ATTACHMENT 23 UNCLASSIFIED 709872 FOR OFFICIAL USE ONLY This is a Joint Report from the Los Alamos Scientific Laboratory of the University of California and the Atomic Energy Project of the University of Rochester School of Medicine and Dentistry. The Report covers a Cooperative Research project initiated under the supervision of the Manhattan Engineer District and completed under Contract No. W-7401-Eng-49 and Contract No. 7405-Eng-36 for the Atomic Energy Commission. September 20, 1950 LA-1151 FOR REFERENCE SEE (11bb16.gif) * Los Alamos Scientific Laboratory of the University of California, Los Alamos, New Mexico ** Formerly of the University of Rochester, presently with the Atomic Energy Project, U.C.L.A., Beverly Hills, California *** Captain, Med. Corps. U.S.A. (Stationed at Los Alamos, New Mexico) HEALTH AND BIOLOGY 3 Classification changed to UNCLASSIFIED by authority of the U.S. Atomic Energy Commission For "illegible" By REPORT LIBRARY "illegible" VERIFIED UNCLASSIFIED "illegible" 6/14/79 DOE/"ILLEGIBLE" 1065951 UNCLASSIFIED OFFICIAL USE ONLY 1065952 ACKNOWLEDGEMENT The authors wish to acknowledge the invaluable aid and interest of a number of persons who directly or indirectly contributed to the execution of these studies and the completion of this report. Dr. Stanford L. Warren was primarily responsible for the initiation of the program under the Manhattan Engineer District. Drs. W. S. McCann, A.H. Dowdy, W.F. Bale, Harold Hodge and L.H. Hempelmann participated in the early planning of the work and frequently made general and specific decisions which contributed much to the success of the program. Dr. Hymer Friedell and Dr. Fred Bryan were of great assistance as representatives of the office of the Medical Director of the Manhattan District. Drs. J.G. Hamilton, Jack Schubert, E.R. Russell, Austin Brues and H.M. Parker contributed some of the information used in this report and in some cases reviewed parts or all of the manuscript. Dr. L.H. Hemplemann, T.N. White, Frederick Reines, E.C. Anderson, J.T. Brennan and G.W. Taylor reviewed the report and contributed many constructive criticisms. 4 UNCLASSIFIED OFFICIAL USE ONLY 1065953 November 30 1952 CIRCULATION LIMITED HEALTH AND BIOLOGY Distribution No. of Copies Argonne National Laboratory 2 Armed Forces Special Weapons Project 2 Atomic Energy Commission 3 Brookhaven National Laboratory 1 Bureau of Medicine and Surgery 1 Chicago Operations Office 1 Columbia University (Failla) 1 General Electric Company, Richland 2 Hanford Operations Office 1 Idaho Operations Office 1 Knolls Atomic Power Laboratory 1 Naval Radiological Defense Laboratory 1 NEPA Project 1 New York Operations Office 1 North American Aviation, Inc. 1 Oak Ridge National Laboratory 2 Patent Branch, Washington 1 Public Health Service 1 Technical Information Division, ORE 2 UCLA Medical Research Laboratory (Warren) 1 University of California Radiation Laboratory 1 University of Chicago Toxicity Laboratory 1 University of Rochester 5 Western Reserve University (Friedell) 1 Sanda Corporation 1 J.R. Oppenheimer 1 AFSWP, Sandia 1 Los Alamos 12 ____ 50 UNCLASSIFIED OFFICIAL USE ONLY 1065954 5 Fig. 1 Nuclear Track Autoradiograph Showing Localization of Plutonium in the Bone of the Rate (A. Williams, J. Wellnitz; Photomacrography by Los Alamos Photographic Laboratory). 6 FOR REFERENCE SEE (11bb17.gif) 7 UNCLASSIFIED OFFICIAL USE ONLY 1065956 DISTRIBUTION AND EXCRETION OF PLUTONIUM ADMINISTERED INTRAVENOUSLY TO MAN 1. Introduction It is now a well established fact that the deposition of radioactive material (Ra, its isotopes and daughter products) i the skeletal system of radium dial painters was responsible for the bone necrosis, radiation osteitis, osteogenic sarcoma and other pathological changes in bone which characterizes the condition commonly known as chronic radium poisoning. Hamilton and co-workers (1) were the first to demonstrate that plutonium, like radium, concentrates in the skeletal system of the rat. Numerous reports have emphasized that bone is a major site of plutonium deposition regardless of the animal species, the valence state of the material or the route of administration (2), (3a, b, c). Autogradiographic studies of the mode of deposition of plutonium in bone (4), (5), (6), (7) showed that it was deposited in a pattern quite different from that of radium. The latter element tends to be incorporated in a pattern quite different from that of radium. The latter element tends to be incorporated into the bone salts exclusively and becomes buried in the calcified structure in the manner to be expected from a member of the calcium family in the periodic table. Plutonium, however, shows some deposition in soft tissues (especially in the liver) and a remarkable affinity for the non- calcified, non-cartilaginous areas of bone. The material is highly localized in the epiphyseal line, the periosteum and the endosteum so that localization is predominantly in regions of trabecular bone (See Fig. 1, frontpiece). The general conclusion was that the mode of deposition of plutonium made it potentially more hazardous than radium. Although there is only limited proof that the above conclusion is justified, it must be considered when evaluating the potential chronic toxicity of the material. Subsequent