ARGONNE NATIONAL LABORATORY Contract No. (unreadable) THE DISTRIBUTION AND EXCRETION OF PLUTONIUM IN TWO HUMAN SUBJECTS E. R. RUSSELL AND J. J. HICKSON, M.D. Assisted by W. Monroe, R. Lesko, L. O. Jacobson Report Received August 29, 1946 Figures Received: September 13, 1946 Issued: October 2. 1946 UNREADABLE TEXT UNREADABLE TEXT 2 CASE NO. 2 A fifty-five year old white female was admitted to the Billings Hospital in December, 1945 for diagnosis and treatment. Six pathy. The months later (August, 1945), UNREADABLE , aggravated on motion, developed in the UNREADABLE. On admission to the Billings Hospital in December, 1945 the essential physical findings were the presence of bilateral non-tender, moderately enlarged lymph nodes in the cervical UNREADABLE, and inguinal regions and generalized tenderness to pressure over the ribs. X-ray UNREADABLE of the chest, pelvis, skull, and spine revealed many small, rounded areas of decreased density scattered throughout the bones examined. In addition, partial collapse and wedging of the last thoracic and first and second lumbar vertebrae with some associated calcification was noted. Laboratory examinations were essentially negative except for a moderate UNREADABLE-chromic anemia and leukocytosis. Wasserman and Kahn were negative. Study of UNREADABLE of the tumor excised from the skull and left axilla revealed UNREADABLE tissue. It was felt that carcinoma probably originated in the left breast. The patient's general condition was poor at the time of admission and deteriorated UNREADABLE throughout the period of hospitalization. On December 27, 1945 at 9:02 AM, 94.91 micrograms of +6 plutonium citrate were injected intravenously. The salt was contained in 4.4 cc of an isotonic saline solution 0.01 LI in citrate at pII 6.5. The clinical course was not visibly altered following the injection. The patient expired on January 13, 1945. The major autopsy findings were: (1) an adenocarcinoma probably arising in autopic left axillary breast tissue with metastases to the UNREADABLE of the small intestine, lumbar vertebrae, ribs, skull and pelvic. Numerous healing pathological fractures of the ribs were found. (2) A lymphoblastoma involving eh axillary, UNREADABLE, peribronchial, periaortic, and pelvic lymph nodes. Thus the patient had two co-existing presumably independent tumors, an unusual finding. The weight at autopsy was recorded at 85 pounds (38.6 kg.). Histologically, the bone marrow in all places examined was almost entirely replaced by tumor. The spleen showed a UNREADABLE... The kidneys showed many convoluted tubules filled with UNREADABLE. The tubular epithelium showed evidence of degeneration and repair. Comparison of the biopsy sections with the post mortem sections shows no evident difference in the character of the tumor following the injection of plutonium. The cells characteristic of lymphoblastoma are UNREADABLE present in the biopsy sections. II. PERIODS The control period in Case I was one week long and was used primarily to determine the approximately daily urinary output available for analytical purposes. In Case II the control period was somewhat shorter and was used for the same purpose. UNREADABLE cases the specimens were collected in the usual animals and UNREADABLE UNREADABLE being transformed in the case of the urine, to a gallon bottle to UNREADABLE ... hydrochloric acid has been added. The addition of the REMAINDER OF THIS PARAGRAPH UNREADABLE. 3 In case II because of the condition of the patient, adequate separation of the urine and fecal specimens was not always possible. As a result adequate fecal excretion data could not be obtained. Hematological studies made at frequent intervals in both cases included: hemoglobin in grams per ml; crythrocytes, UNREADABLE, platelets per cubic mm; UNREADABLE in per cent; UNREADABLE differential; sedimentation rate UNREADABLE; and UNREADABLE reading. Liver function tests were performed in Case II by S. UNREADABLE using the cephalin flocculation and thymol turbidity tests and UNREADABLE determinations. UNREADABLE: The autopsies were performed by members of the Pathology Department of the School of Medicine of the University of Chicago. The specimens were placed in 95 per cent alcohol as experience elsewhere had shown that the usual ten per cent formalin preservative tends to leach plutonium out of the specimen. Insofar as possible the specimens were placed in individual containers. RESULTS Case I UNREADABLE of Plutonium in the Urine: For forty-eight hours following intravenous injection of the plutonium solution, each specimen of urine was collected and analyzed separately. The first voiding was approximately six hours after the injection. The results of the analyses are given in Tables I, II and III and Figure I. It is interesting to note that there is very little difference in the percent of the plutonium excreted in the third through the twelfth specimens though the unit concentration of plutonium in the urine varies widely. After forty-eight hours, the specimens voided in each 12 hour period were pooled for six days, followed by pooling of specimens for each twenty-four hour period for the duration of the experiment. The results are given in Tables III and IV. The twenty-four urine volumes ranged from 1500 ml to 3600 ml. There was little correlation between urinary volume and quantity of plutonium excreted. The urinary excretion of plutonium in the first 24 hour period is very nearly 50 per cent of the total excreted in the urine throughout the entire period of observation, and is 36 percent of the total excreted in both urine and UNREADABLE. The rapidity with which the rate of excretion diminishes is remarkable. Within 24 hours, the excretion level had fallen to approximately one- hundredth of that UNREADABLE during the first six hours. In approximately two weeks the excretion rate had fallen to approximately 0.004 times the initial rate. 4 Table I. Percent of Plutonium Excreted in Urine in the First 38Hours. (Individual Specimens) Specimen No. Volume of c/m per 100 ml urine % of injected Specimen plutonium (cc) Excreted 1 (6 hours) 152 6550 2.23 2 218 355 0.175 3 325 45 0.023 4 245 65 0.036 5 414 37 0.035 6 (24 hours) unreadable 78 0.032 7 108 133 0.033 8 122 137 0.022 9 73 95 0.020 10 97 92 0.030 11 148 67 0.024 12 (48 hours) 160 100 0.024 Table II, Percent of Plutonium Excreted - 2nd to 8th Day. 12 Hour Urinary Output Analyzed Days after Volume of c/m per 100 ml urine % of Injected Injection Specimen Plutonium (cc) Excreted 2.4 258 77 0.045 3 415 41 0.139 3.5 630 54 0.035 4 540 39 0.035 4.5 515 10 unreadable 5 430 20 0.020 5.5 660 15 0.012 6 485 16 0.017 6.5 600 10.5 unreadable 7 380 11 0.0094 7.5 920 6.5 0.013 8 895 5 0.0095 5 Table III. Percent of Plutonium Excreted - 9th to 155th Day. Days after Volume of c/m per 100 ml urine % of Injected Injection Specimen Plutonium (cc) Excreted 9 2510 5 unreadable 10 3250 4.7 0.034 11 3275 6.6 unreadable 12 3220 5.2 0.047 13 1490 5.4 0.018 14 2635 5.7 0.094 15 2480 4.7 0.026 16 2520 2.1 0.012 17 2650 4.5 0.028 18 2920 4.0 0.026 19 3300 2.1 0.015 20 3060 5.6 0.038 21-30 avg. 2723 3.2 0.045 31-40 avg. 3018 1.9 0.012 41-60 avg. 3346 2.2 0.017 61-80 avg. 3020 3.3 0.021 81-100 avg. 2505 2.9 0.015 101-125 avg. 2125 1.7 0.008 126-138 avg. ---- 2.0 0.010 139-155 avg. ---- 1.7 0.008 FOR REFERENCE SEE (2bb20) 6 Fecal Plutonium Excretion. During the first four days after injection seven individual fecal specimens were collected and analyzed for plutonium. Following this period the samples were collected at 24 hour intervals for several months and then 24 hour specimens were taken everry four days until death. The results are given in Tables IV and V and Figure II. Table IV. Fecal Plutonium Excretion Individual Fecal Specimens Collected in First 96 Hours. Sample Time of Collection Weight of c/m per gm % of Injected No. after Injection Specimens of feces Plutonium (gms) Excreted 1 6 hours 13.0 26.0 0.076 2 28 hours 189.5 3.7 0.197 3 40 hours 45.5 16.2 0.161 4 51 hours 106.9 11.2 0.270 5 not recorded 141.5 6.2 0.195 6 not recorded 318.7 3.7 0.264 7 96 hours 76.2 9.1 0.154 Table V. Fecal Plutonium Excretion Daily Specimens from the 5th to the 138th Day Days after Weight of c/m per % of Injected Injection Specimen gram Plutonium (gms) feces Excreted 5 49.5 19.3 0.214 6 57.0 8.7 0.109 7 54.2 6.3 0.076 8 64.4 7.3 0.105 10 278.3 3.2 0.200 12 129.9 2.8 0.082 13 144.7 1.2 0.040 14 70.1 2.8 0.044 15 166.7 1.0 0.042 16 122.7 1.1 0.029 18 232.1 0.6 0.031 19 128.9 0.9 0.027 20 130.0 0.53 0.0154 21-30 avg. 112.4 0.59 0.0745 31-40 avg. 115.5 0.29 unreadable unreadable 123.0 0.18 unreadable unreadable 143.6 0.21 unreadable unreadable 08.2 0.16 0.0031 FOR REFERENCE SEE (2bb21) Figure II Excretion of putonium in the feces of a sixty-eight year old white male following intravenous injection of 6.50 micrograms of plutonium citrate. 