Characterization of Arsenic and Atrazine Contaminations in Drinking Water in Iowa: A Public Health Concern.

Arsenic and atrazine are two water contaminants of high public health concern in Iowa. The occurrence of arsenic and atrazine in drinking water from Iowa's private wells and public water systems was investigated over several decades. In this study, the percentages of detection and violation of regulations were compared over region, season, and water source, and factors affecting the detection and concentration of arsenic and atrazine were analyzed using a mixed-effects model. Atrazine contamination in drinking water was found to vary by region, depending on agricultural usage patterns and hydrogeological features. The annual median atrazine levels of all public water systems were below the drinking water standard of 3 ppb in 2001-2014. Around 40% of public water systems contained arsenic at levels > 1 ppb in 2014, with 13.8% containing arsenic at levels of 5-10 ppb and 2.6% exceeding 10 ppb. This unexpected result highlights the ongoing public health threat posed by arsenic in drinking water in Iowa, emphasizing the need for continued monitoring and mitigation efforts to reduce exposure and associated health risks. Additionally, an atrazine metabolite, desethylatrazine, should be monitored to obtain a complete account of atrazine exposure and possible health effects.

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 (NO3-N) in public water supplies (PWS) in relation to incident primary endometrial cancer (1986-2014). For women using their PWS >10y 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; 40µg/L TTHM; 30µg/L HAA5; 5mg/L NO3-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 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 ≥93µg/L, HAA5 ≥49µg/L) were associated with endometrial cancer risk (TTHM: HR95vsQ1=2.19, 95% CI: 1.41, 3.40; HAA5: HR95vsQ1=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: HR36+vs0y=1.61, 95% CI: 1.18, 2.21; HAA5: HR38+vs0y=1.85, 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: HRQ4vsQ1=2.12, 95% CI: 1.17, 3.83; p-trend=0.008) than for high-grade tumors (TTHM: HRQ4vsQ1=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. https://doi.org/10.1289/EHP10207.

Ingestion of Nitrate and Nitrite and Risk of Stomach and Other Digestive System Cancers in the Iowa Women's Health Study.

Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC) which are potent animal carcinogens for the organs of the digestive system. We evaluated dietary intakes of nitrate and nitrite, as well as nitrate ingestion from drinking water (public drinking water supplies (PWS)), in relation to the incidence (1986-2014) of cancers of the esophagus (n = 36), stomach (n = 84), small intestine (n = 32), liver (n = 31), gallbladder (n = 66), and bile duct (n = 58) in the Iowa Women's Health Study (42,000 women aged from 50 to 75 in 1986). Dietary nitrate and nitrite were estimated using a food frequency questionnaire and a database of nitrate and nitrite levels in foods. Historical nitrate measurements from PWS were linked to the enrollment address by duration. We used Cox regression to compute hazard ratios (HR) and 95% confidence intervals (CI) for exposure quartiles (Q), tertiles (T), or medians, depending on the number of cancer cases. In adjusted models, nitrite intake from processed meats was associated with an increased risk of stomach cancer (HRQ4vsQ1 = 2.2, CI: 1.2-4.3). A high intake of total dietary nitrite was inversely associated with gallbladder cancer (HRQ4vsQ1 = 0.3, CI: 0.1-0.96), driven by an inverse association with plant sources of nitrite (HRQ4vsQ1 = 0.3, CI: 0.1-0.9). Additionally, small intestine cancer was inversely associated with a high intake of animal nitrite (HRT3vsT1 = 0.2, CI: 0.1-0.7). There were no other dietary associations. Nitrate concentrations in PWS (average, years ≥ 1/2 the maximum contaminant level) were not associated with cancer incidence. Our findings for stomach cancer are consistent with prior dietary studies, and we are the first to evaluate nitrate and nitrite ingestion for certain gastrointestinal cancers.

Impact of residential mobility on estimated environmental exposures in a prospective cohort of older women.

