Disinfection By-products Exposure Research Articles

Temporal variability in trihalomethane and haloacetic acid concentrations in Massachusetts public drinking water systems

Previous epidemiological studies in Massachusetts have reported a risk of adverse health outcomes in relation to disinfection by-product (DBP) exposures. Measurement error due to the use of indirect exposure surrogates can lead to misclassification bias in epidemiological studies; therefore, it is important to characterize exposure variability in these populations to assess the potential for exposure misclassification. We used 19,944 trihalomethane (THM) samples and 9291 haloacetic acid (HAA) samples collected in 201 public water systems (PWSs) in Massachusetts to examine temporal variability under different drinking water sources and disinfection types. Annual and seasonal variability was also examined in 46 PWSs with complete quarterly THM4 (i.e., the sum of 4 individual THMs) data from 1995 to 2004 and 19 PWSs with complete HAA5 (i.e., the sum of 5 individual HAAs) data from 2001 to 2004. The quarterly ratio of THM4 and HAA5 and correlations between THM4, HAA5 and individual DBP species were examined to determine the adequacy of using different exposure surrogates in epidemiological studies. Individual PWSs were used to examine monthly variability in relation to quarterly averages. Based on all available matched samples ( n=9003) from 1995 to 2004 data, we found a correlation of 0.52 for THM4 and HAA5. The correlation was stronger among the 62 ground water systems ( r s =0.62) compared to the 81 surface water ( r s =0.45) and 40 mixed water ( r s =0.39) systems. Mean THM4 levels were fairly stable over the 10-year study period for 46 PWSs including 39 PWSs that did not change disinfection. Large reductions (∼40 μg/L) in mean THM4 data were found among seven systems that switched from chlorination to alternative disinfectants. As expected, the highest mean THM4 values were detected for Quarter 3, while the lowest values were found in Quarter 1. The highest HAA5 values were detected in Quarters 2 and 3 and the lowest was found in Quarter 4. Data from four systems showed mean differences up to 66 μg/L (67% change) in successive months and by 46 μg/L compared to quarterly mean concentrations. Although longer-term disinfection by-product temporality may be minimal in this study population, the use of monthly average concentrations for exposure assessment may be needed for some PWSs to minimize misclassification of narrow critical periods of exposure in epidemiological studies.

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action

Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures. As a first step in a mixtures risk assessment for DBP developmental effects, this paper identifies developmentally toxic DBPs and examines data relevant to the mode of action (MOA) for DBP developmental toxicity. We identified 24 developmentally toxic DBPs and four adverse developmental outcomes associated with human DBP exposures: spontaneous abortion, cardiovascular defects, neural tube defects, and low birth weight infancy. A plausible MOA, involving hormonal disruption of pregnancy, is delineated for spontaneous abortion, which some epidemiologic studies associate with total trihalomethane and bromodichloromethane exposures. The DBP data for the other three outcomes were inadequate to define key MOA steps.

Exposure to Disinfection By-products During Pregnancy

O-30C6-4 Background/Aims: Many studies of disinfection by-products (DBPs) in drinking water and adverse birth outcomes have been limited by a lack of individual-level data on water use for exposure assessment, and by potential residual confounding. Uncertainty remains as to the most important factors driving exposure to DBPs, and which factors may be potential confounders. We have investigated these issues whilst performing exposure assessment for a new birth cohort. Methods: Patterns of water consumption, showering, bathing, and swimming were analyzed for women in the Born in Bradford cohort (n = 4045). These individual-level water use data were collected by questionnaire and validated in a nested study (n = 39), using a 7-day exposure diary. Semi-individual metrics of exposure to trihalomethanes (THMs) during pregnancy were calculated for 2710 women combining individual-level water use data and modeled area-level THM concentrations. Semi-individual exposure metrics were analyzed using ANOVA to assess the contribution of spatial, temporal, and individual components of variability. Results: Preliminary results show that water consumption, showering, bathing, and swimming differ according to demographic and lifestyle variables (eg, combined showering/bathing per week decreases across increasing age groups, with a difference of almost 2 hours between youngest and oldest age groups), and suggest accuracy of self-reported water use data differs according to employment status. Whilst underlying patterns of spatial and temporal variation in THM concentrations at the tap can be observed in semi-individual THM exposure metrics their contributions to total variability are very small, and it appears the majority (83%–96%) of variability in THM exposure is explained by individual variation in water use behavior. Conclusion: This study provides important insights into the accuracy of self-reported exposure data and the factors driving DBP exposure amongst pregnant women. The findings are valuable to inform exposure assessment and epidemiological analysis in studies assessing the relationship between DBPs and adverse birth outcomes.

