INTERNAL EMITTERS QH 652 .N293 National Academy off Sciences- National Research Council Publication 883 NATIONAL ACADEMY OF SCIENCES— NATIONAL RESEARCH COUNCIL COMMITTEES ON THE BIOLOGICAL EFFECTS OF ATOMIC RADIATION In 1955, Detlev W. Bronk, president of the National Academy of Sciences, appointed a group of scientists to conduct a continuing appraisal of the effects of atomic radiations on living organisms. This study has been supported and funds provided by The Rockefeller Foundation. The study is divided into six parts, each assigned to a separate Committee. The areas under consideration are (I) genetics, (2) pathology, (3) agriculture and food supplies, (4) meteorology, (5) oceanography and fisheries, and (6) disposal of radioactive wastes. The Committees themselves do not perform research; like many other NAS-NRC Committees, they are asked to maintain appro- priate surveillance within their own fields; to evaluate, in the light of their own experience and judgment, the significance of reported findings; and to recommend effective programs of action. In consequence, the published reports not only summarize present knowledge but also recommend needed research, reveal areas of concern or confidence, and project larger problems associated with potential hazards of the future. The reports vary greatly in the extent of technical detail they contain. Some are intended for the lay reader, to tell the citizen what science has learned about the potential effects of atomic radiation on himself, his progeny, and the race as a whole, so that he may par- ticipate more intelligently in making necessary public decisions about atomic energy. Others contain the results of specialized studies made by the Committees of various aspects of the problems. This study will be a continuing one since many of the problems involve basic scientific questions that will take many years to answer. Also, new questions may be expected to arise as the uses of atomic energy continue to expand. The members of these Committees, numbering more than 100, are among the most distin- guished scientists in their fields in the United States. They have given generously of their time and . talents in making these analyses. They serve as individuals, contributing their knowledge and their judgment as scientists and as citizens, not as representatives of the institutions, companies, or Gov- ernment agencies with which they are affiliated. The studies are greatly assisted by consultations with many authorities in private and Government organizations. Following is a list of the Committees participating in this study, and their chairmen: Committee on Genetic Effects of Atomic Radiation Subcommittee on Neuropathologic Aspects James F. Crow, University of Wisconsin Webb Haymaker, Armed Forces Institute of Committee on Pathologic Effects of Atomic Radiation Pathology, Washington Shields Warren, New England Deaconess Hospital, Committee on Effects of Atomic Radiation on Agri- Boston culture and Food Supplies Subcommittee on Hematologic Effects A. G. Norman, University of Michigan Eugene P. Cronkite, Brookhaven National Labo- committee on Meteorologic Aspects of Effects of '■^'"'■y Atomic Radiation Subcommittee on Inhalation Hazards Harry Wexler, U. S. Weather Bureau, Washington Harry A. Kornberg, General Electric Company, . Richland, Washington Committee on Effects of Atomic Radiation on Ocean- Subcommittee on Internal Emitters r. K n it • •• .,* /^„if«~,„ .,» t , i^iio . . ., „ . VI •■ I T „i,„,o..,r„ Roger Revele, University of California at La J olla Austin M. Brues, Argonne National Laboratory ^ Subcommittee on Long-Term Effects of Ionizing Committee on Disposal and Dispersal of Radioactive Radiations from External Sources Wastes Harry A. Blair, University of Rochester Abel Wolman, Johns Hopkins University Report of the Subcommittee on Internal Emitters of the Committee on Pathologic Effects of Atomic Radiation . IT I 1-^ I m i CO i -fl \ nj i □ i '-' i CD : m I D i CD Publication 883 ■ National Academy of Sciences — National Research Council Washington, D. C. 1961 SUBCOMMITTEE ON INTERNAL EMITTERS Austin M. Brues, Chairman Argonne National Laboratory Argonne, Illinois Thomas F. Dougherty, University of Utah, Salt Lake City, Utah Miriam P. Finkel, Argonne National Laboratory, Argonne, Illinois Hymer L. Friedell, Western Reserve University, Cleveland, Ohio Wright H. Langham, Los Alamos Scientific Laboratory, Los Alamos, New Mexico Kermit H. Larson, University of California, Los Angeles, California Hermann Lisco, Argonne National Laboratory, Argonne, Illinois William P. Norris, Argonne National Laboratory, Argonne, Illinois J. Newell Stannard, University of Rochester, Rochester, New York Joseph D. Teresi, U. S. Naval Radiological Defense Laboratory, San Francisco, California Roy C. Thompson, General Electric Company, Richland, Washington Raymond E. Zirkle, University of Chicago, Chicago, Illinois Library of Congress Catalog Card No. : 61-60032 FOREWORD With the artificial production of radioactive nuclides, man greatly increased the potential radiation hazards arising from materials de- posited in his own body. The complete evaluation of these hazards re- quires a vast amount of experimental information, much of which is not presently available. Information on distribution, retention, and ex- cretion of each nuclide must be known in considerable detail. The prob- lem is compounded by the fact that each of these three factors may depend upon the physical and chemical state in which the nuclide enters the body. Absorbed dose calculations are complicated by the irregular patterns of retention; the effects of the rapidly varying dose rates that exist in close proximity to an emitter are largely unknown. Although a complete hazard assessment is in general not now possible, a good start has been made, and some practically useful ap- proximations can be made. The interim report of the Subcommittee on Internal Emitters is in the nature of a status report. The pertinent factors in hazard evaluation from internal emitters are discussed in general terms and the present situation summarized. It is hoped that future research results will permit a more detailed discussion in later reports. Shields Warren, Chairman Committee on Pathologic Effects CONTENTS Page I. INTRODUCTION 1 11. GENERAL NATURE AND PRESENT STATUS 2 in. PHYSICAL AND RADIOLOGICAL CONSIDERATIONS 3 IV. SPECIAL PROBLEMS 4 A. Localization of Radiation 4 B. Transmutation 4 C. Relative Biological Effectiveness (RBE) 5 V. MODES OF ENTRY INTO ANIMALS AND MAN 6 A. Ingestion 6 B. Inhalation "7 C. Skin Absorption 7 VI. EFFECTS OF RADIONUCLIDES AFTER ABSORPTION 8 A. Acute and Subacute Effects 8 B. Chronic Effects 8 Vn. CONSIDERATION OF PARTICULAR RADIONUCLIDES 10 A. The Alkaline Earths (Calcium, Strontium, Barium, Radium) 10 1. Radium-226 10 2. Radiostrontium 11 B. The Lanthanide and Actinide Rare Earths (Including Yttrium) 12 C. Cesium-137 12 D. Iodine-131 13 E. Other Radionuclides 13 1. Ruthenium- 106, Ruthenium- 103 13 2. Zinc-65 14 3. Other Minor Radionuclides 14 F. General Considerations 14 VIII. MAXIMUM PERMISSIBLE EXPOSURE (MPE) LEVELS FOR RADIOACTIVE MATERIALS 16 IX. CURRENT AND RECOMMENDED RESEARCH 18 X. CONCLUSIONS 20 XI. REFERENCES 21 V Chapter I INTRODUCTION In the four years since the preparation of the first report of