Chelation Modeling of a Plutonium-238 Inhalation Incident Treated with Delayed DTPA.

This work describes an analysis, using a previously established chelation model, of the bioassay data collected from a worker who received delayed chelation therapy following a plutonium-238 inhalation. The details of the case have already been described in two publications. The individual was treated with Ca-DTPA via multiple intravenous injections and then nebulizations beginning several months after the intake and continuing for four years. The exact date and circumstances of the intake are unknown. However, interviews with the worker suggested that the intake occurred via inhalation of a soluble plutonium compound. The worker provided daily urine and fecal bioassay samples throughout the chelation treatment protocol, including samples collected before, during, and after the administration of Ca-DTPA. Unlike the previous two publications presenting this case, the current analysis explicitly models the combined biokinetics of the plutonium-DTPA chelate. Using the previously established chelation model, it was possible to fit the data through optimizing only the intake (day and magnitude), solubility, and absorbed fraction of nebulized Ca-DTPA. This work supports the hypothesis that the efficacy of the delayed chelation treatment observed in this case results mainly from chelation of cell-internalized plutonium by Ca-DTPA (intracellular chelation). It also demonstrates the validity of the previously established chelation model. As the bioassay data were modified to ensure data anonymization, the calculation of the "true" committed effective dose was not possible. However, the treatment-induced dose inhibition (in percentage) was calculated.

Modified human respiratory tract model to describe the retention of plutonium in scar tissues.

The Human Respiratory Tract Model described in Publication 130 of the International Commission on Radiological Protection provides some mechanisms to account for retention of material that can be subject to little to no mechanical transport or absorption into the blood. One of these mechanisms is 'binding', which refers to a process by which a fraction ('bound fraction') of the dissolved material chemically binds to the tissue of the airway wall. The value of the bound fraction can have a significant impact on the radiation doses imparted to different parts of the respiratory tract. To properly evaluate-and quantify-bound fraction for an element, one would need information on long-term retention of the element in individual compartments of the respiratory tract. Such data on regional retention of plutonium in the respiratory tract of four workers-who had inhaled materials with solubility ranging from soluble nitrate to very insoluble high-fired oxides-were obtained at the United States Transuranium and Uranium Registries. An assumption of bound fraction alone was found to be inconsistent with this dataset and also with a review of the literature. Several studies show evidence of retention of a large amount of Pu activity in the scar tissues of humans and experimental animals, and accordingly, a model structure with scar-tissue compartments was proposed. The transfer rates to these compartments were determined using Markov Chain Monte Carlo analysis of the bioassay and post-mortem data, considering the uncertainties associated with deposition, dissolution and particle clearance parameters. The models predicted that a significant amount-between 20 and 100% for the cases analyzed-of plutonium retained in the respiratory tract was sequestered in the scar tissues. Unlike chemically-bound Pu that irradiates sensitive epithelial cells, Pu in scar tissues may not be dosimetrically significant because the scar tissues absorb most, if not all, of the energy from alpha emissions.

Effectiveness of Surgical Excision Following Plutonium-contaminated Wounds: Inferences from Historical Cases.

ABSTRACT: As with any medical treatment, the decision to excise a wound contaminated with actinides is a risk-benefit analysis. The potential benefits of surgical excision following such contaminated wounds are reduction in the probability of stochastic effects, avoidance of local effects, and psychological comfort knowing that radioactive material deposited in the wound is prevented from being systemic. These benefits should be balanced against the potential risks such as pain, numbness, infection, and loss of function due to excision. To that end, the responsibility of an internal dosimetrist is to provide advice to both the patient and the treating physician about the likely benefits of excision that include, but not limited to, averted doses. This paper provides a review of the effectiveness of surgical excisions following plutonium-contaminated wounds and finds that excisions are highly effective at removing plutonium from wounds and at averting the doses they would have caused.

Plutonium Systemic Biokinetic Model for Rats.

