Report: Distribution and Excretion of Plutonium Administered Intravenously to Man (Joint Report, Los Alamos Scientific Laboratory of University of Ca and AEC Project of the University of Rochester

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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 This document consists of 4S pages NO. 49 of 50 copies, Series AADMINISTERED INTRAVXNOUSLY TO MAN Jeanne Carr it t Helen E. Van Alstine Los Alarnos Scientific Laboratory of the University of California, Los Alamos, New Mexico Formerly of the Univers ll y of Rochester,presently with the Atomic Energy Project, Captain, Med. Corps, U. S. A.(Stationed at Los Alarnos; New Mexico).

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The authors wish to acknowledge the invaluable aid and interest of a number of persons who directly o r indirectly contributed to the execution of these studies and the completion of this report. Dr. Stafford L. Warren was primarily responsible for the initiation of the program under the Manhattan Engineer District. L. H. Hempelmann participated in the e a r l y planning of the work and frequently made general and specific decisions which contributed much to the success of the program. as representatives of the office of the Medical Director of the Manhattan 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. Hymer Friedell and Dr. Fred Bryan were.of great assistance

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HEALTH AND BIOLOGY Argonne National Laboratory Armed Forces Special Weapons Project Atomic Energy Commission Brookhaven National Laboratory Bureau of Medicine and Surgery Chicago Operations Office Columbia University (Fail la) General Electric Company, Richland Hanford Operations Office Idaho Operations Office Knolls Atomic Power Laboratory Naval Radiological Defense Laboratory New York Operations Office North American Aviation, Inc. Oak Ridge National Laboratory Patent Branch, Washington Public Health Service Technical In form tion Division,. ORE UCLA Medical Research Laboratory (Warren) University of California Radiation Laboratory University of Chicago Toxicity Laboratory University of Rochester No. of Copies

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Fig. 1 Nuclear Track Autoradiograph Showing Localization of Plutonium in the Bone Photomicrography by Los Alamos

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ADMINISTERED INTRAVENOUSLY TO MAN It is now a well established fact that the deposition of radioactive material(Ra,its isotopes and daughter products) in the skeletal system of radium dial painters was responsible for the bone necrosis, radiation osteitis, osteogenic s a r c o m a and other pathological changes i n bone which characterize the condition commonly known a s chronic radium poisoning, concentrates in the skeletal system of the rat. is a major site of plutonium deposition regardless of the animal species, the valence state 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 f r o m 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 s o that localization is predominately in regions of trabecular bone ( S e e Fig. 1, frontpiece). T h e general conclusion was that the mode of deposition of plutonium made it potentially m o r e hazardous than radium. 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(S) have demonstrated that plutonium is quite effective in producing pathological changes in bone including osteogenic sarcoma(See Fig. 2). Brues (10) compared the relative chronic toxicity of equivalent micro curie amounts of plutonium and radium by following 1000 r a t s , 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 12-15/1 on the basis of injected dose o r about 4-5/1 on the basis of the necessity of employing extremely rigid control over all plutonium operations. health problem associated with plutonium processing is, of course, the possibility that small amounts of plutonium accumulated in the skeletal s y s t e m s of workers may, Over a period of from ten to thirty years, cause hone changes similar to those observed in chronic radium missible body burden as i s currently done with radium. of Standards established a tentative maximum permis,sible body content of 0.5 pg (0.032 p c ) of the Atomic Energy Commission a s the official maximum permissible tolerance f o r plant to the evaluation and interpretation of the maximum permissible body tolerance. specifically such studies s e e m highly important for the following purposes: Hamilton and co-workers (1)were the first to demonstrate that plutonium, like radium, Numerous reports have emphasized that bone The above observations and the experiences of the radium dial industry have emphasized The possibility is serious enough to justify the adopticn of a rigid maximum per - Only recently the sub cop mitte e on internal radiation tolerances of the National Bureau "his value was adopted immediately by the Division of Biology and Medicine Adequate information a s to the fixation and excretion of plutonium by man is essential 1 . T o minimize the degree of uncertainty inherent in extrapolating the vast amount o f animal experimental data t o man.

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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. initiated April 10, 1945 ( 1 2 ) . Shortly thereafter, both the Chicago and Berkeley groups initiated similar studies (13), (14). studied a s a joint project of the Los Alamos Scientific Laboratory of the University of California and the Atomic Energy P r o j e c t of the University of Rochester School of Medicine with the present ones providing a collection of data from sixteen cases. Laboratory has had approximately six y e a r s experience with exposure problems associated with the processing of large amounts of plutonium. used to enlarge and supplement the data collected from the plutonium t r a c e r studies presented in this report. The first tracer study was This report is the final presentation of the results of twelve plutonium tracer cases The results of the studies conducted by the Berkeley and Chicago groups are correlated In addition t o the twelve tracer cases mentioned above, the Los Alamos Scientific Wherever applicable, the Laboratory's experiences with the exposure of personnel a r e A . Selection and Description of Subjects The life expectancy of the individual was carefully considered a s a basis of selection Asa rule, the subjects chosen were past forty-five years of age andof subjects for study. 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 orat most a few years, would be much greater. y e a r s old, and has since died of Cushing's Syndrome. died of their diagnosed illness. of the five terminated cases. Furthermore, a n opportunity to obtain post-mortem material within a few months, One was only eighteenOf twelve patients chosen, ten were past the age of forty-five. Up to the time of this report, and 1 approximately five years since the initiation of the first study, five subjects are known to have ' ; Autopsies and tissue samples were obtained from only three Brief summaries of the medical histories Gf the gubjects of these studies are as follows: This patient, a sixty-seven y e a r old white male with a nine year history of peptic ulcer, was admitted to the hospital following a severe gastrointestinal hemorrhage. of a duodenal ulcer was confirmed by x-ray examination and a traction diverticulum of the esophagus was noted. with secondary anemia, and esophageal diverticulum. Clinical diagnoses included duodenal ulcer, gastrointestinal hemorrhage