Longitudinal studies of environmental hazards often rely on exposure estimated at the participant's enrollment residence. This could lead to exposure misclassification if participants move over time. METHODS: We evaluated residential mobility in the Iowa Women's Health Study (age 55-69 years) over 19 years of follow-up (1986-2004). We assessed several environmental exposures of varying spatial scales at enrollment and follow-up addresses. Exposures included average nitrate concentrations in public water supplies, percent of agricultural land (row crops and pasture/hay) within 750 m, and the presence of concentrated animal feeding operations within 5 km. In comparison to gold standard duration-based exposures averaged across all residences, we evaluated the sensitivity and specificity of exposure metrics and attenuation bias for a hypothetical nested case-control study of cancer, which assumed participants did not move from their enrollment residence. RESULTS: Among 41,650 participants, 32% moved at least once during follow-up. Mobility was predicted by working outside the home, being a former/current smoker, having a higher education level, using a public drinking water supply, and town size of previous residence. Compared with duration-based exposures, the sensitivity and specificity of exposures at enrollment ranged from 94% to 99% and 97% to 99%, respectively. A hypothetical true odds ratio of 2.0 was attenuated 8% for nitrate, 9%-10% for agricultural land, and 6% for concentrated animal feeding operation exposures. CONCLUSIONS: Overall, we found low rates of mobility and mobility-related exposure misclassification in the Iowa Women's Health Study. Misclassification and attenuation of hypothetical risk estimates differed by spatial variability and exposure prevalence.

Pilot study of global endocrine disrupting activity in Iowa public drinking water utilities using cell-based assays.

Some anthropogenic substances in drinking water are known or suspected endocrine disrupting compounds (EDCs), but EDCs are not routinely measured. We conducted a pilot study of 10 public drinking water utilities in Iowa, where common contaminants (e.g., pesticides) are suspected EDCs. Raw (untreated) and finished (treated) drinking water samples were collected in spring and fall and concentrated using solid phase extraction. We assessed multiple endocrine disrupting activities using novel mammalian cell-based assays that express nuclear steroid receptors (aryl hydrocarbon [AhR], androgenic [AR], thyroid [TR], estrogenic [ER] and glucocorticoid [GR]). We quantified each receptor's activation relative to negative controls and compared activity by season and utility/sample characteristics. Among 62 samples, 69% had AhR, 52% AR, 3% TR, 2% ER, and 0% GR activity. AhR and AR activities were detected more frequently in spring (p =0 .002 and < 0.001, respectively). AR activity was more common in samples of raw water (p =0 .02) and from surface water utilities (p =0 .05), especially in fall (p =0 .03). Multivariable analyses suggested spring season, surface water, and nitrate and disinfection byproduct concentrations as determinants of bioactivity. Our results demonstrate that AR and AhR activities are commonly found in Iowa drinking water, and that their detection varies by season and utility/sample characteristics. Screening EDCs with cell-based bioassays holds promise for characterizing population exposure to diverse EDCs mixtures.

Ingested nitrate, disinfection by-products, and risk of colon and rectal cancers in the Iowa Women's Health Study cohort.

BACKGROUND: N-nitroso compounds (NOC) formed endogenously after nitrate/nitrite ingestion and disinfection by-products (DBPs) are suspected colorectal carcinogens, but epidemiologic evidence of these associations is limited. OBJECTIVES: We investigated the relationship between drinking water exposures and incident colorectal cancers in a cohort of postmenopausal women. METHODS: Using historical nitrate-nitrogen (NO3-N) measurements and estimates of total trihalomethanes (TTHM), the sum of 5 or 6 haloacetic acids (HAAs), and individual DBPs in public water supplies (PWS), we computed average exposures and years of exposure above one-half the U.S. maximum contaminant level (>1/2-MCL; >5 mg/L NO3-N and >40 µg/L TTHM). Nitrate/nitrite intakes from dietary sources were estimated using a food frequency questionnaire. We estimated hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression models. We assessed NO3-N interactions with DBPs and with factors influencing endogenous NOC formation. RESULTS: We identified 624 colon and 158 rectal cancers (1986-2010) among 15,910 women reporting PWS use >10 years. Ingestion of NO3-N from drinking water was not associated with risk. Colon cancer risks were non-significantly associated with the average TTHM levels >17.7 µg/L (HRQ5vsQ1 = 1.13, CI = 0.89-1.44; ptrend = 0.11) and were elevated for any duration of exposure >1/2-MCL. Rectal cancer risks were associated with the highest TTHM levels (HRQ5vsQ1 = 1.71, CI = 1.00-2.92; ptrend = 0.22) but not with years >1/2-MCL. Bromodichloromethane (HRQ4vsQ1 = 1.89, CI = 1.17-3.00; ptrend = 0.09) and trichloroacetic acid (HRQ4vsQ1 = 1.92, CI = 1.20-3.09; ptrend = 0.18) levels were also associated with risk of rectal cancer. We found no evidence of interaction between TTHM and NO3-N on the risk of either cancer. Dietary analyses yielded a positive colon cancer association with red meat, but not with processed meat intake or estimated nitrate/nitrite from specific dietary sources. CONCLUSIONS: Our results suggest that exposure to TTHM in drinking water is associated with increased risk of rectal cancer. Positive findings for individual THMs and HAAs for both colon and rectal cancers require replication in other studies. We found no associations for nitrate overall or in subgroups with presumed higher NOC exposure.

