Modeling Plutonium Decorporation in a Female Nuclear Worker Treated with Ca-DTPA after Inhalation Intake.

ABSTRACT: The present work models plutonium (Pu) biokinetics in a female former nuclear worker. Her bioassay measurements are available at the US Transuranium and Uranium Registries. The worker was internally exposed to a plutonium-americium mixture via acute inhalation at a nuclear weapons facility. She was medically treated with injections of 1 g Ca-DTPA on days 0, 5, and 14 after the intake. Between days 0 and 20, fecal and urine samples were collected and analyzed for 239Pu and 241Am. Subsequently, she was followed up for bioassay monitoring over 14 y, with additional post-treatment urine samples collected and analyzed for 239Pu. The uniqueness of this dataset is due to the availability of: (1) both early and long-term bioassay data from a female with plutonium intake; (2) data on chelation therapy for a female; and (3) fecal measurement results. Chelation therapy with Ca- and/or Zn-salts of DTPA is known to aid in reducing the internal radiation dose by enhancing the excretion of plutonium and americium from the body. Such enhancement affects plutonium biokinetics in the human body, posing a challenge to the internal dose assessment. The current radiation dose assessment practice is to exclude the data affected by Ca-DTPA from the analysis. The present analysis is the first to explicitly model the chelation-affected bioassay data in a female by using a newly developed chelation model. Thus, the bioassay data collected during and after the Ca-DTPA administrations were used for biokinetic modeling and dose assessment. The Markov Chain Monte Carlo method was used to investigate model parameter uncertainty, based on the bioassay data and assumed prior probability distributions. A χ2/nData (number of data points) ≈ 1 was observed in this study, which indicates self-consistency of the data with the model. Results of this study show that the worker's 239Pu intake was 12 Bq, with a committed effective dose to the whole-body of 1.2 mSv and a committed equivalent dose to the bone surfaces, liver, and lungs of 37.8, 9.1, and 0.8 mSv, respectively. This study also discusses the worker's dose reduction due to chelation treatment.

The ICRP, MELODI, and ALLIANCE workshop on effects of ionizing radiation exposure in offspring and next generations: a summary of discussions.

PURPOSE: Task Group 121 - Effects of ionizing radiation exposure in offspring and next generations - is a task group under the Committee 1 of the International Commission on Radiological Protection (ICRP), approved by the Main Commission on 18th November 2021. The main goals of Task Group 121 are to (1) review and update the scientific literature of relevance to radiation-related effects in the offspring of parent(s) exposed to ionizing radiation in both human and non-human biota; (2) to assess preconceptional and intrauterine effects of radiation exposure and related morbidity and mortality; and, (3) to provide advice about the level of evidence and how to consider these preconceptional and postconceptional effects in the system of radiological protection for humans and non-human biota. METHODS: The Task Group is reviewing relevant literature since Publication 90 'Biological effects after prenatal irradiation (embryo and fetus)' (2003) and will include radiation-related effects on future generations in humans, animals, and plants. This review will be conducted to account for the health effects on offspring and subsequent generations in the current system of radiological protection. Radiation detriment calculation will also be reviewed. Finally, preliminary recommendations will be made to update the integration of health effects in offspring and next generations in the system of radiological protection. RESULTS: A Workshop, jointly organized by ICRP Task Group 121 and European Radiation Protection Research Platforms MELODI and ALLIANCE was held in Budapest, Hungary, from 31st May to 2nd June 2022. Participants discussed four important topics: (1) hereditary and epigenetic effects due to exposure of the germ cell line (preconceptional exposure), (2) effects arising from exposure of the embryo and fetus (intrauterine exposure), (3) transgenerational effects on biota, and (4) its potential impact on the system of radiological protection. CONCLUSIONS: Based on the discussions and presentations during the breakout sessions, newer publications, and gaps on the current scientific literature were identified. For instance, there are some ongoing systematic reviews and radiation epidemiology reviews of intrauterine effects. There are newer methods of Monte Carlo simulation for fetal dosimetry, and advances in radiation genetics, epigenetics, and radiobiology studies. While the current impact of hereditary effects on the global detriment was reported as small, the questions surrounding the effects of radiation exposure on offspring and the next generation are crucial, recurring, and with a major focus on exposed populations. This article summarizes the workshop discussions, presentations, and conclusions of each topic and introduces the special issue of the International Journal of Radiation Biology resulting from the discussions of the meeting.

