Stephen J. Bertke

Cancer Mortality through 2005 among a Pooled Cohort of U.S. Nuclear Workers Exposed to External Ionizing Radiation

Nuclear workers worldwide have been studied for decades to estimate associations between their exposure to ionizing radiation and cancer. The low-level exposure of these workers requires pooling of large cohorts studied over many years to obtain risk estimates with appropriate latency and good precision. We assembled a pooled cohort of 119,195 U.S. nuclear workers at four Department of Energy nuclear weapons facilities (Hanford site, Idaho National Laboratory, Oak Ridge National Laboratory and Savannah River site) and at the Portsmouth Naval Shipyard. The cohort was followed at the start of the workers beginning their radiation work (at earliest, between 1944 and 1952) through 2005, and we compared its mortality to that of the U.S. population. We also conducted regression-modeling analysis to evaluate dose-response associations for external radiation exposure and outcomes: all cancers, smoking- and nonsmoking-related cancers, all lymphatic and hematopoietic cancers, leukemia (excluding chronic lymphocytic), multiple myeloma, cardiovascular disease and others. The mean dose observed among the cohort was 20 mSv. For most outcomes, mortality was below expectation compared to the general population, but mesothelioma and pleura cancers were highly elevated. We found an excess relative risk (ERR) per 10 mSv of 0.14% [95% confidence interval (CI): −0.17%, 0.48%] for all cancers excluding leukemia. Estimates were higher for nonsmoking-related cancers (0.70%, 95% CI: 0.058%, 1.5%) and lower for smoking-related cancers (−0.079%, 95% CI: −0.43%, 0.32%). The ERR per 10 mSv was 1.7% (95% CI: −0.22%, 4.7%) for leukemia, which was similar to the estimate of 1.8% (95% CI: 0.027%, 4.4%) for all lymphatic and hematopoietic cancers. The ERR per 10 mSv for multiple myeloma was 3.9% (95% CI: 0.60%, 9.5%). The ERR per 10 mSv for cardiovascular disease was 0.026% (−0.25%, 0.32%). Little evidence of heterogeneity was seen by facility, birth cohort or sex for most outcomes. The estimates observed here are similar to those found in previous large pooled nuclear worker studies and also (with the exception of multiple myeloma) to those conducted in the Life Span Study of Japanese atomic bomb survivors. The tendency of observed risks to persist many years after exposure for most outcomes illustrates the importance of continued follow-up of nuclear worker cohorts.

Exposure–response relationships for select cancer and non-cancer health outcomes in a cohort of US firefighters from San Francisco, Chicago and Philadelphia (1950–2009)

Objectives To examine exposure–response relationships between surrogates of firefighting exposure and select outcomes among previously studied US career firefighters. Methods Eight cancer and four non-cancer outcomes were examined using conditional logistic regression. Incidence density sampling was used to match each case to 200 controls on attained age. Days accrued in firefighting assignments (exposed-days), run totals (fire-runs) and run times (fire-hours) were used as exposure surrogates. HRs comparing 75th and 25th centiles of lagged cumulative exposures were calculated using loglinear, linear, log-quadratic, power and restricted cubic spline general relative risk models. Piecewise constant models were used to examine risk differences by time since exposure, age at exposure and calendar period. Results Among 19 309 male firefighters eligible for the study, there were 1333 cancer deaths and 2609 cancer incidence cases. Significant positive associations between fire-hours and lung cancer mortality and incidence were evident. A similar relation between leukaemia mortality and fire-runs was also found. The lung cancer associations were nearly linear in cumulative exposure, while the association with leukaemia mortality was attenuated at higher exposure levels and greater for recent exposures. Significant negative associations were evident for the exposure surrogates and colorectal and prostate cancers, suggesting a healthy worker survivor effect possibly enhanced by medical screening. Conclusions Lung cancer and leukaemia mortality risks were modestly increasing with firefighter exposures. These findings add to evidence of a causal association between firefighting and cancer. Nevertheless, small effects merit cautious interpretation. We plan to continue to follow the occurrence of disease and injury in this cohort.

