Building a job-exposure matrix for early plutonium workers at the Sellafield nuclear site, United Kingdom.

The potential for adverse health effects from internal exposure to Plutonium has been recognised since its discovery in the 1940s. However, in the absence of specific information, potential risks from Plutonium exposure have always largely been controlled through knowledge of radiation exposure risks in general, much of which comes from external radiation exposures. To try to obtain more direct estimates of potential internal exposure risks, epidemiological studies of Plutonium workers need to be conducted. Such epidemiological analyses require individual Plutonium exposure estimates that are as accurate and unbiased as possible. The UK Sellafield workforce includes one of the world's largest cohorts of Plutonium workers, which constitutes, by some considerable margin, the group of workers most comprehensively monitored for internal exposure to this alpha-particle-emitter. However, for several hundred workers employed at the start of Plutonium work at the facility, during the period from 1952 through to 1963, the historical urinalysis results available cannot provide sufficiently accurate and unbiased exposure assessments needed for use in epidemiological studies. Consequently, these early workers have had to be excluded from epidemiological analyses and this has significantly reduced the power of these studies. A promising quantitative methodology to overcome the issue of missing or deficient exposure data, is to use exposure data from other sources to estimate the average exposure a 'typical worker' would have received, and to collate this information for specific occupations and years. This approach is called a Job-Exposure Matrix (JEM). Work on a pilot study to construct a population-specific quantitative JEM for the early Plutonium workers at Sellafield during 1952-1963, for whom reliable urinalysis results do not exist, has shown the potential for a JEM approach to produce more reliable and useful exposure estimates for epidemiological research.

Construction, Validation and Sensitivity Analyses of a Job Exposure Matrix for Early Plutonium Workers at the Sellafield Nuclear Site, United Kingdom.

Plutonium is a radiologically significant alpha-particle emitter. The potential for adverse health effects from internal exposures due to plutonium intakes has been recognized since the 1940s. The workforce of the Sellafield nuclear facility (Cumbria, UK), includes one of the world's most important groups of plutonium-exposed workers for studying the potential health risks of this internal exposure. However, for several hundred workers employed at the start of plutonium work at the facility (1952-1963), historical monitoring records based on measurements of urinary excretion of plutonium are not sufficiently reliable to provide the accurate and unbiased exposure assessments needed for epidemiological studies. Consequently, these early workers have had to be excluded from such studies, significantly reducing their power. We constructed a population-specific quantitative job exposure matrix (JEM) to estimate the average intakes of "typical plutonium workers" in this period, from 1952-1963, and assessed its validity and sensitivity to exposure assessment decisions. We conducted internal cross-validation using an a priori 10% extracted sample to evaluate reliability of estimates, explored JEM sensitivity to assumptions in the exposure assessment, and assessed the impact of uncertainty in urinalysis measurements on the precision of annual intake estimates using Markov Chain Monte Carlo (MCMC) methodology. Pairwise correlations ( RP) of estimated (JEM) and measured (10% sample) annual intakes were moderate to high ( RP > 0.4) for 10 out of 13 JEM groups, while absolute differences were <20% for 11 out of 13 JEM groups. There was little evidence of a temporal trend in correlations ( P = 0.13) or absolute differences ( P = 0.34). The median JEM-derived cumulative intake of 95.2 (IQR, 55.0-130.0) Bq was comparable to those based on alternative assumptions in the exposure assessment (median range, 95.2-100.0 Bq; 75th percentiles, 130.0-146.0 Bq). Measurement error simulation resulted in a 40-60% reduced median cumulative intake but higher maximum cumulative intakes. The JEM finds a balance between reliability and precision that makes it useful for epidemiological purposes and is relatively insensitive to specific choices in the exposure assessment. This JEM will allow the inclusion of workers with longest follow-up and who could not be included up until now in epidemiological studies without introducing significant bias.

Mortality from Circulatory Diseases and other Non-Cancer Outcomes among Nuclear Workers in France, the United Kingdom and the United States (INWORKS).