experiments with rodents by Brues, Lisco and Finkel (8) and others (9) have demonstrated that plutonium is quite effective in Producing pathological a changes in bone including osteogenic sarcoma (See Fig. 2). Brues (10) compared the relative chronic toxicity of equivalent microcurie amounts of plutonium and radium by following 100 rats, 600 mice throughout life and 37 rabbits for over 400 days. A comparison of survival time, radiographically determined bone damage, pathological fractures and bone tumors in these animals appeared to bear out a plutonium-radium chronic toxicity ratio of "illegible" on the basis of injected dose or about 4-5/1 on the basis of retained material. The above observations and the experiences of the radium dial industry have emphasized the necessity of employing extremely rigid control over all plutonium operations. The major health problems associated with plutonium processing is, of course, the possibility that small amounts of plutonium accumulated in the skeletal systems of workers may, over a period of from ten to thirty years, cause bone changes similar to those observed in chronic radium poisoning. The possibility is serious enough to justify the adoption of a rigid maximum permissible body burden as is currently done with radium. Only recently the subcommittee on internal radiation tolerances of the National Bureau of Standards established a tentative maximum permissible body content of 0.5 ug (0.0322 uc) for plutonium. This value was adopted immediately by the Division of Biology and Medicine of the Atomic Energy Commission as the official maximum permissible tolerance for plant personnel (11). Adequate information as to the fixation and excretion of plutonium by man is essential to the evaluation and interpretation of the maximum permissible body tolerance. More specifically such studies seem highly important for the following purposes. 1. To minimize the degree of uncertainty inherent in extrapolating the vast amount of animal experimental data to man 9 UNCLASSIFIED OFFICIAL USE ONLY 1065952 2. To provide the best possible quantitative basis for the diagnosis of degree of exposure of personnel to plutonium. 3. To determine the degree of fixation of plutonium by man and establish criteria for the period of retirement from further exposure of workers having received a maximum permissible dose. 4. To provide more extensive and quantitative data on the deposition and excretion of plutonium by man as a basis for future consideration of maximum permissible body tolerance. Need for the above information was recognized several years ago. It was also recognized that such information could be obtained only by administering small tracer amounts of plutonium to persons with a relatively short life expectancy. The first tracer study was initiated April 10, 1945 (12). Shortly thereafter, both the Chicago and Berkeley groups initiated similar studies (13) (14). This report is the final presentation of the results of twelve plutonium tracer cases studied as a joint project of the Los Alamos Scientific Laboratory of the University of California and the Atomic Energy Project of the University of Rochester School of Medicine and Dentistry. The results of the studies conducted by the Berkeley and Chicago groups are correlated with the present ones providing a collection of data from sixteen cases. In addition to the twelve tracer cases mentioned above, the Los Alamos Scientific Laboratory has had approximately six years experience with exposure problems associated with the processing of large amounts of plutonium. Wherever applicable, the laboratory's experience with the exposure of personnel are used to enlarge and supplement the data collected from the plutonium tracer studies presented in this report. METHODS A. Selection and Description of Subjects The life expectancy of the individual was carefully considered as a basis of selection of subjects for study. As a rule, the subjects chosen were pat forty-five years of age and suffering from chronic disorders such that survival for ten years was highly improbable. By adhering to these criteria, the possibility of late radiation effects developing would be avoided. Furthermore, an opportunity to obtain post-mortem material within a few months, or at most a few years, would be much greater. Of twelve patients chosen, ten were past the age of forty- five. One was only eighteen years old, and has since died of Cushing's Syndrome. Up to the time of this report, and approximately five years since the initiation of the first study, five subjects are known to have died of their diagnosed illnesses. Autopsies an tissue samples were obtained from only three of the five terminated cases. Brief summaries of the medical histories of the subjects of these studies are as follows: Hp-1 This patient, a sixty-seven year old white male with a nine year history of peptic ulcer, was admitted to the hospital following a severe gastrointestinal hemorrhage. The presence of a duodenal ulcer was confirmed by x-ray examination and a traction diverticulum of the esophagus was noted. Clinical diagnoses included duodenal ulcer, gastrointestinal hemorrhage with secondary anemia, and esophageal diverticulum. 