Dose Estimation for a Study of Nuclear Workers in France, the United Kingdom and the United States of America: Methods for the International Nuclear Workers Study (INWORKS).
ABSTRACT: In the framework of the International Nuclear Workers Study conducted in France, the UK and the U.S. (INWORKS), updated and expanded methods were developed to convert recorded doses of ionizing radiation to estimates of organ doses or individual personal dose equivalent [H(p)(10)] for a total number of 308,297 workers, including 40,035 women. This approach accounts for differences in dosimeter response to predominant workplace energy and geometry of exposure and for the recently published ICRP report on dose coefficients for men and women separately. The overall mean annual individual personal dose equivalent, including zero doses, is 1.73 mSv [median = 0.42; interquartile range (IQR): 0.07, 1.59]. Associated individual organ doses were estimated. INWORKS includes workers who had potential for exposure to neutrons. Therefore, we analyzed neutron dosimetry data to identify workers potentially exposed to neutrons. We created a time-varying indicator for each worker, classifying them according to whether they had a positive recorded neutron dose and if so, whether their neutron dose ever exceeded 10% of their total external penetrating radiation dose. The number of workers flagged as being exposed to neutrons was 13% for the full cohort, with 15% of the cohort in France, 12% of the cohort in the UK and 14% in the U.S. We also used available information on in vivo and bioassay monitoring to identify workers with known depositions or suspected internal contaminations. As a result of this work, information is now available that will allow various types of sensitivity analyses.
Project description: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.
Project description: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.
Project description: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.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.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).This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia.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.
Project description:BACKGROUND:There is considerable scientific interest in associations between protracted low-dose exposure to ionizing radiation and the occurrence of specific types of cancer. METHODS:Associations between ionizing radiation and site-specific solid cancer mortality were examined among 308,297 nuclear workers employed in France, the United Kingdom, and the United States. Workers were monitored for external radiation exposure and follow-up encompassed 8.2 million person-years. Radiation-mortality associations were estimated using a maximum-likelihood method and using a Markov chain Monte Carlo method, the latter used to fit a hierarchical regression model to stabilize estimates of association. RESULTS:The analysis included 17,957 deaths attributable to solid cancer, the most common being lung, prostate, and colon cancer. Using a maximum-likelihood method to quantify associations between radiation dose- and site-specific cancer, we obtained positive point estimates for oral, esophagus, stomach, colon, rectum, pancreas, peritoneum, larynx, lung, pleura, bone and connective tissue, skin, ovary, testis, and thyroid cancer; in addition, we obtained negative point estimates for cancer of the liver and gallbladder, prostate, bladder, kidney, and brain. Most of these estimated coefficients exhibited substantial imprecision. Employing a hierarchical model for stabilization had little impact on the estimated associations for the most commonly observed outcomes, but for less frequent cancer types, the stabilized estimates tended to take less extreme values and have greater precision than estimates obtained without such stabilization. CONCLUSIONS:The results provide further evidence regarding associations between low-dose radiation exposure and cancer.
Project description:Bystander effects have been observed repeatedly in mammalian cells following photon and alpha particle irradiation. However, few studies have been performed to investigate bystander effects arising from neutron irradiation. Here we asked whether neutrons also induce a bystander effect in two normal human lymphoblastoid cell lines. These cells were exposed to fast neutrons produced by targeting a near-monoenergetic 50.5 MeV proton beam at a Be target (17 MeV average neutron energy), and irradiated-cell conditioned media (ICCM) was transferred to unirradiated cells. The cytokinesis-block micronucleus assay was used to quantify genetic damage in radiation-naïve cells exposed to ICCM from cultures that received 0 (control), 0.5, 1, 1.5, 2, 3 or 4 Gy neutrons. Cells grown in ICCM from irradiated cells showed no significant increase in the frequencies of micronuclei or nucleoplasmic bridges compared to cells grown in ICCM from sham irradiated cells for either cell line. However, the neutron beam has a photon dose-contamination of 5%, which may modulate a neutron-induced bystander effect. To determine whether these low doses of contaminating photons can induce a bystander effect, cells were irradiated with cobalt-60 at doses equivalent to the percent contamination for each neutron dose. No significant increase in the frequencies of micronuclei or bridges was observed at these doses of photons for either cell line when cultured in ICCM. As expected, high doses of photons induced a clear bystander effect in both cell lines for micronuclei and bridges (p<0.0001). These data indicate that neutrons do not induce a bystander effect in these cells. Finally, neutrons had a relative biological effectiveness of 2.0 ± 0.13 for micronuclei and 5.8 ± 2.9 for bridges compared to cobalt-60. These results may be relevant to radiation therapy with fast neutrons and for regulatory agencies setting standards for neutron radiation protection and safety.
