The Importance and Quantification of Plutonium Binding in Human Lungs.

Epidemiological studies have shown that the main risk arising from exposure to plutonium aerosols is lung cancer, with other detrimental effects in the bone and liver. A realistic assessment of these risks, in turn, depends on the accuracy of the dosimetric models used to calculate doses in such studies. A state-of-the-art biokinetic model for plutonium, based on the current International Commission on Radiological Protection biokinetic model, has been developed for this purpose in an epidemiological study involving the plutonium exposure of Mayak workers in Ozersk, Russia. One important consequence of this model is that the lung dose is extremely sensitive to the fraction (fb) of plutonium, which becomes bound to lung tissue after it dissolves. It has been shown that if just 1% of the material becomes bound in the bronchial region, this will double the lung dose. Furthermore, fb is very difficult to quantify from experimental measurements. This paper summarizes the work carried out thus far to quantify fb. Bayesian techniques have been used to analyze data from different sources, including both humans and dogs, and the results suggest a small, but nonzero, fraction of < 1%. A Bayesian analysis of 20 Mayak workers exposed to plutonium nitrate suggests an fb between 0 and 0.3%. Based on this work, the International Commission on Radiological Protection is currently considering the adoption of a value of 0.2% for the default bound fraction for all actinides in its forthcoming recommendations on internal dosimetry. In an attempt to corroborate these findings, further experimental work has been carried out by the US Transuranium and Uranium Registries. This work has involved direct measurements of plutonium in the respiratory tract tissues of workers who have been exposed to soluble plutonium nitrate. Without binding, one would not expect to see any activity remaining in the lungs at long times after exposure since it would have been cleared by the natural process of mucociliary clearance. Further supportive study of workers exposed to plutonium oxide is planned. This paper ascertains the extent to which these results corroborate previous inferences concerning the bound fraction.

Risk of Lung Cancer Mortality in Nuclear Workers from Internal Exposure to Alpha Particle-emitting Radionuclides.

BACKGROUND: Carcinogenic risks of internal exposures to alpha-emitters (except radon) are poorly understood. Since exposure to alpha particles-particularly through inhalation-occurs in a range of settings, understanding consequent risks is a public health priority. We aimed to quantify dose-response relationships between lung dose from alpha-emitters and lung cancer in nuclear workers. METHODS: We conducted a case-control study, nested within Belgian, French, and UK cohorts of uranium and plutonium workers. Cases were workers who died from lung cancer; one to three controls were matched to each. Lung doses from alpha-emitters were assessed using bioassay data. We estimated excess odds ratio (OR) of lung cancer per gray (Gy) of lung dose. RESULTS: The study comprised 553 cases and 1,333 controls. Median positive total alpha lung dose was 2.42 mGy (mean: 8.13 mGy; maximum: 316 mGy); for plutonium the median was 1.27 mGy and for uranium 2.17 mGy. Excess OR/Gy (90% confidence interval)-adjusted for external radiation, socioeconomic status, and smoking-was 11 (2.6, 24) for total alpha dose, 50 (17, 106) for plutonium, and 5.3 (-1.9, 18) for uranium. CONCLUSIONS: We found strong evidence for associations between low doses from alpha-emitters and lung cancer risk. The excess OR/Gy was greater for plutonium than uranium, though confidence intervals overlap. Risk estimates were similar to those estimated previously in plutonium workers, and in uranium miners exposed to radon and its progeny. Expressed as risk/equivalent dose in sieverts (Sv), our estimates are somewhat larger than but consistent with those for atomic bomb survivors.See video abstract at, http://links.lww.com/EDE/B232.

Correction of confidence intervals in excess relative risk models using Monte Carlo dosimetry systems with shared errors.

