Metabolism and Toxicity of Transuranium Elements and Other Radioactive Bone-Seekers

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UNIVERSITY OF CALIFORNIA LAWRENCE RADIATION LABORATORY 4. BUDGET ACTIVITY NO. IESCRIPTION OF PROJECT AND WORK PLANNED 5 , Description of Project This project is in the general category of Assessment, Evaluation, and Control of Radiation, specifically, Exposure to Internal Radiation. The aim of this project i s the measurement of retention and elimination of t h e transuranic elements and other bone-seeking radionuclides and the elucidation of t h e mechanisms of accumulation, translocation, retention, and elimination of these elements. There a r e some important research by-products i n that metabolic experiments conducted at tracer levels (that is, avoiding radiation damage) contribute tothe understanding of mineral metabolism, bone physiology, and bone aging. A. Metabolic and Actoradiographic Studies with the Transuranic Elements A life-span metabolic study was conducted i n 150 10-day old female cal analyses of excreta and tissues were completed several years were prepared for inclusion i n Ref. 6. were analysed with the following findings, highlights also to be During FY 1972 some of the metabolic data from this experiment Soft tissue autoradiographs t i m e of 7 days leading t o an infinite-time radiation dose of 17 rad, At this dose level liver damage was slight and transient. the period of observation, 1to 779 days post irradiation, alpha tracks were found generally distributed throughout liver tissue. During the first 15 days when concentration w a s high, more 241-Am could be found near the arterial circulation. Average initial liver uptake was 509 with a clearance half -

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REPO-SITORY: OFFICE OF HUMAN RADIATION COLLECTION : PLUTONIUM INJECTION INVESTIGATION FOLDER: EXTRA COPIES

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1 May 1972Metabolism and Toxicity of Transuranium Elements and Other Radioactive Bone-Seekers DESCRIPTION OF PROJECT AND WORK PLANNED (CONTINUED) Blood and whole-body measurements have been made periodically. tion data have been summarized for Ref. 4. lated, and summaries appear i n Refs. 1 and 6. radiographs were examined with the following findings (also to be Bone data have been tabuKidney and liver autotime of 70 days, and the total radiation dose was calculated t o be subsequent changes are much like those seen inthe rat except that the time scale is extended. During the first 100 days p.i. alpha tracks were distributed diffusely -- initially at slightly higher concentrations i n the areas closest to the arterial circulation. Thereafter, superimposed on the declining background of single tracks, occasional aggregations of tracks were found associated with pigment i n Kupfer cells (located most frequently near central veins). Aggregations did not disappear with time as w a s seen i n the rat, but were still observed as long as 938 days.p.i. Slight liver damage was observed (binucleated o r pyknotic hepatic cells) towards the end of the first year, but was not seen thereaf'ter. Average initial liver uptake was 5O$ with a clearance half - The initial distribution of 241-Am i n monkey liver and its the microscopic distribution of 241-Am inthe monkey kidney was like that seen inthe rat. After the disappearance of much of the early diffuse distribukion of single tracks, and i n addition t o aggregates of tracks associated with calculi, multiple alpha tracks could also be found associated with pigment i n tubule cells or macrophages located most often i n the medulla. Except for an extended time scale i n the sequence of events, The first 88-inch cyclotron bombardment of 235-U t o make 237-Pu, a 45-day photon-emitting Pu isotope w a s completed. The alpha beam energy was low, and the yield was correspondingly low. Enough was prepared t o standardize the measuring equipment and begin a small tracer study of high-specific activity plutonium i n the mouse. Preliminary tests i n a new computational system (MIMIC)of some published data of 239-P~uptake i n rats yielded a working model of Pu uptake kinetics and some new insights into Pu uptake by tissues. The important implications of the model are (a) Pu circulates both unbound and bound t o protein; (b) Protein binding i s dominant but

