Abstract

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

中文翻译：

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饮用水消毒副产物、摄入硝酸盐和绝经后妇女患子宫内膜癌的风险

摘要

背景：

摄入硝酸盐后内源性形成的消毒副产物 (DBP) 和N-亚硝基化合物 (NOC) 是可疑的子宫内膜致癌物，但流行病学研究有限。

目标：

我们在一个大型前瞻性队列中调查了这些暴露与子宫内膜癌风险的关系。

方法：

在爱荷华州妇女健康研究队列的绝经后妇女中，我们评估了两大类 DBP，即总三卤甲烷 (TTHM) 和五卤乙酸 (HAA5)，以及硝酸盐氮 (${\mathrm{不}}_3\text{-N}$) 在与原发性子宫内膜癌相关的公共供水 (PWS) 中（1986-2014 年）。对于使用 PWS 的女性$>10\mathrm{是的}$入学时（$n=10,501$;$\text{案例}=261$)，我们计算了年度浓度的历史平均值；暴露被分类为分位数，并在可能的情况下$\ge 95\text{th}$百分位。我们还计算了 PWS 使用年限超过美国最大污染物水平的二分之一（$>½\text{\hspace{0.17em}MCL}$;$40\mathrm{\mu }\mathrm{G}/\mathrm{大号}$TTHM;$30\mathrm{\mu }\mathrm{G}/\mathrm{大号}$HAA5;${5\mathrm{毫克}/\mathrm{大号}\mathrm{不}}_3\text{-N}$）。从食物频率问卷估计膳食硝酸盐/亚硝酸盐摄入量。我们通过 Cox 模型估计了风险比 (HR) 和 95% 置信区间 (CI)，该模型根据年龄、子宫内膜癌风险因素 [例如，体重指数、激素替代疗法 (HRT)] 进行了调整，并相互调整了${\text{DBPs}\text{\hspace{0.17em}或者\hspace{0.17em}}\mathrm{不}}_3\text{-N}$. 我们评估了低等级（$\text{案例}=99$) 与高档 ($\text{案例}=114$) I 型肿瘤。我们评估了暴露与子宫内膜癌风险因素和影响 NOC 形成的饮食因素之间的相互作用。

结果：

较高的 DBP 平均浓度（第 95 个百分位：TTHM$\ge 93\mathrm{\mu }\mathrm{G}/\mathrm{大号}$, HAA5$\ge 49\mathrm{\mu }\mathrm{G}/\mathrm{大号}$）与子宫内膜癌风险相关（TTHM：${\text{人力资源}}_{95\text{VSQ}1}=2.19$, 95% CI: 1.41, 3.40; HAA5：${\text{人力资源}}_{95\text{VSQ}1}=1.84$, 95% CI: 1.19, 2.83;$p\text{趋势}<0.01$）。对于使用 PWS 的中位年限以上的女性，同样观察到相关性与水平$>½\text{\hspace{0.17em}MCL}$，与零年相比（TTHM：${\text{人力资源}}_{36+\text{对比}0\mathrm{是的}}=1.61$, 95% CI: 1.18, 2.21; HAA5：${\text{人力资源}}_{38+\text{对比}0\mathrm{是的}}=1.85$, 95% CI: 1.31, 2.62)。对于低级别肿瘤（TTHM：${\text{人力资源}}_{\mathrm{问}4\text{VSQ}1}=2.12$, 95% CI: 1.17, 3.83;$p\text{-趋势}=0.008$) 比高级别肿瘤 (TTHM:${\text{人力资源}}_{\mathrm{问}4\text{VSQ}1}=1.40$, 95% CI: 0.80, 2.44;$p\text{-趋势}=0.339$），但差异无统计学意义（$p\text{-异质性}=0.43$）。与非 HRT 用户相比，HRT 用户与 TTHM 的关联更强（$p\text{-相互作用}<0.01$）。我们没有观察到与${\mathrm{不}}_3\text{-N}$在饮用水或饮食中。

讨论：

我们报告了我们爱荷华州队列的最高 DBP 水平与子宫内膜癌之间的新关联，值得未来评估。https://doi.org/10.1289/EHP10207