this Subcommittee , advances in radiobiology have contributed significantly to our understanding of the hazards to man from exposure to radionuclides. Research in a wide variety of fields has added to our knowledge of the consequences of the internal deposition of radio- elements in human beings, notably in cases of radium poisoning, and in experimental animals, particularly with regard to radiostrontium, plutonium, and radium. During recent years, quantitative aspects of the effects of internal irradiation and of the relation between dose and damage in various tissues, especially bone, have moved into the foreground of much of the experimental work. There has been an in- creasing effort to evaluate radiation risks directly through the study of exposed human populations, thus avoiding the uncertainties of extrapolation from laboratory animals to man. However, it is still necessary to use experimental animals because many factors cannot be studied in man. The Subcommittee has decided to issue this report as an interim statement, embodying only few specific data and presenting a brief general survey of the status of the problems. We believe, however, that a future critical analysis of existing data and preparation of a more comprehensive report is desirable. Chapter II GENERAL NATURE AND PRESENT STATUS Recent accomplishments in nuclear physics and engineering have resulted in the production of large quantities of "unnatural" radionuclides and have increased the radioactivity of the biosphere. It is not possible to eliminate all risk, since radio- active contamination is already present. Moreover, it is neither practicable nor sensible to try to eliminate all further sources of risk. Clearly, the hazards should be evaluated in terms of the scientific, social, and economic gains to be achieved. In preparing the 1956 report, we recognized this fact fully and considered the criteria that must be employed in evaluating small but widespread risks, A number of other organizations and committees, whose membership represents the most informed judgment available, have also considered the problem. Among these are the National Committee on Radiation Protection and Measurements (NCRP)2,3^ the NAS-NRC Committees on the Biological Effects of Atomic Radiationl.4^ the Medi- cal Research Council^, the United Nations Scientific Committee on Effects of Atomic Radiation^, the International Commission on Radiological Protection (ICRP) "^.S, and the recently formed Federal Radiation Council^. The NCRP, ICRP, and FRC have recommended basic protection standards for radionuclide concentrations in air, water, and the human body for people who work with radioactive materials. All these organiza- tions have given consideration to the exposure of the general population and have agreed that such exposures should be much more restricted than exposures of the smaller oc- cupationally- involved groups. With present knowledge, we cannot completely evaluate the risk associated with the continued use of radionuclides that may enter the body. The assumptions on which present radiation protection standards are based must be re-examined repeatedly as more knowledge is accumulated and as production and use of radioactive materials becomes more widespread. Research must continue on uptake, distribution, retention, and biological effects of radionuclides in the biosphere, including man, in order to pro- vide the new information needed as a basis for a progressively informed judgment. During 1959, the industrial and medical use of radionuclides increased approxi- mately 20 percent over that of 1958. This increase may be expected to continue. THe use of nuclear energy for the propulsion of submarines and ships and for production pf commercial electrical power is just beginning and may be expected to increase several fold. Although the disposition of the fission products produced in these appli- cations is carefully controlled, the large amounts that will be produced will increase the potential for environmental contamination. We also expect that nuclear energy will be applied increasingly to airborne propulsion and space exploration. Such systems are now under development. A prototype nuclear system for rocket propulsion has been tested, and reactors and isotope units for rocket auxiliary power supplies have been developed. Although such systems produce or contain amounts of radioactivity that are small compared to those produced by nuclear weapons, their use would result in a finite and perhaps significant contribution to the radioactive contamination of man's environment. These applications, and perhaps others not presently foreseen, will introduce new problems, even though there has been considerably less unnatural radioactivity in the atmosphere since the cessation of nuclear tests. Chapter III PHYSICAL AND RADIOLOGICAL CONSIDERATIONS The hazards of exposure to radionuclides depend greatly on their physical and chemical properties as well as the chemical form in which they are encountered. These characteristics influence the rate of entry into the body, distribution to various organs, and retention. The duration of radiation exposure is determined by the factors that influence retention and by the physical half-life of the radionuclide. In some in- stances the situation is complicated by decay chains and the biological redistribution of the radioactive daughters. The nature of the emitted radiations determines the volume of tissue exposed and hence the pattern of injury. For example, an energetic alpha ray penetrates no further than 0. 07 mm in tissue; beta rays deposit their energy largely within the organ of deposition; and gamma ray energy is absorbed in a much larger volume of tissue, some escaping the body altogether. In addition, the degree of biological damage depends to some extent on the concentration of ions produced along the path of ioniza- tion. In general, ionization density is greatest in the case of those emissions with the shortest range; i. e. , alpha rays. In recent years, attention has been centered upon the long-term hazards of radio- nuclides of long half-life, including Ra'^'^", Sr^", andCs^'. However, intermediate and short-lived radionuclides may be of comparable importance. In the event of ac- cidental discharge of radioactive material from reactors and after nuclear detonations, a large variety of fission products and some activation products may contaminate local areas. Even in the case of global fallout from thermonuclear tests, some of the de- posited fission products of intermediate half-life are the source of gamma irradiation which, for a few months after detonation at high latitudes, has exceeded that from Csl37^ 10 When the time between the release of fission products and human exposure is a few weeks or less, I^^-'- is a principal contributor (see Sect. VII. D). Ru 106 The important radionuclides of intermediate half-life include Ba^^O^ j^^lOS^ , Ce''^^ , Ce^'*'*, Y^l, Zr^^, and Sr^^. Some of these are so poorly absorbed that for practical purposes their only effect is to irradiate the gastrointestinal tract as they pass through it. Ba-'-'*'^ and Sr^^ are absorbed and must be considered along with Sr^O as contributing to the skeletal dose-^-^. Detailed studies of local fallout patterns after tests at the Nevada test sitel2 have shown