Risk of Stillbirth in Relation to Disinfection By-products in Taiwan

S-29C6-3 Background/Aims: Recent findings suggest that exposure to disinfection by-products may increase the risk of stillbirth. The results of these studies are inconsistent, but warrant further attention. Methods: To assess the effect of water chlorination by-products on stillbirth, we conducted a population-based case-control study of 3289 cases of stillbirth and a random sample of 32,890 control subjects from 396,049 Taiwanese newborns in 2001–2003 using information from the Birth Registry and Waterworks Registry in Taiwan. We compared the risk of stillbirth in 4 disinfection by-product exposure categories based on the levels of total trihalomethanes (TTHMs) representing high (TTHMs 20+ μg/L), medium (TTHMs 10–19 μg/L), low exposures (TTHMs 5–9 μg/L), and 0–4 μg/L as the reference category. Results: In logistic regression analysis adjusting for gender, maternal age, plurality, conception of season, and population density of the municipality where the mother lived during pregnancy, the odds ratio for stillbirth was 1.10 (95% CI: 1.00–1.21) for medium exposure and 1.06 (95% CI: 0.96–1.17) for high exposure compared to reference category. Conclusion: The risk of stillbirth may associate with women exposure to disinfection by-products in Taiwanese drinking water.

Disinfection By-products and Bladder Cancer: Common Genetic Variants May Confer Increased Risk

Vol. 118, No. 11 NewsOpen AccessDisinfection By-products and Bladder Cancer: Common Genetic Variants May Confer Increased Risk Kris S. Freeman Kris S. Freeman Search for more papers by this author Published:1 November 2010https://doi.org/10.1289/ehp.118-a491aCited by:1AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Disinfection of the water supply is an important and cost-effective tool to reduce morbidity and mortality from a wide range of infectious diseases. However, the chemicals used to treat water also can produce potentially toxic compounds known as disinfection by-products (DBPs). A new study shows strong associations between DBP exposure and bladder cancer among individuals who carry inherited variants in three genes (GSTT1, GSTZ1, and CYP2E1) that code for key enzymes that metabolize DBPs [EHP118(11):1545–1550; Cantor et al.].DBPs form when disinfectants (such as chlorine) react with organic matter that collects in water (such as algae or humic acids from decayed leaves). Most DBP exposure is due to ingestion of drinking water, although some DBPs can be inhaled or absorbed through the skin during bathing, showering, or swimming in a pool. Laboratory studies show that many DBPs are mutagenic or carcinogenic, but epidemiologic studies to date have revealed only a modest association between DBP exposure and cancer in humans.In the present study, 595 men and 85 women newly diagnosed with bladder cancer were recruited from 18 hospitals in Spain and matched with controls (622 men and 92 women) who had been hospitalized with conditions thought to be unrelated to bladder cancer. The authors estimated DBP exposure since age 15 years by linking participants’ residential histories with documented and estimated levels of trihalomethanes (THMs)—a DBP often used as a marker for total DBP exposure—in municipal water systems. Participants were genotyped for variations in GSTT1, GSTZ1, and CYP2E1.Across the study population cancer risk nearly doubled between the highest and lowest levels of DBP exposure, and the association with DBP exposure was even stronger among participants who carried one of three variant genotypes. Smokers also had a higher risk (smoking is the most significant known risk factor for bladder cancer).One of the genotypes appeared to increase the association between DBPs and bladder cancer codes for the active form of the enzyme glutathione transferase theta-1 (GSTT1), which metabolizes brominated THMs to mutagens. Another increases the activity of cytochrome P450 2E1 (CYP2E1), which catalyzes the primary oxidation of THMs. There is evidence the third genotype may reduce the activity of glutathione transferase zeta-1 (GSTZ1), which transforms haloacetic acids, another type of DBP, to less toxic compounds.Among individuals who carried both of the GSTT1 and GSTZ1 genotypes noted above (28% of study participants), those with the highest DBP exposure were at a 1.5 times increased risk of bladder cancer compared with carriers with the lowest DBP exposure. These genotypes are relatively common, occurring jointly in more than 20% of the controls in the study population. The findings from this study therefore may have significant public health implications for cancer prevention.FiguresReferencesRelatedDetailsCited by Hall D, Yeung K and Peng H (2020) Monohaloacetic Acids and Monohaloacetamides Attack Distinct Cellular Proteome Thiols, Environmental Science & Technology, 10.1021/acs.est.0c03144 Vol. 118, No. 11 November 2010Metrics About Article Metrics Publication History Originally published1 November 2010Published in print1 November 2010 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Disinfection By-products: A Question of Balance

