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.

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.

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.

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.

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].

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.

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.

IMPROVED EMPIRICAL LIKELIHOOD FUNCTION BASED ON NORMALIZATION-DEPENDENT REPLICATE MEASUREMENTS.

Based on $n$ replicate measurements that require known normalization factors and assuming an underlying normal distribution for individual measurements but with unknown standard deviation, a combined likelihood function is derived that takes the form of a Student's $t$-distribution with $\nu = n-1$ degrees of freedom and $t=(\psi -\overline{Y})/s$, where $\psi $ is the true value of the measurement quantity calculated from the forward model, and $\overline{Y}$ and $s$ are average and standard error of the mean obtained from the $n$ measurements defined with weighting proportional to the inverse of the normalization factor squared. Assuming an underlying triangle distribution rather than a normal distribution does not produce a large change for six replicates. Examples of replicate data from an animal study and sequential occupational urine and fecal monitoring are given. The use of the empirical likelihood function in data modeling is discussed.

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.

Uncertainties of Mayak urine data.

A method of parameterising the likelihood functions representing the uncertainty of Mayak plutonium urine bioassay measurements is described. The Poisson-lognormal model is assumed and data from 63 cases (1,087 urine measurements in all) are used to empirically determine the lognormal normalisation uncertainty, given the measurement uncertainties obtained from count quantities. An outlier-insensitive procedure is used to fit the cumulative probability distribution of scaled deviations in order to determine the normalisation uncertainty. The natural logarithm of the geometric standard deviation of the total normalisation uncertainty is found to be 0.34 including a measurement component estimated to be 0.2.

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.

Analytical approximation of exact Poisson-lognormal likelihood functions.

Simple analytical approximations of exact Poisson-lognormal likelihood functions are obtained numerically. The Poisson-lognormal statistical model describes counting measurements with lognormally distributed normalization factors. The analytical expressions for the likelihood function allow maximum likelihood data fitting using nonlinear-least-squares-minimization computer programs. A computer program that converts count data into analytical approximation parameters as described in this note is freely available for downloading from the Los Alamos Bayesian Web site (www.lanl.gov/bayesian).

Variability and uncertainty of biokinetic model parameters: the discrete empirical Bayes approximation.

In the Bayesian approach to internal dosimetry, uncertainty and variability of biokinetic model parameters need to be taken into account. The discrete empirical Bayes approximation replaces integration over biokinetic model parameters by discrete summation in the evaluation of Bayesian posterior averages using Bayes theorem. The discrete choices of parameters are taken as best-fit point determinations of model parameters for a study subpopulation with extensive data. A simple heuristic model is constructed to numerically and theoretically study this approximation. The heuristic example is the measurement of heights of a group of people, say from a photograph where measurement uncertainty is significant. A comparison is made of posterior mean and standard deviation of height after a measurement, (i) using the exact prior describing the distribution of true height in the population and (ii) using the approximate discrete empirical Bayes prior obtained from measurements of some study subpopulation.

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.

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.

Statistical modelling of Poisson/log normal data.

In statistical data fitting, self consistency is checked by examining the closeness of the quantity chi(2)/NDF to 1, where chi(2) is the sum of squares of data minus fit divided by standard deviation, and NDF is the number of data minus the number of fit parameters. In order to calculate chi(2) one needs an expression for the standard deviation. In this note several alternative expressions for the standard deviation of data distributed according to a Poisson/log-normal distribution are proposed and evaluated by Monte Carlo simulation. Two preferred alternatives are identified. The use of replicate data to obtain uncertainty is problematic for a small number of replicates. A method to correct this problem is proposed. The log-normal approximation is good for sufficiently positive data. A modification of the log-normal approximation is proposed, which allows it to be used to test the hypothesis that the true value is zero.

Uranium dose assessment: a Bayesian approach to the problem of dietary background.

Workers are routinely monitored by urinalysis for exposure to uranium at Los Alamos National Laboratory. Urine samples are analysed by alpha spectroscopy for 234U, 235U and 238U. Interpretation of the data is complicated by the presence of natural uranium in the workers' drinking water and diet. Earlier methods used drinking water samples to estimate the dietary component in urine excretion. However, there proved to be insufficient correlation between drinking water concentration and excretion rate. Instead, an iterative calculation is used to identify a typical excretion rate for each individual in the absence of occupational intakes. Bayesian dose-assessment methods, first developed for plutonium bioassay at Los Alamos, have been adapted for uranium. These methods, coupled with an algorithm for identifying each individual's baseline level of uranium from environmental sources, yield improved reliability in the identification of occupational intakes.

Technical basis for using nose swab bioassay data for early internal dose assessment.

One of the challenges to the dose assessment team in response to an inhalation incident in the workplace is to provide the occupational physicians, operational radiation protection personnel and line managers with early estimates of radionuclide intakes so that appropriate consequence management and mitigation can be done. For radionuclides such as Pu, where in vivo counting is not adequately sensitive, other techniques such as the measurement of removable radionuclide from the nasal airway passages can be used. At Los Alamos National Laboratory (LANL), nose swabs of the ET1 region have been used routinely as a first response to airborne Pu releases in the workplace, as well as for other radionuclides. This paper presents the results of analysing over 15 years of nose swab data, comparing these with dose assessments performed using the Bayesian methods developed at LANL. The results provide empirical support for using nose swab data for early dose assessments. For Pu, a rule of thumb is a dose factor of 0.8 mSv Bq(-1), assuming a linear relationship between nasal swab activity and committed effective dose equivalent. However, this value is specific to the methods and models used at LANL, and should not be applied directly without considering possible differences in measurement and calculation methods.

Use of air monitoring and experimental aerosol data for intake assessment for Mayak plutonium workers.

One of the major uncertainties in reconstructing doses to Mayak Plutonium (Pu) workers is the unknown exposure patterns experienced by individuals. These uncertainties include the amounts of Pu inhaled, the temporal exposure pattern of Pu air concentration, the particle-size distribution and solubility of the inhaled aerosols. To date, little individual and workplace-specific information has been used to assess these parameters for the Mayak workforce. However, extensive workplace-specific alpha activity air monitoring data set has been collated, which, if coupled with individual occupational histories, can potentially provide customised intake scenarios for individual Mayak workers. The most available Pu air concentration data are annual averages, which exist for over 100 defined work stations at radiochemical and chemical-metallurgical manufacturing facilities and basically for the whole period of Mayak production operations. Much sparser but more accurate data on Pu concentrations in workers' breathing zone are available for some major workplaces and occupations. The latter demonstrate that within a working shift, Pu concentrations varied over a range of several orders of magnitude depending on the nature of the operations performed. An approach to use the collated data set for individual intake reconstruction is formulated and its practical application is demonstrated. Initial results of ongoing experimental study on historic particle size at Mayak PA and their implications for intake estimation are presented.

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.