that the geographical distribution of these radionuclides depends on a number of factors, including the altitude of explosion and the nature and amount of surrounding material. Size and solubility of radioactive particles, both of which obviously affect the degree of exposure, vary with distance from point of release, prevailing meteor- ological conditions, and other factors. Each nuclear accident is likely to produce a unique hazard pattern. Chapter IV SPECIAL PROBLEMS A, Localization of Radiation There are good reasons to believe that, when radiation is uniformly delivered to tissues, the biological effects may differ from those of the radiation from focal aggregations of radioactive material (point sources)13. in the latter case, dose rates close to the point source are different from those near the end of the range of the particles. An extremely high dose rate is found near the origin. These spatial dif- ferences in dose may have considerable importance if the relationship between bio- logical injury and energy absorbed is not linear. When the radioelement is diffusely deposited, the probability of injury is the same for all cells in the tissue as a whole; in discrete deposition, the probability of injury to the cells close to the focal aggregate has increased, but that of injury to the cells far away from the focal aggregate has been reduced. Of course, spatial distribution will be of significance when particular tissue ele- ments are selectively irradiated. It is also of significance insofar as the relation be- tween dose and the degree or probability of any type of injury is not linear. Our present information is not adequate to define differences in hazard between focal and diffuse radiation, a question of special importance in the estimation of hazards from internal emitters. B. Tr ansmu tation When radioelements are introduced into the internal structure of biological sys- tems, certain of these may be incorporated into vital molecules. While the ensuing biological effects result for the most part from ionization, some effects may arise from disturbance of the molecule by the transmutation of the incorporated element. The new daughter element has different and. in most instances, incompatible bonding characteristics, and also receives recoil and excitational energy in the process of transmutation. In general, the ionization and excitation resulting from the ionizing particle are so large compared with the recoil energy that in most considerations of radiation injury the former process outweighs the importance of the transmutation process. However, certain radioelements which might be deposited preferentially in vital molecules could, upon transmutation, produce unique biological effects not readily accomplished by ionization or excitation from a charged particlel*. 15. There is no conclusive evidence that transmutation is of critical importance when radioelements are incorporated into biological molecules. However, some experimental data, together with theoretical considerations, indicate that it should receive increased attention as a possible factor in the toxicity of internally deposited radioelements, such as C ^4. The atomic number of the radioelement, the type of decay, the valence change, and the energy are obviously important in evaluating the significance of the transmutation process. C. Relative Biological Effectiveness (RBE) RBE is a concept designed to express the comparative effectiveness of two dif- ferent radiations. It is the ratio of the doses, measured in the physical sense as ergs/gram, that produce the same biological effect. Certain ionizing particles, especially those in which the energy transfer per unit path length (linear energy transfer, or LET) is great, produce relatively intense bio- logical changes in higher organisms. The exact relationship between LET and biological effects is not a proportional one and appears to have a certain maximum value. The use of RBE in assessing radiation hazards presents certain difficulties in that it is not readily applicable in all instances. Experimental work has thus far failed to yield satisfactory information on the RBE relating alpha and beta rays with respect to acute or chronic mammalian damage-*-". The term RBE has validity only when the mode, type, and method of radiation are stated, the particular biological effects clearly circumscribed, and the acute or chronic nature of the study properly evaluated. For excimple, the RBE of a group of particles for interference with DNA synthesis may differ from the RBE for certain cellular changes, such as chromosomal breakage or inhibition of mitosis, and it may again differ from the RBE in a complex organism for a long-range effect such as the production of neoplasms. Also, in a complex organism the RBE's of two particles may differ widely for long-term and short-term effects. The RBE becomes even more difficult to assess under special physiological conditions, such as changes in the state of oxygenation. Because of the many difficulties, the concept of RBE can be applied only in a very general way, particularly to internal emitters, and great care must be exercised when utilizing it in establishing standards of radiation safety for various types of ionizing radiation. It may be stated categorically that an RBE assigned to any particular ionizing radiation cannot be applied uniformly to all biological effects- under all conditions. Chapter V MODES OF ENTRY INTO ANIMALS AND MAN A. Ingestion Gastrointestinal absorption is the most important route of uptake of such radio- nuclides as Sr^O, Cs-'-'^'^, and I . The levels of these nuclides in animals and man are correlated with their levels in the diet. It is extremely important to establish whether these and other radionuclides get into plants largely by way of the soil or largely through direct foliar contamination. Insofar as entry into the diet is due largely to direct contamination of plants, the levels in man will depend on the rate of injection of radionuclides into the environment. Insofar as it is due largely to uptake from the soil through the root system of plants, levels in man will depend on the integrated contamination level of the soil. Knowledge of the ecological characteristics of specific radionuclides is most important for as- sessing the potential hazards of general environmental contamination. * Another factor bearing on ingestion as a potential route of entry is whether the radionuclide is an isotope of an element required by the body or of one chemically similar to a required element. The actinide and lanthanide rare earth series of ele- ments have no chemically similar counterparts among the required body constituents and are usually poorly absorbed by plants and animals. For these radionuclides, in- halation may be relatively more important than ingestion, although the direct irradia- tion of the intestinal surface must be given consideration. Whereas some generalizations are possible on the basis of similarities of ele- ments within families of the periodic table and similarities to required body consti- tuents, each radioelement exhibits its own metabolic properties. There is a continuing * Since the 1956 report, considerable understanding of the ecological behavior of Sj;.90 and Cs^'^''' has been gained. Burton et aL of the United