In epidemiological studies, exposures of interest are often measured with uncertainties, which may be independent or correlated. Independent errors can often be characterized relatively easily while correlated measurement errors have shared and hierarchical components that complicate the description of their structure. For some important studies, Monte Carlo dosimetry systems that provide multiple realizations of exposure estimates have been used to represent such complex error structures. While the effects of independent measurement errors on parameter estimation and methods to correct these effects have been studied comprehensively in the epidemiological literature, the literature on the effects of correlated errors, and associated correction methods is much more sparse. In this paper, we implement a novel method that calculates corrected confidence intervals based on the approximate asymptotic distribution of parameter estimates in linear excess relative risk (ERR) models. These models are widely used in survival analysis, particularly in radiation epidemiology. Specifically, for the dose effect estimate of interest (increase in relative risk per unit dose), a mixture distribution consisting of a normal and a lognormal component is applied. This choice of asymptotic approximation guarantees that corrected confidence intervals will always be bounded, a result which does not hold under a normal approximation. A simulation study was conducted to evaluate the proposed method in survival analysis using a realistic ERR model. We used both simulated Monte Carlo dosimetry systems (MCDS) and actual dose histories from the Mayak Worker Dosimetry System 2013, a MCDS for plutonium exposures in the Mayak Worker Cohort. Results show our proposed methods provide much improved coverage probabilities for the dose effect parameter, and noticeable improvements for other model parameters.

THE MAYAK WORKER DOSIMETRY SYSTEM (MWDS-2013): TREATMENT OF UNCERTAINTY IN MODEL PARAMETERS.

Different dose estimates have been produced for the Mayak PA workforce over recent years (DOSES-2000, DOSES-2005, MWDS-2008). The dosimetry system MWDS-2013 described here differs from previous analyses, in that it deals directly with uncertainty in the assumed model parameters. This paper details the way in which uncertainty is dealt with within MWDS-2013 to produce the final output represented by a multiple hyper-realisation of organ doses. More specifically, the paper describes: Application of the WeLMoS method to calculate Bayesian posterior probability distributions of organ doses.Extension of the WeLMoS method for dealing with multiple intake regimes.How shared and unshared parameters are dealt with using a multiple realisation method.A practical algorithm for the generation of multiple hyper-realisations.How to deal with uncertainty in the intake and the intake regime. The resulting multiple hyper-realisation contains all of the information required to take account of model parameter uncertainty and the effects of shared and unshared parameters in any epidemiological analysis, which uses this information, although it is acknowledged that in practice, certain data simplifications may be required to make such analyses tractable, and comparable to previous analyses. Such simplifications are outside the scope of this paper.

The Mayak Worker Dosimetry System (MWDS-2013): Uncertainty in the Measurement of Pu Activity in a 24-Hour Urine Sample of a Typical Mayak PA Worker.

In the Mayak Worker Dosimetry System (MWDS-2013), intakes of plutonium and organ doses are assessed on the basis of measurements made on the plutonium content of 56 400 urine samples. Altogether, there were urine bioassays for 7591 (29%) of the 25 757 cohort members who were employed any time at Mayak between 1948 and 1982. These measurements are subject to uncertainty due to many factors (e.g. whether or not creatinine is measured, the volume of the sample, whether diethylenetriaminepentaacetic acid was administered, etc.) and this uncertainty will affect not only the uncertainty in the estimated doses, but also the values of the doses themselves. Therefore, it is important for the estimated uncertainty to be as accurate as possible. The input to the dose calculation requires an estimate of the plutonium activity in a true 24-hour sample. The uncertainty in this activity is approximated by a lognormal distribution. The aim of this paper is to describe and justify how the parameters of this lognormal distribution are derived from the raw data. Histograms of the distribution of sample volumes are given for both sexes. The method of calculation of the decision threshold and relative standard uncertainty (RSU) of a measurement result for Pu activity in a worker's urine sample is shown. Diagrams of correlation between Pu activity in collected urine and its RSU are given.

