Diesel Exhaust In Miners Study Research Articles

The Diesel Exhaust in Miners Study (DEMS) II: Temporal Factors Related to Diesel Exhaust and Lung Cancer Mortality

The Diesel Exhaust in Miners Study (DEMS) II: Temporal Factors Related to Diesel Exhaust and Lung Cancer Mortality

Diesel exhaust and respiratory dust exposure and mortality from ischemic heart disease in the Diesel Exhaust in Miners Study II

Diesel exhaust and respiratory dust exposure and mortality from ischemic heart disease in the Diesel Exhaust in Miners Study II

Worker exit and suicide and overdose mortality in a cohort of male non-metal mine workers

BackgroundSuicides, overdoses, and drug-related liver diseases (deaths of despair) are greatly elevated in the mining and extraction industries compared to other industries. To better understand the drivers of these deaths, we examined suicide or overdose mortality in relation to age at worker exit among a retrospective cohort of 11,009 male mine workers from the Diesel Exhaust in Miners Study II. MethodsWe calculated age-adjusted mortality rates (1947–2015) and estimated hazard ratios (HRs) and 95% Confidence Intervals (CI) for suicide or overdose death in relation to age at worker exit (leaving work). The mining industry curtailed its workforce in the early 1980s due to economic downturn; therefore, separate models were fit for worker exit pre- and post-1980. ResultsSuicide deaths peaked between 1980 and 1989 at 67.2 per 100,000, more than double the rate in the general population. The hazard rate for suicide or overdose was 2.56 times higher for inactive versus actively employed workers (95% CI: 1.88, 3.50). Based on 187 suicides or overdoses, associations between younger age at worker exit and suicide or overdose death were null or protective before 1980. However post-1980, those who exited between ages 30–39 years had an elevated risk of death HR = 1.33, 95% CI (0.70, 2.53) and those who exited before age 30 had a HR for suicide or overdose of 1.57 (0.83, 2.96) compared to those who exited work after age 55. ConclusionWorker exit may contribute to the elevated mortality from suicide or overdose among male mine workers, particularly among younger age groups.

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

BackgroundDiesel 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. ObjectivesTo assess the relationship between occupational diesel exhaust and respirable dust exposures and COPD mortality, while addressing issues of survivor bias in exposed miners. MethodsThe 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. ResultsCox 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). ConclusionsOur 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.

Risk assessment for conventional diesel exhaust (before 1990) and lung cancer in a cohort of miners.

Diesel exhaust in the latter half of the 20th century has been found to be a lung carcinogen. Conventional diesel emissions continue in the transportation, mining, construction, and farming industries. From the Diesel Exhaust in Miners Study, a public-use dataset was used to calculate the excess lifetime risk of lung cancer associated with diesel exposure (1947-1997). Excess rates of lung cancer mortality associated with respirable elemental carbon (REC) and possible other mining exposures (e.g., oil mists, explosives emissions) were investigated using Poisson regression methods. Lung cancer mortality declined with increasing employment duration while increasing with cumulative REC and non-diesel exposures, suggesting a strong worker survivor effect. Attenuation of the REC effect was observed with increasing cumulative exposure. After adjustment for employment duration, the excess rate ratio for lung cancer mortality was 0.67 (95% CI=0.35-0.99) for a 10-year lagged exposure to 200μg/m3 REC, a typical below-ground exposure in the study mines. At exposures of 200, 10, and 1μg/m3 REC, the estimated excess lifetime risks, respectively, were 119, 43, and 8.7 per thousand. Analysis of an inception cohort hired after dieselization commenced produced smaller and less certain estimates of lifetime risk. From exposures to conventional diesel engine exhaust common in occupational groups in the past, the excess lifetime risk of lung cancer was more than 5%. Ambient REC exposures in the general population were estimated to confer lifetime risks of 0.14 to 14 per thousand, depending on assumptions made.

