Drinking Water Disinfection Byproducts, Ingested Nitrate, and Risk of Endometrial Cancer in Postmenopausal Women

BACKGROUND: Disinfection byproducts (DBPs) and N-nitroso compounds (NOC), formed endogenously after nitrate ingestion, are suspected endometrial carcinogens, but epidemiological studies are limited. OBJECTIVES: We investigated the relationship of these exposures with endometrial cancer risk in a large prospective cohort. METHODS: Among postmenopausal women in the Iowa Women’s Health Study cohort, we evaluated two major classes of DBPs, total trihalomethanes (TTHM) and five haloacetic acids (HAA5), and nitrate-nitrogen ([Formula: see text]) in public water supplies (PWS) in relation to incident primary endometrial cancer (1986–2014). For women using their PWS [Formula: see text] at enrollment ([Formula: see text]; [Formula: see text]), we computed historical averages of annual concentrations; exposures were categorized into quantiles and when possible [Formula: see text] percentile. We also computed years of PWS use above one-half the U.S. maximum contaminant level ([Formula: see text]; [Formula: see text] TTHM; [Formula: see text] HAA5; [Formula: see text]). Dietary nitrate/nitrite intakes were estimated from a food frequency questionnaire. We estimated hazard ratios (HR) and 95% confidence intervals (CI) via Cox models adjusted for age, endometrial cancer risk factors [e.g., body mass index, hormone replacement therapy (HRT)], and mutually adjusted for [Formula: see text]. We evaluated associations for low-grade ([Formula: see text]) vs. high-grade ([Formula: see text]) type I tumors. We assessed interactions between exposures and endometrial cancer risk factors and dietary factors influencing NOC formation. RESULTS: Higher average concentrations of DBPs (95th percentile: TTHM [Formula: see text] , HAA5 [Formula: see text]) were associated with endometrial cancer risk (TTHM: [Formula: see text] , 95% CI: 1.41, 3.40; HAA5: [Formula: see text] , 95% CI: 1.19, 2.83; [Formula: see text]). Associations were similarly observed for women greater than median years of PWS use with levels [Formula: see text] , in comparison with zero years (TTHM: [Formula: see text] , 95% CI: 1.18, 2.21; HAA5: [Formula: see text] , 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: [Formula: see text] , 95% CI: 1.17, 3.83; [Formula: see text]) than for high-grade tumors (TTHM: [Formula: see text] , 95% CI: 0.80, 2.44; [Formula: see text]), but differences were not statistically significant ([Formula: see text]). Associations with TTHM were stronger among ever HRT users than non-HRT users ([Formula: see text]). We observed no associations with [Formula: see text] in drinking water or diet. DISCUSSION: We report novel associations between the highest DBP levels and endometrial cancer for our Iowa cohort that warrant future evaluation. https://doi.org/10.1289/EHP10207