Kingdom have reported^ ' that soil uptake was responsible for 20 percent or less of Sr^O in the British diet during 1958 and that 80 percent or more was a result of direct foliar contamination. While this ratio will undoubtedly vary with time, this suggests that the equilibrium level of Sr90 in the bones of the population from environmental contamination will be lower than that previously predicted. Measurements of Csl37 in human beings and in milk, carried out at Los Alamos since 1956, suggest that contamination levels are largely dependent on the rate of nuclear weapons testing and not on the total fission energy releasees. During 1960, Csl37 levels in milk failed to show the broad spring peak characteristic of past years. Some of the 1960 Cs^^? levels have already dropped to the lower limit of detection, and the average level in the U.S. population was 10 to 15 percent lower than during 1959. It is too early, however, to say whether the average yearly level in the population will be proportional to the rate of decay of the integral soil level or whether it will be pro- portional to the rate of stratospheric fallout. need, therefore, for specific data on gastrointestinal absorption of all radionuclides that are potential contaminants of the environment. B. Inhalation In industry, inhalation has generally been considered the most important route of entry of potentially hazardous materials. Inhalation of radionuclides creates two potential hazards: (1) absorption into the systemic circulation and subsequent deposi- tion in a critical tissue or organ, and (2) irradiation of the pulmonary tissues themselves from materials deposited on the respiratory surfaces and accumulated in the bronchial lymph nodes. The various aspects of air pollution resulting from the development and use of atomic energy and the potential hazards of inhalation of radioactive materials are the subject of a comprehensive report by the Subcommittee on Inhalation Hazards^^. C. Skin Absorption Absorption of radionuclides through the skin has not been sufficiently studied. The skin is not normally considered an actively absorbing organ, especially for in- organic substances. Applicability of animal experiments is limited because anatomical and physiological dissimilarities between human skin and that of the common laboratory animals lead to considerable problems of interpretation. The skin does not appear to be an important route of entry of nuclides contami- nating the general environment. However, skin absorption of radioactive material should not be ignored as a mode of entry. A specific example is tritium in the form of tritium water (H^O). The amount of atmospheric tritium water that exchanges with the moisture in the skin surface and enters the circulation is about equal to that entering the body through inhalation of the same tritium -containing atmosphere20, 21. Absorp- tion of a few other radionuclides through human skin has been studied. Iodine- 131 is appreciably absorbed from an aqueous solution in contact with the skin^^. Introduction of radionuclides through wounds or abrasions are special problems of industrial or laboratory handling. Chapter VI EFFECTS OF RADIONUCLIDES AFTER ABSORPTION The biological consequences of radiation originating from materials situated within the body are fundamentally similar to those of external radiation. Important differences stem from the facts that (1) radionuclides are not distributed uniformly within the body, and (2) they serve as more or less continuous sources of radiation. A. Acute and Subacute Effects In animals, hematologic symptoms of acute radiation disease appear in seven to ten days after the parenteral administration of lethal amounts of radionuclides^S, 24_ Subacute effects, which are frequently seen between one and five months after administra- tion of somewhat smaller amounts, may include hematologic and hematopoietic symptoms as well as evidence of malfunction of those organs in which the radionuclide is most heavily deposited. For example, plutonium and the rare earths lead to liver and bone damaee radioiodine to thyroid damage, polonium to kidney damage, and radiostrontium pc; _9Q to bone damage "^ " . It is exceedingly unlikely that many human cases of acute or subacute poisoning due to exposure to internal emitters will ever occur. In the event of nuclear war the chance of serious damage from external radiation will greatly overshadow the chance of damage from radionuclides that might enter the body. On the other hand, the long- term effects of small amounts of these materials might become a serious problem. B. Chronic Effects Experience with the chronic effects of internal emitters in man is essentially limited to radium, which has been used therapeutically and in the dial-painting industry; to thorium, which has served as a contrast medium for roentgenographic diagnosis; and to elements in the decay chains of radium and uranium, to which miners have been ex- posed. An increased incidence of cancer has been observed in these groups of indivi- duals"^"'^^. More recently radiophosphorus, radioiodine, and other new nuclides have been used in treatment and diagnosis. So far, reports of tumor induction following use of these therapeutic agents have been scanty. A recent follow-up study of patients treated with 1^31 has failed to show an increase in the incidence of leukemia . In man, radium has produced epithelial tumors in the mastoid cavity and the ac- cessory nasal sinuses, in addition to the usual sequela of bone malignancy^S. Tumors may appear in those tissues in which the nuclide is located and also in adjacent tissues lying within range of the radiation. Thus radiostrontium, which localizes in bone, induces in mice both osteosarcomas and epidermoid carcinomas of the oral and nasal mucosa^^. There is also evidence in this species that lymphocytic neoplasms may result when tissues elsewhere in the body are irradiated-^ . The relationship between tumor induction and absorbed dose of radiation is ob- scured by a series of problems that require individual solution. The basic difficulty lies in the fact that, unlike external irradiation, internal irradiation from deposited radionuclides continues at an ever-changing intensity in a changing cellular environ- ment. Consequently, such questions as the relative importance of dose rate and total dose, with respect to both time and space, are difficult to attack experimentally. There are several lines of evidence indicating that dose rate is a major factor in the induction of osteosarcomas by nuclides that localize in bone^S. In mice, for example, the incidence of these tumors has increased as the second or third power of the ad- ministered dose, and has varied with the time pattern of administration's, 34_ There are other instances of radiation carcinogenesis in which the data also suggest that response varies as a power of the dose'^°. An increased incidence of leukemia after the administration of internal emitters has been observed in mice^?. The disease has been reported in a radium patient, who, however, was also exposed to much external gamma radiation^S. in detailed studies of tumor induction in dogs by radium and other radionuclides deposited in the skeleton, no leukemias have been observed and there has been no apparent increase in soft tissue