7 Total excretion of plutonium for 138 days is estimated as 8.18 percent of the injected dose. The urinary excretion is estimated as 5.24 percent of the injected dose, the fecal excretion as 2.90 percent of the injected dose. The average excretion figures are multiplied by the appropriate factor in UNREADABLE at the above estimates, since average figures only are given throughout much of the period of study. Clinical Studies of Peripheral Blood. No changes were observed in the hematological constituents of the peripheral blood which could be attributed to the action of the isotope administered. These data are recorded in Table VI and in Figures III, IV and V. Table VI Blood Findings Case I FOR REFERENCE SEE (2bb22) GRAPHIC FOR REFERENCE SEE (2bb23) Figure III Total white blood cell, polymorphonuclear call, and lymph cell counts per cubic millimeter, in Case I. FOR REFERENCE SEE (2bb24) GRAPHIC Figure IV Hematocric reading, red blood cell count, hemoglobin determination in Case I. The injection was given on April 26, 1945. Figure V CH-3607 Pleatelet and reticulocyte counts in Case I. FOR REFERENCE SEE (2bb25) GRAPHIC 9 Post mortem findings. The patient died 155 days after the injection of plutonium. The analytical data is recorded in Table VII. The specimen of marrow and spicules showed the greatest activity per gram of tissue. The plutonium content per gram of liver was nearly as great. The activity of the cortex of the rib was one-tenth that of the bone marrow. No activity could be detected in the sample of bile analyzed. The effects of plutonium on normal and tumor tissue was looked for in the post mortem material by H. Lisco. He found no changes which he felt could be attributed to the action of the plutonium. Table VII. Distribution of plutonium in tissues of Case I, 155 days after the injection of 6.5 micrograms of plutonium. Tissue Weights Gms of Observed Cts/gm ug/gm Relative of Organs Tissue Counts of of Affinity (gms) Analyzed per/min. Tissue Tissue for per/min (x 10-3)Plutonium Marrow & Spiculas 0.8292 58.8 70.9 1.043 10.13 Liver 2050 34.11 2040.0 59.8 0.880 8.54 Sternum 4.38 111.1 1 20.6 0.303 2.94 unreadable (rib) 0.1215 2.12 20.0 0.299 2.06 Spleen 260 32.12 354.9 11.1 0.164 1.59 Lung Tumor 2.03 14.8 7.4 0.109 1.06 Cancer Tissue 2.87 20.9 7.2 0.106 1.03 Rib (cortex) 1.0125 6.06 1 7.0 0.103 1.00 L.Nodes (aortic) 0.63 4.17 6.7 0.099 0.96 Lungs 1950 15.39 40.7 2.6 0.038 0.37 Testicle (gl. portion) 4.3425 10.0 2.3 0.034 0.33 Kidneys 340 27.35 53.3 1.7 0.025 0.24 Heart 4.9435 6.0 1.2 0.018 0.17 Diaphragm 35.73 33.3 1.0 0.015 0.14 Fat (abd.) 17.05 3.? 0.2 0.003 0.03 Bile 8 cc 2.6 ? 0.000 ---- ____________________ + Counts per gram/counts per gram assuming uniform distribution of plutonium 1 90% correction factor applied to observed counts to give actual counts/gm. 10 Case II. Excretion Studies. The urinary excretion data is listed in Table VIII and plotted in Figure VI. Unfortunately no comparison of fecal and urinary excretion can be made in this case. The collection of separate urine and stool samples was impossible. In fact the graph of urine excretion in Figure VI might with greater truth be called the graph of total product excretion. The 24 hour excretion rate was 0.152 percent of the amount injected. This represents an excretion of 0.144 micrograms of the 94.9 micrograms injected. Following the initial 24 hour period the excretion rate was comparable to that in the other cases studied. The total known excretion was 0.684 percent of the amount injected,or 0.UNREADABLE9 micrograms. Table VIII. Daily Plutonium Urinary Excretion, Case II. Days after 24-hour Alpha Count/ % of Injected Injection Volume min/100 cc. Dose Excreted 1 1660 ml 594 0.152 2 1725 622 0.167 3 1750 250 0.067 4 1150 186 0.033 5 2020 134 0.042 6 1300 207 0.042 7 1190 132 0.0243 8 1500 110 0.0254 9 1400 89 0.019 10 1280 154 0.030 11 1120 108 0.019 12 940 100 0.014 13 875 251 0.034 14 630 99 0.009 15 830 124 0.016 16 150 164 0.004 Studies of the Peripheral Blood: No alterations in the hematological constituents of the peripheral blood occurred following the administration of 97.2 micrograms of plutonium which could be attributed to the presence of the element. The interpretation of changes in the thymol turbidity and cephalin flocculation tests, and in the amount of bilirubin in the blood serum was not possible because of the terminal state of the subject. These data are presented in Table II and in Figure VII. TO: Dr. J. J. Nickson FROM: K. R. Russell IN RE: Human fecal Plutonium Excretion 6.5 ug I. V. Injection 4/26/45 Time of Weight of % Of Injected Specimen Specimen Pu Excreted 4/26 6 hrs 13.05 gms 0.076 4/27 A.M. 189.5 0.157 4/27 P.M. 45.5 0.161 4/28 106.9 0.270 4/29 A.M. 318.7 0.264 4/29 P.M. 141.5 0.195 4/30 76.2 0.154 5/1 49.6 0.214 5/2 57.0 0.109 5/3 54.2 0.076 5/4 64.4 0.105 5/6 (1) 112.0 0.121 5/6 (2) 166.3 0.042 5/8 129.9 0.082 5/9 144.7 0.040 5/10 70.1 0.044 5/11 166.7 0.042 5/12 122.7 0.029 5/14 232.1 0.031 5/16 130.0 0.0154 5/17 112.7 0.0156 5/18 83.6 0.0179 5/19 86.7 0.0174 5/20 155.0 0.0158 5/21 21.3 0.0091 5/22 A.M. 123.9 0.0136 5/22 P.M. 52.3 0.0082 (5/15 128.6 0.027) 5/23 129.7 0.0110 5/24 78.5 0.0219 5/25 172.3 0.0078 5/26 108.6 0.0063 5/27 197.7 0.0150 5/28 126.7 0.0058 5/29 69.3 0.0071 5/30 87.4 0.0056 5/31 115.0 0.0074 6/1 (1) 67.9 0.0043 6/1 (2) 71.0 0.0031 6/2 85 0 0.0051 6/4 275.2 0.0043 6/5 59.1 0.0038 6/6 127.7 0.0042 6/7 76.4 0.0061 6/8 174.5 0.0056 6/9 141.8 0.0049 6/10 97.6 0.0043 6/11 (1) 99.6 0.0043 6/11 (2) 54.0 0.0043 6/12 125.0 0.0038 6/13 97.5 0.0031 6/14 79.7 0.0025 6/15 122.0 0.0048 6/16 75.1 0.0043 6/17 169.9 0.0038 _______ Total excreted to date 2.33 % Analyses by H. Delaney cc Dr.Stone Mr. Rose FOR REFERENCE SEE (2bb26) GRAPHIC Figure VI Excretion of plutonium in the urine following the injection of 94.9 migrograms of plutonium citrate. FOR REFERENCE SEE (2bb27) GRAPHIC Figre VIII Hematocrit, hemoglobin, red blood cell and reticulocyte findings in Case II. Table IX Blood Findings in Case II FOR REFERENCE SEE (2bb28) GRAPHIC 12 Distribution of Plutonium in the Tissues. The Plutonium content of the tissues analyzed is listed in Table I. The marrow and rib specimens showed the highest specific activity, as would be expected from the animal work. The plutonium content per gram of liver tissue was roughly one-tenth that of the bone marrow. The specific activities per gram of muscle and fat were respectively one-twentieth and one-thirty-fifth that of the bone marrow. H. Lisco reviewed the histological material for evidence of changes similar to that attributed to