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 endome-trial 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 trihalome-thanes (TTHM) and five haloacetic acids (HAA5), and nitrate-nitrogen (NO₃-N) in public water supplies (PWS) in relation to incident primary endo-metrial cancer (1986–2014). For women using their PWS >10 y at enrollment (n = 10,501; cases = 261), we computed historical averages of annual concentrations; exposures were categorized into quantiles and when possible ≥95th percentile. We also computed years of PWS use above one-half the U.S. maximum contaminant level (>½ MCL; 40 lg/L TTHM; 30 lg/L HAA5; 5 mg/LNO₃-N). 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, endome-trial cancer risk factors [e.g., body mass index, hormone replacement therapy (HRT)], and mutually adjusted for DBPs or NO₃-N. We evaluated associations for low-grade (cases = 99) vs. high-grade (cases = 114) 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 ≥93 lg/L, HAA5 ≥49 lg/L) were associated with endometrial cancer risk (TTHM: HR_95vsQ1 =2:19, 95% CI: 1.41, 3.40; HAA5: HR_95vsQ1 =1:84, 95% CI: 1.19, 2.83; ptrend <0:01). Associations were similarly observed for women greater than median years of PWS use with levels >½ MCL, in comparison with zero years (TTHM: HR_36+vs0y =1:61, 95% CI: 1.18, 2.21; HAA5: HR_38+vs0y =1:85, 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: HR_Q4vsQ1 =2:12, 95% CI: 1.17, 3.83; p-trend = 0:008) than for high-grade tumors (TTHM: HR_Q4vsQ1 =1:40, 95% CI: 0.80, 2.44; p-trend = 0:339), but differences were not statistically significant (p-heterogeneity = 0:43). Associations with TTHM were stronger among ever HRT users than non-HRT users (p-interaction <0:01). We observed no associations with NO₃-N 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.