Survival Causes of Death and Estimated Tissure Doses in a Group of Human Beings Injected with Plutonium

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SURVIVAL, CAUSES OF DEATH, AND ESTIMATED TISSUE DOSES I N A GROUP OF HUMAN BEINGS INJECTED WITH PLUTONIUM*t The HEALTH EFFECTS of University of Utah College of Medicine Salt Lake City, Utah - 1976

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SURVIVAL, CAUSES OF DEATH, AND ESTIMATED TISSUE DOSES IN A GROUP OF HUMAN BEINGS INJECTED WITH PLUTONIUM* To determine the relationship between urinary excretion and plutonium body content, 18 persons of short life expectancy were injected with plutonium between 1945 and 1947. have been identified; eight were found to have survived for at least eight years and four are still alive today (1975). of 13 of these individuals have been determined from death certificates; none appear to be related to the administered plutonium. Doses to the liver and to the cells on the surface of bone have been calculated for these plutonium cases. to be carcinogenic, but comparison of the bone-surface doses with radium doses that have induced bone tumors indicates that six of these cases have received doses high enough to be considered carcinogenic. However, no bone tumors have yet appeared. Seventeen of these 18 individuals The causes of death The liver doses do not appear to be high enough In order to obtain information relating plutonium body content to plutonium excretion in human beings, hospitalized individuals of relatively short life expectancy were given intravenous injections of plutonium in 1945-1947, and excreta were collected and measured for as long as they remained hospitalized (Langham et al. 1950). Following the initial discovery by Durbin (1972) that some of these individuals were still living, she and, subsequently, the Center for Human Radiobiology at the Argonne National Laboratory made an effort to identify, trace, and learn the whereabouts of all of these unique cases. The purpose of this report is to detail what is known today about these individuals and their causes of death, and to estimate the liver and bone doses accumulated during -*Work performed under the auspices of the U.S. Energy Research and Devel- **Argonne National Laboratory, Argonne, Illinois 60439. 'Lawrence Berkeley Laboratory, Berkeley, California. 94720.

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The calculated radiation doses to the liver and to the skeleton are based on the assumption, inferred from ICRP (1972), that the fractional retention of plutonium inthe organs of interest is Here tis the time after administration of plutonium and A is the ef fec - ti ve elimination constant,obtained from the appropriate radioactive decay and biological elimination constants. The organ dose is then given by where I is the The value of fraction of the injected isotope in the organ, appropriate dose rate per unit activity,in radlvci-day, time after injection,in days, and average a - ray dose inrad. f used for both skeleton and liver is 0.45, as recommended by ICRP (1972). The initial injection levels were obtained from the original report on the cases by Langham etal. (1950), from Durbin's reviews of the data (1972) and, for case Cal - I,the original report by Crowley etal. (1946). The existing information on this last case is re - The time T over which the doses were calculated was from the date of injection to the date of death or,for those cases that are still alive,to July 31, 1975. The calculated liver and bone doses are tabulate d in Table I ; the complete details of the dose calculations are dates of injection and death. SURVIVAL AND CAUSES OF DEATH Table I also lists the injection levels and the Survival time was calculated from date of injection, as given by Langham etal. (1950), to date of death as given on the death certificate. Ofthe 18 cases, one remains unidentified,four are still alive (as o f 7/31/75), and death certificates have been obtained for the remaining The causes o f death as given on the death certificates are listed

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From the listed causes of death it appears that plutonium cannot be considered t o be a contributing cause for any of these cases. individuals were all gravely ill at the time of the plutonium injections ; some died in the hospital shortly after the injections,others survived only t o succumb eventually to their diagnosed illnesses. The cases with long survival are, o f course, more aptto show the effects of this boneand liver-seeking isotope, No bone- or liver - related malignancies appear in the listed causes of,death or the contributing causes on the death certificates, except for those cases i n which it was the diagnosed disease atthe time of the injection. the cases still living show no plutonium-related effects. Further,to our knowledge today (1975), Bone tumors have been induced by radium i n human beings, and t h e From the U.S.r isk from plutonium can be estimated from these cases. radium cases who have carried 226Ra o r 228Ra ora mixture of the two iso - topes, the lowest average skeletal dose associated with a bone tumor i s 888 rad (Rowland etal. 1973). The shortest time between first exposure and the diagnosis ofa bone tumor was seven years (Rowland etal. 1973). From the more recent study of the effects of 224Ra i n man, an average skeletal dose of only 90 rad was observed as the lowest dose associated with a bone tumor, and four years was the shortest time between ac quis i - tion and diagnosis (Spiess and Mays 1970). Following Spiess and Mays (1970), we have converted t h e s e "lowest" average skeletal doses into the average doses delivered to the 10-pmthick volume of cells adjacent tothe bone surfaces ; here we will call these the average endosteal doses. The relationships between average skeletal dose and this average endosteal dose are listed in Table I11 for plutonium were calculated by use of the new ICRP bone masses--5000 g for males, 3400 gfor females (ICRP 1974)--these lowest average skeletal doses associated with bone tumors f o r 226Ra and 224Ra must first b e recalculated on this basis. Since all of our average skeletal doses The calculation for 226Ra i s straightforward; the case with the bone tumor a t 888 rad was female with an assumed 5-kg skeleton. Therefore, we re calculate the average skeletal dose tobe