A baseline compartmental model (relative to modeling decorporation) of the distribution and retention of plutonium (Pu) in the rat for a systemic intake is derived. The model is derived from data obtained from a study designed to evaluate the behavior of plutonium in the first 28 days after incorporation. The model is based on a recently published model of americium (Am) in rats, which incorporated a pharmacokinetic (PK)-front-end modeling approach, which was used to specify transfer to and from the extracellular fluids (ECF) in the various tissues in terms of vascular flow and volumes of ECF. In the americium model, the approach was "cell-membrane limited," meaning that rapid diffusion of americium occurred throughout all the extracellular fluids (i.e., the blood plasma and interstitial fluids), while back-end rates representing transport into and out of the cells were determined empirically. However, this approach was inconsistent with the plutonium dataset. A good fit to the data is obtained by incorporating aspects of the Durbin et al. model structure, with plutonium in plasma separated into "free" and "bound" components. Free plutonium uses a cell-membrane-limited front end as for americium. Bound plutonium uses a capillary-wall-limited front end, where transfer rates from blood plasma into the interstitial fluids are relatively slow, and must be determined either empirically or from a priori knowledge. As in the Durbin et al. model, both free and bound plutonium are available for deposition in bone. In addition, our model has some bound plutonium associated with uptake to the gastrointestinal (GI) tract. Uncertainties in transfer rates were investigated using Markov Chain Monte Carlo (MCMC). It is anticipated that this model structure of plutonium will also be useful in interpreting comparable data from decorporation studies done in experimental animals.

MODELING THE LONG-TERM RETENTION OF PLUTONIUM IN THE HUMAN RESPIRATORY TRACT USING SCAR-TISSUE COMPARTMENTS.

The respiratory tract tissues of four former nuclear workers with plutonium intakes were radiochemically analyzed post mortem by the United States Transuranium and Uranium Registries. Plutonium activities in the upper respiratory tract of these individuals were found to be higher than those predicted using the most recent biokinetic models described in publications of the International Commission on Radiological Protection. Modification of the model parameters, including the bound fraction, was not able to explain the data in one of the four individuals who had inhaled insoluble form of plutonium. Literature review points to the presence of-and a significant retention of-plutonium in the scar tissues of the lungs. Accordingly, an alternate model with scar-tissue compartments corresponding to larynx, bronchi, bronchioles, alveolar-interstitium and thoracic lymph nodes was proposed. The rates of transfer to the scar tissue compartments were determined using Markov Chain Monte Carlo analysis of data on urinary excretion, lung counts and post-mortem measurements of liver, skeleton and individual respiratory tract compartments, as available. The posterior models predicted that 20-100%-depending on the solubility of the material inhaled-of the activities retained in the respiratory tract were sequestered in the scar tissues.

Long-term Retention of Plutonium in the Respiratory Tracts of Two Acutely-exposed Workers: Estimation of Bound Fraction.

ABSTRACT: Inhalation of plutonium is a significant contributor of occupational doses in plutonium production, nuclear fuel reprocessing, and cleanup operations. Accurate assessment of the residence time of plutonium in the lungs is important to properly characterize dose and, consequently, the risk from inhalation of plutonium aerosols. This paper discusses the long-term retention of plutonium in different parts of the respiratory tract of two workers who donated their bodies to the US Transuranium and Uranium Registries. The post-mortem tissue radiochemical analysis results, along with the urine bioassay data, were interpreted using Markov Chain Monte Carlo and the latest biokinetic models presented in the Occupational Intakes of Radionuclides series of ICRP publications. The materials inhaled by both workers were found to have solubility between that of plutonium nitrates and oxides. The long-term solubility was also confirmed by comparison of the activity concentration in the lungs and the thoracic lymph nodes. The data from the two individuals can be explained by assuming a bound fraction (fraction of plutonium deposited in the respiratory tract that becomes bound to lung tissue after dissolution) of 1% and 4%, respectively, without having to significantly alter the particle clearance parameters. Effects of different assumptions about the bound fraction on radiation doses to different target regions was also investigated. For inhalation of soluble materials, an assumption of fb of 1%, compared to the ICRP default of 0.2%, increases the dose to the most sensitive target region of the respiratory tract by 258% and that to the total lung by 116%. Some possible alternate methods of explaining higher-than-expected long-term retention of plutonium in the upper respiratory tract of these individuals-such as physical sequestration of material into the scar tissues and possible uptake by lungs-are also briefly discussed.

Modelling of long-term retention of high-fired plutonium oxide in the human respiratory tract: importance of scar-tissue compartments.