Effects of ionising radiation exposure in offspring and next generations: dosimetric aspects and uncertainties.

PURPOSE: The impact of the exposure to ionizing radiation in the offspring and next generation has been investigated in the last decades and currently is the subject of study of the ICRP Task Group 121. Studying the effects of radiation exposure in pre-conceptional and post-conceptional phases can be a challenge since potential effects to the fetus vary depending on the stage of fetal development. Epidemiology and radiobiology studies are the two sources of information one can use to correlate the radiation dose to the human body and tissues and the resulting effects. For a proper evaluation of the outcomes of such studies, and a correct appraisal of the exposure/dose-effect relationship, (i) reliable dosimetry, (ii) accurate reporting, and (iii) reproducibility of results are required. Although variables related to dose, including for instance source of radiation, geometry of irradiation, dose rate etc., are usually known, especially in radiobiology studies, often important details of the irradiation are not reported. CONCLUSIONS: Based on standards developed by the National Cancer Institute (NCI), the National Institute of Allergy and Infectious Disease (NIAID) and the National Institute of Standards and Technology (NIST), a review of the scientific studies used by the UNSCEAR to estimate the risk of hereditary effects, and by the ICRP in its current recommendations, was conducted to evaluate the way dosimetry was reported. Dosimetry and the related uncertainties were not adequately described in the vast majority of those studies. This does not necessarily mean that they do not provide relevant information, however it prevents from a thorough verification and reproduction of their findings. In order to guarantee the reliability and robustness of the process of revision of the estimates of risk and detriment it is therefore considered mandatory to include a careful check of the new relevant literature with regard to the criteria on the completeness and reproducibility of the dosimetric information.

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.

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.

Chelation Model Validation: Modeling of a Plutonium-238 Inhalation Incident Treated with DTPA at Los Alamos National Laboratory.

ABSTRACT: Accidental inhalation of plutonium at the workplace is a non-negligible risk, even when rigorous safety standards are in place. The intake and retention of plutonium in the human body may be a source of concern. Thus, if there is a suspicion of a significant intake of plutonium, medical countermeasures such as chelation treatment may be administered to the worker. The present work aimed to interpret the bioassay data of a worker involved in an inhalation incident due to a glovebox breach at Los Alamos National Laboratory's plutonium facility. The worker was treated with intravenous injections of calcium salts of diethylenetriaminepentaacetic acid (DTPA) in an attempt to reduce the amount of plutonium from the body and therefore reduce the internal radiation dose. It is well known in the internal dosimetry field that the administration of chelation treatment poses additional challenges to the dose assessment. Hence, a recently developed chelation model was used for the modeling of the bioassay data. The objectives of this work are to describe the incident, model the chelation-affected and non-affected bioassay data, estimate the plutonium intake, and assess the internal radiation dose.

Use of Nasal Swab Activity to Estimate Intake in Internal Dosimetry.

ABSTRACT: In addition to a review of theoretical analyses, this work presents an empirical study of nasal swab data from the Los Alamos National Laboratory (LANL) database correlated with intake obtained from plutonium internal dosimetry calculations. As a result of this work, several "intake-versus-nasal-swab" models were derived. We advocate quantitative use of nasal swab measurements in dose assessment calculations and discuss ways that this can be done. The best description of the LANL plutonium internal dose database is arguably intake = A + Bx, where A = 2.7 Bq, B = 3.8, and x = summed nasal swab activity. The geometric standard deviation was found to be 8.2. This relationship, obtained using plutonium data, should apply also for other radionuclides.

Dose Assessment Following a 238 Pu Inhalation Incident at Los Alamos National Laboratory.