Drinking Water Nitrate and Human Health: An Updated Review.

Nitrate levels in our water resources have increased in many areas of the world largely due to applications of inorganic fertilizer and animal manure in agricultural areas. The regulatory limit for nitrate in public drinking water supplies was set to protect against infant methemoglobinemia, but other health effects were not considered. Risk of specific cancers and birth defects may be increased when nitrate is ingested under conditions that increase formation of N-nitroso compounds. We previously reviewed epidemiologic studies before 2005 of nitrate intake from drinking water and cancer, adverse reproductive outcomes and other health effects. Since that review, more than 30 epidemiologic studies have evaluated drinking water nitrate and these outcomes. The most common endpoints studied were colorectal cancer, bladder, and breast cancer (three studies each), and thyroid disease (four studies). Considering all studies, the strongest evidence for a relationship between drinking water nitrate ingestion and adverse health outcomes (besides methemoglobinemia) is for colorectal cancer, thyroid disease, and neural tube defects. Many studies observed increased risk with ingestion of water nitrate levels that were below regulatory limits. Future studies of these and other health outcomes should include improved exposure assessment and accurate characterization of individual factors that affect endogenous nitrosation.

Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women.

Nitrate and nitrite are precursors of N-nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by-products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986-2011). We used historical monitoring and treatment data to estimate levels of long-term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one-half the maximum contaminant level (>½ MCL; 5 mg/L nitrate-nitrogen, 40 µg/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N = 15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HRp95vs. Q1 = 1.16, 95% CI: 0.51-2.64). Associations with average TTHM levels were also null (HRQ4vs. Q1 = 0.70, 95% CI:0.42-1.18). We observed no trend with increasing years of exposure to either contaminant at levels >½ MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HRp95vs. Q1 = 1.66, 95% CI 1.00-2.75;ptrend = 0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer.

Case study approach to modeling historical disinfection by-product exposure in Iowa drinking waters.

In the 1980s, a case-control epidemiologic study was conducted in Iowa (USA) to analyze the association between exposure to disinfection by-products (DBPs) and bladder cancer risk. Trihalomethanes (THMs), the most commonly measured and dominant class of DBPs in drinking water, served as a primary metric and surrogate for the full DBP mixture. Average THM exposure was calculated, based on rough estimates of past levels in Iowa. To reduce misclassification, a follow-up study was undertaken to improve estimates of past THM levels and to re-evaluate their association with cancer risk. In addition, the risk associated with haloacetic acids, another class of DBPs, was examined. In the original analysis, surface water treatment plants were assigned one of two possible THM levels depending on the point of chlorination. The re-assessment considered each utility treating surface or groundwater on a case-by-case basis. Multiple treatment/disinfection scenarios and water quality parameters were considered with actual DBP measurements to develop estimates of past levels. The highest annual average THM level in the re-analysis was 156µg/L compared to 74µg/L for the original analysis. This allowed the analysis of subjects exposed at higher levels (>96µg/L). The re-analysis established a new approach, based on case studies and an understanding of the water quality and operational parameters that impact DBP formation, for determining historical exposure.

Ingested Nitrate, Disinfection By-products, and Kidney Cancer Risk in Older Women.

