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Background: N-nitroso compounds are hypothesized human bladder carcinogens. We investigated ingestion of N-nitroso compound precursors nitrate and nitrite from drinking water and diet and bladder cancer in the New England Bladder Cancer Study., Methods: Using historical nitrate measurements for public water supplies and measured and modeled values for private wells, as well as self-reported water intake, we estimated average nitrate concentrations (mg/L NO3-N) and average daily nitrate intake (mg/d) from 1970 to diagnosis/reference date (987 cases and 1,180 controls). We estimated overall and source-specific dietary nitrate and nitrite intakes using a food frequency questionnaire (1,037 cases and 1,225 controls). We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). We evaluated interactions with factors that may affect N-nitroso compound formation (i.e., red meat, vitamin C, smoking), and with water intake., Results: Average drinking water nitrate concentration above the 95th percentile (>2.07 mg/L) compared with the lowest quartile (≤0.21 mg/L) was associated with bladder cancer (OR = 1.5, 95% CI = 0.97, 2.3; P trend = 0.01); the association was similar for average daily drinking water nitrate intake. We observed positive associations for dietary nitrate and nitrite intakes from processed meat (highest versus lowest quintile OR for nitrate = 1.4, 95% CI = 1.0, 2.0; P trend = 0.04; OR for nitrite = 1.5, 95% CI = 1.0, 2.1; P trend = 0.04, respectively), but not other dietary sources. We observed positive interactions between drinking water nitrate and red meat (P-interaction 0.05) and processed red meat (0.07)., Conclusions: Our results suggest the importance of both drinking water and dietary nitrate sources as risk factors for bladder cancer.

Background: Nitrate is converted to nitrite in the human body and subsequently can react with amines and amides in the gastrointestinal tract to form N-nitroso compounds (NOCs), which are known to be carcinogenic in animals. Humans can be exposed to nitrate via consumption of drinking water and diet, especially green leafy vegetables and cured meat. The contribution of nitrate from drinking water in combination with meat intake has not been investigated thoroughly. Therefore, in the present pilot study, we examined the effect of nitrate from drinking water, and its interaction with the consumption of white and processed red meat, on the endogenous formation of NOCs, taking into account the intake of vitamin C, a nitrosation inhibitor., Methods: Twenty healthy subjects were randomly assigned to two groups consuming either 3.75 g/kg body weight (maximum 300 g per day) processed red meat or unprocessed white meat per day for two weeks. Drinking water nitrate levels were kept low during the first week (< 1.5 mg/L), whereas in week 2, nitrate levels in drinking water were adjusted to the acceptable daily intake level of 3.7 mg/kg bodyweight. At baseline, after 1 and 2 weeks, faeces and 24 h urine samples were collected for analyses of nitrate, apparent total N-nitroso compounds (ATNC), compliance markers, and genotoxic potential in human colonic Caco-2 cells., Results: Urinary nitrate excretion was significantly increased during the high drinking water nitrate period for both meat types. Furthermore, levels of compliance markers for meat intake were significantly increased in urine from subjects consuming processed red meat (i.e. 1-Methylhistidine levels), or unprocessed white meat (i.e. 3-Methylhistidine). ATNC levels significantly increased during the high drinking water nitrate period, which was more pronounced in the processed red meat group. Genotoxicity in Caco-2 cells exposed to faecal water resulted in increased genotoxicity after the interventions, but results were only significant in the low drinking water nitrate period in subjects consuming processed red meat. Furthermore, a positive correlation was found between the ratio of nitrate/vitamin C intake (including drinking water) and the level of ATNC in faecal water of subjects in the processed red meat group, but this was not statistically significant., Conclusions: Drinking water nitrate significantly contributed to the endogenous formation of NOC, independent of the meat type consumed. This implies that drinking water nitrate levels should be taken into account when evaluating the effect of meat consumption on endogenous formation of NOC., Trial Registration: Dutch Trialregister: 29707 . Registered 19th of October 2018. Retrospectively registered.

