Mary K. Schubauer-Berigan

The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: Estimates of radiation-related cancer risks

Abstract Cardis, E., Vrijheid, M., Blettner, M., Gilbert, E., Hakama, M., Hill, C., Howe, G., Kaldor, J., Muirhead, C. R., Schubauer-Berigan, M., Yoshimura, T., Bermann, F., Cowper, G., Fix, J., Hacker, C., Heinmiller, B., Marshall, M., Thierry-Chef, I., Utterback, D., Ahn, Y-O., Amoros, E., Ashmore, P., Auvinen, A., Bae, J-M., Bernar, J. S., Biau, A., Combalot, E., Deboodt, P., Diez Sacristan, A., Eklöf, M., Engels, H., Engholm, G., Gulis, G., Habib, R. R., Holan, K., Hyvonen, H., Kerekes, A., Kurtinaitis, J., Malker, H., Martuzzi, M., Mastauskas, A., Monnet, A., Moser, M., Pearce, M. S., Richardson, D. B., Rodriguez-Artalejo, F., Rogel, A., Tardy, H., Telle-Lamberton, M., Turai, I., Usel, M. and Veress, K. The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: Estimates of Radiation-Related Cancer Risks. Radiat. Res. 167, 396– 416 (2007). A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI <0, 20.6; 83 deaths) and ill-defined and secondary cancers (ERR/Sv 1.96, 90% CI −0.26, 5.90; 328 deaths). Stratification on duration of employment had a large effect on the ERR/Sv, reflecting a strong healthy worker survivor effect in these cohorts. This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date. Further studies will be important to better assess the role of tobacco and other occupational exposures in our risk estimates.

Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries

Abstract Objectives To provide direct estimates of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures. Design Multinational retrospective cohort study of cancer mortality. Setting Cohorts of workers in the nuclear industry in 15 countries. Participants 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years. Main outcome measurements Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities. Results The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation. Conclusions These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study.

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

Summary 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.

The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: Design, epidemiological methods and descriptive results

Abstract Vrijheid, M., Cardis, E., Blettner, M., Gilbert, E., Hakama, M., Hill, C., Howe, G., Kaldor, J., Muirhead, C. R., Schubauer-Berigan, M., Yoshimura, T., Ahn, Y-O., Ashmore, P., Auvinen, A., Bae, J-M., Engels, H., Gulis, G., Habib, R., Hosoda, Y., Kurtinaitis, J., Malker H., Moser, M., Rodriguez-Artalejo, F., Rogel, A., Tardy, H., Telle-Lamberton, M., Turai, I., Usel, M. and Veress, K. The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: Design, Epidemiological Methods and Descriptive Results. Radiat. Res. 167, 361–379 (2007). Radiation protection standards are based mainly on risk estimates from studies of atomic bomb survivors in Japan. The validity of extrapolations from the relatively high-dose acute exposures in this population to the low-dose, protracted or fractionated environmental and occupational exposures of primary public health concern has long been the subject of controversy. A collaborative retrospective cohort study was conducted to provide direct estimates of cancer risk after low-dose protracted exposures. The study included nearly 600,000 workers employed in 154 facilities in 15 countries. This paper describes the design, methods and results of descriptive analyses of the study. The main analyses included 407,391 nuclear industry workers employed for at least 1 year in a participating facility who were monitored individually for external radiation exposure and whose doses resulted predominantly from exposure to higher-energy photon radiation. The total duration of follow-up was 5,192,710 person-years. There were 24,158 deaths from all causes, including 6,734 deaths from cancer. The total collective dose was 7,892 Sv. The overall average cumulative recorded dose was 19.4 mSv. A strong healthy worker effect was observed in most countries. This study provides the largest body of direct evidence to date on the effects of low-dose protracted exposures to external photon radiation.

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.

Occupational Exposure Assessment in Carbon Nanotube and Nanofiber Primary and Secondary Manufacturers: Mobile Direct-Reading Sampling

UNLABELLED RESEARCH SIGNIFICANCE: Toxicological evidence suggests the potential for a wide range of health effects from exposure to carbon nanotubes (CNTs) and carbon nanofibers (CNFs). To date, there has been much focus on the use of direct-reading instruments (DRIs) to assess multiple airborne exposure metrics for potential exposures to CNTs and CNFs due to their ease of use and ability to provide instantaneous results. Still, uncertainty exists in the usefulness and interpretation of the data. To address this gap, air-monitoring was conducted at six sites identified as CNT and CNF manufacturers or users and results were compared with filter-based metrics. METHODS Particle number, respirable mass, and active surface area concentrations were monitored with a condensation particle counter, a photometer, and a diffusion charger, respectively. The instruments were placed on a mobile cart and used as area monitors in parallel with filter-based elemental carbon (EC) and electron microscopy samples. Repeat samples were collected on consecutive days, when possible, during the same processes. All instruments in this study are portable and routinely used for industrial hygiene sampling. RESULTS Differences were not observed among the various sampled processes compared with concurrent indoor or outdoor background samples while examining the different DRI exposure metrics. Such data were also inconsistent with results for filter-based samples collected concurrently at the same sites [Dahm MM, Evans DE, Schubauer-Berigan MK et al. (2012) Occupational exposure assessment in CNT and nanofiber primary and secondary manufacturers. Ann Occup Hyg; 56: 542-56]. Significant variability was seen between these processes as well as the indoor and outdoor backgrounds. However, no clear pattern emerged linking the DRI results to the EC or the microscopy data (CNT and CNF structure counts). CONCLUSIONS Overall, no consistent trends were seen among similar processes at the various sites. The DRI instruments employed were limited in their usefulness in assessing and quantifying potential exposures at the sampled sites but were helpful for hypothesis generation, control technology evaluations, and other air quality issues. The DRIs employed are nonspecific, aerosol monitors, and, therefore, subject to interferences. As such, it is necessary to collect samples for analysis by more selective, time-integrated, laboratory-based methods to confirm and quantify exposures.