BACKGROUND: N-nitroso compounds formed endogenously after nitrate/nitrite ingestion are animal renal carcinogens. Previous epidemiologic studies of drinking water nitrate did not evaluate other potentially toxic water contaminants, including the suspected renal carcinogen chloroform. METHODS: In a cohort of postmenopausal women in Iowa (1986-2010), we used historical measurements to estimate long-term average concentrations of nitrate-nitrogen (NO3-N) and disinfection by-products (DBP) in public water supplies. For NO3-N and the regulated DBP (total trihalomethanes [THM] and the sum of five haloacetic acids [HAA5]), we estimated the number of years of exposure above one-half the current maximum contaminant level (>½-MCL NO3-N; >5 mg/L). Dietary intakes were assessed via food frequency questionnaire. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox models, and evaluated interactions with factors influencing N-nitroso compound formation. RESULTS: We identified 125 incident kidney cancers among 15,577 women reporting using water from public supplies >10 years. In multivariable models, risk was higher in the 95th percentile of average NO3-N (HRp95vsQ1 = 2.3; CI: 1.2, 4.3; Ptrend = 0.33) and for any years of exposure >½-MCL; adjustment for total THM did not materially change these associations. There were no independent relationships with total THM, individual THMs chloroform and bromodichloromethane, or with haloacetic acids. Dietary analyses yielded associations with high nitrite intake from processed meats but not nitrate or nitrite overall. We found no interactions. CONCLUSIONS: Relatively high nitrate levels in public water supplies were associated with increased risk of renal cancer. Our results also suggest that nitrite from processed meat is a renal cancer risk factor.

Atrazine in public water supplies and risk of ovarian cancer among postmenopausal women in the Iowa Women's Health Study.

BACKGROUND: Few studies have evaluated environmental chemical exposures in relation to ovarian cancer. We previously found an increased risk of ovarian cancer among postmenopausal women in Iowa associated with higher nitrate levels in public water supplies (PWS). However, elevated nitrate levels may reflect the presence of other agricultural chemicals, such as atrazine, one of the most commonly detected pesticides in Iowa PWS. METHODS: We evaluated the association between atrazine in drinking water and incident ovarian cancer (N=145, 1986-2010) among 13 041 postmenopausal women in the Iowa Women's Health Study who used their PWS for ≥11 years as reported in 1989. Average levels of atrazine (1986-1987), nitrate-nitrogen (NO3-N, 1955-1988) and estimated levels of total trihalomethanes (TTHM, 1955-1988) from PWS monitoring data were linked to the participants' cities of residence. We computed HRs and 95% CIs by categories of the average atrazine level (not detected, ≤ or >0.37 parts per billion=median) using Cox proportional hazards regression adjusting for ovarian cancer risk factors. RESULTS: Atrazine was detected in water samples from 69 cities where 4155 women (32%) lived and levels were moderately correlated with NO3-N (ρ=0.35) and TTHM (ρ=0.24). Atrazine levels were not associated with ovarian cancer risk with or without adjusting for NO3-N and TTHM levels (p-trend=0.50 and 0.81, respectively). Further, there was no evidence for effect modification of the atrazine association by NO3-N or TTHM levels. CONCLUSIONS: In our study with low atrazine detection rates, we found no association between atrazine in PWS and postmenopausal ovarian cancer risk.

Assessing the relationship between groundwater nitrate and animal feeding operations in Iowa (USA).

Nitrate-nitrogen is a common contaminant of drinking water in many agricultural areas of the United States of America (USA). Ingested nitrate from contaminated drinking water has been linked to an increased risk of several cancers, specific birth defects, and other diseases. In this research, we assessed the relationship between animal feeding operations (AFOs) and groundwater nitrate in private wells in Iowa. We characterized AFOs by swine and total animal units and type (open, confined, or mixed), and we evaluated the number and spatial intensities of AFOs in proximity to private wells. The types of AFO indicate the extent to which a facility is enclosed by a roof. Using linear regression models, we found significant positive associations between the total number of AFOs within 2km of a well (p trend <0.001), number of open AFOs within 5km of a well (p trend <0.001), and number of mixed AFOs within 30km of a well (p trend <0.001) and the log nitrate concentration. Additionally, we found significant increases in log nitrate in the top quartiles for AFO spatial intensity, open AFO spatial intensity, and mixed AFO spatial intensity compared to the bottom quartile (0.171log(mg/L), 0.319log(mg/L), and 0.541log(mg/L), respectively; all p<0.001). We also explored the spatial distribution of nitrate-nitrogen in drinking wells and found significant spatial clustering of high-nitrate wells (>5mg/L) compared with low-nitrate (≤5mg/L) wells (p=0.001). A generalized additive model for high-nitrate status identified statistically significant areas of risk for high levels of nitrate. Adjustment for some AFO predictor variables explained a portion of the elevated nitrate risk. These results support a relationship between animal feeding operations and groundwater nitrate concentrations and differences in nitrate loss from confined AFOs vs. open or mixed types.

