Nitrate and disinfection by-products in drinking water and risk of ovarian cancer

Background: N-Nitroso compounds formed endogenously after nitrate/nitrite ingestion cause ovarian cancer in animals. Few epidemiologic studies have evaluated the associations between drinking water nitrate, disinfection by-products (DBPs), and dietary nitrate/nitrite intake with ovarian cancer risk. Methods: We evaluated ovarian cancer risk in relation to drinking water nitrate and DBPs and dietary nitrate/nitrite in the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina (enrollment 1993-1997, N = 33,689). We computed average nitrate-nitrogen and DBPs (total trihalomethanes and haloacetic acids) levels at enrollment addresses on public water supplies using historical monitoring data. We estimated nitrate concentrations in private wells using random forest models. Dietary nitrate/nitrite intakes were estimated from a food frequency questionnaire at follow-up (1999-2003, N = 11,518). We computed hazard ratios (HR) and 95% confidence intervals (CIs) adjusted for age, body mass index, smoking, and menopausal status using Cox regression. We tested the interactions of drinking water nitrate with vitamin C and red meat intake among those with dietary data. Results: We identified 166 ovarian cancers (enrollment through 2021). Risk was elevated with increasing levels of drinking water nitrate-nitrogen (per 5 mg/L; HR = 1.15; 95% CI: 0.96, 1.39) and total trihalomethanes (per 37 µg/L; HR = 1.06; 95% CI: 1.02, 1.10). Increasing dietary nitrate intake was associated with ovarian cancer risk (per 10 mg/day; HR = 1.08; 95% CI: 1.01, 1.15) but there was no association with dietary nitrite. We found no statistical interactions with vitamin C or red meat intake. Conclusions: These drinking water and dietary exposures deserve further study as potential novel ovarian cancer risk factors.