plutonium in the experimental animals. No such change was observed. It should be pointed out that the amounts per gram of body weight were greater in the animals in which changes were seen. Table I. Plutonium Distribution in Tissue 16 Days after Injection. Tissue Weight Weight of Total Count/1 Micro- Relative of Sample Count 1 gm of grams Affinity Organ (gms) in Sample Tissue Pluton- for (gms) ium/gram Pluto- of tissue nium2 (x 10-3) Marrow(Rib) 0.2065 289 1399 20 8.49 Rib (Cortex) 0.430 558 1299 18.6 7.88 Callus and Bone 0.1933 160 828 11.2 5.02 Callus(bone free) 0.2621 405 34 7.7 3.17 Kidney 190 6.00 2162 360 5.1 2.18 Thyroid 2.64 597 226 3.2 1.37 Contents (lower bowel) 10.05 1833 183 2.6 1.11 Liver 1110 8.70 1405 162 2.3 1.00 Pancreas 60 6.04 5893 148 2.1 0.90 Periosteum 0.461 57 123 1.7 0.75 Lung 490 14.40 1533 107 1.5 0.65 Fat,Wesenteric 5.850 560 96 1.2 0.58 Spleen 85 10.850 1021 94 1.2 0.57 Tumor(Liver) 1.970 140 71 1.0 0.43 Heart 250 9.40 660 70 1.0 0.42 Ovary, L. 1.975 122 63 0.90 0.38 Lymph Node(abd.) 1.53 73 48 0.70 0.29 Intestines(small) 3.40 151 45 0.64 0.27 Inrwarinwa(large) 6.87 291 43 0.60 0.26 Muscle(Str.) 15.32 613 40 0.57 0.24 Blood(heart Clot) 1.835 40 22 0.31 0.13 __________________________ 1 - Alpha counts per minute from plutonium. 2 - Counts/gram found divided by counts/gram assuming eual distribution of this plutonium. 13 DISCUSSION It must be emphasized that the data discussed above, while obtained on humans, may not be applicable to the population with which we are mostly concerned. The majority of occupationally exposed persons are in the 20-40 year ago group and are in good general health. The persons discussed above both had carcinomas, one of which had widespread metastases. In case #2, the injection was made but seventeen days before death and the terminal state may have influenced the metabolic behavior of the element. In case #1 no gross evidence of other than local disease, except for the metastasis to the lung, was noted at the time of injection. Thus, barring the alterations due to age, the early distribution ofthe plutonium was presumably a "physiological" one. However, it must bepointed out that we have no information on the early distribution of the plutonium in this case. The data given in Table VII represents the distribution of the injectate 155 days later, after profound metabolic disturbances, causing nos death, had occurred. It is impossible to say what influence this may have had in altering the early distribution pattern. As is well-known, the biological behavior of a given agent varies greatly from one species of mammal to another. Hence, experience with humans injected with plutonium was vital to any interpretation of the data obtained from animals. The rate of plutonium excretion in rats(2), mice(2), rabbits(3), and dogs(4) varies widely. The rout of excretion varies from species to species (2,4). Since our estimate of the body content, hand hence ultimately of the desirability of removing a given worker from his hob, depended upon the excretion rate of plutonium in the human, it became necessary to determine that rate directly in the species concerned. Knowledge of the distribution of the element as well as its rate and route of elimination from the human body provided information which could be correlated with the more extensive experimental investigation in animal and provided information which made possible the estimation of the amount of plutonium already deposited in the workers by the determination of the daily plutonium excretion rate of the individual concerned. Clinical Picture. Insofar as can be determined the clinical course in neither of the two cases was influenced by the injection of plutonium. In Case #1, the concentration of that material was 0.085 micrograms per kilogram of body weight immediately following the injection. In the second case the concentration of plutonium was 2.46 micrograms per kilogram of body weight. That the amount of plutonium injected in these subjects produced no appreciable clinical effect is likely in view of the fact that the amount on plutonium necessary to produce damage is far grater. Table XI lists some of the experimental values(2). Table XI. Comparison of Dose Levels of +6 Plutonium in Animals and Their Effects. ug/kg Effects Time Rats 700 - 1000 LD 50%in 30 Days Rats 200 - 600 LD 50%in 150 Days Rats 10 None 420 Days It will be seen that the level of 10 micrograms per kilogram is approximately 117 times the dosage level in Case I and 4 times the dosage level in Case II. 14 Hematological Studies. No hematological changes of the peripheral blood were observed in either subject. In view of the very slow excretion rate and long half-life of deposited plutonium it might be assumed however that a condition comparable to that described by Hartland(5), Castle(8) and Bomford and Rhoads(9) in individuals with chromic radium poisoning (severe anemia, leukopenia and thrombocytopenia with or without bone sarcoma) might well develop in either case were it possible to observe subjects over extended periods of time. The difficulty which arises in attempting to extrapolate from the radium damage data on the human to the expected effect of the impossibility of estimating what the ingested dose might have been in the individuals who have succumbed to radium poisoning. While bone sarcomas have been reported in individuals with a total of 0.5ug of radium in the body at death, little information is available as the amount which was in the body initially and this initial dose may be the critical amount. Case I Excretion Studies. The fact that the rate of excretion of plutonium apparently had not reached a constant eve 100 days after injection deserves emphasis. The rate of fall is slight by definite. This point deserves emphasis as it nay indicate that the excretion rate 1000 days after exposure may be even loss than the average of 0.012 per cent found after 150 days in this case. Evidence for continued diminution in the excretion rate of plutonium 238 (isotope of plutonium 239) is found in the patient studied by the University of California group which is described in the biology volume of this report. In this patient, 158 days after injection, the daily excretion rate is approximately 0.0015 per cent of the injected dose (6), a figure definitely lower than our figure of 0.012 per cent one hundred and fifty days after injection. Should the lower figure prove to be the more correct one the difficulty detecting tolerance concentrations of plutonium by means of the urinary excretion of that element is materially increased. It is interesting to note the totals of urinary and fecal excretion for the time periods of 0-214 hours, 2-10 days and 11-100 days. Table III gives these data for Case I in terms of percent of the injected dose: Table III Summary of Plutonium Excretion for Indicated Time Periods, Case I Time Urine Stool Total 0-24 hours 2.53% 0.233% 2.764% 2-10 days0.638% 1.748% 2.386% 11-100 days1.902% 0.767% 2.669% 15 It is apparent that the total excretion is roughly equal for each of the various periods. One might speculate that the next order of magnitude, that is 101-1000 days, night also show a total plutonium excretion of approximately 2.5 percent. If this percentage excretion for the 101-1000th days period is subsequently borne out by experimental observation, it would paint a rather discouraging picture from the point of view of the normal excretion rate for plutonium. The fecal excretion pattern is similar to that described for the excretion in the urine. No sharp early peak in the excretion rate is noted however. On the other hand, the rapidity with which the rate falls is not so marked. Indeed, the total plutonium excreted from