The Diesel Exhaust in Miners Study (DEMS) II: Temporal Factors Related to Diesel Exhaust Exposure and Lung Cancer Mortality in the Nested Case-Control Study.

The Diesel Exhaust in Miners Study (DEMS) was an important contributor to the International Agency for Research on Cancer reclassification of diesel exhaust as a Group I carcinogen and subsequent risk assessment. We extended the DEMS cohort follow-up by 18 y and the nested case-control study to include all newly identified lung cancer deaths and matched controls (DEMS II), nearly doubling the number of lung cancer deaths. Our purpose was to characterize the exposure-response relationship with a focus on the effects of timing of exposure and exposure cessation. We conducted a case-control study of lung cancer nested in a cohort of 12,315 workers in eight nonmetal mines (376 lung cancer deaths, 718 controls). Controls were selected from workers who were alive when the case died, individually matched on mine, sex, race/ethnicity, and birth year (within 5 y). Based on an extensive historical exposure assessment, we estimated respirable elemental carbon (REC), an index of diesel exposure, for each cohort member. Odds ratios (ORs) were estimated by conditional regression analyses controlling for smoking and other confounders. To evaluate time windows of exposure, we evaluated the joint OR patterns for cumulative REC within each of four preselected exposure time windows, , 5-9, 10-19, and y prior to death/reference date, and we evaluated the interaction of cumulative exposure across time windows under additive and multiplicative forms for the joint association. ORs increased with increasing 15-y lagged cumulative exposure, peaking with a tripling of risk for exposures of [; 95% confidence interval (CI): 1.47, 7.10], followed by a plateau/decline among the heavily exposed (; 95% CI: 0.85, 4.04). Patterns of risk by cumulative REC exposure varied across four exposure time windows (), with ORs increasing for exposures accrued primarily 10-19 y prior to death (). Results provided little support for a waning of risk among workers whose exposures ceased for y. DEMS II findings provide insight into the exposure-response relationship between diesel exhaust and lung cancer mortality. The pronounced effect of exposures occurring in the window 10-19 y prior to death, the sustained risk 20 or more years after exposure ceases, and the plateau/decline in risk among the most heavily exposed provide direction for future research on the mechanism of diesel-induced carcinogenesis in addition to having important implications for the assessment of risk from diesel exhaust by regulatory agencies. https://doi.org/10.1289/EHP11980.

Diesel Exhaust Exposure and Cause-Specific Mortality in the Diesel Exhaust in Miners Study II (DEMS II) Cohort.

With the exception of lung cancer, the health effects associated with diesel exhaust for other cancers and nonmalignant health outcomes are not well understood. We extended the mortality follow-up of the Diesel Exhaust in Miners Study, a cohort study of 12,315 workers, by 18 y (ending 31 December 2015), more than doubling the number of observed deaths to , to evaluate associations between mortality and diesel exhaust exposure. Quantitative estimates of historical exposure to respirable elemental carbon (REC), a surrogate for diesel exhaust, were created for all jobs, by year and facility, using measurements collected from each mine, as well as historical measurements. Standardized mortality ratios (SMRs) and hazard ratios (HRs) were estimated for the entire cohort and by worker location (surface, underground). We observed an excess of death for cancers of the lung, trachea, and bronchus (; ; 95% CI: 1.13, 1.37). Among workers who ever worked underground, where the majority of diesel exposure occurred, excess deaths were evident for lung, trachea, and bronchus cancers (; ; 95% CI: 1.11, 1.42). Several nonmalignant diseases were associated with excess mortality among workers ever-employed underground, including ischemic heart disease (; 95% CI: 1.00, 1.16), cerebrovascular disease (; 95% CI: 1.04, 1.43), and nonmalignant diseases of the respiratory system (; 95% CI: 1.01, 1.26). Continuous 15-y lagged cumulative REC exposure was associated with increased lung cancer risk (; 95% CI: 1.24, 3.03), but the risk declined at the highest exposures (; 95% CI: 0.74, 2.26). We also observed a significant trend in non-Hodgkin lymphoma (NHL) risk with increasing 20-y lagged cumulative REC (; 95% CI: 1.00, 9.79; ). Increased risks of lung cancer mortality observed in the original study were sustained. Observed associations between diesel exposure and risk of death from NHL and the excesses in deaths for diseases of the respiratory and cardiovascular system, including ischemic heart disease and cerebrovascular disease, warrant further study and provide evidence of the potential widespread public health impact of diesel exposure. https://doi.org/10.1289/EHP12840.