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Metabolism and Toxicity of Transuranium Elements and Other Radioactive Bone-Seekers the transport of both bound and f r e e Pu; only unbound Pu; (e) The liver takes up aggregated o r unbound PU, but appears not t o accumulate protein-bound Pu; ( f ) Bone takes up unbound Pu (as it does other multicharged cations), and i n addition a mechanism i s present i n bone, which we believe to lie in the red marrow, that permits bone t o accumulate FU from the protein-bound (c) Extracellular fluid is an important component of (d) The kidney excretes These findings are presented i n Ref. 3 . The review of the data fromthe 18 persons who were injected with 239-Pu i n 1945-46 was completed and published i n Ref. 1 and 2. A follow-up was started to learn (a) the identities of the individuals, '(b) their subsequent medical histories, and (c) the place and time material -- biological specimens from those that might still be living and a complete skeleton from which the internal distribution i n the human skeleton could be determined. The a i m was eventually t o obtain two valuable kinds of The three California cases were completely traced. hospital and death records are on file. living and his last known address i s on file ; Two are dead; A s of 1968 one was still hospital records are Eleven Rocheste? cases were traced. presume me was very ill with a long-standing heart condition and was transferred toa veteran's home), and three were still living as of December 1971. All hospital records are on file, and two death certificates are on file. Seven a r e knuwn dead, and one The Tennessee case was identified. His status as an employee of a local. Oak Ridge contractor w a s established. His last known whereabouts was Atlanta, Ga. as of 1947. nesses, he i s presumed dead. Because of h i s age and illHospital records are known t o have Completion of the review article begun last FY on the metabolism and toxicity of the transplutonium elements (Ref. 6) was postponed i n order t o take advantage of the 1971 Transuranium Symposium at lished information about, these elements. That symposium nearly dovlbled t h e total amount of pubPreprints of all pertinent

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Metabolism and Toxicity of Transuranium Elements iand Other Radioactive Bone-Seekers DESCRIPTION OF PROJECT AND WORK PLANNED (CONTINUED) papers have been received. with these elements and tables summarizing measurements of absorption, and distribution, and tables summarizing acute and chronic toxicity are complete. The t e x t should be completed by t h e end of FY 1972. Aobrief review of the metabolism and presence of lanthanide radionuclides i n various life forms was prepared for inclusion i n Ref. 6 t o serve as an aid i n predicting the behavior of the actinides for which there i s no comparable information. Master tables of a l l mammalian studies B. 90-Strontium i n the Rhesus Monkey The 90-Sr injected rhesus monkey colony (lhcaca mulatta) now numbers both a l i v e and dead 14 males (1infant, 3 adolescents, and 10 adults) and 29 females (1 infant, 18 adolescents, and 10 adults). Thirteen monkeys with injected doses ranging from 6 t o 13 PCi/kg (roughly comparable t o the 3-level 90-Sr dogs i n the Utah project) are still liv lng. Their longevity postinjection is as follows: two, 5 yr; nine, 8 t o 9 yr; and two, 14 t o 15 y r . Periodic whole-body counts, blood sampling and excretion collections continued during FY 1972. Radiation doses i n 11 of the 1-3 living monkeys and in6 dead monkeys are more than 50'$ of the lowest dose at which the iJtah dogs developed bone tumors and blood dyscrasias. deaths o r bone o r blood diseases i n the mor,keys that could be at tri bu - tedto their g04r burdens. (One monkey was reported erroneously last year as dyipg with a lymphosarcoma. have been re-examined by several veterinary pathologists, and the diagnosis has been revised t o generalized endometriosis which i s not uncommon i n older female monkeys. ) Thus far, there have been no The his to logical sections The excre'tion data have been sumnarized t o date f o r each monkey. Bone radioassay data have been compiled for each dead monkey, and a brief smary was included i n the Appendix t o Ref. 1for comparison with the intra skeletal distributions of other alkaline earth elements i n dog and man. C. Studies of the Growth and Senescence of t h e Mmmalian Skeleton Bone weights and measurements from nearly 1000 female Charles River rats ranging i n age from birth to 1000 days have been compiled, and summary tables of bone weights (fresh and ashed) have been prepared. During the period of rapid growth the increase i n bone mass had