Reconstruction of Internal Doses for the Alpha-Risk Case-Control Study of Lung Cancer and Leukaemia Among European Nuclear Workers.

The Alpha-Risk study required the reconstruction of doses to lung and red bone marrow for lung cancer and leukaemia cases and their matched controls from cohorts of nuclear workers in the UK, France and Belgium. The dosimetrists and epidemiologists agreed requirements regarding the bioassay data, biokinetic and dosimetric models and dose assessment software to be used and doses to be reported. The best values to use for uncertainties on the monitoring data, setting of exposure regimes and characteristics of the exposure material, including lung solubility, were the responsibility of the dosimetrist responsible for each cohort. Among 1721 subjects, the median absorbed dose to the lung from alpha radiations was 2.1 mGy, with a maximum dose of 316 mGy. The lung doses calculated reflect the higher levels of exposure seen among workers in the early years of the nuclear industry compared to today.

The Mayak Worker Dosimetry System (MWDS-2013): Plutonium Binding in the Lungs-An Analysis of Mayak Workers.

Estimates of plutonium lung doses from urine bioassay are highly dependent on the rate of absorption from the lungs to blood assumed for the inhaled aerosol. Absorption occurs by dissolution of particles in lung fluid followed by uptake to blood. The latter may occur either rapidly or dissolved ions may first become temporarily bound within airway tissue. The presence of long-term binding can greatly increase lung doses, particularly if it occurs in the bronchial and bronchiolar regions. Analyses of autopsy data from Beagle dogs and USTUR Case 0269, obtained following exposure to plutonium nitrate, suggest that a small fraction of 0.2-1.1 and 0.4-0.7%, respectively, of plutonium becomes permanently bound within the lungs. The present work performs a further analysis using autopsy data of former plutonium workers of the Mayak Production Association to determine values of the bound fraction that are supported by these data. The results suggest a bound fraction value of 0-0.3%. The results also indicate that the Mayak worker population median values of the particle transport clearance parameters from the alveolar-interstitial region are largely consistent with expected values, but suggest the rate from the alveolar region to the interstitium may be lower than initially thought.

The Mayak Worker Dosimetry System (MWDS-2013): Internal Dosimetry Results.

The distribution of calculated internal doses has been determined for 8043 Mayak Production Associate (Mayak PA) workers. This is a subset of the entire cohort of 25 757 workers, for whom monitoring data are available. Statistical characteristics of point estimates of accumulated doses to 17 different tissues and organs and the uncertainty ranges were calculated. Under the MWDS-2013 dosimetry system, the mean accumulated lung dose was 185 ± 594 mGy (geometric mean = 28 mGy; geometric standard deviation = 9.32; median value = 31 mGy; maximum value = 8980 mGy). The ranges of relative standard uncertainty were from 40 to 2200% for accumulated lung dose, from 25-90% to 2600-3000% for accumulated dose to different regions of respiratory tract, from 13-22% to 2300-2500% for systemic organs and tissues. The Mayak PA workers accumulated internal plutonium lung dose is shown to be close to log normal. The accumulated internal plutonium dose to systemic organs was close to a log triangle. The dependency of uncertainty of accumulated absorbed lung and liver doses on the dose estimates itself is also shown. The accumulated absorbed doses to lung, alveolar-interstitial region, liver, bone surface cells and red bone marrow calculated both with MWDS-2013 and MWDS-2008 have been compared. In general, the accumulated lung doses increased by a factor of 1.8 in median value, while the accumulated doses to systemic organs decreased by factor of 1.3-1.4 in median value. For the cases with identical initial data, accumulated lung doses increased by a factor of 2.1 in median value, while accumulated doses to systemic organs decreased by 8-13% in median value. For the cases with both identical initial data and all of plutonium activity in urine measurements above the decision threshold, accumulated lung doses increased by a factor of 2.7 in median value, while accumulated doses to systemic organs increased by 6-12% in median value.

