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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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.
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.
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 1333 controls. Median positive total alpha lung dose was 2.42mGy (mean8.13mGy; maximum316mGy); for plutonium the median was 1.27mGy and for uranium 2.17mGy. 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.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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.
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.
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.
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