Background: Previous studies have reported that specific pesticide exposures are associated with increased risks of certain malignancies, including non-Hodgkin lymphoma and prostate cancer. However, the mechanisms underlying these associations are not well understood. Many of these prior studies have focused on organochlorine and organophosphate pesticides; as a result, less is known about other pesticides. Moreover, most studies to date have been conducted in predominately male, occupational cohorts; consequently, less is known about risk of cancer at lower levels of exposures or among women. Objective: This dissertation was designed to examine: (a) the association between use of carbaryl and risk of cancer overall and by site among pesticide applicators in the Agricultural Health Study (AHS) cohort; (b) the association between carbaryl and risk of cancer overall and by site among female spouses of pesticide applicators in the AHS cohort, and (c) potential mechanisms of pesticide carcinogenesis by assessing the association between occupational pesticide use and relative leukocyte telomere length among pesticide applicators in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study within the AHS. Methods: Data from the AHS, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina, and BEEA, a molecular sub-study of male pesticide applicators in the AHS, were used. The association between carbaryl exposure and risk of incident cancer among pesticide applicators and their female spouses was evaluated using Poisson regression. Linear regression models were used to assess the association between occupational pesticide use and relative telomere length (RTL) among pesticide applicators in BEEA.
Results: Among 52,625 pesticide applicators in the AHS, approximately 50% reported use of carbaryl and 8,713 incident cancers were diagnosed. Increasing use of carbaryl was associated with an increased risk of stomach cancer (third tertile vs. never use; Risk Ratio (RR)T3=2.07, 95% Confidence Interval (CI): 1.05-4.07, p-trend=0.02). Ever use of carbaryl was associated with elevated risks of esophageal (RR=1.52, 95% CI: 1.01-2.27) and tongue (RR=1.91, 95% CI: 0.95-3.81) cancers, as well as aggressive prostate cancer when exposure was lagged by 30 years (RR Q4=1.56, 95% CI: 1.18-2.07, p-trend=0.002). Among 29,723 female spouses in the AHS cohort, 30% reported personal use of carbaryl and 4,157 incident cancers were identified. Personal use of carbaryl was associated with increased risks of stomach (RR=1.83, 95% CI: 0.90, 3.73), pancreatic (1.46, 95% CI: 0.97, 2.18), and uterine cancers (RR=1.15, 95% CI: 0.92, 1.42) as well as follicular lymphoma (RR: 1.54, 95% CI: 0.90, 2.61). Among 1,539 male pesticide applicators from BEEA, mean RTL was associated with increasing use of the insecticides lindane (highest quartile vs. never use: percent change = 4.51%, 95% CI –0.22% to 9.46%; p-trend=0.048) and diazinon (highest quartile vs. never use percent change=4.77%, 95% CI: 0.17 to 9.58, p-trend=0.055), as well as with ever-use of aldicarb (percent change=3.27, 95% CI: 0.23 to 6.40, p=0.035). Increasing use of the insecticide heptachlor or the herbicide 2,4,5-TP was inversely associated with RTL. Discussion: This dissertation provides novel evidence of potential associations between carbaryl use and increased risk of specific malignancies, including stomach cancer, which was noted among both pesticide applicators and their female spouses. These studies are the largest and most comprehensive of carbaryl to date and provide important insight into the carcinogenic potential of carbaryl. Moreover, analysis of the results from BEEA, particularly those related to lindane and diazinon, provides novel evidence that use of certain pesticides is associated with altered telomere length. As greater emphasis is placed upon mechanistic studies, these findings may inform future assessments of the carcinogenic potential of pesticides by organizations such as the International Agency for Research on Cancer, the United States Environmental Protection Agency, and other public health agencies.