tumors, under conditions that produce bone sarcoma in a high incidence's. Reduction life expectancy is an important consequence of radiation from long retained internal emitters, and this response has been observed in populations of mice irradiated at levels that failed to display an increased incidence of neoplasms^'^. At such levels of radiation, it has not been possible to attribute the reduction in life span to any specific degenerative or infectious disease. The animals die with the same variety of pathologic conditions observed in control populations. It is impossible to say, on the basis of our present understanding, whether life shortening from exposure to internal emitters can be attributed mainly to specific pathologic changes or to generalized processes resembling those of aging. Chapter VII CONSIDERATION OF PARTICULAR RADIONUCLIDES '^^ A. The Alkaline Earths (Calcium, Strontium, Barium, Radium) The alkaline earths are metabolized in a manner qualitatively similar to calcium. Consequently, in the animal body they are rapidly and almost exclusively deposited in the skeleton. Unless the physical half-life of the isotope in question is sufficiently short, some of the radionuclide deposited in the skeleton will remain there through- out life. Unlike the rare earths, the alkaline earths may be readily absorbed from the intestine. A single exposure, or multiple exposures of reasonably short duration, produce a very heterogeneous pattern of deposition in bone. Continued exposure re- sults in a much more uniform pattern of deposition. The dependence of distribution on duration of exposure further complicates definition of the effectiveness of given doses (see Sect. IV. A). 1. Radium-226 Radium-226 is of especial importance; its toxicity in man has long been estab- lished and has, therefore, been used as the basis for estimating the potential toxicity of other bone-seeking radioelements. These estimates are generally made on the basis of experimental observations using the expression: Effect of Ra in human ^ Effect of X in human Effect of Ra in animal Effect of X in animal There has been no direct evidence regarding the applicability of this expression. As the experimental animal approaches the size and life span of man, the difficulties in applying the equation are presumably diminished. In 1941 the maximum permissible body burden of Ra226 in man was set^Z at 0. 1 ^}g. This decision was based on the observation that no definite manifestations of injury from radium had at that time been seen in any individual bearing less than 1 fxg. Since some effects attributed to Ra226 have now been noted at slightly lower levels, it has been suggested that the 0. l-^g value for maximum permissible burden be decreased^S, It must be emphasized that the permissible burden was established at 0. 1 ^xg without reference to the time or the magnitude of the initial exposure. The manifesta- tions of radium injury have been found in individuals some 20 to 30 years after ex- posure to radium. During the period immediately following intake, the amount of radium in the body was certainly considerably higher than that finally measured. The best estimates44 are that an individual retaining 0. 1 ^g Ra226 30 years after intake must have initially absorbed about 10 |jig. Much of our information on Ra226 toxicity is derived from studies on persons exposed in the dial-painting industry and from patients given radium therapeutically. 10 An important complication is that many of the former group were also exposed simul- taneously to unknown proportions of other «-emitting elements, including Ra^^S ^^^ Th228_ Consequently, they received a greater radiation dose than that estimated from Ra226 burdens alone. For these reasons, it would appear that the maximum permissible burden assigned to Ra^^^ for man is conservative. These conservative factors are inherent in the estimate of maximum permissible burdens of other radio- active bone-seekers when they are determined by comparisons with Ra226^ Recently, new studies on the distribution of radium in human bones have extended the basis for comparison among the radioactive bone seekers. While the radium hot spots were found to deliver very high local doses, the relatively uniform diffuse dis- tribution was observed to contain almost half of the skeletally-bound radium and thus to deliver a dose to all the cells in bone. This may be of considerable significance in long-term damage^^"'^'^. The difficulties in assessing hazards from various bone- seeking radionuclides on the basis of dosage comparison between alpha and beta emitters have been discussed35,48, 49_ Finally, there have been no clinical observations indicating the extent to which the effects of Ra^^B j^^ children might be different from those observed in adults, and there has been little experimental work in this area. 2. Radio strontium Both Sr^9 and Sr^*^ are beta- ray emitters, as is the Y^^ daughter of the latter. Their half-lives are 50. 5 days (Sr^S) and 27. 7 years (Sr^O), so that the latter becomes increasingly important with the passage of time after fission. Strontium-85 is a gamma- ray emitter and is used in clinical studies, since it can be measured in vivo in very small amounts by whole-body counting techniques. Strontium- 90 has been found universally in the biosphere. In the western hemis- phere, its primary source for man is calcium-rich food, especially milk. While the metabolic course of Sr^O is qualitatively similar to that of calcium, there are some quantitative differences. For example, there is greater absorption of calcium than strontium from the gastrointestinal tract and greater renal excretion of strontium than of calcium ^^. Growing animals have been shown to retain strontium more ef- ficiently than adults, a reflection of the fact that calcium deposition proceeds more actively in younger animals"'-^. Recent measurements of Sr^^ retention in normal, adult humans have shown results similar to those found in animals^^. The retention of the alkaline earths, including Sr^^, can be described by a power function of the form R^.Atb where R^ is retention at time ;^in days after injection, ^is equal to R^t ^t one day, and b is the ¥lope of the log-log line^S, The slope b for strontium in man is about one-half that estimated for Ra226 in man. In other words, the rate of excretion of radiostrontium at time t is considerably 11 less than the rate of excretion of Ra226 ^t the same time after exposure. However, experiments with rats and dogs have given somewhat different results. These dif- ferences may be related to the fact that in rats and dogs radium and strontium are excreted in roughly equal quantities in the urine and feces^'^. This is also true of strontium in the human; however, radium is excreted from man almost exclusively by way of the gut44. B. The Lanthanide and Actinide Rare Earths (Including Yttrium) The lanthanide rare earths are produced in high yields in fission reactions; the parent materials in such reactions are members of the actinide rare earth series. These elements behave similarly in their predominant chemical and biochenaical re- actions. However, there is a progression (with increasing atomic number) in chemi- cal behavior within these groups (particularly the lanthanides)^^, which is reflected in systematic changes in their biologic behavior'^". Although radioisotopes of these elements are distributed over the earth as a re- sult of the use of nuclear devices, they have not as yet been identified in appreciable quantity in mammals and man. This is undoubtedly a consequence of their extremely low solubility under biological conditions and correspondingly low absorption from the intestine. In experimental animals, less than 0. 