
and after the establishment of the circulation and comparing

100 Applied Biophysics

the results.^'*'' So long as the circulation is intact, recovery from
the direct effects of exposure is hastened ; when the blood supply
is compromised, the injurious results are additive.

The indirect effect of radiation upon embryonic tissue has
been strikingly demonstrated by means of tissue-culture experi-
ments ^^^ in which it was shown that the cells of a six-day
embryo, irradiated i}i ova and explanted shortly afterwards, could
be cultivated in vitro in an apparently healthy condition for days.
If the embrvos were incubated iii ova for 21 to 25 hours after
irradiation, however, they showed no trace of growth when
explanted in vitro. The cause of cell death was shown to be due
to the absence of gaseous exchange in the tissues of the chick
when incubated in the shell, resulting from the arrest of the
blood circulation shortly after irradiation.

The level to which the dose must be raised to affect the
circulation is considerably above that which causes a direct
effect upon tissue cells. For the chick the doses differ by a
factor of about 10.

Of the various body systems, the blood vessels and l^lood-
forming tissue were among the first in whicli the direct effects
of radiation were observed. -•^' ^^' ^^^ These studies have recently
been greatly extended by the use of radioactive substances, intro-
duced into the body and selectively absorbed in the ])lood-forming
tissues, in place of external radiation by gamma or X-rays.
The range of sensitivity of these tissues is remarkable ; less
than 10 r of X-radiation is required to affect the leucocytes of
the blood, while a dose of 100,000 r has no demonstrable effect
on the isolated (frog's) heart. ^-^' ^-*^

Alteration in the blood count in man is an early and convenient
warning of injurious exposure to radiation, but there is no
agreed opinion as to where the danger line can be precisely
marked. ^^^ The lymphocytes show the more marked change in
patients who have been irradiated, while the polymorphonuclear
cells may be the first to show any change in blood counts of the
therapeutic staff. .Small doses of gamma rays spread over a long
time may lead to a specific aplastic anemia which is not seen after
X-radiation.

Biological Effects of Penetrating Radiations 101

Exposure to X-rays or gamma rays has pronounced effects on
the embryological development of all species of animals which
have been investigated. In general, sensitivity during develop-
ment decreases as the age of an individual increases. This, so
far as the direct effect of radiation is concerned, is probably
associated with, although not wholly explained by, cell multipli-
cation and growth rate. A determination of all the factors in-
volved is one of the central problems of radiation.^*' ^^' ^^' ^^

Some light is thrown on the problem by studying the inhibitory
effect of radiations upon regeneration, which has demonstrated
a differing susceptibility of different types of cells. Or to put it
another way — the potencies of specific types of cells play a
significant part in determining the result of any given irradiation.
There is evidence that, under certain conditions of irradiation,
the process of differentiation among embryological cells is pro-
moted,^^' ^^^ although sensitivity to radiation is lost as differentia-
tion proceeds. ^^' '^^^

The response of the skin and its appendages to radiation has
perhaps been more extensively studied than in any other sys-
tem.^^' ^^' ^^' ^^^ In these investigations the ultimate aim is often
to discover ways and means of protecting the skin from injury,
while permitting effective irradiation to reach the underlying
tissues.*^' «^

Observations upon the direct effects of irradiation on the gen-
erative system of the male rat led to one of the earliest gen-
eralizations on the biological effects of radiations,"* which empha-
sized the relative radiosensitvity of proliferating cells and the
relative radioresistance of differentiated cells. Subsequent ob-
servations have shown that this applies to all species of animals
investigated, though the dose level at which mitotic activity is
affected differs for different species.

While such comparative studies of radiation effects on dif-
ferent biological material have a considerable interest, perhaps
more useful information is obtained by comparing the effects
of gradually increased doses of radiation on the same type of
tissue. This is perhaps most easily seen when the data are
arranged in tabular form (see table III). A definite gradation

102

Applied Biophysics

in the results immediately becomes apparent, especially if the
issue is uncomplicated by the intervention of any indirect effects.

TABLE III

Change in Biological Response of Avian Fibroblasts Grown in Vitro and
Exposed to Increasing Doses of Radiation *

Intensity in

Duration

Dose in

Ray

r per min.

in hours

r

Effect

Y

81.5

24

117,000

"Immediate" death of all
cultures

Y

81.5

18

108,000

Death within 2 days of all
cultures

Y

81.5

12

58,600

Death within 4 days of all
cultures

Y

81.5

9

54,000

Death within 8 days of all
cultures

Y

33

24

48.000

Death within 8 days of all
cultures

Y

81.5

6

29,000

Death within 10 days of all
cultures

Y

81.5

4i

22.000

Death within 13 days of all
cultures

Y

81.5

3

14,600

Death within 18 days ; some
cultures recovered

Y

33

9

18,000

Death within 18 days ; some
cultures recovered

X

100

If

10,000

75% degeneration ; peak at
3 hours

X

100

5,000

60% degeneration; peak at
3 hours

X

100

2,500

50% degeneration; peak at
3 hours

X

100

1,000

7% degeneration at 3 hours,
coimt rising

X

100

500

7% degeneration at 3 hours,
count rising

X

100

100

2% degeneration at 3 hours,
count rising

Y

33

33

Reduction in mitosis, no
degeneration, ultimate re-
covery

The X-ray data are taken from Lasnitzki.'*

Biological Effects of Penetrating Radiations 103

The table shows that there is no single type of response
which can with any justification be called tJie biological effect
of radiation, but that at various dose levels a change in behavior
occurs in the irradiated cells. At the highest dose level the result
is "immediate" death, presumably caused by a breakdown of the
physicochemical structure of cell protoplasm ; at lower dose levels,
however, death of cells results from different kinds of initial
injury ; at the threshold dose for any observable change, com-
plete recovery of the cell from the effect of radiation occurs.
These dose levels are altered if the physical conditions of irradia-
tion are changed. Thus, there is a minimum amount of radiation
energy required to produce any given type of biological response
in organic tissue, which can only be determined by the method
of trial and error.

Siiminary of Effects on Normal Tissue

The biological effects of radiation upon normal tissue may be
summed up as follows :

Radiations are always injurious to the cells which absorb
them ; the changes produced may be transitory ( reversible
effects) or permanent ( irreversible effects), with an intermediate
class of effect where the radiation changes disappear completely
but leave the tissue in a state of lowered resistance to further
radiation (conditioned reversible effect). There is a latent
period between irradiation and the recognition of the biological
effect it produces. ^^

There is a tenthousandfold difference between the extremes
of sensitivity among different types of living cells when measured
by the lethal effect.^-^

Radiation has a marked effect in interfering with cell prolifera-
tion, and the dose which produces the first recognizable changes
in cell proliferation is always small relative to the direct lethal
dose for the same tissue.

During development, radiosensitivity decreases as the age of
the individual increases, but the decrease is not necessarily pro-
gressive throughout development. Sensitivity to radiation is

/

Scheme (After Glucksmann) Illustrating the Relationship Between Cell
Division and Cell Differentiation in Different Types of Normal Tissue

FIG. 1 represents the relatively simple conditions in a hanging-drop preparation
of chick fibroblasts tn vitro. The culture presents a form of growth consisting only
of proliferating or of potentially proliferating ("resting") cells (magnification X 10).

FIG. 2 represents condition in the rat embryo where the processes of prolifera-
tion and differentiation are separated in lime. Photomicrographs show section
through eye of 2-day (left) and 10-day (right) postnatal rat (magnification X 210).

FIG. 3 represents condition in the eye of the frog tadpole where differentiation
and proliferative activity are separated in space, the central parts being fully
differentiated and functioning while proliferation still continues in the peripheral
region (X 360). (Figure reproduced from Proc. Roy. Soc. Med. 1942, 35, 597.)

104

Scheme (After Glucksmann) Illustrating the Relationship Between Cell
Division and Cell Differentiation in Different Types of Normal Tissue

DIVIDING
CELL

)IFFEREN-
TIATING
CELL

FIG. 4. Irradiated tissue culture showing generalized destruction.

FIG. 5. Eye of 2-day rat (left) showing degeneration only in the undiiferenti-
ated layers of the retina; eye of 10-day rat (right) showing differentiated retina and
absence of degeneration after exposure to radiation.

FIG. 6. Part of the eye of the frog tadpole showing degenerate cells restricted
to the germinative zone.

CiExetic Effects of Radiation

(c)

''A

FIG. 7. Photoiniciosraphs of chromosomes in Tradcscantia pollen-grains that
have been X-rayed. (<;) A dicentric chromosome, arisen by sister chromatid-union in
a chromosome-break, forms a bridge at anaphase joining the two polar groups of
chromosomes, (fe) An acentric fragment-chromosome lags at the equator of the
spindle at anaphase, (c) Asymmetrical chromatid-interchange and a chromosome-
break at metaphase.

105

106

Applied Biophysics

^n^

t

M(iili>ii»ri"i>iiiiiiiiiii>

(b)

c

I

FIG. 8. Photomicrographs of chromosomes at metaphasc blocked by colchicine in
pollen tubes of Tradcscautia. («) Chromosome-break (i) witli sister chromatid-
unions in both the centric and acentric fragments, (b) Chromatid-breaks, C

FIG. 9. Photomicrograph of part of the nucleus of a salivary-gland cell of
Drosophila, showing an inversion-loop (lower left). The loop is pro.luced by tb.e
intimate pairing of the parts of the inversion-chromosome with the homologous parts
of the normal chromosome.

lost as differentiation proceeds ; in certain circumstances radia-
tion may promote the process of differentiation. Apart from a
direct lethal effect, cells may be so injured by radiation as to be
incapable of successful division, and thus either perish on at-
tempting mitosis or }:)roduce n(jnvial)]e daughter cells. The
degeneration which is linked with interference with mitosis can
be distinguished from that resulting from the breakdown of the
so-called resting cells. ^-'

Biological Effects of Penetrating Radiations 107

Radiation and Malignancy

Much of the experimental work on the biological effects of
radiations has some relation to the radiotherapy of maHgnant
disease. The demonstration that radiation can cure a cancerous
tumor raises the question of how this effect is brought about.
There is a tendency for the results of experiments in any one of
the fields of experimental radiology which we have considered
to be applied too exclusively to the cancer problem. For ex-
ample, the effect of radiation up on a prohferating tissue is so
striking that it has been suggested that maHgnant cells die
mainly by degenerative mitosis. '^^' ^^ Although this has been
disputed/^' -^ the idea has been revived by recent genetical work
which has attributed the death of the cancer cell to the effects of
radiations on chromosomes.

There can be no doubt that very many irradiated cells die
when mitosis is attempted after irradiation. That this action of
radiation is frequently due to direct hits on chromosomes seems
also beyond dispute. In the light of Dale's work, however, there
is now the further possibility that radiation may act also on
dissolved enzymes via the solvent molecules, and where dosage is
high enough to affect blood supply, the destructive effect on
malignant cells of damage to the circulation is obviously an-
other important factor. Objections can be raised against accept-
ing any one of these explanations as the principal means by which
radiotherapy achieves its success. Thus, as regards the mitotic
effect, the low percentage of dividing cells present at the time
of any one irradiation leaves the majority of cancer cells in a
tumor unaccounted for, and a high proportion of mitotic cells in
a tumor is not in itself an indication of marked radiosensitivity.
A direct lethal action upon all tumor cells seems to be excluded
(except where radiation is used as a cautery) in view of the
high dosage required to produce such an effect under experi-
mental conditions, while the suggestion that all therapeutic effects
are the result of an indirect effect of radiation on the blood
circulation is against clear experimental evidence ^^ and has
never received any substantial support.

108 Applied Biophysics

The problem can be approached from another angle. Instead
of attributing the destruction of a tumor to a single radiation
effect, irradiated malignant tissue may be examined to see how
many types of action can be recognized, and an attempt can be
made to assess the relative importance of each in the eradication
of the growth. If serial biopsies are taken from tumors during
and after radiation treatment, it is possible to follow histologically
the changes in cellular activity in a quantitative manner for
each type of cell present.^*' ^^ Radiosensitivity measured by
rapidity of disappearance of the tumor soon after irradiation is
by no means synonymous with radiocurability, i.e., permanence
of radiation effect.*' Thus, while much emphasis is often placed
on the marked changes produced in anaplastic tumors by radia-
tion, several observers have pointed out that the differentiating
tumors, which seem clinically to respond to radiation more
slowly, give on the whole a more satisfactory ultimate re-
sponse.^' ^^' ^^^' -^^*^ These clinical results may be explained in
the following w^ay. It is obvious that, if sterilization of all poten-
tial dividing tumor cells could be achieved, their total destruction
by radiation would be unnecessary, since the altered cells would
gradually disappear in the normal course of events. In a differ-
entiating tumor, many of the daughter cells resulting from cell
division become sterile because they differentiate, although ab-
normally. In this connection, the fact that radiation can promote
differentiation as w^ell as injuring proliferating cells is of some
significance,'*^^' ^^' ^^"^ since, with suitable types of malignant
tumors, radiation may exert a curative action both by mitotic
inhibition and by sterilization. In the undifferentiated or ana-
plastic tumor, on the other hand, even a marked destruction
of cells following a heavy dosage may lead to a recrudescence
of the tumor from residual cells, incapable of sterilization by
differentiation, which have survived the radiation.

It must be recognized, however, that a tumor, capable of
responding to radiation by an increase of differentiation, may
be adversely affected by excessive exposures which interfere
with, instead of promoting, this process. Over-irradiated normal
tissues show an increase in cell division and a decrease in cell

Biological Effects of Penetrating Radiations 109

differentiation which has sometimes resuhed in radiation car-
cinomata.'*^' '*'^' ^^^' Such growths can, however, be treated by
further radiation, if it is so deHvered that prohferative tendencies
of potential dividing cells are checked and the differentiation
processes promoted. ^"'^

The conditions under which the inhibiting action of radia-
tion on cell division is best achieved are beginning to be
understood, and it remains to determine the best physical condi-
tions for sterilizing cells by promoting differentiation.

In this connection the combination of radiation with chemo-
therapy would seem a profitable field for future research, as
well as the effect of combining two or more different types of
radiation in the treatment of a single tumor. The problem
needs to be attacked from many aspects — hormonal, genetical,
chemical (including organizer substances), physical, and nutri-
tional— and upon its solution, in all probability, depends the next
substantial advance in the treatment of malignancy.

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COMPAKATIVE STUDIES OF THE BIOLOGICAL

EFFECTS OF X-RAYS, NEUTRONS, AND OTHER

IONIZING RADIATIONS

L. H. GRAY, M.A., Ph.D.
The Mount Vernon Hospital, ISorthicood, Middlesex

Introduction

THE immense literature dealing with the biological effects
of ionizing radiations is dominated by experiments in
which the radiation employed has been therapeutic
X-radiation, that is, radiation from tubes operated at voltages of
between 80 and 200 kilovolts. This is not surprising, since the
majority of the investigations have been undertaken with the
object of obtaining information immediately applicable to thera-
peutic practice. Of the remainder, the approach has more fre-
quently been that of the biologist seeking to explore the effects
of radiation on different organisms and on different aspects of
cellular activity, than of the physicist attempting to trace one
particular lesion — such as a mutation, the breaking of a chromo-
some, or the inhibition of mitosis — to the interaction of the
radiation with a particular set of atoms within the cell.

For the former purpose, the type of radiation employed
appeared to be of little consequence, and either the gamma rays
from radium or therapeutic X-radiation were generally employed
as most convenient. For the latter, we need to employ a diversity
of radiations, so that we may study the effects of changing in
a known manner the distribution of the ions produced through-
out the cell. Within fairly recent times, comparative studies
with different ionizing radiations, such as gamma rays, X-rays,
neutrons, and alpha particles, have led to the establishment of
important and often remarkable facts, such as that the death

114

Biological Effects of Ionising Radiations 115

of a cell may result from the generation within a certain
small region of an amount of energy which, if spread over the
whole cell, would not raise its temperature by more than one
hundred-millionth of a degree Centigrade. With the advent of
the high-voltage X-ray tube, the betatron, and the cyclotron, the
study of the influence of radiation type or quality upon biological
response has assumed a practical importance, for with the help
of these machines, it is possible to generate almost any type of
ionizing radiation under conditions which are suitable for the
treatment of a deep-seated tumor.

Linear Ion Density, the Distinguishing Feature of an
Ionizing Radiation, from the Biological Standpoint

The discovery of radium followed quickly upon the discovery
of X-rays, and some of the earliest biological experiments with
ionizing radiations were carried out with "naked" and "screened"
radium. As the screens used were of just sufficient thickness
to absorb all the beta rays, the experiments were, in effect, com-
parative studies of the effects of the beta and alpha rays as they
are generated by a small quantity of radium. Striking differences
were at once noticed. ^^' ^^ Hardy ^^ observed that an alkaline
solution of serum globulin, i.e., on the negative side of the iso-
electric point, was coagulated, and that an acid solution became
clearer when exposed to naked radium. When screens were
introduced to absorb all the alpha rays, so that the drop of
solution was exposed only to the beta rays, no effect was ob-
served even after twenty times the exposure. Chambers and
Russ ^ observed that erythrocytes were hemolyzed when exposed
to both alpha and beta rays, but not when the alpha rays were
eliminated. Colwell and Russ ^ found that, when emulsions of
bacteria were exposed to both alpha and beta rays, marked
agglutination occurred before the lethal point was reached. When
the alpha rays were eliminated, there was no agglutination, al-
though a lethal condition was reached.

A consideration of the physical differences which obtained
in these experiments will serve to illustrate important points in

116 Applied Biophysics

the intercomparison of ionizing radiations in general. The beta

ravs are electrons, i.e., particles having — -- of the mass of a

^ 1850

hydrogen atom and carrying unit negative charge, while the
alpha particles are helium nuclei having 4 times the mass of the
hydrogen atom and carrying two positive charges. Since it was
the negatively-charged globulin molecules which were discharged
in Hardy's experiments, the effect was at first attributed to the
neutralizing action of the positive charge caused by the alpha
particles. This now appears in the highest degree improbable.*
All the chemical and biological effects ^^o far studied are refer-
able to the excitation and ionization of the molecules in the path
of the ionizing particle, and it would be impossible to say of any
individual excited or ionized molecule whether it had been
produced by an electron or an alpha particle.

The essential difference between the two rays lies in the num-
ber and distribution in space of the ions and excited molecules
which they produce. Tn the second place, it is important to
notice that while the beta and alpha particles emitted by naked
radium are comparable in numbers, the beta rays have initially
an average energy of about a million volts, which is gradually
transformed into ionization and excitation throughout a total
path of several millimeters of water or tissue, whereas the 6
million volts initial energy of an alpha particle is dissipated in

less than — millimeter. Within the — ■ miUimeter immediately
20 20

surrounding the radium, the total numl)er of ions formed by the

alpha rays may therefore be several hundred times as great as

that produced by the beta rays, and it is not surprising on this

ground alone that the alpha rays appeared very much more

effective.

We shall discuss in detail only experiments in which the

total number of ions formed by the radiation per unit volume

* In somewhat analoprous experiments with colloidal graphite, Cray, Read and
Liebmann " observed that similar changes in the charged condition of the particles
were produced by negatively-charged electrons and positively-charged protons. The
two radiations differed only in their numerical efficiency.

Biological Effects of Ionising Radiations 117

of tissue has been estimated with reasonable accuracy. From
such experiments, we learn that biological effect is not in gen-
eral uniquely determined by the total number of ions, but that
it is also conditioned by the spatial distribution of these ions ;
the effect of a small number of particles, each producing a large
number of ions, is not necessarily the same as that of a large
number of particles, each producing few ions.

To take a concrete example, consider the effect of equal doses
(25 rontgen) of beta radiation and alpha radiation on the
meristematic cells in the root tip of the broad bean, Vicia faba.
The total ionization produced in a nucleus lOji in diameter is,
in each case, 23,400 ions. In the first case, the total is made
up of the contribution from 500 beta particles, each producing
on an average 7 ions per micron of path. In the second case,
the whole ionization is produced by the transit of a single alpha
particle producing ions at the rate of 3,500 per micron. The
beta radiation w'\\\ produce an appreciable diminution in mitotic
activity 3 hours after irradiation, but the effect on the subse-
quent growth of the root will be scarcely detectable. The alpha
radiation has no detectable immediate effect on mitosis, but six
days later the average growth rate of the roots will be less than
a third of its normal value, and a small proportion of the roots
will cease to grow altogether.

The contrast between the effects of beta and alpha rays is
sometimes striking, as in the example just given, because these
two radiations lie almost at the opposite extremes of the known
radiations in regard to the density of the ionization along the
tracks of the particles. Even in this case, however, the differ-
ences are quantitative and not qualitative. A sufficiently large
dose of alpha radiation has an immediate effect on mitosis, and a
sufficiently large dose of beta radiation will kill the roots. Radia-
tions intermediate between beta rays and alpha rays are not
always intermediate in the effectiveness of a given amount of
ionization, since there may be an optimum linear ion density
for any given biological effect which is not at either extreme,
but in the cases so far studied it has almost alwavs * been found

An exception is noted on p. 129.

TABLE I

Ion Density Proouced by Different Ionizing Particles

RADIATION

MODE OF GENERATION

MEAN
LINEAR

ION
DENSITY

(ions per

micron

of tissue)

J Theoretical minimum ion density for any particle -6 •^~

Very high energy 20-30 million volt betatron Fp ^

beta and gamma Natural ana artificial rbclioelements,\ °''^

radiation. *-

Gamma Radium screened by at least _ //

rod iation 0'5 mm, pbtinum as used m radiotherapy

'Supervoltage "lOOOk V installation 15

"Deep Therapy 200 kV installation QO

X-ray tubes, operated at 30-180 kV-. _ 100
"Characteristic' X rays Cyclotrons

Copper K (8 kVU—y^'^l-^"-

X radiation —

Neutron
radiation

-Silver Li 3 kV).

.146
12 million volts 290 —

.300

8 million volts 380 —

..4S0

_ Aluminium K(l-5kV) -^ -

High-voltage ion tubes
- 900 kV Deuterium ions bomt)arding lithium 840

—400kVDeutenum ions bombarding deuterium- _ 1100 ■

IONIZING
PARTICLE

Electron

— Proton

Alpha .
radiation

.3700
.4500

Natural disintegration of radon

Natural disintegration of poionium „

Artificial disintegration c/ boron or

lithium by s/onv neutrons 9000

Atomic rays

. Alpha
particle

Uranium fissure 130.000 -,

Atomic
particle

As an ionizing particle slows clown, it produces ions at an ever-increasing rate
until it has been brought nearly to rest. The ion density, therefore, increases
along the length of the track of any ionizing particle. The figures quoted in the
table are average values for all the particles generated by a given type of radiation.
It will be seen that this average value increases with decreasing voltage for each-
type of particle. Thus very high voltage X-rays give rise to the particles of lowest
ion density, and high-energy neutron radiation is less densely ionizing than low.

118

Biological Effects of Ionising Radiations 119

that there is a smooth and progressive variation of effectiveness
with the density of the ionization along the track of the ionizing
particle irrespective of whether the particle is an electron, a
proton, or an alpha particle.

The subject, therefore, admits of a great simplification, for
in general it is not necessary to contrast the numerous types
of radiation, but only to discuss the influence of the "linear
ion density" on the total amount of ionization required to bring
about a given biological effect. Experimentally, also, this in-
volves a simplification, since there are sometimes alternative
ways of generating particles of a given ion density, as shown in
table I.

Certain points of therapeutic interest emerge from a con-
sideration of the data contained in this table. It will be
observed that strongly-filtered radium gamma rays, the beta
rays from radium, and both the beta rays and the X-rays from
a betatron operated at voltages up to 30 million volts, are
all bracketed at the level of 6 to 8 ions per micron. Theoretically
no charged particle can produce less than 6 ions per micron ;
moreover, the minimum is a flat one, rising particularly slowly
on the high-voltage side, as has been checked experimentally by
the study of cosmic-ray particles. While, therefore, the betatron
ofifers attractive possibilities from the standpoint of radiological
technique, there are no a priori grounds for expecting a marked
difference in biological effectiveness between, say, 30 million volt
X-rays and heavily-filtered radium gamma rays.

A second point in the table, at w4iich large changes in the
conditions of generation result in little or no change in the ion
density of the radiation produced, occurs in the range of X-rays
commonly used in radiotherapy. From the biological standpoint,
the quality of an X-ray beam may be specified by stating the
average ion density of the secondary electrons to which it gives
rise in the irradiated tissue. Some of these electrons (photoelec-
trons) have the full energy of the X-ray quantum ; others (recoil
electrons) have only a fraction of this energy. As the kilovoltage
of the X-ray tube is increased, the energy of both types of elec-
trons increases, but those having only a small fraction of the

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120

Biological Effects of Ionizing Radiations 121

quantum energy become relatively more numerous, with the
result that the mean energy of all the electrons of both types
changes only very slowly. Detailed calculation ^^ shows that the
average energy, and, therefore, the average ion density of the
secondary electrons, is almost constant for all X-ray-quantum
energies between 15 and 90 kilovolts — i.e., roughly for the radia-
tions from X-ray tubes operated at all voltages between 30 and
180 kilovolts. In consequence, it is not to be expected that a
change in X-ray quality within this range will be accompanied
by any appreciable change in the biological effect of a given
total amount of ionization per unit volume of tissue.* The
number of experimental investigations dealing with this point
is legion, because the range of X-ray qualities in question
happens to be at the same time the most accessible and the most
interesting in current radiotherapy As might be expected, these
investigations do not all lead to the same conclusion. It may be
said, however, that there are no solid grounds for doubting the
accuracy of the inference from ion-density considerations, and
it would be possible to point to a number of very careful investi-
gations, outstanding among which are probably those of
Packard,^'^' ^^ who studied the percentage mortality among ir-
radiated Drosophila eggs, which show particular biological effects
to be independent of X-ray quality over this range to a high
degree of accuracy. It appears, indeed, almost in the light of a
freakish prank of Nature that she should have tempted so many
to investigate a region destined to bear so little fruit.

The Influence of Ion Density on Radiochemical Yield

Many substances are decomposed when exposed to any of
the ionizing radiations. When the decomposition takes place in
the gaseous phase, the number of molecules decomposed is
usually of the same order as the number of ions found by the

* This does not necessarily imply, of course, that the biological effect of a given

dose, measured in rontgens, will be independent of X-ray quality. It is just in this

region that the ratio of the ionization produced in tissue to the doge in rontgens
ma,y show ^ marked dependence on X-ray quality.

122 Applied Biophysics

radiation, and is roughly the same for beta rays (A ^ 10) and
alpha rays (A = 3,500 ).t This is true of the decomposition of
ammonia, nitrous oxide, and hydrogen iodide. The decompo-
sition of water vapor, however, appears to be exceptional in
that the yield is very low with X-rays. Equality of yield with
beta and alpha radiation has also been observed in the case of
the synthesis of ammonia, hydrogen bromide, and ozone, and
though there are no published data of this sort for neutrons or
other radiations of intermediate ion density, it may be presumed
that the yield will be completely independent of ion density in
those cases in which it is the same for beta and alpha rays.

Chemical reactions in solution, and particularly in dilute
aqueous solution, are of much greater interest from the biological
standpoint. The decomposition of water itself is notoriously
controversial, even in regard to the experimental facts, and it is
not possible to say with certainty whether the much higher
yield generally found with alpha radiation '^' ^■'^' -'' than with
X-rays "*' ^^' ^^ is to be referred to differences in ion density
or to extraneous circumstances, such as the presence or absence
of dissolved oxygen.

The position, as far as the published findings are concerned,
is hardly less satisfactory with regard to dilute solutions, since
there appears to be no reaction which has been studied at two
different ion densities by the same author, and the difficulties
associated with these experiments are such that small differences
in the yield obtained by different authors cannot be relied upon.
The evidence in the case of the decomposition of hydrogen
bromide and hydrogen iodide, and the reduction of potassium
permanganate, points to the absence of any dependence on ion
density. It seems fairly clear, on the other hand, that the dif-
ference between Stenstrom and Lohmann's estimated yield

M
( — = 0.1) for the decomposition of tyrosine by X-rays and

N

M
Nurnberger's figure ( — = 0.003)-^* for alpha ravs is evidence of

t The symbol A will be used throughout for the linear ion density, i.e., the
average nximber of ions formed per micron in water.

Biological Effects of Ionising Radiations 123

a sharp fall in the proportion of molecules decomposed to ions
formed by the radiation as the ion density increases from 50 to
3,500 ions per micron. Dale and Meredith, in collaboration with
the writer, have recently examined carefully the inactivation of
dilute solutions of the enzyme carboxypeptidase by X-rays and
alpha rays. The alpha-yield was found to be only about one-
twentieth of the X-ray yield, indicating a sharp fall in efficiency
of the radiation with increasing ion density. It would appear
that, in the case of the densely-ionizing alpha particles, a high
proportion of the products resulting from the ionization of the
water becomes ineffective before they reach the enzyme mole-
cules awaiting inactivation. More experiments of this kind are
urgently needed to throw light on the mechanism by which such
inactivations are brought about in dilute aqueous solutions, par-
ticularly in view of their relevance to the biological studies. The
influence of ion density on the inactivation of enzyme systems
under in vivo conditions also awaits investigation.

Ion Density in Relation to the Inactivation of
Elementary Biological Units

Perhaps the best understood examples of ion-density de-
pendence are in connection with the direct inactivation of
elementary biological units, such as viruses and genes, by the
ionization of their constituent atoms. As separate articles of
this series are devoted to viruses and genes, a brief reference
will suffice.

The distinctive feature of the .effects under consideration is
that they are produced whenever an ionizing particle leaves two
or three ion-pairs anywhere within the unit. It is possible that
a single ion-pair suffices, but ion-pairs are, in fact, formed in
clusters of 1, 2 or more pairs, the average number being 3 pairs,
and rather accurate experiments would be necessary to be certain
that the effect is invariably produced by a single ion-pair.
Whether this is so or not, it is clear that since each cluster
contains an average of 3 ion-pairs, the distance apart of the

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Biological Effects of Ionizing Radiations 125

3
clusters will be given by — micra where A is the ion density of

A

3
the radiation. For gamma rays, — is about 300 m^, for hard

A

X-rays 60 m\x, for soft X-rays 20 m^, and for alpha rays

0.85 mfi.*

The diameters of the smaller viruses range from 15 to 50 mji.
The relation between the size of the virus and the spacing of
the ions is thus roughly that shown in figure 1 for the four
radiations mentioned. Even allowing for unevenness in the
spacing of the ion clusters, it is evident that only rarely will
a single ionizing particle give rise to more than one ion cluster
within a virus particle irradiated by gamma rays. As long as
this obtains, the chance that a cluster is formed within any
given virus particle is just equal to the total number of clusters
formed per unit volume of the medium multiplied by the volume
of the virus, and, therefore, the inactivation dose should be
independent of ion density.

On the other hand, an alpha particle will produce many ion
clusters within even the smallest virus particle or gene, so that,
if one cluster suffices for inactivation, this radiation must neces-
sarily be inefficient, and a large dose will be needed to produce
a given degree of inactivation.

In figure 2, the experimentally determined efficiencies of a
number of radiations in inactivating virus preparations are
plotted against the mean distance between ion clusters for six
virus particles, ranging in size from 16 to 64 mji.** The
theoretical variations for spheres of 15 and 50 m^ diameter
are drawn in full. It will be seen, that, in accordance with ex-
pectation, the experimental values of the efficiency begin to show
a dependence on ion density just at the point where the distance
between clusters is comparable with the size of the particle.

The relation between inactivation dose and ion density thus

* The millimicron (m|Ll) "= 1/1,000 micron = lO-" millimeter.

** The term "efficiency of a radiation" will be used throughout this article to
mean a quantity inversely proportional to the total amount of ionization per unit
volume of tissue required to produce a given biological effect.

126 Applied Biophysics

provides a very useful approximate estimate of the size of the
biological unit in cases where this unit may be inactivated by a
single ion cluster. It is interesting to note that, on the basis
of such studies. Lea and Salaman -^ put forward the view,
before an internal structure was demonstrated by electron micro-
graphs, that vaccinia virus should be regarded as a single-celled
organism containing a considerable number of discrete struc-
tural units analogous to genes.

The Structural Changes Induced in Chromosomes by
Different Types of Ionizing Radiation

The nature of the chromosome structural changes induced
by radiation is discussed in detail in another article. Many of
these structural changes are known to be injurious and some
to be lethal to the daughter cells, and they are produced by
relatively low doses of radiation — in the materials studied, the
doses employed have rarely exceeded 500 rontgens of X-radia-
tion, or a tenth of this dose of alpha radiation. There can be
little doubt, therefore, that they play an important part in the
response of many types of cell to radiation, including probably
the response of normal and malignant tissue to X-radiation
in certain types of radiotherapeutic techniques. ^*^

Before considering the influence of the type of radiation on
the response of cells, organisms, and tissues, it will be con-
venient to summarize the information regarding the chromo-
some structural changes. The production of a chromosome
break requires that a particle shall pass through (or in the
immediate vicinity of) the chromosome, leaving an adequate
number of ions within the chromosome. The exact number of
ions required probably varies from one type of cell to another,
and may well vary with the stage of development of any one
cell. Experimentally, it is found that high ion-density radiations
are more effective than low ones in breaking the pollen grain
chromosomes of the plant Tradescantia at prophase (figure 3),
and in fact, it appears that only radiation which produces at
least 200 ions per micron of track has a high break-producing

Biological Effects of Jonizing Radiations

127

efficiency. Since the diameter of the chromated thread at pro-
phase is about O.lu, it is inferred that a break is only hkely to
follow when at least 20 ions are formed at one locus within
the thread. No other material has been analyzed for chromosome
structural changes in such detail as Tradescantia, but a restricted
analysis ^^' ^^' -"* of the changes produced by X-rays and neutrons
in root tips of the broad-bean, the pea, the tomato, three mouse
tumors — sarcoma 180, a mammary carcinoma, and a lympho-
sarcoma— and a carcinoma and lymphosarcoma of the rat, showed

I Or
9
8

\ Gross
injuries

Chromosome

structural

changes

X-

Inhibition
of mitosis

lO

t
Minimum damma

value rays

A lOO

Deep
therapy
X-rays

I.OOO

Neutrons

t

Alpha

particles

lO.OOO

FIG. 3. Relative Efficiencies of Ionizing Radiations

X

+

o

A

Chromatid-breaks ) Produced in Tradescantia pollen-grains by

Isochromatid-breaks j irradiation at prophase.

Inhibition of growth of wheat-seedlings.

Mouse tumors rendered inviable by irradiation in vitro.

Cessation of growth ) t/- • j- ?

rp _ . u-u-4.- c -^-4. • f yicia jaba roots.

lemporary inhibition of mitosis j •'

Abscissae = linear ion density in ions per \\,
Ordinates = relative efficiency of radiation

128 Applied Biophysics

that for all these materials, more structural changes were pro-
duced by neutrons than by an equal dose of X-rays, from which
we may infer that in all these cases the conditions for break
production are of the same general types as those in Tradescantia.
There is some evidence, on the other hand, that in Drosophila
sperm, a single ion cluster may suffice.

Since the ion density along an electron track exceeds 200
ions per micron only when its energy is less than v3.5 kilovolts,
not only is much of the ionization produced by the more energetic
electrons generated by, say 200 kilovolt X-rays, wasted as re-
gards chromosome-break production in Tradescantia and similar
materials, but any one particle is unlikely to break two chromo-
somes separated by a distance greater than the range of a 3.5
kilovolt electron, i.e., greater than 0.4 micron.

For this reason, structural changes arising from the inter-
change of partners between two broken chromosomes almost
always involve the action of two separate electrons. It follows
that, when the dose is delivered in a short time, the number of
such configurations produced will increase as the square of the
dose. Furthermore, as the duration over which the total dose is
spread is increased, fewer abnormal configurations will be pro-
duced because each individual break may reform the original
chromosome, and the chance of this happening in preference to
an interchange formation increases with the interval between
the production of the two breaks. The same restriction does not
apply to the recoil protons generated by neutrons or to alpha
particles which maintain the required ion density over distances
much greater than the diameter of the whole cell. It thus comes
about that in Tradescantia:

a. Simple breaks produced at any time in the cell cycle, and
certain structural changes (the so-called "isochromatid breaks"),
arising from the breaking of two sister chromatids lying almost
in contact at prophase, increase in proportion to dose, and are
independent of the duration of exposure for all radiations. The
number produced by a given dose increases with ion density.

h. Structural changes involving two chromosomes, other than
the isQchromatid breaks referred to in a, increase in proportion

Biological Effects oj Ionising Radiations 129

to the square of the dose when the exposure time is constant,
and decrease with increasing duration of exposure for all types
of X-radiation ; they increase in proportion to the dose and are
independent of the duration of exposure (except in so far as this
affects the state of development of the cells irradiated) for
neutrons and alpha particles. The more densely ionizing radia-
tions produce more structural changes of this type per unit dose
than X-rays when the dose is small, and fewer when it is large.

It is interesting to note that we have here an exception to the
general rule that, from the biological standpoint, a radiation
may be characterized by its ion density. Very soft X-rays,
on account of the limited range of the secondary electrons, do
not exactly parallel neutrons, even when the ionizing particles
generated by these two radiations have the same average ion
density as was demonstrated experimentally by Catcheside and
Lea.^

c. The ratio of the number of certain types of structural
change produced by X-rays to the number produced by an equal
dose of neutrons varies with the stage of development of the
cell at the time of irradiation.