Doses and lung cancer risks from exposure to radon and plutonium.

PURPOSE: Epidemiological studies of the French uranium miners and the plutonium workers at the Mayak nuclear facility have provided excess relative risk (ERR) estimates per unit absorbed lung dose from alpha radiation. The aim of this paper was to review these two studies and to derive values of the relative biological effectiveness (RBE) of alpha particles for the induction of lung cancer. MATERIALS AND METHODS: We examined and compared the dosimetry assumptions and methodology used in the epidemiological studies of uranium miners and the plutonium workers. Values of RBE were obtained by comparing risk coefficients including comparison of lifetime risks for a given population. To do this, preliminary calculations of lifetime risks following inhalation of plutonium were carried out. RESULTS AND CONCLUSIONS: Published values of risk per unit dose following inhalation of radon progeny and plutonium were in agreement despite the very different dose distributions within the lungs and the different ways the doses were calculated. Values of RBE around 10-20 were obtained by comparing ERR values, but with wide uncertainty ranges. Comparing lifetime risks gave similar values (10, 19 and 21). This supports the use of a radiation weighting factor of 20 for alpha particles for radiation protection purposes.

A revised model for the deposition and clearance of inhaled particles in human extra-thoracic airways.

The International Commission on Radiological Protection (ICRP) Task Group that developed the Human Respiratory Tract Model for Radiological Protection (HRTM) identified a lack of published information on aspects of the clearance of inhaled particles deposited in the human nasal passage. Using the results of a recent human volunteer study on the clearance of inhaled particles from the nose, a revised model of clearance from the extra-thoracic (ET) airways has been developed that addresses important issues for which simplifying assumptions had to be made in the ICRP Publication 66 HRTM ET model. This ET clearance model has been adopted by ICRP for inclusion in the revised HRTM. The derivation of the model and parameter values from the experimental data are explained.

Mayak Worker Dosimetry System 2008 (MWDS-2008): assessment of internal dose from measurement results of plutonium activity in urine.

A new modification of the prior human lung compartment plutonium model, Doses-2005, has been described. The modified model was named "Mayak Worker Dosimetry System-2008" (MWDS-2008). In contrast to earlier models developed for workers at the Mayak Production Association (Mayak PA), the new model more correctly describes plutonium biokinetics and metabolism in pulmonary lymph nodes. The MWDS-2008 also provides two sets of doses estimates: one based on bioassay data and the other based on autopsy data, where available. The algorithm of internal dose calculation from autopsy data will be described in a separate paper. Results of comparative analyses of Doses-2005 and MWDS-2008 are provided. Perspectives on the further development of plutonium dosimetry are discussed.

Application of Bayesian inference to the bioassay data from long-term follow-up of two refractory PuO2 inhalation cases.

The dominant contribution to the uncertainty in internal dose assessment can often be explained by the uncertainty in the biokinetic model structure and parameters. The International Commission on Radiological Protection (ICRP) is currently updating its biokinetic models, including the Human Respiratory Tract Model (HRTM). Gregoratto et al. (2010) proposed a physiologically-based particle transport model that simplifies significantly the representation of particle clearance from the alveolar interstitial region. Bayesian inference using the Weighted Likelihood Monte-Carlo Sampling (WeLMoS) method is applied to the bioassay and autopsy data from the U.S. Transuranium and Uranium Registries' (USTUR) tissue donors 0202 and 0407 exposed to "high fired," refractory PuO2 aerosols in order to examine the applicability of the revised model and to estimate the uncertainties in model parameters and the lung doses as expressed by the posterior probability distributions. It is demonstrated that, with appropriate adjustments, the Gregoratto et al. particle transport model can describe situations involving exposure to highly insoluble particles. Significant differences are observed in particle clearance pattern characteristics to these two individuals' respiratory systems. The respiratory tract of registrant 0202 was most likely compromised by his prior occupational exposure to coal dust, smoking habit, and chronic obstructive pulmonary disease, while donor 0407 was a non-smoker and had no prior history of lung disorder. However, the central values of the particle transport parameter posterior distributions for both cases are found to be still within the 68% probability range for the inter-subject variability derived by Gregoratto et al. PuO2 particles produced by the plutonium fire were extremely insoluble, with about 99% absorbed into blood at a rate of approximately 4.8 × 10 d (Case 0202) and 5.1 × 10 d (Case 0202). When considering this type of plutonium material, doses to other body organs are small in comparison to those to tissues of the respiratory tract. More than 95% of the total committed weighted equivalent dose is contributed by the lungs.

