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.

The polonium-210 poisoning of Mr Alexander Litvinenko.

Mr Litvinenko died on 23 November 2006 after having been poisoned with polonium-210 on 1 November. Measurements of the polonium-210 content of post-mortem tissue samples and samples of urine and blood showed the presence of large amounts of 210Po. Autoradiography of hair samples showed two regions of 210Po activity, providing evidence of an earlier poisoning attempt during October 2006, resulting in absorption to blood of about one-hundredth of that estimated for 1 November. Intake by ingestion on 1 November was estimated to be around 4 GBq, assuming 10% absorption to blood, and the resulting organ doses reached estimated values that were generally in a range from about 20 Gy to over 100 Gy. Comparison with estimates of protracted alpha particle doses required to cause irreversible organ damage supported the conclusion that death was the inevitable consequence of multiple organ failure, with destruction of the haemopoietic bone marrow, as well as damage to kidneys and liver, being important contributors. If the earlier poisoning during October 2006 had not been followed by a second major intake on 1 November, it is possible that the earlier intake of around 40 MBq, with absorption of 4 MBq to blood, might have caused irreversible kidney damage over a prolonged period of months or years, with doses of approaching 3 Gy.

Concerted Uranium Research in Europe (CURE): toward a collaborative project integrating dosimetry, epidemiology and radiobiology to study the effects of occupational uranium exposure.

The potential health impacts of chronic exposures to uranium, as they occur in occupational settings, are not well characterized. Most epidemiological studies have been limited by small sample sizes, and a lack of harmonization of methods used to quantify radiation doses resulting from uranium exposure. Experimental studies have shown that uranium has biological effects, but their implications for human health are not clear. New studies that would combine the strengths of large, well-designed epidemiological datasets with those of state-of-the-art biological methods would help improve the characterization of the biological and health effects of occupational uranium exposure. The aim of the European Commission concerted action CURE (Concerted Uranium Research in Europe) was to develop protocols for such a future collaborative research project, in which dosimetry, epidemiology and biology would be integrated to better characterize the effects of occupational uranium exposure. These protocols were developed from existing European cohorts of workers exposed to uranium together with expertise in epidemiology, biology and dosimetry of CURE partner institutions. The preparatory work of CURE should allow a large scale collaborative project to be launched, in order to better characterize the effects of uranium exposure and more generally of alpha particles and low doses of ionizing radiation.

US Transuranium and Uranium Registries case study on accidental exposure to uranium hexafluoride.

The United States Transuranium and Uranium Registries' (USTUR) whole-body donor (Case 1031) was exposed to an acute inhalation of uranium hexafluoride (UF6) produced from an explosion at a uranium processing plant 65 years prior to his death. The USTUR measurements of tissue samples collected at the autopsy indicated long-term retention of inhaled slightly enriched uranium material (0.85% (235)U) in the deep lungs and thoracic lymph nodes. In the present study, the authors combined the tissue measurement results with historical bioassay data, and analysed them with International Commission on Radiological Protection (ICRP) respiratory tract models and the ICRP Publication 69 systemic model for uranium using maximum likelihood and Bayesian statistical methods. The purpose of the analysis was to estimate intakes and model parameter values that best describe the data, and evaluate their effect on dose assessment. The maximum likelihood analysis, which used the ICRP Publication 66 human respiratory tract model, resulted in a point estimate of 79 mg of uranium for the occupational intake composed of 86% soluble, type F material and 14% insoluble, type S material. For the Bayesian approach, the authors applied the Markov Chain Monte Carlo method, but this time used the revised human respiratory tract model, which is currently being used by ICRP to calculate new dose coefficients for workers. The Bayesian analysis estimated that the mean uranium intake was 160 mg, and calculated the case-specific lung dissolution parameters with their associated uncertainties. The parameters were consistent with the inhaled uranium material being predominantly soluble with a small but significant insoluble component. The 95% posterior range of the rapid dissolution fraction (the fraction of deposited material that is absorbed to blood rapidly) was 0.12 to 0.91 with a median of 0.37. The remaining fraction was absorbed slowly, with a 95% range of 0.000 22 d(-1) to 0.000 36 d(-1) and a median of 0.000 31 d(-1). The effective dose per unit intake calculated using the dissolution parameters derived from the maximum likelihood and the Bayesian analyses was higher than the current ICRP dose coefficient for type F uranium by a factor of 2 or 7, respectively; the higher value of the latter was due to use of the revised respiratory tract model. The dissolution parameter values obtained here may be more appropriate to use for radiation protection purposes when individuals are exposed to a UF6 mixture that contains an insoluble uranium component.

Assessing the reliability of dose coefficients for inhaled and ingested radionuclides.

Consideration of uncertainties on doses can provide numerical estimates of the reliability of the protection quantities (dose coefficients) used in radiation protection to assess exposures to radionuclides that enter the body by ingestion or inhalation ('internal emitters'). Uncertainty analysis methods have been widely applied to quantify uncertainties on doses, including effective dose. However, it is not always clear how the distributions of effective dose per unit intake that result from such analyses should be interpreted with respect to the intended use of effective dose in radiation protection and the use of dose coefficients as reference values. The ICRP system of radiological protection is reviewed briefly and it is argued that the reliability of an effective dose coefficient as a protection device can best be determined by comparing the nominal detriment adjusted cancer risk associated with the dose coefficient, with a best estimate of risk for the exposure pathway and exposed population group, considering uncertainties in biokinetic, dosimetric and risk parameters. Because it is the uncertainty on the population mean of this quantity that is required, the effect of parameter variability should be distinguished from the effect of parameter uncertainty when performing uncertainty analyses. A methodology for performing the uncertainty analysis is discussed and studies that quantify uncertainty on doses and risk from intakes of radionuclides are reviewed.

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.

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): 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.

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.

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.