Comparative Studies with Other Biological Material

Lethal Ejfect on Drosophila Eggs

Many experiments have been made to determine the propor-
tion of fertilized eggs which hatch after receiving varying doses
of radiation. The eggs are usually irradiated about 2 hours
after laying, when about 8 mitotic cycles have been completed
and the &gg contains above a hundred nuclei. The careful
observation of Packard -^ showed that a given dose produced
the same degree of mortality whatever the quality of the radia-
tion within the X-ray therapeutic range, but this, as we have
seen, throws little light on the question of a possible dependence
of the efficiency of the radiation on ion density. Packard,-*" Hen-
shaw and Francis,^-'' and others, extended the investigations to
supervoltage X-rays and gamma rays. It appeared at first that

130 Applied Biophysics

a rather large dose of radiation was needed to produce a given
mortality, but the measurements were carried out at a time
when some uncertainty on the physical side was attached to
measurements of gamma-ray dose.-*' Packard (1932) extended
the measurements in the other direction down to 8 kilovolt
X-rays, and conchides that between 8 kilovolts and 1,000 kilo-
volts, the mortahty is independent of X-ray quahty. The cor-
responding range of ion densities is from 150 ions per (.i to
15 ions per |.i.

The effects of 200 kilovolt X-rays and neutrons (A ^ 400 ions
per |.i ) were compared by Zirkle and Lampe.^^ The mortality
curve, as a function of dose, for neutrons had the same shape
as that for X-rays, so that the relative effects of the two radia-
tions could be expressed by a single figure which was 0.8 for
eggs 1^ hours old, 1.2 for eggs Ah hours old, and 1.1 for eggs
6 hours old. It is doubtful whether the variation with age is
significant, and we conckide that neutrons and X-rays are
roughly equally efficient, i.e., that the effect is independent of
ion density up to 400 ions per \i.

As was mentioned earlier, there is evidence that, under the
conditions prevailing in the sperm, the chromosomes of Droso-
phila may be broken by an ionizing particle which leaves only
one or two ion clusters within the chromosome thread. If the
same is true of the chromosomes in the egg, then the fact that
the mortality does not depend on ion density over the range
investigated would ont exclude chromosome structural changes
as a possible origin of the lethal effect of the radiation. It would
be of great interest to investigate the effect of a further tenfold
increase in ion density by the use of alpha radiation.

Lethal and Sublethal Effects on Root Tips,
Particularly of \^icia faba

The meristematic cells in the shoot and root tips of organisms
are very sensitive to radiation, and the damage caused by 200
to 1,000 rontgens of X-radiation will lead to the death of a
variety of roots. In passing from gamma radiation (A ^ 11 ions

Biological Effects of Ioni::ing Radiations 131

per fx) to X-radiation (A := 80 ions per |.i), the efficiency of the
radiation has generally been found to increase by about 50%.

Zirkle and Lampe ^^ compared the inhibition of growth of
both the shoot and root of wheat seedlings, when irradiated by
neutrons, for which A -=z 400 ions per ii, with that produced
by X-rays (A = 80 ions per ^). The neutron radiation was
about 3 times as efficient as the X-radiation, making a total
increase in efficiency of 4.5 as the ion density is raised from 11
to 400 ions per \v. Very similar results were obtained by Gray,
Read and Mottram,^- who investigated the lethal effect of gamma
rays. X-rays, neutrons, and alpha particles on the roots of
Vicia faba. Their results are shown in figure 3. The wheat
seedling results fall almost on the same curve.

The primary injury is evidently very sensitive to changes in
ion density over the range 100 to 1,000 ions per micron. This
is just the region of ion density in which, as we have already
seen, there is a rapid increase in the efficiency of ionizing par-
ticles in breaking the chromosomes of a variety of materials
including Vicia faba. Experimental data for two types of chromo-
some break observed in Tradescantia pollen are also shown in
figure 3, since corresponding data for J^icia faba are not yet
available. The trend of one of the curves is .similar, suggesting
that the inhibition of growth may arise from chromosome struc-
tural changes produced in the meristematic cells.

This hypothesis has been tested in a variety of ways, one of
which is of special interest from the point of view of ion-
density studies (Gray and Scholes, unpublished). It will be
recalled that, whereas some types of structural change require
the joint action of two ionizing particles when produced by
X-rays, and, therefore, increase as the square of the dose and
decrease with duration of exposure, all types produced by alpha
particles increase in direct proportion to the dose and are
independent of duration of exposure. Methods have been evolved
of estimating the proportion of cells in the root tip which are
injured by exposure to lethal and sublethal doses of radiation,
and it has been found that this proportion does, in fact, increase
linearly with dose in the case of alpha radiation, and is not

132 Applied Biophysics

diminished by prolonging the exposure time even up to 24 hours,
while with X-rays the proportion increases more rapidly than
the first power of the dose, and in the case of the larger doses
falls markedly as the exposure time is increased from a few
minutes to 4 hours. This interrelation between the influence of
ion density and duration of exposure is likely to be found also
when the effects of neutrons and X-rays are compared. It is
interesting to note that the curve for the temporary inhibition
of mitosis in Vicia faba follows an entirely different course,
showing that in this material, certain disturbances in the mitotic
function must be traced to a different primary injury from that
which leads ultimately to the death of the root.

Animal Embryonic Tissue and Tumor Tissue

The immediate effects of a variety of radiations, from heavily
filtered gamma rays to neutrons, on the mitotic activity of chick-
embryo fibroblasts cultured i^t vitro have been the subject of
many investigations, starting with those of Strangeways, and
continued mainly by Spear and his collaborators.^' ^' ^® Spear
and Grimmett ^^ found a marked influence of the hardness of the
gamma rays employed which, if real, would indicate an unusually
rapid increase of efficiency with ion density in the region of 10
ions per micron, since the extreme variation of ion density in
their experiments could only have been about 30%. The effi-
ciency continues to increase with ion density, but more slowly
until the X-ray region is reached (A = 80 ions per micron),
after which there is little if any further increase up to 1,000
ions per micron.

In its general features, the course of the curve, therefore,
closely resembles that for the inhibition of mitosis in root tips,
but no data are available to show whether the curve falls at ion
densities above 1,000 ions per u, as is the case with Vicia faba.

Many experiments by the Strangeways Laboratory team have
shown that the effect of radiation on mitosis is essentially the
same under m vivo as under in vitro conditions. In particular,
Spear and Tansley ^* found that, as in the tissue-culture experi-

Biological Effects of Ionising Radiations 133

ments with chick-embryo fibroblasts, the immediate effect of
neutrons on the mitotic activity of the developing rat retina was
approximately the same as that of an equal dose of X-radiation.
There are certain differences in the subsequent return of mitotic
activity, but these may be bound up with the markedly greater
efficiency of neutrons in causing cell degeneration.

Not only was much more cell degeneration produced in the
rat retina by neutrons than by an equal dose of gamma radia-
tion, but the degenerate cells appeared much earlier. This may
indicate that cell degeneration follows a different course accord-
ing to the radiation which causes the primary injury.

The effects of various radiations have been compared in regard
to their ability to injure tumor tissue by irradiation in vitro
iti such a way that it does not "take" when inoculated into
test animals. It appears to be established, particularly by the
careful experiments of Sugiura (1939), working with mouse
tumors, that X-radiation is about 50% more effective than
gamma radiation. The experiments were extended ^ to neutron
radiation of ion density about 300 ions per [i. The relative
efficiencies of neutrons and X-rays, as tested on a lympho-
sarcoma, a lymphoma, and a carcinoma of the mouse, were 3,
2.3, and 2.4 respectively. When these data are taken in con-
junction with Sugiura's, we find that the ion density curve
(figure 3) follows closely the course of the curve for the lethal
effect on root tips. Experiments at higher ion density are much
needed.

Gray, Mottram, and Read (unpublished) carried out in vivo
irradiations of inoculated mouse tumors, using neutron and
gamma radiation. The neutron radiation appeared to be some
15 times as efficient as gamma radiation. In comparing this result
with the in vitro studies already fnentioned, we have to note first
that the neutron ion densities were much higher in the in vivo
experiments (A =: 1,100 ions per \i) , and, secondly, that the
influence of ion density and duration of exposure may be inter-
connected. The gamma ray and neutron exposures were of
equal duration (3 hours), but the time may have been such that
the effect of the gamma radiation, but not of the neutron radia-

134 Applied Biophysics

tion, was thereby diminished compared with a very short ex-
posure.

Mouse tumor tissue has also been irradiated by the very
densely ionizing particles resulting from the disintegration of
boron or lithium by slow neutrons. Very great technical diffi-
culties were encountered in obtaining quantitative results in the
in vivo experiments. An effect of the disintegration particles
was clearly demonstrated in the /';/ vitro experiments/^ though
it was not possible to estimate their efficiency relative to other
ionizing radiations.

Neutron Therapy

In 1942, Stone and Larkin -^^ reported upon 92 patients suffer-
ing from malignant disease who had been treated by neutrons.
With regard to the clinical results, it is best to quote Stone's ^^
views :

"It is difficult, in discussion of effects of a method of treatment
tried almost entirely on patients with far advanced cancer, to
convey any adequate idea of what actually takes place during
the course of treatment. While the ' survival statistics presented
and the autopsy findings reported appear discouraging, the .general
impression of one watching the patients being treated is that
marked tumor regressions are being produced even when they
were not expected. In many instances, large metastatic nodal in-
volvements disappeared, showing a remarkable effect of the
neutron rays on the tumors. The patients as a whole did not react
so well, either because the tumor had spread beyond the treated
regions and was not controllable for that reason, or because a
debilitating ulcer remained at the site of the primary node. In
many instances, biopsies from the edges of persisting ulcers did
not show evidence of cancer, but because of either the extensive
destruction caused by the cancer or the irreparable damage caused
by the neutron rays, normal tissues would not react in such a
way as to bring about the healing of the ulcer."

Skin reactions to neutron radiation followed the same general
course as after X-radiation. Considerablv smaller doses of

Biological Effects of Ionising Radiations 135

neutron radiation were needed to produce a given degree of
skin reaction, and one may say roughly that the efficiency of
neutrons in this respect appears about 2.5 times as great as
X-rays. It is important to emphasize, however, that, as in X-ray
therapy, the total dose was delivered in a large number of frac-
tions spread over about 3 weeks, and until the influence of
fractionation on the effects of both types of radiation has been
fully investigated, a figure representing their apparent relative
efl^ectiveness gives little guide as to the nature of the processes
involved.*^ It is at least clear, however, that both skin response
and tumor response belong to the class of reactions in which,
proceeding from gamma rays to neutrons, the efifectiveness in-
creases with increasing ion density. It has been pointed out ^^
that, insofar as more favorable tumor response has been obtained
with neutrons than with X-rays, this may be taken to indicate
that the curve (figure 3) for tumor response is rising more
rapidly than that for skin-damage. A further improvement
might therefore be expected by the use of less energetic (greater
ion density) neutrons, and advantage might be taken of the fall
in the average energy of a neutron beam on passing into the
body to increase the damage to the tumor relative to that to
the skin.

Such an advantage, however, falls into the same class as the
technical improvement offered by the increased depth-dose
obtained with high-voltage X-ray tubes and betatrons. At best,
they enable the therapist to deliver any desired dose of radiation
to a mass of tissue which completely envelops all the malignant
cells. There remains the problem of discriminating between
two adjacent cells in such a manner as to destroy either the
malignant character of the tumor cell or the cell itself, without
destroying all its healthy neighbors. Such discriminations must
be based ultimately on a biological difference between the two
cells. Differences in matabolism, chromosome structure, and
rate of development, are known to exist, and these differences,
as we have seen, profoundly affect the manner in which the
various functions of a cell are influenced by radiations of differ-
ing ion density. It would seem that a fuller investigation of

136 Applied Biophysics

these differences may reveal improved methods of obtaining the
desired discrimination.

References

1 Aebersold, P. and J. H. Lawrence (1942) Ami. Rev. Physiol. 4, 25.
-' Canti, R. G. and F. G. Spear (1Q27) Pro.: Roy. Soc. B, 102, 92.
^ Catcheside, D. G. and D. E. Lea (1943) J. Genet. 45, 86.
•1 Chambers, H. and S. Russ (1912) Froc. Roy. Soc. Med. 5, sect.

Path., 198.
5 Colwell, H. A. and S. Russ (1924) Radium. X-rays and the Living

Cell, 2nd ed., London.
6Duane, W. and O. Scheuer (1913) Radium, Paris, 10, i2>.
*? Fricke. H. and E. R. Brownscome (1933) J. Anier. Chem. Soc. 55,

2358. I

8 Gray, L. H. (1944) Brit. J. Radiol. 17, 327.

9 Gray, L. H.. J. C. Mottram, J. Read and F. G. Spear (1940) Brit. J.

Radiol. 13, 371.

10 Gray, L. H. and J. Read (1943) Nature, Loud. 152, 53.

11 Gray, L. H.. J. Read and H. Liebmann (1941) Brit. J. Radiol. 14, 102.

12 Gray, L. H., J. Read and J. C. Mottram (1939) Nature, Lond. 144,

478.
i3Gunther, D. J. and L. Holtzappel (1939) Z. phys. Chem. B, 44, 374.

14 Hardy, W. B. (1903) Chem. Nezvs, 88, 73; J. Physiol. 29, Proc.

Physiol. Soc. p. xxix.

15 Henshaw, P. S. and D. S. Francis (1936) Radiology, 27, 569.

16 Roller, P. C. (1945) Nature, Lond. 155, 778.
i^Kruger, P. G. (1940)' Proc. Nat. Acad. Sci., Wash. 26, 181.
iSLanning, F. C. and S. C. Lend (1938) /. Phys. Chem. 42, 1229.

19 Lasnitzki. L and D. E. Lea (1940) Brit. J. Radiol. 13, 149.

20 Lea, D. E. (1946) Actions of Radiations on Living Cells, Cambridge

[in press].

21 Lea, D. E. and M. H. Salaman (1942) Brit. J. E.vp. Path. 23, 27.

22 Marshak, A. (1939) Proc. Soc. Exp. Biol. Med., N. Y. 41, 176.
23Marshak, A. (1942) Radiology, 39, 621.

24 Marshak, A. and M. Bradley (1945) Proc. Nat. Acad. Sci., Wash.

31, 84.
^^ Xeary, G. T. (1946) Brit. Med. Bull. 4, 30.

26 Nurnberger, C. E. (1934) /. Phys. Chem. 38, 47.

27 Packard, C. (1927) J. Cancer Res. 11, 1.

28 Packard. C. (1936a) Amer. J. Cancer, 16, 1257.

29 Packard. C. (1936b) in Biological Effects of Radiation, edited by

B. M. Duggar, New York, p. 459.
soRisse, O. (1929) Strahlentherapie, 34, 578.

Biological Effects of Ionising Radiations 137

3iSugiura, K. (1939) Aiiier. J. Cancer, 37, 445.

32 Spear, F. G. (1946) Brit. Med. Bull. 4, 2.

33 Spear, F. G. and L. G. Grimmett (1937) Rep. Brit. Eiiip. Cancer

Campgn. 14, 134.

34 Spear, F. G. and K. Tansley (1944) Brit. J. Radiol. 17, 374.

^'' Stone, R. S. (1944) in Medical Physics, edited by O. Glasser, Chicago,

p. 812.
36 Stone, R. S. and J. C. Larkin (1942) Radiology. 39, 608.
37Zahl. P. A., F. S. Cooper and J. R. Dunning (1940) Pror. Nat. Acad.

Sci., Wash. 26, 589.

38 Zirkle, R. E. (1936) in Biological Effects of Radiation, edited by

B. M. Duggar, New York, p. 559.

39 Zirkle, R. E. and I. Lampe (1938) .4wer. J. Roentgenol. 39, 613.

GENETIC EFFECTS OF RADIATIONS

D. G. CATCHESIDE, M.A., D.Se.
Lecturer in Botany, University of Cambridge, and Fellow of

Trinity College

Introduction

GENETICS is concerned with the mechanism of heredity,
with the reasons why offspring resemhle their parents and
in some cases differ from them. The characters of the
human body, or of any other organism, are controlled by genes
present in every cell. The genes are passed from parent to
offspring in the gametes. They are situated in and largely, if
not wholly, constitute the chromosomes, of which there is a
fixed number in a given kind of organism. The gametes con-
tain a haploid set (n), the zygote and body cells a diploid set
(2n) of chromosomes. Thus each chromosome or homologue is
represented once in the gamete and twice in a body cell.

Each gene occupies a fixed position (locus) in its particular
chromosome of the haploid set. The gene present at a given
locus may not always be exactly the same one, but may be
replaced by a slightly different one, called an allelomorph
(or allel). Thus, at a particular genetic locus in two homol-
ogous chromosomes, a given body cell may possess the same
allelomorphic gene and be homozygous, or may possess two
different allelomorphs and be heterozygous, llie number of
allelomorphs of a given gene is not limited. Thus 4 allelo-
morphs controlling the AB l)lood group series are recognized
in man, about 20 allelomorphs of the "a' (white eye) series in
the fruit-fly Drosopliila niclanogastcr, and between 40 and 50
allelomorphs of the gene concerned with incompatibility reac-
tions of pollen grains to style in certain self-sterile flowering

^ 138

Genetic Effects of Radiations 139

' plants. However, in a normal diploid organism no more than
2 allelomorphs of a gene may be present together in the same
individual. Moreover, each of the gametes produced by a given
individual will contain only one allelomorph and, where the
individual is heterozygous, half its gametes will possess one
allelomorph and half the other. For example, the rare nervous
disease Huntington's chorea is transmitted, on the average, to
half the afifected person's children. The particular genes of the
affected persons may be symbolized as // for the abnormal gene
responsible for the manifestation of the disease and h for its
normal allelomorph. The affected person would be Hh and his
(or her) gametes half H and half Ji. Since the disease is so rare,
the spouse would normally be hh and the children therefore, on
an average, half Hh (capable of developing the disease) and the
other half /i/z (normal).

The gene, H, for Huntington's chorea is usually spoken of as
being dominant to the normal gene // which is recessive. In
fact, the term dominant implies that there is no difference in the
appearance (phenotype) of HH and Hh individuals. In man
this particular information is lacking, so the use of the term
"dominant" in this connection is convenient rather than correct.
Probably a majority of genes producing abnormalities in man
are strictly recessive, the homozygous and heterozygous normals
being alike, or else intermediate in their dominance, the heter-
zygous being more like the homozygous normals than the homo-
zygous abnormals, which may be very extreme in their char-
acter.

Gene segregation is orderly and dependent upon the regular
pairing together and separation of the chromosomes at meiosis.
This precedes gamete formation and is constituted by two special
nuclear divisions, in the course of which the number of chromo-
somes contributed to the daughter nuclei becomes half that in
the parent nucleus. The orderliness is such that each daughter
nucleus receives one each of the n different homologous chromo-
somes. IMoreover, in any particular gamete, a given homologue
may be compounded of complementary parts of the two homo-
logues present in the parent. Thus, a parent which in one of a

140 Applied Biophysics

pair of homologous chromosomes has the genes ABcdeFgH
and in the other the genes a b C d E f g h, may produce gametes
which possess for example A B c d E f g h or a b C d E F g H as
well as chromosomes like one or other parental homologue.
This orderly rearrangement comes about by crossing over during
meiosis, the relative frequency of rearrangement occurring
between two particular genes being a measure, technically known
as the linkage value, of their distance apart on the chromosome.
All the genes or loci present in one chromosome together con-
stitute one linkage grou]), the number of possible groups in an
organism being equal to the haploid number of chromosomes.
For a further account of genetics particularly in relation to man
the reader is referred to Ford.^

Stability of Chromosomes and Genes

Apart from the process of crossing over, whereby the chromo-
somes may recombine their differences, the chromosomes are
highly stable structures. However, clianges do occur very rarely,
resulting in alterations in the linear order of the genes within
one chromosome or linkage group, or exchange of blocks of genes
between two non-homologous chromosomes or linkage groups.
The frequency of these structural changes, spontaneously very
rare, is greatly increased by various radiations. Similarly the
genes themselves also possess a high degree of stability. They
have a capacity of self-reproduction which is one of the most
important characteristics of living matter. All the evidence
indicates that they reproduce exactly, and that, if any change
occurs within one of them, the gene reproduces in its changed
form.

Changes in genes do occur spontaneously, but usually the
frequency of such mutations is very small. The normal frequency
is of the order of one change per million genes per nuclear
division cycle, and may be smaller even than this for a great
many genes. A few genes are highly mutable, with a rate of
about one per thousand or ten thousand genes per nuclear cycle. ^
There is, however, no indication that they are fundamentally

Genetic Effects of Radiations 141

different from the stable genes, and probably there is no dis-
continuous range in mutation frequency.

The stability is very little affected by ordinary environmental
fluctuations, temperature being the most potent of such influ-
ences. A 10° C. rise in temperature will increase the rate of
mutation about five times.'*^^ Thus the principal hereditary ma-
terial, the chromosomes and genes of which they are constituted,
is distinguished by a remarkable stability of minute structure,
both as regards the constituent particles, the genes, and the way
in which these are ordered and bound togeher to form chromo-
somes.

The significant genetic effects of radiations are that gene
mutations and chromosome structural changes become much
more frequent under their influence. The order of increase over
spontaneous changes is a hundredfold for quite moderate doses
of X-rays. The chief biological interest lies in the possibilities
of studying the nature of the mutation process and, by extension,
of the gene itself, and also of the manner in which the genes
are tied together to form chromosomes. With the help of
radiations, experiments can be carried out which, if dependent
on spontaneous mutation alone, would be almost impossible.

Medically, the importance lies firstly in . the fact that most
mutations are recessive and deleterious and, therefore, that deep
radiotherapy may run the risk of producing mutations in the
gonads. The mutations may be transmitted to the treated per-
son's children and spread undetected in the population in which,
generations later, homozygous defective individuals may arise.
The genetic change is immediate but the physiological conse-
quences are delayed. Secondly, many kinds of induced chromo-
some structural change are lethal to all cells in which they are
produced, and it is this property, among others, of radiations
that renders them effective in killing unwanted tissues such as
cancers.

Apart from radiations, only a few agents have been found
capable of greatly enhancing mutation rates. The most effective
are certain synthetic chemicals, the naturally-occurring mustard
oil, allyl isothiocyanate,^ and antibodies.®

142 Applied Biophysics

Most researches on the genetic efifects of radiations have heen
confined to a few organisms that are technically favorable from
the point of view of ease in handling the large numbers of
individuals needed in controlled experiments. The principal ones
are the fly Drosophila mclanogastcr, maize, and some fungi such
as Ncurospora, together with the flowering plant, Tradcscantia,
for chromosome studies.

Racliation-indueed Mutation in Drosophila

When adult male flies are exposed to radiations and subse-
quently mated to untreated virgin females, a proportion of the
eggs laid fail to hatch although they have been fertilized. The
premature death of the individual is ascribed to the induction
of a dominant lethal mutation in the sperm. The existence of
such mutations was first proved by MuUer,-" who showed that
their "number was so great that thorough egg counts and efifects
on the sex-ratio evidence could be obtained from them r// masse."
At moderate doses, ^- ^ the graph relating the logarithm of the per-
centage of eggs reaching the larval or adult stages to the dose
is a linear one. Above 4,000 r the gradient becomes steeper,
suggesting that a mixture of "single-hit" and "multiple-hit"
efifects contributes to the total yield of dominant lethals. The
predomiiuant contribution, particularly in the lower dose-range,
is single-hit, and dominant lethals involving more than one hit.
and so increasing more rapidly than the first power of the dose,
become important only at higher doses ( figure 1 , A ) .

The occurrence of dominant lethals is expressed also in the
sex ratio, i.e., the proportion of females relative to males hatch-
ing from a batch of eggs. As the X-ray dose increases, the sex
ratio declines (figure 1, B), owing to the extra probability of a
dominant lethal being induced in an X-chromosome-bearing
sperm as compared with a Y-chromosome-bearing sperm ex-
posed to the same dose. The female-producing X-chromosome
is a little larger than the male-producing Y-chromosome, and
so presents a larger target in which the dominant lethals may
be induced.

b/O

>

bfl
bJO

b£

C
«J

)-r

ID

U
I

X
C/2

2x10 ^rontgen
' ' ^100

-50

-10

-0-5

4 6

Dose (in 1,000 rontgens)

FIG. 1. Relation of frequency of dominant lethals produced in sperm to dose of
X-rays employed. A = percentage of eegs hatching; 1? = percentage of eggs produc-
ing adult flies; C = sex ratio. In each case the logarithm of the frequency is plotted
against dose; points experimental. Reproduced from Catcheside & Lea-" by kind per-
mission of the Editor of the Journal of Genetics.

143

144 Applied Biophysics

Discussion of the nature of the dominant lethals is deferred,
except to indicate that the change in the heredity material does
not produce an immediate effect. Eggs which fail to hatch are
found to have undergone a number of nuclear divisions before
breakdown occurs. ^^

Among the viable offspring of treated male flies, a number
carry mutations. The great majority of these are recessive, and
so do not produce any visible effect immediately, since they are
heterozygous. Special measures have to be taken to obtain
individuals homozygous for such mutations. The simplest are
those for detection of mutations in the X-chromosome, a sex
chromosome that is present twice in the female flies and once
only in the males. It crosses and recrosses in heredity in a
regular fashion from father to daughter and mother to son. Thus,
males will be hemi-zygous for genes in the X-chromosome, and
so will manifest them.

Treated male parents are mated to C I B females,^^ one of
whose X-chromosomes carries a cross-over suppressor (C, ac-
tually an inversion), a recessive lethal (/), and a dominant
marker-gene (B, Bar-eye, which is narrower than the normal
round eye). Among the offspring, females with a Bar-eye are
chosen and mated individually with any suitable males, prefer-
ably with their X-chromsomes suitably marked wnth recessive
genes. Any one of these Fi females will have a treated X-chromo-
some from her father and 3. C I B chromosome 'from her mother.
The C I B chromosome will be lethal to male offspring carrying
it, so all male offspring of Fi females will carry only treated
X-chromosomes from their grandfathers. Inspection of these
males will disclose genes having a visible effect, though their
detection will depend on the skill and experience of the observer.
On the other hand, if a recessive mutation is lethal, the culture
containing it will l)e marked by a complete lack of male offspring.
Such sex-linked lethals are ])roduced by radiations about ten
times as frequently as visible mutitions. They provide an objec-
tive criterion for quantitative work, and have been widely used
in experimental studies on mutation-rates. The recessive lethals,
of course, represent nuitations at a large number of different loci,

Genetic Effects of Radiations 145

and the grouping together of such a heterogeneous group is
justified mainly by the convenience of their frequency.

When viable recessive mutations are to be studied, the
attached-X method may be adopted. In this case, the treated
male is mated to an attached-X female, whose two X-chromo-
somes are joined together and so are segregated together at
gamete formation. Her eggs wnll be of two kinds, one with
two X-chromosomes, and therefore female-producing, and the
other without any X-chromosomes. The latter, with an X-bear-
ing sperm from the irradiated father, will produce a male in
which any visible mutation in the treated X-chromosome could
be detected.

, These techniques, and others like them, are simple but
enormously laborious, since the mutation-rates involved are small
even for fairly large doses of X-rays. Nevertheless, many facts
about the mutation process are well established. In the first
place, the mutations induced by radiations do not dififer qualita-
tively from those occurring spontaneously. In both cases, too,
the mutation rate differs from one locus to another, and from
one allelomorph to another at the same locus. ^^' ^"^ It can be
concluded that the genes differ among themselves in stability,
the less stable ones undergoing the more frequent mutation. An
important point to note is that the radiation cannot determine
what particular mutation is produced. Which gene is activated
and what allelomorph is finally formed is a matter of chance.
The former depends upon the chance of the target, the gene,
being hit, and the latter upon the innate characteristics of the
individual locus ; in particular, apparently, upon the relative
stabilities of the difi:'erent allelomorphs.^^

Further, a given gene A may be changed to the allelomorph
a, and the latter on being irradiated changed back to A. Such
back-mutations, demonstrated first by TimofeeiT-Ressovsky,^^' ^^^
are important in showing that whatever change is involved in the
conversion of ^ to a cannot be a loss that may not be restored
with relative ease.

The quantitative relationship between the mutation rate and
the radiation dosage, intensity, wave length, etc., has be^n

146 Applied Biophysics

determined satisfactorily only for the group of recessive sex-
linked lethals, though sufficient has been done with visible reces-
sive mutations and with mutation in other organisms to suggest
that the results are characteristic. First of all, however, it should
be mentioned that the natural mutation rate in Drosophila
melanogaster (measured by sex-linked lethals) increases with
the age of the tissue tested and with the temperature at which
it is kept. Further, it differs from stock to stock and in a few
cases may be relatively high. Thus, Demerec ^' found that the
Florida stock gave about 1% of sex-linked lethals, the average
of all other stocks being about 0.1%. This he found to be due
to a recessive gene, located on the second chromosome, which
raised the general mutation rate of all the genes in the organism.
This behavior is to be contrasted with the case found by
Rhoades -^ in maize, where the gene Dt increases the mutation
rate only of the gene ai.

The mutation rate induced by X-rays is found to be linearly
proportional to the dosage. The frequency of sex-linked lethals
induced in Drosophila sperm is about 3% per 1,000 r.-^ This
rate is independent of the wave length of the radiation through-
out the gamma ray and X-ray range up to a wave length of
2.6 A. It is independent of the time occupied by the irradiation,
i.e., is independent of intensity down to the lowest tested (0.07 r
per minute) and of whether the dose is fractionated or given in
one exposure. Lastly, it is unaffected by temperature and is
probably independent of the natural mutation rate of the par-
ticular stock employed. Timofeeff-Ressovsky ^^ should be con-
sulted for full details.

These facts indicate that the induced mutations must be due
in quite a direct manner to a single ionization excited in a sensi-
tive volume which may be the gene itself or include the gene
or some part of it.'^^ The ionization adds considerable energy
to the affected gene, and the excited molecule, rendered tem-
porarily unstable, is enabled to slip from one relatively stable
chemical state to another. What the precise change may be is
imknown, but any change in the gene molecule may be expected
to alter the properties of the whole gene and so to be disclosed

Genetic Effects of Radiations 147

as a mutation. A simple account of the physical principles in-
volved is given by Schrodinger.-' Probably not all changes pro-
visionally classed as gene mutations are intramolecular, but the
further consideration of this matter must be left until the grosser
effects of radiations on the chromosomes have been described.
Estimates of the sizes and of the number of genes may be
derived from mutation data. The best estimates are probably
those derived '^^^ '^^' ^" from a comparison of the mutation rates
induced by X-rays and neutrons. These two radiations differ
considerably in their relative efficiency in producing sex-linked
lethals, the ratio being about 1.6:1 for X-rtays : neutrons for a
given dose measured in terms of ionizations.^*^ This leads to an
estimated volume of a single gene of a1)()Ut 2.8 X 10"-" cubic
centimeters, containing about 1,000 atoms, and to there being
about 1,860 genes in the X-chromosomes of Drosophila, each
capable of giving X-linked recessive lethals.

Induced Chromosoiiie Aberrations

The chromosomes in a body cell pass through a cycle of divi-
sion, mitosis, whereby two nuclei, each an exact reproduction of
the parent nucleus, are produced. Before prophase, i.e., in the
resting stage, each chromosome divides lengthwise into two
chromatids, except at the centromere, and during prophase each
assumes a condensed spiral form and becomes coated with
nucleic acid. At metaphase, each chromosome moves on the
spindle so that the centromeres come to lie in the equatorial
plane. At anaphase, each centromere divides, the two halves
each with their attached chromatid then moving to opposite
poles of the spindle. A new^ nucleus is then organized at telophase
from each of the two groups of daughter chromosomes.

Radiations affect the different stages in various ways. A
lengthening of the nuclear-division cycle may be caused, espe-
cially by heavier doses. A further physiological effect, shown by
adhesion or clumping of the chromosomes, occurs in cells already
in division at the time of irradiation.^-' ^^ With large doses,
excessive clumping may prevent the completion of mitosis.

148 Applied Biophysics

Nuclei at resting, or early prophase, stages at the time of
irradiation, although delayed in division, recover and show no
adhesive tendency when they reach metaphase. Instead, they
may show structural changes. These are due to the production
of breaks in the chromosomes, which may be followed by the
formation of structural rearrangements resulting from the re-
combination of the breakage ends in various ways. This subject
has recently been reviewed - and space permits the description
of only some of the manifold changes. The descriptions refer
to the appearance of the afifected chromosomes at the metaphase
of the division cycle in which the changes are induced.

Structural changes are of two kinds : chromosome, where both
the chromatids are similarly affected and chromatid, where only
one of the two chromatids is affected at a given place. The
former are normally produced by irradiation during the resting
stage, at which time the chromosomes are simple undivided
threads. The latter are produced by treatment at the early
prophase, when the chromosomes are divided into two chroma-
tids. In flowering plants, the pollen grains in a given anther
and bud develop approximately synchronously. In Tradescantia,
for example, at 20° C the division cycle, including a prolonged
resting stage, occupies about 10 days, all the grains in one anther
reaching metaphase within a period of less than 24 hours. The
material is thus convenient for radiation work in providing a
group of cells all approximately at the same stage of mitosis.
Chromosome division occurs about 30 hours before metaphase.
A change from chromatid to chromosome structural changes is
shown by metaphases observed respectively less than, and more
than, 30 hours after exposure of pollen grains to radiations.

Other convenient material is provided by germinating pollen
grains on an artificial medium, and using the nuclear division
that takes place in the very thin pollen tube, 7\i in diameter. This
is especially valuable where soft, weakly penetrating radiations
must be studied.

Radiations produce breaks in the chromosomes, and the breaks
suffer various fates (figure 2). A large proportion, estimated
at 90%, undergo restitution, the two fragment chromosomes

Genetic Effects of Radiations 149

rejoining in the original way so that no permanent effect can
be seen.^'^' -^ This restitution is a matter of inference from
intensity experiments to be mentioned later. A further proportion
of breaks undergo reunion in new ways. Thus, two breaks,
one each in two different chromosomes in the same nucleus,
would produce four fragments Ai, Aq, Bi, Bq. Two of them
( Ai and Bi) have centromeres and two (Aq and Bq) are without
these bodies. Reunion in a new way to produce interchanges
could be symmetrical, producing two new viable chromosomes
Ai-Bo and Bi-Ao, each with one centromere; or could be
asymmetrical, producing two defective chromosomes, one
(Ai-Bi) having two centromeres and the other (Aq-Bo) having
none. Similarly, two breaks within one chromosome could pro-
duce symmetrical changes (inversions, cf. figure 5)* or defective
(ring or deficient rod) asymmetrical changes. The defective
chromosomes are not permanently functional, since a chromo-
some without a centromere is inert on the spindle (figure 3/?),*
while in one with two centromeres there is a complete lack of
coordination of the two kinetic bodies. The inertness leads to
loss of parts of chromosomes from the daughter nuclei and, if
this entails the loss of vital genes, the nuclei die. The non-
coordination of two centromeres leads to chromosome bridges at
anaphase, and ultimately to breakdown and death of the cells.
Causes of this type are responsible for those dominant lethals,
referred to earlier, that are dependent upon two or more hits.

A final proportion of the original breaks neither restitute nor
undergo reunion in new ways, but instead remain open as
chromosome breaks, the chromosome being present as two frag-
ments, one centric and the other ^acentric. In some cases the
pairs of sister chromatid ends may undergo sister union (figure
4a),* and in other cases not. Where sister union occurs in the
centric fragment, a bridge would be formed at anaphase (figure
3a), leading ultimately to cell death. Single chromosome breaks,
exhibiting sister union, account for the major proportion of
dominant lethals, namely for those proportional in frequency to
the first power of the radiation dose.^^- ^^' ^^

* Figs. 3 to 5 are on p. 104 and 105.

150 Applied Biophysics

Chromatid breaks produce a series of analogous chromatid
structural changes (simple chromatid breaks are shown in figure
4b* and a chromatid interchange in figure 3c),* some of which
are defective, leading to death, and others of which are fully
functional and viable. In general, a functional nucleus must have
a full complement of genes, and each chromosome must be rod
shaped and have just one centromere. This is not strictly true,
since very small deficiencies (absences of one or a few genes)
may be viable. Thus, a proportion of the recessive lethals induced
in Drosopliila sperm are actually small deficiencies, as is disclosed
by examination of the giant salivary-gland chromosomes.-®

The yield of persistent chromosome breaks and chromatid
breaks is linearly proportional to dose in the case of
X -ray s, -•'••-"■ '^-^ e.g., neutrons, ^^'- ^"^"^ and alpha rays ( Kotval and
Gray, unpublished ) . The yield is also independent of the radia-
tion intensity.^- -"' Therefore, simple breaks are products of
single radiation hits.

The vields of interchanges and other two-break al)errations
produced by X-rays diminish with increase of the time over
which the irradiation is spread, i.e., with decreasing intensity.
These two-break aberrations also increase more rapidly than
the first power of the dose. With high intensities, the yields are
practically proportional to the square of the dose; at lower
intensities, the power of the dose is lowered.-^* A square law
is also found if the dose is varied by varying the intensity at a
constant exposure time. These facts are readily explicable if
the two breaks are produced by separate ionizing particles.
However, the effects may be distorted by restitution of breaks,
unless the irradiation is completed in a short time or the irradia-
tion extends over the same time at all doses. The data also may
be employed to show ^'' that the mean life of an original break
in a Tradcscantia chromosome is about 4 minutes at 20° C. At
lower temperatures, its life is probably longer.