10 FOR REFERENCE SEE (11bb18.gif) 12 UNCLASSIFIED OFFICIAL USE ONLY 1065959 Hp-2 This patient, a forty-nine year old white male, was a known hemophiliac and entered the hospital on this occasion for the thirty-eighth time. Symptoms referable to hypertension had been present for three years. Clinical diagnoses on this admission included hemophilia, essential hypertension with hypertensive cardiovascular disease and coronary insufficiency, and chronic arthritis. Hp-3 This patient, a forty-nine year old white female, was admitted to the hospital with complaints for pigmentation of the skin, pruritic dermatitis and dependent edema. Initial clinical studies were carried out in November and December 1945, at which time diagnoses of hepatitis of unknown etiology and hypoproteinemia were made. She was admitted for follow-up examination in October 1946, when she appeared in good health. Hp-4 This patient, an eighteen year old white female, had a history of Cushing's Syndrome since 1941. Her admission in October 1945 was the fifth period of hospitalization. Chief complaints on this occasion were referable to hypertension and osteoporosis. The clinical diagnoses were basophile adenoma of the pituitary gland with hypertension, hypertensive heart disease, nephropathy with uremia, osteoporosis, and a staphylococcic infection of the urinary tract. The patient ran a down hill course until death in uremia occurred in April 1947. Diagnoses at autopsy included basophile adenoma of the pituitary gland, atrophy of the thyroid gland, hypertrophy of the adrenals, hypertrophy of the left ventricle, hypoplasia of the uterus and ovaries, osteoporosis of the spine and pelvis, and chronic nephritis. Hp-5 this patient, a fifty-six year old white male, was admitted to the hospital in November 1945 with complaints of generalized weakness and difficulty in walking and swallowing of three years duration. The clinical diagnosis was amyotrophic lateral sclerosis. Death occurred in April 1946. The diagnosis at autopsy included amyotrophic lateral sclerosis, bronchopneumonia, generalized arteriosclerosis, renal cysts and adenoma of the right kidney. Hp-6 This patient, a forty-five year old white male with a history of Addison's disease since January 1943, was admitted to the hospital on December 14, 1945, for treatment of numerous infected lesions of the eyelids and toes. He responded to conservative treatment and studies began during convalescence. On readmission in June 1947, his condition was essential unchanged. Hp-7 This patient, a fifty-nine year old white female who had been previously treated for heart disease and hyperthyroidism, was hospitalized on January 21, 1946, for cardiac decompensation. The clinical diagnoses were rheumatic heart disease with mitral insufficiency and auricular fibrillation, and toxic nodular goiter. She expired in October 1945. permission for autopsy was withheld, but the probably cause of death was lobar pneumonia. Hp-8 This patient, a forty-one year old white female, had a history of scleroderma since January 1945, and a duodenal ulcer first diagnosed in 1944. The clinical diagnoses on this admission was scleroderma and duodenal ulcer. 13 UNCLASSIFIED OFFICIAL USE ONLY 1065960 Hp-9 This patient, a sixty-six year old white male, was admitted to the hospital in March with a history of generalized dermatitis and weakness of eighteen months duration. A diagnosis of dermatomyositis was made. The patient expired in July 1947. Diagnoses at autopsy included generalized muscular atrophy, dermatitis, purulent bronchitis and bronchopneumonia, hypertrophy and dilation of the heart, and chronic passive congestion of the liver and spleen. Hp-10 This patient, a fifty-two year old negro male, was admitted to the hospital on March 24, 1946, in acute congestive heart failure. A history of heart disease since 1926 was obtained, and his history included both rheumatic fever and luetic infection. The clinical diagnoses on this admission included rheumatic heart disease, latent treated syphilis and ethmoidal and frontal sinusitis. Hp-11 This patient, a sixty-eight year old white male with history of alcoholism and dietary inadequacies for many years, was admitted to the hospital on December 12, 1945, with complaints of dyspnea and abdominal swelling. He expired on February 26, 1946, and diagnoses at autopsy were cirrhosis of the liver, ascites, and thrombosis of the portal vein. Hp-12 This patient, a fifty-three year old colored male, was hospitalized on March 24, 1945, following an automobile accident in which he sustained commuted fractures of the left femur and right patella and a transverse fracture of the right radius and ulna. Physical findings of note included a left lenticular cataract and marked hypertrophic and atrophic arthritic changes in both knees, together with osteochondromatosis of the left knee. B. Management of Subjects and Collection of Samples Ten of the twelve patients were cared for in the special metabolic ward of Strong Memorial Hospital. The general management of the ward patients was as follows: A control period of about ten days was utilized to instruct the patient in the quantitative collection of urine and fecal specimens. During this period all necessary adjustments to ward routine and all necessary modifications in diet were completed. After the patient had proven himself