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The average endosteal dose i s thus 1310 rad x 0.45 = 590 rad. Table 111. Relationships between average skeletal dose and bone Average skeletal dose rate i226Ra and 30% of three a-emitting daughters, 10.53 MeV per decay. The calculation for 224Ra i s somewhat more complex. The case with the lowest dose was male with an assumed 7-kg skeleton; there cal - culated average skeletal dose is thus 90 rad x 37 k the 90-rad value was based on the assumption that 20% of the injected radium decays in the skeleton, whereas Marshall ' s conversion factors followed ICRP (1973)) i n which only 11.5% of the injected dose decayed case tobe 126 radx -11*5%-- 72 rad. The average endosteal dose is then We thus determine the average skeletal dose for this We thus expect the lowest average endo steal dose a t which plutonium Table IVmight induce bone tumors i n man tobe of the order of 600 rad. lists those cases ,surviving for atleast four years,their average skeletal doses, and their average endosteal doses calculated on the assumption that all of the plutonium resides on the bone surfaces. Table IV.Skeletal radiation doses i n plutonium cases surviving more than four years Survival Average skeletal dose Surface dose

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Eight of these 18 cases survived longer than the four-year period noted above as the shortest induction interval for a radium-induced bone tumor; indeed, all of these eight cases actually survived at least eight years and four are still alive 28-29 years after receiving pluably larger than 600 rad, while two more received doses near enough to this value to be considered to be at considerable risk. cases one can generalize that about 30% of the cases who have accumulated average endosteal doses greater than 600 rad have a bone-related malignancy. Since a few radium-induced tumors have appeared as late as fifty years after first exposure, whereas the longest exposures in this small plutonium-injected group are now only approaching thirty’years, we would predict that between a sixth and a third of the s i x cases at risk should now have bone tumors. In view of the small number of cases Four of these cases received average endosteal doses considerat risk, the fact that no tumors have appeared is certainly not conclusive evidence that these radiation doses from plutonium are not tumorOne might argue that burial of surface-deposited plutonium by appositional bone growth would protect the layer of cells on bone surfaces and thus reduce the risk of bone-deposited plutonium. ly true, but since the same process occurs in the case of 226Ra in bone, the risk estimate derived from experience with this radioisotope takes account of this process. We conclude, from the lack of bone tumors in these cases, the bone-t-morrisk from plutonium is no greater than that from radium, and might be less. Human experience with liver-deposited alpha-emitting isotopes seems to be limited to the radiological contrast medium, Thorotrast. It appears that intravenously injected Thorotrast induces three distinct types of liver tumors: hepatic-cell tumors (Swarm 1968; da Silva Horta 1973). Specific dosimetry on a case-by-case basis is not available, but some general conclusions regarding liver dose can be drawn from the data. Liver dose rates hemangioendotheliomas, bile-duct tumors, and . in Thorotrast cases range from 13 to 41 rad/year (Kaul 1973); the average liver dose in ten cases of liver cancer was 509 rad, while the average liver dose in ten cases of hemangioendotheliomas was 609 rad (Faber

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greater than these values, it is perhaps not surprising that liver tumors have not been seen in these plutonium cases. Since only one ofthe cases listed in Table I had a 1i;er dose Therefore, these cases serve t o demonstrate that plutonium does not appear t o be more carcinogenic than expected and, as far as bone is concerned, may actually be less carcinogenic than expected. The dose calculations described here in were all made by A.T. Keane; in addition he and R.A. Schlenker have provided continual help in prepa ration of this manuscript. Their assistance is gratefully acknowledged.