\\ ith neutrons, the yield of interchanges is independent of the
time over which a given dose is spread, i.e.. of the intensity,
suggesting that a single ionizing particle usually causes both the
breaks in the neutron-induced interchanges.^^ In agreement

FIG. 2. Diagrams of the Mode of Proi^uction of Some Chromosome

Structural Changes

A: Chromosome B: Symmetrical C: Asymmetrical

break interchange interchange

I: .Unbroken; II: Broken; III: Reunion;

IV: Metaphase configuration; V: Anaphase configuration.

151

152 Applied Biophysics

with this inference is the fact that the vield of neutron-induced
interchanges increases in linear proportion to dose.^^- ^^' ^^

X-rays ionize by means of electrons, the ionizations in a path
being in ckisters spaced apart, except very near the end of the
path where the electron has lost most of its energy. Neutrons
ionize by means of protons, the ionizations in the path forming
a dense column. For a given dose, depending upon the X-ray
wave length and the neutron energy respectively, about ten to
twenty times as many electrons as protons would traverse a
nucleus. It is for this reason that, at the low dosages normally
employed, neutron-induced interchanges are predominantly one-
hit, while X-ray-induced interchanges are predominantly two-hit.

Providing that X-ray doses are measured in rontgen units
and neutron doses in z'-units, units which represent approxi-
mately equal energy dissipations in tissue, the ratio of the yields
of chromosome aberrations for equal doses of the two radiations
may be taken to be the ratio of the efficiency per ionization of
the densely ionizing particles (protons) in neutron experiments
to that of the less densely ionizing particles (electrons) in X-ray
experiments. This ratio is about 2 to 4 for chromatid breaks
and chromosome breaks in Tradescantia pollen grains.

The X-ray and neutron data taken together may be used to
derive an estimate of the distance apart, at the moment of
breakage, of breaks which exchange. The order of magnitude
is l\i,^^ and this estimate agrees with those based on other
data.2. 14

It has already been seen that a Tradescantia chromosome can
be broken by a single ionizing particle. If a single ionization
were the causative agent, the efficiency per unit dose should be
less for neutrons than for X-rays, since those ionizations in
excess of the minimum needed to break the chromosome would
be wasted. But neutrons are more efficient and this indicates
that several ionizations are usually needed to break a chromo-
some. The probabilitv of a chromosome being broken when a
proton traverses it is fairly high, most likely between 0.5 and
unity. On the other hand, the probability of breakage by an
electron is rather low for all of its path except the last densely

Genetic Effects of Radiations 153

ionized quarter-micron.^^ It has been estimated that 15 to 20
ionizations represent the minimum amount of energy which, dis-
sipated in a chromosome, is sufficient for the probabihty of
breakage to approach unity. It should be emphasized that these
numerical values refer to Trade scantia chromosomes, and that
quite different values may characterize the chromosomes of other
organisms.

From a genetical point of view, the use for therapeutic pur-
poses of neutrons and similar radiations with densely ionized
paths instead of gamma rays and X-rays, is to be favored, for
the following reasons. For a given dose, neutrons are more
efficient in the production of chromosome structural changes
that will lead to the death of the cells and tissues, while they
are less efficient in the production of gene mutations which,
produced in gonads, could be harmful to future generations.

Finally, reference should be made to ultraviolet radiations.
These can cause excitation but not ionization, i.e., they can
introduce into genes or chromosomes at one time only a small
amount of energy compared with that which may be introduced
by X-rays. Ultraviolet radiations produce the usual range ,of
gene mutations,^^- ^^ the rate being directly proportional to the
dose. The shorter wave lengths, notably those between 2,500
and 3,000 A approximately, are considerably more effective than
slightly longer wave lengths. The ultraviolet is also able to
produce chromosome breaks, although with a remarkably low
efficiency ; ^^ however, there is no certain evidence that inter-
changes or other two-break aberrations can be produced. From
a genetic point of view, the ultraviolet can be extremely useful
in providing mutations free from chromosome structural changes,
always provided of course that the objects to be treated are small
enough to be capable of penetration by the rays.

References

1 Auerbach, C. and J. M. Robson (1944) Nature, Lond. 154, 81.

2 Catcheside, D. G. (1945) Biol Rev. 20, 14.

3 Catcheside, D. G. and D. E. Lea (1945) /. Genet. 47, 1.

4 Catcheside, D. G., D. E. Lea and J. M. Thoday (1946) /. Genet, [in

press].

154 Applied Biophysics

5 Demerec, M. (1935) Bot. Rev. 1, 233.
6Demerec. M. (1937) Genetics, 22, 469.

7 Demerec, M. and U. Fano (1944) Genetics, 29, 348.

8 Emerson. S. H. ( 1944) Proc. Nat. Acad. Sci., Wash. 30, 179.

9 Ford, E. B. (1942) Genetics for Medical Students, London.
10 Giles, N. (1940) Proc. Not. Acad. Sci., Wash. 26, 567.

31 Giles, N. (1943) Genetics, 28, 398.

12 Roller, P. C. (1943) Proc. Roy. Soc. Edinb. B. 61, 398.

13 Lea, D. E. (1940) .1. Genet. 39, 181.

14 Lea, D. E. (1946) Actions of Radiations on Living Cells, Cambridge

[in press].

15 Lea, D. E. and D. G. Catcheside (1942) /. Genet. 44, 216.

16 Lea, D. E. and D. G. Catcheside (1945a) .1. Genet. 47, 10.

17 Lea, D. E. and D. G. Catcheside (1945b) /. Genet. 47, 41.

18 Mackenzie, K. and H. J. Muller (1940) Proc. Roy. Soc. B, 129, 491.

19 Marquardt, H. (1938) Z. Bot. 32, 401.

20 Muller, H. J. ( 1927) Science, 66, 84.

21 Muller, H. j. (1928) Genetics. 13, 279.

22 Pontecarvo, G. and H. J. Muller (1941) Genetics, 26, 165.
23Rhoades. U. (1941) Cold Spring Harbor Symp. Quant. Biol. 9, 138.

24 Sax, K. (1939) Proc. Nat. Acad. Sci., Wash. 25, 225.

25 Sax, K. (1940) Genetics, 25, 41.

26 Sax, K. (1941) Cold Spring Harbor Symp. Quant. Biol. 9, 93.

27 Schrodinger, E. (1944) What is life? Cambridge.

28 Schultz, J. (1936) Biological Effects of Radiations, edited by B. M.

Duggar, New York. chap. 39.
29Slizynski, B. M. (1938) Genetics, 23, 283.

30 Sonnenblick. B. P. (1940) Proc. Nat. Acad. Sci., Wash. 26, 373.

31 Stadler. L. J. and G. F. Sprague (1936) Proc. Nat. Acad. Sci., Wash.

22, 572.

32 Swanson, C. P. (1942) Genetics, 27, 491.
33Thoday, J. M. (1942) /. Genet. 43, 189.

34 Timofeeff-Ressovsky, N. W. (1929) Arch. Entwicklungsmech. Organ.

115, 620.

35 Timofeeff-Ressovsky. N. W. (1930) Naturzvissenschaffen, 18, 434.

36 Timofeeff-Ressovsky, N. W. (1932) Z. indiikf. Abstammnngs u.-

Vererbungslehre, 64, 173.

37 Timofeeff-Ressovsky, X. W. (1933) Z. indukt. Abstammungs u.-

J^ererbungsiehre, 65, 278; 66, 165.

38 Timofeeff-Ressovsky, N. W. (1937) Miitationsforschung in der

J^ererbungslehre, Dresden.

39 Timofeeff-Ressovsky, N. W.. K. G. Zimmer and M. Delbriick (1935)

Nachr. Ges. JViss. Gottingen, n. F. 1, 189.

40 Zimmer. K. G. and X. W. Timofeeff-Ressovsky (1938) Strajilen-

thergpie. 63, 528,

THE ACTION OF RADIATIONS ON VIRUSES

AND BACTERIA

D. E. LEA, M.A., Ph.D.
Strangeways Research Laboratory, Cambridge

Introduction

THE viruses are parasites of bacteria, plants, or animals,
characterized by their small size and their inability to
multiply except in or on the living cells of the appropriate
host. The larger viruses, such as vaccinia, are probably cor-
rectly regarded as single-celled organisms. The smallest viruses
are nucleoproteins, capable of being concentrated and purified
by the methods of protein chemistry, and in some cases obtain-
able in a crystalline form. It is evidently not correct to regard'
these small viruses as cells. From a biological standpoint, they
may be thought of as naked genes. ^^ From a chemical stand-
point, they are to be thought of as large molecules (macromole-
cules) of molecular weight 1 to 100 millions.

Thus, one may expect to find analogies between the mechanism
of action of radiations on viruses (at any rate in the case of
the smallest viruses), and chemical effects of radiation, and we
shall therefore recall the outstanding conclusions of the study
of the chemical effects of radiation. \' '^

Chemical Effects of Radiation

If a chemical substance is irradiated in the pure state by
X-rays or alpha rays, the typical result is that approximately
one molecule is decomposed for each ionization produced. It
appears that the ionization of an atom usually leads to the
decomposition of the molecule of which it is a part, a result

155

156 Applied Biophysics

which is not unexpected in view of the fact that the energy
involved in ionization exceeds the binding energy of an atom
in a molecule. This (approximate) result has been established
for substances in the solid, liquid, and gaseous states, and for
substances ranging in molecular weight from about 20 to about
20,000. There are some notable exceptions, but these are prob-
ably to be explained on the basis, on the one hand, of recom-
bination of the products of decomposition giving low yields, or,
on the other hand, of chain reactions giving enhanced yields.

Many substances undergo chemical change when irradiated
in dilute aqueous solution. Among inorganic solutes, reducing
agents are oxidized, and oxidizing agents are reduced, while
organic solutes are usually eventually converted to CO2 and
hydrogen. These reactions in dilute aqueous solution take place
with doses of radiation much smaller than would be necessary
to produce the same percentage chemical change in the solute
if irradiated dry, and the number of solute molecules reacting
greatly exceeds the number of solute molecules directly ionized
by the radiation. Evidently, the ionization of the water is able
to lead to chemical change in the solute, and it is believed ^^
that the explanation lies in the production of free H atoms and
OH radicals following the ionization of the water.

Inactivation of Viruses

Both the direct action of radiation, i.e., chemical change due
to ionization in the molecule concerned, and the indirect action,
i.e., chemical change in the solute molecules due to ionization in
the solvent, have been demonstrated in studies of the inactivation
of viruses by X-rays. Thus, in figure 1,^^ it is shown that in
sufficiently concentrated solution, the dose required to inactivate
a given percentage of a virus is independent of the concentration
of the solution, indicating that in such solutions the direct action
is predominant, but that in sufficiently dilute solutions, the dose
required to inactivate a given percentage of virus diminishes,
showing that in dilute solution, the indirect action predom-
inates.

Action of Radiations on Viruses

157

3

^

/

X

xlO'
2

X

A

1

"* •

/

•

0

■■■^

10*

•y

^

^^y_ -

-

105

B

>

/

•

10*

•

^

«

in'

10'^ I0-* J0"3 I0-'* 10-^ I0"2 IQ-'

FIG 1. Inactivation of Viruses in Aqueous Suspension by X-rays

Abscissae == concentration of solution in grams per milliliter,
Ordinates = inactivation doses in rontgens.

A. Tobacco mosaic virus.^^

B. Shope rabbit papilloma virus.*

(Reproduced by permission of the ^Cambridge University Press)

Macromoleciilar Viruses

The study of the direct inactivation of viruses has so far yielded

results of greater interest than the study of the indirect action,

* and we, therefore, confine our subsequent discussion to the direct

action. If, on the basis of the results of chemical experiments

already mentioned, we are prepared to accept that, in the cases

158 Applied Biophysics

of the macromoleciilar viruses, every virus particle ionized is
inactivated, we are able to use radiation experiments to estimate
the size of the virus particle.

Suppose that D rontgens is the dose which produces an aver-
age of one ionization per virus particle. Since 1 rontgen corre-
sponds to the production of approximately 2 X 10^" ionizations
per gram, D rontgens corresponds to the production of 1 ioniza-
tion per e^rams. This, then, is the mass of the virus

^ 2 X W~D ^

particle.

This calculation, while satisfactorily illustrating the principle,
is somewhat simplified. The ionizations produced in an irradi-
ated material are not distributed spatially at random, as the
above calculation has tacitly assumed, but are localized along
the paths of ionizing particles, as described by Gray. If an
ionizing particle passes through a virus particle, usually more
than one ionization will be i)r()duced in it, the actual number
depending on the diameter of the virus and the ion-density, i.e.,
the number of ionizations produced per micron path, of the
ionizing particle. The ion-density is greater in alpha-ray ex-
periments than in X-ray experiments, and is greater with X-rays
than with gamma rays. We shall, therefore, expect that the
inactivation doses will increase in the order gamma rays, X-rays,
alpha rays, since a radiation which produces several ionizations
in one virus particle, when one would suffice to inactivate it,
is inefficient.

Table I shows that the experimental results ^^ confirm this
expectation for a bacteriophage. Similar results with plant
viruses have been obtained by Lea and Smith. ^-

TABLE I.
Inactivation of Phage S-13

(Phage diameter 16 m\i)

Gamma X- Alpha

rays rays rays

Inactivation dose in millions of rontgens 0.58 0.99 3.5

Inferred "target" diameter in mu 15.5 15.9 16.0

Action of Radiations on Viruses 159

From the experimental inactivation doses, one can calculate
the "target" diameter, i.e., an estimate of the diameter of the
virus based on the hypothesis that an ionization anywhere in
the virus particle will inactivate it. The agreement between the
three estimates of target diameter and their close approximation
to the size of the virus as determined by other methods (centrifu-
gation and filtration) satisfactorily confirms this hypothesis, and,
incidentally, establishes that this bacteriophage is one of the
macromolecular viruses.

Organism-type Viruses

If we attempt to apply the same type of reasoning to a large
virus, we find that the estimates of the target size deduced
from experiments with the three radiations do not agree, and
are all much smaller than the true size of the virus, as shown
in Table 11.^*^ It is evident that the hypothesis that an ionization

TABLE II.

Inactivation of Vaccinia Virus

(Virus diameter 200 m|.i)

Gamma X- Alpha

rays rays rays

Inactivation dose in millions of rontgens 0.080 0.104 0.211

Inferred "target" diameter in mii 31 41 70

anywhere in the virus particle leads to inactivation is incorrect.
It is believed that a single atom ionized can inactivate the virus,
but it must be an atom, not anywhere in the virus, but in certain
radiosensitive constituents of the virus, these constituents com-
prising only a small fraction of the total bulk of the virus par-
ticle. This differentiation between radiosensitive and radio-
insensitive constituents suggests a cell rather than a macromole-
cule, and it is probable that the radiosensitive material is to be
identified with the genes. The fuller analysis of the radiation
data enables an estimate of the number of genes to be made.^^
We are thus led to regard vaccinia not as a naked gene, as

160 Applied Biophysics

was appropriate for phage S-13, and the plant viruses, but as a
single-celled organism with many genes.

Shortly after this suggestion was made, electron micrographs
were published,'^ showing internal structures in the particles of
vaccinia virus, and making it difficult to doubt that the particle
of vaccinia is a single-celled organism rather than a macro-
molecule.

It appears from these examples that radiation experiments
may be of value in elucidating the nature of viruses. Some
recent experiments ^^ on bacteriophages somewhat larger than
S-13 suggest that these are very primitive organisms with only
10 or 20 genes.

Lethal Mutation in Bacteria

Effects of radiation upon bacteria which have been investigated
are, the production of mutations, i.e., permanent changes in form
or color of colony, the reduction of motility, a temporary inhibi-
tion of division, and the lethal action, the great majority of
investigations being concerned with the last mentioned effect.

What is described as a lethal action in these investigations
is the inability of a bacterium after irradiation to give rise to a
colony visible to the naked eye when inoculated on a nutrient
medium. There are, however, distinct differences between the
"killing" of a bacterium by radiation, and killing by other agents,
e.g., heat or chemical disinfectants. Thus, after irradiation, the
bacterium which is rendered incapable of giving rise to a colony
may still be motile,-^ may still be capable of respiration,- and
may, when cultured and examined microscopically, show some
growth. ^"^ In view of these facts, it is probable that one is dealing
with lethal mutation.

The internal evidence of the radiation experiments supports
this interpretation. It appears ^' ^ that a single ionization is able
to "kill" a bacterium, but that, as with the large viruses, it does
not suffice for it to be produced anywhere in the bacterium. It
must be produced in a radiosensitive part which constitutes only

Action of Radiations on Viruses 161

a small fraction of the total bulk of the bacterium, and which is,
on our interpretation, to be identified with the genes.

Inhibition of Division of Bacteria

Ionization produced in a bacterium but not in the genetical
material is not without effect. The most striking effect is a
temporary inhibition of division. Bacteria grown in a nutrient
medium in the presence of a suitable intensity of radiation con-
tinue to grow, in the sense of increasing in volume, but fail to
divide. In consequence, rod-shaped bacteria grow into long
filaments.^

References

1 Allsopp, C. B. (1944) Trans. Faraday Soc. 40, 79.

2 Bonet-Maury, P., R. Perault and M. L. Erichsen (1944) Ann. inst.

Pasteur, 70, 250.

3 Briiynoghe, R. and W. Mund (1935) Conipt. rend. soc. biol., Paris,

92, 211.
4Friedewald, W. F. and R. S. Anderson (1941) /. Exp. Med. 74, 463.

5 Green, R. H., T. F. Anderson and J. E. Smadel (1942) /. Exp. Med.

75, 651.

6 Lea, D. E. (1940) Nature, Lond. 146, 137.

''Lea, D. E. (1946) Actions of Radiations on Living Cells, Cambridge
[in press].

8 Lea, D. E., R. B. Haines and E. Bretscher (1941) /. Hyg. Camb.

41,1.

9 Lea, D. E., R. B. Haines and C. A. Coulson (1937) Proc. Roy. Soc.

B, 123, 1.

10 Lea, D. E. and M. H. Salaman (1942) Brit. J. Exp. Path. 23, 27.

11 Lea, D. E. and M. H. Salaman (1946) Proc. Roy. Soc. B, [in press].

12 Lea, D. E. and K. M. Smith (1942)-^Parasitology, 34, 227.

13 Lea, D. E., K. M. Smith, B. Holmes and R. Markham (1944) Para-

sitology, 36, 110.
1-^ Luria, S. (1939) Compf. rend. acad. sci.. Paris, 209, 604.
i^'^Muller, H. J. (1922) Amer. Nat. 56, 32.
16 Weiss, J. (1944) Nature, Lond. 153, 748.

QUANTITATIVE HISTOLOGICAL ANALYSIS OF
RADIATION EFFECTS IN HUMAN CARCINOMATA

ALFRED GLUCKSMANN, M.D.

Strangeivays Research Laboratory, Cambridge

Introduction

TUMORS of apparently similar histological type and clini-
cal extent in different parts of the body, or even at the
same site, vary considerably in their local response to
radiotherapy. Thus, good results are obtained in cases of car-
cinoma colli uteri, while almost complete failure attends the
treatment of carcinoma of the esophagus. In carcinoma colli
uteri, clinical stage 2,* 60% of the cases are cured for at
least 5 years, while 40% of the cases fail to respond satisfac-
torily.

Attempts to discriminate between the radiocurable and the
radioresistant cases by means of histological grading have led
to widely divergent results.*' ^"'•- ^^ The most anaplastic types
of tumor tissue,-' ^'^ as well as the most differentiated
types, ^' "• ^' -"^ have been found to give the best radiotherapeutic
results — la finding paralleled by the clinical observation that the
highly differentiated keratinizing epitheliomata of the skin and
lip usually respond favorably to radiation treatment, and that
lymphosarcomata and other growths composed mainly of un-
differentiated cells react dramatically to radiotherapy, at least
locally.

* The clinical stages in carcinoma colli uteri are defined as follows:" Stage 1:
The carcinoma is strictly confined to the cervix. Stage 2: The carcinoma infiltrates
the parametrium on one or both sides, but does not extend to the pelvic wall. Stage
3: The carcinomatous infiltration of the parametrium extends to the pelvic wall on
one or both sides. Stage 4: The carcinoma involves the parametrium up to the pelvic
wall and the bladder.

162

Histological Analysis of Radiation Effects 163

These examples, as well as the rather vague and general
statements composing the "nadiosensitivity tables" of
tumors,^' ^^' ^^' ^^ illustrate the difficulties encountered in an
analysis of the factors determining the radiosensitivity of indi-
vidual growths or groups of tumors, and of the likely response
to any particular type and dose of radiation. Although some
general principles have been elucidated by radiobiological re-
search, their application to the practice of radiotherapy is handi-
capped by the hetergeneous collection of nosological entities
lumped under the term "cancer," ^ and also by the essential
differences in biological characters and reactions of much of the
biological material chosen for experimentation and of maligant
cells and tissues.

The study of the local response of various types of neoplastic
diseases to radiation can be undertaken only by investigating
the actual response of individual tumors to treatment, i.e., by
examining serial biopsies taken before, during, and after treat-
ment, and by correlating the histological with the subsequent
clinical and pathological findings. It is useless, however, to com-
pare biopsies taken at random with one another, since owing to
their localization in the tumor, i.e., whether near the necrotic
center or the well-vascularized growing edge, the specimens
from the same tumor may vary as to the proportion of old and
young foci included. To obtain comparable results in serial
biopsies of an individual case, sections should be taken from the
growing edge of the tumor, and in such specimens only the
young areas should be chosen for a detailed examination of the
reaction of the tumor tissue to treatment. Young foci alone
contribute to the further expansion of the tumor ; they possess
the greatest developmental potentialities in any given malignant
growth, and are best able to react to, and to recover from, the
effects of treatment.

If these precautions are taken, reliable and comparable
"samples" of young foci in the tumor can be obtained. In a'
series of about 20 surgical and pathological specimens of various
carcinomata, a number of small pieces of tissue equivalent to
biopsy sections were taken from the growing edge, comparable

164 Applied Biophysics

young areas were selected in each piece, and their cell population
was classified and counted. The average coefficient of variation
from the mean in the various pieces for any given tumor was
of the order of 10%.^^ Similar observations have been recorded
for the histological grading of various biopsies taken from the
same tumor.^* ^^' ^^

The cellular population of tumors varies with tumor type.
In most epithelial growths, 4 classes of cells can be distin-
guished according to their viability. There are 2 classes of viable
cells :

A : The resting cells, which are the intermitotic "stock" cells
capable both of division and differentiation (depending on the
tumor type). They are relatively small, with a large, often
hyperchromatic, nucleus and with little and basophilic cytoplasm.

B : The mitotic cells, i.e., stock cells actually in division.

There are also two classes of nonviable cells :

C: The differentiafijig cells, which are cells rendered per-
manently incapable of division by the differentiation of their
cytoplasmic structures. Most of these cells are large, with a
great amount of differentiating cytoplasm and a relatively small
vesicular nucleus.

D : The degeneraiing cells, which are the cells in the process
of disintegration. Their structure changes according to the form
of degeneration (fatty, mucoid, parakeratotic, etc.), and to the
cell type from which they are derived.

Very immature growths lack the differentiating cells. Figure
1 depicts diagrammatically the main characteristics of these four
cell categories and their relationship w^ith each other, as indi-
cated by the arrows. The cellular composition of the foci is
influenced by the tumor bed, i.e., the vessels, stroma, and cells
surrounding the tumor strands, which promotes or inhibits
mitosis, differentiation, and degeneration.

Young foci are formed by finger-like projections from tumor
strands, and are characterized by the presence of many mitotic
cells, the preponderance of resting cells, and the dissolution of
the basement membrane at the growing tip of the projection.
The comparison of young foci in serial biopsies is best made

Histological Analysis of Radiation Effects

165

quantitatively by classifying and counting all the cells in care-
fully selected young areas. The cell counts are plotted as per-
centages against time after beginning treatment, and thus a chart
is obtained of the response of a given tumor to a given type of
treatment. ^^

C D

FIG. 1. Diagrammatic Representation of the Four Cell Categories Found in

Most Epithelial Tumors

viable cells.

A: Resting cell |
B: Mitotic cell |
C: Differentiating cell 1
D: Degenerating cell \
T: Symbolizes the tumor bed, i.e., the vessels, stroma, and cells surrounding the
tumor strands.

lonviable cells.

Changes in the cell population of young tumor foci are the
result of direct and of indirect effects of radiation. The direct
effects concern mainly resting and dividing cells. After a tran-
sient mitotic inhibition, resting cells may break down on attempt-
ing division, they may differentiate according to their type and

166 • Applied Biophysics

potentialities, or they may disintegrate immediately after ex-
posure. Enlargement of resting cells often follows an irradia-
tion.

After a period .of mitotic inhibition, cell divison may be
resumed with varying degrees of abnormality. A sufficiently
high dose of radiation delivered at a high intensity may cause
the immediate disintegration of mitotic cells. The direct effects
of radiation thus cause a diminution in number of resting and
dividing cells and promote the "aging" of cells and foci. Apart
from some increase in cell size, the efifect of radiations on cells
in the early stages of differentiation has not yet been precisely
determined.

The indirect effects of radiation are due to the interference
with the vascular and connective-tissue system of the tumor,
and to the induction or exacerbation of inflammatory reactions.
Insufficient blood supply affects the process and the incidence of
cell division, and may cause the disintegration of cells. The
inflammatory reaction leads to the infiltration and the breaking
up of tumor strands by round cells, followed by the formation
of fibrotic scars.

The aim of radiotherapy in malignant disease is to convert
viable into nonviable cells, i.e., to induce the breakdown of
dividing cells and to prevent cell division, to cause the immediate
disintegration of resting cells, or their permanent sterilization by
differentiation. The observed radiation changes in malignant
growths vary according to the tumor type and the dose, dose
rate, and time interval between a given dose and the biopsy
excision. Some types of reaction of young foci to radiotherapy
are illustrated in figures 2 to 5.

Figure 2 represents the reaction chart of a basal-celled car-
cinoma of tile temple treated by a dose of 3,200 r of X-rays
given in 13 days. Cell counts made in selected young foci of
serial biopsies show a diminution and finally a disappearance of
mitotic cells and an initially slow and later rapid disintegration
of resting cells. Clinically, the lesion responded well to treat-
ment and remains healed. This case illustrates the response of
undifferentiated tumor cells to radiotherapy by mitotic inhibition.

Histological Analysis of Radiation Effects

167

degeneration of mitotic cells, and the disintegration of the "aged"
resting cells. A few of the resting cells were apparently killed
directly by the radiation.

The charts in figures 3 to 5 refer to cases of epithelioma
(carcinoma) colli uteri, clinical stage 2, treated by radium
insertions on days 0, 7 and 21 by a modified Stockholm
technique.

Figures 2 to 5 show cell counts in young foci of serial biopsies
taken from the growing edge of tumors before and during
radiation treatment. In these figures :

Abscissae = time in days.
Ordinates = cell counts %.
Viable cells:

^^^^M^i^^^^i^^ii^^ resting cells.
^HMKm^^ M ^^^^H^^Hmitotic cells.
Nonviable cells:

differentiating cells.

degenerating cells.

80 _

40 -

20

FIG. 2. Reaction Chart of Basal-Celled Carcinoma

168

Applied Biophysics

Figure 3 shows the reaction chart of a favorably-responding
tumor which was an epithelioma with keratinized foci,
Broders grade 2.* The maHgnant tissue reacts rapidly to
treatment, with a marked increase in number of dififerentiating

80

40 -

FIG. 3. Reaction Chakt of Epithelioma

cells which subsequently disintegrate. The mitotic and resting
cells decrease in number and disappear. Clinically, healing of
the lesion was noted after 3 months and the patient has remained
well and symptom-free for 5 years.

Figure 4 represents the reaction to treatment of another epi-
thelioma of the cervix uteri, clinical stage 2, Broders grade 3.
The effect of 3 radium insertions in this case is approximately
equal to that of a single insertion in the case of figure 3, i.e.,
there is some reduction in the percentage of viable cells and a
corresponding increase in the percentage of nonviable cells. This
change does not, however, lead to the complete disappearance
of viable cells, and the tumor tissue is thus able to recover from

* Broders's histological grading of malignancy is based on the degree and extent
of cell dedifferentiation. The least malignant, i.e., the most differentiated form, con-
stitutes grade 1 and consists of 0% to 25% of dedifferentiated cells. Grade 2 contains
25% to 50%; grade 3, S07o to 75%; and grade 4, 75% to 100% of dedifferentiated
cells.

o

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170 Applied Biophysics

the radiation effects. This chart indicates a merely temporary
inhibition of growth of the tumor tissue. Qinically, the lesion
appeared to heal and there was no evidence of growth 6 months
after treatment. The tumor reappeared later in the treated area
and caused the death of the patient 16 months after the beginning
of treatment.

Figure 5 illustrates the reaction to treatment of another epi-
thelioma of the cervix uteri, clinical stage 2, Broders grade 3.
There are only minor fluctuations in the cell counts, and the
chart indicates the persistence of tumor activity almost unchanged
by the type of radiation treatment given. Clinically, however,
the lesion appeared to be healed after 3 months. Three months
later a "recurrence" of the tumor in the treated area was diag-
nosed, and the patient died 6 months later with growth in the
treated area and wath extensions.

In these 3 illustrative cases of carcinoma colli uteri (figures
3 to 5 ) , the lesion appeared to be healed 3 to 6 months after treat-
ment, although in 2 of the cases the histologioal-reaction chart
( figures 4 and 5 ) indicated the persistence of active tumor
growth. In both these cases, the tumor recurred subsequently.
In a series of 150 cases of carcinoma colli uteri, 26 cases reported
clinically satisfactory during the first 4 months after treatment
developed a "recurrence" during the succeeding 8 months ; in
each case the reaction chart, obtained within 3 weeks of beginning
treatment, indicated the persistence of tumor activity. ^^

The histological findings based on a quantitative analysis of
the cell population of young foci in serial biopsies seem to give
a reliable and early indication of the likely outcome of radio-
therapy in individual cases, whereas clinical healing is useful
as criterion in the evaluation of therapeutic results only if it
persists for the conventional period of 5 years. Practically all
tumors shrink to some extent under treatment — presumably
owing mainly to the damage inflicted on parts of the vascular
system supplying the growth and to its sequelae — and this shrink-
age allows of the restoration of the normal anatomical configura-
tions in spite of the persistence of active, microscopic tumor foci.
Decrease in tumor volume of itself is no real measure of the

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171

172 Applied Biophysics

efficiency of therapy. As with surgery, radiation treatment of
cancers aims at the complete ehmination or steriHzation of viable
tumor cells, and a 90% success of therapy is ultimately a failure.
The histological-reaction charts (figures 2 to 5) are measures of
tumor activity, and bear no relation to the actual size of the
tumor at the time of the biopsy excision.

The persistence of active microscopic tumor foci in appar-
ently restored sites is the reason why, shortly after treatment,
the histological findings may be at variance with the results of
clinical examinations. Agreement becomes, however, closer with
the lapse of time. For example, in the series of 150 cases referred
to,^- there was agreement between histological and clinical find-
ings in only 50% of the cases after 4 months and in 80% of
the cases 2 years after treatment.

Apart from showing within 3 weeks of beginning treatment
whether or not the aim of therapy is being realized, the histo-
logical analysis gives some useful information about the way in
which the therapeutic results are obtained. In cases like that
of figure 2, the successful treatment is due in particular to the
"mitotic'' eflFect of radiation, i.e., the mitotic inhibition and to
disintegration of dividing cells ; this prevents the further forma-
tion of resting cells which consequently age and, having reached
the limits of their short span of life, die. Some resting cells
are also killed immediately by the radiation and others fall
victims to unfavorable conditions in the tumor bed induced by
radiation.

In epitheliomata like that of figure 3, the mitotic and vas-
cular effect of radiation is supplemented by the "diflferentiation"
effect, i.e., resting cells are forced (either directly or secondarily
to mitotic inhibition) into differentiation, and are thus sterilized.
This observation suggests that the capacity for differentiation in
resting malignant cells and its stimulation by radiation may be
one of the factors in the "radiosensitivity" of tumor tissue.

An indication of the capacity for differentiation of the tumor
tissue — though not of its reaction to radiation — may be gained
from the presence or absence of differentiated foci in the pre-
radiation biopsy of the tumor. Histological classification as to

Histological Analysis of Radiation Effects 173

degree of differentiation of such specimens shows that, cHnical
conditions and treatment methods being equal, the results of
radiotherapy tend to be more satisfactory in the cases with
more differentiated tumor tissue.^- The physical factors of radia-
tion, such as time, dose, dose rate, and type of ray, which are
most likely to elicit differentiation in cells with such potencies,
are as yet little known and understood. It appears feasible that
favorable results may be obtained with changes in technique
in those groups of tumors which so far have proved refractory
to treatment.

There are various limitations in the application of the quantita-
tive histological method of analysis of radiation effects in indi-
vidual cases of malignant disease. Thus, conclusions about a
favorable response to treatment must be limited to the reaction
of the growth in the treated area, presupposing that the radiation
energy was fairly uniformly distributed in this area. In spite
of cures in the treated area, the clinical issue may, of course,
be compromised by the presence of untreated metastases, or even
by fatal hemorrhages due to radiation damage inflicted on the
vascular apparatus. Certain types of cancer are systemic dis-
eases with local manifestations, and obviously the cure of one
of these manifestations cannot prevent the formation of new ones
which may even arise in neighboring precancerous lesions.

Conclusions

To summarize : the quantitative histological examination of
serial biopsies of human tumors provides a useful guide in the
evaluation of the therapeutic result in individual cases. As a
research method, it facilitates the analysis of the "radiosensi-
tivity" of an individual growth, makes possible the study of the
factors influencing the response of a given tumor to a given type
of treatment, and provides a basis for the understanding of
radiation effects on tumor tissue of different types and for the
better knowledge of the natural history of malignant diseases.
The combination of such knowledge with relevant data con-
tributed from radiobiological research is the necessary require-

174 Applied Biophysics

ment for progress in the radiotherapy of neoplastic diseases.
Ewing '^ has pointed out that "there is little significance in dis-
cussing the curability of cancer as a whole. The discussion has
real meaning only when the different types of cancer are con-
sidered separately as nosological entities."

References

1 Blady. J. V. and W. E. Chamberlain (1944) Amer. J. Roentgenol.

51, 481.
2Borak, I. (1932) Strahlcniherapie, 44, 601.

3 Broders, A. C. (1940) in Treatment of Cancer and Allied Diseases,

edited by G. T. Pack and E. M. Livingston, New York, 1, 19.

4 Coutard, H. (1934) Lancet, 2, 1.

»Desjardins, A, U. (1938) in MacKee, G. M. : X-rays and Radium
in the Treatment of Diseases of the Skin, London, p. 255.

6 Evans, N., R. W. Barnes and A. F. Brown (1942) Arch. Path. 34, 473.

'''Ewing, J. (1940) in Treatment of Cancer and Allied Diseases, edited
by G. T. Pack and E. M. Livingston, New York, 1, 3.

8 Ewing, J. (1941) Neoplastic Diseases, Philadelphia and London.

9Fricke, R. E. and H. H. Bowing (1941) Amer. J. Roentgenol. 46, 683.

10 Glucksmann. A. (1941) Brit. J. Radiol. 14, 187.

11 Glucksmann, A. (1946) in Recent Advances in Clinical Pathology [in

press].

12 Glucksmann, A. and F. G. Spear (1945) Brit. J. Radiol. 18, 313.

i-"* Healy, W. P. (1928) Report of International Conference on Cancer,

London, p. 86.
14 Heyman, J. (1938) Atlas Illustrating the Di^'ision of Cancer of the

Uterine Cervix into Four Stages, Stockholm.
1^ Heyman, J., O. Reuterwall and S. Benner (1941) Acta Radiol.,

Stockh. 22, 14.
i«Patey, B. H. and R. W. Scarff (1928) Lancet, 1, 801.
17 Patterson, R. (1933) Brit. J. Radiol. 6, 218.
1^ Patterson, R. (1936) Brit. J. Radiol. 9, 671.

19 Phillips, R. (1931) Lancet, 1, 118.

20 Regaud, CI. (1928) Report of International Conference on Cancer,

London, p. 64.

21 Warren, S. (1931) Arch. Path. 12, 783.

22 Warren, S. (1941) Amer. J. Roentgenol. 45, 641.

THE MEASUREMENT OF RADIATION

G. J. NEARY, M.A., Ph.D.

Physics Department, Mount Vernon Hospital and

The Radium Institute, ISorthwood, Middlesex

Introduction

A COMPREHENSIVE discussion of the whole of the vast
field which might be implied in the above title is clearly
out of the question here, so the present remarks will be
arbitrarily confined to the subject of ionizing radiation, around
, which most interest is centered in the present context, leaving
aside entirely the question of ultraviolet, infrared, and "short
wave" radiations, which are of no less importance in biology
and therapy.

