Three plutonium chelation cases at Los Alamos National Laboratory

Paper THREE PLUTONIUM CHELATION CASES AT LOS ALAMOS NATIONAL LABORATORY Luiz Bertelli,* Tom L. Waters,* Guthrie Miller,* Milan S. Gadd,* Michelle C. Eaton,* and Raymond A. Guilmette† chelation treatments. At the Los Alamos National Laboratory (LANL), a special bioassay sampling protocol is initiated in response to a radiological incident involving intakes of radionuclides by workers at the facility, where specific indicators are present. The radionuclides are promptly identified and in most cases there is only one relevant radionuclide to be monitored. This allows the responders to follow the corresponding monitoring procedures for the isotope. Normally for 239Pu, samples are collected at 1, 3, and 5 d after the incident and analyzed using radiochemical alpha spectrometry (RAS) and thermal ionization mass spectrometry (TIMS) with the possibility for extending the collection schedule beyond the first week depending on the results from the first samples. When DTPA (diethylenetriaminepentaacetate) chelation treatment occurs additional bioassay samples are requested. This is done for two reasons: Abstract—Chelation treatments with dosages of 1 g of either Ca-DTPA (Trisodium calcium diethylenetriaminepentaacetate) or Zn-DTPA (Trisodium zinc diethylenetriaminepentaacetate) were undertaken at Los Alamos Occupational Medicine in three recent cases of wounds contaminated with metallic forms of 239Pu. All cases were finger punctures, and each chelation injection contained the same dosage of DTPA. One subject was treated only once, while the other two received multiple injections. Additional measurements of wound, urine, and excised tissues were taken for one of the cases. These additional measurements served to improve the estimate of the efficacy of the chelation treatment. The efficacy of the chelation treatments was compared for the three cases. Results were interpreted using models, and useful heuristics for estimating the intake amount and final committed doses were presented. In spite of significant differences in the treatments and in the estimated intake amounts and doses amongst the three cases, a difference of four orders of magnitude was observed between the highest excretion data point and the values observed at about 100 d for all cases. Differences between efficacies of Zn-DTPA and Ca-DTPA could not be observed in this study. An efficacy factor of about 50 was observed for a chelation treatment, which was administered at about 1.5 y after the incident, though the corresponding averted dose was very small (LA-UR 09-02934). Health Phys. 99(4):532–538; 2010 1. Experience has shown that data collected prior to 100 d following the final chelation treatment are not suitable for dose assessment purposes because chelation treatment disrupts the normal metabolism of plutonium (or americium or curium). This time delay is necessary to allow metabolism and excretion patterns to return to normal so that an accurate dose estimate can be obtained; and 2. Samples obtained before and after chelation treatments can provide an estimate of the dose averted by the treatments, and hence their effectiveness. This information is of value to medical personnel to make decisions about the benefits of continuing treatment. Key words: chelation; dose assessment; exposure, occupational; plutonium INTRODUCTION THE PURPOSE of this paper is mostly to report the steps taken in dealing with three chelation cases, the corresponding dose assessments and the efficacy of the * RP-2, Health Physics Measurements, Radiation Protection, Mailstop G761, Los Alamos National Laboratory, Los Alamos, NM 87545; † Center for Countermeasures Against Radiation, Toxicology Division, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, SE Albuquerque, NM 87108-5127. For correspondence contact: L. Bertelli, RP-2, Health Physics Measurements, Radiation Protection, Mailstop G761, Los Alamos National Laboratory, Los Alamos, NM 87545, or email at [email protected]. (Manuscript accepted 27 December 2009) As already stressed by La Bone (1994), “Rather than waiting to evaluate the long-term urinary excretion data, we frequently want to estimate the intake before the effects of chelation have subsided. One reason for this impatience is that intake estimates are often requested by management and regulatory agencies within a month or so of the intake.” So, this paper also aims to provide useful information to the internal dosimetrist in dealing 0017-9078/10/0 Copyright © 2010 Health Physics Society DOI: 10.1097/HP.0b013e3181d18c61 532 Three plutonium chelation cases ● L. BERTELLI with plutonium intakes, which involve chelation. This is an ongoing investigation, and at this point the intentions of this paper are 1) to predict the order of magnitude of urinary excretion values of plutonium when the effects of chelation have subsided, using urinary excretion data from samples collected during the early phase after the intake; 2) to verify initial values of the excretion enhancement ratios; 