Reprinted from "actinides in Man and Animals", Subject: the Late Excretion of Plutonium Following Acquisition of Known Amounts (PP 253-260)

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THE LATE EXCRETION OF PLUTONIUM FOLLOWING ACQUISITION OF KNOWN AMOUNTS The urinary and fecal excretion rates of plutonium 1 0 , 0 0 0 days after intravenous injection of known amounts are compared with the predictions of various models. Both Langham's and Durbin's equations underestimated the urinary excretion by about an order of magnitude; the observed fecal excretion rates were also higher than the predictions. The total excretion rate predicted by the ICRP model was in quite good agreement with the observed rate, but it overestimated it at early times (<20 days). These differences are The increase in the excretion rate between 1 5 0 0 days and 10,000 days is real, as shown by the increase in the estimate of body content of 239Pu of former Manhattan Project plutonium workers, as calculated from the measured urinary excretion and application of Langham's equation. In one of these subjects the urinary excretion rate started to increase at about 6000 days, reached a maximum at about 9 5 0 0 days, and declined for the next 2700 days. In the years 1 9 4 5 - 4 7 , 1 8 seriously ill persons were injected with small amounts of plutonium to provide urgently needed information on the excretion rate of this element when it gained access to the blood. Full details of the cases, with reference to the original reports, may be found in a thorough review article by Durbin (Du72). In 1973, at the instigation of Dr. Patricia Durbin and with her assistance, we were able to arrange for the hospitalization on a metabolic ward of three of the subjects who had survived their original illnesses. All urine and feces were collected for at least eight days and the samples were analyzed for plutonium by the method of alpha spectrometric isotope dilution. The isotopic diluent used was 242Pu. The results have been used to Work performed under the auspices of the U.S. Department of Energy.

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calculate the mean daily urinary and fecal excretion rates at about 10,000 days postinjection (27.4 years) for two of the three subjects. (The initial systemic burden of the third subject was not accurately known, and there were no early excretion data (Ru76). This subject will not be considered further.) The excretion rates are compared with the predictions of various models. Pertinent data on the two subjects and their injections are shown in Table 1. In this paper we compare the late excretion rates with the predictions of three models. The detailed results of the analyses have been published in a report from this laboratory (Ru75). We present here only the mean daily excretion rates, in Table 2. The uncertainties shown are the standard errors of the mean values, including the effects of biological (that is, In Table 3 the excretion rates, expressed as percentages of the injected doses, are compared with the predictions of three models. (1) Langham's equations (La50) for the daily urinary (Y,) and fecal (Yf) excretion rates in percent per day of the where t ( > 1) is in days; where the values of the intercepts, ai, are 0.41, 0.12, 0.013, 0.003, and 0.0021 % dose/day, and the values of the biological halflives, (tl/2)i, are 1.2, 5.5, 42, 300, and 4000 days, for components 1-5 respectively, and where the values of the intercepts, bi, are 0.60, 0.16, 0.012, 0.002 and 0.0012 % dose/day, and the values of the biological halflives, (tl/2)i, are 2.0, 6.6, 56, 380, and 4000 days, for components 1-5 respectively; and

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Late Excretion of Plutonium 255 TABLE 1: DETAILS OF THE SUBJECTS AND OF THE INJECTIONS Literature case no. Hp- 3 Hp- 6 Details of injection Date Nov. 27, 1945 Feb. 1 , 1946 TABLE 2: MEASURED EXCRETION RATES OF PLUTONIUM FOR TWO SUBJECTS Mean time since Urinary excretion : days 14 TABLE 3: DAILY EXCRETION AT l o 4 DAYS AS PERCENTAGES OF INJECTED DOSE

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(3) an equation derived from the report of an ICRp Task Group on the metabolism of compounds of plutonium and other actinides (IC72). The retention equation, was differentiated and given a equation for the total excretion negative sign to yield an The observed urinary excretion rates at lo4 days were approximately an order of magnitude higher than the predictions of both Langham's and Durbin's equations: the fecal excretion rates were more than an order of magnitude higher than the prediction of Langham's equation, and 2.5 to 5 times higher than the prediction of Durbin's equation. On the other hand, the total excretion rates were comparable with the prediction of the ICRP Task Group equation. It is worth noting that Durbin's equation gives values for Yu which differ by no more than 39% from those predicted by Langham's equation at any time from 10 days to lo4 days, it being remembered that both the intercept and the halflife for the fifth component of Durbin's equation were estimated (Du72), and that both Durbin's and Langham's equations were derived from the same data. In Figures 1 and 2, all the excretion data for the two subjects respectively are plotted from day 1 onwards, together with curves showing part or all of the behavior of the functions for the three models. It should be noted that the first points plotted in both diagrams are at 1.5 days, and they represent the amounts excreted on the second day after injection, as given in the original paper (La50). Each subsequent point is also plotted at a time 0.5 day earlier than given by Langham, but after 10 days the effect on the presentation is negligible. It is clear that Langham's equation provides quite a good description of the urinary excretion rate to -1500 days for both subjects. Durbin's equation is almost equally good after about 10 days; at earlier times it predicts urinary excretion rates that are a little higher than observed. Both equations grossly underestimate the excretion rate at

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Late Excretion of Plutonium 257 X Url nary ex c ret lon 0 Fecol ex c ret lon Time since InJect ion. days Excretion rates for case 40-009, compared with Durbin's If eco I dot t edl ICRP 13 [ to toll Tlme s ln ce InJect lon. doys Figure 2 As for Fig. 1 but data €or case 40-012.