Disinfection By-products: A Question of Balance

Pooling Data on Pools: Genotoxicity of Chemicals in Indoor Swimming Pools

Disinfection by-products (DBPs) form in swimming pool water from reactions between disinfectants such as chlorine and organic matter such as sweat, skin cells, and urine. A new study described in a set of three articles provides the first comprehensive characterization of DBPs in an indoor pool environment and offers initial evidence of cellular-level effects of these chemicals in swimmers in an indoor chlorinated pool [EHP 118(11):1523–1530; Richardson et al.; EHP 118(11):1531–1537, Kogevinas et al.; EHP 118(11):1538–1544, Font-Ribera et al.]. The authors assessed short-term changes in 49 healthy adults after they swam for 40 minutes in a public indoor chlorinated pool. They observed increases in two biomarkers of genotoxicity relative to the concentration of brominated trihalomethanes (THMs) in exhaled breath, which were used as a proxy of the swimmers’ total DBP exposures. Those biomarkers were micronuclei in blood lymphocytes (which have been associated with cancer risk in healthy subjects) and urine mutagenicity (a biomarker of exposure to genotoxic agents). The team also took detailed measurements of THMs in air around the pool and in exhaled breath of the swimmers before and after swimming. The investigators measured several biomarkers of respiratory effects after swimming and found changes in only one—a slight increase in serum CC16, which suggests an increase in lung epithelium permeability. However, they found no evidence that DBP exposure affected lung function. The research team identified more than 100 DBPs in the water of the chlorinated pool as well as another indoor pool disinfected with bromine. Some of these compounds had never been reported previously in swimming pool water and/or chlorinated drinking water. In vitro assays showed the swimming pool water was mutagenic at levels similar to that of drinking water but was more cytotoxic (could kill cells at a lower concentration) than drinking water. The researchers acknowledge the need for further research on a variety of swimming pools under various conditions of maintenance and use as well as more complete evaluations of the uptake and potential effects of the compounds present in pool water. They also note the importance of timing in the collection of biological samples—a parameter for which there was no precedent, given the lack of previous studies of this type with swimmers. Above all, they emphasize that positive health effects of swimming can be maintained by minimizing pool levels of DBPs.

Chlorination disinfection by-products in drinking water and congenital anomalies: review and meta-analyses

This study aims to review epidemiologic evidence of the association between exposure to chlorination disinfection by-products (DBPs) and congenital anomalies. All epidemiologic studies that evaluated a relationship between an index of DBP exposure and risk of congenital anomalies were analyzed. For all congenital anomalies combined, the meta-analysis gave a statistically significant excess risk for high versus low exposure to water chlorination or TTHM (17%; 95% CI, 3-34) based on a small number of studies. The meta-analysis also suggested a statistically significant excess risk for ventricular septal defects (58%; 95% CI, 21-107), but based on only three studies, and there was little evidence of an exposure-response relationship. It was observed no statistically significant relationships in the other meta-analyses and little evidence for publication bias, except for urinary tract defects and cleft lip and palate. Although some individual studies have suggested an association between chlorination disinfection by-products and congenital anomalies, meta-analyses of all currently available studies demonstrate little evidence of such association.