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Metabolism and Toxicity of Transuranium Elements and Other Radioactive Bone-Se5kers previously been found t o conform toa Gompertz function, but the gradual increase i n bone weight after sexual maturity and the decline i n old age had neither been defined accurately nor had they been adeweXght changes occurring i n these boces after maturity can be correlate d with the gradual changes i n the degree of trabeculation, the changes in external bone shape, and the changes in cortical thickness, It i s presumed that these anatomical changes are also responsible for observed patterns of retention of radioxiuclides of such surface-seeking elements as the lanthanides and actinides. Histologic sections of long bones show t h a t the During the last several years and inthe course of our studies of 241-h and 90-Sr metabolism i n monkeys, fresh, dry, and ash weights of individual bones and of com?letely dissected skeletons have been collected from a large number of monkeys. I n addition 30 carcasses of monkeys of known age have bee2 received from the colony at Yale Medfcal School. These have a l s o been skeletonized and measurements of bone weights recorded. these data can now be made available t o other investigators. The speciEens range i n age from birth Although not yet ready f o r publication, summaries of Three adult monkey skeletons were prepared w i t h great care and measurements made of fresh, dry, defatted, and ash weights and fresh, dry, and ash volumes. method developedklsewhere, it is possible t o celcuiate frou these results the masses of the individual (but anstonisally inseparable) skeleton constituents -- mineral bone, the connective tissue envelope, red marrow, and fatty marrow. The reproducibility of the results and the close approach t o complete material balance achieved i n the calculat ions suggest that this method should be suitable for determination of the mass of marrow i n the human skeleton. Using an improved versior, of a calculation The literature search that was begun i n FY 1970 of measurements o f human bone and skeleton mass i s now complete, and we believe it i n - cludes all such measurements formally reported. All of the informat i o n has been put on punched cards and summaries have been prepared. The best estimates of the weight of the whole fresh human skeleton as a function of body weight and of the fractions of total weight contributed by the various bones were included i n the Appendix of Ref. 1.

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Metabolism and Toxicity of Transuranium Elements and Other Radioactive Bone-Seekers DESCRIPTION OF PROJECT AND WORK PLANNED (CONTINUED) previously been found t o conform toa Gompertz function, but the gradual increase i n bone weight after sexual maturity and the decline i n old age had neither been defined accurately nor had they been adeweight changes occurring i n these boces after maturity can be correlated with the gradual changes i n the degree of trabeculation, the changes i n external bone shape, and the changes in cortical thickness. It is presumed that these anatomical changes are also responsible for observed patterns of retention of radioriuclides of such surface-seeking elements as the lanthanides and actinides. Histologic sections of long bones show t h a t the During the last several years and inthe course of our studies of 241-Am and 90-Sr metabolism i n monkeys, fresh, dry, and ash weights of individual bones and of completely dissected skeletons have been collected from a large number of monkeys. In addition 30 carcasses of monkeys of known age have bee2 received from the colony a t Yale Medical School. These have a l s o been skeletonized and measurements of bone weights recorded. through 30 yr. Although not yet ready for publication, summaries of these data can now be made available t o other investigators. The specimens range i n age from birth Three adult monkey skeletons were prepared w i t h great care and measurements made of fresh, dry, defatted, and ash weights and fresh, dry, and ash volumes. method developedklsewhere, it is possible t o calculate frm these results the masses of the individual (but anstouisslly ioseparable) skeleton constituents -- mineral bone, the connective tissue envelope, red marrow, and fatty marrow. The reproducibility of the results and the close approach t o complete material balance achieved inthe calculat ions suggest that this method sho-crld be suitable for determination of the mass of marrow i n the human skeleton. Using an improved version of a calculation The literature search that was begun i n FY 1970 of measurements of human bone and skeleton mass i s now complete, and we believe it i n - cludes all such measurements formally reported. All of the informat i o n has been put on punched cards and summaries have been prepared. The best estimates of the weight of the whole fresh hman skeleton as a function of body weight and of the fractions of total weight contributed by the various bones were included i n the Appendix of Ref. 1.

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1. PROJECT TITLE 2. DATE Metabolism and Toxicity of Transuranium Elements and Other Radioactive Bone-Seekers "here is no information of the intra skeletal distribution of PU i n tri but ion in man cannot be adequately described by use of distributions i n man from which intra skeletal distributions of these elements could There are good reasons t o believe that the intra skeletal d is - Human data were available f o r 2 2 6 - ~ aand 90-Sr The results of these calculations appear i n the AppenUptake Kinetics of Multi-Charged Cations Kinetic data(for the most part unpublished) are available from this laboratory f o r radioisotopes of several lazthanides and alkaline them suitable for use inthe MIMIC program (see section A above). These data have been calculated and compiled t o make Other Internal Emitter Problems In response toa request from Comit tee2 of the ICRP (Internal Emitters) for …