Temporal factors related to diesel exhaust exposure and lung cancer mortality in the Diesel Exhaust in Miners Study II nested case-control study

BACKGROUND AND AIM: The Diesel Exhaust in Miners Study (DEMS) was an important contributor to the IARC re-classification of diesel exhaust as Group I carcinogen. We extended DEMS cohort follow-up by 18 years and the nested case-control study to include all newly identified lung cancer deaths and matched controls (DEMS II). Our purpose was to further characterize the exposure-response relationship with a focus on the effects of timing of exposure and exposure cessation. METHODS: We conducted a case-control study of lung cancer nested in a cohort of workers in eight nonmetal mines (376 lung cancer deaths, 796 controls). Controls were selected from workers who were alive when the case died, individually matched on mine, sex, race/ethnicity, and birth year (within 5 years). Based on an extensive historical exposure assessment, we estimated respirable elemental carbon (REC), an index of diesel exposure, for each cohort member. Odds ratios (ORs) were estimated by conditional regression analyses controlling for smoking and other confounders. RESULTS: ORs increased with increasing 15-year lagged cumulative exposure, peaking with a tripling of risk for exposures of about 950 to <1700 μg/m3-y (OR = 3.23; 95% CI = 1.47 to 7.10), followed by a plateau/decline among the heavily exposed (OR = 1.85; 95% CI = 0.85 to 4.04). Patterns of risk by cumulative REC exposure varied across four exposure time windows (Phomogeneity<0.001), with ORs increasing for exposures accrued primarily 10-19 years prior to death (Ptrend<0.001). Results provided little support for a waning of risk among workers whose exposures ceased for ≥20 years. CONCLUSIONS: DEMS II preliminary findings provide insight into the exposure-response relationship between diesel exhaust and lung cancer mortality and the effects of timing of exposure, with important implications for the assessment of risk from diesel exhaust by regulatory agencies. KEYWORDS: Diesel exhaust, lung cancer, occupational exposure

Chronic obstructive pulmonary disease mortality: The Diesel Exhaust in Miners Study (DEMS)

BackgroundMiners are highly exposed to diesel exhaust emissions from powered equipment. Although biologically plausible, there is little evidence based on quantitative exposure assessment, that long-term diesel exposure increases risk of chronic obstructive pulmonary disease (COPD). To fill this gap, we examined COPD mortality and diesel exhaust exposure in the Diesel Exhaust in Miners Study (DEMS). MethodsWe fit Cox models to estimate hazard ratios (HRs) for COPD mortality and cumulative exposure (μg/m3-years) to respirable elemental carbon (REC), a key metric for diesel exhaust exposure. Separate models were fit for ever-underground and surface-only miners to allow for effect modification. Exposure was lagged by 0, 10 and 15 years. In a secondary analysis, we addressed the healthy worker survivor effect by applying the parametric g-formula to handle time-varying confounding affected by prior exposure among ever-underground workers. ResultsBased on 140 cases, the HRs for COPD mortality increased as categories of lagged REC exposure increased for all workers. Among surface-only workers, those in the middle exposure category (0 lag) had a significantly elevated hazard ratio of 2.34 (95% CI: 1.11–4.61) relative to those in the lowest category. Among the ever-underground, that ratio was 1.35, with wide confidence intervals. Using the g-formula, we estimated that the lifetime cumulative risk of COPD mortality would have been reduced from the observed 5.0%–3.1% under a hypothetical intervention where all ever-underground workers were always unexposed. ConclusionsOur results suggest long term exposure to diesel exhaust may increase risk of COPD in miners, though power was limited.