Nitrate from Drinking Water and Diet and Bladder Cancer Among Postmenopausal Women in Iowa.

BACKGROUND: Nitrate is a drinking water contaminant arising from agricultural sources, and it is a precursor in the endogenous formation of N-nitroso compounds (NOC), which are possible bladder carcinogens. OBJECTIVES: We investigated the ingestion of nitrate and nitrite from drinking water and diet and bladder cancer risk in women. METHODS: We identified incident bladder cancers among a cohort of 34,708 postmenopausal women in Iowa (1986-2010). Dietary nitrate and nitrite intakes were estimated from a baseline food frequency questionnaire. Drinking water source and duration were assessed in a 1989 follow-up. For women using public water supplies (PWS) > 10 years (n = 15,577), we estimated average nitrate (NO3-N) and total trihalomethane (TTHM) levels and the number of years exceeding one-half the maximum contaminant level (NO3-N: 5 mg/L, TTHM: 40 µg/mL) from historical monitoring data. We computed hazard ratios (HRs) and 95% confidence intervals (CIs), and assessed nitrate interactions with TTHM and with modifiers of NOC formation (smoking, vitamin C). RESULTS: We identified 258 bladder cancer cases, including 130 among women > 10 years at their PWS. In multivariable-adjusted models, we observed nonsignificant associations among women in the highest versus lowest quartile of average drinking water nitrate concentration (HR = 1.48; 95% CI: 0.92, 2.40; ptrend = 0.11), and we found significant associations among those exposed ≥ 4 years to drinking water with > 5 mg/L NO3-N (HR = 1.62; 95% CI: 1.06, 2.47; ptrend = 0.03) compared with women having 0 years of comparable exposure. TTHM adjustment had little influence on associations, and we observed no modification by vitamin C intake. Relative to a common reference group of never smokers with the lowest nitrate exposures, associations were strongest for current smokers with the highest nitrate exposures (HR = 3.67; 95% CI: 1.43, 9.38 for average water NO3-N and HR = 3.48; 95% CI: 1.20, 10.06 and ≥ 4 years > 5 mg/L, respectively). Dietary nitrate and nitrite intakes were not associated with bladder cancer. CONCLUSIONS: Long-term ingestion of elevated nitrate in drinking water was associated with an increased risk of bladder cancer among postmenopausal women. Citation: Jones RR, Weyer PJ, DellaValle CT, Inoue-Choi M, Anderson KE, Cantor KP, Krasner S, Robien K, Beane Freeman LE, Silverman DT, Ward MH. 2016. Nitrate from drinking water and diet and bladder cancer among postmenopausal women in Iowa. Environ Health Perspect 124:1751-1758; http://dx.doi.org/10.1289/EHP191.

Agricultural Compounds in Water and Birth Defects.

Agricultural compounds have been detected in drinking water, some of which are teratogens in animal models. The most commonly detected agricultural compounds in drinking water include nitrate, atrazine, and desethylatrazine. Arsenic can also be an agricultural contaminant, although arsenic often originates from geologic sources. Nitrate has been the most studied agricultural compound in relation to prenatal exposure and birth defects. In several case-control studies published since 2000, women giving birth to babies with neural tube defects, oral clefts, and limb deficiencies were more likely than control mothers to be exposed to higher concentrations of drinking water nitrate during pregnancy. Higher concentrations of atrazine in drinking water have been associated with abdominal defects, gastroschisis, and other defects. Elevated arsenic in drinking water has also been associated with birth defects. Since these compounds often occur as mixtures, it is suggested that future research focus on the impact of mixtures, such as nitrate and atrazine, on birth defects.