3) to estimate the total averted doses for the three cases; 4) to compare the estimated intake through the wound against the wound measurements; and 5) to apply the National Council on Radiation Protection and Measurements (NCRP) wound model to estimate the intake and committed doses (NCRP 2006). METHODS Three cases involving systemic uptake by wounds from a finger puncture are described in this paper. In all cases the wounds were caused by a puncture by a metallic part contaminated with 239Pu. The only additional radionuclides which could contribute with relevant radiological results were 238Pu and 241Am, whose results are also shown for comparison. With the exception of one treatment, each chelation injection had the same dosage of 1 g of DTPA, changing between Zn- and Ca-DTPA. The medical management of the treatment was performed under the guidance of the Radiation Emergency Assistance Center/Training Site (REAC/TS) from the Oak Ridge Institute for Science and Education (ORISE), who also provided the two forms of DTPA. The DTPA injections were administered intravenously with sterile isotonic saline solution. Committed effective doses [E(50)] and the committed equivalent doses [H(50)] to the most affected body organs were calculated for the three cases and are shown below. The E(50)s were calculated using the Bayesian Markov-Chain internal dosimetry code (Version ID2.3e) (Miller et al. 2002a). The Bayesian method requires prior statistical distributions. A collection of biokinetic models constituted the biokinetics prior for wounds, consisting of the NCRP wound model default cases, as well as injection biokinetics using the International Commission on Radiological Protection (ICRP) Publication 67 plutonium systemic model (ICRP 1993), and two other biokinetic models using the NCRP wound model parameterization, but based on two previous LANL wound cases. The prior probabilities of all wound models in this collection were assumed to be equal. The ICRP 60 tissue weighting factors (ICRP 1991) were used. The analysis uses exact Poisson likelihood functions (Miller et al. 2002b) for RAS count data and Gaussian likelihood functions to represent the TIMS data. The calculated ET AL. 533 quantities are probability distributions, which are represented by mean (expectation) values as well as 5% and 95% Bayesian posterior credible limits. From this point on all intake amounts and estimated doses will be represented as “Mean Values” (“5% Limit,” “95% Limit”), for example 74.3 Bq (62.3, 89.3). The averted dose reflects the reduction in E(50) due to the enhanced urinary excretion produced by the chelation therapy. Hence, it is a measure of the efficacy of the chelation treatment. It is conventional wisdom that the efficacy of chelation treatment decreases with time after the intake, as the radionuclide is deposited in the systemic organs. Thus, it is generally recommended that chelation therapy begin as soon as possible after a contamination incident (Volf 1978; Breitenstein et al. 1990; Carbaugh et al. 1989). However, it has been pointed out that optimizing the treatment schedule to match the in vivo solubility of the contaminating material may be a more efficacious approach (Guilmette 1997), because not all materials result in maximal systemic input immediately after exposure (e.g., Guilmette and Muggenburg 1988). In order to calculate the averted dose, we simulated an injection of unit activity of 239Pu into the blood, resulting in a committed effective dose coefficient of 489 ␮Sv Bq⫺1 (Bertelli et al. 2008). It is assumed that all available radionuclide in the circulating blood is removed together with the chelating agent (Volf 1978). The averted dose due to a single chelation procedure was calculated by multiplying the dose coefficient by the activity measured in the urinary excretion collected after the chelation. It must be pointed out that cases reported previously in the literature have based the averted dose estimates on the old ICRP 26 tissue weighting factors (ICRP 1977). In this case, the dose coefficient is 862 ␮Sv Bq⫺1, which could give a false impression of greater efficacy. The estimated E(50) and the H(50) would have been correspondingly higher. Case 1 This person suffered a wound on the left index finger with a screwdriver while working in a glovebox containing Pu metals. After washing and irrigation, the first wound count measured 629 Bq. Assuming as a worst-case scenario that the whole measured activity is absorbed to blood instantaneously, and using the committed effective dose coefficient of 489 ␮Sv Bq⫺1, a total E(50) of 308 mSv would be expected. The chelation therapy, which comprised a total of 29 chelations, was initiated with an injection of 500 mg of Zn-DTPA. On the day after the intake, 1 g of Ca-DTPA was administered. After that, daily injections of 1 g of Zn-DTPA took place on the following days after the intake: 2, 3, 4, 5, 6, 534 Health Physics 8, 9, 10, 11, 15, 17, 22, 24, 29, 31, 44, 52, 58, 66, 78, and 92. Additional injections of 1 g of Ca-DTPA were done at 106, 