The impact of alternative historical extrapolations of diesel exhaust exposure and radon in the Diesel Exhaust in Miners Study (DEMS).

BackgroundPrevious results from the Diesel Exhaust in Miners Study (DEMS) demonstrated a positive exposure–response relation between lung cancer and respirable elemental carbon (REC), a key surrogate for diesel exhaust exposure. Two issues have been raised regarding DEMS: (i) the use of historical carbon monoxide (CO) measurements to calibrate models used for estimating historical exposures to REC in the DEMS exposure assessment; and (ii) potential confounding by radon.MethodsWe developed alternative REC estimates using models that did not rely on CO for calibration, but instead relied on estimated use of diesel equipment, mine ventilation rates and changes in diesel engine emission rates over time. These new REC estimates were used to quantify cumulative REC exposure for each subject in the nested case-control study. We conducted conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals for lung cancer. To evaluate the impact of including radon as a potential confounder, we estimated ORs for average REC intensity adjusted for cumulative radon exposure in underground miners.ResultsValidation of the new REC exposure estimates indicated that they overestimated historical REC by 200–400%, compared with only 10% for the original estimates. Effect estimates for lung cancer using these alternative REC exposures or adjusting for radon typically changed by <10% when compared with the original estimates.ConclusionsThese results emphasize the robustness of the DEMS findings, support the use of CO for model calibration and confirm that radon did not confound the DEMS estimates of the effect of diesel exposure on lung cancer mortality.

The Diesel Exhaust in Miners Study provides no evidence for an increase in risk for lung cancer in miners exposed to diesel engine emissions

The Diesel Exhaust in Miners Study is unquestionably the most suitable data material to date to examine a possible link between diesel engine emissions and lung cancer risk. But the results do not appear to be consistent in themselves. The crucial methodological problem in this study, however, has yet to be discovered, to which the lack of any description of age related information (year of birth, year of hire, year of first exposure, year of death) for the cohort as well as for the cases might have contributed. This information is important to understand the flaws in the analysis. It turns out that the year of birth is associated with the exposure, i.e. with the chance to be exposed over a certain period of time as well as with the chance to be an ever-smoker. A further important issue for the interpretation of the results is the validity of the data on smoking, which are mainly obtained from next of kin for decedents up to 50 years after death. Taking all these aspects into account, it can be concluded that only the SMR-analysis can be considered from all published results.

Chronic Obstructive Pulmonary Disease Mortality in the Diesel Exhaust in Miners Study (DEMS)

Miners are routinely exposed to high levels of diesel exhaust emissions from powered equipment. Although biologically plausible, there is little evidence of elevated risk of chronic obstructive pulmonary disease (COPD) in the literature. To fill this gap, we examined COPD mortality and quantitative exposure to diesel exhaust (respirable elemental carbon (REC)) in an existing cohort of highly exposed miners with well characterized long-term exposure history. The Diesel Exhaust in Miners Study (DEMS) included 11,667 male miners who worked at least one year, on the surface or underground, in eight non-metal US mines.We fit Cox proportional hazard models to estimate hazard ratios (HRs) for COPD mortality and 15-year lagged and non-lagged REC exposure. COPD mortality was defined using ICD codes for underlying and contributing causes of death. Based on 130 cases, we categorized cumulative REC exposure into tertiles. Models were stratified by state and adjusted for respirable dust, worker location (surface and underground), race, year of hire, and calendar year, with age as the timescale. Separate models were then fit for all, underground, and surface miners.HRs for 15-year lagged cumulative REC were elevated in the middle (20-463 µg/m3-yr: HR 1.41 (95%CI: 0.80-2.47)) and highest (&amp;gt;463 µg/m3-yrs: HR 1.62 (0.80-3.30)) exposure categories. The HRs in underground workers were slightly stronger (78 cases). Among surface workers (52 cases), those in the highest category (&amp;gt;24 µg/m3-yrs) had a HR of 3.46 (1.23- 9.74). HRs were attenuated when exposure was unlagged.Our results suggest that REC exposure is associated with increased risk of COPD in both underground and surface workers. The association appears stronger among surface workers, who have exposures far lower than those underground. This may suggest a steeper exposure-response at lower exposures, or the lower HR among underground miners may be due to negative confounding by smoking or healthy worker selection.