Positive associations between external radiation dose and non-cancer mortality have been found in a number of published studies, primarily of populations exposed to high-dose, high-dose-rate ionizing radiation. The goal of this study was to determine whether external radiation dose was associated with non-cancer mortality in a large pooled cohort of nuclear workers exposed to low-dose radiation accumulated at low dose rates. The cohort comprised 308,297 workers from France, United Kingdom and United States. The average cumulative equivalent dose at a tissue depth of 10 mm [Hp(10)] was 25.2 mSv. In total, 22% of the cohort were deceased by the end of follow-up, with 46,029 deaths attributed to non-cancer outcomes, including 27,848 deaths attributed to circulatory diseases. Poisson regression was used to investigate the relationship between cumulative radiation dose and non-cancer mortality rates. A statistically significant association between radiation dose and all non-cancer causes of death was observed [excess relative risk per sievert (ERR/Sv) = 0.19; 90% CI: 0.07, 0.30]. This was largely driven by the association between radiation dose and mortality due to circulatory diseases (ERR/Sv = 0.22; 90% CI: 0.08, 0.37), with slightly smaller positive, but nonsignificant, point estimates for mortality due to nonmalignant respiratory disease (ERR/Sv = 0.13; 90% CI: -0.17, 0.47) and digestive disease (ERR/Sv = 0.11; 90% CI: -0.36, 0.69). The point estimate for the association between radiation dose and deaths due to external causes of death was nonsignificantly negative (ERR = -0.12; 90% CI: <-0.60, 0.45). Within circulatory disease subtypes, associations with dose were observed for mortality due to cerebrovascular disease (ERR/Sv = 0.50; 90% CI: 0.12, 0.94) and mortality due to ischemic heart disease (ERR/Sv = 0.18; 90% CI: 0.004, 0.36). The estimates of associations between radiation dose and non-cancer mortality are generally consistent with those observed in atomic bomb survivor studies. The findings of this study could be interpreted as providing further evidence that non-cancer disease risks may be increased by external radiation exposure, particularly for ischemic heart disease and cerebrovascular disease. However, heterogeneity in the estimated ERR/Sv was observed, which warrants further investigation. Further follow-up of these cohorts, with the inclusion of internal exposure information and other potential confounders associated with lifestyle factors, may prove informative, as will further work on elucidating the biological mechanisms that might cause these non-cancer effects at low doses.

Examining temporal effects on cancer risk in the international nuclear workers' study.

The paper continues the series of publications from the International Nuclear Workers Study cohort that comprises 308,297 workers from France, the United Kingdom and the United States, providing 8.2 million person-years of observation from a combined follow-up period (at earliest 1944 to at latest 2005). These workers' external radiation exposures were primarily to photons, resulting in an estimated average career absorbed dose to the colon of 17.4 milligray. The association between cumulative ionizing radiation dose and cancer mortality was evaluated in general relative risk models that describe modification of the excess relative risk (ERR) per gray (Gy) by time since exposure and age at exposure. Methods analogous to a nested-case control study using conditional logistic regression of sampled risks sets were used. Outcomes included: all solid cancers, lung cancer, leukemias excluding chronic lymphocytic, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, Hodgkin lymphoma and non-Hodgkin lymphoma. Significant risk heterogeneity was evident in chronic myeloid leukemia with time since exposure, where we observed increased ERR per Gy estimates shortly after exposure (2-10 year) and again later (20-30 years). We observed delayed effects for acute myeloid leukemia although estimates were not statistically significant. Solid cancer excess risk was restricted to exposure at age 35+ years and also diminished for exposure 30 years prior to attained age. Persistent or late effects suggest additional follow-up may inform on lifetime risks. However, cautious interpretation of results is needed due to analytical limitations and a lack of confirmatory results from other studies.

A review of job-exposure matrix methodology for application to workers exposed to radiation from internally deposited plutonium or other radioactive materials.