121, 135, 151, and 163 d after the intake. In addition, the person requested a late injection with 1 g of Ca-DTPA, which was done at 590 d after the intake. Fig. 1 shows all urinary excretion data obtained after the incident. The dotted lines represent the chelation treatments. There is a remarkable correlation between the chelation treatments and the higher urinary activity excretion results for samples right after each treatment. There is no apparent explanation for the “peak” that occurred around 200 d after the intake. The same degree of urinary excretion enhancement could be observed for the single chelation treatment which was carried out at 590 d after the incident. The total estimated averted dose was 99.4 mSv. The calculated E(50) and the H(50)s to the most affected body organs, having values greater than 10 mSv, and the corresponding 5% and 95% Bayesian credible limits are shown in Table 1. Values for 238Pu are also shown for comparison. The intake was estimated to be 74.3 Bq (62.3, 89.3). The corresponding doses are shown in Table 1, which is a result of the Bayesian analysis assuming seven possible wound models. Only the data points unaffected by chelation were used in the analysis (last four data points), which correspond to 263, 271, 278, and 285 d after the incident or to 100, 108, 115, and 122 d after the last chelation therapy. The corresponding normalized 24 h excretions and standard deviations in Bq are (4.19 ⫾ 0.77) ⫻ 10⫺3, (4.60 ⫾ 0.44) ⫻ 10⫺4, (5.42 ⫾ 0.52) ⫻ 10⫺4, and (3.82 ⫾ 0.40) ⫻ 10⫺4. Fig. 1. 239 October 2010, Volume 99, Number 4 Table 1. Estimated committed effective dose [E(50)] and the committed equivalent doses [H(50)] to the most affected body organs for Case 1. Nuclide 239 238 Nuclide 239 239 239 Pu Pu Pu E(50) (mSv) Pu Pu 36 (31, 42) 0.54 (0, 1.09) Organ H(50) (mSv) Bone surface Liver Red marrow 1,208 (1,026, 1,404) 254 (215, 296) 58 (49, 68) Table 2 shows the wound models used and their corresponding posterior probabilities or the fractional contributions of several categories of the wound models to the intake estimate through the Bayesian analysis. The posterior probabilities are evenly distributed amongst a single injection and the most soluble categories of the soluble and of the colloid models, as defined in NCRP Report No. 156 (NCRP 2006). The “soluble avid” and the “particle” categories have very little influence on the final result, which shows, as expected, a predominance of a soluble plutonium. The single injection scenario means that no retention at the wound site occurs. As a result, the analysis shows that about 75% of the contribution comes from a wound with residual activity. The last wound counts after all surgical procedures were done ranged from 198.7 to 373.0 Bq. The inferred mean intake amount of 74.3 Bq differs significantly from the latest wound site measurement result, which was around 450 Bq. However, it must be also taken into account that a total of about 205 Bq were measured in all urine bioassay samples collected during the chelation therapy. Pu activity excreted in urine vs. time after the incident showing the chelation treatment (Case 1). Three plutonium chelation cases ● L. BERTELLI Table 2. Biokinetic models considered and their posterior probabilities for Case 1. Model win wdt wss wsa wta wc1 wp1 Description Injection NCRP wound NCRP wound NCRP wound NCRP wound NCRP wound NCRP wound model model model model model model “soluble” customized “soluble strong” “soluble avid” “colloid” customized “colloid” “particle” Posterior probability 0.254 0.295 0.180 0.019 0.245 0.008 0.00002 Case 2 The individual was working in a glovebox machining Pu metal, lost his grip, and hit a sharp-edged surface within the glovebox, making a shallow laceration on the wrist. Prompt decontamination procedures took place until the external levels were reduced to non-detectable. The first wound count measured 62.9 Bq. After another skin decontamination was done, the wound measurement showed 48.1 Bq. Subsequently 1 g of Ca-DTPA was administered, and after the skin flap was removed a subsequent wound count was performed showing no detectable remaining activity. The excised skin flap contained 44.4 Bq, or essentially all the remaining Pu activity. One bioassay sample was collected before and three more after the chelation therapy. The total calculated averted dose was only 150 ␮Sv. Subsequently, more bioassay samples were collected at 90, 96, and 102 d after the incident, which were used to estimate the committed effective dose, which was only 210 ␮Sv (70, 440). Fig. 2 shows the urinary excretion measurements, including an additional urine sample, which was collected at 280 d after the incident. Fig. 2. 