Project description:This is the first study of cataract incidence in a cohort of Mayak Production Association workers first employed at one of the main facilities in 1948-1982 and followed up till the end of 2008 (22,377 workers). Principal advantages of the study are the large size of the cohort, long-term follow-up and sufficient statistical power, available results of annual eye examinations over the entire follow-up period and detailed information on non-radiation confounders. Individual measured doses from external ?-rays and neutrons used in the analyses were provided by the Mayak Worker Dosimetry System 2008 (MWDS-2008). Relative risk (RR) and excess relative risk (ERR) per unit dose (Gy) were calculated based on maximum likelihood using the AMFIT module of the EPICURE software. The RR of cataract incidence was found to be the highest in workers exposed at doses above 2.0 Gy. A significant linear association of cataract incidence with cumulative dose from external ?-rays was found with ERR/Gy equal to 0.28 (95% confidence intervals: 0.20, 0.37). The results obtained varied slightly with inclusion of additional adjustments for non-radiation factors (smoking index, hypertension, glaucoma and body mass index). Adjusting for the dose from neutrons gave a considerable increase in ERR/Gy for cataract incidence.
Project description:The detonation of an improvised nuclear device would produce prompt radiation consisting of both photons (gamma rays) and neutrons. While much effort in recent years has gone into the development of radiation biodosimetry methods suitable for mass triage, the possible effect of neutrons on the endpoints studied has remained largely uninvestigated. We have used a novel neutron irradiator with an energy spectrum based on that 1-1.5 km from the epicenter of the Hiroshima blast to begin examining the effect of neutrons on global gene expression, and the impact this may have on the development of gene expression signatures for radiation biodosimetry. We have exposed peripheral blood from healthy human donors to 0.1, 0.3, 0.5 or 1 Gy of neutrons ex vivo using our neutron irradiator, and compared the transcriptomic response 24 h later to that resulting from sham exposure or exposure to 0.1, 0.3, 0.5, 1, 2 or 4 Gy of photons (X rays). We identified 125 genes that responded significantly to both radiation qualities as a function of dose, with the magnitude of response to neutrons generally being greater than that seen after X-ray exposure. Gene ontology analysis suggested broad involvement of the p53 signaling pathway and general DNA damage response functions across all doses of both radiation qualities. Regulation of immune response and chromatin-related functions were implicated only following the highest doses of neutrons, suggesting a physiological impact of greater DNA damage. We also identified several genes that seem to respond primarily as a function of dose, with less effect of radiation quality. We confirmed this pattern of response by quantitative real-time RT-PCR for BAX, TNFRSF10B, ITLN2 and AEN and suggest that gene expression may provide a means to differentiate between total dose and a neutron component.
Project description:Background: Radiation exposure due to the detonation of an improvised nuclear device remains a major security concern. Radiation from such a device involves a combination of photons and neutrons. Although photons will make the greater contribution to the total dose, neutrons will certainly have an impact on the severity of the exposure as they have high relative biological effectiveness. Results: We investigated the gene expression signatures in the blood of mice exposed to 3 Gy x-rays, 0.75 Gy of neutrons, or to mixed field photon/neutron with the neutron fraction contributing 5%, 15%, or 25% of a total 3 Gy radiation dose. Gene ontology and pathway analysis revealed that genes involved in protein ubiquitination pathways were significantly overrepresented in all radiation doses and qualities. On the other hand, eukaryotic initiation factor 2 (EIF2) signaling pathway was identified as one of the top 10 ranked canonical pathways in neutron, but not pure x-ray, exposures. In addition, the related mTOR and regulation of EIF4/p70S6K pathways were also significantly underrepresented in the exposures with a neutron component, but not in x-ray radiation. The majority of the changed genes in these pathways belonged to the ribosome biogenesis and translation machinery and included several translation initiation factors (e.g. Eif2ak4, Eif3f), as well as 40S and 60S ribosomal subunits (e.g. Rsp19, Rpl19, Rpl27). Many of the differentially downregulated ribosomal genes (e.g. RPS19, RPS28) have been causally associated with human bone marrow failure syndromes and hematologic malignancies. We also observed downregulation of transfer RNA processes, in the neutron-only exposure (p < 0.005). Ingenuity Pathway Analysis (p < 0.05) of differentially expressed genes predicted significantly suppressed activity of the upstream regulators c-Myc and Mycn, transcription factors known to control ribosome biogenesis. Conclusions: We describe the gene expression profile of mouse blood following exposure to mixed field neutron/x-ray irradiation. We have discovered that pathways related to protein translation are significantly underrepresented in the exposures containing a neutron component. Our results highlight the significance of neutron exposures that even the smallest percentage can have profound biological effects that will affect medical management and treatment decisions in case of a radiological emergency. Overall design: Radiation induced gene expression in mouse blood was measured at 7 days after 3 Gy and 0.75 Gy neutron exposure or after 3 Gy mixed-field irradiation of x-rays with neutrons contributing 5%, 15%, and 25% of the total dose. Six independent experiments were performed at each dose and time point.
