Report: Distribution and Excretion of Plutonium Administered Intravenously to Man (Plutonium Injection Experiment)

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DISTRIBUTION AND EXCRETION OF PLUTONIUM ADMINISTERED INTRAVENOUSLY TO rdmi Work Performed By: Jeanne Carr it t Helen E. Van Alstine Report Written By: Los Akmos Scientiflc Laboratory of the Universtty of California, Los Ahmos, New Mexico Formerly of the University of Rochester, presently with the Atomic Energy Project, Captain, Med. Corps, U.S. A. (Stationed at Los Alamos, New Mexico). HEALTH AND BIOLOGY OFFICIAL USE ONLY

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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. Stafford L. Warren was primarily responsible for the initiaticn of the program under the Manhattan Engineer District. L. R. Hempelmann participated i n the early 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 iz form tic n used in this repnrt and in some cases reviewed parts o r a?! sf t h c ,T,anuscii$. 3. T. Brennan and G. W. Taylor reviewed the report and contributed many Dr. Hymer Friedell and Dr. Fred Bryan were of great assistance

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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. T h e Report covers a Cooperative Research Project initialed 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

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

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It is now a well established fact that the deposition of radioactive material ( R a , i t s isotopes and daughter products) in the skeletal system of radium dial painters was responsible for the bone necrosis, radiation osteitis, osteogenic sarcoma and other pathological changes in bone which characterize t.he 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 of the material o r the route of administration (2), ( 3 a , b, c ) . Autoradiographic studies of in a pattern quite different from that of radium. into the bone s a l t s exclusively and becomes buried i n the calcified structure in the manner to be expected from a member of the calcium family in the periodic table. shows some deposition in soft tissues (especially in the l i v e r ) and a remarkable affinity for epiphyseal line, the periosteum and the endosteum s o that localization is predominately in regions of trabecular bone (See Fig. 1, frontpiece). mode of deposition of plutonium made it potentially more hazardous than radium. there is only limited proof that the above conclusion i s justified, it must be considered when evaluating the potential chronic toxicity of the material. have demonstrated that clutonium is quite effective i n p;odur.inT pathola@cal changes in h m e Brues (10) compared the relative chronic toxicity of equivalent microcurie 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 systems of workers may, Over a period of from ten to thirty years, cause bone changes similar to those observed in chronic radium missible body burden a s i s currently done with radium. Of Standards established a tentative maximum permissible body content of 0.5 pg (0.032 p ) Of the Atomic Energy Commission as the official maximum permissible tolerance for 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 latter element tends to be incorporated The material is highly localized i n the The general conclusion was that the The above observations and the experiences of the radium dial industry have emphasized The possibility i s serious er.ough to justify the adopticn of a rigid maximum p e r - Only recently the subcommittee on internal radiation tolerances of the National Bureau This value was adopted immediately by the Division of Biology and RIedicine Adequate information as to the fixation and excretion of plutonium by man is essential 1. To minimize the degree of uncertainty inherent in extrapolating the vast amount of animal experimental data to 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 dzgree of fixation of plutonium by man and establish criteria for t h e period of retirement from further exposure of workers having received a maximum permissible dose. 4. T o provide more extensive and quantitative data on the deposition and excretion of plutonium by man a s a basis for future ccnsideration of maximum permissible body tolerance. Need for the above information was recognized several y e a r s ago. It was also recognized that such information could be obtained only by administering small t r a c e r amounts of plutonium to persons with a relatively short life expectancy. initiated April 10, 1945 (12). 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 Project 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 years 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 The first tracer study was This report is the final presentation of the results of twelve plutonium t r a c e r cases The results of the studies conducted by the Berkeley and Chicago groups a r e correlated In addition to 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 of 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 or a t most a few years, would be much greater. y e a r s old, and has since died of Cushing's Syndrome. approximately five y e a r s since the initiation of the firs: study, five subjects a r e known to have died of their diagnosed illness. of the five terminated cases. A s a rule, the subjects chosen were past forty-five years of age and Furthermore, an 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 Autopsies and tissue samples were obtained from only t h r e e Brief summaries of the medical histories of the subjects of these studies a r e as follows: This patient, a sixty-seven year old white male with a nine year history of peptic u l c e r , 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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T h i s patient, a forty-nine year old white male, was a known hemophiliac and entered the hospital on this occasion lor the thirty-eighth time. had been present for three years. essential hypertension with hypertensive cardiovascular disease and coronary insufficiency, and Symptoms referable t o hypertension Clinical diagnoses on this admission included hemophilia, T h i s patient, a forty-nine year old white female, was admitted to the hospital with complaints of pigmentation of the skin, pruritic 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 she appeared i n good health. She was admitted for follow-up 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. complaints on this occasion were referable to hypertension and osteoporosis. diagnoses were basophile adenoma of the pituitary gland with hypertension, hypertensive heart disease, nephropathy with uremia, osteoporosis, and a staphylococcic infection of the urinary 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. The patient r a n a down hill course until death in uremia occurred in April 1947. i n i s patient, a iiiry-six year oia wnire rnaie, was acimirreu rw rile iiospiiai in iGuverriLer 1945 with complaints of generalized weakness and difficulty in walking and swallowing of three monia, generalized arteriosclerosis, renal cysts and adenoma of the right kidney. The clinical diagnosis was amyotrophic lateral sclerosis. Death occurred The diagnoses at autopsy included amytrophic lateral sclerosis, bronchopneuThis patient, a forty-five year 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 ar.d toes. began during convalescence. On readmission in June 1947, his condition was essentially unT h i s 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 1946. Permission f o r 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 scleroderma since January 1945, and a duodenal ulcer first diagnosed i n 1944. admission were scleroderma and duodenal ulcer. The clinical diagnoses on this