capable of cooperating, a series of control urine and fecal samples were collected for the purposes of "blank" determinations by the method of plutonium analysis. Preceding the injection of plutonium and again at termination, physical and liberator examinations were conducted on each subject. Blood samples were drawn into dry sodium citrate as an anticoagulant. Samples of 15 ml were taken before administration of plutonium and at four hours, one day, three days, six days, ten days, fifteen days, etc., post injection. Urine samples were collected directly into half-gallon fruit jars and preserved with formaldehyde. The urine was usually collected in 24 hour periods except on the day the plutonium was given. During the first day it was collected in two 12 hour periods. Fecal samples were collected in three-liter beakers. The patient was instructed to empty the bladder before defecation to avoid admixture of urine and feces. As a rule feces were pooled during the intervals of four days, except immediately after the plutonium was given when the first two stools were collected separately. All samples were preserved by boiling for ten minutes with 6 N HC 1. Tissue samples of from 25 to 150 g were obtained at autopsy and preserved in 80 per cent alcohol. 14 UNCLASSIFIED OFFICIAL USE ONLY 1065961 C. Administration of Plutonium The plutonium solution used in these studies was prepared by dissolving 5.0 mg of spectrographically pure plutonium metal in 1.0 ml. of 2 N HNO3. The solution was assayed for plutonium by alpha counting. An appropriate aliquot of the plutonium solution was placed in a 10 ml volumetric flask an diluted to volume with sterile 0.41 per cent sodium citrate 2 H2O. The solution prepared in the above manner had a pH of approximately 5.5 and the plutonium was in the form of Pu-4 complex. The technique of injection and the method of assay of the injected dose were as follows: One syringe was filled with sterile saline and a 22-gauge needle attached. The other syringe was discarded. The needle of the syringe containing sterile saline was introduced into a cubital vein and the saline slowly injected to insure unrestricted entry into the vein. The syringe was then carefully detached from the needle, which was still in the vein, and the syringe containing the plutonium injection solution was substituted. The plutonium solution was injected rapidly after which the syringe was rinsed once by drawing it full of the patient's blood and discharging the blood back into the vein. The same syringe and needle used to inject the patients was used to measure 0.5 ml aliquots of the plutonium solution into each of four volumetric flasks. The washing of the syringe and other essential steps of the injection technique were duplicated. The contents of each flask was diluted to volume with 2 N HC 1 and a suitable aliquot of each evaporated directly on platinum discs and assayed for alpha activity. The average of the four assays was taken as the amount of plutonium administered to the patient. The average standard deviation for each set of four results was 3.0 per cent. The amount of material received by each subject and the dates of injection are presented in Table 1. TABLE 1. AMOUNT OF PLUTONIUM ADMINISTERED TO SUBJECTS VIA INTRAVENOUS INJECTION* AND THE DATE OF ADMINISTRATION FOR REFERENCE SEE (11bb20.gif) 15 106591 UNCLASSIFIED OFFICIAL USE ONLY 1065962 D. Analytical Procedures All urine samples were analyzed for plutonium using the cupferron extraction procedure developed at the Los Alamos Scientific Laboratory for the determination of exposure to laboratory personnel (15). Fecal samples were analyzed by a modification of the cupferron procedure published earlier (16). Blood and other tissue samples were "ashed" either in a muffle furnace or with conc.HN03 and H2O2. The ash solution was analyzed for plutonium by the cupferron extraction procedure in exactly the same manner employed for the analysis of urine ash solutions. III. RESULTS A. Clinical Observations Acute toxic effects from the small doses of plutonium administered in these studies were neither expected nor observed. As seen from the summaries of case histories (Pages 10-14), the subjects used in this study were suffering from a variety of conditions. In most cases, however, kidney and liver function appeared to be essentially normal. There were two notable exceptions. Hp-4 was suffering from Cushing's Syndrome and chronic nephritis. The highly abnormal condition of this subject was accompanied by higher plutonium content in blood and urine and apparently a slower rate of plutonium fixation in bone. In fact, several of the urine analysis were ruled non-representative on the basis of the Chauvenet criterion. Hp-11 was moribund at the time the plutonium was administered. Therefore, no plutonium excretion values were obtained. Anatomical diagnosis revealed cirrhosis of the liver with associated ascites, which indicated marked impairment of liver function. The data in Table 2 summarizes some of the clinical laboratory observations. These "illegible" show no consistent trends in hemoglobin, red blood cell count, white blood cell count and differential count as a result of the injection of approximately 5 ug of plutonium. The rise in hemoglobin and red blood cell count in