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.

Exposure to Metalworking Fluids and Cancer Incidence in the United Auto Workers-General Motors Cohort.

In previous studies, investigators have reported increased risks of specific cancers associated with exposure to metalworking fluids (MWFs). In this report we broadly examine the incidence of 14 types of cancer, with a focus on digestive, respiratory, and hormonal cancers, in the United Auto Workers-General Motors (UAW-GM) cohort, a cohort of workers exposed to MWFs (1973-2015). The cohort included 39,132 workers followed for cancer incidence. Cox models yielded estimates of adjusted hazard ratios, with categorical variables for lagged cumulative exposure to 3 types of MWF (straight, soluble, and synthetic). We fitted penalized splines to examine the shape of the exposure-response relationships. There were 7,809 incident cancer cases of interest. Oil-based straight and soluble MWFs were each modestly associated with all cancers combined. Exposure-response patterns were consistent with prior reports from this cohort, and results for splined exposures generally reflected their categorically modeled counterparts. We found significantly increased incidence of stomach and kidney cancer with higher levels of straight MWF exposure and increased rectal and prostate cancer with increasing water-based synthetic MWF exposure. Only non-Hodgkin lymphoma and prostate cancer were associated with soluble MWF. All results for colon and lung cancers were null. Our results provide updated evidence for associations between MWF exposure and incidence of several types of cancer.

Unconventional natural gas development and adverse birth outcomes in Pennsylvania: The potential mediating role of antenatal anxiety and depression.

BACKGROUND: Studies have reported associations between unconventional natural gas development (UNGD) and adverse birth outcomes. None have evaluated potential mediating mechanisms. OBJECTIVES: To evaluate associations between (1) UNGD and antenatal anxiety and depression and (2) antenatal anxiety and depression and preterm birth (<37 weeks gestation) and reduced term birth weight, (3) stochastic direct and indirect effects of UNGD on preterm birth and term birth weight operating through antenatal anxiety and depression, and (4) effect modification by family-level socioeconomic status. METHODS: This retrospective cohort study included mothers without prevalent anxiety or depression at time of conception, who delivered at Geisinger in Pennsylvania between January 2009-January 2013. We assembled phase-specific UNGD activity data from public sources. Mothers were categorized as exposed (quartile 4) or unexposed (quartiles 1-3) based on average daily inverse distance-squared UNGD activity metric between conception and the week prior to anxiety or depression (cases) or the pregnancy-average daily metric (non-cases). We estimated associations with a doubly robust estimator (targeted minimum loss-based estimation) and adjusted for potential individual- and community-level confounding variables. RESULTS: Analyses included 8,371 births to 7,715 mothers, 12.2% of whom had antenatal anxiety or depression. We found 4.3 additional cases of antenatal anxiety or depression per 100 women (95% CI: 1.5, 7.0) under the scenario where all mothers lived in the highest quartile of UNGD activity versus quartiles 1-3. The risk difference appeared larger among mothers receiving Medical Assistance (indicator of low family income) compared to those who did not, 5.6 (95% CI: 0.5, 10.6) versus 2.9 (95% CI: -0.7, 6.5) additional cases of antenatal anxiety or depression per 100 women. We found no relationship between antenatal anxiety or depression and adverse birth outcomes and no mediation effect either overall or when stratifying by Medical Assistance. CONCLUSION: We observed a relationship between UNGD activity and antenatal anxiety and depression, which did not mediate the overall association between UNGD activity and adverse birth outcomes.

In utero tobacco smoke exposure, DNA methylation, and asthma in Latino children.