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T h i s 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 at T h i s patient, a fifty-two year old negro male, was admitted to the hospital on March 24, 1946, in acute congestive heart iailure. and his history included both rheumatic fever and luetic infection. this admission included rheumatic heart disease, latent treated syphilis and ethmoidal and A history of heart disease since 1926 was obtained, The clinical diagnoses on This 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 February 26, 1946, and diagnoses at autopsy were cirrhosis of the liver, ascites, and thrombosis of the portal vein. This patient, a fifty-three year old colored male, was hospitalized on March-25, -1945, following an automobile accident -in which he sustained- comminuted fractures of the left femur of note included a left lenticular cataract and marked hypertrophic and atrophic arthritic changes in both knees, together with osteochondromatosis of the left knee. IB. Management of Subjects and Collection of SampB Ten of the twelve patients were cared for in the special metabolic wLrd of Strong f!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. 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 for the purpase of “blznk” determinations by the method of plutonium analysis. ceding the injection of plutonium and again at termination, physical and laboratory examinations ’were conducted on each subject. During this period all necessary adjustments to After the patient had Blood samples were drawn into dry sodium citrate as an anticoagulant. Samples of 15 m l were taken before administration of phtonium and a t four hours, one day, three days, six days, ten days, fifteen days, etc., post injection. i Urine samples were collected directly into half-gallon fruit j a r s and preserved with The urine was usually collected in 24 hour periods except on the day the During the first day i t was collected in two 12 hour periods. plutonium was given. 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 oF from 25 t o 150 g were obtained a t autopsy and preserved in 80 per Fecal samples were collected in three-liter beakers. The patient was instructed to I

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C. Administration of Piutonium The plutonium solution used in thes tudie wa ared by dissolving 5.0 rng of 2. The solution was assayedspectrographically pure plutonium metal in 1.0 ml. of 2 N for plutonium by alpha counting. in a 10 ml volumetric flask and diluted to volume with sterile 0.41 p e r cent sodium An appropriate aliquotof t h e plutonium solution was placed The solution prepared in the above manner had a pH of approximately 5.5 and 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 filled …