ENDOTOXIN EXPOSURE AS A MODIFIER OF LUNG CANCER RISK AND RESPIRATORY DISEASE MORTALITY AMONG WORKERS AND RESIDENTS IN THE AGRICULTURAL HEALTH STUDY

Background: Agricultural workers experience lower lung cancer incidence and mortality than the general population. This is commonly attributed to a lower prevalence of smoking. However, chronic obstructive pulmonary disease (COPD), another disease attributed to smoking, follows a different pattern with higher COPD prevalence among agricultural workers than the general population, but lower COPD mortality compared to the general population reported in some studies. Exposure to endotoxin, a bacterial component found in agricultural dust, is suspected in the lower lung cancer incidence and higher COPD prevalence. We explored contributions of smoking history and endotoxin exposure to lung cancer incidence and mortality and COPD mortality, and modification of occupational pesticide exposure and lung cancer incidence associations by endotoxin exposure among 89,000 participants in the Agricultural Health Study (AHS).Methods: In farmers and female spouses, we used Cox proportional hazards models to quantify associations of smoking history and endotoxin exposure with lung cancer incidence (Aim 1) and with lung cancer and COPD mortality (Aim 3) and assessed departure from additive interaction using the relative excess risk of interaction. We used Poisson regression (Aim 2) to quantify associations between chlorpyrifos and terbufos exposure and lung cancer incidence and assessed departure from interaction between each pesticide and endotoxin exposure. Outcomes included total lung cancer, adenocarcinoma, and squamous cell carcinoma (SqCC).Results: Sub-additive interaction between smoking and endotoxin exposure was observed in relation to lung cancer incidence, and lung cancer mortality and COPD mortality among farmers, but not spouses. Terbufos exposure was associated with SqCC incidence; sub-multiplicative interaction was observed between chlorpyrifos and terbufos and endotoxin exposure in relation to total lung cancer, adenocarcinoma, and SqCC incidence. Conclusion: This dissertation adds to evidence that endotoxin exposure lowers lung cancer incidence and mortality among agricultural workers. Unmeasured endotoxin exposure may cause underestimation of associations between workplace exposures and lung cancer. The lower mortality from COPD and risk for lung cancer subtypes originating in the peripheral airways provide epidemiologic evidence that is coherent with an elevated prevalence of “endotoxin tolerance,” in which regular endotoxin exposure enhances immunosurveillance and moderates inflammation in the peripheral airways, among agricultural workers.