Project description:Recently an increasing trend in skin cancer rates has been observed in various populations including those exposed to different radiation types. Risk and dose-response following prolonged radiation exposure remain unclear. The present study was aimed to assess skin melanoma (SM) and non-melanoma skin cancer (NMSC) incidence risks in a cohort of workers occupationally exposed to ionizing radiation at low dose rates over prolonged periods. The study cohort included workers of a Russian nuclear production facility, Mayak Production Association (PA), who were first employed in 1948-1982 and followed up till the end of 2013 (the total of 22,377 individuals with 25% of females). Using AMFIT module of EPICURE software, relative risk and excess relative risk per unit dose (RR and ERR/Sv) were calculated. 60 SM and 294 NMSC cases were registered in members of the study cohort. SM and NMSC incidence was dependent on sex, attained age, age at first employment at the enterprise, type of facility, education level and was not dependent on calendar period of first employment, calendar period of diagnosis, duration of employment, smoking and alcohol consumption statuses. The risk of NMSC incidence was found to be significantly increased in workers occupationally exposed to ionizing radiation at cumulative doses above 2.0 Sv (RR = 2.52; 95% CI: 1.60, 3.97) compared to a reference dose category (0-0.05 Sv). NMSC incidence was found to be significantly associated with cumulative external gamma-dose with ERR/Sv of 0.49 (95% CI: 0.22, 0.90) without an adjustment for neutron dose and 0.51 (95% CI: 0.22, 0.93) while adjusted for neutron dose. Results of the analysis did not reveal a significant association of SM incidence with cumulative dose from external gamma-rays with ERR/Sv of 0.22 (95% CI: -0.29, 1.46) not including a neutron dose adjustment and of 0.15 (95% CI: -0.41, 1.31) while adjusted for dose from neutron exposure.
Project description:The detonation of an improvised nuclear device would produce prompt radiation consisting of both photons (gamma-rays) and neutrons. While much effort in recent years has gone into the development of radiation biodosimetry methods suitable for mass triage, the possible effect of neutrons on the endpoints studied has remained largely uninvestigated. We have used a novel neutron irradiator with an energy spectrum based on that 1-1.5 km from the epicenter of the Hiroshima blast to begin examining the effect of neutrons on global gene expression, and the impact this may have on the development of gene expression signatures for radiation biodosimetry. We have exposed peripheral blood from healthy human donors to 0, 0.1, 0.3, 0.5, or 1 Gy of neutrons ex vivo using our neutron irradiator, and compared the transcriptomic response 24 h later to that resulting from exposure to 0.1, 0.3, 0.5, 1, 2 or 4 Gy of photons (x-rays). Overall design: Initially, aliquots of blood were exposed to doses of 0.25, 0.5 or 1 Gy neutrons or 1, 2, or 4 Gy x-rays, or treated as a mock-irradiated control, and RNA was harvested 24 hours later. Six different donors were used in this part of the study. Later, six additional donors were recruited, and their blood was exposed to a lower range of doses: control, 0.1, 0.3, 0.5, or 1 Gy x-rays or neutrons. One each of the 0.5 Gy neutron, 1 Gy x-ra,y and control samples were lost in processing, resulting in a total of 92 samples in the overall study