ABSTRACT: A glovebox breach at the plutonium facility at Los Alamos National Laboratory potentially exposed 15 individuals to 238 Pu aerosols. One of the individuals (P0) received two 1-g intravenous DTPA treatments, one on the day of the intake and another the following day. Several urine samples were collected from the individuals involved in the incident. Particle size analysis on the PPE and solubility analysis of the particles on a filter sample were conducted in vitro. The applicability of the results from the in vitro studies for dose assessment was questionable because of the effect of the cloth mask the workers were wearing for COVID-related protection. Based on several considerations, including the effect of cloth masks on the "effective" particle size inhaled and the analysis of fecal-to-urine ratio, the default Type M 1 µm AMAD model was used to estimate intakes and doses. Using the urinary excretion data collected after 100 d post last chelation treatment, the committed effective dose, E(50), for P0 was calculated to be 5.2 mSv. For all others, the bioassay data were consistent with no intakes or very small intakes [corresponding to E(50) less than 0.1 mSv].

Alternate Analysis of an In Vitro Solubility Study on the Lung Dissolution Rate of 238PuO2 Material Involved in the 2020 Incident at Los Alamos National Laboratory.

ABSTRACT: This work presents an alternate analysis of an in vitro solubility study on the lung dissolution rate of 238PuO2 material involved in a recent inhalation incident at Los Alamos National Laboratory (LANL). The original dataset used in this work was retrieved from a recently published report. The present work shows an analysis of the same dataset by modeling the dissolution in separate time intervals rather than modeling the cumulative dissolution.

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.

Side Effects and Complications Associated with Treating Plutonium Intakes: A Retrospective Review of the Medical Records of LANL Employees Treated for Plutonium Intakes, with Supplementary Interviews.

ABSTRACT: Anecdotal evidence indicates there may be unpublished physical and psychological events associated with the medical treatment of plutonium intakes. A thorough review was conducted of the medical and bioassay records of current and previous Los Alamos National Laboratory (LANL) employees who had experienced plutonium intakes via wound or inhalation. After finding relatively incomplete information in the medical records, the research team interviewed current LANL employees who had undergone chelation therapy and/or surgical excision. Although the dataset is not large enough to reach statistically significant conclusions, it was observed that adverse events associated with treatment appear to be more frequent and more severe than previously reported.

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.

Response to a Skin Puncture Contaminated with 238Pu at Los Alamos National Laboratory.

The three principal pathways for intakes of plutonium are ingestion, inhalation, and contaminated wounds. In August 2018, a glovebox worker at Los Alamos National Laboratory (LANL) sustained a puncture from a thread of a braided steel cable contaminated with Pu. The puncture produced no pain, no blood, and little or no visible mark. As a result, the potential for a contaminated wound was not immediately recognized, and a wound count was not conducted until elevated urine bioassay results were received 12 d after the incident. This paper discusses the circumstances of the incident, along with the medical response and dose assessment, and a discussion of the risks and benefits of the medical interventions.

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.

Validation of a system of models for plutonium decorporation therapy.

A recently proposed system of models for plutonium decorporation (SPD) was developed using data from an individual occupationally exposed to plutonium via a wound [from United States Transuranium and Uranium Registries (USTUR) Case 0212]. The present study evaluated the SPD using chelation treatment data, urine measurements, and post-mortem plutonium activities in the skeleton and liver from USTUR Case 0269. This individual was occupationally exposed to moderately soluble plutonium via inhalation and extensively treated with chelating agents. The SPD was linked to the International Commission on Radiological Protection (ICRP) Publication 66 Human Respiratory Tract Model (HRTM) and the ICRP Publication 30 Gastrointestinal Tract model to evaluate the goodness-of-fit to the urinary excretion data and the predictions of post-mortem plutonium retention in the skeleton and liver. The goodness-of-fit was also evaluated when the SPD was linked to the ICRP Publication 130 HRTM and the ICRP Publication 100 Human Alimentary Tract Model. The present study showed that the proposed SPD was useful for fitting the entire, chelation-affected and non-affected, urine bioassay data, and for predicting the post-mortem plutonium retention in the skeleton and liver at time of death, 38.5 years after the accident. The results of this work are consistent with the conclusion that Ca-EDTA is less effective than Ca-DTPA for enhancing urinary excretion of plutonium.