Ischemic Heart Disease Mortality and Diesel Exhaust and Respirable Dust Exposure in the Diesel Exhaust in Miners Study.

Diesel exhaust is a suggested risk factor for ischemic heart disease (IHD), but evidence from cohorts using quantitative exposure metrics is limited. We examined the impact of respirable elemental carbon (REC), a key surrogate for diesel exhaust, and respirable dust (RD) on IHD mortality, using data from the Diesel Exhaust in Miners Study in the United States. Using data from a cohort of male workers followed from 1948-1968 until 1997, we fitted Cox proportional hazards models to estimate hazard ratios for IHD mortality for cumulative and average intensity of exposure to REC and RD. Segmented linear regression models allowed for nonmonotonicity. Hazard ratios for cumulative and average REC exposure declined relative to the lowest exposure category before increasing to 0.79 and 1.25, respectively, in the highest category. Relative to the category containing the segmented regression change points, hazard ratios for the highest category were 1.69 and 1.54 for cumulative and average REC exposure, respectively. Hazard ratios for RD exposure increased across the full exposure range to 1.33 and 2.69 for cumulative and average RD exposure, respectively. Tests for trend were statistically significant for cumulative REC exposure (above the change point) and for average RD exposure. Our findings suggest excess risk of IHD mortality in relation to increased exposure to REC and RD.

Reanalysis of Diesel Engine Exhaust and Lung Cancer Mortality in the Diesel Exhaust in Miners Study Cohort Using Alternative Exposure Estimates and Radon Adjustment.

The Diesel Exhaust in Miners Study (DEMS) (United States, 1947–1997) reported positive associations between diesel engine exhaust exposure, estimated as respirable elemental carbon (REC), and lung cancer mortality. This reanalysis of the DEMS cohort used an alternative estimate of REC exposure incorporating historical data on diesel equipment, engine horsepower, ventilation rates, and declines in particulate matter emissions per horsepower. Associations with cumulative REC and average REC intensity using the alternative REC estimate and other exposure estimates were generally attenuated compared with original DEMS REC estimates. Most findings were statistically nonsignificant; control for radon exposure substantially weakened associations with the original and alternative REC estimates. No association with original or alternative REC estimates was detected among miners who worked exclusively underground. Positive associations were detected among limestone workers, whereas no association with REC or radon was found among workers in the other 7 mines. The differences in results based on alternative exposure estimates, control for radon, and stratification by worker location or mine type highlight areas of uncertainty in the DEMS data.

Diesel Exhaust and Lung Cancer-Aftermath of Becoming an IARC Group 1 Carcinogen.

The International Agency for Research on Cancer reclassified diesel exhaust from Group 2A (probably carcinogenic to humans) to Group 1 (carcinogenic to humans) in 2012. Since then, reevaluation and reanalysis of 2 major studies (Diesel Exhaust in Miners Study and Trucking Industry Particle Study) that were influential to the International Agency for Research on Cancer evaluation have replicated the original findings and demonstrated the suitability of these epidemiologic data for the quantitative risk assessment needed to set safe exposure limits in occupational and outdoor ambient environments. The challenge now is to protect the workers and general populations in urban areas from the carcinogenicity of diesel exhaust.