Disaggregating measurement uncertainty from population variability and Bayesian treatment of uncensored results.

In making low-level radioactivity measurements of populations, it is commonly observed that a substantial portion of net results is negative. Furthermore, the observed variance of the measurement results arises from a combination of measurement uncertainty and population variability. This paper presents a method for disaggregating measurement uncertainty from population variability to produce a probability density function (PDF) of possibly true results. To do this, simple, justifiable and reasonable assumptions are made about the relationship of the measurements to the measurands (the 'true values'). The measurements are assumed to be unbiased, that is, that their average value is the average of the measurands. Using traditional estimates of each measurement's uncertainty, a likelihood PDF for each individual's measurand is produced. Then using the same assumptions and all the data from the population of individuals, a prior PDF of measurands for the population is produced. The prior PDF is non-negative, and the average is equal to the average of the measurement results for the population. Using Bayes's theorem, posterior PDFs of each individual measurand are calculated. The uncertainty in these bayesian posterior PDFs appears to be all Berkson with no remaining classical component. The method is applied to baseline bioassay data from the Hanford site. The data include (90)Sr urinalysis measurements of 128 people, (137)Cs in vivo measurements of 5337 people and (239)Pu urinalysis measurements of 3270 people. The method produces excellent results for the (90)Sr and (137)Cs measurements, since there are non-zero concentrations of these global fallout radionuclides in people who have not been occupationally exposed. The method does not work for the (239)Pu measurements in non-occupationally exposed people because the population average is essentially zero relative to the sensitivity of the measurement technique. The method is shown to give results similar to classical statistical inference when the measurements have relatively small uncertainty.

Uncertainties on lung doses from inhaled plutonium.

In a recent epidemiological study, Bayesian uncertainties on lung doses have been calculated to determine lung cancer risk from occupational exposures to plutonium. These calculations used a revised version of the Human Respiratory Tract Model (HRTM) published by the ICRP. In addition to the Bayesian analyses, which give probability distributions of doses, point estimates of doses (single estimates without uncertainty) were also provided for that study using the existing HRTM as it is described in ICRP Publication 66; these are to be used in a preliminary analysis of risk. To infer the differences between the point estimates and Bayesian uncertainty analyses, this paper applies the methodology to former workers of the United Kingdom Atomic Energy Authority (UKAEA), who constituted a subset of the study cohort. The resulting probability distributions of lung doses are compared with the point estimates obtained for each worker. It is shown that mean posterior lung doses are around two- to fourfold higher than point estimates and that uncertainties on doses vary over a wide range, greater than two orders of magnitude for some lung tissues. In addition, we demonstrate that uncertainties on the parameter values, rather than the model structure, are largely responsible for these effects. Of these it appears to be the parameters describing absorption from the lungs to blood that have the greatest impact on estimates of lung doses from urine bioassay. Therefore, accurate determination of the chemical form of inhaled plutonium and the absorption parameter values for these materials is important for obtaining reliable estimates of lung doses and hence risk from occupational exposures to plutonium.

Plutonium worker dosimetry.