BACKGROUND: Maternal smoking during pregnancy is a risk factor for chronic disease later in life and has been associated with variability of DNA methylation at specific cytosine-phosphate-guanine (CpG) loci. We assessed the role of DNA methylation as a potential mediator of adverse effects of in utero tobacco smoke exposures on asthma outcomes in Latino children from the US mainland and Puerto Rico. METHODS: Relationships between self-reported exposure and DNA methylation at CpG loci previously reported to be associated with maternal smoking were assessed in a subsample consisting of 572 children aged 8-21 years (310 cases with asthma, 262 healthy controls), sampled from a larger asthma case-control study. Subsequently, we assessed associations between top loci and asthma-related outcomes, followed by mediation analysis for loci for which associations with outcomes were observed. RESULTS: Self-reported maternal smoking was associated with a -1.5% (95% confidence interval (CI) = -2.4%, -0.6%) lower methylation at CpG locus cg05575921 on the AHRR gene; a 1% increase in DNA methylation at the same locus resulted in an odds ratio (OR) of 0.90 (95% CI = 0.83, 0.96) for the odds of asthma. The OR for the indirect effect of maternal smoking on asthma mediated through methylation at the cg05575921 locus was 1.18 (95% CI = 1.07, 1.68), compared to the OR for the total effect of exposure in the parent study of 1.48 (95% CI = 1.03, 2.11). CONCLUSIONS: Our findings suggest potential mediation by DNA methylation in the association between maternal smoking during pregnancy and asthma status.

Gender, Depression, and Blue-collar Work: A Retrospective Cohort Study of US Aluminum Manufacturers.

BACKGROUND: Industrial blue-collar workers face multiple work-related stressors, but evidence regarding the burden of mental illness among today's blue-collar men and women remains limited. METHODS: In this retrospective cohort study, we examined health and employment records for 37,183 blue- and white-collar workers employed by a single US aluminum manufacturer from 2003 to 2013. Using Cox proportional hazards regression, we modeled time to first episode of treated depression by gender and occupational class. Among cases, we modeled rates of depression-related service utilization with generalized gamma regression. RESULTS: Compared with their white-collar counterparts, blue-collar men were more likely to be treated for depression (hazard ratio [HR] = 1.3; 95% confidence interval [CI] = 1.1, 1.4) as were blue-collar women (HR = 1.4; 1.2, 1.6). Blue-collar women were most likely to be treated for depression as compared with white-collar men (HR = 3.2; 95% CI = 2.1, 5.0). However, blue-collar workers used depression-related services less frequently than their white-collar counterparts among both men (rate ratio = 0.91; 95% CI = 0.84, 0.98) and women (rate ratio = 0.82; 95% CI = 0.77, 0.88). CONCLUSIONS: Blue-collar women were more likely to be treated for depression than white-collar workers, and blue-collar women were most likely to be treated for depression compared with white-collar men. However, blue-collar men and women used depression-related healthcare services less frequently than white-collar workers. These findings underscore that blue-collar women may be uniquely susceptible to depression, and suggest that blue-collar workers may encounter barriers to care-seeking related mental illness other than their insurance status.

Metalworking Fluids and Colon Cancer Risk: Longitudinal Targeted Minimum Loss-based Estimation.

Metalworking fluids (MWFs) are a class of complex mixtures of chemicals and oils, including several known carcinogens that may pose a cancer hazard to millions of workers. Reports on the relation between MWFs and incident colon cancer have been mixed. METHODS: We investigated the relation between exposure to straight, soluble, and synthetic MWFs and the incidence of colon cancer in a cohort of automobile manufacturing industry workers, adjusting for time-varying confounding affected by prior exposure to reduce healthy worker survivor bias. We used longitudinal targeted minimum loss-based estimation (TMLE) to estimate the difference in the cumulative incidence of colon cancer comparing counterfactual outcomes if always exposed above to always exposed below an exposure cutoff while at work. Exposure concentration cutoffs were selected a priori at the 90th percentile of total particulate matter for each fluid type: 0.034, 0.400, and 0.003 for straight, soluble, and synthetic MWFs, respectively. RESULTS: The estimated 25-year risk differences were 3.8% (95% confidence interval [CI] = 0.7, 7.0) for straight, 1.3% (95% CI = -2.3, 4.8) for soluble, and 0.2% (95% CI = -3.3, 3.7) for synthetic MWFs, respectively. The corresponding risk ratios were 2.39 (1.12, 5.08), 1.43 (0.67, 3.04), and 1.08 (0.51, 2.30) for straight, soluble, and synthetic MWFs, respectively. CONCLUSIONS: By controlling for time-varying confounding affected by prior exposure, a key feature of occupational cohorts, we were able to provide evidence for a causal effect of straight MWF exposure on colon cancer risk that was not found using standard analytical techniques in previous reports.

Secondhand smoke exposure and asthma outcomes among African-American and Latino children with asthma.