239Pu activity excreted in urine vs. time after the incident (Case 2). ET AL. 535 Case 3 This individual suffered a wound on his right thumb while working in a glovebox. A metallic fragment containing 239Pu became deposited in the wound. Several excisions and four DTPA therapies were used to decontaminate. Twelve urine bioassay samples were submitted and were analyzed for 238Pu using RAS and for 239Pu using both the RAS and the TIMS techniques. These samples have been used to evaluate the efficacy of the decontamination treatment and to estimate the committed effective dose equivalent due to this incident. Fig. 3 shows the measurement results for wound counts, excised tissues, a cotton glove, and the first six urine bioassay measurements, covering the first 10 d after the incident. The four chelation treatments (each with a dosage of 1 g of DTPA), which took place at 0, 1, 5, and 7 d after the incident, are represented by dotted lines. The chelation treatment consisted of injections of 1 g of Ca-DTPA. The text on the right side of the graph shows the estimated averted dose corresponding to each of the first six bioassay samples. A gamma spectrometry analysis was performed on a sample of tissue and material excised from the right thumb. Activities of 39.2 and 6,660 Bq were found for 241 Am and for 239Pu, respectively. The results clearly show that 239Pu was the main radionuclide. A subsequent wound count showed 671.6 Bq for 239Pu. This 7,332 Bq of 239Pu represents the total initial source activity available to become systemic if no countermeasures had been taken. Due mostly to surgical procedures, this value was reduced to only 25.5 Bq in less than 1 d after the incident. Six days later, after all surgical procedures had taken place, the final wound count for 239Pu was only about 18.5 Bq. The 241Am activity was negligible. No other radionuclides were identified as being present. The calculated E(50) and the H(50)s to body organs having values greater than 10 mSv, with the corresponding 5% and 95% Bayesian credible limits, are shown in Table 3. Values for 238Pu are also shown for comparison. Only the data points unaffected by chelation were used in the analysis (last three data points), which correspond to 148, 176, and 185 d after the incident or to 141, 169, and 178 d after the last chelation therapy. The corresponding normalized 24 h excretions and standard deviations in Bq are (1.38 ⫹ 0.06) ⫻ 10⫺3, (1.22 ⫾ 0.05) ⫻ 10⫺3, and (1.80 ⫾ 0.08) ⫻ 10⫺3. The final calculated intake amount was 40.7 Bq, with corresponding 5% and 95% Bayesian credible limits of 15.5 and 55.5 Bq, respectively. This result is consistent with the last wound count result of about 18.5 Bq. As discussed above, the Bayesian analysis considers seven wound models. Table 4 shows the wound models used and their corresponding posterior probabilities. As 536 Health Physics Fig. 3. 239 Pu activity measured in wound, urine and in other relevant samples vs. time after the incident (Case 3). Table 3. Estimated committed effective dose [E(50)] and the committed equivalent doses [H(50)] to the most affected body organs for Case 3. Nuclide 239 238 E(50) (mSv) Pu Pu 18 (8, 26) 0.04 (3.8 ⫻ 10⫺5, 0.22) Nuclide 239 Pu 239 Pu 239 Pu 238 Pu Organ H(50) (mSv) Bone surface Liver Red marrow Bone surface 603 (251, 855) 128 (53, 180) 30 (12, 41) 2 (0, 9) Table 4. Biokinetic models considered and their posterior probabilities for Case 3. Model win wdt wss wsa wta wc1 wp1 October 2010, Volume 99, Number 4 Description Injection NCRP wound NCRP wound NCRP wound NCRP wound NCRP wound NCRP wound model model model model model model “soluble” customized “soluble strong” “soluble avid” “colloid” customized “colloid” “particle” Posterior probability 0.175 0.171 0.166 0.152 0.170 0.136 0.031 observed in Case 1, the posterior probabilities are evenly distributed amongst a single injection and the soluble and colloid categories (NCRP 2006). The particle category shows a contribution of only 3.06% and is practically ruled out. As a result, the analysis shows that about 80% of the contribution comes from a wound with a residual activity. The comparison between the last measured wound counts and the inferred intake amount shows that a somewhat higher inferred activity can be expected since a considerable 239Pu activity amount could have been provided to the systemic organs before the first excision. This corroborates the high agreement found between the calculated intake amount and the last measured wound counts. As explained above, the 239Pu source activity in the wound was reduced from about 7,400 Bq to 25.5 Bq in less than one day after the incident, mostly due to the surgical procedures. In this way, the reduction in the estimated values of the averted doses after the first calculation can be explained by the much reduced availability of 239Pu to be excreted from the body, due to surgeries and chelation. The total estimated averted dose was 11.4 mSv. More details on the results of the averted dose calculations due to individual urinary excretions are shown in the frame of Fig. 3. DISCUSSION Similar to true inhalation cases whose compound solubilities/absorption cannot be exclusively described as a pure Type F, or M, or S but rather as a mixture of solubility types (Bertelli et al. 1998), the probabilistic combination of several wound models from the NCRP 156 family was successfully used to analyze intakes by wounds (NCRP 2006). The behavior of the urinary excretion results after cessation of chelation therapy is presented for all three cases in Fig. 4. This shows the daily urinary excretion normalized to the time of the last chelation. Since Cases 1 and 3 were treated more than once, “negative” time values are shown. The analyses of the data showed that Three plutonium chelation cases ● L. BERTELLI Fig. 4. 