Influence of Alternative Exposure Estimates in the Diesel Exhaust Miners Study: Diesel Exhaust and Lung Cancer.

The landmark Diesel Exhaust in Miners Study (DEMS) studied the relationship between diesel exhaust exposure (DEE) and lung cancer mortality of workers at eight nonmetal mines who were followed from beginning of dieselization of the mines (1947-1967) through December 31, 1997. The original analyses quantified DEE exposures using exposure to respirable elemental carbon (REC) to represent DEE, and CO as a surrogate for REC. However, this use of CO data, and the CO data themselves, have numerous shortcomings. We developed new estimates of REC exposures using historical data on use of diesel equipment, diesel engine horsepower (HP), mine ventilation rates, and the documented reduction in particulate matter emissions per HP in diesel engines from 1975 through 1995. These new REC estimates were applied in a conditional logistic regression of the DEMS nested case-control data very similar to the one applied in the original DEMS analyses. None of the trend slopes calculated using the new REC estimates were statistically significant (p > 0.05). Moreover, these trend slopes were smaller by roughly factors of five without control for radon exposure and factors of 12 with control for radon exposure compared to those estimated in the original DEMS analyses. Also, the 95% confidence intervals for these trend slopes had only minimal overlap with those for the slopes in the original DEMS analyses. These results underscore the uncertainty in estimates of the potency of diesel exhaust in causing lung cancer based on analysis of the DEMS data due to uncertainty in estimates of exposures to diesel exhaust.

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

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. 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. 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. 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.

Reanalysis of the DEMS nested case-control study of lung cancer and diesel exhaust: suitability for quantitative risk assessment.

The International Agency for Research on Cancer (IARC) in 2012 upgraded its hazard characterization of diesel engine exhaust (DEE) to “carcinogenic to humans.” The Diesel Exhaust in Miners Study (DEMS) cohort and nested case-control studies of lung cancer mortality in eight U.S. nonmetal mines were influential in IARC’s determination. We conducted a reanalysis of the DEMS case-control data to evaluate its suitability for quantitative risk assessment (QRA). Our reanalysis used conditional logistic regression and adjusted for cigarette smoking in a manner similar to the original DEMS analysis. However, we included additional estimates of DEE exposure and adjustment for radon exposure. In addition to applying three DEE exposure estimates developed by DEMS, we applied six alternative estimates. Without adjusting for radon, our results were similar to those in the original DEMS analysis: all but one of the nine DEE exposure estimates showed evidence of an association between DEE exposure and lung cancer mortality, with trend slopes differing only by about a factor of two. When exposure to radon was adjusted, the evidence for a DEE effect was greatly diminished, but was still present in some analyses that utilized the three original DEMS DEE exposure estimates. A DEE effect was not observed when the six alternative DEE exposure estimates were utilized and radon was adjusted. No consistent evidence of a DEE effect was found among miners who worked only underground. This article highlights some issues that should be addressed in any use of the DEMS data in developing a QRA for DEE.

Diesel engine exhaust and lung cancer mortality: time-related factors in exposure and risk.

To develop a quantitative exposure-response relationship between concentrations and durations of inhaled diesel engine exhaust (DEE) and increases in lung cancer risks, we examined the role of temporal factors in modifying the estimated effects of exposure to DEE on lung cancer mortality and characterized risk by mine type in the Diesel Exhaust in Miners Study (DEMS) cohort, which followed 12,315 workers through December 1997. We analyzed the data using parametric functions based on concepts of multistage carcinogenesis to directly estimate the hazard functions associated with estimated exposure to a surrogate marker of DEE, respirable elemental carbon (REC). The REC-associated risk of lung cancer mortality in DEMS is driven by increased risk in only one of four mine types (limestone), with statistically significant heterogeneity by mine type and no significant exposure-response relationship after removal of the limestone mine workers. Temporal factors, such as duration of exposure, play an important role in determining the risk of lung cancer mortality following exposure to REC, and the relative risk declines after exposure to REC stops. There is evidence of effect modification of risk by attained age. The modifying impact of temporal factors and effect modification by age should be addressed in any quantitative risk assessment (QRA) of DEE. Until there is a better understanding of why the risk appears to be confined to a single mine type, data from DEMS cannot reliably be used for QRA.