01 percent of an ingested dose is absorbed. There may be an exception in the case of very young animals, since suck- ling mice absorbed 2 to 3 percent of plutonium given orally in milk or as the citrate^ '. When these materials are introduced directly into the blood stream, they behave like colloids and become fixed in the reticulo-endothelial system and in the more ac- cessible surfaces of the skeleton. Their rate of loss from the body is very slow^^. Locally injected solutions of the uncomplexed ions tend to remain at the site of administration. The complexed ions are removed from the site with fair rapidity and follow the pattern of the intravenously injected material^ ^. C. Cesium-137 This element has been found in mammalian and other vertebrate species. In man the concentration of stable cesium is about 10-10 g/g wet tissue. Cesium-137 from nuclear debris has now been measured in foodstuffs and man^". The amount of Csl37 in the body reflects the quantity of radionuclide in the diet, which, in turn, is determined by the degree of radioactive contamination. Be- cause of the relatively short residence time of Csl37 in man (biological half-life about 140 days)^^, the average content of this nuclide in humans is a good reflection of recent fallout rates. The major portion of the Csl37 burden of the United States population is derived from milk; meat products are the second most important source^l. During 1959, the mean Csl37 burden of a U.S. resident reached a maximum, which was estimated62 at 0. 01 fic. This burden contributes an irradiation dose of about 2 mr/yr or about 2 percent of the natural radiation background. Because of the chemical similarities of cesium, potassium, and rubidium, their metabolism is similar. Cesium, like potassium, occurs chiefly within cells, although 12 low concentrations exist in the body fluids and bone. Tissue distribution studies have shown that the muscle mass contains the largest portion (perhaps 60 percent) of the body cesium, with visceral organs, brain, blood, bones, and teeth following in that order^"^. Cesium salts are quite soluble and are quickly and completely absorbed, more or less independently of route of administration. The ion is excreted by the kidney, except in ruminants where a considerable portion is excreted by way of the gut. Tracer studies in the cow show that about 13 percent of a single dose will find its way into the milk within 30 days^'^. D. Iodine- 131 Iodine-131 is produced abundantly in fission and, because of its volatile nature, it is readily liberated. The tendency of iodine to concentrate in the small volume of the thyroid gland is, of course, the primary cause of the hazard of 1^3 1. A situation involving I^^l ig illustrated by the Windscale reactor incident in England in 1957. ^5 An accident during reactor operation allowed the release of fis- sion products from the reactor stack. The fission product escaping through the filters was almost entirely I^^l. Significant downwind contamination covered an area of about 200 square miles. The major vector for human intake of 1^3 1 was milk. Following the incident, milk samples containing more than 1 )j.c/liter were obtained from nearby farms. In order to limit the radiation dose to the thyroids of children to 20 rads, it was necessary to use 0. 1 ^jlC of I^^l/iiter of milk as the maximum permissible con- centration (assuming an intake of 1 liter/day). This necessitated discarding a con- siderable quantity of milk over a period of 6 weeks. The adult thyroid has been found to tolerate quite large doses with no discernible ill effects, but evidence from children treated with X-ray doses in the vicinity of 200 r in the region of the neck suggests that this dose may produce carcinoma of the thyroid in a small proportion of exposed individuals, and, perhaps, under specific conditions of irradiation66. In the child's thyroid weighing around 5 g, 1 (iC of I /g of thyroid will yield an integrated dose of about 130 rads. E. Other Radionuclides The presence of certain other fission or activation products in the environment has been detected. It is sufficient to comment on some of these only briefly, since they are considered to contribute negligibly to the irradiation of man at this time. 1. Ruthenium- 106, Ruthenium- 103 At present these nuclides exist in rather high concentration in the soil, their deposition level being around 800 mc/sq. mi. They have been detected in low concen- tration in meat and other foods and in marine organisms by gamma- ray spectrometry. Ruthenium is absorbed from the rat intestine to the extent of about 3 percent. Its uptake by plants is extremely low, which impedes its passage from soils to man. There is some uncertainty as to the critical organ or tissue for this radionuclide, but the available evidence implicates the gufo?. 13 2. Zinc-65 This isotope, an activation product, is found in the soil to the extent of about 10 mc/sq.mi. Zinc-65 has been detected in small quantities in fish, meat, and other foods68. Trace amounts have been detected in plant tissue. Its presence in persons dwelling near the Hanford Works"", in cyclotron operating personnel, and in the natives of the Rongelap atoll has been detected by gamma- ray spectrometry. Absorp- tion from the gastrointestinal tract of man appears to be greater than the 10 percent assumed previously"' ''^. In a study of 6 human subjects, absorption ranged from 30 to 90 percent of the ingested amount. Considerable interest in this nuclide has de- veloped as a result of observations that it is heavily concentrated from sea water by certain mollusks' . 3. Other Minor Radionuclides Traces of Zr^^ (and its Nb^^ daughter) are found in plants, and Zr^^ has been detected in food^S. Contamination level in soil is around 50 mc/sq.mi. Its absorp- tion from the intestine is exceedingly low. Antimony-125 is presently found in soil in concentrations around 25 mc/sq.mi. It has so far not been detected in plants or in animals. Manganese-54 has been found in soil in very low concentrations. It was detected in some marine organisms after Pacific weapon tests. Tungsten- 181 and W-*-"^ were generated in at least one bomb test as a tracer for atmospheric studies. They have been found only in soil, where their total activity is around 50 mc/sq.mi. Rhodium- 102 was also generated as an atmospheric tracer. It has not been found in the biosphere, except in soil, where its concentration is around 15 mc/sq.mi. F. General Considerations Two problems of special concern in the area of radionuclide metabolism de- serve mention. One is that of estimating the body content of a radionuclide from ex- cretion rates; the other is that of accelerating the excretion of a deposited radio- nuclide by therapeutic measures. Where total-body counting methods are inapplicable due to the radiation char- acteristics of the nuclide, the measurement of levels in the excreta offers the