the second to the tenth day is greater in the feces. However, as pointed out above, the fecal excretion after the twentieth day is distinctly less than the urinary excretion. It will be noted that throughout this paper the excretory rate is given as "percent per day of the injected dose". It would be more accurate to speak of the percent per day of the amount in the body. Because of the low rate of excretion of plutonium the correction factor is small and it is felt that the small inaccuracy introduced by this practice is justifiable, particularly in preliminary studies. Distribution of Plutonium in the Body. It may be useful to compare the relative concentrations of plutonium in the various organs in the two cases. It is recognized that such comparisons cannot be pushed too far because of the many uncontrolled variables. For case of comparison, the values from Case I in Table XIII are adjusted to an injection amount of 94.91 micrograms, the amount injected in Case II, assuming the same distribution would occur with the larger dose. In both cases the bone marrow shows the greatest concentration of plutonium per gram of tissue. On the basis of animal experimentation it is felt that the plutonium probable initially localizes in the osteoblastic and collagenous tissue surrounding the spicules, forming the endosteum. Since the proportion of this tissue is greatest in the marrow specimens, it shows the highest activity. It is of interest also to note the much higher proportional activity of the bone cortex in Case II, where the cortex shows almost as much activity as the marrow. The decalcification of the bones noted in this case would result in a greater proportion of plutonium-containing tissue than found in the comparable specimens in Case I, where the calcium content of the bones was apparently normal. The specimen of callus from the rib i n Case II did not show as high concentration as the cortex or marrow specimens do. Since the callus represents a healing pathologic fracture, it is entirely possible that the up take of plutonium was abnormally low. 16 Table XIII Comparison of the concentration of plutonium per gram of tissue. For case of comparison the values from Case I are adjusted to an injection amount of 94.91 micrograms, the amount injected in Case II. Tissue Case I Case II Gm Pu/gr tissue Gm Pu.gm tissue (x 10-3) (x 10-3) Bone Marrow + Spicules 15.2 20.0 Bone Cortex 1.50 18.6 Kidney 0.36 5.1 Liver 12.8 2.3 Lung 0.55 1.7 Fat .04 1.5 Spleen 2.39 1.2 Tumor 1.59 1.0 Heart 0.26 1.0 Ovary 0.90 Testicle 0.50 L. Nodes 1.44 0.70 Muscle Striated 0.22 0.57 he amounts in the livers are of considerable interest. The reasons for the wide discrepancy shown are not known at the present time. In Case I the liver content at death, some 150 days after injection, constituted approximately one-third of the injected amount. This value is far higher than the data from experimental animals would lead one to anticipate(3). It is true that early values comparable to the one listed here may be found in the experimental animal. A most uniformly,however, the initial high value has dropped by a factor of five or ten by the hundredth day (2). Why, in this instance, the liver should have retained plutonium so tenaciously is not understood. Indeed, it must be admitted that we cannot rule out the possibility that the amount in the liver was at one time lower than the final value. Liver biopsies would be extremely useful in following the plutonium content of that organ over a wide time range. In Case II the content of plutonium in the liver was approximately one-sixth of the amount noted in Case I and constituted approximately one percent of the amount injected. This figure is, if anything, somewhat lower than one would expect the concentration in the liver to be on the 16th day after injection, judging again from the results of animal experiments. (2) The concentration of plutonium in the spleen in Case I, which showed some congestion but no other evidence of pathologic change, was distinctly greater than the concentration in the spleen in Case II where a marked myeloid metaplasia was observed. The relative concentration of plutonium in the spleen observed in these two cases given here are distinctly less than those observed in experimental animals, particularly in dogs(4). In most instances that plutonium concentration in the spleen compares favorably with that of the bone marrow. Certainly the difference noted between the results in the two human cases are far less than the difference between species (2,4). Again UNREADABLE explanation for this fact can be given at this time. 17 It is interesting to note that in both cases the primary tumors, two carcinoma and lymphosarcoma, did not concentrate plutonium to a significant degree. While it is impossible to generalize from two cases, it seems unlikely that plutonium will be of any value in the treatment of carcinomas in humans. As a general principle any radioactive agent injected for the therapeutic purposes must concentrate to a greater degree in the tumor than elsewhere. There is a marked difference in the concentration of plutonium in the kidneys of the two cases. The higher value is found in Case II. Two factors may reasonably be expected to operate in the direction of producing a higher concentration of plutonium in this case. First, and probably more important, is the fact that the death occurred shortly after the injection. The data obtained from animal experiments indicates that the kidney concentration is higher shortly after injection (2). In both cases evidence of degenerative changes in the tubules of the kidneys was noted in the tissue sections. In addition, in Case I changes suggestive of a pyelonephritic lesion were noted. It is possible that the urinary excretion data will be found subsequently to be too low because of the presence of disease in the kidneys. Evidence obtained elsewhere, however, would indicate that the figures for urinary excretion given here are not seriously in error (7). The lack of plutonium in the bile is of considerable interest. Within the limits of the method (approximately 10-4 micrograms of plutonium per gram of tissue) none was found. Similar findings were noted in the plutonium injected dogs (4). The relative activity of the contents of the lower bowel in Case II are higher than would be anticipated from the results of the analysis of the feces. Further, the value is four times higher than that obtained for specimens of the tissue of the large and small intestine in this case. If the assumption is made that the amount of plutonium in the bile was negligible as in Case I, it would seem then that plutonium is being excreted by the large intestine it seems reasonable to tentatively assume that plutonium is also excreted by this route. The assumption cannot be verified until further experimental data is available. In general the relative amount of plutonium per gram of tissue tends to be higher in Case II than in Case I. It is possible that the explanation lies in the comparative lack of fatty tissue in Case II so that the organs and tissues studied tend to have a greater proportion of plutonium than was noted in Case I. The total fat is difficult to estimate from the data at hand and therefore the total amount of plutonium absorbed in the fat. In spite of the lower unit concentration in the fat in Case I, it may be that the proportional amount of plutonium in the total fat was greater in Case I than in Case II. Summary and Conclusions. Distribution and excretion studies have been made of plutonium 239 +6 citrate in two human subjects given total intravenous doses of 5 and 94.91 micrograms of plutonium respectively. The clinical effect was