Short-Term Changes in Respiratory Biomarkers after Swimming in a Chlorinated Pool

BackgroundSwimming in chlorinated pools involves exposure to disinfection by-products (DBPs) and has been associated with impaired respiratory health.ObjectivesWe evaluated short-term changes in several respiratory biomarkers to explore mechanisms of potential lung damage related to swimming pool exposure.MethodsWe measured lung function and biomarkers of airway inflammation [fractional exhaled nitric oxide (FeNO), eight cytokines, and vascular endothelial growth factor (VEGF) in exhaled breath condensate], oxidative stress (8-isoprostane in exhaled breath condensate), and lung permeability [surfactant protein D (SP-D) and the Clara cell secretory protein (CC16) in serum] in 48 healthy nonsmoking adults before and after they swam for 40 min in a chlorinated indoor swimming pool. We measured trihalomethanes in exhaled breath as a marker of individual exposure to DBPs. Energy expenditure during swimming, atopy, and CC16 genotype (rs3741240) were also determined.ResultsMedian serum CC16 levels increased from 6.01 to 6.21 μg/L (average increase, 3.3%; paired Wilcoxon test p = 0.03), regardless of atopic status and CC16 genotype. This increase was explained both by energy expenditure and different markers of DBP exposure in multivariate models. FeNO was unchanged overall but tended to decrease among atopics. We found no significant changes in lung function, SP-D, 8-isoprostane, eight cytokines, or VEGF.ConclusionsWe detected a slight increase in serum CC16, a marker of lung epithelium permeability, in healthy adults after they swam in an indoor chlorinated pool. Exercise and DBP exposure explained this association, without involving inflammatory mechanisms. Further research is needed to confirm the results, establish the clinical relevance of short-term serum CC16 changes, and evaluate the long-term health impacts.

Polymorphisms in GSTT1 , GSTZ1 , and CYP2E1 , Disinfection By-products, and Risk of Bladder Cancer in Spain

BackgroundBladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water.ObjectivesIn 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.MethodsAverage 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.ResultsTHM 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 (pinteraction = 0.021), GSTZ1 rs1046428 CT/TT versus CC (pinteraction = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (pinteraction = 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.ConclusionsPolymorphisms 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.

Long-Term Ambient Ozone Concentrations and Incidence of Emphysema in Nonsmoking California Adults: Results from the Ahsmog Study