Evaluating Plutonium Intake and Radiation Dose Following Extensive Chelation Treatment.

A voluntary partial-body donor (US Transuranium and Uranium Registries case 0785) was accidentally exposed to Pu via inhalation and wounds. This individual underwent medical treatment including wound excision and extensive chelation treatment with calcium ethylenediaminetetraacetic acid and calcium diethylenetriaminepentaacetic acid. Approximately 2.2 kBq of Pu was measured in the wound site 44 y after the accident. Major soft tissues and selected bones were collected at autopsy and radiochemically analyzed for Pu, Pu, and Am. Postmortem systemic retention of Pu, Pu, and Am was estimated to be 32.0 ± 1.4 Bq, 2,172 ± 70 Bq, and 394 ± 15 Bq, respectively. Approximately 3% of Pu whole-body activity was still retained in the lungs 51 y after the accident indicating exposure to insoluble plutonium material. To estimate the intake and calculate radiation dose, urine measurements not affected by chelation treatment, in vivo chest counts, and postmortem radiochemical analysis data were simultaneously fitted using Integrated Modules for Bioassay Analysis Professional Plus software. The currently recommended International Commission on Radiological Protection Publication 130 human respiratory tract model and National Council on Radiation Protection and Measurements Report 156 wound model were used with default parameters. The intake, adjusted for Pu removed by chelation treatment, was estimated at approximately 79.5 kBq with 68% resulting from inhalation and 32% from the wound. Inhaled plutonium was predominantly insoluble type S material (74%) with insoluble plutonium fragments deposited in the wound. Only 1.3% reduction in radiation dose was achieved by chelation treatment. The committed effective dose was calculated to be 1.49 Sv. Using urine data available for this case, the effect of chelation therapy was evaluated. Urinary excretion enhancement factors were calculated as 83 ± 52 and 38 ± 17 for initial and delayed calcium ethylenediaminetetraacetic acid treatments, respectively, and as 18 ± 5 for delayed calcium diethylenetriaminepentaacetic acid. The enhancement factor decreases proportionally to an inverse cubic root of time after intake. For delayed calcium ethylenediaminetetraacetic acid treatment, with five consecutive daily administrations, the enhancement factor increased from day 1 to 4, followed by approximately a 50% drop on day 5. The half-time of plutonium ethylenediaminetetraacetic acid complex removal in urine was evaluated to be 1.4 d.

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.

Improved Modeling of Plutonium-DTPA Decorporation.

Individuals with significant intakes of plutonium (Pu) are typically treated with chelating agents, such as the trisodium salt form of calcium diethylenetriaminepentaacetate (CaNa3-DTPA, referred to hereafter as Ca-DTPA). Currently, there is no recommended approach for simultaneously modeling plutonium biokinetics during and after chelation therapy. In this study, an improved modeling system for plutonium decorporation was developed. The system comprises three individual model structures describing, separately, the distinct biokinetic behaviors of systemic plutonium, intravenously injected Ca-DTPA and in vivo-formed Pu-DTPA chelate. The system was linked to ICRP Publication 100, "Human Alimentary Tract Model for Radiological Protection" and NCRP Report 156, Development of a Biokinetic Model for Radionuclide-Contaminated Wounds and Procedures for Their Assessment, Dosimetry and Treatment." Urine bioassay and chelation treatment data from an occupationally-exposed individual were used for model development. Chelation was assumed to occur in the blood, soft tissues, liver and skeleton. The coordinated network for radiation dosimetry approach to decorporation modeling was applied using a chelation constant describing the secondorder, time-dependent kinetics of the in vivo chelation reaction. When using the proposed system of models for plutonium decorporation, a significant improvement of the goodness-of-fit to the urinary excretion data was observed and more accurate predictions of postmortem plutonium retention in the skeleton, liver and wound site were achieved.