Lung Cancer Risks Associated with Occupational Exposure to Pairs of Five Lung Carcinogens: Results from a Pooled Analysis of Case-Control Studies (SYNERGY)

Abstract

Background: While much research has been done to identify individual workplace lung carcinogens, little is known about joint effects on risk when workers are exposed to multiple agents.

Objectives: We investigated the pairwise joint effects of occupational exposures to asbestos, respirable crystalline silica, metals (i.e., nickel, chromium-VI), and polycyclic aromatic hydrocarbons (PAH) on lung cancer risk, overall and by major histologic subtype, while accounting for cigarette smoking.

Methods: In the international 14-center SYNERGY project, occupational exposures were assigned to 16,901 lung cancer cases and 20,965 control subjects using a quantitative job-exposure matrix (SYN-JEM). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for ever vs. never exposure using logistic regression models stratified by sex and adjusted for study center, age, and smoking habits. Joint effects among pairs of agents were assessed on multiplicative and additive scales, the latter by calculating the relative excess risk due to interaction (RERI).

Results: All pairwise joint effects of lung carcinogens in men were associated with an increased risk of lung cancer. However, asbestos/metals and metals/PAH resulted in less than additive effects; while the chromium-VI/silica pair showed marginally synergistic effect in relation to adenocarcinoma (RERI: 0.24; CI: 0.02, 0.46; $p$ = 0.05). In women, several pairwise joint effects were observed for small cell lung cancer including exposure to PAH/silica (OR = 5.12; CI: 1.77, 8.48), and to asbestos/silica (OR = 4.32; CI: 1.35, 7.29), where exposure to PAH/silica resulted in a synergistic effect (RERI: 3.45; CI: 0.10, 6.8).

Discussion: Small or no deviation from additive or multiplicative effects was observed, but co-exposure to the selected lung carcinogens resulted generally in higher risk than exposure to individual agents, highlighting the importance to reduce and control exposure to carcinogens in workplaces and the general environment. https://doi.org/10.1289/EHP13380.

Figure 1.

Prevalence of occupational exposure to asbestos, silica, PAH, chromium-VI, and nickel among SYNERGY study participants with one or two exposures ($n=\mathrm{12,398}$ men, $n=\mathrm{2,073}$ women). The total of the columns represents the overall—individual plus co-exposed—prevalence of each exposure, while within the column the proportion of “co-exposure” to each of the other exposures is also shown. Percentages lower than 0.4% are not displayed because of lack of visibility. Note: PAH, polycyclic aromatic hydrocarbons.

Figure 2.

Individual and joint effects (ORs) of occupational exposures, RERIs, and tests for multiplicative interaction (p-values) between occupational exposures in relation to lung cancer risk in SYNERGY for men ($n=\mathrm{13,605}$ lung cancer cases and 16,451 control subjects). Note: CI, confidence interval; OR, odds ratio; PAH, polycyclic aromatic hydrocarbons; RERI, relative excess risk due to interaction.

Figure 3.

Individual and joint effects (ORs) of occupational exposures, RERIs, and tests for multiplicative interaction (p-values) between occupational exposures in relation to major histological subtypes of lung cancer in SYNERGY for men ($n=\mathrm{11,353}$ lung cancer cases and $n=\mathrm{16,451}$ control subjects). Note: CI, confidence interval; OR, odds ratio; PAH, polycyclic aromatic hydrocarbons; RERI, relative excess risk due to interaction.

Figure 4.

Individual and joint effects (ORs) of occupational exposures, RERIs, and tests for multiplicative interaction (p-values) between occupational exposures in relation to lung cancer risk in SYNERGY for women ($n=\mathrm{3,296}$ lung cancer cases and $n=\mathrm{4,514}$ control subjects). Note: CI, confidence interval; OR, odds ratio; PAH, polycyclic aromatic hydrocarbons; RERI, relative excess risk due to interaction.

Figure 5.

Individual and joint effects (ORs) of occupational exposures, RERIs, and tests for multiplicative interaction (p-values) between occupational exposures in relation to major histological subtypes of lung cancer in SYNERGY for women ($n=\mathrm{2,632}$ lung cancer cases and $n=\mathrm{4,514}$ control subjects). Note: CI, confidence interval; OR, odds ratio; PAH, polycyclic aromatic hydrocarbons; RERI, relative excess risk due to interaction.

Figure 6.

Individual and joint effects (ORs) of occupational exposure to asbestos, chromium-VI, nickel, PAH, and silica, RERIs, and test for multiplicative interaction (p-values) among male workers ($n=\mathrm{13,605}$ lung cancer cases and $n=\mathrm{16,451}$ control subjects) in SYNERGY by smoking status (never, former, and current cigarette smokers). Note: CI, confidence interval; OR, odds ratio; PAH, polycyclic aromatic hydrocarbons; RERI, relative excess risk due to interaction.