BACKGROUND: Secondhand smoke (SHS) exposures have been linked to asthma-related outcomes but quantitative dose-responses using biomarkers of exposure have not been widely reported. OBJECTIVES: Assess dose-response relationships between plasma cotinine-determined SHS exposure and asthma outcomes in minority children, a vulnerable population exposed to higher levels of SHS and under-represented in the literature. METHODS: We performed analyses in 1172 Latino and African-American children with asthma from the mainland USA and Puerto Rico. We used logistic regression to assess relationships of cotinine levels ≥0.05 ng/mL with asthma exacerbations (defined as asthma-related hospitalisations, emergency room visits or oral steroid prescription) in the previous year and asthma control. The shape of dose-response relationships was assessed using a continuous exposure variable in generalised additive logistic models with penalised splines. RESULTS: The OR for experiencing asthma exacerbations in the previous year for cotinine levels ≥0.05 ng/mL, compared with <0.05 ng/mL, was 1.40 (95% CI 1.03 to 1.89), while the OR for poor asthma control was 1.53 (95% CI 1.12 to 2.13). Analyses for dose-response relationships indicated increasing odds of asthma outcomes related with increasing exposure, even at cotinine levels associated with light SHS exposures. CONCLUSIONS: Exposure to SHS was associated with higher odds of asthma exacerbations and having poorly controlled asthma with an increasing dose-response even at low levels of exposure. Our results support the conclusion that there are no safe levels of SHS exposures.

Lung cancer mortality and exposure to synthetic metalworking fluid and biocides: controlling for the healthy worker survivor effect.

OBJECTIVES: Synthetic metalworking fluids (MWFs), widely used to cool and lubricate industrial machining and grinding operations, have been linked with increased risk of several cancers. Estimates of their relation with lung cancer, however, are inconsistent. Controlling for the healthy worker survivor effect, we examined the relations between lung cancer mortality and exposure to synthetic MWF, as well as to biocides added to water-based fluids to control microbial growth, in a cohort of autoworkers. Biocides served as a marker for endotoxin, which has reported antitumour effects, and were hypothesised to be the reason prior studies found reduced lung cancer risk associated with exposure to synthetic fluids. METHODS: Using the parametric g-formula, we estimated risk ratios (RRs) comparing cumulative lung cancer mortality under no intervention with what would have occurred under hypothetical interventions reducing exposure to zero (ie, a ban) separately for two exposures: synthetic fluids and biocides. We also specified an intervention on synthetic MWF and biocides simultaneously to estimate joint effects. RESULTS: Under a synthetic MWF ban, we observed decreased lung cancer mortality risk at age 86, RR=0.96 (0.91-1.01), but when we also intervened to ban biocides, the RR increased to 1.03 (0.95-1.11). A biocide-only ban increased lung cancer mortality (RR=1.07 (1.00-1.16)), with slightly larger RR in younger ages. CONCLUSIONS: Findings suggest a modest positive association for synthetic MWF with lung cancer mortality, contrary to the negative associations reported in earlier studies. Biocide exposure, however, was inversely associated with risk of lung cancer mortality.

Estimating Counterfactual Risk Under Hypothetical Interventions in the Presence of Competing Events: Crystalline Silica Exposure and Mortality From 2 Causes of Death.

Exposure to silica has been linked to excess risk of lung cancer and nonmalignant respiratory disease mortality. In this study we estimated risk for both these outcomes in relation to occupational silica exposure as well as the reduction in risk that would result from hypothetical interventions on exposure in a cohort of exposed workers. Analyses were carried out using data from an all-male study population consisting of 2,342 California diatomaceous earth workers regularly exposed to crystalline silica and followed between 1942 and 2011. We estimated subdistribution risk for each event under the natural course and interventions of interest using the parametric g-formula to adjust for healthy-worker survivor bias. The risk ratio for lung cancer mortality, comparing an intervention in which a theoretical maximum exposure limit was set at 0.05 mg/m3 (the current US regulatory limit) with the observed exposure concentrations, was 0.86 (95% confidence interval: 0.63, 1.22). The corresponding risk ratio for nonmalignant respiratory disease mortality was 0.69 (95% confidence interval: 0.52, 0.93). Our findings suggest that risks from both outcomes would have been considerably lower if historical silica exposures in this cohort had not exceeded current regulatory limits.