Meta-Analysis of Lung Cancer Risk from Exposure to Diesel Exhaust: Vermeulen et al. Respond

Crump asserts that we “inappropriately mixed data from exposures lagged 5 years and 15 years” in our study published in Environmental Health Perspectives (Vermeulen et al. 2014). Exposure metrics from different studies available for meta-analysis are rarely, if ever, completely comparable. Therefore, even exposures labeled exactly the same (e.g., “cumulative exposure lagged 15 years”) differ between studies because of differences in exposure assessment (cumulative exposure is accrued in different ways in different populations) and because of differences in age composition and extent of follow-up. As a result, in epidemiological studies, optimal lag times to exclude exposures not affecting risk may be variable across studies. For our meta-regression, we included the exposure–response relationships that were presented as the main analyses in the respective papers. For the two trucking studies (Garshick et al. 2012; Steenland et al. 1998), the exposure metric was lagged 5 years, whereas for the Diesel Exhaust in Miners Study (DEMS; Silverman et al. 2012) it was 15 years. Results for an analysis using a 5-year lag in DEMS were not published, although the 5-year lag had been included in analyses to examine changes in model fit as a function of lag. From those analyses (Silverman et al. 2012, Supplementary Figure 1), it is apparent that a 5-year lag showed the worst model fit of all lags (0–25 years); thus, it does not make sense to use this particular analysis as the primary exposure–response relation simply because the label “5-year lag” coincides with that of the other two studies. We acknowledge that the interpretation of the risk function may be affected by differences in exposure between lag times. For this reason, we performed sensitivity analyses that included different lags from each study; overall results changed only slightly. We extended our earlier sensitivity analyses by including the unpublished 5-year lagged data from Silverman et al. (Silverman DT, personal communication).We note again, however, that these 5-year lagged data from the DEMS do not fit nearly as well as the 15-year lagged data. We stress our belief that they should not be the primary data for use in any risk assessment/meta-regression. Crump argues that his alternative analyses using the 5-year lagged data were more consistent with the underlying DEMS data. Figure 1 includes the individual risk estimates for all three studies, with three alternative lag times for DEMS. It is clear from Figure 1 that the 5-year lagged risk estimates for DEMS selected by Crump for his meta-analysis are considerably lower than those of the two trucking studies and the alternative lag times for DEMS. We also included in the figure three different regression lines based on the two trucking studies and one of three different sets of results for DEMS, obtained using the exposure data lagged 0, 5, and 15 years. All models are fitted using the full estimated covariance matrix to appropriately account for the correlation between categorical point estimates from the same study, a correction ignored by Crump. The lowest meta-regression slope, using the 5-year lagged exposure results from DEMS, a) is higher than that reported by Crump using the variance estimates only; b) is statistically significant (0.00065; 95% CI: 0.00028, 0.0010); and c) falls within our previous sensitivity analyses (Vermeulen et al. 2014). It is also clear that the exposure–response function derived using the 15-year lagged exposure data from DEMS is a much better fit overall. Figure 1 Predicted exposure–response curve of cumulative elemental carbon (EC) and lung cancer risk using different lag-times based on a log-linear regression model using relative risk estimates from the three cohort studies. In summary, we strongly disagree with the assertions made by Crump in his letter that we inappropriately mixed lag times. On his other points, we note that adjustment for employment duration in the trucking industry cohort study was not a second exposure measure, but appropriately reduced bias attributable to a healthy worker survivor effect. Additional analyses presented here confirm that the original findings from the meta-analyses are robust. Therefore, we firmly stand with the conclusions of our original paper.