Toxicology of Radioactive Materials (Annual Review of Medicine, Vol 9, 1958)

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DAVID A. RYTAND, Editor Stanford Ufiiuersity School of Medicine WILLIAM P. CREGJZR, Associate Editor Stanford University School of MedicinC

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Library of Congress Catalog G r d Number: AS1-1659 Firrt Edition -- Prlnted and bound in the United Stater of Ame?k. by GEORGE BANTA COMPANY, Inc. Second Edition - - 1963. Photolithoprinted and bound by

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dbu Therapy Nncirer bid. 77. 5% 'inm Thmapy Nucltar Hid., 76, 39-46 iinm The & Nnclm Mid., 77. 64-65 Thtmpy Nvclror Mid., 76. 1141-43 TOXICOLOGY OF RADIOACTIVE MATERIALS' Lar AIamos Srimfifi Laborobry, UniuCrriry of Cdifardo, La; Abmos, N w Mrxico Of the thousand or so radioactive nuclides (1) that have been di3coveied or identified, there are actually only about twenty that are produced or used, or both, in sufficiently large quantities or have sulhciently long b d f - lives to constitute potential health hazards. I n general, these are natdy - occurring, nuclear pile-produced, or result from fallout. A listing of t h e e together with a compilation of significant data for evaluating their pot did toxicity, are presented in Table I. This table is adapted from tables given in the Recommendations of the In tenu tio d Commission on Radiologiul Protection (2) and the N & i d Bureau of Standards Handbook 52 (3). The particular nuclides which were selected for listing and discussion are those: (a) which, on entry into the body, remain there for a long period and continuously irradiate selected organs. Thew nuclides, in general, localize in the skeleton and are toxic hi extremely minute quantities; ( b ) which arc not as toxic as the bone seeker8 but are used in large quantities, as judged from the distribution statistics of the Olk Ridge National Laboratory (4, S), and hence have a high probability of exposure to a significant number of people; and ( C ) which are persistent fallout products and present a long-term, low-level hazard to the population in general. The data contained in Table I are taken directly from the tables indicated above unless otherwise indicated. The orilinnl murces of the data can be obtained by referring to t h e e tables. The data apply only to soluble inorganic forms of the nuclides unless otherwise indicateh In a general sense, a radiation source produces the same effect 011 telb whether it is within the body or irradiating it from the outside, Le., it produces ion pairs which, in mae as yet unknown fashion, disrupt nucltopteins or alter enzyme systems. However, for an adquate evaluation and underltPnding of the toxicity of a specific ndioactive nuclide with the accumulation of the same type of information as is necessary for the toxhlogy of the so-called conventional poisons. the chemical toxina, is required. For instance, in both cases it is desirable to know ( 0 ) the form of the material, Le., whether soluble or insoluble; ( b ) the route of entry; (c) the extent of absorption across the gastrointestinal tract; (d) the amount absorbed through the lung alveoli; ( # ) the rate of resorption from an intramuscular or subcutaneouo rite; ( f ) the routes and rate of elimination; ' Thc survey of the literature pertiking to thii review was concluded in J u a ~