239Pu activity excreted in urine vs. time after the last chelation. considerably different intake amounts and corresponding doses were estimated for the three cases. However, in spite of this fact and in spite of the different number of treatments, a difference of four orders of magnitude can be seen between the highest excretion data point and the values observed at about 100 d for all cases. The simulation of a single injection of 239Pu (ICRP 1993) using the AIDE software (Bertelli et al. 2008) showed that the decrease in the daily urinary excretion values between the first and the hundredth day is two orders of magnitude. Hence the extra factor of 100 can be attributed to the efficacy of the chelation, which is normally greatest at early times after the intake. Since in all cases the administered dosages were 1 g of either Zn-DTPA or Ca-DTPA, a correlation with an efficacy factor of 100 could be tentatively established. La Bone (1994) has observed efficacy factor values ranging from 1 to 150, where one means that chelation had no effect. He also recommended an average value of 50 for the initial evaluation of urinary excretion data following an intake of 239Pu. Differences between efficacies of ZnDTPA and Ca-DTPA could not be observed in this study. As shown in Fig. 1, Case 1 included a chelation at 590 d after the incident. The excretion peak is similar to those for chelations at earlier times. The efficacy factor is about 50, which shows that the chelation was still effective more than 1.5 y after the incident. The averted dose due to this chelation can be approximately calculated by multiplying the urinary excretion value of 0.13 Bq by the committed effective dose coefficient due to a single injection of 239Pu, which is 489 ␮Sv Bq⫺1. The resulting averted dose was only about 64 ␮Sv. The International Atomic Energy Agency (IAEA) Technical Report Series Number 184 (Volf 1978) has ET AL. 537 long been recognized as being an excellent reference for chelation treatments. It is stated on page 17 that “For extrapolation of animal data to man, Ca-DTPA doses have been more recently expressed as human dose equivalents (1 HD ⫽ 30 ␮mol kg⫺1 or about 1 g Ca-DTPA per 70 kg of body weight).” This is exactly the recommended dosage by REAC/TS (2002), which was used in the cases described in this paper. However, the same reference states that a 44-wk treatment of rats with little above 3 HD (100 ␮mol kg⫺1) involving both Ca-DTPA and Zn-DTPA twice weekly did not bring any adverse effects in the treated animals or their offspring. Based on these facts, this work suggests that more studies should be carried out to test the efficacy and the toxicity of higher dosages of Zn-DTPA and Ca-DTPA in chelation therapies. Moreover, new chelating agents have been developed and tested throughout the last decades, which have proved to be much more efficient than DTPA. They should be pursued for application to human contamination with transuranic radionuclides as expeditiously as possible (Durbin 2008). In the future, we intend to study older chelation cases associated with intakes of radionuclides by puncture wounds, where sufficient documentation exists. These and the three cases described here will be used to develop and to test procedures for evaluation of intakes of actinides in early phases after the intake, to estimate the efficacy of chelation therapy, and to validate the available chelation models published in the literature (Hall et al. 1978; La Bone 1994; Breustedt et al. 2009). CONCLUSION The study of three wound cases reported in this paper allowed to draw the following conclusions. In spite of the fact that considerably different intake amounts and corresponding doses were estimated for the three cases, and in spite of the different number of treatments, a difference of four orders of magnitude was observed between the highest excretion data point and the values observed at about 100 d for all cases. A decrease of two orders of magnitude in the daily urinary excretion during this time period can be attributed to a regular excretion of plutonium from the body. Hence, the remaining excretion enhancement of two orders of magnitude can be explained by the chelation treatments. Differences between efficacies of Zn-DTPA and Ca-DTPA could not be observed in this study. An efficacy factor of about 50 was observed for a chelation treatment which was administered at about 1.5 y after the incident, though the corresponding averted dose was very small. 538 Health Physics REFERENCES Bertelli L, Puerta A, Wrenn ME, Lipsztein JL, Moody JC, Stradling GN, Hodgson A, Fell TP. 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