Risk of leukaemia mortality from exposure to ionising radiation in US nuclear workers: a pooled case-control study

Objective To follow-up on earlier studies of the leukaemogenicity of occupational ionising radiation exposure. Methods We conducted a nested case-control analysis of leukaemia mortality in a pooled cohort of US nuclear workers followed through 2005. Each case was matched to four controls on attained age. Exposures were estimated from available records. General relative risk models were used to estimate the excess relative risk (ERR) of leukaemia, excluding chronic lymphocytic (CLL), acute myeloid leukaemia, chronic myeloid leukaemia and CLL while controlling for potential confounders. Preferred exposure lags and time-windows of risks were calculated using joint maximum likelihood. Dose-response was also examined using linear, linear-quadratic, categorical and restricted cubic spline models. Results There were 369 leukaemia deaths in 105 245 US nuclear workers. The adjusted ERR for non-CLL leukaemia was 0.09 (95% CI −0.17 to 0.65) per 100 mGy. Elevated non-CLL risks were observed from exposures occurring 6–14 years prior to attained age of cases (ERR per 100 mGy=1.9; 95% CI <0 to 8.0). Lagged models indicated non-linearity of risk at very low (<10 mGy) and high (>100 mGy) doses, which contributed to the imprecision of results in linear models. Similar risk attenuation was not evident in time-windows-based models. Conclusions Risk estimates were in reasonable agreement with previous estimates, with the temporality of non-CLL leukaemia risk as a dominant factor in dose-response analyses. Future research should focus on methods that improve evaluations of the dose-response, particularly in the low-dose range.

Trends in Worker Hearing Loss by Industry Sector, 1981–2010

BACKGROUND The purpose of this study was to estimate the incidence and prevalence of hearing loss for noise-exposed U.S. workers by industry sector and 5-year time period, covering 30 years. METHODS Audiograms for 1.8 million workers from 1981-2010 were examined. Incidence and prevalence were estimated by industry sector and time period. The adjusted risk of incident hearing loss within each time period and industry sector as compared with a reference time period was also estimated. RESULTS The adjusted risk for incident hearing loss decreased over time when all industry sectors were combined. However, the risk remained high for workers in Healthcare and Social Assistance, and the prevalence was consistently high for Mining and Construction workers. CONCLUSIONS While progress has been made in reducing the risk of incident hearing loss within most industry sectors, additional efforts are needed within Mining, Construction and Healthcare and Social Assistance.

Mortality and ionising radiation exposures among workers employed at the Fernald Feed Materials Production Center (1951–1985)

Objectives To examine mortality patterns and dose-response relations between ionising radiation and mortality outcomes of a priori interest in 6409 uranium workers employed for at least 30 days (1951–1985), and followed through 2004. Methods Cohort mortality was evaluated through standardised mortality ratios (SMR). Linear excess relative risk (ERR) regression models examined associations between cause-specific mortality and exposures to internal ionising radiation from uranium deposition, external gamma and x-ray radiation, and radon decay products, while adjusting for non-radiologic covariates. Results Person-years at risk totalled 236 568 (mean follow-up 37 years), and 43% of the cohort had died. All-cause mortality was below expectation only in salaried workers. Cancer mortality was significantly elevated in hourly males, primarily from excess lung cancer (SMR=1.25, 95% CI 1.09 to 1.42). Cancer mortality in salaried males was near expectation, but lymphohaematopoietic malignancies were significantly elevated (SMR=1.52, 95% CI 1.06 to 2.12). A positive dose-response relation was observed for intestinal cancer, with a significant elevation in the highest internal organ dose category and a significant dose-response with organ dose from internal uranium deposition (ERR=1.5 per 100 μGy, 95% CI 0.12 to 4.1). Conclusions A healthy worker effect was observed only in salaried workers. Hourly workers had excess cancer mortality compared with the US population, although there was little evidence of a dose-response trend for any cancer evaluated except intestinal cancer. The association between non-malignant respiratory disease and radiation dose observed in previous studies was not apparent, possibly due to improved exposure assessment, different outcome groupings, and extended follow-up.

Mortality among styrene-exposed workers in the reinforced plastic boatbuilding industry

Background We updated mortality through 2011 for 5203 boat-building workers potentially exposed to styrene, and analysed mortality among 1678 employed a year or more between 1959 and 1978. The a priori hypotheses: excess leukaemia and lymphoma would be found. Methods Standardised mortality ratios (SMRs) and 95% CIs and standardised rate ratios (SRRs) used Washington State rates and a person-years analysis programme, LTAS.NET. The SRR analysis compared outcomes among tertiles of estimated cumulative potential styrene exposure. Results Overall, 598 deaths (SMR=0.96, CI 0.89 to 1.04) included excess lung (SMR=1.23, CI 0.95 to 1.56) and ovarian cancer (SMR 3.08, CI 1.00 to 7.19), and chronic obstructive pulmonary disease (COPD) (SMR=1.15, CI 0.81 to 1.58). Among 580 workers with potential high-styrene exposure, COPD mortality increased 2-fold (SMR=2.02, CI 1.08 to 3.46). Conclusions COPD was more pronounced among those with potential high-styrene exposure. However, no outcome was related to estimated cumulative styrene exposure, and there was no change when latency was taken into account. We found no excess leukaemia or lymphoma mortality. As in most occupational cohort studies, lack of information on lifestyle factors or other employment was a substantial limitation although we excluded from the analyses those (n=3525) who worked <1 year. Unanticipated excess ovarian cancer mortality could be a chance finding. Comparing subcohorts with potential high-styrene and low-styrene exposure, COPD mortality SRR was elevated while lung cancer SRR was not, suggesting that smoking was not the only cause for excess COPD mortality.