noted which could be attributed to the biological action of the element in 155 and 16 days of observation respectively. Such changes as occurred in the hematological picture and in liver functions can be attributed to the terminal state of the subject, to the underlying disease, or both. It is difficult to make other than very tentative generalizations because of the considerations mentioned above and because of the fact that only two cases are reported here. From what is known from the cases reported here (and from other cases reported elsewhere) the 18 following tentative conclusions may be drawn. It must be recognized clearly that these are not in the true sense of the word conclusions but are only working hypotheses that must be confirmed and elaborated upon by subsequent investigations. (1) The urinary rate of excretion of plutonium in humans is exceedingly low. The best evidence available at this time would indicate that the "chronic" (150th day) excretion rate does not exceed 0.01 percent per day of the amount fixed in the body. (2) The fecal rate of excretion of plutonium fixed in the body is lower than the urinary rate by a factor of approximately three. What evidence we have would indicate that the rate of fecal excretion does not exceed 0.003 percent per day of the amount in the body. (3) The highest concentration of the plutonium fixed in the body is found in the bone marrow. The liver concentration has varied so widely in the two cases here reported that it is impossible to predict on a reasoned basis what the general picture might be. (4) The concentration of plutonium in the neoplastic tissue of these cases was not high. BIBLIOGRAPHY (1) Russell, E. R., Schubert, J., et al. "The Quantitative Determination of Plutonium in Biological Tissues", PPR, Vol. 20-B. (2) Snyder, R., and Kisieleski, W., "Acute Toxicity of Plutonium for Mice and Rats", PPr, Vol. 22. (3) Russell, E. R., WDC-ERR-83, "Collected Data on Excretion", May, 1945. (4) Painter, E., Russell, E. R., and Prosser, L., "Clinical Physiology of Dogs Injected with Plutonium, PPR, Vol. 22. (5) Wartland, H. S., "Occupational UNREADABLE in Manufacture in Luminous Dials", J.A.W.A., Vol. 92, P. 552, 1929. (6) Stone, R. S., WUC-RSS-569, November, 1945 (7) Iangham, Wright, personal communication. (8) Castle, W. B., Drinker, K., and Drinker, C., "Wecroads of the Jaw in Workers Employed in Applying a Laminous Paint Containing Radium", Jr. Indust. Hyg. and Toxicol. 7:371, 1925 (9) Bomford, R. R., and Rhoads, C. P., "Refractory Anemia - Part I, Clinical and Pathological Aspects, Part II, Aetiology and Treatment". Qr. Jr. of Wed. 10:39, 1941 FOR REFERENCE SEE (2bb29) GRAPHIC FOR REFERENCE SEE (2bb30) GRAPHIC FOR REFERENCE SEE (2bb31) GRAPHIC This is a joint report from the Los Alamos Scientific Laboratory of the University of California and the Atomic Energy Project of the University. The report covers cooperative Research Project initiated under supervision of the Manhattan Engineer District and completed under contract NO. W.7401-ENG-49 and contract No. 7405-ENG-36(c) the Atomic Energy Commission. September 20, 1950 DISTRIBUTION AND EXCRETION OF PLUTONIUM ADMINISTERED INTRAVENOUSLY TO MAN Work Performed By: Report Written By: Helen Baldwin Wright H. Langham Samuel H. Bassett Samuel H. Bassett Jeanne Carritt Payne S. Harris W. W. Foreman Robert E. Carter David Goldring UNREADABLE Leonard S. Kogan Wright H. Langham Elizabeth Maxwell Arthur Murry, III UNREADABLE Hannah Silverstein Helen F. Van Alstine Christine Waterhouse ACKNOWLEDGEMENT The author wish to acknowledge the UNREADABLE and interest a number of persons who directly or indirectly UNREADABLE Fig 1 Nuclear Task Autoradiography Showing Location of Plutonium in the Bone of the Rat. (A. William, J. Wellnitz; Photomicrography by Los Alamos Photography Laboratory GRAPHIC DISTRIBUTION AND EXCRETION OF PLUTONIUM ADMINISTERED INTRAVENOUSLY TO MAN I. Introduction FOR REFERENCE SEE (2bb32) UNREADABLE TEXT - 9 - FOR REFERENCE SEE (2bb33) UNREADABLE TEXT & GRAPHIC 10 - 12 HP-2 The 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 UNREADABLE had been present for three years. Clinical diagnosis on this admission included hemophilia, essential hypertension with hypertensive cardiovascular disease and coronary insufficiency and chronic UNREADABLE. HP-3 This patient, a forty-nine year old white female, was admitted to the hospital with complaints of pigmentation of the skin, UNREADABLE... and dependent edema UNREADABLE clinical studies were carried out in November and Decemnber 1945, at which time diagnoses of hepatitis of unknown UNREADABLE ... were made she was admitted for follow-up examination in October 1948, when she appeared in good health. HP-4 This patient, an eighteen year old white female, had history of Cushing's Syndrome since 1941. Her admission in October 1947 was the fifth hospitalization. Chief complaint on this occasion were UNREADABLE to hypertension and osteoporosis. The clinical diagnoses were basophile adenoma of the pituary gland with hypertension, hypertensive heart disease, rephiopathy with uremia osteoporosis, and a staphylococetic detection of urinary tract. The patient ran down hill course until death in uremia occurred in April 1947. Diagnoses at actopsy include basophile adenoma of the pituitary gland, atrophy of the thyroid gland, hypertrophy of the ademona, hypertrophy of the left ventricle, hopoplasia of the uterus and ovaries, osteoporosis of the spine and pelvis, and chronic nephrills. 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 occured in April 1946. The diagnoses at autopsy included amytrophic lateral sclerosis, bronchopneumonia, generalized arteriosclerosis, renal cysts and adnoma of the right kidney. HP-6 This patient, a forty-five year old white male with a history of Addison's disease since January 1945, 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 especially unchanged. HP-7 This patient a fifty-nine year old white female who had been previously treated for heart disease and hyperthyrodism was hospitalized on January 29, 1946, for cardiac decompensation. The clinical diseases were rheumatic heart disease with nutral insufficiency and auricula fibrillation, and toxic modular UNREADABLE. She expired in October 1946. Permission for autopsy was withheld, be the probable cause of dealth was lobar pneumonia. HP-8 This patient, a forty-one year old white female, had a history of UNREADABLE since January 1945, and a UNREADABLE ulcer first diagnosed in UNREADABLE. The clinical diagnoses on this admission were UNREADABLE and UNREADABLE ulcer. - 13 - HP-9 UNREADABLE TEXT(page) - 14 - 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. As appropriate UNREADABLE of the plutonium solution was placed in a 10 ml volumetric flask and diluted to volume with sterile 0.41 per cent sodium citrate - 2H2O. The solution prepared in the above manner had a pH of approximately 5.5 and the plutonium was in the form of Pu4 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 filled with 0.5 ml of the plutonium solution and the needle used for filling the 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 injected 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 patient was used to measure 0.5 ml UNREADABLE of the plutonium solution into each of four volumetric flasks. The washing of the syringe and the 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 UNREADABLE ... of each evaporated directly on platinum discs and assayed for alpha activity. The average standard deviation for each set of four results was 2.0 per cent. The amount of material received by each subject and the date of injection are presented in Table 1 TABLE 1 AMOUNT OF PLUTONIUM ADMINISTERED TO SUBJECT