only practical means for estimation of body radionuclide content. The establishment of relationships between body content and excretion rates, as a function of time follow- ing exposure and route of exposure, is therefore an important practical objective of studies in large animals and in persons who have received occupational exposures resulting in detectable levels of radionuclide excretion '2. Recent efforts to increase the excretion of deposited radionuclides have been encouraging with respect to certain heavy metals, such as plutonium, thorium, yttrium, and the rare earths '^3, por these elements, the chelating agent diethyle- netriaminepentaacetate (DTPA) has proven much superior to the earlier studied ethylenediaminetetraacetate (EDTA) and should be a practically useful agent for the 14 prompt treatment of accidental exposure to radioisotopes of these elements '^4. In- deed, chronic treatment with DTPA is effective in removing substantial fractions of firmly deposited plutonium from bone'^^^ Prospects for the removal of strontium or radium appear less hopeful, and no practically useful treatment can be recommended for radioisotopes of these elements. 15 Chapter VIII MAXIMUM PERMISSIBLE EXPOSURE (MPE) LEVELS FOR RADIOACTIVE MATERIALS The establishment of MPE levels for radioactive materials presents many problems similar to those associated with maximum exposure levels for external radiation. The biological effects of ionizing radiation are qualitatively similar whether the source is inside or outside the body. Although the standards applicable to external sources can be and are utilized for internal emitters to a considerable extent, there are several important differences. 1. The spatial and temporal distribution of the radiation dose from internal emitters is a function both of the half-life and of the physiological behavior of the particular radionuclide and the compound in the particular organism. The lack of detailed information concerning the physiological behavior of these radioisotopes in man is a source of uncertainty not encountered in the evaluation of external irradiation hazards. The ICRP and NCRP have recently published an ex- tensive tabulation of the metabolic data on which they base their estimates of the hazards of exposure to approximately 240 radionuclides 3, 8, These data, which necessarily form the basis of recommendations about exposure levels, have many shortcomings. For many radioelements, there are simply no data of the type needed for hazard evaluation, and assumptions must be made on the basis of known behavior of pre- sumably similar elements. For those internal emitters of principal concern, a sub- stantial body of metabolic data are available. In most instances, however, there is a lack of such detailed information as the effect of the chemical or physical form of the radionuclide, and the effect of physiological variables such as age, nutritional status, etc. While gross distribution patterns are known, the fine structure of radionuclide distribution within tissues, which may be of critical significance in determining toxicity, is often unknown. For nearly all radioelements, the available data cover only brief periods of exposure or brief periods of retention following a single exposure. For most radioelements, there are few or no data directly appli- cable to man, and animal data may be misleading. 2. Application of external radiation standards to radionuclides in the body has required use of the concept of the "critical organ". Theoretically, the critical organ should be the most vulnerable tissue under the given circumstances of deposition and retention, and with external radiation it can indeed be so chosen. However, with radionuclides, the organ with the highest concentration is very frequently selected as "critical"'^' ^. This is conservative inasmuch as, with few exceptions, no organ system is permitted a dose greater than that permitted for whole-body external radiation. However, the organ of highest concentration varies with time, route of administration, etc. As a result, as many as twelve potentially critical organs may be chosen for each radionuclide'^ •> °. The one yielding the minimal MPC value is usually 16 taken as controlling the final choice. This procedure is admittedly cumbersome and sometimes may be unnecessarily restrictive. However, the basis for the maximum permissible body burden of those elements that deposit selectively in bone is quite different from that used for other elements. Here experience with the effects of radium in man assumes controlling importance. Elements that behave like radium now have their MPC values determined by com- parison of their potency and effects with those of radium. The choice of critical organ is unnecessary; and little information is needed on organ deposition, retention, etc. , except for the final calculation of permissible air and water concentration. This provides the internal emitter field with a "double standard" for maximum per- missible dose estimates. The clinical data from both external radiation experience and the radium experience can be applied. The calculated MPC values allow somewhat different radiation doses to the critical organ (bone) when estimated by these two methods, but the difference is surprisingly small. This relative coincidence of values lends credence to the soundness of both approaches. 3. The genetic effects of internal emitters are presumed to be similar to those caused by external radiation sources. If the element in question is rather uniformly distributed in the body or if the gonads are the critical organ, then the potential genetic effects control the MPC in the same way as for external radiation. The possi- bility of a "transmutation effect" over and above the effect of ionizing radiation has been considered theoretically^'^' ^^. Experimental information on the importance of this effect and indeed on the genetic effects of potentially important internal emitters is almost wholly lacking. 17 Chapter IX CURRENT AND RECOMMENDED RESEARCH Since the previous report of this Subcommittee^, substantial progress has been made in overcoming certain of the deficiencies discussed above. The accumulation of fallout Sr90 and Cs^^T ^^ man has provided an opportunity to check on a global scale the accuracy of predictions based on limited laboratory and clinical experience. Of particular interest has been the demonstration of a relatively small degree of in- dividual variation in the accumulation of these fallout radionuclides— a finding which could not have been confidently deduced from laboratory or clinical data . The pro- portionally higher levels of Sr90 accumulated by children, while not unexpected, has emphasized the need for a consideration of age in the evaluation of internal emitter hazards. In the past few years there has been an intensification of efforts to locate and study more of those persons exposed 30 or more years ago to radium and, more recently, to thorium. The continued study of these persons offers an opportunity for obtaining data on both metabolism and toxicity which will probably not again be available. Epidemiological studies of populations living in areas where the background radioactivity of food and water are above average constitute an important supplementary area of investigation in this field. The construction during the past several years of a considerable number and variety of sensitive total-body counting facilities should greatly improve the prospects for obtaining data from planned tracer experiments in man. Such instruments are now so sensitive that the metabolism of gamma-emitting isotopes can be followed for several weeks after administration of only 0. 