Hp-12 probably was a result of therapeutic measures. The observations in Table 2 were quite in accord with those made by Russell and Nickson (13) who collected excellent clinical laboratory data from two cases following administration of plutonium. One individual received 6.5 ug of plutonium and was followed for 155 days. Another subject received 95 ug of plutonium and was followed for sixteen days. No alterations attributable to plutonium were found in the constituents of the peripheral blood of either patient. In the present series clinical evidence suggestive of liver damage did not appear. While specific tests of liver function ere not as a rule listed in the protocols, the possibility that injury to this organ might appear was considered. Admittedly the observations made during this study provide no evidence of what may happen in 10-30 years. It may be said, however, that these studies and those of other investigators indicate that the intravenous injection of a single dose of 5 to 100 ug of plutonium was without acute subjective or objective clinical effects. B. Deposition of Plutonium in the Body. Since the beginning of this study, four of the subjects (hp- 4, 5, 7 and 9) have died as a result of their diagnosed illnesses. Another subject, Hp-11, was in the terminal phase at the time of injection. Autopsy and tissue samples were obtained in only three of the five cases. Two bone specimens were obtained from Ho-12 during open reduction of fractures and a number of his teeth were obtained at a later date. Bloods samples were obtained from all 16 UNCLASSIFIED OFFICIAL USE ONLY 1065963 TABLE 2 CLINICAL DATA ON SUBJECTS RECEIVING INTRAVENOUS INJECTION OF APPROXIMATELY 5 ug OF PLUTONIUM AS Pu-4 CITRATE FOR REFERENCE SEE (11bb21.gif) subjects before plutonium injection and at frequent intervals thereafter. All tissue samples were analyzed for plutonium by the cupferron extraction procedure subsequent to ashing. The data in Table 3 show the results of analyses of the various samples for plutonium. The results obtained by Russell and Nickson (13) (referred to as Chi, I, II, III) and Hamilton et al (14) (referred to as Cal. I) are presented also. Two important points must be kept in mind when considering these data: (1) The samples of human tissues were, for obvious reasons, rather than unsatisfactory. In most cases they were too small, poorly representative and were usually what could be obtained under the circumstances rather than what were desired; (2) The subjects were chronically ill and/or elderly and the results may not represent exactly the distribution of plutonium in tissues of healthy persons of average working age. These data, however, are all that are available and, therefore, must provide the basis for our present concept of the distribution of plutonium in the organs and tissues of man. They must also provide a basis for comparison with the results obtained from the numerous studies of plutonium deposition in experimental animals. 1. Deposition in the Skeleton Animal experiments (1), (2) reveal that approximately 60 percent of plutonium injected as PuO2-- and Pu-4- citrate is localized in bone. If the vertebra, sternum and whole rib are taken a representative bones of the skeleton, and the average plutonium content (.00657%/g), 17 FOR REFERENCE SEE (11bb22.gif) 18 UNCLASSIFIED OFFICIAL USE ONLY 1065965 multiplied by the skeletal weight of the "Standard Man" (17), then 65.7 per cent of the injected dose is the estimated amount of plutonium in the skeleton of a 70 kg man. Although the latter value was established rather arbitrarily, it is in good agreement with the value expected from animal experiments. The data in Table 3 indicate a rather high plutonium content in bone marrow. The average of four determinations from three different laboratories was 0.0187 per cent of the injected dose per gram of marrow. On the basis of 3000 g of bone marrow, there would be 56 per cent of the injected dose concentrated in the marrow of a 70 kg man. Animal studies do not show appreciable concentrations of plutonium in the marrow. The major areas of plutonium concentration in rats and mice are the endosteum, periosteum and the epiphyseal line. It is quite possible that the samples of human marrow were too small to be representative, contained endosteum or spicules, or that the high deposition was an indication of an age factor related to the fact that the epiphyses of man unlike those of the rat unite at maturity. 2. Deposition in the Liver The average plutonium in the liver for the five cases was 0.0136 per cent of the injected dose per gram, which corresponds to 23.1 per cent of the dose in a 1700 gram liver (Standard Man). Table 4 presents the liver data in more detail, including the two cases reported by the Chicago investigators (13). TABLE 4 LIVER DEPOSITION OF PLUTONIUM ADMINISTERED INTRAVENOUSLY TO MAN FOR REFERENCE SEE (11bb23.gif) Two cae (Hp-11 and Chi.