IA INTRAVENOUS INJECTION AND THE DATE OF ADMINISTRATION. TABLE UNREADABLE - 15 - FOR REFERENCE SEE (2bb34) UNREADABLE TEXT & TABLE 16 - 17 FOR REFERENCE SEE (2bb35) UNREADABLE TEXT & TABLES 18 - 19 FOR REFERENCE SEE (2bb36) UNREADABLE TEXT & TABLES 20 - 21 FOR REFERENCE SEE (2bb37) GRAPHIC - 22 - FOR REFERENCE SEE (2bb38) UNREADABLE TEXT - 23 - FOR REFERENCE SEE (2bb39) GRAPHIC TABLES 26 - 27 FOR REFERENCE SEE (2bb40) GRAPHIC TABLES {MISSING INFORMATION} Table 8 PLUTONIUM URINE ASSAYS ON LOS ALAMOS PERSONNEL AFTER REMOVAL FROM FURTHER PLUTONIUM EXPOSURE GRAPHIC Figure 5 shows the adjusted curve through 1750 days represented as a heavy broken line. The points representing the three sets of data collected form HP-3 and HP-8 beyond 130 days after injection are shown on the graph as triangles. Points originating from the urine assays of the three Los Altamos workers are shown as circles and the theoretical curve (2) UNREADABLE days is given as a heavy solid line for comparison. The standard error of UNREADABLE for the adjusted expression is 42 per cent due largely to the poorer UNREADABLE during the first few days nd to the small number of observations during the later time period REMAINDER UNREADABLE 2. Fecal Excretion The same cases used for urinary excretion studies were used for the study of fecal elimination of plutonium following intravenous administration of UNREADABLE. Fecal samples were collected daily for the first few days. Later stools were pooled at four day intervals because of the uncertainty of obtaining representative 24-hour samples. Plutonium analyses were made on UNREADABLE of each specimen using methods described earlier. The results of analysis of individual fecal specimens are given in Table 9. Results are expressed as per cent of the administered dose excreted per day. Fecal excretion data could be obtained for only one of the cases CH-1) reported by Russell and Nickson (13). The original data were no longer available and it was necessary to read individual values from the graph given in their report. The original fecal excretion data were not available for the one case studied. FOR REFERENCE SEE (2bb41) GRAPHIC TABLES 30 - 31 FOR REFERENCE SEE (2bb42) GRAPHIC TABLES 32 - 33 chronic variable exposure dose in terms of an effective single dose given at some effective time between the limits of exposure. This interpretation was accomplished by fitting the slope of the urinary excretion curve of these individuals to the slope of the 138 day curve in the following manner: If Y =0.23 X -0.77 gives the percent (Y u) of a single dose excreted on day X, then 0.0023 DX -0 is the expression for the measured activity, UNREADABLE, counts per minute, excreted on day X when the single dose (D) is expressed in the UNREADABLE units. If the assumption is made that a chronic variable exposure dose may be represented by a single effective dose (D -E) then the activity (Y q) in the sample excreted effective days after this single dose is given by the expression. GRAPHIC This expression gives an approximation of the total body burden of a person chronically exposed to plutonium. The body burden is expressed in terms of a single effective dose as determined from two urinary excretion measurements GRAPHIC taken sufficiently far apart (with no exposure between) so that the two measurements are significantly different. The method of interpretation given above was applied to the urinary plutonium excretion data from these Los Alamos personnel and their average total plutonium body content approximated in terms of an effective dose at some effective UNREADABLE. The effective doses for W.B.G., W. A. D. and D.I., W. were estimated at 1.3, 1.2 and 1.0 respectively at respective effective times of 37, 53 and 42 days before the first time assay used in the calculation. Assuming the above doses, all urinary excretion data (Table 8) collected from these persons were used to adjust the experimental urinary excretion curve (2) extending it to 1750 data again using least squares analysis. The adjusted expression is GRAPHIC FOR REFERENCE SEE (2bb43) GRAPHIC CHART - 29 - by 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 UNREADABLE for the observed means was established by the method of UNREADABLE squares and was found to be: Y 0.63X -100 with a standard error of estimate of 28 per cent. In the above expression Y is the amount of plutonium excreted in the feces on a specific day (expressed as per cent of the injected dose) and X is the day of measurement in days after injection. The agreement between the observed values andthe derived expression is shown graphically in Fig. 4 (Page 23). In this figure the derived expression is represented by a heavy broken line and the observed points are represented as open triangles. The fecal excretion of plutonium in per cent of the injected dose excreted per day is plotted against time in days. No representative fecal excretion data beyond 138 days were available from Los Alamos personnel because of small but significant contamination of feces from swallowed material removed from the longs of workers by UNREADABLE action. One may ask why the small amount of lung contamination does not prevent the use of the urinary excretion results from these workers to adjust the 138 day urinary excretion curve to 1750 days. The material does not trace (probably less than 0.01 per cent). The small amount of material which has reached the UNREADABLE is being absorbed into the blood at an intestinal rate. Of the amount absorbed only a fraction of a per cent contributes to the daily urinary excretion. Studies of the excretion of plutonium by mice, rats, rabbits and dogs (1), (2), (18), (19) showed the urinary excretion of all species was quite uniform. The plutonium excretion in the urine thirty to fifty days after injection was 0.01 - 0.02 per cent of the administered dose per day. The urinary fecal excretion ratio varied widely, however, for the various species. The ratio was UNREADABLE... for the rat and only 1 2 - 3 for the dog. Russell and Nickson (13) reported a plutonium urinary fecal excretion ratio of 3/1 in man based on the observation of one case through 140 days. The California group (14) reported an excretion of 3-4/1 by one subject followed for 341 days. The adjusted urinary excretion curve for 0 to 1750 days and the fecal excretion curve for 0 to 138 days UNREADABLE be solved for the urinary to fecal excretion ratio: GRAPHIC The urinary, fecal ratio is 1 8/1 at 138 days post injection and 4.4/1 at 1750 days when calculated from the above expression. Unfortunately no applicable fecal excretion data are available from the Los Alamos personnel to permit adjustment of the expression for fecal excretion beyond 138 days. If the urinary/fecal ratios at 138 and 1750 days are calculated from UNREADABLE ... REMAINDER OF THIS PARAGRAPH UNREADABLE - 34 - of the injected dose excreted through day n: GRAPHIC From the above expression A = 2.98 per cent through the first 138 days. 3. Total Excretion (Urine plus Feces) From the practical point of view the total urinary plus fecal excretion rate of plutonium is extremely important. The UNREADABLE elimination rate determines how long a worker should avoid further exposure to plutonium after having reached an accepted maximum permissible body level. The observed mean urinary plus fecal plutonium excretion values are given to Table 7 (Page 28). Results are expressed as per cent of injected dose excreted per day. The means were obtained from the individual urinary excretion data from fifteen cases and the individual fecal excretion data from eleven. The results reported by the Chicago and California groups were used when available and applicable. Application