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Background: By-products are formed when disinfectants react with organic matter in source water. The most common class of disinfection by-products, trihalomethanes (THMs), have been linked to bladder cancer. Several studies have shown exposure-response associations with THMs in drinking water and bladder cancer risk. Few epidemiologic studies have evaluated gene-environment interactions for total THMs (TTHMs) with known bladder cancer susceptibility variants., Objectives: In this study, we investigated the combined effect on bladder cancer risk contributed by TTHMs, bladder cancer susceptibility variants identified through genome-wide association studies, and variants in several candidate genes., Methods: We analyzed data from two large case-control studies-the New England Bladder Cancer Study ( n / n = 989 cases/1,162 controls), a population-based study, and the Spanish Bladder Cancer Study ( n / n = 706 cases/772 controls), a hospital-based study. Because of differences in exposure distributions and metrics, we estimated effects of THMs and genetic variants within each study separately using adjusted logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CI) with and without interaction terms, and then combined the results using meta-analysis., Results: Of the 16 loci showing strong evidence of association with bladder cancer, rs907611 at 11p15.5 [leukocyte-specific protein 1 ( LSP1 region)] showed the strongest associations in the highest exposure category in each study, with evidence of interaction in both studies and in meta-analysis. In the highest exposure category, we observed OR = 1.66 (95% CI: 1.17, 2.34, p -trend = 0.005 ) for those with the rs907611-GG genotype and p -interaction = 0.02 . No other genetic variants tested showed consistent evidence of interaction., Discussion: We found novel suggestive evidence for a multiplicative interaction between a putative bladder carcinogen, TTHMs, and genotypes of rs907611. Given the ubiquitous exposure to THMs, further work is needed to replicate and extend this finding and to understand potential molecular mechanisms. https://doi.org/10.1289/EHP9895.

Background: Ingestion of disinfection byproducts has been associated with bladder cancer in multiple studies. Although associations with other routes of exposure have been suggested, epidemiologic evidence is limited., Objectives: We evaluated the relationship between bladder cancer and total, chlorinated, and brominated trihalomethanes (THMs) through various exposure routes., Methods: In a population-based case–control study in New England ( n =(1,213) cases; n =(1,418) controls), we estimated lifetime exposure to THMs from ingestion, showering/bathing, and hours of swimming pool use. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression adjusted for confounders., Results: Adjusted ORs for bladder cancer comparing participants with exposure above the 95th percentile with those in the lowest quartile of exposure (based on the distribution in controls) were statistically significant for average daily intake mg/d of total THMs [OR=1.53 (95% CI: 1.01, 2.32), p -trend=0.16] and brominated THMs [OR=1.98 (95% CI: 1.19, 3.29), p-trend=0.03]. For cumulative intake mg, the OR at the 95th percentile of total THMs was 1.45 (95% CI: 0.95, 2.2), p -trend=0.13; the ORs at the 95th percentile for chlorinated and brominated THMs were 1.77 (95% CI: 1.05, 2,.99), p -trend=0.07 and 1.78 (95% CI: 1.05, 3.00), p -trend=0.02, respectively. The OR in the highest category of showering/bathing for brominated THMs was 1.43 (95% CI: 0.80, 2.42), p -trend=0.10. We found no evidence of an association for bladder cancer and hours of swimming pool use., Conclusions: We observed a modest association between ingestion of water with higher THMs (>95th percentile vs.<25th percentile) and bladder cancer. Brominated THMs have been a particular concern based on toxicologic evidence, and our suggestive findings for multiple metrics require further study in a population with higher levels of these exposures. Data from this population do not support an association between swimming pool use and bladder cancer. https://doi.org/10.1289/EHP89.

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.

Background: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans., Objectives: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed., Discussion: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed., Conclusions: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.

Background: Altered DNA methylation has been associated with various diseases., Objective: We evaluated the association between levels of methylation in leukocyte DNA at long interspersed nuclear element 1 (LINE-1) and genetic and non-genetic characteristics of 892 control participants from the Spanish Bladder Cancer/EPICURO study., Methods: We determined LINE-1 methylation levels by pyrosequencing. Individual data included demographics, smoking status, nutrient intake, toenail concentrations of 12 trace elements, xenobiotic metabolism gene variants, and 515 polymorphisms among 24 genes in the one-carbon metabolism pathway. To assess the association between LINE-1 methylation levels (percentage of methylated cytosines) and potential determinants, we estimated beta coefficients (βs) by robust linear regression., Results: Women had lower levels of LINE-1 methylation than men (β = -0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers (β = -0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation (β = -3.6, p = 0.003). By contrast, iron (β = 0.002, p = 0.009) and nickel (β = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217-per allele, β = 0.3, p = 0.002), TCN2 (rs9606756-GG, β = 1.9, p = 0.008; rs4820887-AA, β = 4.0, p = 4.8 × 10-7; rs9621049-TT, β = 4.2, p = 4.7 × 10-9), AS3MT (rs7085104-GG, β = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: β = 0.5 and CC vs. TT: β = -0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: β = 0.3 and TT vs. CC; β = -0.8, global p = 0.05) were associated with LINE-1 methylation., Conclusions: We identified several characteristics, environmental factors, and common genetic variants that predicted DNA methylation among study participants.