The U.S. Transuranium and Uranium Registries whole-body tissue donor Case 0407 had an acute intake of 'high-fired' plutonium oxide resulting from a glove-box fire in a fabrication plant at a nuclear defence facility. The respiratory tract of this individual was dissected into five regions (larynx, bronchi, bronchioles, alveolar-interstitial, and thoracic lymph nodes) and analysed for plutonium content. The activities in certain compartments of the respiratory tract were found to be higher than expected from the default models described in publications of the International Commission on Radiological Protection. Because of the extremely slow rate of dissolution of the material inhaled, the presence of bound fraction is incapable of explaining the higher-than-expected retention. A plausible hypothesis-encapsulation of plutonium in scar tissues-is supported by the review of literature. Therefore, scar-tissue compartments corresponding to the larynx, bronchi, bronchioles and alveolar-interstitial regions were added to the existing human respiratory tract model structure. The transfer rates between these compartments were determined using Markov Chain Monte Carlo analysis of data on urinary excretion, lung counts and post-mortem measurements of the liver, skeleton and regional retention in the respiratory tract. Modelling of the data showed that approximately 30% of plutonium activity in the lung was sequestered in scar tissues. The dose consequence of such sequestration is qualitatively compared against that of chemical binding.

Dose Assessment Following a 238Pu-contaminated Wound Case with Chelation and Excision.

The urinary excretion and wound retention data collected after a Pu-contaminated wound were analyzed using Markov Chain Monte Carlo (MCMC) to obtain the posterior distribution of the intakes and doses. An empirical approach was used to model the effects of medical treatments (chelation and excision) on the reduction of doses. It was calculated that DTPA enhanced the urinary excretion, on average, by a factor of 17. The empirical analysis also allowed calculation of the efficacies of the medical treatments-excision and chelation averted approximately 76% and 5.5%, respectively, of the doses that would have been if there were no medical treatment. All bioassay data are provided in the appendix for independent analysis and to facilitate the compartmental modeling approaches being developed by the health physics community.

Development of a New Chelation Model: Bioassay Data Interpretation and Dose Assessment after Plutonium Intake via Wound and Treatment with DTPA.

The administration of chelation therapy to treat significant intakes of actinides, such as plutonium, affects the actinide's normal biokinetics. In particular, it enhances the actinide's rate of excretion, such that the standard biokinetic models cannot be applied directly to the chelation-affected bioassay data in order to estimate the intake and assess the radiation dose. The present study proposes a new chelation model that can be applied to the chelation-affected bioassay data after plutonium intake via wound and treatment with DTPA. In the proposed model, chelation is assumed to occur in the blood, liver, and parts of the skeleton. Ten datasets, consisting of measurements of C-DTPA, Pu, and Pu involving humans given radiolabeled DTPA and humans occupationally exposed to plutonium via wound and treated with chelation therapy, were used for model development. The combined dataset consisted of daily and cumulative excretion (urine and feces), wound counts, measurements of excised tissue, blood, and post-mortem tissue analyses of liver and skeleton. The combined data were simultaneously fit using the chelation model linked with a plutonium systemic model, which was linked to an ad hoc wound model. The proposed chelation model was used for dose assessment of the wound cases used in this study.

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 Systemic Biokinetic Model for Rats.

In this work, a baseline compartmental model of the distribution and retention of americium in the rat for a systemic intake was derived. The model was derived from data obtained from a study designed to evaluate the behavior of americium in the first 28 days after incorporation. A pharmacokinetic (PK)-front-end modeling approach was used to specify transfer to and from the extracellular fluids (ECF) in the various tissues in terms of vascular flow and volumes of ECF. Back-end rates representing transport into and out of the cells were determined empirically. Uncertainties in transfer rates were investigated using Markov chain Monte Carlo (MCMC). The combination of PK-front-end model and the back-end model structure used allowed for extrapolation to the earliest times with small uncertainty. This approach clearly demonstrated the rapid transfer of material from ECF to liver and bone. This model provides a baseline for modeling the action of decorporation agents, such as DTPA.

Biokinetics of 238Pu oxides: inferences from bioassay data.