Exposure-Lag-Response in Longitudinal Studies: Application of Distributed-Lag Nonlinear Models in an Occupational Cohort.

Prolonged exposures can have complex relationships with health outcomes, as timing, duration, and intensity of exposure are all potentially relevant. Summary measures such as cumulative exposure or average intensity of exposure may not fully capture these relationships. We applied penalized and unpenalized distributed-lag nonlinear models (DLNMs) with flexible exposure-response and lag-response functions in order to examine the association between crystalline silica exposure and mortality from lung cancer and nonmalignant respiratory disease in a cohort study of 2,342 California diatomaceous earth workers followed during 1942-2011. We also assessed associations using simple measures of cumulative exposure assuming linear exposure-response and constant lag-response. Measures of association from DLNMs were generally higher than those from simpler models. Rate ratios from penalized DLNMs corresponding to average daily exposures of 0.4 mg/m3 during lag years 31-50 prior to the age of observed cases were 1.47 (95% confidence interval (CI): 0.92, 2.35) for lung cancer mortality and 1.80 (95% CI: 1.14, 2.85) for nonmalignant respiratory disease mortality. Rate ratios from the simpler models for the same exposure scenario were 1.15 (95% CI: 0.89, 1.48) and 1.23 (95% CI: 1.03, 1.46), respectively. Longitudinal cohort studies of prolonged exposures and chronic health outcomes should explore methods allowing for flexibility and nonlinearities in the exposure-lag-response.

Occupational silica exposure and mortality from lung cancer and nonmalignant respiratory disease: G-estimation of structural nested accelerated failure time models.

BACKGROUND: Occupational exposure to crystalline silica is known to increase risks of both lung cancer and noninfectious nonmalignant respiratory diseases (NMRD). However, associations between silica exposure and survival times have not been described. METHODS: In a longitudinal cohort of diatomaceous earth workers exposed to crystalline silica (primarily cristobalite) and followed from 1942 to 2011, we applied g-estimation of structural nested accelerated failure time models to adjust for time-varying confounding that could result in healthy worker survivor bias. A continuous measure of exposure was used in analyses estimating the hypothetical effect of banning exposure to silica on survival time. Since a ban is infeasible, sensitivity analyses examined the hypothetical effects of enforcing various Occupational Exposure Limits. RESULTS: The estimated median number of years of life lost per worker (for all natural causes) due to silica exposure was 0.48 (95% confidence interval = 0.02, 1.01). For NMRD deaths, the corresponding estimate was 3.22 (0.82, 7.75) and for lung cancer deaths, 2.21 (0.97, 3.56). Cause-specific estimates were sensitive to the use of weights to adjust for competing events. Lung cancer mortality, which tended to occur at younger ages, was an important competing event for NMRD mortality. Sensitivity analyses supported the main results, but with larger estimates, and suggested that a strict limit would be nearly as effective as a complete ban on silica exposure. CONCLUSIONS: Workplace exposure to crystalline silica in this industry appears to shorten survival times significantly, particularly for those who die of lung cancer or NMRD. More stringent exposure limits are probably warranted.

Breast Cancer Incidence and Exposure to Metalworking Fluid in a Cohort of Female Autoworkers.

Breast cancer is the leading cancer diagnosed among women, and environmental studies have produced few leads on modifiable risk factors for breast cancer. Following an Institute of Medicine recommendation for occupational studies of women highly exposed to potential breast cancer risk factors, we took advantage of an existing cohort of 4,503 female autoworkers in Michigan exposed to metalworking fluid (MWF), complex mixtures of oils and chemicals widely used in metal manufacturing worldwide. Cox proportional hazards models were fit to estimate hazard ratios for incident breast cancer (follow-up, 1985-2013) and cumulative exposure (20-year lag) to straight mineral oils (a known human carcinogen) and water-based soluble and synthetic MWF. Because the state cancer registry began decades after the cohort was defined, we restricted our analyses to subcohorts of women hired closer to the start of follow-up. Among those hired after 1969, the hazard ratio associated with a 1 interquartile-range increase in straight MWF exposure was 1.13 (95% confidence interval: 1.03, 1.23). In separate analyses of premenopausal breast cancer, defined by age at diagnosis, the hazard ratio was elevated for exposure to synthetic MWF (chemical lubricants with no oil content), possibly suggesting a different mechanism in the younger women with breast cancer. This study adds to the limited literature regarding quantitative chemical exposures and breast cancer risk.