-II were in the terminal phase of illness at the time plutonium was administered. Both showed advanced liver diseae. The value for plutonium deposition in the liver of these cases is highly questionable. The result in the other three caes, however, were rather striking. A pointed out by Rusell and Nickon (13), the content of 19 UNCLASSIFIED OFFICIAL USE ONLY 1065966 plutonium in the liver was much higher than was expected from results in experimental animals. Even though one of their cases survived 155 days after receiving plutonium in "illegible" valence state (a form known to give low liver deposition in rats (1)(2)), 28.5 per cent of the injected dose was found in the liver. Subject Hp-5 had 42.8 per cent of the plutonium injected as Pu-4-citrate deposited in the liver after 151 days. The third case (Hp-9) survived 456 days and had 23.0 percent of the injected material deposited in the liver. Considering the elapsed time after injection, the plutonium content of the liver in the two latter cases was even higher than that observed by Russell and Nickson (13). The apparent higher deposition in the latter cases might indicate the destruction of Pu-4-citrate complex by the human liver. The results compare favorably with those obtained when rats were injected with uncomplexed quadrivalent plutonium (1), (2), (3). The limited data presented in table 4 indicated rather strongly that the retention of plutonium by the liver may be much greater for man than for rats and ice, and may be of the order of 20-40 per cent of the injected dose during the first year. A comparison of the survival times and the amounts of plutonium deposited in the livers of Hp-5 and Hp-9 seems to indicate a "plutonium retention half-time" in the liver of one year or greater for man as compared to 40 - 60 days for rats. 3. Concentration in Blind The data in Table 5 show the concentration of plutonium in blood at various times after the intravenous injection of approximately 5 ug of plutonium as Pu-4-citrate. The results are expressed in per cent of the injected dose in the total blood volume. The blood was assumed to be 7.71 per cent of the total body weight (17). The individual observations varied widely, especially during the first four days. The mean values, however, fell on a smooth curve (shown in Fig. 3). The drop in blood plutonium content was very rapid at first, and reflected the very rapid rate of fixation of the material in the body. The mean blood concentration 4 hours after injection was 35.7 per cent, at one day 15.7 per cent, at 10 days 1.2 per cent. Thirty "illegible" after injection the blood concentration of plutonium in the circulating blood eliminates blood analysis by the usual counting procedures as a means of diagnosing the degree of exposure of personnel. The application of techniques employing the counting of alpha tracks registered by alpha sensitive nuclear track photographic emulsions may prove possible. Deposition in Other Organs. The amounts of plutonium deposited in organs and tissues other than skeleton, liver and blood were rather small. When the per cent per organ was calculated, based on the organ weight of the "Standard Man", the results were in reasonable agreement with what was anticipated from animal experiments. The data showing the per cent of dose per gram of organ and per cent per organ are given in Table 3 (Page 18). The kidney and spleen each had a estimated average plutonium content of 0.4 per cent of the injected dose per organ. The relative affinity of the various tissues for plutonium was calculated by dividing the per cent of the dose per gram of organ by the per cent of the dose per gram of body weight when the material was assumed to be equally distributed in a 70 kg man. The bone, bone marrow and liver were the only tissues that showed a relative plutonium affinity appreciably greater than unity. The spleen was 12.5; all other tissues and samples were 1.0 or less. Obviously the skeletal system and liver are the tissues of major interest when considering the plutonium tolerance, as these two organs alone account for 90 per cent or more of the total plutonium in the entire body. 20 UNCLASSIFIED OFFICIAL USE ONLY 1065967 TABLE 5 PLUTONIUM CONTENT OF BLOOD SAMPLES* FOLLOWING INTRAVENOUS INJECTION OF APPROXIMATELY 5 ug OF PLUTONIUM AS Pu-4-CITRATE FOR REFERENCE SEE (11bb24.gif) C. Excretion of Plutonium 1. Urinary Excretion The urinary excretion of plutonium was studied in eleven of the subjects following the intravenous injection of approximately 5 ug of plutonium a Pu-4 of the 0.4 per cent solution of sodium citrate-2H2O. With the exception of the first day, urine from all subjects was collected in 24 hour samples through 22 days post injection. After 22 days the collection of 24 hour urine samples was continued as long as the patients were available for study. It was not possible to retain the subjects as long as was desired and the major weakness in these results is the short time interval over which the studies were continued. Two subjects were followed 22 days, one for 23 days, one for 27, and the remainder for 30 days or longer after injection. The Chicago cases (13) were followed for 16, 140, and 186 days and the California cases (14) was followed for a period of 341 days. Because of the great importance of measurements at longer time intervals, the Chicago and California data have been incorporated 21 FOR REFERENCE SEE (11bb19.gif) 22 FOR REFERENCE SEE (11bb25.gif) 23 FOR REFERENCE SEE (11bb26.gif) 24 FOR REFERENCE SEE (11bb27.gif) 25 FOR REFERENCE SEE (11bb28.gif) 26 FOR REFERENCE SEE (11bb29.gif) 27 FOR REFERENCE SEE (11bb30.gif) 28 FOR REFERENCE SEE (11bb31.gif) 29 FOR REFERENCE SEE (11bb32.gif) 30 FOR REFERENCE SEE (11bb33.gif) 31 FOR REFERENCE SEE (11bb34.gif) 32 FOR REFERENCE SEE (11bb35.gif) 33 Hamilton and co-workers (14) and it was not feasible to include their results. The present report of the fecal elimination of plutonium is, therefore, confined to twelve cases. The means, revised means, and standard deviations for the daily fecal excretion of plutonium from 0 to 138 days post injection are given in Table 7 (Page 26). The best curve of fit for the observed means was estimated by the method of least squares and was found to be: FOR REFERENCE SEE (11bb36.gif) 34 FOR REFERENCE SEE (11bb37.gif) 35 (ILLEGIBLE) 10 compares the observed and calculated values of total plutonium excretion for various (illegible) intervals using the integrated expression [14]. These results emphasize the relatively slow rate of elimination of systemically deposited plutonium by man. According to these data only 8.7 per cent of a single injected dose is excreted in 1750 days (approximately 5 years). FOR REFERENCE SEE (11BB38.GIF) IV. DISCUSSION A. Distribution of Plutonium in Tissues and Organs of Man Table 3 (Page 18) contains all available data (up to the time of this report) on the distribution of plutonium in the tissues and organs of man. These data were the results of analysis of a miscellaneous group of samples collected from seven human subjects. The subjects were elderly persons or persons suffering from an incurable chronic disease. The samples were often small and poorly representative and not obtained from the seven cases at comparable times after injection of plutonium. These unavoidable difficulties must be recognized and accepted when considering the results. Despite the above difficulties, the data are extremely valuable as a supplement to a much greater and more reliable mass of data 36 UNCLASSIFIED OFFICIAL USE ONLY 1065983 concerning the a distribution of plutonium in the tissues and organs of laboratory animals. The data on man are in good agreement with results of similar studies in rats, mice, rabbits, and dogs. The good agreement permits the conclusion that there are no major differences in the quantitative distribution of plutonium in the tissues and organs of man and those of common laboratory animals with perhaps one exception - the liver. The results indicate that the retention of plutonium in the liver following its intravenous injection as Pu-4-citrate complex and as plutonium may be 20-40 percent for man as compared to 10 percent or less for rats. The "biological half-time" of plutonium in the liver of man is probably much greater than that for rats. The average amount of plutonium found in vertebra, sternum and rib was 0.0066 per cent of the injected dose per gram of whole bone. Assuming vertebra, sternum and rib as representative of the entire skeleton, 66 per cent of the injected dose would be deposited in a 10 kg skeletal system (7 kg of bone, 3 kg of marrow) of a 70 kg man. The observed concentration of plutonium in bone may be used to estimate the radiation dose received per gram of skeletal system when a "standard man" has accumulated the official maximum permissible plutonium body content of 0.5 ug (0.032 uc). Using the dosage rate formula: rep day = 54 CE (where C = concentration of radioisotope in uc/g, E = energy of the radiation in Mev, and the rep = 93 ergs/g), the radiation dosage received per gram of skeleton from 0.032 uc of plutonium is as follows: rep day = 54 x 6.6 x 10-5 x 0.032 uc x 5.15 Mev = .00057 A similar calculation for the official maximum permissible radium content of 0.1 uc may be made for comparison. If 50 per cent of the radon from radium decay is retained in the body, then approximately 15 Mev of energy will be released in the body by the alpha particles per decay. If 100 per cent of the radium is deposited in a 10 kg skeletal system, then the radiation dosage in rep per day is given as follows: rep day = 54 x 1 x 10-5 x 15 = 0.0061 According to the above calculation, the radiation dosage per gram of skeleton delivered by 0.1 ug of radium would be 14 times that delivered by the maximum permissible dose of plutonium if the two materials were distributed in a comparable manner in the skeleton. Autoradiographic studies show conclusively, however, that radium and plutonium do not distribute in a comparable manner. Plutonium is more localized and concentrates in the endosteal and periosteal surfaces. The chance of a more conservative body tolerance dose for plutonium was made to allow for its more specific localization in the skeletal system. It should be noted, however, that radium does not distribute uniformly throughout bone and Evans (20) has reported that analyses of bone samples from radium cases showed the radium to be unevenly distributed by as much as a factor of 10. It may be necessary, therefore, for plutonium to be concentrated by a factor of 140 over radium in order that 0.5 ug will give radiation intensities comparable to that which may occur with 0.1 ug of radium. Evans (2) has also pointed out that the presence of mesothorium in the radium responsible for the early radium poisoning cases may account for an additional safety factor of 5 in the 0.1 ug radium tolerance. The above discussion supports the