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 (NO 3 -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 NO 3 -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 NO 3 -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 NO 3 -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 (HR Q5vsQ1  = 1.13, CI = 0.89-1.44; p trend  = 0.11) and were elevated for any duration of exposure >1/2-MCL. Rectal cancer risks were associated with the highest TTHM levels (HR Q5vsQ1  = 1.71, CI = 1.00-2.92; p trend  = 0.22) but not with years >1/2-MCL. Bromodichloromethane (HR Q4vsQ1  = 1.89, CI = 1.17-3.00; p trend  = 0.09) and trichloroacetic acid (HR Q4vsQ1  = 1.92, CI = 1.20-3.09; p trend  = 0.18) levels were also associated with risk of rectal cancer. We found no evidence of interaction between TTHM and NO 3 -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., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Unregulated private wells in the United States are susceptible to many groundwater contaminants. Ingestion of nitrate, the most common anthropogenic private well contaminant in the United States, can lead to the endogenous formation of N-nitroso-compounds, which are known human carcinogens. In this study, we expand upon previous efforts to model private well groundwater nitrate concentration in North Carolina by developing multiple machine learning models and testing against out-of-sample prediction. Our purpose was to develop exposure estimates in unmonitored areas for use in the Agricultural Health Study (AHS) cohort. Using approximately 22,000 private well nitrate measurements in North Carolina, we trained and tested continuous models including a censored maximum likelihood-based linear model, random forest, gradient boosted machine, support vector machine, neural networks, and kriging. Continuous nitrate models had low predictive performance (R 2  < 0.33), so multiple random forest classification models were also trained and tested. The final classification approach predicted <1 mg/L, 1-5 mg/L, and ≥5 mg/L using a random forest model with 58 variables and maximizing the Cohen's kappa statistic. The final model had an overall accuracy of 0.75 and high specificity for the higher two categories and high sensitivity for the lowest category. The results will be used for the categorical prediction of private well nitrate for AHS cohort participants that reside in North Carolina., (Copyright © 2018. Published by Elsevier B.V.)

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.

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 (HR p95 vs . Q1  = 1.16, 95% CI: 0.51-2.64). Associations with average TTHM levels were also null (HR Q4 vs . 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 (HR p95 vs . Q1  = 1.66, 95% CI 1.00-2.75;p trend  = 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., (2017 UICC.)

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.

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., Competing Interests: This study was approved by the institutional review boards of the University of Minnesota and the University of Iowa. We thank J. Kantamneni of the Center for Health Effects of Environmental Contamination at the University of Iowa for providing us with the public water supply data, and we also thank C.-P. Hong of the University of Minnesota and M. Butcher at Information Management Services for their programming support on this study. The authors declare they have no actual or potential competing financial interests.

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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

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 >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 µg/L TTHM; 30 µg/L HAA5; 5 mg/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 =93 µg/L, HAA5 =49 µg/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: HR95vsQ1 = 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. [ABSTRACT FROM AUTHOR]

• Nitrate is one of the most common pollutants found in drinking water worldwide. • Our study included over one million births with individual level estimates of nitrate. • We observed an association between nitrate and childhood nervous system cancers. • We did not observe an association between nitrate and other childhood cancers. • Current EU and US standards for nitrate in drinking water may not be adequate. There is limited evidence that nitrate, a common contaminant in drinking water, increases the risk of childhood cancers. Our objective was to examine this association in Denmark. We conducted a nationwide case-control study based on all singletons liveborn to Danish-born parents from 1991 to 2015 (N = 1,219,140) that included 596 leukemias, 180 lymphomas, and 310 central nervous system cancers (CNC) who were ≤15 years of age at diagnosis and were identified from the Danish Cancer Registry. Approximately 100 controls were randomly selected and matched to each case on date of birth and sex. Nitrate measurements in public water systems were linked with an address registry to estimate individual average nitrate concentrations during preconception, prenatal, and postnatal periods. Odd ratios (OR) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression controlling for the matching variables, and birth order, birthweight, urbanicity, maternal education, employment, income and smoking, and parental age. There was no evidence of an association of nitrate with leukemia or lymphoma. An association between CNC and the highest category of nitrate exposure (>25 mg/L nitrate) was observed for preconception (OR = 1.82, 95%CI:1.09 to 3.04), prenatal (OR = 1.65, 95%CI:0.97 to 2.81), and postnatal exposure (OR = 1.48, 95%CI:0.82 to 2.68) in fully adjusted models. There was also some evidence of an exposure–response in models of continuous nitrate exposure and CNC. Our findings provide some evidence that exposure to nitrate from drinking water may increase the risk of childhood CNC cancer, but not leukemia or lymphoma. [ABSTRACT FROM AUTHOR]