Nitrate and nitrite ingestion and risk of ovarian cancer among postmenopausal women in Iowa.

Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women's Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow-up survey. Nitrate-nitrogen (NO3 -N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman's duration at the residence. We computed multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI = 1.22-3.38, ptrend = 0.003) in the highest quartile (≥2.98 mg/L) compared with the lowest quartile (≤0.47 mg/L; reference) of NO3 -N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR = 1.53, CI = 0.93-2.54) compared with the same reference group. Associations were stronger when vitamin C intake was

Assessing bottled water nitrate concentrations to evaluate total drinking water nitrate exposure and risk of birth defects.

Previous epidemiologic studies of maternal exposure to drinking water nitrate did not account for bottled water consumption. The objective of this National Birth Defects Prevention Study (NBDPS) (USA) analysis was to assess the impact of bottled water use on the relation between maternal exposure to drinking water nitrate and selected birth defects in infants born during 1997-2005. Prenatal residences of 1,410 mothers reporting exclusive bottled water use were geocoded and mapped; 326 bottled water samples were collected and analyzed using Environmental Protection Agency Method 300.0. Median bottled water nitrate concentrations were assigned by community; mothers' overall intake of nitrate in mg/day from drinking water was calculated. Odds ratios for neural tube defects, limb deficiencies, oral cleft defects, and heart defects were estimated using mixed-effects models for logistic regression. Odds ratios (95% CIs) for the highest exposure group in offspring of mothers reporting exclusive use of bottled water were: neural tube defects [1.42 (0.51, 3.99)], limb deficiencies [1.86 (0.51, 6.80)], oral clefts [1.43 (0.61, 3.31)], and heart defects [2.13, (0.87, 5.17)]. Bottled water nitrate had no appreciable impact on risk for birth defects in the NBDPS.

Prenatal nitrate intake from drinking water and selected birth defects in offspring of participants in the national birth defects prevention study.

BACKGROUND: Previous studies of prenatal exposure to drinking-water nitrate and birth defects in offspring have not accounted for water consumption patterns or potential interaction with nitrosatable drugs. OBJECTIVES: We examined the relation between prenatal exposure to drinking-water nitrate and selected birth defects, accounting for maternal water consumption patterns and nitrosatable drug exposure. METHODS: With data from the National Birth Defects Prevention Study, we linked addresses of 3,300 case mothers and 1,121 control mothers from the Iowa and Texas sites to public water supplies and respective nitrate measurements. We assigned nitrate levels for bottled water from collection of representative samples and standard laboratory testing. Daily nitrate consumption was estimated from self-reported water consumption at home and work. RESULTS: With the lowest tertile of nitrate intake around conception as the referent group, mothers of babies with spina bifida were 2.0 times more likely (95% CI: 1.3, 3.2) to ingest ≥ 5 mg nitrate daily from drinking water (vs. < 0.91 mg) than control mothers. During 1 month preconception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI: 1.1, 3.1), 1.9 (95% CI: 1.2, 3.1), and 1.8 (95% CI: 1.1, 3.1) times more likely than control mothers to ingest ≥ 5.42 mg of nitrate daily (vs. < 1.0 mg). Higher water nitrate intake did not increase associations between prenatal nitrosatable drug use and birth defects. CONCLUSIONS: Higher water nitrate intake was associated with several birth defects in offspring, but did not strengthen associations between nitrosatable drugs and birth defects.

Maternal dietary intake of nitrates, nitrites and nitrosamines and selected birth defects in offspring: a case-control study.