Epidemiological studies of the relationship between risk and internal exposure to plutonium are clearly reliant on the dose estimates used. The International Commission on Radiological Protection (ICRP) is currently reviewing the latest scientific information available on biokinetic models and dosimetry, and it is likely that a number of changes to the existing models will be recommended. The effect of certain changes, particularly to the ICRP model of the respiratory tract, has been investigated for inhaled forms of (239)Pu and uncertainties have also been assessed. Notable effects of possible changes to respiratory tract model assumptions are (1) a reduction in the absorbed dose to target cells in the airways, if changes under consideration are made to the slow clearing fraction and (2) a doubling of absorbed dose to the alveolar region for insoluble forms, if evidence of longer retention times is taken into account. An important factor influencing doses for moderately soluble forms of (239)Pu is the extent of binding of dissolved plutonium to lung tissues and assumptions regarding the extent of binding in the airways. Uncertainty analyses have been performed with prior distributions chosen for application in epidemiological studies. The resulting distributions for dose per unit intake were lognormal with geometric standard deviations of 2.3 and 2.6 for nitrates and oxides, respectively. The wide ranges were due largely to consideration of results for a range of experimental data for the solubility of different forms of nitrate and oxides. The medians of these distributions were a factor of three times higher than calculated using current default ICRP parameter values. For nitrates, this was due to the assumption of a bound fraction, and for oxides due mainly to the assumption of slower alveolar clearance. This study highlights areas where more research is needed to reduce biokinetic uncertainties, including more accurate determination of particle transport rates and long-term dissolution for plutonium compounds, a re-evaluation of long-term binding of dissolved plutonium, and further consideration of modeling for plutonium absorbed to blood from the lungs.

Comparison of radon lung dosimetry models for the estimation of dose uncertainties.

In order to investigate the degree of dose uncertainty produced by different models, three dosimetry models were compared with each other, representing different classes of models: (i) The RADEP/IMBA model based on the ICRP Human Respiratory Tract Model, a deterministic regional compartment model, (ii) the RADOS model, a deterministic airway generation model and (iii) the IDEAL dosimetry model, a stochastic airway generation model. The outputs of the three models for defined mining exposure conditions were compared at three different levels: deposition fractions for attached and unattached radon progeny; nuclear transformations, reflecting the combined effect of deposition and clearance; and resulting cellular doses. Resulting dose exposure conversion factors ranged from 7.8 (median) mSv/WLM (IDEAL) to 11.8 mSv/WLM (RADEP/IMBA), with 8.3 mSv/WLM (RADOS) as an intermediate value. Despite methodological and computational differences between the three models, resulting dose conversion factors do not appreciably differ from each other, although predictions by the two generation models are consistently smaller than that for the RADEP/IMBA model.

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.

Comparative dosimetry of BEIR VI revisited.

The BEIR VI Committee applied recent developments in the comparative dosimetry of radon exposures in mines and homes to evaluate the so-called K-factor used to extrapolate the excess relative risk of lung cancer determined for underground uranium miners to exposures in homes. This paper describes methodological aspects of these developments that were specified ambiguously in the BEIR VI report. Specifically, in the section dealing with dosimetry (Appendix B of the BEIR VI report), the K-factor was unusually defined in terms of exposure to radon gas (K(gas)), and not in terms of exposure to potential alpha energy (K). An incorrect value of unity was calculated for K(gas). This implies a value of 0.44 for K. In this paper, we describe how application of the ICRP Publication 66 lung and dosimetric models to evaluate the regional lung dose per unit exposure to potential alpha-energy in mines and homes yields the value of K = unity. This confirms the BEIR VI Committee's choice of K = 1 for application in their risk extrapolation model. The paper also reviews the use of doses to specific sub-cellular targets in the evaluation of K. This yields a somewhat greater divergence in the corresponding estimates of K, but again an overall average value of K = unity. The paper describes the methods used to calculate alpha particle hit probabilities for specific subcellular targets, and the resulting estimates of single- and multiple-hit probabilities obtained for exposures in mines and homes, as a function of the respective exposure rates.