Estimating impacts of reducing acrylonitrile exposure on lung cancer mortality in an occupational cohort with the parametric g-formula.

OBJECTIVES: To inform the potential human carcinogenicity of acrylonitrile, we estimate associations between acrylonitrile exposures and lung cancer mortality in US workers with the objectives of (1) assessing potential for healthy worker survivor bias and (2) adjusting for this bias while assessing the expected lung cancer mortality under different hypothetical occupational exposure limits on acrylonitrile exposure using the parametric g-formula. METHODS: We used data from a cohort of 25 460 workers at facilities making or using acrylonitrile in the USA. We estimated HRs to quantify associations between employment and lung cancer mortality, and exposure and leaving employment. Using the parametric g-formula, we estimated cumulative lung cancer mortality at hypothetical limits on acrylonitrile exposure. RESULTS: Recent and current employment was associated with lung cancer, and exposure was associated with leaving employment, indicating potential for healthy worker survivor bias. Relative to no intervention, reducing the historical exposure under limits of 2.0, 1.0 and 0.45 parts per million would have been expected to reduce lung cancer mortality by age 90 by 4.46 (95% CI 0.78 to 8.15), 5.03 (95% CI 0.96 to 9.11) and 6.45 (95% CI 2.35 to 10.58) deaths per 1000 workers, respectively. A larger lung cancer mortality reduction would be expected under elimination of exposure: 7.21 (95% CI 2.72 to 11.70) deaths per 1000 workers. CONCLUSIONS: Healthy worker survivor bias likely led to underestimation of excess risk. Our results corroborate previous study findings of an excess hazard of lung cancer among the highest exposed workers.

Diesel exhaust and respiratory dust exposure in miners and chronic obstructive pulmonary disease (COPD) mortality in DEMS II.

BACKGROUND: Diesel exhaust and respirable dust exposures in the mining industry have not been studied in depth with respect to non-malignant respiratory disease including chronic obstructive pulmonary disease (COPD), with most available evidence coming from other settings. OBJECTIVES: To assess the relationship between occupational diesel exhaust and respirable dust exposures and COPD mortality, while addressing issues of survivor bias in exposed miners. METHODS: The study population consisted of 11,817 male workers from the Diesel Exhaust in Miners Study II, followed from 1947 to 2015, with 279 observed COPD deaths. We fit Cox proportional hazards models for the relationship between respirable elemental carbon (REC) and respirable dust (RD) exposure and COPD mortality. To address healthy worker survivor bias, we leveraged the parametric g-formula to assess effects of hypothetical interventions on both exposures. RESULTS: Cox models yielded elevated estimates for the associations between average intensity of REC and RD and COPD mortality, with hazard ratios (HR) corresponding to an interquartile range width increase in exposure of 1.46 (95 % confidence interval (CI): 1.12, 1.91) and 1.20 (95 % CI: 0.96, 1.49), respectively for each exposure. HRs for cumulative exposures were negative for both REC and RD. Based on results from the parametric g-formula, the risk ratio (RR) for COPD mortality comparing risk under an intervention eliminating REC to the observed risk was 0.85 (95 % CI: 0.55, 1.06), equivalent to an attributable risk of 15 %. The corresponding RR comparing risk under an intervention eliminating RD to the observed risk was 0.93 (95 % CI: 0.56, 1.31). CONCLUSIONS: Our findings, based on data from a cohort of nonmetal miners, are suggestive of an increased risk of COPD mortality associated with REC and RD, as well as evidence of survivor bias in this population leading to negative associations between cumulative exposures and COPD mortality in traditional regression analysis.

Occupational exposure to organic solvents and risk of bladder cancer.

BACKGROUND: Bladder cancer has been linked to several occupations that involve the use of solvents, including those used in the dry-cleaning industry. OBJECTIVES: We evaluated exposure to solvents and risk of bladder cancer in 1182 incident cases and 1408 controls from a population-based study. METHODS: Exposure to solvents was quantitatively assessed using a job-exposure matrix (CANJEM). Exposure to benzene, toluene and xylene often co-occur. Therefore, we created two additional sets of metrics for combined benzene, toluene and xylene (BTX) exposure: (1) CANJEM-based BTX metrics and (2) hybrid BTX metrics, using an approach that integrates the CANJEM-based BTX metrics together with lifetime occupational histories and exposure-oriented modules that captured within-job, respondent-specific details about tasks and chemicals. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated using logistic regression. RESULTS: Bladder cancer risks were increased among those ever exposed to benzene (OR = 1.63, 95% CI: 1.14-2.32), toluene (OR = 1.60, 95% CI: 1.06-2.43), and xylene (OR = 1.67, 95% CI: 1.13-2.48) individually. We further observed a statistically significant exposure-response relationship for cumulative BTX exposure, with a stronger association using the hybrid BTX metrics (ORQ1vsUnexposed = 1.26, 95% CI: 0.83-1.90; ORQ2vsUnexposed = 1.52, 95% CI: 1.00-2.31; ORQ3vsUnexposed = 1.88, 95% CI: 1.24-2.85; and ORQ4vsUnexposed = 2.23, 95% CI: 1.35-3.69) (p-trend=0.001) than using CANJEM-based metrics (p-trend=0.02). IMPACT: There is limited evidence about the role of exposure to specific organic solvents, alone or in combination on the risk of developing bladder cancer. In this study, workers with increasing exposure to benzene, toluene, and xylene as a group (BTX) had a statistically significant exposure-response relationship with bladder cancer. Future evaluation of the carcinogenicity of BTX and other organic solvents, particularly concurrent exposure, on bladder cancer development is needed.