The bioassay data collected from several workers involved in 238Pu inhalation incidents have been analysed using the most recent biokinetic models described in the Occupational Intakes of Radionuclides (OIR) series of publications. Although all exposures were thought to be to 238Pu oxides, the observed urinary excretion patterns differed in different inhalation incidents. The urinary excretion from individuals involved in one of the incidents increased steadily with time, peaking around two to three years before decreasing. This pattern is described in Part 4 of the OIR series using the '238PuO2, ceramic' model. This non-monotonic behaviour, explained as being due to fragmentation and dissolution, was not specific to the incident, but observed in other incidents. The urinary excretion data collected from individuals involved in another incident showed dissolution behaviour between Type M and Type S. Finally, the bioassay data from yet another incident showed a pattern that appears to represent behaviour more insoluble than Type S, which is possibly a result of self-heating due to the decay heat from 238Pu. The urinary excretion patterns and corresponding dose coefficients have been calculated and compared.

Mitigating the Psychological Harm from Actinide Intakes.

Investigations into possible actinide intakes, as well as the intakes themselves, may result in significant psychological harm that should be mitigated by the internal dosimetrist. Many aspects of this psychological impact are unique to actinide intakes and have not been discussed in the literature. This paper discusses some of these unique considerations and describes how the Internal Dosimetry Team at Los Alamos National Laboratory (LANL) has, with input and guidance from LANL psychologists, tried to address them. We feel that much of the psychological harm can be mitigated by educating employees specifically about internal dosimetry and internal doses, and by improving communication with radiation workers.

Some Considerations for Chelation Treatment and Surgical Excision Following Incorporation of Plutonium in Wounds.

After a plutonium-contaminated wound, the role of an internal dosimetrist is to inform the patient and the physician of the dosimetric considerations. The doses averted due to medical treatments (excision or chelation) are higher if the treatments are administered early; therefore, the internal dosimetrist needs to rely on limited information on wound counts and process knowledge for advising the physician. Several wound cases in the literature were reviewed to obtain estimates of the efficacies of surgical excision and chelation treatment after plutonium-contaminated wounds. The dose coefficients calculated by coupling the NCRP 156 wound model with the systemic model were used to derive the decision guidelines that may indicate medical treatment based on 1) the concept of saved doses proposed by the NCRP 156 wound model, 2) the limits recommended by the CEC/DOE guidebook, and 3) the Clinical Decision Guidelines proposed in NCRP Report No. 161. These guidelines by themselves, however, are of limited use for several reasons, including 1) large uncertainties associated with wound measurements, 2) exposure to forms of radionuclides that cannot be assigned to a single category in the NCRP 156 framework, 3) inability of the NCRP 156 model to explain some of the wound cases in the literature, 4) neglect of the local doses to the wound site and the pathophysiological response of the tissue, 5) poorly understood relationship between effective doses and risks of late health effects, and 6) disregard of the psychological aspects of radionuclide intake.

Bayesian Analysis of Plutonium Bioassay Data at Los Alamos National Laboratory.

The main concern of operational internal dosimetry is to detect intakes and estimate doses to the worker from a series of bioassay measurements. Although several methods are available, the inverse problem of internal dosimetry-i.e., determination of time, amount, and types of intake given a set of bioassay data-is well suited to a Bayesian approach. This paper summarizes the Bayesian methodology used at Los Alamos National Laboratory to detect intakes and estimate doses from plutonium bioassay measurements. Some advantages and disadvantages of the method are also discussed. The successful application of Bayesian methods for several years at Los Alamos National Laboratory, which monitors thousands of workers annually for plutonium, indicates that the methods can be extended to other facilities.

Second-order Kinetics of DTPA and Plutonium in Rat Plasma.

In 2008, Serandour et al. reported on their in vitro experiment involving rat plasma samples obtained after an intravenous intake of plutonium citrate. Different amounts of DTPA were added to the plasma samples and the percentage of low-molecular-weight plutonium measured. Only when the DTPA dosage was three orders of magnitude greater than the recommended 30 µmol/kg was 100% of the plutonium apparently in the form of chelate. These data were modeled assuming three competing chemical reactions with other molecules that bind with plutonium. Here, time-dependent second-order kinetics of these reactions are calculated, intended eventually to become part of a complete biokinetic model of DTPA action on actinides in laboratory animals or humans. The probability distribution of the ratio of stability constants for the reactants was calculated using Markov Chain Monte Carlo. These calculations substantiate that the inclusion of more reactions is needed in order to be in agreement with known stability constants.