By "ionizing radiations." we mean those types of radiation
which in their interaction with matter are able, by virtue of
their high intrinsic energy, actually to disrupt the individual
atoms or molecules by the splitting-off of an electron. The
electron thus set free quickly attaches itself to some other mole-
cule, and so, dispersed among the normal electrically neutral
molecules, there appear positively and negatively charged mole-
cules or clusters known as ions, which may exist independently
in the medium for considerable lengths of time, and endow it
with the property of electrical conductivity.

If left to themselves, the ions will gradually neutralize each
other, but the exact status quo may not be restored, for obviously
the chance that various types of atomic and molecular rearrange-
ment, i.e., chemical change, will occur is considerable. It is
believed that such changes caused by ionization are the more
immediate causes of the biological efifects produced. On the
other hand, by the application of sufficiently large electric field, it

175

176 Applied Biophysics

may be possible, in a gas at any rate, continuously to remove
the ions to the two electrodes almost as fast as they are produced
by the ionizing radiation, before any appreciable recombination
can take place. The electric current in such circumstances is
called the "saturation current" and, in most cases arising in
practice, it is very minute.

Examples of ionizing radiations are the electromagnetic type
as in X-rays, and the gamma rays from radioactive substances,
the swift electrons in cathode rays and the beta rays from
radioactive substances, protons, alpha particles, etc., the neu-
trons, all of which have a similar ultimate mode of action in
biology.

The necessity for some system of measurement of radiation
in biological and therapeutic studies need hardly be emphasized,
but in practice it has proved an exacting pursuit, aptly illustrat-
ing Kelvin's historical remark that no phenomenon can be
understood till it can be measured and expressed in numerical
terms. The difficulties lie in deciding on, and realizing prac-
tically, a suitable measure of "amount" of radiation, and arise
partly from that common feature of the radiations which is most
obvious, namely, their power of penetrating matter, and partly
from the very small amounts of energy involved. For example,
the total amount of energy communicated to the tissues in a
typical complete therapeutic treatment would suffice only to
augment the temperature of the mass by about one hundredth
of a degree Centigrade.

To keep our discussion to a reasonable length, it will be
necessary to confine ourselves to what is by far the most
important method in this branch of radiation measurement, the
ionization method, and to concentrate on the principles involved,
omitting detailed descriptions of techniques. In an adequate
historical account, considerable interest would attach to the
photographic method of measurement,* but here, we merely
remark in passing that it has been developed as a precision
technique only in certain rather restricted fields, though it

* Some of the earliest dosimetry was done by finding the time required to
photograph a hand!

The Measurement of Radiation 177

remains a very useful and often simpler alternative to the ioniza-
tion method when high accuracy is unnecessary — for example,
in the recording of stray radiation in questions of staff protec-
tion. Other methods, such as chemical methods, change of color
or fluorescence of salts, selenium cells, etc., proved unsatisfactory
and are of historical interest only.

Again, comparative studies have been made by using some
standard biological test material, for example, Drosophila eggs,
but it is clear that far greater importance attaches to the more
fundamental problem of relating biological effects to the radia-
tion producing them, evaluated in precise physical terms. The
radiations hitherto most commonly met with are X-rays and
the gamma rays of radium, and they will, of necessity, occupy
most of our attention.

X- and Gamma Radiation

Quantum Character and Interaction with Matter

These radiations are different examples of essentially the
same type of radiation, and it may not be out of place to
state briefly some of the most important facts relating to their
interaction with matter. The radiation is electromagnetic in
character, propagated with the speed of light. For our purpose,
it is best to concentrate on the quantum character of the radia-
tion, i.e., the energy of the beam of radiation is concentrated
in discrete units rather like a hail of bullets, the amount per
unit being given by Einstein's equation

E=hv

c

where h is Planck's universal constant, and v = — , where v, X

and c are the frequency, wave length and velocity of the radia-
tion, the latter also being a universal constant. These quanta,
or photons, interact with matter in several different ways :

1. ''Unmodified/' or Thomson scattering. A quantum is
merely deflected from its course without loss of energy by an

178 Applied Biophysics

individual electron, so that a unidirectional beam becomes diffuse.
Unmodified scattering is not of great importance in our present
considerations.

2. "Modified;' or Compton scattering. A quantum '^collides"
with an individual electron, projecting it in one direction while
itself rebounding in another (and related) direction, with a
reduced energy (and. therefore, longer wave length) depending
on the direction taken. The detailed theory of the fractions of
the energv of an incident beam of quanta imparted to the recoil-
ing electrons and scattered quanta and their angular distribution
has been given by Klein and Nishina, and is in very good agree-
ment with experiment. The phenomenon is only slightly affected
by the atomic number of the substance.

3. Photoelectric absorption. A quantum is absorbed com-
pletely by the atom as a whole. Nearly all the energy (a very
small fraction is expended in atomic recoil) is expended in
extracting an electron from the atom and endowing it with
kinetic energy. The phenomenon is practically completely de-
scribed by theoretical and empirical relations. The fraction of
energy of the incident beam converted, reckoned per electron,
is approximately proportional to the cube of the atomic number,
i.e., the effect is much more pronounced in "heavy" than in
"light'' elements. Apart from certain well-understood discontinui-
ties, the energy conversion varies roughly as the cube of the
wave length of the radiation, i.e., it becomes less important for
higher quantum energies.

4. Various nuclear effects. Production of electron and posi-
tron pairs and nuclear disintegrations becomes of importance
only for quanta of high energy. These effects are practically
negligible even for radium gamma rays. They vary with the
atomic number of the nucleus.

These processes all contribute to a removal of quanta from
a beam ; the fraction of the energy removed is termed an absorp-
tion coefficient, and may be reckoned per electron, per unit mass,
or per unit volume of the material.* Some of the energy is

* The absorption coefficients of any one atomic type are practically independent
of its state of chemical combination.

The Measurement of Radiation 179

imparted to fast electrons, the so-called "corpuscular emission."
It is these swift secondary electrons which actually ionize and
excite the atoms and molecules of the medium.

The Concept of Quality

The "quality" of a beam of radiation refers to its intrinsic
characteristics such as wave length, or quantum energy. It may
be investigated exactly by spectrographic methods (crystal
diffraction ) or by measurements of the energy of the secondary
electrons produced in matter. A quick practical method, par-
ticularly useful for approximate results with heterogeneous
beams, is to measure the absorption or attenuation of the radia-
tion in some suitable standard substance, from which an average
or effective wave length of the radiation may be estimated.
Thus, it is usual to quote the half-value layer (HVL) of a
given beam of X-rays in aluminum, or copper, i.e., the thickness
of material required to reduce the "intensity" (dose rate, see
below) to one half.

By suitable developments of these principles, it is possible in
some cases to form an estimate of the effective wave length
of the diffuse radiation produced during the passage of a beam
through matter. Thus, the measurement of "quality" is achieved
by the application of familiar physical ideas and need not be
dealt with here in detail. It may be mentioned in passing, that
the particular aspect of quality of greatest biological significance
is the spacing of the ions along the tracks of the ionizing par-
ticles, the "ion density." As the energy of the ionizing particle
becomes less, the shorter the interval between successive ions.

The Concept of Quantity or Dose

When we come to the question of "quantity," it is necessary
to break new ground. Normally, "amount" of radiation is ex-
pressed in terms of intensity, defined as quantity of energy
flowing through unit area of the beam per unit time, but any
arbitrary measure of "amount" related to this, however in-

180 Applied Biophysics

directly, would serve. Obviously, it is desirable to choose as a
measure that physical quantity which stands in the closest
relationship to the biological effects produced by the radiation.
By making a shrewd choice in this matter, the interrelation of
physical cause and biological effect will not be obscured by a
long chain of essentially irrelevant intermediate processes.

There is general agreement that the key quantity is the ioniza-
tion produced in the biological substance. With a few exceptions,
however, it has for technical reasons proved quite impracticable
to measure the actual ionization in a solid or liquid, but a
quantity which is almost as acceptable as ionization, as a
measure of the radiation, is the energy communicated to the
medium. The reason for this is that the proportion of this
energy which goes to the production of ionization is probably
independent of the quality of the radiation — this is certainly
almost exactly true for air, where about half the energy goes
to the production of ionization, the rest being expended in
excitation, and thus the ionization is known apart from a
constant of proportionality characteristic of the medium. In one
of the very few investigations of a liquid, in this case carbon
disulphide, Taylor has shown that the proportion of energy ex-
pended in ionization is not greatly different from that expended
for air. In actual fact, however, the direct measurement of the
energy communicated to the medium is also well-nigh impossible
because of the minute amount required even for the most extreme
biological effects. We shall see later how it is possible to derive
this energy from other measurements.

The Rbntgen

With these general ideas in mind, it is easy to see why, in
actual historical fact, the ionization produced in air came to be
adopted as a measure of radiation, partly as a matter of ex-
pediency on account of the relatively simple technical problems,
and partly because it was realized that, on account of the
general similarity of the atomic types in air and tissue, the
energy conversion of X- and gamma radiation in these two

The Measurement of Radiation 181

media would be roughly parallel for all qualities. If the average
atomic mmibers of two media are fairly close, then the relative
importance of any one type of energy-conversion process (Comp-
ton, photoelectric, etc.) will be similar in the two media, and
so the variation of the gross energy conversion with quality will
be similar for the two media.

Thus Villard in 1908 first suggested a unit based on air ioniza-
tion : that quantity of radiation which, by ionization, liberates one
electrostatic unit of electricity per cubic centimeter of air under
normal conditions of temperature and pressure. Much work re-
mained to be done, however, before a satisfactory realization of
the idea underlying this proposal was possible. Much of the
difficulty lay in the phenomenon of the ''wall effect" of the ioniza-
tion chamber. The radiation causes the emission of secondary
electrons from the walls of the chamber, so that the observed
ionization in the air of the chamber, instead of depending uniquely
on the radiation itself, is determined by a complex set of factors
such as the nature of the walls and the size of the chamber. The
surmounting of these difficulties and the development of the
theory of the ionization chamber will be referred to later.

The necessity for general agreement on a satisfactory unit
became ever more pressing, and in 1923, the first steps were
taken by the British Rontgen and Physical Societies. Discus-
sions followed with the first international congress of radiology
in 1925, and finally matured at the second international congress
in 1928. The unit of X-ray quantity, or dose, called the "ront-
gen" (symbol, r) was defined as "the quantity of X-radiation
which, when the secondary electrons are fully utilized, and the
wall effect of the chamber is avoided, produces in 1 cubic centi-
meter of atmospheric air at 0° C and 760 millimeters mercury
pressure, such a degree of conductivity that one electrostatic unit
of charge is measured at saturation current."

The ''Free-air" Chajnber

In order to make measurements in accordance with this
definition, a rather special technique is necessary, namely, the

182 Applied Biophysics

use of the "free-air" chamber. A narrow beam of radiation,
accurately defined by a diaphragm, is passed through a large
chamber of air and out through a hole in the far end, completely
avoiding the walls. A iniiform electric field between two parallel
plates on either side of the beam collects the ions as fast as they
are formed. A measurement is made of the current to a small,
separately insulated section near the middle of one plate. The
length of this section and the cross-sectional area of the beam
define an effective "ionized volume" of air, so the ionization
current per cubic centimeter of air may be deduced — that is,
the dose rate in rontgens per second.*

The details of such a measurement call for very careful
attention, but an intercomparison of the various national stand-
ards in 1931 showed that there was agreement to within -^%.

The ''Thimble" Chamber

Parallel with these developments was the gradual emergence
of the small ionization chamber, the so-called "thimble" cham-
ber, the theory of which will be referred to below. The "free-
air" chamber is clearly a special laboratory instrument and,
further, is inapplicable to the measurement of the diffuse radia-
tion produced when a beam enters matter. It was realized that
the difficulty of the wall-effect of a "thimble" chamber would
not arise if the material of the walls themselves behaved like
air in its interaction with the radiation. It was hoped that a
chamber with walls, the effective atomic number of which, in
relation to the photoelectric process, was the same as that of
air, would give readings exactly paralleling those of the "free-
air" chamber for any quality, i.e., that it would be "wave length
independent." Unfortunately this is not strictly borne out in
practice, the precise reasons for the discrepancy still not being
fully understood.

However, by suitable choice of such factors as the materials

* If the cross section of the beam at the defining diaphragm is used in the
calculation of the ionized volume, tlien the dose rate so deduced refers to the
strength of the beam at the diaphragm.

The Measurement of Radiation 183

of the wall and the central electrode, the wall thickness and
chamber size, it has proved possible to produce empirically
chambers having a sufficiently close response to that of the
"free-air" chamber, and the chambers can be calibrated to read
directly in rontgens. The precise quality of the very hetero-
geneous radiation within a given medium is not in general
calculable, or even easily measurable, and so it is of great prac-
tical importance that the "thimble" chamber to be used should
not require an appreciable quality correction. It is clearly also
of importance that the chamber should be as small as possible
in order to define closely the .precise location of the measure-
ment, and that it should be sufficiently transparent to the radia-
tion not to produce an appreciable "shadow."

Doserneters

"Thimble" chamber dosemeters may be used in the direct
measurement of dose rate or of dose. In the first case, the
actual ionization current is determined by measuring the voltage
drop across a high resistance. In the second case, the ionization
current is allowed to charge a condenser, the final voltage of
which is a measure of the total dose. In either case, a sensitive
voltmeter of the electrometer type is likely to be required. All
insulations must be of very high standards, for the currents
dealt with are very small, for example, the relatively high dose
rate of 1 rontgen per second produces in a chamber of 1 cubic
centimeter volume a current of only one three-thousandth of a
microampere. In some instruments, the ionization chamber,
electrometer system, and recording mechanism are permanently
connected, often with long cables, so that readings may be taken
at relatively long distances from the point of measurement.

In the condenser-dosemeter, the ionization chamber is entirely
separate from the electrometer and measuring devices during
exposure to the radiation. The ionization current serves partially
to discharge the originally fully charged capacity formed by
the chamber itself, and any added condenser. The charge lost
is thus ^ measure of the dose, This type of chamber is particu-

184 Applied Biophysics

larly suitable for direct use in body cavities during therapeutic
treatment. Very compact vmits have been developed, with small
ionized volume and large electrical capacity, so that large doses
can be measured. Chambers are now being used inside needle-
like sheaths which can actually be inserted into the tissues,
during treatment. Condenser chambers have the advantage that
several may be used simultaneously, so that an extended field
of radiation may be rapidly surveyed. Another particularly suit-
able application is the so-called ''protection chamber" for record-
ing the dose received by workers owing to small amounts of
stray radiation.

The Meastirement of Gamma Rays in Rontgens

To turn again to the more theoretical side of radiation
measurement, the desire to measure gamma radiation in rontgens
has resulted in great advances in the understanding of the
ionization chamber and of the energy exchange between radia-
tion and matter generally. Special interest attached to the prob-
lem of the gamma radiation from radium, in particular the dose
rate produced by 1 milligram of radium at 1 cubic centimeter,
when filtered by 0.5 millimeter of platinum (to cut out the
primary beta radiation) — the so-called specific gamma-ray dose
rate of radium.

As early as 1931, Mayneord ^^ estimated this quantity from
the known energy output of the radium gamma radiation (ob-
tained by calorimetric measurements by Ellis and Wooster),
and from the known absorption coefficient of air, to be 8.7 r
per hour, and a measurement with a "thimble" chamber cali-
brated by comparison with an X-ray dosemeter gave 9.2 r per
hour, in reasonable agreement. Mayneord, in 1933,^^ further
estimated this quantity from Eve's constant (the number of ion
pairs per second per unit volume produced in air at 1 cubic
centimeter from the quantity of radium C in equilibrium with
1 gram of radium) as 8.9 r per hour. But at the same time,
attempts to measure the specific gamma-ray dose rate directly
with "free-air" chambers led to values of only about one-third

The Measurement of Radiation 185

of the above, so that there was considerable fear that the ex-
pression of gamma-ray quantity in rontgens was without
meaning.

This disharmony was resolved by Kaye and Binks in 1937/^
who showed conclusively that on accotmt of the large range in
air of the secondary electrons produced by the gamma radiation,
the dimensions of the ''free-air" chamber need to be very much
greater than in the case of X-radiation, for the equilibrium in-
tensity of the secondary electrons to be reached, and for their
energy to be fully utilized in producing ionization. The current
obtained from the "free-air" chamber with gamma radiation no
longer originates in the simple "ionized volume" as in the case
of X-rays but, provided the dimensions are large enough, a
geometrical argument shows that full compensation exists and
the same simple calculation is valid. Kaye and Binks ^^ found
a value of approximately 8.0 r per- hour for the specific gamma-
ray dose rate of radium.

Friedrich provided further confirmation in 1938 '^ by measur-
ing the ionization in a small thin-walled chamber suspended in
air in the center of a large hall, so that it was influenced solely
by the secondary electrons (in ec[uilibrium) produced in the air.
In this way, a value of 7.8 r per hour was found for the constant.
Lastly, Taylor and Singer in 1940 "^ made very precise measure-
ments with a "free-air" chamber operated at ten atmospheres'
pressure, in order to reduce the size, and obtained the figure
8.16 r per hour. All doubts as to the legitimacy of measuring
gamma rays in rontgens have thus been finally dispelled.

True Energy Absorption and the Theory of the
''Thimble'' Chamber

Of greater fundamental physical importance, however, was
the work on the "thimble" chamber method of measurement,
referred to several times above. The essence of this idea was
provided in 1911 by Bragg,^ rediscovered by Fricke and Glasser
in 1925,^ and again independently by Gray in 1929. Innumer-
able other workers have made contributions of various kinds, but

186 Applied Biophysics

it was only after Gray's detailed treatment that an adequate
insight into the problem was attained, and the idea of radiation-
dose advanced a stage further than the rontgen unit.

It must be borne in mind that the rontgen is solely a measure
of exposure to radiation — it merely describes what the beam
of radiation will do in air, and not what it will do in any other
medium, although it gives a good approximate guide to the
latter in the case of light elements, such as occur, for example,
in tissue. Furthermore, the energy absorption in a medium
other than air cannot in general be calculated from the rontgen
dose by correcting with the ratio of the absorption ( "energy
conversion") coefificients of the medium and air, because nor-
mally the quality of the radiation, on which these coefficients
depend, is unknown.

Gray's theory removes this element of vagueness, for it enables
the actual energy communicated to any medium to be deduced
from measurements of the ionization produced in a small gas-
filled cavity in that medium. If E is the energy communicated
to the medium per unit volume, J the ionization per unit volume
of the gas-filled cavity, and q the ratio of the rates at which
a secondary particle loses energy in the medium and in the
gas of the cavity, and W is the average energy expended by the
secondary particles in producing an ion pair in the gas of the
cavity, then

E = eWJ

The detailed derivation and exposition of this relationship,
called by Gray the "principle of equivalence" must be sought
in the original publication. There are certain restrictions : (1 ) the
fraction of their energy lost by the secondary particles in cross-
ing the cavity must be negligible;* (2) the cavity must be
surrounded on all sides by a thickness of the medium at least
equal to the maximum range of the secondary particles ; (3) the

• Restriction (1) is unnecessary if the gas in the cavity is of the same constitu-
tion as the walls.

The Measurement of Radiation 187

strength of the beam of radiation must be sensibly uniform
over the cavity.*

In some cases, particularly in the ordinary X-ray region,
the behavior of small "thimble" chambers appears to deviate
from the foregoing analysis. On general grounds, it may be
presumed that the conditions attaching to the principle of
equivalence have not been fulfilled in these cases. Although
the deviations are not usually large, and the use of such chambers
can be avoided in practice, yet the effects are of considerable
intrinsic interest and have received much attention.

The Redejxnition of the Rontgen and the Extrapolation Chamber

With the development of the work on the measurement of
gamma radiation, the need was increasingly felt for a rewording
of the definition of the rontgen. One reason was the desirability
of admitting the "thimble" chamber, previously excluded by the
clause about avoiding wall effect, as a valid device for measur-
ing in rontgens, but more important was the practical necessity
to disentangle the fundamental dose unit from the complexities
surrounding the actual ionization in air in certain conditions.

For example, because of the relatively long range of the sec-
ondary electrons produced by gamma radiation, the ionization
at any point may not bear any simple relation to the strength
of the radiation beam there, i.e., the energy actually communi-
cated to the medium at a given point may not come from energy
conversion of the radiation at this point, but from various points,
depending on the geometry of the environment. Normally, a
complete compensation exists, and^the energy converted is equal
to the energy communicated to the medium at the same place,

* Strictly, it must be sensibly uniform throughout all that part of the medium
from which secondary particles can reach the cavity. One particular application
of the theory is to determine the specific gamma-ray dose rate of radium by measure-
ments with a "thimble" chamber. For a chamber wall of light elements, for ex-
ample, graphite, the energy conversion of this quality of radiation is the same (per
electron) as for air. Thus, by correcting the observed ionization in the chamber,
according to the quantity q (which is known), the ionization in a true "air wall"
chamber is deduced. The specific gamma-ray dose rate of radium determined in this
way is very close to 8.4 r per hour.

188 Applied Biophysics

but this will not strictly obtain ( 1 ) if the strength of the radia-
tion varies appreciably over a distance comparable to the max-
imum range of secondary particles reaching the point, or (2) in
the region of a boundary between two different media. The
question in such cases, therefore, is whether "energy conversion"
or "energy communication" is to be adopted as the measure of
dose. From the point of view of biological effect, the latter
quantity is the important one. while the former is, logically
speaking, irrelevant, but far simpler to deal with in practice,
and it was adopted at the fifth international congress of radiology
in 1937.

**The rontgen shall l^e the quantity of X- or gamma radiation
such that the associated corpuscular emission per 0.001293 gram
of air (the mass of 1 cubic centimeter of air at 0° C and 760
millimeters of mercury pressure) produces, in air, ions carrying
1 electrostatic unit of quantity of electricity of either sign."

This is effectively the same as the 1928 definition with cer-
tain ambiguities removed.

In a detailed consideration of the biological effects of radia-
tion in the borderline cases referred to above, it is necessary
to bridge the gap between a knowledge of the energy conversion
in air and the energy actually communicated to the medium.
For this purpose a very thin-walled chamber is used, the ioniza-
tion in which gives an indication of the secondary particles
(the "corpuscular emission") effective at the point.* The
"extrapolation" chamber introduced by Failla ^ is of this type.
The procedure is to take observations with a gradually decreased
spacing between the walls of the chamber, and extrapolate the
results to obtain the value for a chamber of negligible width.
With the very high-energy X-rays that can now be produced by
the betatron, studies of this kind, particularly for surface effects,
i.e., at the skin of the patient, will become increasingly important.

* Note that such a chamber gives an indication of the effect of the secondary
particles on air (which is normally used in the chamber) and not on the medium.
To investigate the latter, it would be necessary to fill the chamber with a gas
whose effective atomic number was the same as that of the medium, and to know
the energy required to produce a pair of ions in the gas. Alternatively, the energy
absorption in the medium could be fairly closely calculated from that in air if
the composition of the former is known.

The Measurement of Radiation 189

Neutrons

The consideration of the measurement of neutron radiation
follows on naturally from that of X- and gamma radiation, for
neutron radiation also produces ionization by an indirect means,
namely, through the agency of secondary particles.

A neutron is a material particle of mass approximately unity
on the atomic scale, that is, its mass is very similar to the mass
of the nucleus of the hydrogen atom, the proton. But, whereas
the proton has a positive unit elementary charge, the neutron
has no charge at all, and so, unlike radiations consisting of
charged particles, it is unable to drag electrons out of the atoms
near which it passes. Thus it loses practically no energy by
ionization, and will penetrate very much greater thicknesses of
matter than, say, a proton of similar energy.

The interaction of the neutron is almost entirely with the
nuclei of the atoms, and the commonest process is a simple
collision which deflects the neutron with a reduced energy, and
causes the nucleus to recoil with the balance of the original
energy. The average energy transfer in a collision is greatest
when the neutron and the nucleus have equal masses, and be-
comes progressively less as the mass of the recoiling nucleus
increases. The energy transfer is greatest in hydrogen, when
the neutron energy is on the average reduced to about 37% at
each collision.

In addition to these scattering collisions, a neutron may be
captured by a nucleus and provoke nuclear disintegrations of
various kinds, sometimes resulting in the production of "artificial
radioactivity." The relative probability of such processes is
generally small, however, until the neutron has been made very
slow by repeated collisions. In the case of biological material,
these nuclear disintegrations may usually be ignored in consider-
ing the energy communicated to the medium by a beam of
neutrons. It may be mentioned in passing, that the induced
radioactivity produced in suitable substances is of help in making

190 Applied Biophysics

relative measurements of the "strength" of a neutron beam, and
in discriminating between neutrons of different energy.

An immediate extension of the definition of the rontgen to
include neutron radiation would not be very suitable for use in
biology and therapy because, as pointed out above, the energy
conversion of the neutrons varies rapidly with the atomic type,
even for "light" elements, in contrast to the energy conversion
of X- or gamma radiation. In other words, air is no longer a
satisfactory approximation to tissue (which contains so much
hydrogen in the form of water and various organic compounds).
For example. Gray and Read ^- have calculated that when soft
tissues are irradiated by fast neutrons, about 92% of the energy
converted goes to the recoil protons, 5% to the recoil oxygen
nuclei, 2% to the recoil carbon nuclei, and 1% to other effects,
and that 1 gram of average tissue would absorb seven times as
much energy as 1 gram of air for neutrons of particular energy
about 3 million electron volts.

For reasons such as these. Gray and Read ^^ have proposed
that energy absorption in water should replace that in air for
the purpose of neutron dosimetry. The unit dose is then that
quantity of neutron radiation which communicates to unit volume
of water the same energy that is communicated by one rontgen
of gamma radiation, i.e., about 94 ergs. This unit may be
thought of as an "equivalent rontgen."

For the actual measurement of energy absorption in a given
medium, use may be made of Gray's Principle of Equivalence.
In a hydrogenous material, the "corpuscular emission" is pre-
dominantly composed of recoil protons. The application of the
method has been treated in detail by Gray. A relative measure
of exposure that has been widely used in practice is the ioniza-
tion produced by the neutron beam in the Victoreen type of
X-ray "thimble" chamber dosemeter. This arbitrary unit is
known as the "n" unit.

Charged-Partiole Radiations

All charged-particle radiations may be considered together,
for they have this in common, that by virtue of their charge

The Measurement of Radiation 191

they ionize directly, and in a qualitatively similar manner. Such
radiations include electrons (beta particles), and the whole range
of swiftly moving atomic nuclei, best-known of which are the
helium nuclei or alpha particles, emitted by natural radioactive
substances. Of these, electrons are practically the only kind
of radiation used as an external beam, and even these not
widely. But with the development of the betatron for producing
very intense beams of high-energy electrons, the therapeutic
applications may well be extended.

Since X- and gamma radiations produce their effects via the
intermediary or secondary electrons, it is clear that the rontgen
unit may legitimately be used for expressing dose in the case
of a primary beam of electrons. A measurement of the ionization
per unit volume of air gives the dose directly in rontgens.* This
concept is also satisfactory for any other directly-ionizing radia-
tion. The ionization in a "thimble'' chamber is now independent
of the nature of the walls, provided the primary radiation is not
appreciably attenuated or reflected by them. Thus the dose rate
of the primary beta radiation from ''unscreened" radium plaques
has been measured in rontgens.

In some cases, the radioactive substances are dispersed
throughout the biological material. For example, radioactive
prosphorus is used therapeutically for leukemia, and biological
specimens have been immersed in an aqueous solution of radon.
For such cases, slightly different concepts are appropriate, for
the radiation is usually absorbed completely within the medium.
Thus, knowing the total quantity of radioactive substance intro-
duced, and the total energy emitted by each disintegrating atom,
the quantity of energy communicated to the medium is known,
i.e., the fundamental biological quantity is known at the outset.
It merely remains to compare this true energy absorption (de-
termined solely by the radioactive substance and entirely inde-
pendent of the medium in which the substance finds itself) with
that which is produced by other radiations in order to express
it in ''equivalent rontgens." This involves the adoption of some
convention.

* The true energy absorption for a medium of specified atomic make-up could
be calculated from this rontgen dose.

192 Applied Biophysics

The actual energy liberated in 1 gram of the medium may be
compared with the energy communicated by one rontgen of X-
or gamma radiation to 1 gram of air, which is a definite quantity
equal to about 85 ergs ; or it may be compared with the energy
communicated by one rontgen of X- or gamma radiation to
1 gram of the medium in question, which is not a definite
quantity, but depends on the quality of the radiation and the
nature of the medium. In view of the heterogeneous nature of
"tissue," it is perhaps as well to base the comparison on energy
absorption in air.* Thus, to arrive at the dose in equivalent
rontgens, it is merely necessary to know the total amount of the
radioactive material, the energy emission per distegrating atom,
and the total mass through which the material is dispersed, from
which is deduced the energy liberated per unit mass of the
medium, which is divided by 85.

References **

1 Bragg, W. H. (1912) Studies in Radioactivity, London.

2Clarkson, J. R. and W. V. Mayneord (1939) Brit. J. Radiol. 12, 168.

3 Compton, A. H. and S. K. Allison (1935) X-rays in Theory and

Experiment, New York,
4Failla, G. (1937) Amer. J. Roentgenol. 29, 202.
5 Farmer, F. T. (1945) Brit. J. Radiol. 18. 148.
fiFricke, H. and O. Glasser (1925) Fortschr. Rontgenstr. 33, 239.
^Friedrich, W. (1938) Amer. J. Roentgenol. 40, 69.

8 Glasser, O. (1944) Medical Physics, Chicago.

9 Glasser, O., E. H. Quimby, L. S. Taylor and J. L. Weatherwax

(1944) Physical Foundations of Radiology, New York.

10 Gray, L. H. (1937) Brit. J. Radiol. 10, 600 and 721.

11 Gray, L. H. (1944) Proc. Camb. Phil. Soc. 40, 72.

12 Gray, L. H. and J. Read (1939) Nature, Land. 144, 439.

13 Holthusen, H. and R. Braun (1933) Grundlagen iind Praxis der

Rontgenstrahlen-Dosierung, Leipzig.

14 Jones, D. E. A. and L. H. Clark (1943) Brit. J. Radiol. 16, 166.

* The energy absorption in water (for hard gamma radiation"), i.e., Cray's
energy unit, is in many cases a better basis for comparisons. This "equivalent
rontgen" corresponds to about 94 ergs per gram.

** A comprehensive bibliography of this subject would be out of place here. The
selection of references is arbitrary and in no way representative. It merely
includes work referred to explicitly in the text and a few random papers which
may serv^ as a possible entry point into the literature,

The Measurement of Radiation 193

iSKaye, G. W. C, G. E. Bell, W. Binks and W. E. Perry (1939) Rep.

Progr. Phys. 6, 95.
i« Kaye, G. W. C. and W. Binks (1937) Proc. Roy. Soc. A. 161, 564.
I' Mayneord, W. V. (1931) Brit. J. Radiol. 4, 693.
iSMayneord, W. V. (1933) Brit. J. Radiol. 6, 598.
19 Mayneord, W. V. (1937) Acta. Int. Un. Against Cancer 2, 271.
-'<• Mayneord, W. V. (1940) Brit. J. Radiol. 13, 235.
^1 Mayneord, W. V. and J. E. Roberts (1935) Brit. J. Radiol. 8, 341.
^2Neary, G. J. (1943) Rep. Brit. Emp. Cancer Campgn. 20, 35.
-^Rutherford, E., J. Chadwick and C. D. Ellis (1930) Radiations from

Radioactive Substances, Cambridge.
24Sievert, R. M. (1932) Acta Radiol., Stockh. suppl. 14.

25 Spiers, F. W. (1943) Rep. Brit. Emp. Cancer Campgn. 20, 41.

26 Spiers, F. W. (1944) Rep. Brit. Emp. Cancer Campgn. 21, 45.

27 Taylor, L. S. (1932) Bur. Stand. J. Res., Wash. 8, 9 and 325.

28 Taylor, L. S. (1937) Radiology. 29, 323.

29 Taylor, L. S. and G. Singer (1940) Amer. J. Roentgenol. 44, 428.

30 Wilson, C. W. (1945) Radium Therapy — Its Physical Aspects, London.

TOTAL ENERGY ABSORPTION IN RADIOTHERAPY

FRANK ELLIS, M.Sc, M.D., F.F.R.
Medical Director, Radiotherapy Department, London Hospital

Introduction

THE dose of radiation absorbed at a point affecting indi-
vidual structures, such as chromosomes, determines the
local effect on these structures, and is the effect which is
desired by the radiotherapist in the neighborhood of the
malignant tumor. To enhance this effect by variations in quality,
dose, dosage rate, fractionation, and total time is one of the
chief aims of the radiotherapist. At the same time, however,
general effects are produced by the radiation and manifest them-
selves in organs which have not been irradiated. These effects
are troublesome and difficult to avoid and, in attempting to
correlate them with dose, I perceived the necessity for estimates
of the total energy absorption by the body. I, therefore, asked
Dr. Happey to investigate the problem so as to provide an
estimate of the volume dose in ^'rontgen cubic centimeters"
(rcm.^). Mayneord, however, was also engaged in a similar
investigation on different lines, and had coined the terms "in-
tegral dose" and "megagram-rontgen." The latter is a more
convenient unit and a more euphonious term, and so is to be
l)referred to the term "rontgen cubic centimeter." It is intended
in this short paper to discuss briefly the physical approaches,
attempts at correlation with biological effects, and then the
practical value of the conception of volume dose.

Physical Estimates

Happey '•*• ^*^* points out that the energy absorbed in the axial
pencil of a very large field is maximal because the proportion

194

Total Energy Absorption in Radiotherapy

195

of scatter is maximal. If all the radiation scattered outside the
geometrical beam were confined to it then, for any size of field,
the energy absorbed at any point of the beam would be the same,
at the same depth, as for the saturated pencil. Thus, assuming
that all the scattered radiation is absorbed and that none
escapes from the body, the volume dose is estimated by the
product of the area of the field on the skin, the dosage in rontgens
(corrected to allow for the *'unsaturation" of the field) and a
graph reading. The graph (figure 1 ) is obtained by integrating
the area under the depth-dose curve for the saturated axial
pencil of a very large field. The correction for unsaturation is
the ratio of the dosage rate with maximum scatter to the
measured axial skin dose of the field concerned.

-<

1744

16

1524

CI.

14

1308

c
«>

2P

12

1090

=2

10

872

E

8

654

E

6

436

•

4

tr) u

2l8$?u

2

FSD.

0 2 4 6 8 10 12 14 16 IB 20 22 24 26 28 50
Thickness of Tissue in centimetres.

FIG. 1. Graph Relating \'olume Dose per Rontgen at Skin Surface to
Thickness of Tissue through Which the Beam Passes. (From Ellis."*)

Thus, comparing a field of 400 square centimeters and one of
50 square centimeters, we have the following factors (200 kilo-
volts, constant potential 1 millimeter Cu 1 millimeter Al 40
centimeters FSD *) :

Tissue

Volume dose

Field size

Dose rate

thickness

Graph

per rontgen

(cm2)

(r/min)

(cm)

reading

at skin

400

92

20

13

13 X 400 X g

50

76

20

13

13 X 50 X g

* FSD ^ Focus-skin distance.

196 Applied Biophysics

Mayneord approached the problem on different Hnes, and
has done a great deal of work alone, and with his collabo-
rators, on the theoretical and practical aspects of the problem.
His original paper ^- described a method of integrating the dose
by measuring the volume of rotation between the isodose sur-
faces of a beam by practical measurement of the moment of the
area, and gives values for volume doses of different types of
radiation which throw into sharp contrast their differences in
this respect. (See table I.)

He discusses ^^ the mathematical theory of volume dose and
derives the following interesting generalizations. For a beam
in which the dose contours in a given plane-section are straight
lines perpendicular to the axis of the beam, and the dose falls
linearly with depth, the integral dose is given by the product
of the mass of the body concerned and the dose at its center
of gravity. From investigations made in collaboration with
Clarkson, ^^ on a wax model of a man, tables were constructed
giving the "average" dose throughout a patient of a given thick-
ness and a given quality of beam. (A body of mass M receives

an average or mean dose D when the Integral or Volume Dose

2: — D.M.) This ''average dose," corrected for focus-skin
distance and multiplied by the mass of the patient gives the
"integral dose."

Mayneord further ^'^ discusses the mathematical theory of
integral dose in radium therapy. It appears that, for concentric
shells about a radium source, the volume dose of each shell
is proportional to its thickness and the number of milligram-
hours (mgh) at the center. Moreover, there is a reciprocal
relationship between the source emitting radiation and the vol-
ume receiving it. "The integral dose throughout any volume
whatever, due to a finite source, uniformly filled with radio-
active material, is equal to the integral dose throughout the
original source if the 'receiver' be filled with radiating material
of the same uniform density." A graph is given from which the
integral dose per mgh for point sources near the center of an
absorbing mass, may be read (figure 2). For a sphere of radius

u

6

u

tn

biO
u

w

CO

o

CO

CM

o
o

o

o

CO

rrT

«o

CO

V^ (J

LT)

CM

o

l-O

ON

o
o

o

On

00

^ -^

<u

(U

^ O '^

LO

00

(L)

^^ '^H ^.— -^

c5
O

O

o

p

o

o

p

rv)

CNJ

VO

o
>-o

o

lO

00

pq
<

U2

fe

o

0\

CO

ro

CM

T— 1

o

O

o

:3
o'

On

vO

o

O

o

only
n. Ni

3

u

-tJ

ll>

a; c

3 CM

e

s

J3

3

£

E

;3

H

H o

r-l

-^

o
o

:3

-4->

s

CO

p

o

>

cr

O

c

o

rt

(U >
O O'

lO

cr>

o

O

^

"^

o

o

O

<n

CM

'^

p.