S (ACE) AEP Vol. 20, No. 9 September 2010: 691–724 706 emphysema with OR 1.07(95% CI: 1.01–1.22) and 1.24 (95% CI: 1.05–1.47) respectively. Sensitivity analysis was conducted to further evaluate association between PM10 and incidence of emphysema by gender. This showed that the association between PM10 and incidence of emphysema was limited to females with an OR of 1.37 (95% CI: 1.11– 1.69) for each increase of 10 mg/m3 in PM10 as well as a significant association with exceedance frequencies of PM10 (40 days/year in excess of 40, 60, 80 and 100 mg/ m3) (Table 6). These point estimates did not change significantly as SO2, NO2 and O3 was added to the models one at a time. For males no association was observed betweenmean concentration of PM10, O3, and SO2 and incidence of emphysema. In conclusion, a significant positive association was observed between ambient PM10 and incidence of emphysema in females after adjusting for relevant confounders, including packyears of smoking. This association remained after adjusting for O3 in two-pollutant models. Also, a significant positive association was found between incidence of emphysema and each increment of 40 days/year that PM10 exceeded several cutoff points. The PM10 regression estimates increased as the cutoffs increased. For males, no significant associations were found. Our findings are in line with other studies that indicate a gender difference in effect of ambient air pollution on cardio-pulmonary disease. Further research with larger study size is needed to better understand the gender difference in the relationship between incidence of emphysema and PM10. P43 LONG-TERM AMBIENT OZONE CONCENTRATIONS AND INCIDENCE OF EMPHYSEMA IN NONSMOKING CALIFORNIA ADULTS: RESULTS FROM THE AHSMOG STUDY S Metghalchi, L Beeson, S Knutsen, Loma Linda University, Loma Linda, CA The aim of this study was to evaluate the relationship of long-term concentrations of ozone (O3) and risk of emphysema in nonsmoking California adults. A cohort study of 6,338 nonsmoking, non-Hispanic, white Californian adults, ages 27–95, was followed from 1977 to 2000 for recently diagnosed emphysema. Monthly ambient air pollution data were interpolated to zip code centroids according to home and work location histories and averaged over time. We observed significant associations between incidence of emphysema and 10 ppb increase in mean concentration of ozone in females with OR of 1.87 (95% CI: 1.11–3.15). In addition, we observed a significant associations between incidence of emphysema and 10-h average annual increment of ozone 100 and 120 (ppb) in females with OR of 1.15 (95% CI: 1.02–1.28), and OR of 1.17 (95% CI: 1.01– 1.37). These risk estimates remained virtually unchanged in two-pollutant analysis with PM10. In summary, we found that subjects living in areas that regularly experience high ozone levels, have increasing risk of developing emphysema even after adjusting for smoking and other potential confounding variables. The risk increased in a dose-response fashion with those experiencing levels above 150 ppb having the highest risk. Further research is needed to better understand the relationship between incidence of emphysema and ozone exposure and also to better separate the independent effects of PM10, O3, SO2, and NO2. P44 EFFECTS OF TRIHALOMETHANES ON BIRTH OUTCOMES S Kumar, S Forand, New York State Department of Health, Troy, NY PURPOSE: Disinfection by-products (DBPs), including trihalomethanes (THMs), result from the reaction between chlorine and natural organic matter in drinking water. The possible reproductive effects of DBPs exposure during pregnancy are receiving considerable interest because of the wide-spread occurrence of DBPs in drinking water. To understand the effect of total trihalomethane (TTHM) exposure on birthweight and gestation period, we studied the association of four THMs that are routinely monitored in drinking water with low birthweight and prematurity. METHODS: All singleton live births from 1998 through 2003 in New York were linked with public water supply system boundary based on mother’s residential address on birth certificate. THMmeasurements of water supply system were assigned geographically and temporally to each birth record. Individual level maternal information including mother’s race, ethnicity, education, employment status, age, adequacy of prenatal care along with infant’s gender was used to adjust for confounding. We used several regression model including linear, logistic, GLM and quantile based regression model. Of all the tested models, we selected quantile based regression model because of its features that includes the use of input data for model training, validation and testing. RESULTS: A small but inconsistent association was detected between term low birthweight births and TTHM exposure, suggesting some increase in risk for low birth weight is associated with maternal exposure to water containing THMs. CONCLUSION: Though there is a possibility of potential misclassification due to maternal mobility, water use, and daily change in the level of THMs, our findings are consistent with other published work.

Model development for predicting changes in DBP exposure concentrations during indoor handling of tap water

Disinfection by-products (DBPs) in municipal drinking water are a matter of concern because of their possible risks to human health. Risk assessment studies often use measurements of DBPs in water distribution systems, whereas populations are typically exposed to the indoor tap water. Further to this, consumers often employ several indoor strategies to handle tap water (e.g., storing in a refrigerator, boiling, filtering, etc.) prior to use. The indoor handling of municipal water may have implications on DBPs' exposure assessment. This study investigates and develops models to predict the effects of various indoor handling strategies on trihalomethanes (THMs) and haloacetic acids (HAAs). Linear and nonlinear models are developed to predict changes in THM and HAA concentrations due to various indoor water manipulation strategies. The models are capable of assessing representative exposure concentrations of THMs and HAAs as a result of indoor handling, which might be useful in gaining a better understanding of exposure and risks from DBPs in municipal drinking water.