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On the other hand,the total excretion equation derived from the ICRP retention function grossly underestimates the excretion rate at early times, overestimates it by a factor of more than2at -1500 days, and yet is approximately correct at lo4days. The agreement may b e € or tui to us. There is clearly a need for more data for the crucial time period 103-104 days after in take. Such data can obviously not be obtained for subjects who received known amounts of plutonium,but the shape of the curve of urinary excretion rate versus time may become available from the data that have been accumulated in the study of former Manhattan Project plutonium workers (FIe73). The questions to be answered are (1) Does the excretion rate increase at late times in all subjects ? (2)If so, when do the observed rates deviate significantly from the pre dic - t ions of the Langham equation ? (3) Is the magnitude of the deviation at a given late time the same (within a factor of, say, 2) in all subjects, o r is it a function of the age or physiological status of the subject, as well as of the length of time that the plutonium has been in the I t is not expected that the questions can be answered completely from the study at Los Alamos Scientific Laboratory (LASL) because the range of ages of the subjects was small, but tentative answers to all three questions can be deducted from the data published in 1973 (He73). In Table4of that paper were set out estimates of the systemic plutonium content of 25 subjects for 1953, 1957, 1962, and 1972. The estimates for 1953 and 1957 were in agreement for 24 cases for whom data are presented,but the entries for 1962 and 1972 showed a progressive increase in the estimated contents for14ofthe 25 subjects,while there was a definite increase from 1953 or 1957 to 1972 in seven others. In only three cases were the estimates of the contents for 1972 lower than those for 1953. The increases were the direct results of corre s - pond ing increases in the urinary excretion rates, and in a later report allowance was made for this (Vo77). One might then conclude that the answers to the three questions are (1) The excretion rate seems to increase for most, and perhaps all, subjects if followed for a sufficient period of time. (2)Significant deviations from the Langham equation seem to be apparent after about 6000 days (16.4 years). (3)mai nation of Table4of He73 shows that the deviations vary among the subjects, from a factor of about two to a factor of about five,at 10 days after in take .4 I t must be emphasized that these are tentative answers to our three questions. More complete answers can only come from a more thorough examination of all the available data,including the latest follow - u p studies. The urinary excretion data for these subjects were kindly made available to the author by J.N.P. Lawrence o f LASL (these data will be li shed soon(Vo79)).Since 1944 many samples have been analyzed for "'Pu for one of these subjects, and the data are plotted in Figure3. Each point represents the mean of several daily urine samples; the

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Late Excretion of Plutonium Figure 3 Mean urinary excretion rates in 1000-day intervals for a Manhattan Project plutonium worker. Figures by points are numbers of individual 24-hour urine samples contributing to mean values. Data kindly supplied by J.N.P. Lawrence of number of samples in each 1000-day period ranged from 4 to 18 as shown, and the mean daily excretion rate was plotted at a mean time of from about 1400 days to about 12,100 days after the probable last intake. The date of the latter was taken as October 1, 1945, and this could be in error by several hundred days. This possibility should be borne in mind. The results suggest that there was an intake just prior to the mean time of 2500 days, but otherwise they show an expected decrease until 6500 days. After this time they increased substantially, reached a maximum at 9400 days, and then decreased to less than two thirds of the maximum value. This trend is completely unexpected, and difficult The increase from 1500 days to lo4 days postinjection in the excretion rate of each of our two subjects seems to be genuine, because it is confirmed by the results for the Manhattan Project plutonium workers. It does not seem to be a consequence of the undoubted improvement in analytical techniques between about 1950 and the 1 9 7 0 ' ~ ~which might have been an explanation. "he reason for the increase remains unknown; osteoporosis might offer a plausible explanation, but this argument

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tends to be countered by the fact that the increase appears to start after about 6000 days in the Manhattan Project plutonium workers, when they were only around 40 years old. The totally unexpected decrease after 10,000 days in the excretion rate of one subject studied extensively at Los Alamos is a complete mystery. The final point in Figure 3 (0.72 pCi/day at 12,111 days) represents the mean of only four observations and it needs confirmation with more data, but the trend is well defined by the three previous points. It is to be earnestly hoped that more data can be collected for this important case, as well as for the other living cases in this series. Durbin, P.W. 1972. Plutonium in man: A new look at the old data, in: Radiobiology of Plutonium, Stover, B.J., and Jee, W.S.S., and eds., pp. 469-530, Salt Lake City, The J.W. Press. G.L. 1973. Manhattan project plutonium workers: A twenty-seven year follow-up study of selected cases, Health Phys. 25: 461-479. International Commission on Radiological Protection. 1972. The metabolism of compounds of plutonium and other actinides, Report of a Task Group of Committee 2, ICRP Publication -19, (New York, 1950. Los Alamos Scientific Laboratory Rep. LA-1151. and Robinson, J.J. 1976. The excretion rate and retention of plutonium 10,000 days after acquisition, in: Diagnosis and Voelz, G.L., and Hempelmann, L.H. 1977. Health of Los Alamos plutonium workers, in: Biomedical -and Environmental Research Program of the LASL Health Division January-December 1976, Peterson, D.F., and Sullivan, E.M., compilers, Los Alamos 1979. A 32-year medical follow-up of Manhattan Project plutonium workers, Health Phys. 37: 445-405.