Chelation Modeling: The Use of Ad Hoc Models and Approaches to Overcome a Dose Assessment Challenge.

Chelating agents are administered to treat significant intakes of radioactive elements such as plutonium, americium, and curium. These drugs may be used as a medical countermeasure after radiological accidents and terrorist acts. The administration of a chelating agent, such as Ca-DTPA or Zn-DTPA, affects the actinide's normal biokinetics. It enhances the actinide's rate of excretion, posing a dose assessment challenge. Thus, the standard biokinetic models cannot be directly applied to the chelation-affected bioassay data in order to assess the radiation dose. The present study reviews the scientific literature, from the early 1970s until the present, on the different studies that focused on developing new chelation models and/or modeling of bioassay data affected by chelation treatment. Although scientific progress has been achieved, there is currently no consensus chelation model available, even after almost 50 y of research. This review acknowledges the efforts made by different research groups, highlighting the different methodology used in some of these studies. Finally, this study puts into perspective where we were, where we are, and where we are heading in regards to chelation modeling.

Americium biodistribution in rats after wound contamination with different physicochemical forms in the presence or absence of plutonium: analyses using STATBIODIS.

Americium (Am) biodistribution data obtained after wound contamination in rats were analysed to evaluate and quantify the influence of different physicochemical forms of Am in the presence or absence of plutonium (Pu). The biodistribution data were individual Am daily urinary excretion and tissue retention. The data were analysed with STATBIODIS, a statistical tool developed in the laboratory and based on the R language. Non-parametric methods were selected to comply with the data characteristics. Am systemic tissue retention and urinary excretion data were much greater for contamination with soluble physicochemical forms than insoluble forms. Meanwhile, Am relative biodistribution between the main retention tissues (skeleton, liver and kidney) remained the same. Hence, after absorption into blood the radionuclide behaviour was independent of the physicochemical form. The presence of Pu did not change the Am biodistribution. Comparisons of the biodistribution data from the laboratory with mean values published by other laboratories showed that soluble to moderately soluble forms of Am resulted in similar urine excretion after contamination, whether it was intravenous, intramuscular, subcutaneous injection or incision. Findings from this work will contribute to improve the understanding and interpretation of wound contamination cases with different physicochemical forms and mixtures of actinides including Am.

30-y follow-up of a Pu/Am inhalation case.

In 1983, a young man inhaled accidentally a large amount of plutonium and americium. This case was carefully followed until 2013. Since no decorporation measures had been taken, the undisturbed metabolism of Pu and Am can be derived from the data. First objective was to determine the amount of inhaled radionuclides and to estimate committed effective dose. In vivo and excretion measurements started immediately after the inhalation, and for quality assurance, all types of measurements were performed by different labs in Europe and the USA. After dose assessment by various international groups were completed, the measurements were continued to produce scientific data for model validation. The data have been analysed here to estimate lung absorption parameter values for the inhaled plutonium and americium oxide using the proposed new ICRP Human Respiratory Tract Model. As supplement to the biokinetic modelling, biological data from three different cytogenetic markers have been added. The estimated committed effective dose is in the order of 1 Sv. The subject is 30 y after the inhalation, of good health, according to a recent medical check-up.

Skull counting in late stages after internal contamination by actinides.

Monitoring preparation for internal contamination with actinides (e.g. Pu and Am) is required to assess internal doses at nuclear fuel cycle-related facilities. In this paper, the authors focus on skull counting in case of single-incident inhalation of (241)Am and propose an effective procedure for skull counting with an existing system, taking into account the biokinetic behaviour of (241)Am in the human body. The predicted response of the system to skull counting under a certain counting geometry was found to be only ∼1.0 × 10(-5) cps Bq(-1) 1y after intake. However, this disadvantage could be remedied by repeated measurements of the skull during the late stage of the intake due to the predicted response reaching a plateau at about the 1000th day after exposure and exceeding that in the lung counting. Further studies are needed for the development of a new detection system with higher sensitivity to perform reliable internal dose estimations based on direct measurements.

Whole-body distribution of americium in rats for different pathways of intake.