Concentration, Chlorination, and Chemical Analysis of Drinking Water for Disinfection Byproduct Mixtures Health Effects Research: U.S. EPA’s Four Lab Study

The U.S. Environmental Protection Agency's "Four Lab Study" involved participation of researchers from four national Laboratories and Centers of the Office of Research and Development along with collaborators from the water industry and academia. The study evaluated toxicological effects of complex disinfection byproduct (DBP) mixtures, with an emphasis on reproductive and developmental effects that have been associated with DBP exposures in some human epidemiologic studies. This paper describes a new procedure for producing chlorinated drinking water concentrate for animal toxicology experiments, comprehensive identification of >100 DBPs, and quantification of 75 priority and regulated DBPs. In the research reported herein, complex mixtures of DBPs were produced by concentrating a natural source water with reverse osmosis membranes, followed by addition of bromide and treatment with chlorine. By concentrating natural organic matter in the source water first and disinfecting with chlorine afterward, DBPs (including volatiles and semivolatiles) were formed and maintained in a water matrix suitable for animal studies. DBP levels in the chlorinated concentrate compared well to those from EPA's Information Collection Rule (ICR) and a nationwide study of priority unregulated DBPs when normalized by total organic carbon (TOC). DBPs were relatively stable over the course of the animal studies (125 days) with multiple chlorination events (every 5-14 days), and a significant portion of total organic halogen was accounted for through a comprehensive identification approach. DBPs quantified included regulated DBPs, priority unregulated DBPs, and additional DBPs targeted by the ICR. Many DBPs are reported for the first time, including previously undetected and unreported haloacids and haloamides. The new concentration procedure not only produced a concentrated drinking water suitable for animal experiments, but also provided a greater TOC concentration factor (136×), enhancing the detection of trace DBPs that are often below detection using conventional approaches.

DRINKING WATER QUALITY: Better Biomarker of DBP Exposure

DRINKING WATER QUALITY: Better Biomarker of DBP Exposure

Disinfection By-Products and Congenital Anomalies: Evidence Still Inconclusive

Many observational studies have investigated a possible association between maternal exposure to mutagenic disinfection by‐products (DBPs) in the water supply and congenital anomalies in offspring, but literature reviews to date have shown the evidence to be inconclusive. Now researchers have reviewed newer epidemiologic studies that include more categories of anomalies, but again have found the evidence inconsistent [EHP 117:1486–1493; Nieuwenhuijsen et al.]. They suggest several guidelines that would help future studies clarify this issue. The authors reviewed all published epidemiologic studies that examined the association between congenital anomalies and exposure to DBPs, which form when organic matter in treated water reacts with chlorine disinfectant. The studies used a variety of indices of exposure, including the use of chlorination, DBP measurements in the public water supply, and information from participants about activities such as drinking, showering, and bathing. When three or more studies evaluated the same exposure index and the same congenital anomalies, the authors performed a meta‐analysis to derive a summary risk estimate comparing high‐ and low‐exposure groups. When five or more studies investigated the relationship between total trihalomethane (TTHM) concentration and a specific anomaly, the authors conducted a meta‐analysis to arrive at exposure–response relative risk estimates per 10 μg/L TTHM. TTHM concentrations in local water sources have often been used in epidemiologic studies as a proxy for DBP exposure. These meta‐analyses provide little evidence for an association. For all congenital anomalies combined, a statistically significant excess risk was found for high versus low exposure to chlorinated water or to TTHM, but the analysis was based on a small number of studies. The authors also found a statistically significant excess risk for ventricular septal defects, but that analysis included only three studies, and there was little evidence of an exposure–response relationship. In addition, the meta‐analyses were weakened by the fact that studies used very different exposure criteria. For instance, among studies that measured TTHM, one defined low exposure as lower than 60 μg per L water, whereas another defined high exposure as higher than 20 μg/L. The authors point to the need for studies that take into account the complex mixtures of DBPs to which people are exposed, which can vary over time, by geographical area, and by route of exposure. This includes conducting studies in places with water supplies that have large amounts of specific DBPs, such as Barcelona, Spain, or Perth, Australia, which have high levels of brominated DBPs. Furthermore, showering, bathing, and swimming activities should be examined in more detail because these activities may yield different levels of exposure compared with drinking water exposure. The review also calls for studies that focus on specific congenital anomalies for which there is likely to be complete case diagnosis and reporting, in addition to case–control studies that follow up on possible associations with ventricular septal defects, which are particularly prone to under‐reporting in registry‐based studies.