Assessment of the healthy worker survivor effect in cancer studies of the United Autoworkers-General Motors cohort.

OBJECTIVE: The healthy worker survivor effect (HWSE) can affect the validity of occupational studies when data are analysed incorrectly. HWSE depends on three underlying conditions: (1) leaving work predicts future exposure, (2) leaving work is associated with disease outcome and (3) prior exposure increases probability of leaving work. If all these conditions are satisfied, then employment status is a time-varying confounder affected by prior exposure, and standard regression will produce bias. We assessed these conditions for cancer outcomes in a cohort of autoworkers exposed to metalworking fluids (MWF). METHODS: The cohort includes 31 485 workers followed for cancer incidence from 1985 to 1994. As occupational exposures to straight, soluble and synthetic MWFs are necessarily zero after leaving work, condition (1) is satisfied. Cox models for cancer incidence and for employment termination were used to assess conditions (2) and (3), respectively. Employment termination by select ages was examined to better gauge the presence of condition (2). RESULTS: The HR for leaving work as a predictor of all cancers combined and prostate cancer was null, but elevated for lung and colorectal cancers among men. Condition (2) was more clearly satisfied for all cancer outcomes when leaving work occurred by age 50. Higher exposures to all three MWF types were associated with increased rates of leaving work (condition (3)), with the exception of straight MWF among women. CONCLUSIONS: We found evidence for the structural conditions underlying HWSE in a cohort of autoworkers. G-methods should be applied to reduce HWSE bias in studies of all cancers presently examined.

Risk of renal cell carcinoma following exposure to metalworking fluids among autoworkers.

OBJECTIVES: Metalworking fluids (MWF), used to cool and lubricate metal in occupational settings, are linked to several cancers but data on kidney cancer are limited. We examine how MWF influence the rate of renal cell carcinoma (RCC) in a large prospective study. METHODS: A cohort of Michigan autoworkers consisting of 33 421 individuals was followed from 1985 to 2009. The cohort was linked to the Michigan Cancer Registry to identify new cases of RCC. We analysed RCC in relation to cumulative exposure to each specific type of MWF (straight, soluble and synthetic) and all 3 types pooled into a single MWF variable, with a 15-year lag. Cox proportional hazards regression with splines were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), controlling for age, gender, race, calendar year, year hired, time since hire, plant and other MWF types. RESULTS: There were 135 incident cases. A linear increase in the log-HR was observed for RCC with increasing cumulative exposure to each MWF type and total MWF exposure. At the mean of total MWF exposure (18.80 mg/m(3)-year), the estimated HR was 1.11 (95% CI 1.04 to 1.19). CONCLUSIONS: Our results provide evidence for a dose-dependent association between MWF exposure and RCC. The influence of components of oil-based and water-based MWF needs further examination.

Ischemic Heart Disease Incidence in Relation to Fine versus Total Particulate Matter Exposure in a U.S. Aluminum Industry Cohort.

Ischemic heart disease (IHD) has been linked to exposures to airborne particles with an aerodynamic diameter <2.5 µm (PM2.5) in the ambient environment and in occupational settings. Routine industrial exposure monitoring, however, has traditionally focused on total particulate matter (TPM). To assess potential benefits of PM2.5 monitoring, we compared the exposure-response relationships between both PM2.5 and TPM and incidence of IHD in a cohort of active aluminum industry workers. To account for the presence of time varying confounding by health status we applied marginal structural Cox models in a cohort followed with medical claims data for IHD incidence from 1998 to 2012. Analyses were stratified by work process into smelters (n = 6,579) and fabrication (n = 7,432). Binary exposure was defined by the 10th-percentile cut-off from the respective TPM and PM2.5 exposure distributions for each work process. Hazard Ratios (HR) comparing always exposed above the exposure cut-off to always exposed below the cut-off were higher for PM2.5, with HRs of 1.70 (95% confidence interval (CI): 1.11-2.60) and 1.48 (95% CI: 1.02-2.13) in smelters and fabrication, respectively. For TPM, the HRs were 1.25 (95% CI: 0.89-1.77) and 1.25 (95% CI: 0.88-1.77) for smelters and fabrication respectively. Although TPM and PM2.5 were highly correlated in this work environment, results indicate that, consistent with biologic plausibility, PM2.5 is a stronger predictor of IHD risk than TPM. Cardiovascular risk management in the aluminum industry, and other similar work environments, could be better guided by exposure surveillance programs monitoring PM2.5.