UNLABELLED: Abstract Purpose: To compare data on the whole-body distribution of americium-241 ((241)Am) in rats following intravenous injection (IV), inhalation, and wound (intramuscular injection, IM). MATERIAL AND METHODS: Following exposure, each rat was placed in an individual metabolism cages for the duration of the study, 28 days (d). Urine and feces were collected daily. Tissues and organs were collected and measured. RESULTS: Liver and skeleton were the main sites of deposition for all routes of exposure but the content differed substantially. By 28 d, (241)Am content in liver was similar for IV and IM administrations (12 ± 4% and 14 ± 5%, respectively), which was 3-fold higher compared to inhalation. Americium-241 content in skeleton was 27% by the end of the IV study; which was 50% higher compared to the IM study and 6-fold higher compared to inhalation. The cumulative excretion in 28 d was 54% for IV (44% by feces and 10% by urine); 38% for IM (34% by feces and 4% by urine); and 84% for inhalation (83% by feces and 1% by urine). CONCLUSION: Unperturbed rat models for the three routes of administration are the baseline for evaluating the efficacy of chelating agents.

Increased retention of americium in kidneys as compared with plutonium in an actinide wound contamination model in the rat.

PURPOSE: Americium-241 ((241)Am) presents a potential risk for nuclear industry workers associated with reactor decommissioning and aging combustible materials. The purpose of this study was to investigate Am renal retention after actinide contamination by wounding in the rat. MATERIALS AND METHODS: Anesthetized rats were contaminated with Mixed Oxide (MOX) (7.1% Plutonium [Pu] by mass and containing 27% Am as % total alpha activity), Pu or Am nitrate following an incision wound of the hind leg. Times of euthanasia ranged from 2 hours to 5 months after contamination. Pu and Am levels were quantified following radiochemistry and alpha-spectrophotometry. RESULTS: Initial data show that over the experimental period the proportion of Am in kidneys as a fraction of total kidney alpha activity was elevated as compared to MOX powder indicating a specific retention in this organ. The percentage of Pu was similar to the powder. After MOX contamination, kidney to liver ratios appeared to increase more markedly for Am (from 0.2 at 7 days to 0.6 at 90 days) as compared with Pu (0.1 at 7 days to 0.2 at 90 days). In accordance with tissue actinide retention the dose from Am to the kidney increases with time. For comparison, the ratio of estimated equivalent doses due to Am to kidney is 1.5-fold greater than for Pu (around 90 versus 60 mSv). CONCLUSION: After actinide contamination of wounds, Am is concentrated in the kidneys as compared to Pu leading to potential exposure of renal tissue to both alpha particles and gamma radiation.

Absorption of americium compounds in the respiratory tract.

PURPOSE: To improve the dosimetry of incorporated americium (Am) and to contribute to radiation protection by characterizing the absorption kinetics of inhaled Am compounds. MATERIAL AND METHODS: In vitro dissolution tests, animal experiments and human contamination cases published in the literature were reviewed. The data were analyzed with biokinetic models consistent with the current publications of the International Commission on Radiological Protection. RESULTS: Material-specific dissolution parameter values with consequent assignment to absorption Types are proposed as well as representative central values for the different chemical forms of Am. CONCLUSIONS: The absorption of Am oxide is consistent with the moderate absorption Type M while Am nitrate appears more soluble. Am associated with plutonium oxide usually follows its slow absorption Type S. However, the large variability observed stresses the value of investigating the specific absorption kinetics for Am compounds which represent a significant risk of internal exposure.

Uncertainty analysis of doses from ingestion of plutonium and americium.

Uncertainty analyses have been performed on the biokinetic model for americium currently used by the International Commission on Radiological Protection (ICRP), and the model for plutonium recently derived by Leggett, considering acute intakes by ingestion by adult members of the public. The analyses calculated distributions of doses per unit intake. Those parameters having the greatest impact on prospective doses were identified by sensitivity analysis; the most important were the fraction absorbed from the alimentary tract, f(1), and rates of uptake from blood to bone surfaces. Probability distributions were selected based on the observed distribution of plutonium and americium in human subjects where possible; the distributions for f(1) reflected uncertainty on the average value of this parameter for non-specified plutonium and americium compounds ingested by adult members of the public. The calculated distributions of effective doses for ingested (239)Pu and (241)Am were well described by log-normal distributions, with doses varying by around a factor of 3 above and below the central values; the distributions contain the current ICRP Publication 67 dose coefficients for ingestion of (239)Pu and (241)Am by adult members of the public. Uncertainty on f(1) values had the greatest impact on doses, particularly effective dose. It is concluded that: (1) more precise data on f(1) values would have a greater effect in reducing uncertainties on doses from ingested (239)Pu and (241)Am, than reducing uncertainty on other model parameter values and (2) the results support the dose coefficients (Sv Bq(-1) intake) derived by ICRP for ingestion of (239)Pu and (241)Am by adult members of the public.