O

a!

p-5

s

s

03

a

s-

-<->

u

•<->

biD
1

*s

bfl

1

C

T— I

3

lO

;3

o .2
H 5

tn

t/2

CO

^

to

(A

>>

>,

>.

>^

>.

b

rt

03

OJ

03

03

rt

ll

v->

u

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1-4

ll

X

X

X

X

CJ

s

.2

03
u

CM

CO

197

lO

VO

198

Applied Biophysics

a, the volume dose throughout the sphere was calculated by
Mavneord to be

where F = 2a -1-

a'

8.3 X -^^^ X F per mgh

a-\- c

loge

a

c being the distance of the point source of radium from the center
of the sphere, and the relationship of F to c/a is given in figure 3,
taken from Mayneord. Examples of volume doses are given
for certain situations and techniques met with in practical
radium therapy.
For example :

1. In treating a carcinoma of the maxillary antrum with a
dose of 3,000 mgh, the volume dose is assumed to be that
for a sphere of radius 9.8 centimeters and of mass approxi-
mately 4 kilograms with the radium relatively centrally
placed :

2 = 3,000 X 0-89 =: 2.7 megagram-rontgens,

0.89 being the graph reading (see figure 2).

1100
1000
«k 900
^ 800
Z 700
« 600

s: 500

^ 400
Z 500
J 200
- 100

u

tiO-90

"^ — ^

>2080

^■^~

-..«.__

2 070

" "^

W

2

Elongc

tion

^ ^ - - '

IC

0 2(

)0 3-1

)0 4h

?0 5(

W, _ - - - -

a. ..

- '

***

, '^

^""^

-«v^

• —

£

^^^^

/

/

/

\

II 0

100

90^

80 >

70 1

60 "^

5 0 °

4 0 ^

3-0 S
2 0 ■

10

500 1000 2000 3000 4000

MASS IN GM= VOLUME IN CZ.

5000

FIG. 2. Integral dose per mgh for point sources near the center of an absorbing
mass of known volume and mass. (From Mayneord. !■*)

2. In treating carcinoma of the cervix uteri with a dose of
6,000 mgh, the integral dose is calculated as about 9.8

Total Energy Absorption in Radiotherapy

199

megagram-rontgens, neglecting the absorption by the filters
in which the radium is packed.

Measurements of Volume Dose

Measurements of volume dose have been attempted by
Boag/ using the model constructed by Grimmett/- ^ This model
consists of spaced plates 6 millimeters thick, of density 0.985,
graphited and spaced 2 millimeters apart by thick washers of

1.00

O.flO

^x

060

\

040

^

V

0,?0

v^

1

:

I I

J A

\ 5

c a

FIG. 3. Curve relating

a2 _ c2 a + c
F(= 2a -1 log, )

to — where c is the distance of a point source of radium from
a
the center of a sphere of radius a. (From Mayneord.'*)

the same material (cellulose acetate) as the plates. Alternate
plates are connected together, thus forming two groups of plates,
each of which is connected to opposite poles of a battery with a
sensitive galvanometer in circuit, to measure the total ioniza-
tion current collected from all the air-gaps, i.e., from the whole
body under radiotherapeutic conditions. Under these conditions,
guard rings were found to be necessary to prevent insulation
leakage, and allowance had to be made for their effect. More-
over, the absorption conditions for a wide range of wave lengths
and various angles of incidence of the X-ray beam had to be
similar to those for the human body. These points were all

200

Applied Biophysics

dealt with, and curves were constructed from which volume
doses delivered with X-rays of HVL 2 to 4 millimeters Cu
can be estimated quickly and fairly accurately. Boag's measure-
ments indicate that the volume dose depends principally upon
the area and site of the field. The FSD linear dimensions of
the patient and HVL of the beam have much less effect.

Photographs of the model are shown in figures 4 and 5, and
curves representing some results in figures 6 and 7 from Boag.^

FIG. 4. CIrimmett's ionization-cliamber '"man" in position for treatment to tlie head.

(From Boag.^)

_. ^ — "--^

w

W

HB^^^^^^^^^k

i

^^SBBS^^^^^^^s !

t

i^^^^^^

-:

■^

^^^K^E^?S»~S5*«S^ !

%

^9

B i

'Z'

wMS^-

k-.

^p- 1

-"

Wt:

';^

wm.

J;

^^B

^-

^^^^

fc

^H^^i ^m ^^.„,,„B»«

%■-

^^^^^Sha 1 ffl^Sff**'**'*'**'^^ "■'

f

^^BBb^^j^^^

tt

V|P

^^bT i^^iri

1

rM

v^ ^

\

t 1

Ik'^V

mmmm^

m^- ^

FIG. 5. Photograph showing the general appearance and method of construction of
the trunk of Grimmett's ionization-chamber "man." (From Boag.^)

Total Energy Absorption in Radiotherapy

201

Mayneord and Clarkson ^^ also constructed a wax model for
making measurements to estimate the volume dose when the
whole body is irradiated. The actual measurements were made
in slabs filled with the suggested powder mixture of Spiers,^ ^

400

FIG. 6. Relation of volume dose to field area for irradiation of the pelvis. Inset
curve shows relation for rontgen dose measured without scatter, which is linear up
to 200 square centimeters. (From Boag.i)

and estimated both by the average-dose method and by planimeter
measurements of the areas between isodose curves in the body-
section (figure 8). Their results are represented graphically in
figures 9 and 10, which show the volume dose in gram-rontgens
per rontgen to the surface of the body (70 kilograms ) for various
half-value layers. It is seen that there is a rapid rise up to
HVL = 0.2 millimeter Cu (= about 100 kilo volts with 0.15
millimeter Cu filter) followed by a less rapid change.

202

Applied Biophysics

Value of the Conception of Volume Dose in Radiotherapy

The volume dose might conceivably help in deciding on modi-
fications of technique, and might help in correlating physical
dose with general effects of radiation.

It must be realized, however, that the physical methods hitherto
described for estimating volume dose suflfer from certain in-
accuracies. The chief of these are due to the fact that allowance
is not made, in the physical methods, for the variable tissues
and their densities in the human body, while biologically one
cannot expect uniform behavior of various tissues for a given
physical dose.

Physical Factors

The author has attempted elsewhere to show the effects of
certain physical factors on volume dose.^- ^

500

FIG. 7. Relation of volume dose to field area for chest irradiation. The lower curve
is for the shorter FSD (40 centimeters). (From Boag.^)

Total Energy Absorption in Radiotherapy 203

TABLE II

Effect on Volume Dose of Increased FSD (Carcinoma of Esophagus,
40 Centimeters FSD and 100 Centimeters FSD)

200 kv
1.5 mm Cu HVL Tumor dose = 6,000 r

Field size 15 X 4 cm^ Eight fields

FSD = 40 cm

FSD =

100 cm

Field dose = 3,400 r

Field dose

= 2,800

1 r

r cm^/cm-Zr * Field

thickness

(cm)

r cm^/cmVr

13.4

1

19

11.79

13.4

2

19

11.79

13.82

3

22

12.47

13.82

4

22

12.47

13.82

5

22

12.47

13.82

6

22

12.47

15.3

7

30

13.6

15.3

S

30

-

13.6

112.68

100.66

Total Energy Absorption

92 92

3,400 X 60 X 126 X — — rcm^ 2,800 X 60 x 101 x —- r cm^

76.3 76.3

= 3.11 X lO'rcmS — 2.05 X 10" rcm3

(125%) (100%)

Field Area

The volume dose is almost proportional to the field area.

Focus-Skin Distance

A comparison is made in Table II of the volume dose using
two techniques for treating carcinoma of the esophagus, the only
difference between them for a given tumor dose being the dif-
ference in FSD. These estimates are based on Happey's

204

Applied Biophysics

method ^^ and it should be pointed out that Boag's graph (figure
7), for a similar technique, shows no appreciable difference with
the two FSD and gives a rather higher value (36 megagram-
rontgens) than either of the two techniques compared above.

The Arrangenieiit and Number of Fields

The author has discussed ^ the effect of these factors for two
sets of conditions :

0.05 r

D. 40 kv

ic 0.0 99 r
O.lr

yO.lr

->0.5r
>0.6r

^ 0.8r
$^0.9r

1.1 r

1.2 r
'l.5r
'l.4r

FIG. 8. Isodose distributions in a cross-section of the trunk for various qualities
of radiation. (From Mayneord & Clarkson.^'^)

Total Energy Absorption in Radiotherapy

205

Quality of the Beam

The effect of the quaHty of the beam as determined for whole-
body radiation has been mentioned already (see figures 9, 10).
Also Phillips ^^ demonstrated that for a given tumor dose, there
is a considerable difference in volume dose between techniques
using 200 kilovolts and 1,000 kilovolts (see table III).

TABLE III

200 kv

For a tumor dose of 6,000 r

1,000 kv

2,400 r

Dose per field

1,620 r

5,030 r

Max. skin dose

3,400 r

67

Volume dose (megagram-r)

41

60^600

50,000

40,000

30,000

20,000

10,000

HalF-value layer mm Cu
FIG. 9.*

206

Applied Biophysics

40,000

^

^^

}

In powder

y

^-^

L

30,000

/ ^

^

vx

A

7 X

20,000

//

//

10,000

f/

If

1/

t
f

1
1

.

1
1
1
1
1
1

t

0-1 0-2 0-5 0-4

HalF-vafue layer mm. Cu.
FIG. 10.*

* Figures 9 and 10 show a comparison of the values of integral dose obtained in a
model patient constructed wholly of wax and in a model constructed of Spiers' mix-
ture for various radiation qualities. (From Mayneord and Clarkson.^^)

a. Using Ungar's ^^ conception of the economy quotient,
it can be shown that the greater the homogeneity of dosage, the
smaller the volume dose. Ungar gives examples of arrange-
ments of fields for treating a case of carcinoma of the cervix
in relation to the "economy quotient" and the volume dose. The
economy quotient is the ratio of the minimum tumor dose to the
difference between the maximum and minimum tumor doses,
and is a measure of the efficiency of the technique. It seems that,
other things being e(|ual. the arrangement which gives the greater
economy quotient gives the smaller volume dose. Since the
economy quotient is highest when tlie difference between the
maximum and minimum tumor doses is smallest, it follows that
the greater the homogeneity, the smaller the volume dose (see
figure 11).

FIG. 11

TOP

Y^t =120%

max.

D< =110%

min.

D ' — D^ =

max. mm.
max. mm.

= 30% (heterogeneity factor)

90

= 3 the economy quotient

Het. Factor

30

BOTTOM

Y^t = 120%
max.

mill.
Economy quotient

•

110

= = 11

10

Volume dose = 4.36 megagram-r
(From Ellis.*)

208

Applied Biophysics

h. Using two wedge fields as described by Ellis and Miller ^
(see figure 12) , the volume dose for 1,000 r tumor dose calculated
by me from measurements made by Boag/ is 1,42 megagram-
rontgens. An appropriate technique to achieve the same treat-
ment without wedge fields would be to use two lateral 10 X 8
square centimeter fields and one 6 X ■+ square centimeter, e.g.,
to the skull. Under these conditions, the volume dose for 1,000 r
tumor dose is 2.4 megagram-rontgens — obviously higher than
that for the wedge fields.

FIG. 12. Diagram of the isodose distributions produced by combining two X-ray
beams at right angles, using wedge filters. (From Ellis and Miller. s)

Volume Dose and Tolerance Dose

Mayneord and Clarkson ^•'' by their work on whole-body ir-
radiation have put the energy absorption by the body under such
conditions in true perspective, and a new aspect of the concep-
tion "tolerance dose" has emerged. For whole-body irradiation,
the volume dose relationships for 40 kilovolt, 200 kilovolt, and

Total Energy Absorption in Radiotherapy

209

gamma radiation respectively are in the ratio of 15 : 35 : 40, for
a wide beam enclosing the body, and a very large FSD — i.e., the
conditions under which radiation is received by medical workers.
In other words, for a given dose in "rontgens" to the skin — which
is the present method of estimating tolerance dose — the energy
absorbed by the body may vary considerably from one type of
radiation to another. Since the biological effect considered in
the internationally accepted figure of 10"^ r per second is a gen-
eral effect rather than a local one, it would seem more accurate
to aim at a volume dose estimation rather than a surface dose.
It is interesting to note that the international figure for diagnostic
X-rays (10'^ r per second) is three times that for gamma rays,
and that this ratio, decided by experience, is of the order of the
ratio of the volume doses of 40 kilovolt X-rays and gamma rays.
The following table (IV) shows the influence of technique on
the volume dose in treating cancer of various sites.

TABLE IV

Technique and Total Absorption or Volume Dose. HVL-0.15 mm Cu FSD-40 cm

Dose

Region 1,000 r

Tonsil 4.5

Fauces 4.0

Larynx 5.0

Brain 4.0^

Bladder 5.6

Pelvis 3.0

(supplement to radium) 3.0

Esophagus 6.0

Lung 4.0

Lung 5,5

Fields
No. cm^

2 X 10/8
2x 6/4

2 X 10/15
2x 6/4

2x 6/8

1 X 6/4

2 X 10/8
IX 6/8

8x 8/10

2 X 10/15
2 X 10/15

8 X 15/4

4 X 10/15

5X 6/8

Total

absorption

r cm3

777 X 106

11.26 X 106

4.53 X 106

11.97 X 106
17.24 X 106
25.97 X 106

31.1 X 106
30.3 X 106
19 X 106

210

Applied Biophysics

The discrimination now possible between volume . dose and
surface dose should permit of new standards. That limiting the
permissible general radiation should be a volume dose, and that
limiting the local radiation a surface dose, which might presum-
ably be higher than the figure used hitherto, which, in effect,
has no real value for those working with radium.

Correlation of Biological Eflferts with Volume Dose

The ultimate practical value of the conception of volume dose,
will depend on the possibility of using it as a criterion for modify-
ing technique, and as a means of obtaining more knowledge of
the action of radiation. The physical factors hitherto discussed
indicate the manner of influencing volume dose by technical
variations.

Modification of technique will be considered by a radiotherapist
only if the general effect of the radiation is of such magnitude
as to interfere with the delivery of a local dose. General effects,

3000

UJ

>

O
O

I

a.
>

2000-

1000-

5 10 15 20 25 50 35

FIG. 13. Lymphocyte Counts in IxnivinuAL Patients

Abscissae = days after commencement of radiation. The volume doses received
are indicated on the curves. Note that althouRh the trend is marked, each curve
shows a rise at some time during treatment. (From Ellis."*)

Total Energy Absorption in Radiotherapy 211

as distinct from local effects, however, might be due to the local
effects of radiation. Thus, the local effect of radiation on the
mouth and esophagus might have a profound effect indirectly
on the general nutrition, the lighting-up of local infection might
also have a marked general effect, while local edema in such
specialized structures as the lung and brain might have a marked
effect on general well-being. Moreover, the variable structure
of the human body makes estimates of the usual accuracy de-
manded in physics almost impossible. In addition, different
regions of the body differ in sensitivity, while the variation from
one human being to another, due to metabolic, physical and
psychological differences, conspires, with the influences men-
tioned above, to make difficult the correlation of biological
phenomena with volume dose, Nevertheless, some attempts
have been made.

The Volume Dose Limiting Radiation Technique

In table IV the volume dose for lung and esophagus of about
30 megagram-rontgens in one month is near the limit of what
the patient can tolerate. Levitt,^ ^ in an account of trunk-bath
radiation, finds that the maximum dose to the surface which can
be tolerated is 1,500 r (measured with backscatterj, though
treatment under such conditions has not to be stopped because
of local effects, e.g., on skin. This corresponds to a volume dose
of about 30 megagram-rontgens in 6 weeks. Phillips '^^ found
that 40 megagram-rontgens was less than the maximum dose that
could be tolerated in about 4 weeks in treating a rectum. At the
London hospital, I find that treatment to the whole abdomen
permits of a volume dose of about 40 megagram-rontgens in
3 weeks, so that it appears that a patient will tolerate a large
volume dose to a smaller part of the body more readily than to
a large part.

Apart from therapeutic conditions such as these, it does not
seem from table 1\ that the volume dose is likely to limit tech-
nique as at present developed. It is possible to imagine condi-
tions, however, under which such limitation might occur. Sup-

212 Applied Biophysics

pose, for instance, that instead of being delivered in one month,
a volume dose of 7 or 8 megagram-rontgens is to be given to
a patient in treating a tongue in one day. It might be that,
under such conditions, volume dose is a limiting factor. Such
a possibility is not inconceivable in the light of the hypothesis
suggested by Gray ^ that the number of fractions rather than
the total time is more important. If this is true, then techniques
might be developed necessitating the administration of very large
doses in many fractions in a very short time.

What Biological Phenomena Can Be Correlated With
Volume Dose?

The phenomena must be general, as distinct from local, and
may be subjective or objective.

Subjective phenomena such as malaise, nausea, vomiting, and
headache are very difficult to correlate, especially since so many
of these symptoms might be produced by general upsets not due
to radiation.

Objective phenomena may be measurable or not. Here we
shall consider measurable phenomena only. They may be divided
into (a) blood counts, (b) other measurements.

Blood counts are the easiest tangible evidence to obtain of
the effects of radiation.

Ellis "^ tried to correlate the blood counts, corpuscular volume,
and other factors, with volume dose. No correlation was pos-
sible. Figure 13 shows types of lymphocyte counts obtained.
Althought there is an average trend, individual counts behaved
very differently, even rising during relatively rapid administra-
tion of radiation at some part of every curve. Other types of
cell are much more erratic. Thus correlation in individual cases
is impossible. From the work of Bush,- however, there appears
almost a mathematical correlation. Figure 14 is based on average
lymphocyte counts of 26 cases treated for carcinoma of the
mouth, pharynx and larynx. The possibility of individual varia-
tions as in figure 13 still, of course, exists. Experience of
abdominal-bath treatments provides the same type of curves as

Total Energy Absorption in Radiotherapy

213

in figure 13. Thus the volume dose cannot be correlated with
the lymphocyte count (and still less with other cell counts) in
individual cases.

1

CHANGE IN LYMPHOCYTE COUNT

10
09
OS
07
06
05
04
03

DURING TRE>
26 CASES)

f^TMENT (

MEAN OF

s\

00 Z \
oo ID \

X _i

;nts

INIT

•>-

ss

-2

>2

t \ t

^^^'-^

0-2

0 1

n

X

O t-)
X <

Q. CC

0 1 2 3 4 5

MEGAGRAMME - RONTGENS

FIG. 14. Curve of average lymphocyte counts of 26 patients all treated by a similar
technique related to volume dose in megagram-rontgens. (From Bush.^)

The effect of X-rays on the blood concentration of ascorbic acid
in animals and patients has been investigated by Kretzschmar,

TABLE V

Ascorb

ic acid mg %

in

plasma

Treatment (200 kv)

Immediately

Diagnosis

(tumor dose)

Before

after

Breast carcinoma

Post-operational
X-ray 300 r

0.501

0.435

Breast carcinoma

Post-operational
X-ray 300 r

0.836

0.794

Mediastinal tumor

X-ray 350 r

0.303

0.286

Breast carcinoma

Pre-operational
X-ray 1,200 r

0.420

0.336

214 Applied Biophysics

working with the author.^ There is no doubt that X-ray treat-
ment reduces the ascorbic acid content of the blood and of the
tissues in animals, and the ascorbic acid content of the blood
in patients. Table \' shows a diminution of the plasma ascorbic
acid during treatment in three breast cases and a case of medias-
tinal tumor.

The technical arrangements for the breast cases are similar
in all three patients, and it is obvious, on a su])erficial examina-
tion of the figures, that there is a qualitative but not a quanti-
tative correlation with volume dose even in these few cases.

It seems likely that the chemical changes which occur in the
body soon modify any substances which might be formed, so that
it might be impossible even to achieve l)iol()gical correlation,
although the most hopeful line of attack on the problem would
be to try to estimate breakdown products, such as adenosine, as
being the possible initial substances. Other effects seem likely
to be secondary, whether chemical, cytological or ])hysiological,
and as such will not offer any real correlation.

Acknowledgment. — The illustrations are reproduced from the
British Journal oj Radiology by kind permission of the editor
and of the authors concerned.

Rf.ferences

1 Boag, J. W. (1945) Brit. J. Radiol. 18, 235.

2 Bush, F. (1943) Brit. J. Radiol. 16, 109.

3 Ellis, F. (1942) Brit. J. Radiol. 15, 174 and 194.
•* Ellis, F. (1945) Brit. J. Radiol. 18, 240.

5 Ellis, F. and H. Aliller (1944) Brit. J. Radiol. 17, 90.

6 Gray, L. H. (1944) Brit. .J. Radiol. 17, 327.
"^Grimmett, L. G. (1939) Amcr. J. Roentgenol. 41, 432.
SGrimmett, L. G. (1942) Brit. J. Radiol. 15, 144.

9 Happey, F. (1940) Nature, Lond. 145, 668; 146, 96.
lOHappey, F. (1941) Brit. J. Radiol. 14, 235.

11 Levitt, W. M. (1938) Brit. J. Radiol. 11, 183.

12 Alayneord, W. V. (1940) Brit. J. Radiol. 13, 235.
i-^Mayneord. W. V. (1944) Brit. .J. Radiol. 17, 359.
i4Mayneord, W. V. (1945) Brit. J. Radiol. 18, 12.

Total Energy Absorption in Radiotherapy 215

i^Mayneord, W. V. and J. R. Clarkson (1944) Brit. J. Radiol. 17, 151

and 177.
ic Phillips, R. (1942) Froc. Roy. Soc. Med. 35, 768.
17 Spiers, F. W. (1943) Brit. J. Radiol. 16, 90.
isUngar, E. M. (1943) Brit. J. Radiol. 16, 376.

ON TECHNICAL METHODS IN X-RAY THERAPY

J. READ, B.Sc, Ph.D.
Physicist, Radiotherapy Department of the London Hospital

General Survey

X-RAY therapy is often roughly divided into various
classes — contact therapy, superficial X-ray therapy, deep
X-ray therapy, supervoltage therapy — yet these classes, and
the various methods within each, all have certain physical prin-
ciples in common. Firstly, it is desired to produce a chosen
distribution of X-ray dose through a patient's tissues by combin-
ing the necessary number and arrangement of fields. It mav be
considered adequate to produce more than a certain minimum
dose throughout a region, such as a tumor, with as httle as
possible elsewhere, without caring what the maximum in this
region may be. A more stringent requirement is that the dose
be uniform throughout the region. Ungar *^' has shown that
under certain conditions, the total radiation absorbed by the
body is a minimum, for a given tumor dose, when that dose is
uniform throughout the tumor. A general requirement is that
the dose at the skin, where each beam enters, shall not exceed a
certain value, account being taken of all contributions from
other beams. There may also be other regions where it is
particularly necessary to keep the dose small.

Secondly, it is desired to keep the radiation dose absorbed by
all the healthy tissues as small as possible in relation to that
absorbed in the treated volume. This recjuirement not only in-
fluences the manner in which the X-ray fields are arranged to
give the desired dose distribution ; it also largely determines the
class of therapy chosen. If a lesion is near the surface of the
body, or accessible through a body cavity, or with the aid of

216

Technical Methods in X-Ray Therapy

217

surgery, it is generally better to use a beam of less penetration
and small focus-skin distance, so that the dose in the healthy
tissues beyond the lesion diminishes rapidly with the depth in
the tissues. A rough measure of this total body dose is obtained
by summing the product of dose and volume throughout the
body, though it is evident that this is only a rough guide, as the
susceptibility to radiation of each element of volume as well
as the dose there determines the aggregate effect.^

I

I

©k

i

y

/

^**N,^

O,^-'^

\
\

\

45 KV. FS.D 2-2cm.
FILTER 2-5mm.AL FIELDIcm.CIRCLE
HV.L 1-61 mm. Al.

FIG. la. IsoDOSE Curves for a Contact-Therapy Field

Field 1 cm circle, focus-skin distance 2.2 cm, radiation generated by 45 kv and filtered
by 2.5 mm aluminum, HVL 1.6 mm aluminum (Mayneord ^)

The possible ways of combining X-ray fields to produce a
desired distribution are studied with the aid of isodose charts.
Typical charts are shown in figure la (for a low-voltage contact-
therapy tube), and figure lb (for a deep-therapy tube).^^ The
dose distribution in a plane through the body due to a certain
field is described by curves, which each join points of the same
dose rate expressed as percentages of that at the center point of
the field on the skin. Strictly speaking, these charts are not
obtained by measurements in the human body, but in a "phantom"
constructed of material the absorption and scattering of X-rays

218

Applied Biophysics

of which approximate to that of tissues. Generally water is
chosen, but sometimes wax. mixtures such as rice flour and
sodium bicarbonate, and "pressedwood" — compressed wood-pulp
boards — are used. Also, for the sake of standard conditions, the

FIG. lb. IsoDOSE Curves for a Deep-Therafy Fi.eld

Field 6 cm circle, focus-skin distance 50 cm. radiation generated by 200 kv and filtered
by 1 mm copper and 1 mm aluminum, HVL 1.5 mm copper (Mayneord ^)

measurements are made in a phantom large enough to approxi-
mate to a semiinfinite slab. Deviations from these charts which
are likely to occur in practice, due to the nature of the human
body, are considered later.

When a suitable distribution of fields has been chosen to give

TecJinical Methods in X-Ray TJierapy 219

a desired dose distribution on paper, means must be found to
direct the X-ray beams sufficiently accurately to give this distri-
bution in practice. If the absorption of the radiation in the
healthy tissues is to be a minimum, beams no wider than neces-
sary must be used. This makes accurate aiming very important.
Rarely is more than one tube used at a time ; usually a single
tube is directed successively in the desired ways. This may be
done by adjustment of the tube applicator to skin markings, with
orientation of the tube to calculated angles. To assist in this,
numerous beam-direction devices have been developed. Alterna-
tively, jigs can be made, which are attached to the patient in
fixed positions, and aid in the correct adjustment of the tube.
Finally, methods must be mentioned in which there is a relative
rotation of X-ray tube and patient, so that the axis of rotation
and the X-ray beam pass through the tumor roughly at right
angles to each other.

The desirability of beams being no wider than necessary was
mentioned earlier. A broad beam provides a greater depth dose
than a narrow beam, as the dose is enhanced by the scattering
from a greater block of tissue. Beams broader than the tumor
cross section have been used to give an adequate tumor dose at
a depth, but it is preferable to use more beams with a cross-fire
technique, or use a more penetrating radiation, so that the min-
imum beam width will suffice.

Illustrative Dose Distributions

a. Single fields. These are suitable for treatments where the
maximum dose must be given to the surface. In this case, it is
desirable that the dose rate should decline rapidly, and an easily
absorbed X-ray quality, i.e., one generated by a relatively small
kilovoltage, is therefore chosen — the so-called Chaoul or contact
therapy. Meredith -^' -^ has shown that the dose received by
the first millimeter or so of tissue is appreciably altered by
secondary radiation from the applicator and metal parts in the
tube, and can be reduced in relation to the dose at 5 millimeter
depth by spraying the applicator with aluminum paint and cov-
ering the tube window with aluminum foil.

220

Applied Biophysics

h. Multiple fields. When it is desired to produce a relatively
uniform dose distribution through a volume, or to dose a tumor
at a depth to a greater degree than the skin at the area of entry
of the X-rays, it is evident that a number of beams must be used
which all include the tumor, but enter through different skin
areas. The simplest case is that of two oppositely directed beams.
This is useful in the treatment of the lip, eyelid, or nose, by con-
tact therapy, and gives a fairly uniform dose distribution.^^ It
has been discussed by Smithers ^* and by Wilson. ^^ With the
usual deep-therapy conditions — 40 to 100 centimeters FSD
(focus-skin distance), about 1 millimeter copper HVL (half
value layer) — a dose varying between 90% and 105% of the
skin dose (the sum of contributions from both fields) can be
obtained through a thickness of about 12 centimeters, i.e., the
diameter of the average neck.

Two fields at right angles give a region of maximum dose on
the bisector, and nearer to the apex of the angle than the point
of intersection of their axes, \\jlson ^^ has shown that this can be
put to advantage, for example, in the treatment of a tumor of
the lung, situated near the anterior chest wall (figure 2).

FIG. 2. FiEi.ns Prearranged Using Dose Contours

Tumor uniformly irradiated with maximum dose equal to 120% of maximum

skin dose. 2 10 X 8 cm fields only

•

Irradiation of a tumor of the lung near the anterior chest wall by two fields at right

angles. The maximum dose occurs on the bisector of the angle between the fields, but
nearer to the apex of the angle than the point of intersection of the axes of the two
beams. The fields are arranged to give this region of maximum dose at the site of

the tumor (Wilson *^)

Technical Methods in X-Ray Therapy

221

Skill in arrangement of multiple beams is acquired by a study
of existing dose distributions, of model isodose surfaces,-^ and
by trial arrangement of isodose charts and modifications of these
arrangements. A few examples are given below. When the
beam axes are coplanar, the case is simpler. Wilson ^^ has shown
an arrangement of three fields to give a good dose distribution
for treatment of a larynx (figure 3). A case in which it is
desired to keep the X-ray dose low over a region is in the treat-
ment of the cervix uteri by combined X-ray and radium. Intra-
uterine and vaginal radium applicators, which give an adequate
local dose, give too little to the more distant parts of the pelvis,
which must therefore be dealt with by X-rays. The beams are
directed to give maximum efi^ect at the lateral wall of the pelvis,
but be limited where the gamma rays are efifective, the two
together giving a uniform distribution. Reference should be
made to papers by Walker,"*^^ and Sandler ^- for diagrams which
give the dose distribution throughout the pelvis.

FIG. 3. Fields Prearranged Using Dose Contours

Larynx uniformly irradiated with a dose equal to 140% of maximum skin dose

Arrangement of three fields with coplanar axes to give a relatively uniform dose
distribution through the larynx 1.4 times that of the maximum skin dose (Wilson ■'i}

222 Applied Biophysics

More complicated cases of summation of three and of four
beams, whose axes are not coplanar, have been given by Lamer-
ton and Mayneord ^ ^ and l^y Ungar '^^ respectively. Ungar de-
velops methods of treating vertebrae with 200 kilovolt radiation
which give a dose at the lesion about 1.4 times as great as that
at any skin area, except for certain small field overlaps not
exceeding 5 square centimeters.

The method of rotating the patient (or tube) carries the
multiple-beam technique to the limit, where the skin area of entry
of the beam becomes a continuous belt round the patient.
Nielsen -^ has described the application of this method in the
treatment of cancer of the esophagus. The patient sits on a
stool which rotates him once in about 15 minutes about an axis
along the esophagus, which is 50 centimeters from the tube
focus. A narrow beam is used, and to insure that it includes the
esophagus the shadow pattern of this beam is viewed on a
fluorescent screen. With radiation of 0.9 millimeter copper
HVL, the skin dose on the anterior and posterior surfaces is 40%
to 509c, and in the axillae 25% to 35%^ of the central dose.
The longer radius from the axis of rotation to the axilla gives
the skin in this region a greater linear velocity, so that it more
quickly crosses the X-ray beam. Jensen ^' has described irradia-
tion of the pelvis with a tube which rotates through 180° about
an axis in the supine (and then prone) patient. \'arious modi-
fications are possible in these methods — the shutter can be closed
during part of the rotation, the angular velocity can be varied
at different parts of the arc, and by tilting the beam axis at an
angle to the axis of rotation, first in one direction and then in
the other, the tumor can be irradiated through two zones of
skin to provide a still greater ratio of tumor to skin dose. In
the last case, however, the position of the maximum dose may
be shifted along the axis of rotation away from the point of
intersection of the beam axis.

c. Wedge fields. VAVis and Aliller ' have shown that an X-ray
beam can be so modified by a wedge-shaped filter that two such
fields at right angles, with the thick edges of the wedges con-
tiguous, give a fairly uniform dose distribution through the block

Technical Methods in X-Ray Therapy

223

of tissue of which the two fields are adjacent sides. The dose
dechnes rapidly outside this block. The single field with the
wedge-filter, and the two fields added at right angles, are shown
in figures 4a and 4b. To produce a field like 4a, the wedge must
cause a very considerable absorption, so that the useful dose rate
is seriously diminished. However, if adequate dose rate is avail-
able, the arrangement is very convenient for the irradiation of
lesions situated a few centimeters deep to the skin, and is specially
suitable to use with a jig to give accurate direction of the beams.
When a number of fields are chosen to give a uniform dose
distribution, a complete set should be administered to a patient
at one treatment, and not at intervals of a day or so.

cm

10

FIG. 4a. IsoDOSE Curves as Modified by a Brass Wedge-Filter of Maximum
Thickness 6.3 mm. Field 8X8 cm, Focus-Skin Distance HVL of th^ Radiation
1,5 mm Copper (Ellis and Miller 7)

224

Applied Biophysics

FIG. 4b. Dose Distribution of Two Fields of Type Illustrated in Figure 4a,
Arranged at Right Angles, the Positions of the Thick Edge of the Wedge
Being Contiguous. The Distribution Is Fairly Uniform Through the Block
OF Tissue Enclosed i:y the Fields and Declines Rapidly Outslde (Ellis and
Miller '')

Methods of Study of the Dose Distribution from a
Number of X-rav Beams

Most X-ray treatments require for their study the summation
of the dose distrihutions of several beams. If the axes of these
beams are coplanar, the distribution in that plane can be found
by superimposing, in the correct relative positions, isodose charts
drawn on transparent sheets, and summing them in succession
at the points of intersection of the curves. A convenient method
is that of Ungar,"^'*^ who cut blue-base film (discarded diagnostic
X-ray films freed from gelatin) to the shapes of isodose curves,
and stacked them, so that points which had, for example, per-
centage dose rates of 60 to 70 had six thicknesses of film below
them. Put on a viewing box, the depth of color showed the

Technical Methods in X-Ray Therapy 225

range within which the percentage dose lay, and when one set
for each beam was overlapped, the summation isodose curves
could be drawn on a superimposed celluloid sheet by considera-
tion of the depth of color.

For a knowledge of the dose distribution throughout a volume,
a summation of dose in parallel planes is desirable. Also, if the
X-ray beams are not coplanar, isodose curves in planes which
do not contain the beam axis are necessary. When the beam
has circular symmetry, there are geometric methods by which
isodose curves in any plane can be drawn from those in a plane
containing the axis. However, Mayneord ^^ has devised an in-
strument, the *'dose contour projector," which enables this to be
done much more easily. Flanders ^^ has described methods by
which sections through isodose surfaces can be made visible by
arranging a thin plane sheet of light to cut semitransparent
models. The isodose curves in the required section can be
sketched in with the aid of a camera obscura, and this method
can be used with beams which have not circular symmetry.

Another instrument devised by Mayneord ^^ is the "dose
finder," which aids in the studv of dose distribution in three
dimensions. A dummy applicator is adjusted to a shell moulded
to the shape of the part of the body under treatment. The shell
is then moved 20 centimeters from the applicator, into which
is plugged a plane carrying isodose curves (when there is cir-
cular symmetry), so that they occupy the correct position in
space in relation to the applicator. A rod, with pointers at right
angles 20 centimeters apart, is so arranged that when one pointer
is adjusted to a chosen point in the shell, the other pointer gives
the corresponding position in the region of the isodose curves.
The plane carrying these curves is rotated about its axis until
the pointer touches it, and the dose is read at the point of con-
tact. Rectangular fields can also be studied with a slightly more
complicated arrangement.-^- "^^ Light beams have been used in-
stead of mechanical pointers. ^^' "*- From a study of each field
in turn, the dose distril)ution due to a number of beams can be
plotted in a number of parallel planes through the treated region.
These can be drawn on glass plates, which also carry anatomical

226 Applied Biophysics

drawings, and stacked in correct relation to each other, so that
a three-dimensional representation of the dose distribution and
anatomical features is obtained. ^^

Means of Realizing a Desired Dose Distribution

If the paper plan of fields to produce a chosen distribution
of dose is to be successful, the fields must be applied to the patient
accurately. Various appliances have been devised to make this
easier and quicker. First, the center of the region it is desired
to treat must be located radiographically — by relating it to bone
or soft-tissue shadows, by insertion of an inactive gold seed,
skin clip, small balloon catheter containing iodine, lead-shot
catheter, lipiodol, or gelatin-barium pellet, or by barium- or
thorium-air contrast, according to the site. Skin markings are
used to give two lines which intersect at this point. Or the
vertical depth below a skin marking can be found by standard
radiographic methods. This localization must be done with the
patient in the exact position he is to occupy during treatment. ^^

The X-ray tube can then be set to angles measured by a
''parallelogram beam director" or "arc beam director," which
is removed before adjustment of the tube, or to lines scribed on
a protractor spanning the patient, or arc attached to the tube.
Simplest of all, a sheet of cardboard is cut to fit the contour of
the body, and the lines along which the applicator should be
directed are drawn on it.