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This patient, a forty-nine y e a r old white male, was a known hemophiliac and entered the hospital on this occasion for the thirty-eighth time. had been present for three years. essential hypertension with hypertensive cardiovascular disease and coronary insufficiency, and Symptoms referable to hypertension Clinical diagnoses on this admission included hemophilia, This patient, a forty-nine y e a r old white female, was admitted to the hospital with complaints of pigmentation of the skin, pr uri tic dermatitis and dependent edema. Initial clinical studies were carried out in November and December 1945, a t which time diagnoses of hepatitis of unknown etiology and hypoproteinemia were made. examination in October 1946, when s h e appeared in good health. She was admitted for follow-up This patient, an eighteen year old white female, had a history of Gushing's Syndrome since 1941. Her admission in October 1945 was the fifth period of hospitalization. complaints on this occasion were referable to hypertension and osteoporosis. diagnoses were basophile adenoma of the pituitary gland with hypertension, hypertensive h e a r t disease, nephropathy with uremia, osteoporosis, and a staphylococcic infection of the urinary tract. The patient rana 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 u t e r u s and ovaries, osteoporosis of the spine and pelvis, and chronic nephritis. This patient, a fifty-six year old white male, was admitted to the hospital in November 1945 with complaints of generalized weakness and difficulty i n walking and swallowing of t h r e e i n April 1948. The diagnoses a t autopsy included amytrophic lateral sclerosis, bronchopneumonia, generalized arteriosclerosis,renal cysts and adenoma of the right kidney, ?' 'The clinical diagnosis was amyotrophic lateral sclerosis. Death occurred This patient, a forty-five y e a r old white male with a history of Addison's disease since He responded to conservative treatment and studies January 1945, was admitted to the hospital on December 14, 1945, for treatment of numerous infected lesions of the eyelids and toes. began during convalescence. On readmission in June 1947, his condition was essentially unThis 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 mitra l insufficiency and auricular fibrillation, and toxic nodular goiter. She expired i n October 1946. Permission for autopsy was withheld, but the probable cause of death was lobar pneumonia. This patient, a forty-one year old white female, had a history of scl erode rma since January 1945, and a duodenal ulcer first diagnosed in 1944. admission were scl erode rma and duodenal ulcer. The clinical diagnoses on this

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This patient, a sixty-six year old white male, was admitted to the hospital in March 1946 with a history of generalized dermatitis and weakness of eighteen months duration.' A diagnosis of dermatomyositis was made. autopsy included generalized muscular atrophy, dermatitis, purulent bronchitis and bronchopneumonia, hypertrophy and dilatation of the heart, and chronic passive congestion of the liver The patient expired in July 1947. Diagnoses a t This patient, a fifty-two y e a r old negro male, was admitted to the hospital on March 24, 1946, in acute congestive heart failure. and his history included both rheumatic fever and luetic infection. this admission included rheumatic h e a r t disease, latent treated syphilis and ethmoidal and A history of heart disease since 1926 was obtained, The clinical diagnoses on T h i s patient, a sixty-eight year old white male with history of alcoholism and dietary inadequacies for many y e a r s , was admitted to the hospital on December 12, 1945, with complaints of dyspnea and abdominal swelling. He expired on F e b r u a r y 26, 1946, and diagnoses at autopsy were cirrhosis of the liver, as cites, and thrombosis of the portal vein. This patient, a fifty-three y e a r old colored male, was hospitalized on March 25, 1945, following an automobile accident in which he sustained comminuted fractures of the left femur and right patella and a transverse fracture of the right radius and ulna. 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 SampTen of the twelve patients were c a r e d for in the special metabolic ward of Strong collection of urine and fecal specimens. ward routine and all necessary modifications in diet were completed. proven himself capable of cooperation, a s e r i e s of control urine and fecal samples were collected f o r the purpose of "blank" determinations by the method of plutonium analysis. ceding the injection of plutonium and again a t termination, physical and laboratory examinations were conducted on each subject. 15 m l were taken before administration of plutonium and at four hours, one day, t h r e e days, six days, ten days, fifteen days, etc., post injection. plutonium was given. Fecal samples were collected in three-liter beakers. empty the bladder before defecation to avoid admixture of urine and feces. A s a rule feces were pooled during 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 oi from 25 to 150 g were obtained a t autopsy and preserved in 80 per T h e general management of the ward patients was as follows: A control period of about ten days was utilized t o instruct the patient in the quantitative During this period all necessary adjustments to After the patient had Blood samples were drawn into dry sodium citrate a s an anticoagulant. Samples of Urine samples were collected directly into half-gallon fruit jars and preserved with T h e urine was usually collected i n 24 hour periods except on the day the During the first day i t was collected i n two 12 hour periods. The patient was …