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

Abstract

Background: 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.

Objective: Our purpose was to 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 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, $<5$, 5-9, 10-19, and $\ge 20$ 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.

Results: ORs increased with increasing 15-y lagged cumulative exposure, peaking with a tripling of risk for exposures of $\sim 950\text{to}<\mathrm{1,700}{\mu g/m}^3\text{-y}$ [$\text{OR}=3.23$; 95% confidence interval (CI): 1.47, 7.10], followed by a plateau/decline among the heavily exposed ($\text{OR}=1.85$; 95% CI: 0.85, 4.04). Patterns of risk by cumulative REC exposure varied across four exposure time windows ($p_{\text{homogeneity}}<0.001$), with ORs increasing for exposures accrued primarily 10-19 y prior to death ($p_{\text{trend}}<0.001$). Results provided little support for a waning of risk among workers whose exposures ceased for $\ge 20$ y.

Conclusion: 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.

Figure 1.

ORs for average REC intensity for the full range (A) and restricted range (B) and cumulative REC exposure for the full range (C) and restricted range (D) lagged 15 y by expanded categories from Table S3 (solid squares) and various fitted models for continuous exposure (d). Models include: a) a power model, $\text{OR}\left(d\right)=\text{\hspace{0.17em}exp\hspace{0.17em}}[\mathrm{\beta }\text{\hspace{0.17em}ln}\left(d\right)]$ (dot-dot-dash line); b) a log-linear OR model, $\text{OR}\left(d\right)=\text{\hspace{0.17em}exp\hspace{0.17em}}\left(\mathrm{\beta }d\right)$ model (dotted line); c) a linear excess OR model, $\text{OR}\left(d\right)=1+\mathrm{\beta }d$ (dash line); and d) a linear-exponential excess OR model, $\text{OR}\left(d\right)=1+\mathrm{\beta }d\text{\hspace{0.5em}exp\hspace{0.17em}}\left(\mathrm{\gamma }d\right)$ (solid line). For each exposure metric and for the full and restricted exposure ranges, the fitted continuous models are adjusted to a common referent value, namely, the mean exposure among controls and the weighted mean of the category-specific ORs. (B) and (D) reflect common aspect ratios. DEMS II, United States, 1947–2015, 376 lung cancer deaths and 718 controls. Source data: Table S3. Note: DEMS, Diesel Exhaust in Miners Study; exp, exponential function; OR, odds ratio; REC, respirable elemental carbon.

Figure 2.

ORs for cumulative REC exposures (${\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3\text{-y}$) accrued within time windows, $<5$, 5–9, 10–19, and $\ge 20$ y prior to date of death/reference date by categories with 95% CIs (from Table S6) (solid squares) and a fitted continuous regression model (solid line). Dashed line in the $\ge 20\text{-y}$ window represents the fitted model omitting workers with cumulative REC $\ge \mathrm{1,280}{\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3\text{-y}$. The preferred model with minimum Akaike Information Criterion had an additive log-linear form, $\text{OR}\left(d\right)={\sum }_k\text{\hspace{0.17em}exp\hspace{0.17em}}\left({\mathrm{\beta }}_k{d}_k\right)-3$, where $d_k$ was the cumulative REC within the kth window, $k=\mathrm{1,2,3,4}$. Within time window, the fitted continuous model is adjusted to a referent value defined by the mean exposure among controls and the weighted mean of the category-specific ORs. DEMS II, United States, 1947–2015, 376 lung cancer deaths and 718 controls. Source data: Table S6. Note: CI, confidence interval; DEMS, Diesel Exhaust in Miners Study; exp, exponential function; OR, odds ratio; REC, respirable elemental carbon.