Chlorination Disinfection By-Products in Drinking Water and Congenital Anomalies: Review and Meta-Analyses

ObjectivesThe aim of this study was to review epidemiologic evidence, provide summary risk estimates of the association between exposure to chlorination disinfection by-products (DBPs) and congenital anomalies, and provide recommendations for future studies.Data sources and extractionWe included all published epidemiologic studies that evaluated a relationship between an index of DBP exposure (treatment, water source, DBP measurements, and both DBP measurements and personal characteristics) and risk of congenital anomalies. When three or more studies examined the same exposure index and congenital anomaly, we conducted a meta-analysis to obtain a summary risk estimate comparing the highest exposure group with the lowest exposure group. When five or more studies examined total trihalomethane (TTHM) exposure and a specific congenital anomaly, we conducted a meta-analysis to obtain exposure–response risk estimates per 10 μg/L TTHM.Data synthesisFor all congenital anomalies combined, the meta-analysis gave a statistically significant excess risk for high versus low exposure to water chlorination or TTHM [17%; 95% confidence interval (CI), 3–34] based on a small number of studies. The meta-analysis also suggested a statistically significant excess risk for ventricular septal defects (58%; 95% CI, 21–107), but this was based on only three studies, and there was little evidence of an exposure–response relationship. We observed no statistically significant relationships in the other meta-analyses. We found little evidence for publication bias, except for urinary tract defects and cleft lip and palate.ConclusionAlthough some individual studies have suggested an association between chlorination disinfection by-products and congenital anomalies, meta-analyses of all currently available studies demonstrate little evidence of such an association.

Determinants of Whether or Not Mixtures of Disinfection By-Products are Similar

Reactive chemicals have been used to disinfect drinking waters for over a century. In the 1970s, it was first observed that the reaction of these chemicals with the natural organic matter (NOM) in source waters results in the production of variable, complex mixtures of disinfection by-products (DBP). Because limited toxicological and epidemiological data are available to assess potential human health risks from complex DBP mixture exposures, methods are needed to determine when health effects data on a specific DBP mixture may be used as a surrogate for evaluating another environmental DBP mixture of interest. Before risk assessors attempt such efforts, a set of criteria needs to be in place to determine whether two or more DBP mixtures are similar in composition and toxicological potential. This study broadly characterizes the chemical and toxicological measures that may be used to evaluate similarities among DBP mixtures. Variables are discussed that affect qualitative and quantitative shifts in the types of DBP that are formed, including disinfectants used, their reactions with NOM and with bromide/iodide, pH, temperature, time, and changes in the water distribution system. The known toxicological activities of DBP mixtures and important single DBPs are also presented in light of their potential for producing similar toxicity. While DBP exposures are associated with a number of health effects, this study focuses on (1) mutagenic activity of DBP mixtures, (2) DBP cancer epidemiology, and (3) toxicology studies to evaluate similarity among DBP mixtures. Data suggest that further chemical characterization of DBP mixtures and more systematic study of DBP toxicology will improve the quality and usefulness of similarity criteria.