BACKGROUND: Dietary intake of nitrates, nitrites, and nitrosamines can increase the endogenous formation of N-nitroso compounds in the stomach. Results from animal studies suggest that these compounds might be teratogenic. We examined the relationship between maternal dietary intake of nitrates, nitrites (including plant and animal sources as separate groups), and nitrosamines and several types of birth defects in offspring. METHODS: For this population-based case-control study, data from a 58-question food frequency questionnaire, adapted from the short Willett Food Frequency Questionnaire and administered as part of the National Birth Defects Prevention Study (NBDPS), were used to estimate daily intake of dietary nitrates, nitrites, and nitrosamines in a sample of 6544 mothers of infants with neural tube defects (NTD)s, oral clefts (OC)s, or limb deficiencies (LD)s and 6807 mothers of unaffected control infants. Total daily intake of these compounds was divided into quartiles based on the control mother distributions. Odds ratios (OR)s and 95% confidence intervals (CI)s were estimated using logistic regression; estimates were adjusted for maternal daily caloric intake, maternal race-ethnicity, education, dietary folate intake, high fat diet (>30% of calories from fat), and state of residence. RESULTS: While some unadjusted ORs for NTDS had 95% (CI)s that excluded the null value, none remained significant after adjustment for covariates, and the effect sizes were small (adjusted odds ratios [aOR]<1.12). Similar results were found for OCs and LDs with the exception of animal nitrites and cleft lip with/without cleft palate (aORs and CIs for quartile 4 compared to quartile 1 =1.24; CI=1.05-1.48), animal nitrites and cleft lip (4th quartile aOR=1.32; CI=1.01-1.72), and total nitrite and intercalary LD (4th quartile aOR=4.70; CI=1.23-17.93). CONCLUSIONS: Overall, odds of NTDs, OCs or LDs did not appear to be significantly associated with estimated dietary intake of nitrate, nitrite, and nitrosamines.

Interaction of nitrate and folate on the risk of breast cancer among postmenopausal women.

Ingested nitrate can be endogenously reduced to nitrite, which may form N-nitroso compounds, known potent carcinogens. However, some studies have reported no or inverse associations between dietary nitrate intake and cancer risk. These associations may be confounded by a protective effect of folate, which plays a vital role in DNA repair. We evaluated the interaction of dietary and water nitrate intake with total folate intake on breast cancer risk in the Iowa Women's Health Study. Dietary intake was assessed at study baseline. Nitrate intake from public water was assessed using a historical database on Iowa municipal water supplies. After baseline exclusions, 34,388 postmenopausal women and 2,875 incident breast cancers were included. Overall, neither dietary nor water nitrate was associated with breast cancer risk. Among those with folate intake ≥400 µg/day, breast cancer risk was significantly increased in public water users with the highest nitrate quintile (HR = 1.40, 95% CI = 1.05-1.87) and private well users (HR = 1.38, 95% CI = 1.05-1.82) compared to public water users with the lowest nitrate quintile; in contrast, there was no association among those with lower folate intake. Our findings do not support a previous report of increased risk of breast cancer among individuals with high dietary nitrate but low folate intake.

Nitrate intake and the risk of thyroid cancer and thyroid disease.

BACKGROUND: Nitrate is a contaminant of drinking water in agricultural areas and is found at high levels in some vegetables. Nitrate competes with uptake of iodide by the thyroid, thus potentially affecting thyroid function. METHODS: We investigated the association of nitrate intake from public water supplies and diet with the risk of thyroid cancer and self-reported hypothyroidism and hyperthyroidism in a cohort of 21,977 older women in Iowa who were enrolled in 1986 and who had used the same water supply for >10 years. We estimated nitrate ingestion from drinking water using a public database of nitrate measurements (1955-1988). Dietary nitrate intake was estimated using a food frequency questionnaire and levels from the published literature. Cancer incidence was determined through 2004. RESULTS: We found an increased risk of thyroid cancer with higher average nitrate levels in public water supplies and with longer consumption of water exceeding 5 mg/L nitrate-N (for >or=5 years at >5 mg/L, relative risk [RR] = 2.6 [95% confidence interval (CI) = 1.1-6.2]). We observed no association with prevalence of hypothyroidism or hyperthyroidism. Increasing intake of dietary nitrate was associated with an increased risk of thyroid cancer (highest vs. lowest quartile, RR = 2.9 [1.0-8.1]; P for trend = 0.046) and with the prevalence of hypothyroidism (odds ratio = 1.2 [95% CI = 1.1-1.4]), but not hyperthyroidism. CONCLUSIONS: Nitrate may play a role in the etiology of thyroid cancer and warrants further study.