Carbon nanotube dosimetry: from workplace exposure assessment to inhalation toxicology

BackgroundDosimetry for toxicology studies involving carbon nanotubes (CNT) is challenging because of a lack of detailed occupational exposure assessments. Therefore, exposure assessment findings, measuring the mass concentration of elemental carbon from personal breathing zone (PBZ) samples, from 8 U.S.-based multi-walled CNT (MWCNT) manufacturers and users were extrapolated to results of an inhalation study in mice.ResultsUpon analysis, an inhalable elemental carbon mass concentration arithmetic mean of 10.6 μg/m3 (geometric mean 4.21 μg/m3) was found among workers exposed to MWCNT. The concentration equates to a deposited dose of approximately 4.07 μg/d in a human, equivalent to 2 ng/d in the mouse. For MWCNT inhalation, mice were exposed for 19 d with daily depositions of 1970 ng (equivalent to 1000 d of a human exposure; cumulative 76 yr), 197 ng (100 d; 7.6 yr), and 19.7 ng (10 d; 0.76 yr) and harvested at 0, 3, 28, and 84 d post-exposure to assess pulmonary toxicity. The high dose showed cytotoxicity and inflammation that persisted through 84 d after exposure. The middle dose had no polymorphonuclear cell influx with transient cytotoxicity. The low dose was associated with a low grade inflammatory response measured by changes in mRNA expression. Increased inflammatory proteins were present in the lavage fluid at the high and middle dose through 28 d post-exposure. Pathology, including epithelial hyperplasia and peribronchiolar inflammation, was only noted at the high dose.ConclusionThese findings showed a limited pulmonary inflammatory potential of MWCNT at levels corresponding to the average inhalable elemental carbon concentrations observed in U.S.-based CNT facilities and estimates suggest considerable years of exposure are necessary for significant pathology to occur at that level.

Radon Exposure and Mortality Among White and American Indian Uranium Miners: An Update of the Colorado Plateau Cohort

Studies of uranium miners on the US Colorado Plateau have identified associations between exposure to radon progeny and risk of lung cancer. This study added 15 years of mortality follow-up for the 4,137 miners (primarily white or American Indian) in the Colorado Plateau cohort. The cohort experienced 209 new lung cancer deaths. For white miners, the standardized mortality ratio for lung cancer compared with the regional population was 3.99 (95% confidence interval: 3.43, 4.62) for the period 1991-2005. For American Indian miners, the lung cancer standardized mortality ratio was 3.27 (95% confidence interval: 2.19, 4.73). These standardized mortality ratios have not declined substantially since the 1980s. Internally standardized rate ratios by radon exposure category over the entire follow-up period are similar to those based on earlier follow-up, although estimates within smoking categories demonstrated improved precision. The apparent interaction between radon and smoking in causing lung cancer remains submultiplicative but greater than additive. Mortality rates from silicosis remain highly elevated in the cohort. Elevated mortality rates were observed from interstitial pulmonary fibrosis, multiple myeloma, and non-Hodgkin lymphoma. Significant trends were observed with increased radon exposure in silicosis and pulmonary fibrosis mortality and in the incidence of diabetes-related end-stage renal disease among white miners.

Issues in the development of epidemiologic studies of workers exposed to engineered nanoparticles.

Objective: Capitalizing on phenomena at the nanoscale may present great benefits to society. Nevertheless, until the hazards and risks of engineered nanoparticles are determined, the technological products and advances of nanotechnology may be impeded by the societal concerns. Although animal data provide the necessary first step in hazard and risk assessment, ultimately epidemiological studies will be required, especially studies of workers exposed to engineered nanoparticles. It may be too soon to conduct informative epidemiological studies but it is now appropriate to identify issues that will be pertinent and prepare strategies to address them. Methods: The published scientific literature on incidental and engineered nanoparticles and air pollution were reviewed to identify issues in the conduct of epidemiological studies of workers exposed to engineered nanoparticles. Results: Twelve important issues were identified—the most critical pertaining to particle heterogeneity, temporal factors, exposure characterization, disease endpoints, and identification of the study population. Conclusion: Consideration of these issues provides the foundation for initiating epidemiologic research on workers exposed to engineered nanoparticles.

Chronic lymphocytic leukaemia: an overview of aetiology in light of recent developments in classification and pathogenesis

This overview of the epidemiology of chronic lymphocytic leukaemia (CLL) summarizes the evolution of classification and coding systems and describes the intersection of pathogenesis and aetiology. The role of the putative precursor to CLL, monoclonal B‐cell lymphocytosis (MBL), is considered, and ideas for future investigations of the MBL‐CLL relationship are outlined. We discuss the epidemiology of CLL, focusing on descriptive patterns and methodological considerations. Postulated risk factors are reviewed including the role of ionizing and non‐ionizing radiation, occupational and environmental chemical exposures, medical conditions and treatments, and lifestyle and genetic factors. We conclude by raising key questions that need to be addressed to advance our understanding of CLL aetiology. Recommendations for future epidemiological studies are given, including the standardization of reporting of CLL across cancer registries, the clarification of the natural history of MBL, and the circumvention of the methodological shortcomings of prior epidemiological investigations in relation to radiation, chemical exposures and infectious agents.