ANALYSIS OF URINARY EXCRETION DATA FROM THREE PLUTONIUM-CONTAMINATED WOUNDS AT LOS ALAMOS NATIONAL LABORATORY.

The National Council on Radiation Protection (NCRP)-156 Report proposes seven different biokinetic models for wound cases depending on the physicochemistry of the contaminant. Because the models were heavily based on experimental animal data, the authors of the report encouraged application and validation of the models using bioassay data from actual human exposures. Each of the wound models was applied to three plutonium-contaminated wounds, and the models resulted in a good agreement to only one of the cases. We then applied a simpler biokinetic model structure to the bioassay data and showed that fitting the transfer rates from this model structure yielded better agreement with the data than does the best-fitting NCRP-156 model. Because the biokinetics of radioactive material in each wound is different, it is impractical to propose a discrete set of model parameters to describe the biokinetics of radionuclides in all wounds, and thus each wound should be treated empirically.

The Role Of Extracellular Fluid in Biokinetic Modeling.

The pharmacokinetic equations of Pierson et al. describing the behavior of bromide in rat provide a general approach to the modeling of extracellular fluid (ECF). The movement of material into ECF spaces is rapid and is completely characterized by tissue volumes and vascular flow rates to and from a tissue, the volumes of the tissue, and the ECF associated with the tissue. Early-time measurements are needed to characterize ECF. Measurements of DTPA disappearance from plasma by Wedeking et al. are discussed as an example of such measurements. In any biokinetic model, the fastest transfer rates are not determinable with the usual datasets, and if determined empirically, these rates will have very large and highly correlated uncertainties, so particular values of these rates, even though the model fits the available data, are not significant. A pharmacokinetic front-end provides values for these fast rates. An example of such a front-end for a 200-g rat is given.

Application of NCRP 156 Wound Models for the Analysis of Bioassay Data from Plutonium Wound Cases.

The NCRP 156 wound model was heavily based on data from animal experiments. The authors of the report acknowledged this limitation and encouraged validation of the models using data from human wound exposures. The objective of this paper was to apply the NCRP 156 wound models to the bioassay data from four plutonium-contaminated wound cases reported in the literature. Because a wide variety of forms of plutonium can be expected at a nuclear facility, a combination of the wound models-rather than a single model-was used to successfully explain both the urinary excretion data and wound retention data in three cases. The data for the fourth case could not be explained by any combination of the default wound models. While this may possibly be attributed to the existence of a category of plutonium whose solubility and chemistry are different than those described by the NCRP 156 default categories, the differences may also be the result of differences in systemic biokinetics. The concept of using a combination of biokinetic models may be extended to inhalation exposures as well, where more than one form of radionuclide-particles of different solubility or different sizes-may exist in a workplace.

Plasma Retention and Systemic Kinetics of 90Sr Intramuscularly Injected in Female Nonhuman Primates.

Thirteen female Rhesus macaques were intramuscularly injected with Sr(NO3)2 diluted in sodium citrate solution. The biokinetic data from these animals were compared against the predictions of the NCRP 156 wound models combined with the ICRP systemic models. It was observed that the activities measured in plasma of these nonhuman primates (NHPs) were consistently lower than those predicted by the default human biokinetic models. The urinary excretion from the NHPs at times immediately after injection was much greater than that in humans. The fecal excretion rates were found to be in relatively better agreement with humans. Similarly, the activities retained in the skeleton of the NHPs were lower than those in humans. These differences were attributed to the higher calcium diet of the NHPs (0.03 to 0.12 g d kg body weight) compared to that of humans. These observations were consistent with the early animal and human studies that showed the effect of calcium on strontium metabolism, specifically urinary excretion. Strontium is preferentially filtered at a much higher rate in kidneys than calcium because it is less completely bound to protein than is calcium. These differences, along with large inter-animal variability, should be considered when estimating the behavior of strontium in humans from the metabolic data in animals or vice versa.