Mortality in a Combined Cohort of Uranium Enrichment Workers

OBJECTIVE To examine the patterns of cause-specific mortality and relationship between internal exposure to uranium and specific causes in a pooled cohort of 29,303 workers employed at three former uranium enrichment facilities in the United States with follow-up through 2011. METHODS Cause-specific standardized mortality ratios (SMRs) for the full cohort were calculated with the U.S. population as referent. Internal comparison of the dose-response relation between selected outcomes and estimated organ doses was evaluated using regression models. RESULTS External comparison with the U.S. population showed significantly lower SMRs in most diseases in the pooled cohort. Internal comparison showed positive associations of absorbed organ doses with multiple myeloma, and to a lesser degree with kidney cancer. CONCLUSION In general, these gaseous diffusion plant workers had significantly lower SMRs than the U.S. POPULATION The internal comparison however, showed associations between internal organ doses and diseases associated with uranium exposure in previous studies. Am. J. Ind. Med. 60:96-108, 2017. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Maternal occupational pesticide exposure and risk of congenital heart defects in the National Birth Defects Prevention Study.

BACKGROUND Congenital heart defects (CHDs) are common birth defects, affecting approximately 1% of live births. Pesticide exposure has been suggested as an etiologic factor for CHDs, but previous results were inconsistent. METHODS We examined maternal occupational exposure to fungicides, insecticides, and herbicides for 3328 infants with CHDs and 2988 unaffected control infants of employed mothers using data for 1997 through 2002 births from the National Birth Defects Prevention Study, a population-based multisite case-control study. Potential pesticide exposure from 1 month before conception through the first trimester of pregnancy was assigned by an expert-guided task-exposure matrix and job history details self-reported by mothers. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. RESULTS Maternal occupational exposure to pesticides was not associated with CHDs overall. In examining specific CHD subtypes compared with controls, some novel associations were observed with higher estimated pesticide exposure: insecticides only and secundum atrial septal defect (OR = 1.8; 95% CI, 1.3-2.7, 40 exposed cases); both insecticides and herbicides and hypoplastic left heart syndrome (OR = 5.1; 95% CI, 1.7-15.3, 4 exposed cases), as well as pulmonary valve stenosis (OR = 3.6; 95% CI, 1.3-10.1, 5 exposed cases); and insecticides, herbicides, and fungicides and tetralogy of Fallot (TOF) (OR = 2.2; 95% CI, 1.2-4.0, 13 exposed cases). CONCLUSION Broad pesticide exposure categories were not associated with CHDs overall, but examining specific CHD subtypes revealed some increased odds ratios. These results highlight the importance of examining specific CHDs separately. Because of multiple comparisons, additional work is needed to verify these associations.

Examining temporal effects on cancer risk in the International Nuclear Workers' Study (INWORKS)

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.

Factors associated with employment status before and during pregnancy: Implications for studies of pregnancy outcomes

BACKGROUND Potential confounding or effect modification by employment status is frequently overlooked in pregnancy outcome studies. METHODS To characterize how employed and non-employed women differ, we compared demographics, behaviors, and reproductive histories by maternal employment status for 8,343 mothers of control (non-malformed) infants in the National Birth Defects Prevention Study (1997-2007) and developed a multivariable model for employment status anytime during pregnancy and the 3 months before conception. RESULTS Sixteen factors were independently associated with employment before or during pregnancy, including: maternal age, pre-pregnancy body mass index, pregnancy intention, periconceptional/first trimester smoking and alcohol consumption, and household income. CONCLUSIONS Employment status was significantly associated with many common risk factors for adverse pregnancy outcomes. Pregnancy outcome studies should consider adjustment or stratification by employment status. In studies of occupational exposures, these differences may cause uncontrollable confounding if non-employed women are treated as unexposed instead of excluded from analysis. Am. J. Ind. Med. 60:329-341, 2017.