Background: Ingestion of inorganic arsenic in drinking water is recognized as a cause of bladder cancer when levels are relatively high (≥ 150 µg/L). The epidemiologic evidence is less clear at the low-to-moderate concentrations typically observed in the United States. Accurate retrospective exposure assessment over a long time period is a major challenge in conducting epidemiologic studies of environmental factors and diseases with long latency, such as cancer., Objective: We estimated arsenic concentrations in the water supplies of 2,611 participants in a population-based case-control study in northern New England., Methods: Estimates covered the lifetimes of most study participants and were based on a combination of arsenic measurements at the homes of the participants and statistical modeling of arsenic concentrations in the water supply of both past and current homes. We assigned a residential water supply arsenic concentration for 165,138 (95%) of the total 173,361 lifetime exposure years (EYs) and a workplace water supply arsenic level for 85,195 EYs (86% of reported occupational years)., Results: Three methods accounted for 93% of the residential estimates of arsenic concentration: direct measurement of water samples (27%; median, 0.3 µg/L; range, 0.1-11.5), statistical models of water utility measurement data (49%; median, 0.4 µg/L; range, 0.3-3.3), and statistical models of arsenic concentrations in wells using aquifers in New England (17%; median, 1.6 µg/L; range, 0.6-22.4)., Conclusions: We used a different validation procedure for each of the three methods, and found our estimated levels to be comparable with available measured concentrations. This methodology allowed us to calculate potential drinking water exposure over long periods.

Background: Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water., Objectives: In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case-control study in Spain., Methods: Average exposures to trihalomethanes (THMs; a surrogate for DBPs) from 15 years of age were estimated for each subject based on residential history and information on municipal water sources among 680 cases and 714 controls. We estimated effects of THMs and GSTT1, GSTZ1, and CYP2E1 polymorphisms on bladder cancer using adjusted logistic regression models with and without interaction terms., Results: THM exposure was positively associated with bladder cancer: adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.2 (0.8-1.8), 1.8 (1.1-2.9), and 1.8 (0.9-3.5) for THM quartiles 2, 3, and 4, respectively, relative to quartile 1. Associations between THMs and bladder cancer were stronger among subjects who were GSTT1 +/+ or +/- versus GSTT1 null (P(interaction) = 0.021), GSTZ1 rs1046428 CT/TT versus CC (P(interaction) = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (P(interaction) = 0.035). Among the 195 cases and 192 controls with high-risk forms of GSTT1 and GSTZ1, the ORs for quartiles 2, 3, and 4 of THMs were 1.5 (0.7-3.5), 3.4 (1.4-8.2), and 5.9 (1.8-19.0), respectively., Conclusions: Polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk. The consistency of these findings with experimental observations of GSTT1, GSTZ1, and CYP2E1 activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms as well as the classes of compounds likely to be implicated.

Background: Inhalation of high levels of airborne inorganic arsenic is a recognized cause of respiratory cancer. Although multiple epidemiologic studies have demonstrated this association, there have been few analyses of the mathematical relationship between cumulative arsenic exposure and risk of respiratory cancer, and no assessment as to whether and how arsenic concentration may modify this association., Objectives: The objective is an evaluation of the shape of the relationship between respiratory cancer mortality and cumulative inhaled arsenic exposure among copper smelter workers, and the modification of that relationship by arsenic concentration., Methods: We used Poisson regression methods to analyze data from a cohort of arsenic-exposed copper smelter workers under a linear-exponential model for the excess relative risk., Results: Within categories of arsenic concentration, the association between respiratory cancer and cumulative arsenic exposure was consistent with linearity. The slope of the linear relationship with cumulative exposure increased with increasing arsenic concentration category., Conclusions: Our results suggested a direct concentration effect from inhaled inorganic arsenic, whereby the excess relative risk for a fixed cumulative exposure was greater when delivered at a higher concentration and shorter duration than when delivered at a lower concentration and longer duration.

Background: We previously conducted a study to assess whether household exposures to tap water increased an individual's internal dose of trihalomethanes (THMs). Increases in blood THM levels among subjects who showered or bathed were variable, with increased levels tending to cluster in two groups., Objectives: Our goal was to assess the importance of personal characteristics, previous exposures, genetic polymorphisms, and environmental exposures in determining THM concentrations in blood after showering., Methods: One hundred study participants completed a health symptom questionnaire, a 48-hr food and water consumption diary, and took a 10-min shower in a controlled setting. We examined THM levels in blood samples collected at baseline and 10 and 30 min after the shower. We assessed the significance of personal characteristics, previous exposures to THMs, and specific gene polymorphisms in predicting postshower blood THM concentrations., Results: We did not observe the clustering of blood THM concentrations observed in our earlier study. We found that environmental THM concentrations were important predictors of blood THM concentrations immediately after showering. For example, the chloroform concentration in the shower stall air was the most important predictor of blood chloroform levels 10 min after the shower (p < 0.001). Personal characteristics, previous exposures to THMs, and specific polymorphisms in CYP2D6 and GSTT1 genes were significant predictors of both baseline and postshowering blood THM concentrations as well as of changes in THM concentrations associated with showering., Conclusion: The inclusion of information about individual physiologic characteristics and environmental measurements would be valuable in future studies to assess human health effects from exposures to THMs in tap water.