Any potential health effects of radiation emitted from radionuclides deposited in the bodies of workers exposed to radioactive materials can be directly investigated through epidemiological studies. However, estimates of radionuclide exposure and consequent tissue-specific doses, particularly for early workers for whom monitoring was relatively crude but exposures tended to be highest, can be uncertain, limiting the accuracy of risk estimates. We review the use of job-exposure matrices (JEMs) in peer-reviewed epidemiological and exposure assessment studies of nuclear industry workers exposed to radioactive materials as a method for addressing gaps in exposure data, and discuss methodology and comparability between studies. We identified nine studies of nuclear worker cohorts in France, Russia, the USA and the UK that had incorporated JEMs in their exposure assessments. All these JEMs were study or cohort-specific, and although broadly comparable methodologies were used in their construction, this is insufficient to enable the transfer of any one JEM to another study. Moreover there was often inadequate detail on whether, or how, JEMs were validated. JEMs have become more detailed and more quantitative, and this trend may eventually enable better comparison across, and the pooling of, studies. We conclude that JEMs have been shown to be a valuable exposure assessment methodology for imputation of missing exposure data for nuclear worker cohorts with data not missing at random. The next step forward for direct comparison or pooled analysis of complete cohorts would be the use of transparent and transferable methods.

Risk of cancer from occupational exposure to ionising radiation: retrospective cohort study of workers in France, the United Kingdom, and the United States (INWORKS).

STUDY QUESTION: Is protracted exposure to low doses of ionising radiation associated with an increased risk of solid cancer? METHODS: In this cohort study, 308,297 workers in the nuclear industry from France, the United Kingdom, and the United States with detailed monitoring data for external exposure to ionising radiation were linked to death registries. Excess relative rate per Gy of radiation dose for mortality from cancer was estimated. Follow-up encompassed 8.2 million person years. Of 66,632 known deaths by the end of follow-up, 17,957 were due to solid cancers. STUDY ANSWER AND LIMITATIONS: Results suggest a linear increase in the rate of cancer with increasing radiation exposure. The average cumulative colon dose estimated among exposed workers was 20.9 mGy (median 4.1 mGy). The estimated rate of mortality from all cancers excluding leukaemia increased with cumulative dose by 48% per Gy (90% confidence interval 20% to 79%), lagged by 10 years. Similar associations were seen for mortality from all solid cancers (47% (18% to 79%)), and within each country. The estimated association over the dose range of 0-100 mGy was similar in magnitude to that obtained over the entire dose range but less precise. Smoking and occupational asbestos exposure are potential confounders; however, exclusion of deaths from lung cancer and pleural cancer did not affect the estimated association. Despite substantial efforts to characterise the performance of the radiation dosimeters used, the possibility of measurement error remains. WHAT THIS STUDY ADDS: The study provides a direct estimate of the association between protracted low dose exposure to ionising radiation and solid cancer mortality. Although high dose rate exposures are thought to be more dangerous than low dose rate exposures, the risk per unit of radiation dose for cancer among radiation workers was similar to estimates derived from studies of Japanese atomic bomb survivors. Quantifying the cancer risks associated with protracted radiation exposures can help strengthen the foundation for radiation protection standards. FUNDING, COMPETING INTERESTS, DATA SHARING: Support from the US Centers for Disease Control and Prevention; Ministry of Health, Labour and Welfare of Japan; Institut de Radioprotection et de Sûreté Nucléaire; AREVA; Electricité de France; US National Institute for Occupational Safety and Health; US Department of Energy; and Public Health England. Data are maintained and kept at the International Agency for Research on Cancer.

Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): an international cohort study.

BACKGROUND: There is much uncertainty about the risks of leukaemia and lymphoma after repeated or protracted low-dose radiation exposure typical of occupational, environmental, and diagnostic medical settings. We quantified associations between protracted low-dose radiation exposures and leukaemia, lymphoma, and multiple myeloma mortality among radiation-monitored adults employed in France, the UK, and the USA. METHODS: We assembled a cohort of 308,297 radiation-monitored workers employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France, the Departments of Energy and Defence in the USA, and nuclear industry employers included in the National Registry for Radiation Workers in the UK. The cohort was followed up for a total of 8.22 million person-years. We ascertained deaths caused by leukaemia, lymphoma, and multiple myeloma. We used Poisson regression to quantify associations between estimated red bone marrow absorbed dose and leukaemia and lymphoma mortality. FINDINGS: Doses were accrued at very low rates (mean 1.1 mGy per year, SD 2.6). The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2.96 per Gy (90% CI 1.17-5.21; lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Gy 10.45, 90% CI 4.48-19.65). INTERPRETATION: This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia. FUNDING: Centers for Disease Control and Prevention, Ministry of Health, Labour and Welfare of Japan, Institut de Radioprotection et de Sûreté Nucléaire, AREVA, Electricité de France, National Institute for Occupational Safety and Health, US Department of Energy, US Department of Health and Human Services, University of North Carolina, Public Health England.