1 to 1 percent of a daily maximum permissible dose of the radionuclide. Studies of the gross retention of several ele- ments, notably the alkali metals, in a variety of animals, including man, have been reported '7'^, and much additional data of this sort may be anticipated in the future. Perhaps most significant among the recent animal studies are the experiments with larger animals which were initiated a number of years ago and which are only now beginning to produce critical data. Such studies with radium and other bone- seeking radionuclides in dogs have furnished detailed confirmation of retention and excretion patterns predicted from very limited data on man. The superiority of the power function in describing the retention of bone-seeking radionuclides seems clearly established by these results^^. Such long-term studies in large animals require extensive facilities and many years of effort before results are obtained. Recent expansion of efforts along these lines is therefore particularly encouraging. Current experiments with smaller mammals, mice in particular, are focused upon the relationship between the distribution of the absorbed dose, with respect to both time and space, and the pathologic sequelae. Particular attention is being given to the quantitative differences between the effects of exposure by way of a single intravenous injection and exposure by way of continuous ingestion. Emphasis is also 18 being placed on investigations of the fundamental mechanisms involved in the induction of osteosarcomas by internal emitters. The ICRP and NCRP have made available an invaluable collection of information and methodology and have chosen wisely on the basis of present knowledge. Yet there are areas where much work still needs to be done. We feel that part of our function is to highlight such areas and to help stimulate scientific efforts directed toward sup- plying the needed information to those charged with the responsibility of setting the maximum permissible dose standards. A perusal of this report will indicate that, while progress is being made and advantage is being taken of new approaches, there are many areas in which further information is essential. We recommend that special attention be given to the fol- lowing areas: 1. Studies in a variety of animals of long-term physiological and pathological changes resulting from chronic irradiation by deposited radionuclides should be con- tinued, with increased reference to variables such as age and nutritional status of the animal, chemical and physical form of the nuclide, route of administration, and duration of exposure. 2. Studies of the effects of such variables on uptake, retention, and anatomical distribution of radionuclides should be continued, and, where possible, such data should include man himself. 3. Further studies of the relationship between excretion levels and body content of radionuclides should be carried out, with particular reference to those not readily measurable by external counting techniques. Studies aimed at finding methods for promoting the excretion of deposited radionuclides are also of prime practical im- portance. 4. Study on a global scale of the accumulation and retention of fallout radio- nuclides in man should be pursued on a continuing basis as fully as is necessary to obtain representative information, since this may be an irreplaceable opportunity to secure this type of human data. For similar reasons, full emphasis should be given to continued study of groups of persons who have been exposed to radioactive materials and of populations that have lived in areas having greater than average levels of radioactivity. 5. Concepts that are used in the assessment of relative degrees and hazards of exposure to radionuclides, such as RBE and critical organ, should be kept under con- tinued scrutiny with the accumulation of new basic knowledge. 19 Chapter X CONCLUSIONS Previous evaluations and conclusions of this Subcommittee have been incorporated in the 1956 and 1960 reports of the Committee on Pathologic Effects of Atomic Radia- tion-^''*. While much new information pertinent to the toxicity of internal emitters has been and is being collected, we feel that, in the light of present knowledge of the sub- ject, the basic principles stated before continue to express our present evaluation of the problem. We would emphasize that while progress in such a field as this is necessarily- slow, a number of new trends in research will favor eventual acquisition of data that are necessary for solution of many problems. Among these are (1) the establishment of experimental colonies of large animals, (2) the development of highly sensitive techniques for estimating total body content of radionuclides, and (3) the exploitation of population studies in groups of persons having various degrees of exposure above the average for mankind. Certain basic areas of information are also being sought and this will add greatly to the interpretation of empirical data. Studies of the precise localization of deposited radionuclides are progressing along with further investigation of the biological and pathologic importance of localization in terms of the significance of radiation dose rate and of quality of radioactive emission. These may be expected not only to ensure progress in the more practical areas of radiation protection, but to add greatly to our store of knowledge of the nature and etiology of various pathologic processes, including the development of malignant disease. 20 Chapter XI REFERENCES 1. Pathologic Effects of Atomic Radiation, National Academy of Sciences— National Research Council Publication 452, Washington, D.C., 1956. 2. Permissible dose from external sources of ionizing radiation. Recommendations of the National Committee on Radiation Protection and Measurements, National Bureau of Standards Handbook 59, Government Printing Office, Washington, D.C. , 1954. Also Addendum to Handbook 59, April 15, 1958. 3. 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R. , Retention and excretion of radionuclides of the alkali metals by five mammalian species, Los Alamos Scientific Laboratory Report LAMS- 2445, p. 71, 1960. 26 The National Academy of Sciences National Research Council The National Academy of Sciences — National Research Council is a private non-profit organization of scientists, dedicated to the furtherance of science and to its use for the general welfare. The Academy itself was established in 1863 under a Congressional charter signed by President Lincoln. Empowered to provide for all activities appropriate to academies of science, it was also required by its charter to act as an adviser to the Federal Government in scientific matters. This provision accounts for the close ties that have always existed between the Academy and the Government, although the Academy is not a governmental agency. 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