Environmental and occupational particulate matter exposures and ectopic heart beats in welders.

OBJECTIVES: Links between arrhythmias and particulate matter exposures have been found among sensitive populations. We examined the relationship between personal particulate matter ≤2.5 µm aerodynamic diameter (PM2.5) exposures and ectopy in a panel study of healthy welders. METHODS: Simultaneous ambulatory ECG and personal PM2.5 exposure monitoring with DustTrak Aerosol Monitor was performed on 72 males during work and non-work periods for 5-90 h (median 40 h). ECGs were summarised hourly for supraventricular ectopy (SVE) and ventricular ectopy (VE). PM2.5 exposures both work and non-work periods were averaged hourly with lags from 0 to 7 h. Generalised linear mixed-effects models with a random participant intercept were used to examine the relationship between PM2.5 exposure and the odds of SVE or VE. Sensitivity analyses were performed to assess whether relationships differed by work period and among current smokers. RESULTS: Participants had a mean (SD) age of 38 (11) years and were monitored over 2993 person-hours. The number of hourly ectopic events was highly skewed with mean (SD) of 14 (69) VE and 1 (4) SVE. We found marginally significant increases in VE with PM2.5 exposures in the sixth and seventh hour lags, yet no association with SVE. For every 100 µg/m(3) increase in sixth hour lagged PM2.5, the adjusted OR (95% CI) for VE was 1.03 (1.00 to 1.05). Results persisted in work or non-work exposure periods and non-smokers had increased odds of VE associated with PM2.5 as compared with smokers. CONCLUSIONS: A small increase in the odds of VE with short-term PM2.5 exposure was observed among relatively healthy men with environmental and occupational exposures.

Incident Ischemic Heart Disease After Long-Term Occupational Exposure to Fine Particulate Matter: Accounting for 2 Forms of Survivor Bias.

Little is known about the heart disease risks associated with occupational, rather than traffic-related, exposure to particulate matter with aerodynamic diameter of 2.5 µm or less (PM2.5). We examined long-term exposure to PM2.5 in cohorts of aluminum smelters and fabrication workers in the United States who were followed for incident ischemic heart disease from 1998 to 2012, and we addressed 2 forms of survivor bias. Left truncation bias was addressed by restricting analyses to the subcohort hired after the start of follow up. Healthy worker survivor bias, which is characterized by time-varying confounding that is affected by prior exposure, was documented only in the smelters and required the use of marginal structural Cox models. When comparing always-exposed participants above the 10th percentile of annual exposure with those below, the hazard ratios were 1.67 (95% confidence interval (CI): 1.11, 2.52) and 3.95 (95% CI: 0.87, 18.00) in the full and restricted subcohorts of smelter workers, respectively. In the fabrication stratum, hazard ratios based on conditional Cox models were 0.98 (95% CI: 0.94, 1.02) and 1.17 (95% CI: 1.00, 1.37) per 1 mg/m(3)-year in the full and restricted subcohorts, respectively. Long-term exposure to occupational PM2.5 was associated with a higher risk of ischemic heart disease among aluminum manufacturing workers, particularly in smelters, after adjustment for survivor bias.

Occupational Diesel Exposure, Duration of Employment, and Lung Cancer: An Application of the Parametric G-Formula.