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( 9 ) the distribution in the body with time and rpecik o w o r of locphti0rr; (k) the pathologic effects; (i)the rymptomrtology; and (j) methods of treatment. In addition, for the further characterization of the harard from a radioactive material, one must know the rate of decay, the mode of decay, and the energy of the emanation. The rate of decay is indicated by the physical half-life in days in Table I. The physical half-life, togethe with the rate of elimination (indicated by the biological half-life). r d t in a net loss of the activity from the body, indicated as ”effective half-life.” The effective half-life T,can be calculated from the following relationhip: where T, and T, are physical and biological half-lives, respectively. Tbe mode of decay, whether by alpha, beta, or gatnma emrnation, determba the range over which the energy of decay is dissipated. The data 011 energy of decay, together with the mode of decay and information on the unifor&y of distribution of the nuclide in the tissue, are necessary for the calculation of the radiation d o e delivered. A useful index of the toxicity of a radioactive material is the so-calltd maximum permissible dose (MPD). The more toxic a nuclide, the lower is the MPD. As delined by Stone (7), the MPD ii the amount of irotOpe which provides “a dose of iooizing radiation that in the light of present knowledge i s not expected to UUH appreciable bodily injury to a person “any bodily injwy or ef€cct that a person would regard as being objdolrable or which competent medical authorities would regard as bekg deletento be the amount of nuclide that will deliver 0.3 rep per week to the “critical” orgra, i.e., the orgao likely to receive the mort dunrge, tither because the isotope is concentrated in the organ or because the o r p v l especially radiosensitive. T h e MPD for “bone seekers” is tied to radium It is the quantity of nuclide that delivers a radiation dose equivalent to tbe dose delivered by 0.1 pg. of radium to the skeleton. T h e MPD is a more desirable index of toxicity thrn LD,,, because it provides a stroclard agPind which to judge the continuance of a worker on a specific task. Excellent discussions of the concept of MPD are given by Stone (7, 8), M 0 g . n (9. lo), Taylor ( l l ) , Jasinki (12), Thompson (13), aod Stlnnrrd (14). As can be seen from the topic headings, many of the data indicated above for evaluating the hazard from given nuclides are presented in Table I. Following is a dircussion rummoruing additional information on certain of the nuclides. In 1953, a comprehensive bibliography w a s published which dstractcd the literature on the toxicology of inteulIy-deposited rrdioelt ments through 1951 (IS). The following rerictlr wilt be devoted largely to reports occurring since that time, although some reference will be amde to the earlier literature when it is pertinent to do SO. In 1955, a preponderance of work in the field of radionuclides was summarized at the InternationA~

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Conference for Peaceful Gses of Atomic Energy at Geneva. Since many of the reports were either review artides or contained extensive bib*- raphies, or both, reference was made to these, when possible. Rodium**8.-Radiurn1n and its congeners are the prototypes of the radioactive poisons. The first cases of radioactive poisoning which w e n recognized and described were radium and mesothorium c u e s (16, 17). Since that time ( 1924), hundreds of people have, in various ways, by intent as part of supposed therapy or inadvertently from occupational exposure, accumulated body burdens of radium (18). Many of the cases were wdlstudied and iconsiderable body of literature on radium poisoning ha1 been In recent times, because of the atomic energy program, there has been 8 renewal of interest in these u s e s since they are a rich and euentirlly the only source of information on the Long-term effects of radioactive poisoning in man. In 1952, Aub ti d. (21) reported on a series of 30 cases who had stored internally-deposited radioactivity over many years. As might have been expected from earlier studies, the principal findings were in the osteitis,” pathological fractures, osteosarcomas, fibrosarcoma of P joint capsule. There were three cases of epidermoid carcinoma of the IUSOpharynx. Three cases with body burdens of 10 to 23 w.stored as long u 25 years showed no apparent deleterious effects at the time of the study. The lowest dose at which atypical rims were evident was 0.3 to 0.5 w. These were roentgenographic changes. Marshk (22) reports a similar finding in a case with a body burden of 0.4 le. Probably the most comprehensive study on radium poisoning ir reported by Looney and his co-workers (23, 24, 25). Among the objectives of this study was the gathering of information on the so-called “minim1 bone lesion.” Lesions which possibly might be attributed to radium radiation were found in individuals with body burdens of 0.15 ~rg.in one case, and 0.06 pg. in two other cases. On the basis of his studies, particularly on the miere scopic studies, Looney (26) has concluded that the MPD for radium ahould be lowered from 0.1 to 0.05 pg. and perhaps as low as 0.02 pg., if the dose is accumulated very early in life. Studies on the early urinary excretion of radium in man were reported by Rajewsky (27) and on the late (i.e., long after the radium had been administered) urinary excretion by Norris and his colleagues (28, 29). Norrio points out that the urinary excretion of radium is best described by a power function Spiers (30) presents a discussion on the radiation dose delivered by radium. An excellent review on the carcinogenic action of radium has been compiled by Furth & Tullis (31). Plutolcium*’*.-Plutoni~’” is produced on a large scale. It is used in weapons and as a fuel for nuclear piles. With the vast projected usc of