of the method of least squares gives the expression GRAPHIC as the best curve of UNREADABLE for the urinary plus fecal excretion data for 0 to 138 days. The standard error of estimate of the computation is 17 per cent. Y is the total plutonium excreted in feces plus urine on a particular day (expressed as per cent of injected dose) and X to the time after injection in days. The observed means and derived expressions are compared graphically in Fig. 4 (Page 28). Observed values are represented by squares and the derived expression by the heavy broken line designated Y. The expression Y 0.79 X -0.91 represents the total excretion of plutonium only through the 138th day. Adjustment can be made, however, for urinary excretion measurements through 1750 days by summing the expression for local elimination (9) and the adjusted expression for urinary excretion (7). GRAPHIC The equation is adjusted to include all urinary excretion results from Los Alamos Laboratory personnel through 1750 days, and gives the total per cent of an injected dose of plutonium which may be excreted on a given day (x) after the time of injection. The adjusted expression for fecal elimination rate (Y ) through approximately five years and the observed means are UNREADABLE graphically in Fig. 5 (page 31) for comparison with the adjusted urinary excretion rate (Y ) for the same time interval. Integration of the adjusted expression for total elimination rate between X = 1/2 and X=n+1/2 days, gives the total amount of plutonium expected to be excreted up to and including day n. GRAPHIC - 35 - Table 10 compares the observed and calculated values of total plutonium excretion for various time 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). TABLE 10 OBSERVED AND DERIVED TOTAL URINARY PLUS FECAL PLUTONIUM EXCRETION VALUES FOR VARIOUS TESTS AFTER ADMINISTRATION OF SINGLE DOSE OF PLUTONIUM TO MAN TIME AFTER PER CENT OF INJECTED DOSE INJECTION OBSERVED CALCULATED * 10 days 2.43 2.56 20 days 3.06 3.17 30 days 3.41 3.53 40 days 3.70 3.81 50 days 3.90 4.03 60 days 4.11 4.21 70 days 4.27 4.36 80 days 4.42 4.50 90 days 4.54 4.02 100 days 4.67 4.74 120 days 4.87 4.93 140 days 5.01 5.10 1 year 6.26 2 years 7.22 3 years 7.83 4 years 8.30 5 years 8.68 10 years 9.96 20 years 12.17 __________________________ * Calculated from the integrated expression for adjusted urinary plus fecal excretion (14). The calculated values appear higher than the observed values by a constant amount because of the decision to accept a poor curve fit during the first ten days (see page 23) 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 person 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 the 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 UNREADABLE of data 36 concerning the 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 UNREADABLE ravenous injection as Pu-4 citrate complex and as plutonyl ion may be 20 - 40 percent for man as compared to 10 per cent 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 UNREADABLE per cent of the injected dose per gram of whole bone. Assuming vertebra, sternum and rib s 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 g (0.032 c). Using the dosage rate formula: rep/day 54 CE (where C= concentration of radioisotope in c/g, E= energy of the radiation in Mcv, and the rep= 93 crgs/g), the radiation dosage received per gram c skeleton from 0.032 c of plutonium as follows rep/day =54 x 0.6 x10 -5 x 0.032 pc x 5.15 Mev = .00057 A similar calculation for the official maximum permissible radium content of 0.1 pu 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 UNREADABLE in the body by the alpha particles per decay. If 100 per cent of the radium is deposited in a 10kg skeletal system, then the radiation dosage in rep per day is given as follows GRAPHIC FORMULA According to the above calculation, the radiation dosage per gram of skeleton delivered by 0.1 pg 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 UNREADABLE and periosteal surfaces. The choice of a more conservative body tolerance dose for plutonium was made to allow for its more UNREADABLE localization in the skeletal system. It should be noted, that analyses of bone samples from radium UNREADABLE 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 0.3 will give radiation intensities comparable to that which may occur with 0.1 g of radium. Evans (21) has also pointed out that the presence of UNREADABLE in the radium responsible for the early radium poisoning cases may account for an additional safety factor of 5 in the 0.1 g radium tolerance. The above discussion supports the possibility that the 0.5 g 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 metabolic processes are primarily - 37 - first order reactions. Whatever the true process is from the data and curves given in this report, it is possible to calculate the absolute minimum half-time of plutonium in the body. It is assumed (not unreasonably) that the excretion of the plutonium measured in terms of the amount in the body at a given time does not increase at some time. If one takes the last point on the combined urinary plus fecal excretion curve (a single value of the ordinate in Fig. 5) and assumes exponential excretion thereafter, an absolute minimum value is obtained for the biological half-time. On this figure, which is a plot of AC/Co UNREADABLE exponential excretion would be represented by a straight line with zero slope. Examination of the adjusted curve shows that 0.001 +- .00035 per cent per day is excreted at 1750 days (approximately 5 years) after exposure. Up to five years 8.7 per cent of the total has been excreted. The time required to excrete an additional 41.3 per cent (assuming exponential excretion beyond 1750 days) is 41.3/0.001 +- 0.0035 =41,300 days =113 years with limits of 84 and 175 years Thus, the mean minimal biological half-time estimate is 118 years. From the above, one may conclude that the excretion coefficient is too small to be of any practical significance in elevating the maximum permissible dose of plutonium or in permitting the return to work of an individual who has reached the maximum permissible body burden. Once a worker is retired from work with plutonium because of maximum tolerance exposure, it must abe assumed that he is retired from such work for the balance of his lifetime. C. Determination of Plutonium Body Burden from Urinary Excretion In the determination of exposure doses by the use of excretion data, one is primarily concerned with three different situations. First is the case of single acute exposure dose occurring at a known time. Second is the case of a variable chronic or subacute dose with only the total exposure time being known. Third is the case of a chronic UNREADABLE (usually low level) exposure dose with the time limits known. The evaluation of the single acute exposure dose occurring at a known time is the basis of this paper. A urinary excretion curve through 138 days after a single acute exposure is given in Fig. 4 (Page 28) This curve has been extended beyond the observation limit to 1750 days (Fig. 5) by applying data collected on exposed personnel from the Los Alamos Laboratory. The method used to apply these data was explained earlier (Pages 23 and 29). It is worth noting that the difference between the adjusted curve and the extrapolated 138 day curve at 1750 days is less than the standard error of estimate of the former. This finding shows more confidence in further extrapolation beyond 1750 days post exposure. The calculation of the body burden from a single acute exposure is simple GRAPHIC THIS PARAGRAPH UNREADABLE In the Los Alamos exposures, we have an illustration of the variable chronic exposure case with known