Twenty-four years of follow-up for a Hanford plutonium wound case.

A 1985 plutonium puncture wound resulted in the initial deposition of 48 kBq of transuranic alpha activity, primarily 239+240Pu and 241Am, in a worker's right index finger. Surgical excisions in the week following reduced the long-term residual wound activity to 5.4 kBq, and 164 DTPA chelation therapy administrations over 17 mo resulted in urinary excretion of about 7 kBq. The case was published in 1988, but now 24 y of follow-up data are available. Annual bioassays have included in-vivo measurements of 241Am in the wound, skeleton, liver, lung, and axillary lymph nodes, and urinalyses for plutonium and 241Am. These measurements have shown relatively stable levels of 241Am at the wound site, with gradually increasing amounts of 241Am detected in the skeleton. Liver measurements have shown erratic detection of 241Am, and the lung measurements indicate Am but as interference from activity in the axillary lymph nodes and skeleton rather than activity in the lung. Urine excretion of Pu since termination of chelation therapy has typically ranged from 10 to 20 mBq d, with Am excretion about 10% of that for 239+240Pu. Annual routine medical exams have not identified any adverse health effects associated with the intake.

Structure of a single model to describe plutonium and americium decorporation by DTPA treatments.

The aim of this study is to propose a single modeling structure to describe both plutonium and americium decorporation by DTPA, which is based on hypotheses mostly validated by experimental data. Decorporation efficacy of extracellular retention depends on the concentration ratio of DTPA vs. actinides and varies in each compartment according to the amount of biological ligands and their affinity for actinides. By contrast, because the relatively long residence time of DTPA after its cell internalization and the stability of actinide-DTPA complexes, intracellular decorporation efficacy is mainly controlled by a DTPA/actinide ratio, which is specific to each retention compartment. Although the affinity of DTPA is much lower for americium than for plutonium, a larger decorporation of americium can be obtained, which is explained by different biological ligands and/or their affinity for the actinide. Altogether, these results show that the relative contribution of intra vs. extracellular decorporation varies depending on the actinide, the chemical form of radionuclides, the galenic formulation of DTPA, and the treatment schedule.

A case of wound intake of plutonium isotopes and 241Am in a human: application and improvement of the NCRP wound model.

Plutonium isotopes (239Pu and 238Pu, and 241Am) with a total activity of 269 kBq were accidentally deposited in a puncture wound of the right index finger of a nuclear worker at the Mayak Production Association. Tissues surrounding the wound site contaminated with radionuclides were excised 4.5 h after the injury. Residual contamination within the wound amounted to 0.05% of the initial contamination. The 10-d therapy with CaNa3-diethylene triamine pentaacetate acid (CaNa3-DTPA) was performed in parallel with in vivo measurements of the wound site and daily urine bioassays. The wound intake of radionuclides was consistent with two forms of radioactive materials detected within the wound site, i.e., soluble compounds and a large fragment, which was completely removed by excision. On day 9 after the injury, the clearance rate from the wound site was 1.8 times higher than the rate predicted by the National Council on Radiation Protection and Measurements (NCRP) model for soluble compounds of plutonium and americium. The NCRP model parameters of transfer rates from the colloid and intermediate state (CIS) into soluble, and particles, aggregates and bound state (PABS) compartments were modified to eliminate any difference. As a result, a difference between the observed wound site radionuclide content and the value predicted by the modified wound model did not exceed 14% up to 9 days after the injury. For a longer period from 7 to 24 months, the value predicted by the modified model was consistent with results of the corresponding in vivo measurements. The treatment reduced the effective dose (50 years) from internal exposure by at least 480 times. The dose estimated (without accounting for a contribution of exposure dose to the regional lymph nodes draining the wound site) did not exceed 11 mSv.

Case study: three acute 241Am inhalation exposures with DTPA therapy.