BACKGROUND: If less healthy workers terminate employment earlier, thus accumulating less exposure, yet remain at greater risk of the health outcome, estimated health effects of cumulative exposure will be biased downward. If exposure also affects termination of employment, then the bias cannot be addressed using conventional methods. We examined these conditions as a prelude to a reanalysis of lung cancer mortality in the Diesel Exhaust in Miners Study. METHODS: We applied an accelerated failure time model to assess the effect of exposures to respirable elemental carbon (a surrogate for diesel) on time to termination of employment among nonmetal miners who ever worked underground (n = 8,307). We then applied the parametric g-formula to assess how possible interventions setting respirable elemental carbon exposure limits would have changed lifetime risk of lung cancer, adjusting for time-varying employment status. RESULTS: Median time to termination was 36% shorter (95% confidence interval = 33%, 39%), per interquartile range width increase in respirable elemental carbon exposure. Lung cancer risk decreased with more stringent interventions, with a risk ratio of 0.8 (95% confidence interval = 0.5, 1.1) comparing a limit of ≤25 µg/m respirable elemental carbon to no intervention. The fraction of cases attributable to diesel exposure was 27% in this population. CONCLUSIONS: The g-formula controlled for time-varying confounding by employment status, the signature of healthy worker survivor bias, which was also affected by diesel exposure. It also offers an alternative approach to risk assessment for estimating excess cumulative risk, and the impact of interventions based entirely on an observed population.

Lung Function in Rural Guatemalan Women Before and After a Chimney Stove Intervention to Reduce Wood Smoke Exposure: Results From the Randomized Exposure Study of Pollution Indoors and Respiratory Effects and Chronic Respiratory Effects of Early Childhood Exposure to Respirable Particulate Matter Study.

BACKGROUND: COPD is the third most frequent cause of death globally, with much of this burden attributable to household biomass smoke exposure in developing countries. As biomass smoke exposure is also associated with cardiovascular disease, lower respiratory infection, lung cancer, and cataracts, it presents an important target for public health intervention. METHODS: Lung function in Guatemalan women exposed to wood smoke from open fires was measured throughout the Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) stove intervention trial and continued during the Chronic Respiratory Effects of Early Childhood Exposure to Respirable Particulate Matter (CRECER) cohort study. In RESPIRE, early stove households received a chimney woodstove at the beginning of the 18-month trial, and delayed stove households received a stove at trial completion. Personal exposure to wood smoke was assessed with exhaled breath carbon monoxide (CO) and personal CO tubes. Change in lung function between intervention groups and as a function of wood smoke exposure was assessed using random effects models. RESULTS: Of 306 women participating in both studies, acceptable spirometry was collected in 129 early stove and 136 delayed stove households (n = 265), with a mean follow-up of 5.6 years. Despite reduced wood smoke exposures in early stove households, there were no significant differences in any of the measured spirometric variables during the study period (FEV1, FVC, FEV1/FVC ratio, and annual change) after adjustment for confounding. CONCLUSIONS: In these young Guatemalan women, there was no association between lung function and early randomization to a chimney stove or personal wood smoke exposure. Future stove intervention trials should incorporate cleaner stoves, longer follow-up, or potentially susceptible groups to identify meaningful differences in lung function.

Hypothetical exposure limits for oil-based metalworking fluids and cardiovascular mortality in a cohort of autoworkers: structural accelerated failure time models in a public health framework.

Occupational exposure to aerosolized particles of oil-based metalworking fluid was recently linked to deaths from ischemic heart disease. The current recommended exposure limits might be insufficient. Studying cardiovascular mortality is challenging because symptoms can induce sicker workers to reduce their exposure, causing healthy-worker survivor bias. G-estimation of accelerated failure time models reduces this bias and permits comparison of multiple exposure interventions. Michigan autoworkers from the United AutoWorkers-General Motors cohort (n = 38,666) were followed from 1941 through 1994. Separate binary variables indicated whether annual exposure exceeded a series of potential limits. Separate g-estimation analyses for each limit yielded the total number of life-years that could have been saved among persons who died from specific cardiovascular causes by enforcing that exposure limit. Banning oil-based fluids would have saved an estimated 4,003 (95% confidence interval: 2,200, 5,807) life-years among those who died of ischemic heart disease. Estimates for cardiovascular disease overall, acute myocardial infarction, and cerebrovascular disease were 3,500 (95% confidence interval: 1,350, 5,651), 2,932 (95% confidence interval: 1,587, 4,277), and 917 (95% confidence interval: -80, 1,913) life-years, respectively. A limit of 0.01 mg/m(3) would have had a similar impact on cerebrovascular disease but one only half as great on ischemic heart disease. Analyses suggest that limiting exposure to metalworking fluids could have saved many life-years lost to cardiovascular diseases in this cohort.