A second method is the use of a calliper, fixed to the tube,
which carries a pointer coincident with the beam axis, which
can be made to slide to touch the patient at the point of emergence.
Green's calliper will also indicate points at known distances
normal to the beam axis — a help when setting glancing fields —
while Grimmett has adapted a calliper to give audible warning
if the patient moves appreciably from the correct set-
ting.^- ^' !-• ^^' -^^

Mayneord ^^ has described an optical device which shows
the exit point of the beam axis by a light spot on the patient.
A small lamp can be arranged in an applicator to give a beam

Technical Methods in X-Ray Therapy 227

of light along what is later the X-ray beam axis. A tube with
cross wires and sighting aperture, at the other side of the room,
is aligned with this light beam. The tube can also throw a light
beam back in the same direction, so that, when the patient is
adjusted to the applicator, a light spot on the patient shows the
position of emergence of the beam. The use of this appliance
in the treatment of esophageal growths is described by Adams. ^
It eliminates error due to whip in mechanical callipers, but has
the disadvantage that the patient must be adjusted to the ap-
plicator, which must not be moved out of line with the light
beam.

By *'jig" is meant an appliance which can l)e fitted to a patient
in a reproducible position, and which has surfaces or sockets in
correct positions, to which the applicator is adjusted. A simple
illustration is the jig to insure that two wedge fields are applied
to a patient correctly at right angles. The jig is formed of two
"perspex" (transparent plastic) plates, each the size of the ap-
plicator end, and fixed at right angles to each other. It is ad-
justed on the patient so that the block of tissue it is desired
to treat is within the right angle. Skin markings are made so
that it can be replaced in the same position. A metal replica is
substituted for the perspex one, and any space between it and
the skin is filled with "radium compo" (see below), a thermo-
plastic material. The radium-compo mold is detached from the
metal replica, and used in the same position in the perspex jig.
The fact that the radium compo has taken the shape of the body,
together wnth the skin markings, makes it easy to replace the
jig in the same position for each treatment. It is a simple matter
to bring the X-ray-tube applicator into contact with each plane
surface in turn.

Flood and Smithers ^^ illustrate a nose built up with a wax
mold to form a parallel-sided slab to aid in the correct adjust-
ment of two opposed fields.

Another method is to produce a rigid shell, to fit the part of
the patient's body under treatment, from plastic materials —
nidrose, plaster bandage, or bexoid — and to cast on it wax
sockets into which the applicator will slip in correct positions.*'*

228 Applied Biophysics

The radium compo or wax not only helps in the correct fitting
of the jig to the patient, but also fills up air spaces with tissue-
like material, so that the standard isodose charts give the correct
dose distribution.

It is also necessary that the correct quantity of dose should
be given to each field. Frequently, this is done by making a
daily measurement of the X-ray output of the tube, and then
controlling the doses by stop watch and adjustment of the tube
milliamperes and kilovoltage. The latter are often difficult to
keep in correct adjustment, especially when radiographers must
watch more than one tube, and the switching on and ofif of tubes
aflfects the line voltage. The aggregate error in a dose may be
considerable, and can be avoided by the use of an integrating
dosemeter with an ionization chamber built into the master cone
of the tube on which the various applicators fit. Such a dose-
meter has been developed by Farmer.^

Theory and Practice

It is evident from the above discussion that much effort can
be spent on the study of dose distributions based on sets of
isodose curves. It is, therefore, well to consider to what extent
the actual dose distributions obtained in the human body may
differ from the charts. The latter are usually based on measure-
ments made in water, so that one step is to consider what dif-
ferences are to be expected in the body. However, although in
the ideal, water-phantom measurements should be made for each
individual tube and applicator, in practice this is too time con-
suming, and usually a radiotherapy center assumes that pub-
lished charts of depth-dose values for the same quality of radia-
tion, focus-skin distance, and field area, will apply. Tables of
depth-dose values based on a survey of published values have
been compiled by Mayneord and Lamerton,-^ and by Quimby.-*^

There are considerable differences between British and Amer-
ican values. This may be due to the use of different phantom
materials — pressedwoods, wax, and rice flour, in addition to
water; to different types of ionization chambers — the thimble

Technical Methods in X-Ray Therapy 229

chamber and the extrapolation chamber ; "^ or even, perhaps, to
the prevalence of a different type of tube in the two countries.
Oil-immersed tubes, where the beam emerges through a layer
of oil, seem to give a more rapid diminution of dose rate with
distance, near the tube, as the oil, by scattering, acts as a sec-
ondary source nearer than the focus. Spiers ^^ has compared
the behavior of a number of materials with water, as phantom
materials. Paraffin wax and rice flour differed in the 200 kilo-
volt range, and pressedwoods in the 100 kilovolt range. ^ The
most suitable substitute for water (suitable also for the filling
of scatter-bags) for the 200 kilovolt range was a mixture by
weight of about 60% rice flour and 40% sodium bicarbonate.

When jigs are fitted to the body with wax molds, it is im-
portant that the wax should behave towards the X-rays in the
manner of water. Some of the dental waxes are much too
absorbent, being loaded with elements of relatively high atomic
number. If a dosemeter is immersed in a water-phantom, and
a piece of wax, etc., is interposed between the dosemeter and
the X-ray source, the change in dosemeter reading is an index
of the difference of the wax from water. Slabs 3 centimeters
thick gave the following diminution of dose rate: parabar (gum
kauri, stearine, and magnesium silicate), 12%; perspex, 4%;
radium compo (gum kauri, stearine, and charcoal powder), 1.7%.

If it is desired to use isodose charts in the study of treatment
of parts of the body of smaller dimensions than the phantom,
e.g., the neck, then the body must be built up with scatter-bags
approximately to the full size. Reinhard and Goltz ^^ have
studied the changes produced by the lack of an adequate thick-
ness. With radiation of 0.9 millimeter copper HVL, about 5
centimeters of material beyond appoint of measurement is neces-
sary to give adequate backscatter there ; differences could be
observed 8 to 10 centimeters preceding the exit surface. The exit
doses were less than those in a deep phantom by 20% for a
10 centimeter thickness, 29% for a 20 centimeter thickness, and
16% for a 30 centimeter thickness.

Sometimes a better dose distribution can be obtained by dis-
carding scatter-bags. Reinhard and Goltz ^^ have shown how

230 Applied Biophysics

isodose curves for beams incident at an angle to the skin, are
affected by omitting scatter material from the wedge-shaped
space between applicator and skin. Considerably greater depth
doses were obtained towards the margin of the beam remote from
the applicator edge in contact with the skin.

Even though it is not possible for a radiotherapy center to
explore, in a water-phantom, all the fields used, a few check
measurements should be made, as wide deviations from pub-
lished values may occur. It cannot even be assumed that an
applicator end is filled with radiation ; sometimes strips as wide
as 1 centimeter at the sides are almost devoid of radiation. This
might be particularly detrimental when glancing-field techniques
are used. Studies of the distribution of dose rate in air across
various fields have been published by Thayssen,^^ Jacobsen,^^
and Attlee and Trout.- Sometimes fields are badly asymmetric.
Ways in which these can be improved by specially designed filters
have been described by Spiegler,^' Meredith and Stephenson,-^
and Flood and Smithers.^^

There still remains the possibility that dose distributions in
the human body may differ from water-phantom measurements.
The bones are more absorbent, particularly of the radiations of
longer wave length, and beams which are tangential to, say, the
ribs or skull, are likely to be considerably affected. The lungs
and air cavities, on the other hand, will give a greater trans-
mission than water. Ouimby, Copeland, and Woods -^ made an
extended series of measurements with 200 kilovolt radiation
filtered by 0.5 millimeter copper and 2.5 millimeters aluminum,
both in a cadaver and in the vaginas of patients wdio were
irradiated both from the anterior and the posterior surfaces of
the pelvis. Backscatter factors agreed well with water-phantom
values for all fields of irradiation. Depth doses in the pelvis were
also in agreement, but through the chest they became progres-
sively greater. Measurements in the thigh agreed with water
measurements until the bone was reached, beyond which they
were up to 30% less. Measurements of radiation transmitted
through the head of the humerus also gave definitely lower depth
dose values.

Technical Methods in X-Ray Therapy 231

The present author has measured the transmission of radiation
of quaHty 0.9 milHmeter copper HVL passed anteroposterior^
through the midregion of a patient's kmg. A dosemeter sand-
wiched between the appHcator and chest wall measured a
backscatter factor of 1.33, compared with the water-phantom
value 1.31. The dosemeter was then arranged at the beam's
exit point on the posterior surface 17 centimeters from the
applicator, and scatter-bags were packed around it to give
a measurement comparable with that at a depth of 17 centimeters
in a water-phantom. The depth dose was 20.5% compared with
1 1 % in water. The fact that the backscatter factor was unaltered
suggests that the diminution of scatter from any particular part
of the lung is compensated by the less absorption of this scattered
radiation on its way to the point considered. Accordingly, it is
assumed that any point in the lung will receive the same amount
of scattered radiation as the corresponding point in water, but
the primary beam will he less absorbed. If the primary beam
has passed through a distance d centimeters of lung tissue of
density o grams per cubic centimeter this is equivalent in ab-
sorption to only od centimeters of water. The radiation which
reaches any point in the water-phantom can be divided into
primary and scattered radiation by the method of Meredith and
Neary.^^ At 17 centimeters deep in water, a surface dose of 131
provides a primary beam dose of 2.20 and a scattered radiation
dose of 12.8. The absorption coefficient in water of the primary
beam is 0.19 centimeter"^, and if we assume there is a 12 centi-
meter path in lung tissue of density about 0.3 this is equivalent
to 3.6 centimeters of water. Therefore the primary beam value
2.20 must be increased by a factor (? + oi9x8.4 __ 5 44^ [^^ it l3e_

comes 12.0. The total dose should therefore be 24.8, and the
corresponding depth dose 19%. This agrees reasonably with
the measured value 20.5%, and suggests that this method could
be used to deduce doses in lung tissue.

Conclusion

It has been the purpose of this paper to survey what seem
to the physicist the best technical methods in X-ray therapy.

232 Applied Biophysics

However, they have been developed in many centers, and it is
doubtful whether there is any one center which employs, as a
routine, a very large proportion of them.

Each radiotherapist develops his own methods. There are,
for example, many skilled radiotherapists who prefer to direct
the beam by judgment, using no special device, except perhaps,
to indicate the position and direction of the central ray. It may
be argued that physical methods can be developed beyond the
clinically useful point, and readers should refer to a communica-
tion by Jacobs ^^ on this question.

References

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2 AUlee, Z. J. and E. D. Trout (1943) Radiology 40, 375.
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5 Ellis, F. (1943) Brit. J. Radiol. 16, 31.

6 Ellis, F. (1946) Brit. Med. Bull. 4, 36 [BMB 804].

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26 Meredith, W. J. and S. K. Stephenson (1943) Brit. J. Radiol. 16, 239.

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Technical Methods in X-Ray Therapy 233

28Quimby, E. H. (1944) in Medical Physics, edited by O. Glasser, New

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39Ungar, E. M. (1945) Brit. J. Radiol. 18, 76.

40 Walker, J. Z. (1940) Brit. J. Radiol. 13, 1.

41 Wilson, C. W. (1942a) Brit. J. Radiol. 15, 355.

42 Wilson, C. W. (1942b) Brit. J. Radiol. 15, 145.

43 Wilson, C. W. (1943a) Brit. J. Radiol. 16, 247.

44 Wilson, C. W. (1943b) Brit. J. Radiol. 16, 2>Z.

ON TECHNICAL METHODS IN RADIUM THERAPY

S. RUSS, C.B.E., D.Sc.

Professor of Physics in the University of London ;

Physicist to the Middlesex Hospital

Introduction

TECHNIQUE in the therapeutic use of radium has been
developed as a result of the changing outlook of the ther-
apist. Surgeons were quick to employ radium when proper
appliances had been devised for containing and manipulating
this substance, but the tendency now is towards a diminishing
use of radium by surgeons for implantation into the tissues.
Dermatologists were no less ready to treat lesions of the skin
with preparations of radium that could easily be applied to the
surface of the body. By suitable choice of metal enclosure, the
therapist could carry out this kind of work with beta-plus-gamma
or pure gamma radiation. This technique survives, but it is
unusual to use beta-ray sources except for lesions which are
essentially skin lesions. Gynecologists have been perhaps the
most outstandingly successful of radium therapists, because their
work has led to far less actual surgery in uterine cancer, and
the miseries of uterine hemorrhage promise to be a thing of
the past.

The advances in technique fall into natural groupings which
have been determined in one of two ways, e.g., a new technique
may be developed as the result of a new medical point of view,
for instance, the substitution of surface for interstitial applica-
tions largely arose from the view that damage to the tissues
was to be avoided at all cost ; or again, a new technique was
developed as a result of the ingenuity of physicists in preparing
radon sources which can sometimes be used in preference to

234

Technical Methods in Radium Therapy 235

radium. But no amount of ingenuity in itself can make any
headway in treatment unless it is embodied in an instrument or
in a process which convinces the therapist of its undoubted
utility and safety.

External Irradiation

The range of this method varies from the application of a few
milligrams in the form of a capsule, to the use of 10 grams at a
time. At the present time, considerable diversity of opinion
exists about the utility of these gram units (the use of the de-
plorable term "bomb" for these units is happily declining ) . What
need is there for mounting 5 or 10 grams of radium into a single
unit as a gamma-ray source when this type of radiation can so
nearly be duplicated by X-rays? The argument may, how^ever,
be presented with equal logic the other way round ; w^hy go to
the trouble of installing complicated and expensive apparatus
which will almost certainly have to be discarded after 10 years'
service, when one can have a most useful source of radiation
requiring little apparatus and a minimum of servicing by a
staff of engineers, a source, moreover, that shows an inappre-
ciable decline over the same period of time ?

As a matter of fact, there are very good reasons why one
source does not exclude the other. It is true that the quantitative
yield of penetrating X-rays from a modern tube at a quarter
of a million volts far exceeds that from a 10-gram radium unit
(perhaps 10 times as big), but the latter has many advantages.
It is often easier to apply to the patient, it is especially suitable
when repeated and prolonged treatments are needed, and its
servicing is so effective that one can almost say that these units
do not suffer from breakdowns. "So it may reasonably be ex-
pected that these units, ranging from 1 to 10 grams of radium,
will be more and more used, provided that the present downward
trend in the cost of radium continues.

Intracavitary Irradiation

The introduction of radium (and radon) into the natural
cavities of the body when they are the seat of disease has been

236 Applied Biophysics

developed on lines which insure, as far as possible, an adequate
dose to the malignant regions with no overdose to the normal
contiguous structures. This is most successfully done, perhaps,
in the treatment of cancer of the uterus and in buccal cancer, but
when growths originate in the rectum or esophagus, there are
greater difficulties in insuring the necessary conditions.

In the treatment of uterine cancer, radium is put into the
body of the uterus, the cervical canal, and the fornices, by means
of special applicators containing radium in platinum thick enough
to insure that practically homogeneous gamma rays are being
used. Supplementary to this disposition of the radium, every
effort is made by the use of packs to keep the normal tissues well
away from the zones of most intense irradition. This is also
attempted when radium is applied to the rectum in cases of
malignancy ; one of the most successful appliances is that devised
by Margaret Tod, who arranged the radium inside a pneumatic
device which could be expanded in situ ; this helps to push the
normal structures awav from the irradiated zones.

For growths of the esophagus, the device of Souttar allows
the introduction of radium into the lumen of the esophagus,
but immediate contact is prevented by means of a Souttar's tube,
which holds the radium axially. A valuable measure of control
and protection is afforded by this device.

Interstitial Radium

Dominici was among the first to introduce radium enclosed
in platinum into the tissues ; the method was developed so that
large volumes of tissue such as occur in mammary cancer were
penetrated at many points by radium tubes 6 centimeters or
more in length with a diameter of several millimeters. An
extensive though not uniform irradiation of the malignant
process occurred under these conditions, but the disadvantages
of 'the method, with its associated trauma, brought interstitial
work into disfavor, and today, it is probably true to say that
if radium therapy can be carried out without recourse to inter-
stitial methods then it is so done. Nevertheless, there are several

Technical MetJwds in Radium Therapy 237

sites where such methods are still the best ; for instance, lesions
of the tongue where, owing to involuntary movement, it is
almost impossible to use any other method properly.

No account of interstitial methods in treatment would be
complete without mention of radon technique. The gas from
radium can be purified so completely that one can handle quan-
tities that represent extreme purity ; the volume of 1 curie is just
less than 0.6 cubic millimeter, and one gram of radium in solu-
tion can yield 25 curies during the course of a year, so that
the total volume of pure gas is only 15 cubic millimeters; the
refinements of technique allow this to be shared among no less
than 10,000 capillary tubes which, when mounted in platinum,
serve as gamma-ray sources, their lengths ranging from 5 milli-
meters to 3 or 4 centimeters.

In any technical discussion upon the use of radon, it soon be-
comes apparent that, in spite of contraindications, it continues
to be used because objections are outweighed by advantages.
It can be said that the outstanding advantage is the adaptability
that attends its use ; in other words, the size, shape, content,
and filtration can be altered to suit the clinical need of the
moment ; moreover, radon "seeds" can be inserted into the
tissues and left there without danger to the patient. Against
this, we have the decline of its activity, which renders it unsuit-
able for treatment which lasts more than a few days, the high
cost of running a radon center, and the danger to technicians
engaged in the work of purification and concentration of the
radon.

Therapeutic Aims and Methods

The three outstanding technical methods of using radium
(and radon) in treatment have been discussed. It remains to
say something of what is the aim behind these methods. What-
ever the radiotherapeutic method in treating malignant disease,
the aim is certainly to destroy all malignant cells, but it is
equally certain that in many cases this is quite imposible if any
regard is paid to the normal tissues of the body of the patient.

238 Applied Biophysics

In most cases, this is due to the fact that growths are ill-defined
in their extent, and this being so, it is evident that unless irradia-
tion is extended well beyond the probable limits of the growth,
some of the malignant cells will escape. We are, in fact, dealing
largely with probabilities, not certainties, in the treatment of
malignant disease ; and an experienced radiotherapist is more
likely to discern these probabilities than an equally clever but
less experienced one. On this basis, it is evident that technical
methods are developments of ingenuity in the best means of
balancing the manifold considerations that are involved in the
irradiation of a malignant growth.

There is indeed a wide difference in outlook between those
who, for instance, plan an extensive irradiation of a breast tumor
by the implantation of radium needles, and those who seek the
same end by the use of externally applied gamma radiation
which can be repeated at intervals determined by the day-to-day
response of the organism. It is the latter working philosophy
which originated in the French School, and which has been
given a rather different orientation by the work of Spear and his
colleagues of the Strangeways Laboratory, Cambridge ; here,
in fact, is a technical method which combines the virtues of
sound biological intuition with the asset of rigid physical control.

If technical methods are to be improved, there must be a
happy balance between biological probabilities and physical cer-
tainties ; it is well, however, not to insist too much on the latter.
Isodose curves are usually derived from measurements upon
media having about the same density as the average of the
tissues concerned in treatment, but there need be no insistence
on the general crudeness of any such similarity. Any assessment
of the differential response of the various structures of the body
to irradiation is a matter not for the physicist ])ut for the
radiologist. It need not be emphasized that judgment upon this
crucial matter will depend not only upon the clinical sense of
the radiotherapist, but on his pathological knowledge. It is one
of the greatest claims to eminence in the field of radiotherapy,
that the French School, led by Regaud, and now by Lacassagne,
has so persistently maintained that this pathological knowledge,

Technical Methods in Radium Therapy 239

not only of the nature of malignant growths, but of their indi-
vidual reactions to irradiation, should be the basis of the scientific
method.

A few words may be said about technical methods in radium
therapy other than in malignant disease. One of the most suc-
cessful applications is in the treatment of uterine hemorrhage,
and it is somewhat remarkable that, in spite of the generally
good results obtained, there is a considerable difference in the
dose employed at different clinics. Early in the study of this
condition, it was found that the dose required to bring about
a cessation of the dominant symptoms varied with the age of
the patient. The following quotation is taken from Elizabeth
Hurdon, Cancer of ilie Uterus (London, 1942).

"The treatment of simple metropathic hemorrhage depends partly
upon the age of the patient, but the severity of the anemia due to
hemorrhage, and the presence of myomata, have also to be con-
sidered. The cases are divided into three groups in relation to the
age incidence and the reproductive function:

Group I Adolescent cases — patients under 20 years of

age.
Group II Child-bearing period — patients from 20 to 40 years

of age.
Group III Includes the menopausal, 40 to 50 years of age, and

post-menopausal cases.

Typical doses for each age group are as follows :

Group I

250 to

300 mg hr

Group II

600 to

750 mg hr

Group III 1,100 to 1,200 mg hr
Screenage is 1 mm platinum and 1.5 mm rubber."

It will be seen that the biggest dose found necessary in the
treatment of this condition is 1,200 milligram hours (50 milli-
grams for 24 hours), yet there are many British workers who
consider that treatment is not adequate with less than 48 hours'

240 Applied Biophysics

exposure, using 50 milligrams of radium. The question arises,
in view of the fact that the technical methods are practically
identical, as to why this wide disparity of doses continues to
operate. If the bigger dose is indeed necessary, how is it that
97% of the menopausal cases cited by Hurdon remained well
without further treatment? On the other hand, if the shorter
exposure is adequate, what ]:»urpose is served by a more severe
one?

Technical Methods in the Future

The methods which have been most highly developed tech-
nicially up till now are the methods developed in the use of the
gram units and in the use of radon ; both big and small quantities
call foi* specialization in design and management.

Advances in pure science in the last 15 years have shown
the feasibility of making ordinary substances radio-active, and
the time may soon be at hand when these will be used in medical
treatment as well as in research. Advances in applied science
during the last year have drawn attention to the possibilities
of using atomic power on a more liberal scale than we have so
far enjoyed. Mere power, however, has not the first claim in
the selective list of requirements among radiotherapists ; what
is primarily wanted is some form of energy which will give a
wider margin of response between normal and malignant tissues,
and at the same time be easily adapted to the purely technical
demands of those called upon to treat malignant growths in any
part of the body.

MILLION- VOLT THERAPY

G. S. INNES, B.Sc, A.M.I.E.E., A.Inst.P.

Physicist and Engineer to the Sassoon Department,

St. Bartholomew^ s Hospital

Introduction

UP TO the year 1930, the maximum voltage X-ray equip-
ment available for X-ray therapy was of the order of 200
kilovolts. With such equipment, it had been demonstrated
that in some types of cancer it was possible to attain a cure
without irreparably damaging the patient. It was not known
whether the failure in many lesions in certain sites was due to a
difference in radiosensitivity, or whether it was due to the im-
possibility of delivering a sufficiently high dose to the lesion.
The problem was not a simple one, being complicated by many
factors.

No matter how high a dose is administered to a lesion, there
are always some malignant cells left intact, and these have to
be overcome by local normal cells if the lesion is to be eradicated.
This can take place only if the normal cells have been less dam-
aged by the radiations than have the malignant ones — that is,
if the normal cells are less radiosensitive. Whether this radio-
sensitivity factor varied with the wave length of the radiations
was not known, but the hope that this might be the case war-
ranted investigation into the unexplored shorter wave lengths.

For optimum results, damage to the normal tissue surrounding
the malignant zone should be reduced to a minimum, otherwise
blood supplies to the normal cells in the zone of destruction will
be cut, reducing their effectiveness. This requires a rapid de-
cline of the X-ray dose outside the zone of required destruction,
and it was forecast that this could be accomplished with the

241

242 Applied Biophysics

shorter wave lengths, due to the sharper dehmitation of the
heam edges.

A third factor arises which might he called the patient's vitality,
over which the therapist has only some small control ; namely,
in making certain that the total radiation energy absorbed by the
patient is a minimum commensurate with the necessary lesion
dose.* Provided that all stray radiations have been excluded,
the energy absorption during the treatment then becomes a
question of the most effective geometric distribution of the re-
quired X-ray beams, both physically and clinically, and of the
physical properties of the radiation used.

Treatment at wave lengths shorter than those obtained with
a 200 kilovolt equipment had l)een carried out in the use of
radium on surface lesions, interstitially, in body cavities, or in
mass in the radium-bomb units. The nearest approach to the
methods employed in X-ray therapy are those of the radium
bomb. The main difference is that owing to the low gamma-ray
output from radium bombs, treatments can be carried out only
at short distances from the patient, limiting the use of the bomb
to lesions at short distances from the skin surface. In order to
obtain the same radiation intensity as that emanating from a 200
kilovolt tube operating at 10 milliamperes 40 centimeters FSD
[Focus-Skin Distance], 1.0 millimeter copper HVL, 1,000 grams
of radium would be required.

However, it had been estaljlished from theory and experiment
that the shorter the wave length of the X-rays, i.e., the higher
the voltage applied to the X-ray tube, the more penetrating the
rays would be and the less the absorption would vary with the
density of the medium. One of the problems in 200 kilovolt
therapy was, and is, the distortion, due to intervening bone, of
the theoretical dosage distribution by an unknown factor. With
the shorter wave lengths this unknown factor .should become less
disturbing.

* The lesion dose is the average dose throughout the lesion specified in rontgens.
It is estimated from a mathematical analysis of the dose distrihution in the patient,
arrived at hy the summation of dose-distribution charts for each X-ray beam. These
charts are obtained by ionization-chamber measurements in a water-phantom.

Million-Volt Therapy 243

X-ray Equipment: Some Technical Considerations

By 1933, a few experimental high-voltage X-ray equipments
had been constructed in the United States, operating at vohages
up to one miUion, but they were too unreHable in operation
to give biological and clinical results which could be as-
sessed. Usually these tubes had at the most only two fixed beam-
directions, necessitating tilting of the patient to the tube, in order
to accomplish cross-fire techniques. This method is deprecated
in Britain, since it is argued that unless the patient is prone,
supine or, for a restricted number of sites, sitting up, it is im-
possible to know the exact position of the various body organs.
Angulation of the tube to the patient is therefore demanded
as one of the essential features of an X-ray tube.

The main ditficultv encountered in sealed tubes in the
attainment of higher voltages was that the increased electrical
stresses applied to the electrodes and envelopes extracted
occluded gas from them, resulting in internal electrical break-
down between the electrodes, and often in the puncturing of the
glass envelope. In one or two instances, tubes were supplied
to withstand 350 kilovolts, but they were never really robust.

In 1932, a pair of 200 kilovolt steel and porcelain, demount-
able X-ray tubes, continuously evacuated by their attached oil
dififusion-pumps, were installed in Sheffield Radium Center.
The oil dif¥usion-pumps operated on the newly developed low-
vapor-pressure Apiezon oils, and did not need the expensive
liquid air traps required on mercury-vapor condensation pumps.
Continuous evacuation and demountability made possible the
cheap replacement of target and ^lament by any mechanically
minded member of the X-ray department. Instead of the usual
sealed-ofT thermionic rectifiers in the attached high-voltage gen-
erator, a pair of continuously-evacuated demountable rectifiers
was fitted.

With the advent of these new oil dififusion-pumps, and the
demonstration that continuous evacuation was feasible and re-
liable, the development of high-voltage continuously-evacuated

H

J-
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244

Million-Volt Therapy 245

tubes became an economical proposition. These tubes had walls
and envelopes electrically better than those of the sealed-off
tubes, but they had previously been barred by their prolonged
gassing.^' ^' ^

Million-volt Equipment at St. Bartholomew's
Hospital, London

The hospital is indebted to the foresight of its Radium
Committee, the generosity of Mrs. Meyer Sassoon, and the
technical skill of the Research Department of Messrs. Metro-
politan-Vickers Electrical Co., Ltd., Manchester, for envisaging
and making available the million-volt plant installed in the
hospital in 1936. The equipment was guaranteed to operate at
600 kilovolts d.-c. 3 milliamperes, with the proviso that con-
tinuous operation at one million volts would be aimed at. In
the first hour after final erection, 700 kilovolts 4 milliamperes
was attained, but at voltages greater than this, the tube became
unstable in operation.^

During the next two years, while many modifications and
additions were made to the tube, treatments were carried out
at 700 kilovolts, giving the medical and physical staff an insight
into the problems to be encountered at higher voltages. By 1938,

a Rotable applicator cylinder

b Moving floor

c Adjustable diaphragm for limiting size of emergent beam

d 8-ton lead protection cylinder, used as sbutter by rotating

e Steel tube vacuum envelope

/ Gold or copper target head

g Aperture in lead cylinder

h Lead block suspended from roof, blocking upwards beam, when shutter

in "safe" position (as shown)

i Parallel plate ionization chamber across beam

/ Cathode support tube

k Six-element filament assembly

I Negative mid-potential steel sheath

tn Target support tube

n Positive mid-potential steel sheath

0 Support insulators

p 04 (vacuum) pumping plants

q Treatment couch

r Control pedestal for tube angulation and floor movement

X Barytes X-ray protection walls between treatment room and H.T. rooms

FIG. lb. MlLLION-VOI.T X-RAY TuBE

Tube in the treatment room, showing the light-centering device and diaphragm

246

Million-Volt Therapy 247

the plant was operating continuously at one million volts and
since then some 10,000 hours of operation have been accom-
plished in spite of many near misses by bombs and V-weapons.
Although there was considerable damage to the buildings on
many occasions, the plant suffered little and at no time were
treatments not carried out on schedule, except when power
supplies were interrupted.

The equipment is so designed that, as far as possible, methods
of treatment previously employed at 200 kilovolts can be repeated
with the new tube . The tube (figure 1 a, b) spans the treatment
room (X to X) and from the center of its span can emerge the
X-ray beam, the direction of which can be varied from pointing
vertically downwards to 110° upwards. This is accomplished
by rotation of the outer sheath of the tube (a). Adjustment of
the patient to the tube beam is accomplished by making the
center part of the treatment room floor (b) under the tube
traversible vertically through 7 feet [about 2.2 meters]. This is
necessary, since it would have been difficult to traverse the 32
feet long [about 9.75 meters] tube, which weighs nearly 12 tons
[about 12,192 kilograms]. The minimum FSD obtainable with
ease is 60 centimeters, comparable with that used at 200 kilovolts.

Beam limitation at 200 kilovolts is done by lead-lined boxes
called applicators, fitted with end limiting stops of the required
size. At a million volts and 100 centimeters FSD, such appli-
cators, to be effective, would weigh some 200 pounds [91 kilo-
grams] and would be rather expensive and difficult to change.
An adjustable diaphragm (c) was therefore fitted on to the
tube outer sheath, built up of twin 1.5 inch [about 3.8 centi-
meters] thick adjustable lead stops, giving any beam size from
5 X 5 to 40 X 40 centimeters at 100 centimeters FSD. It is pos-
sible to use the diaphragm down to 60 centimeters FSD, but
beam positioning then becomes awkward. The diaphragm has
a light-beam device attached, indicating the size and position
of the X-ray beam in space. The X-ray beams obtained from
the diaphragm are not perfect, since they have penumbral edges
caused by combination of a large focal spot, 2.5 centimeters,
with the position of the stops at half the distance from the focus.

248 Applied Biophysics

when used at 100 centimeters. The advantages, however, out-
weigh this imperfection, and in the future a Hght secondary
diaphragm may be added.

Inside the outer sheath (a) on which is mounted the dia-
phragm, is a protective lead cyHnder (d), which itself surrounds
the steel vacuum envelope of the tube (e). This lead cylinder,
which weighs 8 tons, gives an effective protection of 6 inches
of lead in any direction relative to the focal spot on the target
(f). The protection is so effective that with the tube operating
at full excitation — one million volts 4.5 milliamperes — the X-ray
leakage into the treatment room is only one half of tolerance
dose (10^ rontgens per second), a degree of protection rarely
encountered in 200 kilovolt tubes. The lead cylinder is also
used as the X-ray shutter of the tube. There is one aperture
in the lead cylinder opposite the target head, which aperture (g)
in the safe position points upwards into a six-inch-thick lead
block suspended from the treatment room roof. This block pre-
vents the emergence of the X-rays upwards into the treatment
room. Providing the treatment room doors are shut, the whole
of the lead cylinder can be made to rotate by pushing a control
button in the control room, and by automatic interlocks it stops
rotating when its aperture is aligned to that of the diaphragm
on the outer sheath, so permitting the emergence of the X-ray
beam in* the required direction through the diaphragm stops.
Just behind the diaphragm is mounted a three-plate ionization
chamber (i), which indicates on an instrument on the control
desk either the X-ray intensity or the dose given during an
exposure. Mounted on tlie control desk are also direct-reading
kilovoltmeters, indicating the actual kilovoltage applied to either
end of the tube and the sum of these, irrespective of load current.
These are electrostatic voltmeters which operate from a definite
proportion of the kilovoltage applied to each end of the tube,
obtained from oil-immersed resistance potentiometers connected
from each end of the tube to earth.

The high voltage for the tube is supplied by two 500 kilovolt
Cockcroft zb d.-c. generators, comprising transformer, con-
densers, and four continuously-evacuated thermionic rectifiers

Million-Volt Therapy 249

each, and operating from the a.-c. mains. All vacuum and elec-
trical operations are indicated on a power-station type of illumi-
nated diagram, facilitating fault finding.

The treatment and high-tension rooms are enclosed in walls
built of some 125 tons of interlocking barytes bricks, so effec-
tively preventing the egress of X-rays, that it is possible to store
films within a few feet of the treatment room.

In this equipment, we have a simple, controllable, safe source
of high-voltage X-rays, not quite as hard as the gamma rays
from radium, but equal in intensity, under the same geometrical
conditions, to 7,000 grams of radium.

During the war no development work on X-ray tubes and
equipment has been possible in Britain, luit in the United States,
a number of different types of high-voltage X-ray equipments
have been produced, one in particular being very compact, tube
and resonating transformer being housed in a tank some 6 feet
[1.8 meters] long and 4-9- feet in diameter. It is also of interest
to note that during the German occupation of Norway, Nor-
w^egian engineers and physicists constructed and operated a 1.5
million volt Van de Graaff generator and multiacceleration tube.

Physical Investigations on Operating Conditions

When the treatment of patients with the million-volt plant
commenced, there were few physical data available regarding
the properties of the short-wave length rays so generated, and
a complete investigation had to be made to find the optimum
operating conditions to attain ( 1 ) the shortest economical wave
length and (2), at the same time, the best geometric arrange-
ment to give the highest % depth dose in the patient, with a
reasonable X-ray intensity. Since the primary object of the
whole investigation was to find whether the radiosensitivity of
malignant cells, in vivo, increased with reduction in the X-ray
wave length, the tendency w^as to bias (1) in preference to (2).

The properties of generation of X-rays, by the stopping of
high-speed electrons by a target, are such that, although the
electrons have all, in our case, a million volts equivalent velocity,

250 Applied Biophysics

the emergent X-ray beam is a heterogeneous one composed of
wave lengths varying from the shortest, which has a quantum
energy equivalent to that of the original electron, to rays which
just come through the tube wall. The peak intensity is at about
700 kilovolts, and the mean about 450 kilovolts equivalent. Pass-
ing such a heterogeneous beam through single or composite
metal filters, the long wave lengths are absorbed to a greater
degree than the short wave lengths, resulting in a hardening
(shortening) of the average wave length of the emergent beam.
What is more important, however, is that the very soft (long)
wave length rays are completely removed. These cause con-
siderable damage to the first few millimeters of tissue and, as
they do not penetrate further, they do not contribute to the
lesion dose.

It was found that there was little difference between lead
and tin filters, the lead, if anything, being slightly more efficient.
Backing of the lead filter by tin and copper was not found
necessary, presumably since the 4.2 millimeter steel wall of the
tube effectively removed the anomalous lead radiation.^

The distribution of dose in the patient is a much more com-
plicated problem and, to simplify physical investigations, it is
carried out in a medium which has the same electron density
as the average of all the body components. Water is one such
medium, while there are others of more complicated nature. ^^
The relationship between (a) the dose at any point in the medium
to (b) the dose at the surface of the medium at the beam center,
when expressed as a percentage, is called the Percentage Depth
Dose (%DD), while the chart giving the %DD-distribution in
a plane by lines joining points at equal dose levels is called an
isodose. The dose at a depth is made up of many components,
and for general purposes here they can be divided up into three :
direct beam, backscatter, and forward scatter. The direct beam
is that part of the dose originating from the ionization produced
at the point by absorption of X-rays from the part of the main
beam which has penetrated to the depth. Backscatter is the dose
originating from secondary X-rays scattered back from the part
of the medium beyond the point of measurement, while forward

Million-Volt Therapy

251

scatter is from secondary scatter from the part of the medium
above the point of measurement.

Investigation into the variation of %DD with filtration of the
X-ray beam indicated that not only was the lead filter the most
efficient in increasing the ''^ DD, but also that the maximum effi-
ciency was between 0 and 1 millimeter of added filter. With
heavier filters, the improvement was linear but less noticeable.
( See figure 2, curve 4. ) It will be noticed that the criterion of
efficiency is the improvement of %pD in a 10 X 10 centimeter

% DD

♦•os.ofo

T — I r— T 1 — I — I — I 1 — r

XOO 90 ao 70 60 50 40 30 20 10 0

FIG. 2. Percentage of Beam Intensity Left

Abscissae = % intensity. Ordinates = % depth dose at 10 cm depth

Curve 4. Percentage of depth dose with"" increasing lead filtration, filter thickness
marked on the curve, plotted against residual beam intensity. 10 X 10 cm, 100 cm
FSD, 1,000 kv.