possibility that the 0.5 ug maximum permissible tolerance dose for plutonium is extremely conservative. B. "Biological Half-Time" of Plutonium in Man The "biological half-time" of plutonium in man can be estimated from the excretion data presented in this report. Although the adjusted urinary plus fecal excretion curve is (empirically at least) logarithmic in nature, it appears that the curve approaches an exponential for longer times. Such an exponential curve would be in keeping with the assumption that 37 FOR REFERENCE SEE (11bb39.gif) 38 estimating the total exposure dose under such conditions. Past practice at the Los Alamos Laboratory was to assume that an individual contracted his total exposure dose on the last day of the exposure period. His total body burden was then determined by substitution in the urinary excretion formula as shown above. In this case, zero time is the last day of exposure. Obviously this method gives too low a value for the exposure dose as the estimated dose is directly proportional to time. A second method which has been used is exactly the same as the previous one except that zero time is taken as the first day of exposure which assumes that all of the dose was accumulated on exposure day one. It is evident that this estimate of total exposure is too high. The third method, which was used in this paper to determine the adjusted urinary excretion curve, is believed to more closely approximate the true situation. In this method it has been assumed that the toal exposure dose may be represented by a single effective dose occurring at some effective time intermediate to the limits of exposure. The equations and steps to be followed with this method are shown on Pages 23 and 29. Ordinarily the first urine count is used to determine whether an individual should or should not be withdrawn from exposure. It is not used as one of the two significantly different dose determining counts. This is due to the fact that the initial withdrawal count may reflect the high urinary excretion resulting from the previous ten days exposure, and to the relatively high per cent excretion during the first 10 days post-exposure period. The high rate of elimination resulting therefrom may relatively obscure any exposure doses accumulated previous to that time. The case of chronic invariant exposure is probably of primary interest. This is the type of exposure (within limits) that occurs in processing procedures in the plutonium industry in which air concentrations, etc., are rigidly controlled and the work is routine. An analysis of the general case is presented as follows: If m = time of exposure in days, and n = days from the beginning of an exposure to the time a urine analysis is made with n > m (preferably by more than 10 days) then the counts per minute in the urine excreted on day n is: FOR REFERENCE SEE (11bb40.gif) 39 FOR REFERENCE SEE (11bb41.gif) 41 UNCLASSIFIED OFFICIAL USE ONLY 1065988 FOR REFERENCE SEE (11bb42.gif) V. SUMMARY The distribution and excretion of plutonium administered intravenously to man has been studied. The data from twelve subjects have been correlated with similar data collected by other investigators, making a total of sixteen cases considered. The data have been supplemented further with observations made on three Los Alamos Laboratory personnel who absorbed measurable amounts of plutonium in the course of their work. The results of these studies may be summarized as follows. 1. Clinical observations and clinical data collected on the various subjects indicate that the intravenous injection of a single dose of 5 to 100 ug of plutonium is without acute subjective or objective clinical effects. 2. The analysis of tissues following the intravenous injection of plutonium showed that there was little difference in the mode of deposition of plutonium in man 42 FOR REFERENCE SEE (11bb43.gif) 43 UNCLASSIFIED OFFICIAL USE ONLY 1065990 FOR REFERENCE SEE (11bb44.gif) which represents the integrated amount of plutonium in per cent of the injected dose (aua-f) excreted up to and including the nth day after injection. Substitution in this expression showed that only 8.7 per cent of a single injected dose was excreted in approximately five years. 11. Application of the data of this report to the calculation of the "biological half-time" of plutonium in man gives a mean minimum "biological half-time" estimate of 118 years, with a variation of from 84 to 175 years. 12. The urinary excretion data of this report were applied to the diagnosis of the exposure of personnel to plutonium. Three sets of exposure conditions were considered. (a) The application of plutonium urine analysis to estimate the total body dose following a single acute exposure occurring at a known time, (b) The application of plutonium urine analysis to estimate the total body burden of plutonium following variable chronic or sub-acute exposure with only the "illegible" exposure time being known and, (c) The application of urine analysis to estimate the total body burden following chronic "illegible" exposure (such as may occur in a carefully controlled routine plant process) with time of exposure known. Expressions for the calculation of body dose under the conditions set forth in (a), (b) and (c) are included in this report. 44