Background: Findings on water and total fluid intake and bladder cancer are inconsistent; this may, in part, be due to different levels of carcinogens in drinking water. High levels of arsenic and chlorinated by-products in drinking water have been associated with elevated bladder cancer risk in most studies. A pooled analysis based on six case-control studies observed a positive association between tap water and bladder cancer but none for nontap fluid intake, suggesting that contaminants in tap water may be responsible for the excess risk., Objectives: We examined the association between total fluid and water consumption and bladder cancer risk, as well as the interaction between water intake and trihalomethane (THM) exposure, in a large case-control study in Spain., Methods: A total of 397 bladder cancer cases and 664 matched controls were available for this analysis. Odds ratios (OR) were estimated using unconditional logistic regression, controlling for potential confounders., Results: Total fluid intake was associated with a decrease in bladder cancer risk [OR = 0.62; 95% confidence interval (CI), 0.40-0.95 for highest vs. lowest quintile comparison]. A significant inverse association was observed for water intake (for > 1,399 vs. < 400 mL/day, OR = 0.47; 95% CI, 0.33-0.66; p for trend < 0.0001), but not for other individual beverages. The inverse association between water intake and bladder cancer persisted within each level of THM exposure; we found no statistical interaction (p for interaction = 0.13)., Conclusion: Findings from this study suggest that water intake is inversely associated with bladder cancer risk, regardless of THM exposure level.

Increases in non-Hodgkin's lymphoma (NHL) incidence and mortality rates during the past few decades remain largely unexplained. Studies suggest that organochlorine pesticides may contribute to an increased risk of NHL. In 1974, serum samples were obtained from 25,802 participants in the Campaign Against Cancer and Stroke in Washington County, Maryland (USA), and cryopreserved for future study. We measured prediagnostic levels of chlordane, lindane (gamma-hexachlorocyclohexane), beta-hexachlorocyclohexane, transnonachlor, heptachlor, heptachlor epoxide, oxychlordane, dieldrin, and hexachlorobenzene in serum samples of 74 cases of NHL and 147 matched controls. Previously, we found an association between NHL and serum levels of total PCBs (polychlorinated biphenyls), but not DDT (dichlorodiphenyltrichloroethane) and related compounds. In this instance, there was no evidence of an association between NHL risk and serum levels of any of the individual lipid- and recovery-corrected organochlorines that we evaluated, nor of the summed chlordane-related compounds (transnonachlor, heptachlor, heptachlor epoxide, oxychlordane). These findings do not support the hypothesis that the organochlorine compounds included in this study are strongly linked to the development of NHL. The possibility of a weak association cannot be excluded by these data.

Pesticides used in agriculture may cause adverse health effects among the population living near agricultural areas. However, identifying the populations most likely to be exposed is difficult. We conducted a feasibility study to determine whether satellite imagery could be used to reconstruct historical crop patterns. We used historical Farm Service Agency records as a source of ground reference data to classify a late summer 1984 satellite image into crop species in a three-county area in south central Nebraska. Residences from a population-based epidemiologic study of non-Hodgkin lymphoma were located on the crop maps using a geographic information system (GIS). Corn, soybeans, sorghum, and alfalfa were the major crops grown in the study area. Eighty-five percent of residences could be located, and of these 22% had one of the four major crops within 500 m of the residence, an intermediate distance for the range of drift effects from pesticides applied in agriculture. We determined the proximity of residences to specific crop species and calculated crop-specific probabilities of pesticide use based on available data. This feasibility study demonstrated that remote sensing data and historical records on crop location can be used to create historical crop maps. The crop pesticides that were likely to have been applied can be estimated when information about crop-specific pesticide use is available. Using a GIS, zones of potential exposure to agricultural pesticides and proximity measures can be determined for residences in a study.

Concern has recently been voiced over possible chronic toxicity associated with chlorination of public drinking water supplies in the United States. This paper reviews the available evidence and the studies underway to further evaluate hypothesized associations between cancer risk and byproducts of chlorination. Preliminary data from measures of halogenated volatiles and personal exposure histories from respondents in a large epidemiologic study of bladder cancer are presented. These data support the use in epidemiologic studies of categorical measures of exposure and suggest that results from completed case-control studies, based on death certificates, may have underestimated the true risk of exposure to chlorination by-products. The current generation of studies which use a case-control interview design offer many advantages over earlier efforts to evaluate this issue.