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nic Energy at Geneva. Since many rler or contained extensive bibliogo these, when possible. geners are the prototypes of the radioactive poisoning which were and mesothorium casts (16, 17). ~plehave, in various ways, by intent -tently from occupational exposure, 18). Many of the caws were wellature on radium poisoning has becn c energy program, there has been a they are a rich and essentially the e m effects of radioactive poisoning cd on a series of 30 caws who had wer many years. As might have .&eprincipal findings were in the darly in the jawbone), “radiation arcomas, fibrourcoma of a joint pidermoid carcinoma of the nasoof 10 to 23 kg. stored as long as 25 Eects at the time of the study, The re evident was 0.3 to 0.5 pg. These ik (22) reports a similar finding in .dy on radium poisoninpis reported 25). Among the objectives of this attributed to radium radiation were studies, particularly on the microhaps as low as 0.02 Fg., if the dose m of radium in man were reported .., long after the radium had been wris and his colleagues (28, 29). ion of radium is best described by a i discussion on the radiation dose ew on the carcinogenic action of ced on ahrge scale. It is used in s. With the vast projected use of TOXICOLOGY 1 IF RADIOACTIVE MATERIALS 373 nuclear piles for electric power and for power plants for ships, plutOniw will probably become a very important industrial hazard. It is also a cornponent of “fallout.” As can be seen from Table I, Pu** has a long hrlf-fifc, goes to bone on entry into the body and stlys there for the remainder of the lifetime of the individual. Because it continuously irradiatu a p d a - larly radiosensitive area of the body, the bone marrow, an excndindy minute quantity of plutonium caa be very damnging. For this reoron, p l ~ - tonium has been considered among the most toxic substances known. The pathological effects on bone are similar to those of radium and the other radioactive bone seekers. The most intensive studies on the toxicity of plutonium in large animals are now being carried out at the AEC Project in the Radiobiology Laboratory at the University of Utrh (32). Dogs were injected with PuJ**at five different dose levels and are being followed throughout their lifetimes. To date (approximately four yean after the start of the experiment) a number o f the highdose dogs have died. The pathological findings are trabecular fibrosis, abnorrml endosteal bone growth, pathological fractures, atypical osscous tissues, a d osteogenic sarcoma. The clinical findink in the surviving dogs are evidences of pfCmature aging, graying of hair, depigmentation of the iris, retinal changer, and reduced blood volume. Although Pd- is considered primarily a bone seeker, it has been found to be a potent carcinogen in soft tissues as well iu in bone. In an RBE study using development of malignant bone tumors as an endpoint, Finkel (33,34)found the relative carcinogenic potential for plutonium to be 7 :1, u compared to radium. Lixo et d. (35) report the induction of B bros or co ~ at the site of a subcutaneous injection in rats of as little as 1 pg. of Pu(N,),. In studies done by Wager (X), 1 pg. of colloidal plutonium oxide introduced in the mouse lung resulted in epidermoid carcinoma after A very sensitive but complicated procedure for the determination of plutonium in urine has been developed by Schwediman el d (37). The quantitative estimation of the body burden of plutonium is made from the use o f c u m s or equations or both which have becn worked out for the correlation of excretion rate and body burden in nun (38,39). The extreme sensitivity of the assay procedures allows for the detection in urine o f amounts of plutonium corresponding to very low body accumulrtions. As a consequence, it has been possible to show that an appreciable number of individuals have accumulated plutonium internally. Cipriani (40) reports that in the Chalk River operations in the year 1953-199, 10 per cent of the individuals checked for plutonium by urine assay showed accumulation internally. Parker (41) reports that in ten years of operations with plutonium at the Hanford Works, over 100 individuals accumulated plutonium internally. There was no specific exposure incident associated with 45 per cent of these. At Los Alamos, in a report covering six years of operations with plutonium, Hempelmann (42) indicates that 27 individuals reeum-

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ulated body burdens of plutonium. A similar report from the English experience with plutonium has appcarcd (43). It is of interest that the preponderance oi the cases occurred as a result of inhalation exposure. Also, it is noteworthy that none of these cases accumulated body burdens larger than the so-called tolerance levels, with the exception of one Britih case (43) and possibly five of the Los Alamos cases (42). Successful attempts at therapy of plutonium poisoning, namely procedures for hastening the rxcretion of the metal ion, have been reported in animals (44to 53). Because of the limited c u e material, very little experience has been obtained in humans. Foreman presented one case (54) in which the use of calcium ethrlenediaminctetrracetate (G EDTA) brought about a 25 per cent reduction in the body burden over what might have been expected in the untreated situation. In another case, the drug had v u y little effect ( 5 5 ) . Zirconium citrate, another drug which was found to bc very effective in reducing the body burden of plutonium in animals, was tried with little success in humans (56, 5 7 ) . Graham reports very serious, deleterious side effects from the use of …