time of exposure. Only under conditions of stress when safety factors of design may be exceeded will this type of exposure be seen. There are three - 38 - methods of estimating the total exposure 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, believed to more closely approximate the UNREADABLE. In this method it has been assumed that the total exposure dose may be represented by single effective dose occurring at some effective time UNREADABLE to the limits of exposure. The equation and steps to be followed with this method re shown on Pages 23 and 29. Ordinarily the first urine count issued to determine whether an individual should or should not be drawn 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 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 limit) that occurs in processing procedures in the plutonium industry in which UNREADABLE , 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 count per minute in the urine excreted on day n is GRAPHIC FORMULA - 39 - In addition to the empirical formula for o(r) a plot of the real values of o(r) versus (r) for values of r up to 98 days has been included (Fig. 8) from which the values of the sums may be read directly. In the equation for T Dm seven exposure days per work are assumed. The formula for T Dm may be adjusted for six exposure days per week as follows: We assume that exposure begins on the first working day of a week for simplicity. Obviously the only days not contributing to exposure are those on which D j = 0. In the six day week, therefore, FORMULA where a number of weeks worked by the subject. Thus, the terms corresponding to FORMULA etc., must be subtracted from the dose equation. 40 GRAPHIC PAGE {MISSING INFORMATION} 41 GRAPHIC FORMULA In the preceding formulae exposure conditions were assumed to consist of an equal and constant daily exposure dose D j equivalent to a single injected dose. Also the constants 0.0020 and 0.74 were empirically established on the basis of data available at the time of UNREADABLE report. These values may change as more data become available. A specific example of the application of the above dosage calculation is given below, using the expression for seven exposure days per week. In fact, the seven day exposure formula may be valid for either the five or six day week. Such would be the case if one considers that absorption from the lung is the primary source of contamination and that the equilibrium between the UNREADABLE and blood plutonium concentration is not radically altered by the one or two day period of no exposure each week. For purposes of presenting a specific example we may assume the following conditions: Duration of exposure (m) = 330 days Duration of time from beginning of exposure until urine sample taken (n) = 350 days Counts per minute of urine sample (Yn) = 2 c/ ) The total body dose T Dm may be calculated from the formula: GRAPHIC FORMULA 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 100mg 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 and in the common laboratory animals. As in the case of rats and other laboratory animals the skeletal system was the major site of plutonium deposition. Retention of plutonium by the liver of man seemed to be higher and the "biological half-time" in liver longer than for the more UNREADABLE laboratory animals. 3. Concentration of plutonium in the blood following intravenous injection drops very rapidly; only 0.3 percent of the total injected dose was fixed in the total blood volume thirty days after injection. 4. The urinary excretion of intravenously administered plutonium was not exponential. UNREADABLE regression line fitting showed that the urinary excretion through 138 days was best expressed by the fractional logarithmic function. FORMULA 5. The above expression for the urinary excretion through 138 days was adjusted by including data collected on Los Alamos Laboratory personnel. This adjustment permitted the development of an expression for the urinary excretion of plutonium through 1750 days. The adjusted expression is: FORMULA The standard error of estimate of the adjusted expression is 42 per cent. 6. The excretion of plutonium in the feces likewise was not exponential. Application of the method of least squares showed the best curve of fit for the fecal excretion of plutonium through 138 days was: FORMULA In this expression Y f is the per cent the injected dose excreted on a specific day and X is the time of measurement in days post-injection. The standard error of estimate of the above expression is 28 per cent. 7. The urinary to fecal plutonium excretion ratio obtained by solution of the above expressions for urinary and fecal excretion showed the urinary to fecal ratio was not constant. It was essentially 1:1 at 30 days and approached 4:1 at approximately five years. 8. The total (urine and fecal excretion) through 138 days was best expressed by equation: FORMULA 9. The total urine plus fecal excretion through 1750 days could be approximated by adding the expression for the fecal excretion through 138 days and the adjusted expression for the urinary excretion through 1750 days. The expression for the combined excretion is: 43 FORMULA in which Y represents the per cent of the injected dose excreted in the urine plus feces on specific day, and X designates the time of observation in days post-injection. 10. Integration of the above expression between the limits of 1/2 and n + 1/2 days post-injection gives the following expression: FORMULA which represents the integrated amount of plutonium in per cent of the injected dose EQUATION 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 minimal "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 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 know time. (b) The application of plutonium urine analysis to estimate the total body burden of plutonium following variable chronic or UNREADABLE exposure with only the total exposure time being know and, (c) The application of urine analysis to estimate the total body burden following chronic invariant 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 REFERENCES (1) Hamilton, J. G., Metallurgical Project Report 2303. (2) Langham, W., et al, LA-549, J. Biol. Chem., 171, 273 (1947). (3) (a) Finkle, R. D., et al Metallurgical Project Report CN-3167; (b) Snyder, R. H., et al, Metallurgical Project Report CT-3763; (c) Pointer, E. E., et al, Metallurgical Project Report Ch-3858. (4) Bloom, Wm., et al, Metallurgical Project Report: CN-2212. (5) Hamilton, J. G. Radiology 49, 325 (1947); New England J. Med., 340, 863 (1949) (6) Copp, H. D. Axelrod, D.J. and Hamilton, J. G., Am. J. Roentgenol, 48, 10 (1047). (7) Carter, R.E. Langham, W. H., unpublished studies, Los Alamos Sci. Lab. (8) Brues, A. M. Lisco. Hermann, Finkel, Miriam, USAEC Report MDDC-145; Radiology 4D, 361 (1947). (9) Carter, R. E., Langham, W.H. unpublished studies for Los Alamos Sci. Lab (10) Brues, A. m., Private Communication to W. Langham, Jan. 25, 1950 (11) Warren, Sheilds, Communication to Carroll I., Tyler, Mar. 13, 1950 (12) Langham, W. H., Metallurgical Project Report CN-3167. (13) Russell, E.R., and Nickson, J.J., Argonne Ntl Lab. Resear CH-3607 (14) Hamilton, J. G., Argonne Ntl. Lab Report Ch-3589 (15) Langham, W. H., USAEC Report MDDC-1555 (16) Maxwell, E., Fryxell, R., Langham, W. H., J Biol. Chem. 172, 183 (1948) (17) Lisco, Herman, "Project Standard Man", Communication to AEC, July 21, 1947. (18) Finkle, R. D., Jacobson, L. D., Report No. CH-3783. (19) Russell, E. R., Report No. CN-3167 (20) Evans, R. D., Private Communication to W. Langham, Jan. 13, 1950. (21) UNREADABLE R. D., Private Communication to K. 7 Morgan, Feb. 4, 1950 - 45 - October 4, 1978