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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 (${\mathrm{NO}}_3\text{-N}$) in public water supplies (PWS) in relation to incident primary endometrial cancer (1986–2014). For women using their PWS $>10\mathrm{y}$ at enrollment ($n=10,501$; $\text{cases}=261$), we computed historical averages of annual concentrations; exposures were categorized into quantiles and when possible $\ge 95\text{th}$ percentile. We also computed years of PWS use above one-half the U.S. maximum contaminant level ($>½\text{\hspace{0.17em}MCL}$; $40\mathrm{\mu }\mathrm{g}/\mathrm{L}$ TTHM; $30\mathrm{\mu }\mathrm{g}/\mathrm{L}$ HAA5; ${5\mathrm{mg}/\mathrm{L}\mathrm{NO}}_3\text{-N}$). 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, endometrial cancer risk factors [e.g., body mass index, hormone replacement therapy (HRT)], and mutually adjusted for ${\text{DBPs}\text{\hspace{0.17em}or\hspace{0.17em}}\mathrm{NO}}_3\text{-N}$. We evaluated associations for low-grade ($\text{cases}=99$) vs. high-grade ($\text{cases}=114$) 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 $\ge 93\mathrm{\mu }\mathrm{g}/\mathrm{L}$, HAA5 $\ge 49\mathrm{\mu }\mathrm{g}/\mathrm{L}$) were associated with endometrial cancer risk (TTHM: ${\text{HR}}_{95\text{vsQ}1}=2.19$, 95% CI: 1.41, 3.40; HAA5: ${\text{HR}}_{95\text{vsQ}1}=1.84$, 95% CI: 1.19, 2.83; $p\text{trend}<0.01$). Associations were similarly observed for women greater than median years of PWS use with levels $>½\text{\hspace{0.17em}MCL}$, in comparison with zero years (TTHM: ${\text{HR}}_{36+\text{vs}0\mathrm{y}}=1.61$, 95% CI: 1.18, 2.21; HAA5: ${\text{HR}}_{38+\text{vs}0\mathrm{y}}=1.85$, 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: ${\text{HR}}_{\mathrm{Q}4\text{vsQ}1}=2.12$, 95% CI: 1.17, 3.83; $p\text{-trend}=0.008$) than for high-grade tumors (TTHM: ${\text{HR}}_{\mathrm{Q}4\text{vsQ}1}=1.40$, 95% CI: 0.80, 2.44; $p\text{-trend}=0.339$), but differences were not statistically significant ($p\text{-heterogeneity}=0.43$). Associations with TTHM were stronger among ever HRT users than non-HRT users ($p\text{-interaction}<0.01$). We observed no associations with ${\mathrm{NO}}_3\text{-N}$ 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. https://doi.org/10.1289/EHP10207