Three workers incurred inhalation exposures to Am oxide as a result of waste sorting and compaction activities. The exposure magnitudes were not fully recognized until the following day when an in-vivo lung count identified a significant lung deposition of Am in a male worker, and DTPA chelation therapy was initiated. Two additional workers (one female and one male) were then identified as sufficiently exposed to also warrant therapy. In-vivo bioassay measurements were performed over the ensuing 6 mo to quantify the 241Am activity in the lungs, liver, and skeleton. Urine and fecal samples were collected and showed readily detectable 241Am. Clinical lab tests and medical evaluations all showed normal results. There were no significant adverse clinical health effects from the therapy. The estimated 241Am inhalation intakes for the three workers were 1,800 Bq, 630 Bq, and 150 Bq. Lung retention showed somewhat longer pulmonary clearance half-times than standard inhalation class W or absorption Type M assumptions. The three subjects underwent slightly different therapy regimens, with therapy effectiveness factors (defined as the ratio of the reference doses without therapy relative to the final assessed doses) of 4.5, 1.9, and 1.7, respectively.

Isotopic and elemental composition of plutonium/americium oxides influence pulmonary and extra-pulmonary distribution after inhalation in rats.

The biodistribution of plutonium and americium has been studied in a rat model after inhalation of two PuO(2) powders in lungs and extra-pulmonary organs from 3 d to 3 mo. The main difference between the two powders was the content of americium (approximately 46% and 4.5% of total alpha activity). The PuO(2) with a higher proportion of americium shows an accelerated transfer of activity from lungs to blood as compared to PuO(2) with the lower americium content, illustrated by increased urinary excretion and higher bone and liver actinide retention. The total alpha activity measured reflects mostly the americium biological behavior. The activity contained in epithelial lining fluid, recovered in the acellular phase of broncho-alveolar lavages, mainly contains americium, whereas plutonium remains trapped in macrophages. Epithelial lining fluid could represent a transitional pulmonary compartment prior to translocation of actinides to the blood and subsequent deposition in extra-pulmonary retention organs. In addition, differential behaviors of plutonium and americium are also observed between the PuO(2) powders with a higher dissolution rate for both plutonium and americium being obtained for the PuO(2) with the highest americium content. Our results indicate that the biological behavior of plutonium and americium after translocation into blood differ two-fold: (1) for the two actinides for the same PuO(2) aerosol, and (2) for the same actinide from the two different aerosols. These results highlight the importance of considering the specific behavior of each contaminant after accidental pulmonary intake when assessing extra-pulmonary deposits from the level of activity excreted in urine or for therapeutic strategy decisions.

Preferential decorporation of americium by pulmonary administration of DTPA dry powder after inhalation of aged PuO(2) containing americium in rats.

After inhalation of plutonium oxides containing various percentages of americium in rats, we identified an acellular transient pulmonary compartment, the epithelial lining fluid (ELF), in which a fraction of actinide oxides dissolve prior to absorption and subsequent extrapulmonary deposit. Chelation therapy is usually considered to be poorly efficient after inhalation of actinide oxides. However, in the present study, prompt pulmonary administration of diethylenetraminepentaacetic acid (DTPA) as a dry powder led to a decrease in actinide content in ELF together with a limitation of bone and liver deposits. Because americium is more soluble than plutonium, higher amounts of americium were found in ELF, extrapulmonary tissues and urine. Our results also demonstrated that the higher efficacy of DTPA on americium compared to plutonium in ELF induced a preferential inhibition of extrapulmonary deposit and a greater urinary excretion of americium compared to plutonium. All together, our data justify the use of an early and local DTPA treatment after inhalation of plutonium oxide aerosols in which americium can be in high proportion such as in aged compounds.

The biokinetics and radiotoxicology of curium: a comparison with americium.

The human and animal data on the biokinetics of (242)Cm and (244)Cm are reviewed and shown to be very similar to those for (241)Am. Liver and skeleton are the main organs of deposition and the retention of curium in the skeleton is very prolonged in all the species examined. Retention of both curium and americium in the liver appears to be species-dependent, being relatively rapidly removed from the liver of rats, and probably humans, but being tenaciously retained in dogs and some other species. The radiotoxicity of curium is also reviewed and it is shown that, as with (241)Am, lung and bone tumour induction are the major hazards from inhaled and systemically deposited (244)Cm. The use of chelating agents for the treatment of accidental contamination of the human body with (242,244)Cm is also discussed.