Ischemic heart disease in nuclear workers first employed at the Mayak PA in 1948-1972.

Following an earlier study of incidence and mortality of ischemic heart disease (IHD) published in 2010, a second analysis has been conducted based on an extended cohort and five additional years of follow-up. The cohort includes 18,763 workers, of whom 25% were females, first employed at the Mayak PA in 1948-1972 and followed up to the end of 2005. Some of these workers were exposed to external gamma rays only, and others were exposed to a mixture of external gamma-rays and internal alpha-particle radiation. A total of 6,134 cases and 2,629 deaths from IHD were identified in the study cohort. A statistically significant increasing trend was found with total external gamma-ray dose in IHD incidence (ERR/Gy 0.099; 95% CI: 0.045-0.153) after adjusting for non-radiation factors. This value reduced slightly when adjusting for internal liver dose. There was no statistically significant increase trend for internal liver dose in IHD incidence. These findings were consistent with an earlier study. New findings in IHD incidence revealed a statistically significant decrease in IHD incidence among workers exposed to external gamma-rays doses of 0.2-0.5 Gy in relation to the external doses below 0.2 Gy. This decreased risk is heavily influenced by female workers. This finding has never been reported in other studies, and the results should be treated with caution. The findings for IHD mortality are similar to those results in the earlier analysis; there was no statistically significant trend with external gamma-ray dose or for internal liver dose after adjustment for external dose. The risk estimates obtained from these analyses of IHD incidence and mortality in relation to external gamma-rays in the cohort of Mayak workers are generally compatible with those from other large occupational radiation worker studies and the Japanese atomic bomb survivors.

Cerebrovascular diseases in nuclear workers first employed at the Mayak PA in 1948-1972.

Incidence and mortality from cerebrovascular diseases (CVD) (430-438 ICD-9 codes) have been studied in a cohort of 18,763 workers first employed at the Mayak Production Association (Mayak PA) in 1948-1972 and followed up to the end of 2005. Some of the workers were exposed to external gamma-rays only while others were exposed to a mixture of external gamma-rays and internal alpha-particle radiation due to incorporated (239)Pu. After adjusting for non-radiation factors, there were significantly increasing trends in CVD incidence with total absorbed dose from external gamma-rays and total absorbed dose to liver from internal alpha radiation. The CVD incidence was statistically significantly higher among workers with total absorbed external gamma-ray doses greater than 0.20 Gy compared to those exposed to lower doses; the data were consistent with a linear trend in risk with external dose. The CVD incidence was statistically significantly higher among workers with total absorbed internal alpha-radiation doses to liver from incorporated (239)Pu greater than 0.025 Gy compared to those exposed to lower doses. There was no statistically significant trend in CVD mortality risk with either external gamma-ray dose or internal alpha-radiation dose to liver. The risk estimates obtained are generally compatible with those from other large occupational studies, although the incidence data point to higher risk estimates compared to those from the Japanese A-bomb survivors. Further studies of the unique cohort of Mayak workers chronically exposed to external and internal radiation will allow improving the reliability and validating the radiation safety standards for occupational and public exposure.

The "clinic" medical-dosimetric database of Mayak production association workers: structure, characteristics and prospects of utilization.

To study early (deterministic) and long-term effects of radiation exposure, the "Clinic" medical-dosimetric database for the Mayak Production Association worker cohort has been established at the Southern Urals Biophysics Institute (SUBI). This paper describes the principles of organization, structure and prospects of future utilization of this database.