Curve 6. Percentage depth dose with FSD, FSD, marked on the curve, plotted
against residual beam intensity. 10 X 10 cm, 2 mm lead added filter, 1,000 kv.

field at 100 centimeters FSD plotted against percentage of the
beam intensity left. The improvement of the %DD with FSD
is given in figure 2, curve 6, which shows that the maximum
effi^ciency of improvement is produced between 60 and 80 centi-

252 Applied Biophysics

meters FSD ; improvements at distances greater than this being
slower but appreciable. If %DD improvement were the main
object, the optimum condition would be about 0.5 millimeter
added lead filter and as long a FSD as possible, since the effi-
ciency of improvement is greater by FSD than by filtration at
this voltage.

In our case, however, where the main investigation was
whether there was an increase in radiosensitivity of lesions with
reduced wave lengths, a harder beam obtained with a 2 milli-
meter lead filter was decided on, with a FSD of 100 centimeters,
giving an X-ray output of 40 rontgens per minute, comparable
with the output of 200 kilovolt equipment.

Physical Advantages of the High-VoUage Beam

Since previous experience had been confined to 200 kilovolt
X-rays, the main interest physically lay in a comparison between
the behavior of the beams in a phantom, and an attempt has
been made to formulate reasons for the differences. The main
improvement with reduction in wave length is the increased
penetration, but the %DD is a complicated feature in which
variation of back- and forward scatter, FSD, depth, absorption-
coefficient, and field area all play a part, and an attempt was
made to sort out these effects bv measurement and calculation.
Figure 3 gives the proportions of direct, back- and forward
scatter obtained as a percentage of the depth dose on the beam-
center-line for 10 X 10 centimeters beams at 40 centimeters FSD
200 kilovolts and 100 centimeters FSD 1 million volts. At the
surface at 200 kilovolts, the dose is 71% direct, 29% backscatter,
while at 1,000 kilovolts, it is 93^/o direct and 7% backscatter.
As we progress through the phantom at 200 kilovolts, the direct-
beam component decreases more rapidly not only relatively, but
also absolutely, while at 10 centimeters depth it becomes even
less than the backscatter component. At 1,000 kilovolts, the
backscatter component remains only a small portion of the dose.
The forward scatter in both cases increases rapidly and is of the
same order.

Million-Volt Therapy 253

The direct component of the beam can be represented by
Id and is

Id — lu^

where I^ is the air dose at the surface — FSD ; F ; ^i, the absorp-
tion-coefficient and Id the dose at depth d, due to direct beam.
Both the backscatter and forward scatter components will in-
crease with field area up to a maximum, beyond which any
further added beam area will not contribute to the central dose,
since it will be beyond the range of the secondary scatter.

From the curves and the above, certain forecasts can be
made. (1) Since the penetration, i.e., the direct beam, is higher
at 1,000 kilovolts, and the greater portion of the dose at all
depths is due to direct beam, the depth doses will be greater
than those met with at 200 kilovolts (the forward scatters being
nearlv the same). Not onlv will this be the case but, since at
1 ,000 kilovolts so little of the dose at a depth depends on scatter,
there should be little change in %DD with field area, quite
contrary to 200 kilovolt experience, where the %DD is governed
to a greater extent by the backscatter and hence by field area.
Further, the improvement with 1,000 kilovolts will be the
greater, the greater the depth. At 200 kilovolts, there is little
change in %DD with FSD beyond 50 centimeters FSD, and this
can be understood by examining the information in figure 3.
Since the direct-beam contribution is a small portion of the dose
at the depth, any variation in its value due to alteration in F
(in the formula) will be masked in the %DD by the small part
it takes in the whole. At 1,000 kilovolts, on the other hand, the
direct contribution even at 20 centimeters depth is over 50%
of the dose, so increases in the direct component by increase in
the FSD will be appreciable in the %DD.

Figure 2, curve 6, indicates that the last deduction holds,
while figure 4 indicates that the forecasts about relative %DD
at 1,000 kilovolts and 200 kilovolts are along the lines indicated.
The gain in small field sizes is particularly noticeable, being as

254

Applied Biophysics

high as 50% increase at 10 centimeters depth for a field 20
square centimeters. This opens up many new avenues in treat-
ment design, which will be indicated later. Even for large beams,
the improvement, though small (about 12%), is of importance

T — T 1 1 1 1 r

6 10 12 14 16 18 20

FIG. 3.

Abscissae = depth in cm

Ordinates = components as % of % of depth dose

1. 1,000 kv direct beam component as a % of the % of DD

2. 1,000 kv forward scatter as a % of the % of DD

3. 1,000 kv backscatter as a % of the % of DD

4. 200 kv direct beam component as a % of the % of DD

5. 200 kv forward scatter as a % of the % of DD

6. 200 kv backscatter as a % of the % of DD

in many cases of opposed-field technique. Further, with the re-
duction in backscatter, and also since the forward scatter is,
with the higher voltages, more in the forward direction, the
high-voltage X-ray beams show a much sharper delimitation on
the geometric edge of the beam and a flattening of the isodose
contours.

Million-Volt Therapy

255

All these physical improvements make posible many altera-
tions and refinements in techniques developed for 200 kilovolt
therapy, and some methods quite inapplicable at 200 kilovolts
have been introduced. There is one other factor which has to

lo 12 14 16 le 20 cm
Tissue Depth in cm
FIG. 4.

Abscissae = tissue depth in cm

Ordinates = ratio tissue dose 1,000 kv X-rays

tissue dose 200 kv X-rays

Ratio of the tissue dose with 1,000 kv DC. X-rays (9.0 mm Cu

HVL) to that with 200 kv DC. X-rays (2.0 mm Cu HVL) for the

same input skin dose at 100 cm FSD and various field sizes

be brought in, out of sequence, before it is possible to discuss
alterations in treatment technique, viz., skin reaction.

Alteration in Skin Reaction

Tests were carried out on corresponding skin surfaces on
patients with X-ray beams of identical dimensions under the
same physical conditions except for the beam qualities. The
control beam was one of 300 kilovolts (3.35 millimeters Cu

256 Applied Biophysics

HVL), while the experimental beam was 1,000 kilovolts (10
millimeters Cu HVL). The dose required in one sitting to pro-
duce the same skin reaction was 50% greater with the 1 000
kilovolt than with the 300 kilovolt beam. Theoretically, only
part of this alteration in skin response can be accounted for by
the reduction in the photoelectric absorption in the sulphur in
the skin with the shorter wave lengths, the remainder being so
far unexplained, unless it is due to a radiosensitivity change.
The results conform well with those encountered in gamma-
ray treatment. This reduction in skin response also opens up
improvements in technique, but more especially makes possible
a reduction in the skin reaction which has undoubtedly an
indirect effect on the patient's well-being, during and after
treatment.

Modifications in 200 Kilovolt Techniques Possible by
Employing Million-volt X-rays

1. Whereas it was impossible to employ small fields in the
treatment of small lesions buried deep in the body, e.g., rectal
carcinoma, owing to the poor depth dose of such fields, at 1,000
kilovolts, it becomes possible and economical to employ multiple
small fields, even through the remote lateral skin surfaces.

2. In intrinsic carcinoma of the larynx, it is customary and
necessary at 200 kilovolts to employ three fields — two opposed
laterals, and an anterior field. At 1,000 kilovolts only the two
opposed laterals are necessary, which simplifies and increases
the accuracy of the technique.

In this type of case with two opposed beams, it is found that
blocks of tissue up to 14 centimeters thick receive nearly uniform
irradiation throughout by two opposed million-volt X-ray beams.

3. In many cases at 200 kilovolts, it is found necessary to
employ beams angulated in three dimensions (spinal cord and
bladder). So far, at 1,000 kilovolts, it has not been found neces-
sary to employ such beams except in a few brain cases where
the eye has to be avoided. Setting up beams accurately in three
dimensions and calculating the necessary isodoses is a difiicult

Million-Volt Therapy 257

process, and one which should be avoided unless the most
elaborate equipment and calculating devices are available,

4. Where originally at 200 kilovolts it was quite impossible
to attain a uniform and sufficient dose owing to the patient's
size, e.g., carcinoma of the breast of a large woman, even with
the small increase in depth dose in large beams at 1,000 kilovolts,
few cases have been encountered where it is impossibe to ad-
minister a greater uniform dose to the lesion than to the skin.

5. Where, at 200 kilovolts, lesions have had to be approached
by beams through organs, the damaging of which incapacitates
the patient, e.g., glancing beams in carcinoma of the esophagus
damaging lung tissue, at 1,000 kilovolts, most of the lesion dose
can, because of the increase in depth dose and the reduction in
skin response, be contributed by the anterior and posterior fields,
leaving only a small portion to be administered by the glances
through the lung.

Comparison of the Physical Data Obtained for
Treatment of Carcinoma of the Rectum

Figure 5 gives the cross-section outline at the level of the
pubic crest in the case of carcinoma of the rectum. This type
of case has been chosen because it shows very well many of the
advantages of million-volt therapy, when compared with 200
kilovolt therapy. The case is treated with ten 18 X 8 centimeter
beams at the angles indicated, each field being given 100 units
of X-rays on the skin. On the left half of the section is shown
the isodose if the case is treated at 200 kilovolts with the usual
40 centimeter FSD and Thoraeus filter. On the right-hand side
is the isodose if the patient is- treated at 1,000 kilovolts 100
centimeters FSD, 2 millimeter lead filter (HVL 9.3 millimeter
Cu ) .

The dififerences are obvious. The lesion, which is a small one,
is surrounded by the 370*^^ contour at 1,000 kilovolts and by
the 250% contour, approximately, at 200 kilovolts, indicating a
50% improvement with 1,000 kilovolt rays in the lesion dose,
for the same input dose on each field. Outside the lesion, the

258

Applied Biophysics

L.A.L. 18x8

30°

18x3
90"

18x8
65"

FIG. 5. IsoDosES ON A Transverse Section of a Carcinoma of hie Rectum

a. 10—18 X 8 40 cm FSD fields
with 200 kv DC. X-rays (HVL
2.0 mm Cu)

b. 10—18 X 8 100 cm FSD fields
with 1,000 kv DC. X-rays
(HVL 9.0 mm Cu)

dose declines rapidly at 1,000 kilovolts, whereas at 200 kilovolts,
even up to the skin, the dose is still 80% of the lesion dose,
unnecessarily causing damage to normal tissue and disturbances
to the patients. The maximum skin dose is the same in both
cases. If, now, 6,000 r is to be given to the lesion in 5 weeks,
the following results are obtained :

Data 1,000 kv 200 kv

Lesion dose (5 weeks) 6,000 r 6,000 r

Dose per field 1,620 r 2,400 r

Dose per day 650 r 960 r

Maximum skin dose 3,400 r 5,030 r

Integral dose* 40 Mgr 65 Mgr

It is doubtful if it would be possible to attain 6,000 r at the
lesion, at 200 kilovolts, since the skin dose is probably above
the tolerance, also the dose per day is high and would impair
the patient's vitality. The integral dose is a measure of the
dose absorbed by the patient, being the sum of the products
of volumes of tissue and their respective doses. 40 Mgr is nearly

* Megagram-rontgens.

Million-Volt Therapy 259

the upper limit and it is doubtful if many patients would survive
65 Mgr.

Similar conclusions can be arrived at for other lesion sites,
and as a matter of routine all cases are isodosed at a million
volts, each case being treated as an individual case with its
individual problems.

Effect of the Variation of Density through the Body

Considerable investigation has shown that at 200 kilovolts the
isodose curves calculated for treatments have always erred on

20

B>

\:^Y4<^<<^'

J \

7 9^

h

^ 7 \.'

/ J^

\^/^ 0

'"' Vo Art*
\ ^ ""

f *

1. 1 ?9'

FIG. 6. Pin-anu-Akc Device

the optimistic side, particularly where beams have had to pass
through bone. At 200 kilovolts, a particular skull absorbed 15%
more than the same thickness of tissue, while at 1,000 kilovolts
there was only 4.5% more absorption. This would mean that
in the treatment of a brain tumor at 200 kilovolts, the lesion
dose might be at least 15% lower than calculated. A particularly

260

Applied Biophysics

bad case came to light in an investigation into distribution, in
the course of postoperative radiation in carcinoma of the breast,
where, at 200 kilovolts, the measured dose was one-third of that
calculated, mainly due to the fact that the angles of the beams,
at that particular point, were the same as the ribs.

FIG. 7. Device for Measuring the Angle of a Line Joining Two Points

At a million volts, discrepancies have been small and rarely
more than 10%. This may be partly due to the fact that so little
of the dose at a depth depends on scatter, and the surrounding
conditions do not therefore aflfect the dose to any appreciable
degree.

Because of these discrepancies, there is sometimes a tendency
to feel that the complicated and sometimes laborious calculation
of the theoretical distribution of radiation is unnecessary. It
must be pointed out that the cases quoted are the worst en-
countered, and that unless investigations commence from some
mathematical basis, particularly when analyzing a group of sim-

Million-Volt Therapy 261

ilar cases, it will be impossible to draw any dosage conclusions,
or to attempt by models to simulate the actual patient and so
solve the troublesome features mathematically. At a million
volts, the variations are disappearing, and an assessment of
results of different geometric methods of treatment is consider-
ably helped by a full physical investigation.

Aids to Accurate Technique

The light beam indicating the position and size of the X-ray
beam can be made to travel along the axis of the tube and, by
rotation of the outer sheath of the tube, at right-angles to the
tube-axis. These two movements are often of assistance, giving
an accurate idea in many cases of the position of the emergent
beam. Beam direction has been kept as simple as possible, there
being no three-dimensional angulation of beams if it can be
avoided, and the patient is either parallel or at right angles to
the tube-axis. The "pin-and-arc" device* of Dobbie ^ is used
for all angular directions, while a very simple device** is used

* The pin-and-arc device is, in effect, a large protractor, mounted on a stand with
its center removed and a retractable central pointer fitted. In the sketch (figure 6),
the pointer is shown dotted at the center of the protractor (point A). Rays are
marked on the protractor panel at one-degree intervals radiating from A, with zero
vertical. The protiactor is set in the correct position with the aid of a plumb-bob
attached at the right-hand top corner. If it is required to direct the center of a
beam at a definite angle through a point inside a patient, the location of this point
relative to a skin-mark vertically above it being known, the device is used as follows.
In the sketch, the point to be aimed at is A, and it is, say, 9 centimeters below the
skin mark B. The retractable protractor central point is raised 9 centimeters from
its zero point, as indicated on the scale at C, and the device is arranged so that the
point is in contact with the skin mark B. The point A in the patient is then at the
center of all the protractor rays and, if the required angle is produced backwards
onto the patient's skin, the central point of entry, D, of the X-ray beam is obtained.
The depth (AD) of the point A from the central point of entry (D) of the beam
is obtained by measuring the distance of^D from a 30 centimeter arc E, inscribed
on the protractor from the center A. (AD = 30 centimeters less DE centimeters.)
** See figure 7. A hoop, U-shaped, is fitted with a fixed point A, and an adjustable
pointer B on the other arm of the hoop, adjustable so that the distance between A and
B can be varied. On the hoop is fitted a protractor and plumb-bob C, which reads
0 degrees when AB is vertical. If in the sketch the center line of a beam has to
enter at A and emerge at B on a patient's head, the hoop points are adjusted to
these points and the plumb-bob protractor reading is taken. This gives the angle
required relative to the vertical. With the known divergence of a beam's edge the
device can also be used if the required in-and-out positions of the beam edge are
known.

262 Applied Biophysics

for measuring the angle in space of the line joining two points
on a patient. This takes the place of an emergent pointer, which,
to be of any use, must be really rigid, a difficult mechanical
problem at the relevant distances. Instead, the ingoing and
outgoing points required are marked and their angle is measured
directly and set on the tube.

X-ray photography at 1,000 kilovolts on patients has served
as a further check on arrangements, the films obtained being
quite readable, and various bony markings just being visible.
The films are slightly improved if 2 millimeters of lead is placed
between the patient and the film. This tends to eliminate the
scatter. The softer the scatter, the more it obliterates the detail,
since the film response is greater for the longer wave lengths.
The film should be given 2 r. This technique has been particu-
larlv successful in carcinoma of the rectum, where a lead-loaded
catheter in the rectum indicates the required features.

Conclusion

Even with the limitation that 200 kilovolt techniques have
been followed, significant dififerences in favor of million-volt
therapy have been found in the treatment of certain cancers,
e.g., of maxilla and breast. There are striking differences in
carcinoma of the rectum, where, in at least a third of the cases
treated at one million volts, disappearance of the growth has
occurred, while at 200 kilovolts it is extremely rare for this type
of cancer to show any response at all.^

Whether the improved clinical results in the types mentioned
are directly due to the change in wave length of the bombarding
rays, or to the improved and simplified arrangements made
possible by the physical properties of these rays, it is impossible
to say, as the two effects cannot be separated. However, l)oth
the physical and clinical results are such that they lend support
to the view that a further increase in voltage to the 5 to 10
million-volt range, is likely to give still better clinical results.

Acknowledgment. — The author wishes to thank Dr. N. S.
Finzi, director of the X-ray departments, St. Bartholomew's

Million-Volt Therapy 263

Hospital, for permission to publish this article, and acknowledges
the clinical work of Mr. Ralph Phillips, M.S., f.r.c.s., medical
officer in charge of the therapy departments, summarized herein.

References

' 1 AlHbone, T. E. and F. E. Bancroft (1934) Brit. J. Radiol. 7, 65.

2 Allibone, T. K., V. E. Bancroft and G. S. Innes (1939) /. Insin. Elect.

Engrs. 85, 657.

3 Beetlestone. A. and G. S. Innes (1934) Brii. J. Radiol. 7, 83.
4Burch. C. R. (1929) Proc. Roy. Sac. A, 123, 271.

SBurch, C. R. and C. Sykes (1935) /. Instn. Elect. Engrs. 77, 129.
6Dobbie. J. L. (1943) Brit. J. Radiol. 16, 36.

7 Mayneord, W. V. and J. E. Roberts (1935) Brit. .J. Radiol. 8, 341.

8 Phillips. R. F. (1945) Supcrvoltage X-ray Therapy, London.

' 9 Phillips, R. F. and G. S. Innes (1938) Brit. J. Radiol. 11, 498.
10 Spiers, F. W. (1943) Brit. J. Radiol. 16, 90.

PROTECTIVE METHODS IN RADIOLOGY

W. BINKS, M.Sc, F.Inst.P.
Physics Dit^ision, ISational Physical Laboratory, Teildington,

Middlesex

Introduction

WITHIN a few years of the discovery of X-rays and
radium, it had been estabHshed that the rays might be
injurious to the health of the user. Many workers,
through ignorance or indifference, developed burns and derma-
titis, while some even lost their lives. In 1915, following a dis-
cussion on protection for X-ray workers, the Rontgen Society
devised a set of suggestions regarding safety measures, but
during the next few years, due either to continued indifference
of the workers or to a large increase in the amount of X-ray
work undertaken by hospitals as a result of the war of 1914-18,
there occurred a series of fatalities which greatly disturbed public
opinion. This led to the formation in 1921 of the British X-ray
and Radium Protection Committee, which issued its preliminary
report (Memorandum Xo. 1) in July, 1921. Other committees
were set up at about the same time in other countries, e.g., the
Safety Committee of the American Roentgen Ray Society, and
the Commission du Radium, initiated by the Academic de
Medecine.

The preliminary report of the British Committee not only
indicated the way to ensure efficient protection against X-rays
and radium gamma rays, but also drew attention to the necessity
for suitable working conditions, condemning the practice of
locating X-ray departments below ground level, where natural
lighting and ventilation were often inadequate. In Memorandum
No. 2, issued In' the committee in December, 1921, heads of
X-ray departments of hospitals and other institutions were
strongly advised to safeguard themselves and their staffs by

264

Protective Methods in Radiology 265

insisting upon inspection of their departments, and of the various
protective apphances, by the National Physical Laboratory.

Influence of Early Protection Recommendations on
the Design of Sets

The British Committee insisted that a primary precaution in
all X-ray work was to surround the X-ray tube as completely
as possible with adequate protective material. As lead had a
high absorptive value and was easily procurable and workable,
it became the common practice to place the tulles in lead-lined
boxes. These were, however, heavy and clumsy, and hindered
the radiologists in their work. Accordingly, efforts were made
to reduce the size and weight, without sacrificing any of the
protection. These efforts led to the introduction of the so-called
"self-protected" tube, of which the first example was produced
by N. V. Philips' Gloeilampenfabrieken, Eindhoven, Holland.^
The main body of the tube was a chrome-iron cylinder, to which
glass was sealed directly. Surrounding the cylinder was a lead
sheath of sufficient thickness to absorb practically all the pri-
mary radiation from the target, with the exception of the useful
X-ray beam.

Another unsatisfactory feature of early X-ray tubes and high-
tension generators was the risk of electrical shock associated
with their operation, since various parts of the equipment, work-
ing at several thousand volts, were often exposed. The British
Committee suggested various precautionary measures, such as
the introduction of earthed metal guards, the reduction of the
high-tension conduit system to a minimum, and the mounting
of the overhead conductors as high as possible, out of harm's
way. These measures, though obvious, had not previously been
generally adopted. A further advance was made in regard to
high-tension protection by enclosing the tube and transformer
in a single container and immersing them in oil. Generally
speaking, such units were somewhat limited in regard to move-
ment. In 1928, Bouwers "* designed shock-proof equipment which
overcame this disadvantage. The tube was mounted in an earthed

266 Applied Biophysics

case and connected to the high-tension generator by means of
shock-proof cables. This permitted the tube to be freely moved
with respect to the generator. In recent years, particularly with
super-voltage X-ray equipment, operating at voltages of 1 million
volts or more, there has been a reversion to the scheme of
enclosing the tube and generator in a single earthed metal tank.
Reduction in the size of the apparatus has been achieved
by using freon gas *' or air under high pressure -^ as the in-
sulator.

Incidentally, the shielding of high-tension parts has led to
improvements in another aspect of safeguarding the health of
X-ray workers. It had early been observed that workers in
X-ray departments complained of headaches and exhaustion, and
of inflammatory conditions of the respiratory tract. These effects
were attributed to nitrous fumes and ozone, generated by brush-
discharge from sharp angles and points on the high-tension
system. Subsequent experiments indicated that such effects as
irritable cough, exhaustion, and blood changes occurred if the
ozone content of the air exceeded 0.5 milligram per cubic centi-
meter. It was concluded that the eft'ects observed in X-ray
workers bore a great resemblance to the symptoms of ozone
poisoning. Clearly, the introduction of shock-proof systems,
with the consequent elimination of brush-discharge, led to a
further improvement in working conditions.

International Recommendations

At the first international congress of radiology, held in London
in 1925, the question of international agreement on the main
principles of protection was discussed. Three years later, at the
second international congress, held in Stockholm, the British
Committee submitted its recommendations as a basis for agree-
ment, and these were accepted with but few changes. The Inter-
national Commission ^'^ stated that its recommendations were
designed to "deal only with the more essential matters involved,
minor questions of detail being left to each country to elal^orate.
The question of seeking legal authorization for such recom-

Protective Methods in Radiology 267

mendations is left to each country to deal with as appears to
it best."

Most countries have, up to now, preferred not to take legisla-
tive measures. In Great Britain, the safety measures recom-
mended by the British X-ray and Radium Protection Com-
mittee ^^ receive the support of State Departments, such as the
Ministry of Health and the Ministry of Labor and National
Service, but those in charge of X-ray and radium departments
are not compelled to adopt the safety measures nor to submit
to inspection of their departments by the National Physical
Laboratory. The recommendations have, however, in general,
been followed by hospital authorities and factory managements,
while the manufacturers of X-ray equipment have played an
important part in the progressive improvement in conditions
by designing equipment and departments in conformity with
the committee's proposals. It may be mentioned that the Min-
istry of Labor and National Service issued an Order No. 703
on April 1st, 1942, regarding the health and safety provisions
for factory workers engaged in the use of radioactive luminous
compounds. The Order does not, however, specify any tolerance
doses, and the inspections of luminizing departments which are
carried out by the National Physical Laboratory on behalf of
the Ministry are based upon the tolerance doses suggested by
the British Committee.

In the United States, safety recommendations are prepared by
the Advisory Committee on X-ray and Radium Protection. ^-^' ^

Tolerance Doses for Ionizing Radiations

In toxicology, it is important^ to know what quantity of a
particular poison can be tolerated without ill effects. The same
position holds for ionizing radiations of all types, particularly
those of a more penetrating character, since complete protec-
tion against them is, in the light of practical considerations,
impossible. Before any protective schemes can be formulated
on a sound basis, it is necessary to survey the various types
of work undertaken with ionizing radiations and to have a com-

268 Applied Biophysics

plete knowledge of the ill effects which such radiations can
produce. It is further necessary to know what quantity of each
type of radiation a person can receive continuously without
suffering any ill effects. This quantity is called the "tolerance
dose." A subsequent task in formulating the scheme is to try
to express the particular tolerance dose in terms of a specifiable
and reproducible biological standard, which in turn can, for
preference, be measured in terms of a physical unit.

Of the present protective schemes, it can be said that they
are built on as sound a basis as existing knowledge of the ill
effects of various radiations permits. As more evidence regard-
ing blood changes and genetic effects comes to light, it may be
necessary to amend the present estimated tolerance doses and,
consequently, the protective schemes themselves.

As regards the effects of X-rays, clinical observations in
different countries led to various estimates of the tolerance dose
in terms of a somewhat uncertain surface biological effect,
namely, the erythema. An average value of the figures pub-
lished between 1925 and 1928 indicated that a person could

tolerate a dose in 3 davs correspondino[ to of the amount

1,000

of radiation re([uired to produce an erythema. Meanwhile,
work had been in progress with a view to establishing a physical
unit for the measurement of quantities of X-radiation. In 1928,
the rontgen (r) was accepted internationally as the unit of
X-ray quantity. Shortly before this, Kiistner ^^ circulated a
questionnaire to a number of institutions which were using deep-
therapy apparatus (which, at the time, operated mainly at 200
kilovolts), asking them to state the amount of radiation which
produced an erythema. The average of the values given to
Kiistner, when translated into rontgens, was 600 r. The tolerance

dose thus corresponds to rontgens in 3 days, or 0.2 r per

^ 1,000 " ^ ^

day. This value is at present accepted as the basis of the recom-
mendations of the International and British Committees. On
the other hand, the American Advisory Committee on X-ray

Protective Methods in Radiology 269

and Radium Protection take a value of 0.1 r per day as the
tolerance dose.

At the fifth international congress of radiology, held at Chicago
in 1937, the definition of the rontgen was modified in such a
way that it became a unit of gamma rays as well as of X-rays.
As regards the tolerance dose of radium gamma rays, the early
evidence indicated that it was likely to be of the same order
of magnitude as that for X-rays. Accordingly, we find that the
current recommendations of the International and British Com-
mittees state that "the evidence at present available suggests
that a person in normal health can tolerate with impunity ex-
posure to X-rays and radium gamma rays to an extent of about
0.2 international rontgen (r) per day or 1 r per w^ek." In
this respect, the American Advisory Committees have again
chosen the lower tolerance dose of 0.1 r per day.

Integral Dose and Tolerance

It will be seen that the present tolerance doses are expressed
in terms of the radiation falling upon the surface of the body.
It has been emphasized by Mayneord ^'' and others that the total
quantity of energy absorbed throughout the body of an irradiated
person, or "integral dose" as it is called, is of considerable im-
portance, both physically and clinically. For a given dosage
rate of radiation (expressed in rontgens per unit time) incident
upon the surface of the body, the dosage rates at various depths
in the body will be greater the more penetrating the radiation.
It follows, therefore, that the integral dose per unit surface dose
will depend on the quality of the radiation.

A suggested unit of integral dose is the gram-rontgen, which
is the quantity of energy absorbed when 1 rontgen of radiation
is delivered to 1 gram of air. Mayneord and Clarkson ^^ have
drawn attention to the possible importance of integral dose in
protection problems. For X-rays excited at 40 kilovolts ( Siemens'
"Doglas" therapy tube with no added filter; HVL of 0.037
millimeter Cu), they find that the integral dose is of the order
of 13,000 gram-rontgens per rontgen measured on the patient's

270 Applied Biophysics

anterior surface. For X-rays excited at 200 kilovolts (Philips'
therapy tube with 1.1 millimeters Cu added; HVL of 1.35 milli-
meters Cu), the value is about 46,000 gram-rontgens per surface
rontgen. Again, for 1,050 kilovolt X-rays (Metropolitan-
Vickers' tube with filtration of 4.22 millimeters steel -j- 2.0 milli-
meters Pb + 2.0 millimeters Al ; HVL of 10.4 millimeters Cu),
the integral dose is 51,000 gram-rontgens per surface rontgen,
while for radium gamma rays (filter equivalent to 1.3 millimeters
Pt ; HVL of 16 millimeters Cu), the value is 59,000. This varia-
tion of the integral dose indicates that it may, in future, be
necessary to express the tolerance dose of X- or gamma radia-
tion in terms of the integral dose, measured in gram-rontgens,
rather than in terms of the surface dose, measured in rontgens.
Alternatively, since in practice it will be the surface dose which
is likely to be measured, it may be necessary to adopt different
values of the tolerance dose, expressed in rontgens, for various
qualities of radiation.

Genetic Eflfects

At this stage, it would be well to consider briefly the effects
of ionizing radiations on genes and chromosomes and the influ-
ence which this knowledge may have in fixing limits to the
amount of radiation which a person should be given. It is known
that all types of ionizing radiations produce mutations, either
of the individual genes or of the chromosomes, the rate of muta-
tion being linearlv proportional to the amount of radiation
received. That is to say, no matter how small the given dose,
there is a chance that a mutation may occur, although that
chance will be very small. There is, therefore, no such thing
as a tolerance dose for genetic effects, if one interprets the phrase
"tolerance dose" in its ordinary sense, namely, that the human
body suffers no ill effects from such a dose. The genetic effects
of radiation are accumulative and irreversible since, apparently,
the mutation of a stable gene leads to another gene which is
equally stable.

As the majority of hereditable changes are recessive in char-

Protective Methods in Radiology 271

acter, any inherited qualities do not become evident unless a
mutated gene meets another like itself. Muller ^^ has calculated
the chances of the meeting of two genes originating from inde-
pendent mutations and has found that, on the average, at least
30, but more probably 100. generations would pass before a
recessive abnormality of a seriously harmful nature would
manifest itself by this process. There would thus be a "latent
period" of 900 to 3,000 years. Muller has also calculated the
chance of the meeting of two genes descended from the same
original mutated gene, taking into account the degree of in-
breeding. It is found that the latent period in this case is of the
order of 5,000 years. It should be mentioned that spontaneous
gene mutations occur naturally, and that these may be produced
by the effects of natural radioactivity.

Ignoring the ionization produced by the radioelements in the
air, since the ions are largely due to alpha rays, which can have
little effect on the body, it can be shown that the remaining
ionization due to cosmic rays and to beta and gamma rays from
radioelements in the air ^ corresponds to a dosage rate of
2.2 X 10^ 1* per second, or to 0.0002 r per day of 24 hours, or to
0.07 r per year. If all spontaneous mutations are caused by
natural radiation — and this fact has not been established — then
the natural mutation rate can be said to correspond to the irradia-
tion of the whole human race throughout past ages at the rate of
0.07 r per year, that is, to doses up to 5 r during the lifetime
of each person. If then, from now on, only a fraction, e.g., 1%,
of the race is exposed to ionizing radiations, either as workers
or as patients, it seems logical to deduce that the natural mutation
rate would at the most be only doubled even if each person in
this minority received, on the average, 500 r in his lifetime.

In assessing the permissible dose on which to base future
protection schemes, it will be necessary to know what fraction
of the race is to be subjected to artificial radiation and what
increase of the spontaneous mutation rate is justifiable, offsetting
the degree of race degeneration against the benefits bestowed by
radiation. It does appear, however, that the suggestion made
in an earlier paper by IMuller ^^ that the dosage rate should be

272 Applied Biophysics

reduced to 10"^ r per second is much too cautious. i\ssuming
a working week of 35 hours, and 48 working weeks per year,
in conformity with the International and British Recommenda-
tions, Muller's figure corresponds to 0.06 r per year, which is
sHghtly less than the natural radiation intensity. Hence, if the
whole human race were exposed to an additional intensity of
10"^ r per .second, the mutation rate would not be doubled.

The regulations of the Berufsgenossenschaft fiir Gesund-
heitsdienst und W'ohlfahrtspflege recommend that, for the genital
organs, the daily dose should not exceed 0.025 r. This is one-
tenth of the ordinary tolerance dose accepted by the German
X-ray Society. Jaeger and Zimmer ^^ considered that, as the
number of workers using ionizing radiations in 1941 was still a
relatively small proportion of the total population, even this
value of 0.025 r per day represented a very cautious attitude.

Risks by Inhalation or Ingestion

We now turn to the consideration of other classes of radia-
tion workers, namely, those who may sufifer injury from radio-
active materials which have been inhaled or ingested. As regards
radon, the British X-ray and Radium Protection Committee ^^
recommend that "the radon of the air in laboratory, factory,
workshop or other working quarters should not exceed a con-
centration of 10"^^ curie per liter." As regards radium in the
body, the Committee recommend that if, after the person has
remained away from work for 48 hours, "radon then be found
in a concentration of even 10"^^ curie per liter, it is presumptive
evidence of radium in the body and the operator should at once
discontinue such work." In the National Bureau of Standards
Handbook H.27 on the Safe Handling of Luniinoits Compounds,
much lower tolerance levels are advised, namely, "the radon
concentration in the atmosphere of workrooms shall not exceed
10"^^ curie per liter," and "no one shall be engaged as a dial
painter who shows more than 0.1 microgram of deposited
radium as revealed by the expired air test." It is stated that
the latter figure corresponds to 10"^- curie of radon per liter

Protective Methods in Radiology 273

of expired air. Assuming that the tidal respiratory volume per
minute is 5 liters, it can be calculated that, if all the radon formed
from 0.1 [ig of radium in the body appeared in the breath, the
radon concentration of the expired air would be 2.5 X 10"^^ curie
per liter. The American figure of 10"^^ curie per liter thus as-
sumes that 40% of the radon is liberated. On the same basis,
the British figure of 10"^^ curie per liter corresponds to 1 [ig of
radium in the body.

It must be mentioned, however, that the ratio of the liberated
to the trapped radon varies considerably, not wholly in relation
to the length of time during which the radium has been deposited.
In examining luminizers, the National Physical Laboratory, there-
fore, measures not only the exhaled radon but the gamma radia-
tion from the disintegration products of the trapped radon, as
this is the only way in which to assess accurately the total amount
of radium in the body.

There is much conflicting evidence regarding radium poison-
ing:

1. Evans ''^ reported that 7 persons carrying between 0.02 |.ig
and 0.5 \ig for 7 to 25 years revealed no clinical symptoms
of chronic radium poisoning. Similar examples can be
quoted from the results of tests made at the National
Physical Laboratory on workers who have been engaged
in luminizing for periods up to 30 years. In one case, a
person who worked full time on actual luminizing for
30 years was found to have 0.7 \ig radium in her body, and
there were no apparent ill effects.

2. Opposed to the above is the evidence that fatalities have
occurred when the radium burden was above 1.2 \ig.

3. The "normal" amount of radium in the body is between
0.01 and 0.015 ug. Expressing this in another way, ,
Jones and Day ^- calculate that the normal radium content
of the body produces 0.025 X 10^ ions per cubic centimeter
of tissue per second. For comparison purposes, they show
that the radiation tolerance dose of 1 r per week produces
2.69 X 10^ ions per cubic centimeter per second, while a.

274 Applied Biophysics

radon concentration of 10"^^ curie per liter in the at-
mosphere produces only 0.00008 X 10*^ ions per cubic centi-
meter per second.
4. The air of the Joachimstal mines contains from 20 X 10'^^
to 60 X 10"^^ curie of radon per liter, and occasionally as
much as 200 X 10"^-* curie per liter has been measured. Yet
lung carcinoma among the miners is attributed to the dusts
of arsenic and chromium, and not to the radon.

These conflicting facts indicate that much more evidence is
required before the tolerance doses for radium in the body and
for radon and radium dust in the air of the workshop can be
regarded as satisfactory.

Neutrons

There is another type of ionizing radiation, the neutron,
against which adequate protection must be found. The neutron
is approximately the same size as the proton (the nucleus of the
hydrogen atom), and if the two collide, the neutron surrenders
a large part of its energy to the proton, which recoils along a
short path. Neutrons are thus effectively slowed down in
hydrogenous material, such as tissue. The recoiling protons
produce ions in the tissue, the ion density along the proton track
being far more intense than along the tracks of the electrons
which are liberated in tissue by the passage of X- or gamma rays.

Comparisons have l)een made of the biological effects of X-rays,
alpha rays, gamma rays, and neutrons.'^' ^^ These raise the prob-
lem of the measurement of neutron doses. Since neutrons liberate
far more ions in tissue than in the same mass of air, it is not
possible to measure neutron doses directly in rontgens. The
accepted practice is to define an "equivalent rontgen" of neutrons
as the dose which produces the same number of ions per unit
volume of tissue as a dose of 1 rontgen of X- or gamma radiation.
On this basis, it is found that the ratio of gamma-ray energy to
the neutron energy required to produce a biological reaction
varies from about 1.5 to 9, according to the reaction studied.