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amount and isotopic composiThe Plutonium Injection There is uncertainty about both the tion of the plutonium injection of patient Cal-I. (a) Langham et al. (1950) quoted a calculation by J.G. Hamilton: the injected dose of 238Pu and 239Pu was equivalent to 103 pg of 239Pu (6.3 PCi of total alpha activity). Hamilton had used an injected alpha activity of 120,000 counts/sec as originally reported by Crowley et al. (1946), an unknown alpha counting efficiency (probably 0.5), and a 23BPu half-life of 50 yr, the best estimate available at the time (b) Durbin (1972) recalculated the Cal-I dose and obtained a value tion of the original data sheets, which were still in the Lawrence Berkeley Laboratory files, revealed that the injected dose had been 68,000 counts/sec. Evidently, the original report of Crowley et al. (1946) had erroneously shown the dose in units of counts/sec rather than disintegrations/sec. However, Durbin's calculation also contained some and for alpha counting efficiency (0.35) were modern values and not those appropriate to the time the original study was done (1945-1946), and it was erroneously assumed that the isotopic composition of the plutonium solution as stated by Crowley et al. (1946) had been measured directly and was accurately known. A re-examination of the original data sheets and an inquiry into the methods used at the time of the study for preparation of 238Pu and for alpha measurement reveal the following: (1) The injected dose is most likely that stated on the original (2) At the time of the study, alpha activity was measured at the Crocker Laboratory with a parallel-plate ionization chamber which has

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a counting efficiency of 0.5 (Jaffey 1954). platinum disks from which there is backscatter, so that the total alpha counting efficiency was probably 0.517 as calculated by Jaffey (1954). The 238Pu had most likely been prepared in the 60-in. cycloSamples were motinted on . tron at the Crocker Laboratory by deuteron bombardment of natural uranbeam was probably close to 16 MeV, because that beam energy produces the most 238Pu with the least contamination by other plutonium isotopes (4) According to Jaffey (1949), who recalculated the yield data of Seaborg et al. (1949) and Kennedy et al. (1949) for the reaction of 16-MeV deuterons on uranium, the ratio of alpha activities of the isoseparating the plutonium isotopes, so the isotopic composition of the plutonium in the Cal-I injection solution would have been that of the irradiated target. Furthermore, at that time the isotopic composition of the plutonium could have been characterized only by analysis of the and any values given f o r the masses of plutonium isotopes in the injection solution must have been obtained from calculations involving the alpha activities and the estimates of the half-lives then in use (50 and 24,000 yr, respectively, f o r 238Pu and 239Pu). At that time there was no method of Using the available facts and some assumptions that we believe are consistent with the history and circumstances of the production of the injected 238Pu-239Pu sample, we have recalculated the Cal-I dose as . The injected alpha activity was 68,000 counts/sec measured with an overall efficiency of 0.517, so the total injected dose was If the ratio of the alpha activities was 239Pu/238Pu = 0.013, then the

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The organ doses were calculated by assuming an exponential retention function R(t) = e and that the dose is given by D(T) = The appropriate dose rate per unit activity is calculated from m is the organ mass (in g), and The values employed for the relevant quantities are as follows. (1) Organ masses (ICRP 1974) Organ mass (g) For males For females

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233-247 i n Proceedings of the Third International Meeting on the Toxicity of Th oro tra st, The Finsen Institute, Copenhagen 25-27 April 1973, Risb Report No. 294. Danish Atomic Energy Commission Research Establishment Risa, Copenhagen. da Silva Horta, J., 1973. Tumours developed i n people injected with Durbin, P.W., 1972. Plutonium i n man: a new look at the old data. Pages 469-530 i n Radiobiology of Plutonium, J.W. Press,Salt Lake See also Lawrence Berkeley Laboratory Report UCRLFaber, M., 1973. Dose effect relations in hepatic carcinogen es is. Pages 308-316 i n Proceedings ofthe Third International Meeting on the Toxicity of Th oro tra st, The Finsen Institute, Copenhagen 25-27 April 1973, Risb Report No. 294. mission Research Establishment Risd , Copenhagen. Danish Atomic Energy ComICRP, 1972. International Commission on Radiological Protection, Report of a Task Group o f Committee 2 , The metabolism of compounds of plutonium and other actinides. Oxford, 59 pp. ICRP Publication 19, Pergamon Press, ICRP, 1973. International Commission on Radiological Protection, Report of a Task Group o f Committee 2, Alkaline earth metabolism in adult man. ICRP Publication 20, Pergamon Press, Oxford, 92 pp.

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ICRP, 1974. …