Drinking Water Disinfection By-Product Exposure and Fetal Growth

Previous studies suggest that elevated exposure to drinking water disinfection by-products (DBPs)--in particular, total trihalomethanes (TTHMs)--may lead to fetal growth restriction. We examined the effects of exposure to TTHMs, haloacetic acids, and total organic halide on the probability of delivering a small-for-gestational-age (SGA) infant and on birth weight at term. Women early in pregnancy (< or =12 weeks' gestation) or planning a pregnancy were enrolled in a prospective pregnancy study conducted in 3 US communities from 2000 through 2004. Weekly (or biweekly) water samples were collected at each site as well as individual-level participant data. Associations between DBP exposures (TTHMs, haloacetic acids, total organic halide) and fetal growth were assessed using log-binomial regression for SGA (n = 1958) and linear regression for term birth weight (n = 1854). We conducted a Bayesian analysis to examine associations between individual DBP species and fetal growth. Haloacetic acids and total organic halide were not associated with SGA or term birth weight. The probability of delivering an SGA infant was elevated when comparing women with an average third-trimester residential TTHM concentration > or =80 microg/L to women with exposure <80 microg/L (risk ratio = 2.0 [95% confidence interval = 1.1-3.6]), but not when examining other exposure contrasts. Bayesian analyses did not support a consistent association between any DBP species and fetal growth, although these analyses were based on small sample sizes. Our results do not suggest an adverse effect of haloacetic acid or total organic halide exposure on fetal growth. An association of TTHM with SGA was seen only for average residential concentrations above the current regulatory standard.

Drinking Water Disinfection By-Product Exposure and Duration of Gestation

Recent studies suggest elevated exposure to drinking water disinfection by-products (DBPs) may be associated with decreased risk of preterm birth. We examined this association for exposure to total trihalomethanes (TTHMs), 5 haloacetic acids (HAA5), and total organic halides. Analysis included 2039 women in a prospective pregnancy study conducted from 2000 through 2004 in 3 study sites. Water samples were collected and analyzed for DBP concentrations. Participant data were collected through interviews, an early ultrasound, and birth records. We assessed the associations between DBPs and preterm birth (<37-weeks' gestation) using log-binomial regression. Discrete-time hazard analysis was used to model the conditional odds of delivery each week in relation to DBP exposure. Average second trimester DBP levels were associated with lower risk of preterm birth. Adjusted risk ratios for TTHM levels of 33.1-55.0, 55.1-66.3, 66.4-74.8, and 74.9-108.8 microg/L versus 2.2-4.6 microg/L were 0.8 (95% confidence intervals = 0.5-1.3), 0.9 (0.6-1.4), 0.7 (0.4-1.1), and 0.5 (0.3-0.9), respectively. Risk ratios for HAA5 levels of 17.9-22.0, 22.1-31.5, 31.6-40.4, and 40.5-52.8 microg/L versus 0-0.9 microg/L were 1.1 (0.8-1.7), 0.8 (0.5-1.2), 0.5 (0.3-0.8), and 0.7 (0.4-1.1), respectively. The conditional odds of delivery each week were decreased for the highest TTHM and HAA5 exposure groups versus the low exposure group for gestational weeks 33-40. The probability of preterm birth was not increased with high DBP exposure.

Integrated Disinfection By-Products Mixtures Research: Comprehensive Characterization of Water Concentrates Prepared from Chlorinated and Ozonated/Postchlorinated Drinking Water

This article describes the disinfection by-product (DBP) characterization portion of a series of experiments designed for comprehensive chemical and toxicological evaluation of two drinking-water concentrates containing highly complex mixtures of DBPs. This project, called the Four Lab Study, involved the participation of scientists from four laboratories and centers of the U.S. Environmental Protection Agency (EPA) Office of Research and Development, along with collaborators from the water industry and academia, and addressed toxicologic effects of complex DBP mixtures, with an emphasis on reproductive and developmental effects that are associated with DBP exposures in epidemiologic studies. Complex mixtures of DBPs from two different disinfection schemes (chlorination and ozonation/postchlorination) were concentrated successfully, while maintaining a water matrix suitable for animal studies. An array of chlorinated/brominated/iodinated DBPs was created. The DBPs were relatively stable over the course of the animal experiments, and a significant portion of the halogenated DBPs formed in the drinking water was accounted for through a comprehensive qualitative and quantitative identification approach. DBPs quantified included priority DBPs that are not regulated but have been predicted to produce adverse health effects, as well as those currently regulated in the United States and those targeted during implementation of the Information Collection Rule. New by-products were also reported for the first time. These included previously undetected and unreported bromo- and chloroacids, iodinated compounds, bromo- and iodophenols, and bromoalkyltins.