Protective Methods in Radiology 275

On the other hand, the ratio of X-ray energy to gamma-ray
energy shows much smaller variations, the average value being
about 1.5. Clearly, further experiments will have to be made
before a tolerance dose for neutrons can be established.

Reference is made in Smyth's report on Atomic Energy, "^^
to the fact that the National Defense Research Committee of
the United States set up a health group, one of whose tasks
was to carry out research on the effects of radiations on persons
engaged in the operations associated with the atomic pile. The
results of the investigations of the group have not yet been
announced, but doubtless the knowledge of radiation effects will
have been greatly increased.

Elaboration of Protective Sclieines

When the tolerance dose for a particular type of radiation,
say, X-radiation, has been established and is measurable in terms
of a physical unit, the subsequent procedure in determining the
protection in any instance is to measure the dosage rate of the
radiation received at a specified point in terms of the unit
adopted, to determine the transmission values of the radiation
through various thicknesses of various absorbing materials, and
finally to calculate the thickness of the chosen absorbent which
is required to reduce the transmitted radiation received at the
point in question to the tolerance dosage rate.

It is well known that X-rays and radium gamma rays are
absorbed more effectively by lead than by any other common
material. Hence lead or lead-impregnated materials, such as
rubber and glass, have generally been used to secure protection.
It is also customary to express the required protection in terms
of lead and to determine the "lead-equivalents" of other ab-
sorbents.

When using X-ray equipment, steps must be taken to safe-
guard the operator against three types of radiation. In the first
place, the tube itself must be protected in all directions other
than that of the useful beam. Secondly, if the direct beam is
pointed at the operator, as is often the case in screening a

276 Applied Biophysics

patient or object, a protective barrier must be placed in front
of the operator. Thirdly, since all objects which are placed in
the path of the direct beam scatter the radiation in all directions,
the operator must be protected against this secondary radiation,
either by means of a protective barrier or by relying on remote-
ness from the scattering objects.

Many papers have been published regarding the outputs of
X-ray tubes operating under various exciting conditions. The
results have been summarized by Kaye and Binks ^^ and Binks -
for exciting voltages up to 2 million volts. For tubes with
"reflection" targets, that is, where the X-radiation is emitted at
right angles to the electron stream, the outputs with a filtration
of 0.1 millimeter copper are 2T X 10"^ ( kilovolts)^-^ r per minute
per milliampere at 1 meter over the range 75 to 200 kilovolts,
while with a filtration of 0.5 millimeter copper, the outputs are
1.7 X 10 "* (kilovolts)--^ r per minute per milliampere at 1 meter
over the range 200 kilovolts to 2 million volts. For tubes with
"transmission" targets, i.e., tubes in which the direction of the
X-ray beam is a continuation of the electron stream, the X-ray
outputs with a filtration of 0.5 millimeter copper are 2.1 X 10^
(kilovolts)--^ r per minute per milliampere at 1 meter over the
range 600 kilovolts to 2 million volts.

Turning to the corresponding question of the gamma-ray
outputs from known quantities of radium sealed in containers
having a screenage equivalent of 0.5 millimeter platinum, the
outputs can be calculated on the basis that the quantity of radia-
tion received in 1 hour at 1 centimeter from a ''point source"
of 1 milligram radium is about 8 rontgens. For distances other
than 1 centimeter, the calculations are based on the inverse square
law of radiation.

The preceding data on X-ray and gamma-ray outputs refer to
the intensities of the direct beams. Far fewer measurments have
been made of the intensities of scattered radiation,^ but one or
two examples will illustrate the magnitude and importance of the
intensities of scattered radiation encountered in practice. The
dosage rate at the side of a patient who is screened in the couch
position is usually of the order of 100 X 10^ r per second. The

Protective Methods in Radiology 277

daily tolerance dose of 0.2 r would, therefore, be received in just
over 3 minutes, which is about the time taken on one patient only.
Hence the need for a protective screen on the side of the couch.
In the case of X-ray therapy, the intensity of the scattered radia-
tion at 1 meter to the side of a patient, who is exposed to 200
kilovolt X-rays from a tube run at 30 milliamperes and having
a filtration of 0.5 millimeter copper, is about 250 X 10'^ r per
second, corresponding to a dose of 0.2 r in 80 seconds.

The absorption of direct and scattered X-rays and gamma
rays in various materials has been determined experimentally by
workers in many countries. For direct X-rays excited at volt-
ages up to 5 million volts and for radium gamma rays, theoretical
values have also been obtained ^^ for absorption in lead and for
the lead equivalents of barium concrete.

From a knowledge of the outputs of X-ray tubes, working
under various conditions of excitation, and from a knowledge of
the degree of absorption of the rays in lead, it is a simple step
to calculate the thicknesses of lead required to reduce the radia-
tion at any point to the tolerance amount. Binks - has prepared a
simple nomogram, relating kilovoltage, milliamperage, distance,
and the amount of lead protection. By means of this, it is possible
to find the amount of lead required to give adequate protection
for any tube voltage between 200 kilovolts and 3 million volts,
for any tube current between 0.5 and 30 milliamperes, and for
any distance from the tube between 0.5 and 10 meters. A similar
nomogram has been prepared - for the determination of lead
protection against radium gamma rays. The corresponding pro-
tective thicknesses of other materials, such as brick, concrete
and barium concrete, are also known. ^^

During the war, there was a rapid increase in the number of
workers engaged in luminizing instrument dials and in the aver-
age quantity of radioactive luminous compound handled by each
worker. As previously mentioned, the ]\linistry of Labor and
National Service issued an Order in April, 1942, giving fairly
detailed instructions to employers and employees regarding the
protective arrangements w'hich are to be adopted in luminizing
departments. The main features are:

278 Applied Biophysics

1. Protection against gamma radiation from the radium paint
issued to each operator and against gamma radiation from
the main stock of luminous compound possessed by the
firm.

2. Protection of the exposed parts of the body against beta
radiation. Each operator is to work behind a lead-glass
screen, thus preventing beta radiation from the luminized
object from reaching the face.

3. Local ventilation on each working bench, so as to remove
radon and radium dust from the vicinity of the operator.

4. General ventilation of the workroom to remove radon and
radium dust.

5. Provision of special clothing for use in the workroom.

6. Periodical cleaning of bench tops and equipment.

7. Personal hygiene.

Similar proposals were put forward in America in the Bureau
of Standards' Handbook H.27.

Reference has already been made to the fact that neutrons
can be decelerated in hydrogenous materials and are ultimately
reduced to thermal velocities. The "thermal neutrons" are easily
absorbed, in capture processes, by elements such as cadmium
and boron which, in turn, become temporarily radioactive. In
this phenomenon, we hnd a method of protecting personnel
against neutrons, produced by heavy particles accelerated by
apparatus such as the cyclotron. Tanks of water up to 1 meter
thick, or stacks of paraffin wax blocks up to about 70 centimeters
thick, are placed round the neutron source, most of the slow
neutrons being absorbed by salts of cadmium or boron intro-
duced into the water or wax. Any gamma radiation which is
liberated is absorbed in a final .sheet of lead.

Tests on Radiation Workers and Inspections of
Radiological Departments

Since the introduction of the first report of the British X-ray
and Radium Protection Committee, the National Physical Lab-

Protective Methods in Radiology 279

oratory has continued to carry out inspections of radiological
departments. lonometric measurements are made at all points
likely to be occupied by personnel and, if the dosage rate at any
point is found to be in excess of the tolerance amount, methods
of remedying the defective equipment or of improving the tech-
nique are suggested.

During the war, the Ministry of Health was disturbed at the
increasing number of reported cases of low leucocyte counts
and, towards the end of 1942, consulted the Laboratory with a
view to the establishment of a dosage service. On the basis
of many years' experience gained in the use of photographic
films for monitoring the doses of radiation received by members
of its own staff, the Laboratory organized a dosage film service
on behalf of the Ministry. Later the service was extended to
workers in Scotland and in Northern Ireland. In March, 1943,
the Factory Department of the Ministry of Labor and National
Service circularized industrial radiological departments, advising
the managements to make use of the same film service.

Up to the present time, nearly 2,000 medical workers at about
550 hospitals and nearly 1.000 industrial workers at about 150
firms have been examined by the film method, many of the
workers having been tested at three-monthly intervals, and a
few continuously. The results show that over 70% of hospital
X-ray staffs and over 90% of industrial X-ray staffs receive
less than one-tenth of the weekly tolerance dose. When a film
test indicates that the wearer has received an excessive dose and
the result has been confirmed in a repeat test, the Laboratory
sends representatives to inspect the radiological department
concerned. In some cases, it is found that the ecjuipment is
defective ; in others, that the technique is faulty. But it should
be remarked that it has been found necessary to inspect only 9
hospital X-ray departments and only 12 industrial X-ray de-
partments. There appears to be no need, therefore, for alarm
regarding the low leucocyte counts. Indeed, Britton ^ found a
low leucocyte count in 29% of the 552 counts on 68 apparently
healthy nurses not exposed to radiation. He stated that this
appeared to be a war effect of unknown cause.

280 Applied Biophysics

The films which are issued to radium workers are half cov-
ered with sheet lead 1 millimeter thick, which absorbs any beta
radiation. The shielded half of the film thus records the gamma-
ray dose, whereas the unshielded portion records both beta and
gamma radiation. In the case of luminizers, it has been found
that there is a large beta-ray effect, and subsequent inspections
of many of the departments have revealed that most of the dose
is due to contaminated benches and clothing. In the major-
ity of cases, the total doses are now well below the tolerance
level.

It seems possible to use the film technique for the measure-
ment of neutrons which fall on the body. Fast neutrons would
be slowed down in the tissue and would "evaporate" from the
surface of the body with thermal velocities. If the film is covered
with a thin foil of, say, cadmium, rhodium, or indium, which
have a high-capture cross section, these elements would capture
the neutrons, becoming radioactive and emitting ionization radia-
tions which would blacken the film. The radioactivity should,
preferably, be short-lived, so that there w^ould be no need to
take into account the lapse of time between the initial irradiation
of the film and the photographic development.

The inspections of luminizing departments also include tests
of the radon concentration of the air of the workrooms, and
tests of the radium in the bodies of luminizers, part of the radium
being assessed by means of the alpha rays from the radon con-
tained in the exhaled air and part by means of the gamma rays
from the subsequent disintegration products of the radon trapped

in the body. Similar tests have been carried out by Jones and
Day.i2

It will be apparent from the foregoing review that, while there
is much to be learned about the tolerance doses for various types
of ionizing radiation, and while there is an ever-growing number
of radiological workers using an ever-widening range of man-
made radiations, sufficient experience has already been gained
to be able to tackle the new protection problems with high hopes
of evolving effective safety measures,

Protective Methods in Radiology 281

References

1 Binks, W. (1940) Brit. J. Radiol. 13, 322.
2Binks, W. (1943) Brit. J. Radiol. 16, 49.
3 Bouwers, A. (1924) Physica, Eindhoven, 4, 173.
4Bouwers, A. (1928) Acta Radiol., Stockh. 9, 600.
4a British X-ray and Radium Protection Committee (1943) Recom-
mendations, London.
" Britton. C. J. C. (1943) Lancet, 2, 289.

6 Charlton, E. E., W. F. Westendorp, L. E. Dempster and G. HotaUng

(1939) /. Appl. Phys. 10, 374.

7 Evans. R. D. (1943) J. Industr. Hyg. 25, 253.

8 Gray, L. H., J. Read and M. Poynter (1943) Brit. J. Radiol. 16, 125.

9 Hevesy, G. and F. A. Paneth (1938) Radioactivity, London, p. 282.
^0 International X-ray and Radium Protection Commission (1937) Inter-
national Recommendations for X-ray and Radium Protection,
Chicago.

11 Jaeger. R. and K. G. Zimmer (1941) Phys. Z. 42, 25.

12 Jones, J. C. and M. J. Day (1945) Brit. J. Radiol. 18, 126.
iSKaye. G. W. C. and W. Binks (1940) Brit. J. Radiol. 13, 193.
i-^Kaye. G. W. C, W. Binks and G. E. Bell (1938) Brit. J. Radiol. 11,

676.
i^Kiistner, H. (1927) Strahlentherapie, 26, 120.

16 Lasnitzki, L and D. E. Lea (1940) Brit. J. Radiol. 13, 149.

17 Mayneord, W. V. (1940) Brit. J. Radiol. 13, 235.

iSMayneord, W. V. and J. R. Clarkson (1944) Brit. J. Radiol. 17, 177.

19 Muller, J. H. ( 1939) Schwei::. med. Wschr. 60, 845.

20 Muller, ]. H. (1941) Scieyice, 93, 438.

21 Smyth, H. D. (1945) Atomic Energy, Washington.

22 Trump, J. G., R. J. Van der Graaff and R. W. Cloud (1940) Amer

J. Roentgenol. 44, 610.
22a U.S. Bureau of Standards (1936) Handh. Ser. U.S. Bur. Stand.

H.B.20.
22b U.S. Bureau of Standards (1938) Handb. Ser. U.S. Bur. Stand.

H.23.

INDEX

Attached-X method, 145
Audiometer, 49

Action of radiation on viruses and

bacteria, 155
Activated water, 92
Adsorption theory of narcotic

action, 15
Aim of radiotherapy in malignant

disease, 166
Alpha rays, 116

— rays, effects of, 115
American and British values of

dose distribution, 228
/'-Aminobenzoic acid, antisulphon-

amide activity of, 14
Amplifier, resolving power of, 34
Amplifiers, biological, 36
Amplifying stethoscope, 50
Analogy between insect cuticle and

cell membrane, 30
Analysis of radiation effects in

human carcinomata, 162
Analysis. X-ray diffraction, 19
Analytical approach to the study of

drug action, 14
Animal embryonic tissue and tumor

tissue, effects of different radi-
ations on, 132
Antisulphonamide activity of

/'-aminobenzoic acid, 14
Apical phonocardiogram, 44

— phonocardiogram of rheumatic

mitral endocarditis, 45
Applications of electronics in medi-
cine, survey of the, 34

— of physics in medicine, some, 1
Artificial ear, 50

— tanning and hardening of insect

cuticle, 26
Ascorbic acid, effect of X-rays on
blood concentration, 213

Background theory of radiobiology,

84
Backscatter, 250
Bacteria and viruses, action of

radiations on, 155
Bacteria, inhibition of division of,

161
Bacteria, lethal mutation in, 160
Bacteriophage S-13, inactivation of,

158
Basal-celled carcinoma, reaction

chart of, 167
Beam directors, 219, 226
— , half -value layer of, 179
— , quality of the, 179, 205
Beta rays, 116

— rays, effects of, 115
Betatron and cyclotron, 55
Bibliography. See References.
Biological amplifiers, 36

— effect and ionization, 87

— effects and volume dose, 210

— effects of penetrating radiations,

83
■ — effects of radiation on normal
tissue, 103

— effects of X-rays, neutrons and

other ionizing radiations. 114
■ — indicators, 92

— response and physical dose. 87

— response to a variety of radia-

tion doses, 89

— unit, estimate of size, 126

— units, ion density and inactiva-

tion of elementary, 123

283

284

Index

Biology and medicine, influence of

physics in, 10
Biophysical factors in drug action,

13
Blood counts and volume dose, 212
— .- flow, measuring peripheral. 53
Blowfly larva, cuticle of, 24

— larvae, uptake of ethyl alcohol

by, 22
Body dose of radiation, total, 217
Both electrocardiograph, 38
Brain damage from rotation, dis-
tribution of, 79

— injuries, mechanics of, 74

— movement in injuries, skull and,

77, 78
British and American values of

dose distribution, 228
Bronchoscope, 3

Calculation of heat dosage, 64
Callipers, 226
Capillary electrometer, 38
Carcinoma of the rectum, treatment

by high-voltage X-rays, 257
— , reaction chart of basal-celled,

167
Carcinomata, radiation effects in

human. 162
Cathode-ray oscillograph, 39

— oscilloscope, double-beam. 41
Cell categories found in epithelial

tumors, 165

— division and cell differentiation in

normal tissue. 104-106

— membrane, analog}' between in-

sect cuticle and, 30
Cellular population of tumors, 164
Changes in biological response of
avian fibroblasts caused by in-
creasing doses of radiation, 102

— in volume of a brain region, 75
Chaoul therapy. See Contact

therap3^
Charged particle radiation. 190
Chemical effects of radiation. 155
Chemotherapy and radiation, 109

Chromatid breaks. 150
Chromosome aberrations, induced,
147

— abnormality as a quantitative

measure of radiation effect, 96

— breaks, 148, 149

— structural changes, mode of pro-

duction of, 151
Chromosomes and genes, stability
of, 140

— by different ionizing radiations,

structural changes induced in,

126
— , structural changes caused by

radiation. 148
Chronaxie meters and electronic

stimulators. 37
Classification of X-ray therapy,

216
Clinical application of heat, 59
Colorimeters, photoelectric, 52
Comparing the biological effects of

X-rays, neutrons and other ion-
izing radiations, 114
Compton scattering, 178
Condenser dosemeter, 183
Contact therapy, 219

— therapy field, isodose curves for,

217

Continuously evacuated tubes, 243

Contrecoup injuries, 80

Control of culture growth, 51

Convection, heat, 60

Corpuscular emission, 179, 188,
190

Culture growth, control of, 51

Cuticle, effect of mixed drug sys-
tems on insect, 21

— of blowfly larva, 24
Cyclotron and betatron, 55

D

Decomposition of dilute solutions
by radiation, 122

— of molecules by radiation, 121

122

— of water by radiation, 122

Index

285

Deep therapy field, isodose curves
for a, 218

Degenerating cells, 164

Depressant, action of, 15

Determination of the skin erythema
dose, 88

Developing influence of physics in
biology and medicine, 10

Differentiating cells, 164

DiiTraction analysis, X-ray, 19

Dilute solutions by radiation, de-
composition of, 122

Direct beam. 250

Distortion caused bv rotation,
80

Distribution of brain damage from
rotation, 79

Division of bacteria, inhibition of,
161

Dosage, calculation of heat, 64

Dose and biological response, physi-
cal. 87

— contour projector, 225

— contours, irradiation field pre-

arranged using, 220. 221

— distribution, British and Ameri-

can values. 228

— distribution, means of realizing a

desired, 226

— distribution, summation of,

224

— distribution theory and practice,

228

— distributions, illustrative, 219

— finder. 225

— of radiation. 179
Dosemeters, 183
Dosimetry, 87

Double-beam cathode-ray oscillo-
scope, 41

Drug action, biophysical factors in.
13

— action, the analytical approach

to the study of, 14
■ — systems on insect cuticle, effect

of mixed. 21
Drugs by insects, uptake of. 21
— , surface and narcotic activity of,

15

E

Economy quotient, Unger's, 206
Effect of permeability on tanning,

25
Effects of different radiations on

animal embryonic tissue and

tumor tissue, 132

— of mixed drug systems on insect

cuticle, 21

— of physical factors on volume

dose, 202

— of radiation on normal tissue,

summary of, 103

Efficiencies of ionizing radiations,
relative, 127

Efficiency of ionizing radiations for
the inactivation of viruses, rela-
tive, 124

Einstein's equation for the unit
energy of radiation. 177

Electric blanket. 61

Electrical jugular pulse tracing, 45

Electrocardiogram synchronizing,
51

Electrocardiography, 38

Electroencephalography, 46

Electromagnetic radiation, 62. 63

Electromyography, 37

Electron microscope, 54

Electronic pH meters, 51

— stimulators and chronaxie

meters, 37
Electronics, 3

— in medicine, applications of, 34
Embryonic tissue, the indirect ef-
fect of radiation on, 100

Emission, corpuscular. 179. 188. 190
Encephalograph, Marconi, 47, 48
Encephalophone, 48
Energy absorption and biological
response. 87

— absorption and the theory of the

thimble chamber, true. 185

— absorption in radio therapy,

total, 194

— quanta, 62

Enzyme activity and permeability,
27

286

Index

Enzyme, lipid, protein relationship,

pattern of, 20
Epithelial tumors, cell categories

in, 165
Epithelioma, reaction chart of, 168,

169, 171
Equivalence, principle of, 186
Equivalent rontgens, 191
Erythrocyte envelope, investigation

of the, 17
Ethyl alcohol by blowfly larvae,

uptake of, 22
Evaluation of sympathetic denerva-
tion, 54
External irradiation, 235
Extrapolation chamber, redefinition

of the rontgen and the, 187

Fat solvents and permeability,
23-25

— solvents on insect cuticle, mech-
anism of sensitizing action of,
28, 29

Field area and volume dose, 203

Fields, arrangement and number of,
204

Filters, 250

— , wedge, 208

Focus-skin distance, 203

Forces to be considered in brain
injuries, 74

Forward scatter, 250

Free air chamber, 181

Future methods in radiotherapy,
240

Gamma rays, measurement in

rontgens. 184
Gene mutations caused by radiation,

141
— mutations caused by X-rays,

95
Genes, stability of chromosomes

and, 140

Genetic effects of ionizing radia-
tions, 270

— effects of radiation, 95, 138

— effects of ultraviolet radiations,

153
Gram rontgen, 89
Gray's theory, 186
Green's calliper, 226
Grimmett's ionization chamber,

200

H

Half -value layer of a beam. 179
Hardening of insect cuticle, arti-
ficial tanning and, 26
Hearing aids, 50
Heart sounds, recording of, 51
Heat, clinical application of, 60

— convection, 60, 61

— dosage, calculation of, 64

— measurement, special problems

of, 65

— therapy, physical basis of, 59

— tolerance, limits of, 75

— transfer by radiation, 61

— transfer, methods of, 60
Hemoglobinometer, 52
Heterodyne oscillator, 48
High-voltage beam, physical ad-
vantages of, 252

— therapy, alteration in skin re-

action, 255

— X-ray equipment, 243

— X-rays, treatment of carcinoma

of the rectum, 257
Histological analysis of radiation

effects in human carcinomata,

quantitative, 162
History of medical physics, 4
Homologous series, law of, 32
Hot baths, 61

— water bottle, 61
Hot-air cabinet, 60

Human carcinomata, radiation ef-
fects in, 162
Hydrogen-ion concentration, 51

Index

287

Illustrative dose distributions, 219
Inactivation of bacteriophage S-13,
158

— of elementary biological units,

ion density and, 123

— of vaccina virus, 159

— of viruses, 156

— of viruses in aqueous suspension

by X-rays. 157

— of viruses, relative efficiency of

ionizing radiations for the, 124

Indicators, biological, 92

Induced chromosome aberrations,
147

Influence of ion density on radio-
chemical yield, 121

— of linear ion density, 119

— of physics in biology and medi-

cine, 10

Ingestion or inhalation of radio-
active materials, 272

Inhibition of division of bacteria.
161

Inhibitory effect of radiations on
regeneration, 101

Injuries, mechanics of brain, 74

— , skull and brain movement in,
77, 78, 79

Injurious and lethal effects of radi-
ation, 98

Ink-writing electrocardiograph, 39

Insect cuticle and cell membrane,
analogy between, 30

7^ cuticle, artificial tanning and
hardening of. 26

— cuticle as test material, 21

— cuticle, mechanism of sensitiz-

ing action of fat solvents on,
28, 29

— cuticle, structure of, 24
Inspection of radiological depart-
ments, 278

Integral dose, 194
— ^^dose and tolerafice, 269
'■ — dose, mathematical theorv of,
196

— dose, values of, 205, 206

International protective recom-
mendations, 266
Interstitial radium, 236
Intracavitary irradiation, 235
Investigations of the erythrocyte

envelope. 17
Ion clusters, separation of. 120

— density and the inactivation of

elementary biological units, 123

— densitv, influence of linear,

119'

— density on radiochemical yield,

influence of, 121

— density produced by different

ionizing particles, 118
Ionization and biological effect,
87

— chamber, Grimmett's, 200

— chamber, wall effect of, 181

— method of measuring radiation,

176. 177
Ionizing radiations. 175

— radiations, biological effects of,

114

— radiations for the inactivation of

viruses, relative efficiency of,
124

— radiations, genetic effects of, 270

— radiations, relative efficiencies of,

127

— radiations, structural changes in-

duced by chromosomes by dif-
ferent, 126

— radiations, tolerance doses for,

267
Irradiation field prearranged using

dose contours, 220, 221
Isochromatid breaks, 128
Isodose charts, 217

— curves for a contact therapy field,

217

— curves for a deep therapy field,

218

— curves modified by wedge filter,

223. 224

— distribution, 208

— distributions for various qualities

of radiation, 204
Isophotes, 69, 70

288

Index

Jig. 227

Jugular pulse tracing, electrical, 45

Jugular sphygmogram, 46

Law of homologous series, 32
Lethal and sublethal effects of radi-
ations on root tips, 130

— effects of radiation, injurious and,

98

— mutation in bacteria. 160
Limits of heat tolerance, 75
Linear ion density in ionizing radi-
ation, 115

— ion density, influence of. 119
Lipid-protein-enzyme relationship,

pattern of, 20
Lipids and narcotics, 19

— and proteins, 14

Lipoid theory of narcotic action. 15
Lippo-protein complex, 20
Local effects of radiation. 210. 211
Logarithmic apical phonocardio-

gram. 44
Lymphocyte counts in individual

patients, 210

M

Macromolecular viruses, 157
Malignancy, radiation and, 107
Malignant disease, aim of radio-
therapy in, 166
Marconi encephalograph, 47, 48
Mathematical theory of integral
dose. 196

— theory of volume dose, 196
Measurement of gamma rays in

rontgens, 184

— of neutron radiation. 189

— of radiation. 175

— of the pulse velocity, 53

— of volume dose of radiation, 199
Measurements in phantom, 217
Measuring peripheral blood flow, 53
Mechanics of brain injuries, 74

Mechanism of sensitizing action of
fat solvents on insect cuticle,
28, 29

Medical physics, history of, 4

— radiology. 2

Medicine, applications of electron-
ics in, 34

— , influence of physics in biology
and, 10

— , physics in, 1

Megagram-rontgen, 194

Membrane, analogy between insect
cuticle and cell, 30

Metallic object, detecting approxi-
mate position of, 54

Methods of heat transfer, 60

Microscope, electron, 54

Million-volt equipment, 245

— therapy, 241

— X-ray tube, 244, 246

— X-rays, advantages of, 256
Mirror galvanometer, 38
Mitotic cells, 164

— effect of radiation, 172
Modified scattering. 178
Monolayers, 14

Multiple beam arrangement, 221

— field distribution, 220
Muscle action potentials. 36
Mutation in bacteria, lethal, 160

— in Drosophila, radiation induced,

142

N

Narcosis and oxidative processes,

31
Narcotic action, adsorption theory

of. 15

— action, lipoid theory of, 15
Narcotics and lipids, 19
Nerve action potentials. 35

— fiber. 35

Neutron dosimetry, 190

— therapy, 134

Neutrons and other ionizing radia-
ations, biological effects of
X-rays, 114

— , measurement of, 189

Index

289

Neutrons, protection against, 274
Nonviable cells, 164
Nuclear effect on energy quanta,
178

o

Oil diffusion pumps, 243
Operating conditions, physical in-
vestigations of, 249
Optics, physical, 3
Organism-type viruses, 159
Oscillator, heterodyne, 48
Oscillators, radio frequency, 54
Oscillograph, cathod-ray, 39
Oscilloscope, double-beam cathod-
ray, 41
Oxidative processes and narcosis,
31

Pattern of lipid-protein-enzyme re-
lationship. 20
Paucimolecular theory. 18
Penetrating radiations, biological

effects of, 83
Percentage depth dose. 250
Peripheral blood flow measuring, 53
Permeability and enzyme activity,
27

— and fat solvents, 23-25

— on tanning, effect of, 25
pH meters, electronic, 51
Phantom measurements, 217
Phonoelectrocardioscope, 41, 43
Photocells. 52

Photoelectric absorption of radia-
tion quanta. 178

— colorimeters. 52

■ — hemoglobinometer. 52
— plethysmography. 53
Physical advantages of high-volt-
age beam, 252

— basis of heat therapy, 59

— dose and biological response. 87
■ — estimates of energy absorption.

194

Physical factors on volume dose,
effect of, 202

— investigations of operating con-

ditions, 249

— optics, 3

Physics in biology and medicine,
influence of, 10

— in medicine, 1

— in radiotherapy. 7
Piezoelectric microphone, 50
Plethysmography, photoelectric,

53
Potentials, muscle action, 36
— , nerve action, 35
Principle of equivalence. 186
Production of some chromosome

structural changes, mode of,

151
Proliferating cells, radiosensitivity

of, 101
Protection against neutrons. 274
Protective methods in radiologv,

264
Protective schemes, 275
Protein-lipid-enzyme relationship,

pattern of, 20
Proteins and lipids. 14
Pulse tracing, electrical jugular,

45

— velocity, measurement of the, 53
Pyron, 65

Quality of a beam of radiation, 179,

205
■ — of radiation. 71
"Quanta, energy, 62
Quantitative histological analysis of

radiation effects in human car-

cinomata. 162
Quantitv or dose of radiation,

179'
Quantum character of radiations

and interaction with matter,

177
— hit theory. 86
Quinone, tanning action of, 26

290

Index

R

Rad, 87

Radiation and chemotherapy, 109

— and malignancy, 107

— by textiles, transmission of, 71
— , charged particle, 190

— , chemical effects of, 155
— , decomposition of molecules by,
121, 122

— dose, 179

— doses, biological response to a

variety of 89

— efifect. chromosome abnormality

as a quantitative measure of,
96

— effects in human carcinomata,

quantitative histological analy-
sis of, 162

— effects on normal tissue, 103

— , Einstein's equation for the unit
energy of, 177

— , heat transfer by. 61

— , indirect effect on embryonic tis-
sue. 100

— induced mutation in Dropsophila,

142
— , injurious and lethal effects of,

98
— , isodose distribution for various

qualities of. 20-I-

— local effects of, 210, 211

— measurement by the ionization

method, 176, 177
— , measurement of. 175
— , measurement of neutron. 189
— . measurement of volume dose of.

199
— , mitotic effect of, 172
— , quality of a beam of, 179
— , structural changes caused in

chromosomes by, 148

— technique, volume dose limiting.

211
— , total body dose of. 217

— workers, tests on. 278
Radiations, action on viruses and

bacteria. 155
— , biological effects of ionizing, 114

Radiations, biological effects of
penetrating, 83

-^, effects on animal embryonic tis-
sue and tumor tissue, 132

— for the inactivation of viruses,

relative efficiency of ionizing,

124
— , genetic effects of, 95, 138
— , genetic effects of ionizing, 270
— . inhibitory effect on regeneration,

101
— , ionizing, 175
— , lethal and sublethal effects on

root tips, 130
— . relative efficiencies of ionizing,

127
— , response of skin to, 101
— , structural changes induced in

chromosomes by different ion-
izing, 126
— , tolerance doses for ionizing

radiations, 267
Radioactive materials, risks from

inhalation or ingestion. 272
Radiobiologv, background theory

of, 84
Radiochemical yield, influence of

ion density on, 121
Radiochemistry, 91
Radiofrequency oscillators, 54
Radiological departments, inspec-
tion of. 278
Radiology, medical. 2
— , protective methods in, 264
Radiosensitivity of proliferating

cells, 101

— of tumor tissue, 172
— ^of tumors. 162, 163
Radiotherapy in malignant disease,

aim of, 166

— of malignant disease. 107

— of uterine hemorrhage. 239
— . physics in. 7

— , total energy absorption in.
194

— . value of the conception of vol-
ume dose in, 202

Radium, experiments with, 115

Index

291

Radium therapy, technical methods
in, 234

— therapy, therapeutic aims and

methods, 237

Radon technique, 237

Reaction chart of basal-celled car-
cinoma, 167

— chart of epithelioma, 168, 169,

171

Realizing a desired dose distribu-
tion, 226

Receptor theory, 14

Reconciliation of rival theories, 16

Recording of heart sounds, 51

Redefinition of the rontgen and the
extrapolation chamber, 187

References. 32, 57, 73, 82. 136, 153,
161, 174, 192, 214, 232, 281

Regeneration, inhibitory effect of
radiations on, 101

Relation of dominant lethals to dose
of X-ray, 143

— of volume dose to field area for

irradiation of the pelvis, 201
Relative efficiencies of ionizing
radiations, 127

— efficiency of ionizing radiations

for the inactivation of viruses,
124

Resolving power of amplifier, 34

Resting cells, 164

Rival theories, reconciliation of, 16

Rotation, distribution of brain dam-
age from, 79

— of the patient, 222

Rontgen and the extrapolation
chamber, redefinition of, 187

— cubic centimeter, 194

— unit of X-ray dose, 180
Rontgens, equivalent, 191

Skull and brain movement in in-
juries, 77, 78

Sensitizing action of fat solvents
on insect cuticle, mechanism of,
28, 29

Separation of ion clusters, 120

Serum electrodes, 51

Shear strains caused by rotation,

80
Single field distribution, 219
Skin erythema dose, determination

of the, 88

— reaction alteration in high-volt-

age therapy, 255

— reactions to neutron radiation,

134

— . response to radiations, 101

Sound, 49

Special problems of heat measure-
ment, 65

Sphygmogram, jugular, 46

Square wave stimulator, 38

Stability of chromosomes and
genes, 140

Sterilizing effects of X-rays, 95

Stethoscope, amplifying, 50

Stimulators, chronaxie meters and
electronic, 37

String galvanometer, 38

Structural changes in chromosomes
caused by radiation, 126, 148

Structure of insect cuticle, 24

Sulphonamide, 14

Summation of dose distribution, 224

Surface activity of drugs and nar-
cotic activity, 15

Survey of the applications of elec-
tronics in medicine, 34

Sympathetic denervation, evalua-
tion of, 54

Synchronizing the electrocardio-
gram, 51

Tanning action of quinone, 26

— and hardening of insect cuticle,

artificial. 26
— , effect of permeability on, 25
Technical methods in radium

therapy, 234

— methods in X-ray therapy, 216
Technique and volume dose, 209
Test material, insect cuticle as, 21

292

Index

Tests on radiation workers, 278
Textiles, transmission of radiation

by. 71
Therapeutic aims and methods in

radium therapy, 237
Therapy, million-volt, 241
— , neutron, 134
Thermocouple, vacuum, 68
Thermoradiometer, 66, 67
Thermostromuhr apparatus, 51
Thimble chamber, 182

— chamber dosemeter. 183

— chamber, theory of. 185
Thomson scattering. 177

Tissue and tumor tissue, effects of
different radiations on em-
bryonic animal. 132

— .cell division and cell differentia-
tion in normal. 104-106

— , radiation effects on normal, 103

Tolerance dose and volume dose,
208

— doses for ionizing radiations, 267
— . integral dose and. 269

Total body dose of radiation. 217

— energy absorption in radio-

therapy. 194

Transmission of radiation by tex-
tiles, 71

True energy absorption and the
theory of the thimble cham-
ber, 185

Tumor destruction by radiation,
107, 108

— tissue, effects of different radia-

tions on animal embryonic and,

132
— -tissue, radiosensitivity of, 172
Tumors, cell categories found in

ephithelial, 165
— . cellular population of. 164
— , radiosensitivity of, 162, 163
Turbidimetric determinations. 53

u

Unger's economy quotient, 206
Ultraviolet radiations, genetic ef-
fects of, 153

Unit energy of radiation, Einstein's
equation, 177

— of X-ray dose, rontgen. 180
Unmodified scattering, 177
Uptake of drugs by insects, 21

— of ethyl alcohol by blowfly

larvae, 22
Uterine hemorrhage, treatment with
radium, 239

Vaccina virus, inactivation of, 159

Vacuum thermocouple, 68

Value of the conception of volume

dose in radiotherapy, 202
Values of integral dose. 205, 206
Variation of radiation density

through the body, 259
Viable cells. 164
Viruses and bacteria, action of

radiations on, 155
— , inactivation of, 156
— , macromolecular. 157
— .organism-type. 159
— , relative efficiency of ionizing

radiations for the inactivation

of, 124
\'olume dose and biological effects,

210

— dose and blood counts, 212

— dose and field area. 203

— dose and technique. 209

— dose and tolerance dose. 208

— dose, effect of physical factors

on, 202
— dose in radiotherapy, value of
the conception of. 202

— dose limiting radiation technique,

211

— dose, mathematical theory of,

196

— dose of radiation, measurement

of. 199

— dose per rontgen at skin surface

and thickness of tissue through
which the beam passes, 195

— dose to field area for irradiation

of the pelvis, relation of, 201

Index

293

Volume of a brain region, changes
in, 75

w

Wall effect of the ionization cham-
ber. 181 . .
Water, decomposition by radiation,

122
Water-phantom measurements,

228
Wedge fields of irradiation. 223
—filter, isodose curves modified by,

223, 224
— filters. 208

X-radiation and gamma radiation,
1^77

X-ray diffraction analysis, 19

— dose, rontgen unit of. 180

— equipment, high voltage, 243

^ relation of dominant lethals to

dose of. 143

— technique. 261

therapy, technical methods in,

216

— tube, million volt, 244. 246
X-rays, advantages of million-volt,

256 .

— , effect on blood concentration of
ascorbic acid. 213

^ inactivation of viruses in aque-
ous suspension by, 157

—.neutrons and other ionizing
radiations, biological effects of,

114
— , sterilizing effects of. 95