Urinary mutagenicity and bladder cancer risk in northern New England.

The etiology of bladder cancer among never smokers without occupational or environmental exposure to established urothelial carcinogens remains unclear. Urinary mutagenicity is an integrative measure that reflects recent exposure to genotoxic agents. Here, we investigated its potential association with bladder cancer in rural northern New England. We analyzed 156 bladder cancer cases and 247 cancer-free controls from a large population-based case-control study conducted in Maine, New Hampshire, and Vermont. Overnight urine samples were deconjugated enzymatically and the extracted organics were assessed for mutagenicity using the plate-incorporation Ames assay with the Salmonella frameshift strain YG1041 + S9. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer in relation to having mutagenic versus nonmutagenic urine, adjusted for age, sex, and state, and stratified by smoking status (never, former, and current). We found evidence for an association between having mutagenic urine and increased bladder cancer risk among never smokers (OR = 3.8, 95% CI: 1.3-11.2) but not among former or current smokers. Risk could not be estimated among current smokers because nearly all cases and controls had mutagenic urine. Urinary mutagenicity among never-smoking controls could not be explained by recent exposure to established occupational and environmental mutagenic bladder carcinogens evaluated in our study. Our findings suggest that among never smokers, urinary mutagenicity potentially reflects genotoxic exposure profiles relevant to bladder carcinogenesis. Future studies are needed to replicate our findings and identify compounds and their sources that influence bladder cancer risk.

An Updated Evaluation of Atrazine-Cancer Incidence Associations among Pesticide Applicators in the Agricultural Health Study Cohort.

BACKGROUND: Atrazine is a common agricultural herbicide in the United States. Few epidemiologic studies have evaluated cancer risks. Previous analyses within the Agricultural Health Study (AHS) have found some evidence of associations with cancer at some sites. OBJECTIVE: We updated exposure information, incident cases, and follow-up time to assess the associations between atrazine use and cancer at specific sites in the AHS. METHODS: Information about lifetime pesticide use was reported at enrollment (1993-1997) and follow-up (1999-2005). Among 53,562 pesticide applicators in North Carolina and Iowa, we identified 8,915 incident cases through cancer registry linkages through 2014 (North Carolina)/2017 (Iowa). We used Poisson regression to evaluate the association between ever/never and intensity-weighted lifetime days of atrazine use and incident cancer risk controlling for several confounders. We also evaluated lagged exposures and age-stratified risk. RESULTS: Approximately 71.2% of applicators reported ever using atrazine, which was associated with lung cancer [rate ratios (RR)=1.24; 95% confidence interval (CI): 1.04, 1.46]. Aggressive prostate cancer risk was increased in the highest quartile (RRQ4=1.20; 95% CI: 0.95, 1.52; p-trend=0.19), particularly among those <60 years old (RRQ4=3.04; 95% CI: 1.61, 5.75; p-trend<0.001; p-interaction=0.04). Among applicators <50 years of age, ever-atrazine use was associated with non-Hodgkin lymphoma (NHL) (RR=2.43; 95% CI: 1.10, 5.38; p-interaction=0.60). For soft tissue sarcoma, there was an elevated risk in the highest tertile of exposure (RRT3: 2.54; 95% CI: 0.97, 6.62; p-trend=0.31). In analyses with exposure lagged by 25 years, there was an elevated risk of pharyngeal (RRT3=3.04; 95% CI: 1.45, 6.36; p-trend=0.07) and kidney (RRQ4=1.62; 95% CI: 1.15, 2.29; p-trend<0.005) cancers. DISCUSSION: We observed suggestive associations with some malignancies in overall, age-specific, and lagged analyses. Associations with aggressive prostate cancer and NHL were apparent among those diagnosed at younger ages and with cancers of the pharynx and kidney, and soft tissue sarcomas were observed in lagged analyses. Further work is needed to confirm these observed associations and elucidate potential underlying mechanisms. https://doi.org/10.1289/EHP13684.