Discussion of 241Am role as the factor of internal radiation exposure in Mayak PA workers.

Radiation monitoring with whole body counter (WBC) has a series of advantages, as this technique is efficient and is considerably cheaper than indirect urine bioassay method. Experience of WBC operation in the system of Mayak PA worker internal radiation monitoring as well as qualitative analysis of the obtained results is considered. The groups of workers under study are described, and a brief analysis of data obtained in comparison with individual exposure parameters is presented. The number of individuals with 241Am is higher among the workers employed in the early years of Mayak PA operation. Fraction of 241Am in total body burden relative to sum of actinides is higher for workers who started to work in conditions of exposure in the last decade (1990-2000) and sometimes is as high as 25%.

Worldwide bioassay data resources for plutonium/americium internal dosimetry studies.

Biokinetic models are the scientific underpinning of internal dosimetry and depend, ultimately, for their scientific validation on comparisons with human bioassay data. Three significant plutonium/americium bioassay databases, known to the authors, are described: (1) Sellafield, (2) Los Alamos and (3) the United States Transuranium Registry. A case is made for a uniform standard for database format, and the XML standard is discussed.

A step-by-step procedure to aid the assessment of intake and doses from measurement data.

The interpretation of bioassay data to assess intakes and doses depends not only on the biokinetic model used but also on the choice of parameter values made by the assessor. Therefore, it is understandable that different assessors will draw different conclusions from the same datasets even if the same models are used. A systematic step-by-step procedure is proposed for the assessment of cases with comprehensive data in which the time of intake is known. The aims are to promote harmonisation of dose assessments and to assist in obtaining the best available assessment of intake and dose from the monitoring data. The procedure is illustrated by means of an example reported recently in the literature. The case which involves a 6 y follow-up of a subject who inhaled (241)Am, is somewhat unusual in that there are comprehensive in vivo measurements, but few excretion data. The rate at which activity is absorbed from lungs to blood can be one of the largest sources of uncertainty in any inhalation assessment, and significantly improved fits to the measurement data were obtained by choosing appropriate values for the relevant parameters. 'The best estimate' of the resulting effective dose in this case was higher by a factor of approximately 2 or 3, respectively, than those obtained assuming ICRP default values for Type M or Type S.

Soil-plant transfer of plutonium and americium in contaminated regions of Belarus after the Chernobyl catastrophe.

Experimental data are presented for the soil to plant transfer of plutonium and americium into the main species of grass vegetation of Belarusian grasslands contaminated as a result of the Chernobyl catastrophe of 1986. The content of radionuclides in pore soil solutions and the total reserve of biologically available forms of plutonium and americium in rooting layers of different soil varieties have been established. The distribution coefficients of (239,240)Pu and 241Am between the solid phase and pore waters of soils have been evaluated. The migration ability and biological availability of radionuclides in soils with different structures of the absorbing complex have been analyzed for various landscape conditions. The dependence of soil to plant transfer of plutonium and americium on the content and composition of organic matter, and other characteristics of the soil complex has been studied. On the basis of these data, predictions of the contamination levels of the main grass species of natural and agricultural ecosystems by 241Am are presented.

Validation of ICRP metabolic models for the transuranics in a Japanese population.

Distributions of (239,240)Pu and 241Am in the tissues of Japanese were determined and then compared to those estimated using recent ICRP metabolic models. Intakes by inhalation and ingestion were calculated and used as input to the ICRP-30 model or a combination of the ICRP-66 lung model and the ICRP-67 metabolic model. The (239,240)Pu distribution in the lung, liver, skeleton, kidney, and muscle using the combination ICRP-66 and 67 models agreed well with the measured data. However, the measured plutonium concentration in the spleen was higher than predicted and than found in the kidney or muscle and indicates that the spleen should be treated as a separate organ in the ICRP model. The fractional uptake via ingestion of (239,240)Pu was estimated to be 11% with 5 x 10(-4) as the f1 value. The combination of ICRP-66 and 67 models were adequate descriptors of the organ burdens of 241Am measured in Akita and Niigata district populations. The 241Am ingrowth from 241Pu taken into in the human body contributes 90% of the measured burden.