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There are no studies investigating the association of chlorinated drinking water with the risk of cardiovascular diseases (CVDs) among young and middle-aged adults. This study was aimed to assess the associations between trihalomethanes (THMs) in drinking water and the risk of CVDs in in the target group in Petropavlovsk, Kazakhstan. 448 dwellers of Petropavlovsk were asked about their demographic, socioeconomic, lifestyle, behavioural characteristics, and drinking water preferences. THMs exposure was assessed to each participant based on their residence address. We used multivariable logistic regression analysis to assess the risk of CVDs in young and middle-aged adults. The results showed that the risk of hypertension in the adjusted logistic regression model was increased by 68%   and a 2.7-fold   in the second and third THM tertiles, respectively. Participants in the second and third THM exposure tertiles had a 2.3-fold and a 4.8-fold increase in the risk of arrhythmia.

This study aimed to assess the global spatiotemporal variations of trihalomethanes (THMs) in drinking water, evaluate their cancer and non-cancer risks, and THM-attributable bladder cancer burden. THM concentrations in drinking water around fifty years on a global scale were integrated. Health risks were assessed using Monte Carlo simulations and attributable bladder cancer burden was estimated by comparative risk assessment methodology. The results showed that global mean THM concentrations in drinking water significantly decreased from 78.37 μg/L (1973-1983) to 51.99 μg/L (1984-2004) and to 21.90 μg/L (after 2004). The lifestage-integrative cancer risk and hazard index of THMs through all exposure pathways were acceptable with the average level of 6.45 × 10 -5 and 7.63 × 10 -2 , respectively. The global attributable disability adjusted of life years (DALYs) and the age-standardized DALYs rate (ASDR) dropped by 16% and 56% from 1990-1994 to 2015-2019, respectively. A big decline in the attributable ASDR was observed in the United Kingdom (62%) and the United States (27%), while China experienced a nearly 3-fold increase due to the expanded water supply coverage and increased life expectancy. However, China also benefited from the spread of chlorination, which helped reduce nearly 90% of unsafe-water-caused mortality from 1998 to 2018., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Colorectal cancer is the third most common malignancy worldwide and is strongly linked to lifestyle and environmental risk factors. Although several drinking-water disinfection by-products are confirmed rodent carcinogens, the evidence in humans for carcinogenicity associated with these by-products, including colorectal cancer, is still inconclusive., Methods: We assessed the association of long-term exposure to trihalomethanes (THMs), the most prevalent disinfection by-products in chlorinated drinking water, with incidence of colorectal cancer in 58 672 men and women in 2 population-based cohorts. Exposure was assessed by combining long-term information of residential history with drinking water-monitoring data. Participants were categorized according to no exposure, low exposure (<15 µg/L), and high exposure (≥15 µg/L). Incident cases of colorectal cancer were ascertained by use of the Swedish National Cancer Register., Results: During an average follow-up of 16.8 years (988 144 person-years), 1913 cases of colorectal cancer were ascertained (1176 cases in men and 746 in women, respectively). High THM concentrations in drinking water (≥15 µg/L) were associated with increased risk of colorectal cancer in men (hazard ratio = 1.26, 95% confidence interval = 1.05-1.51) compared with no exposure. When subsites were assessed, the association was statistically significant for proximal colon cancer (hazard ratio = 1.59, 95% confidence interval = 1.11 to 2.27) but not for distal colon cancer or rectal cancer. In women, we observed overall no association of THMs with colorectal cancer., Conclusion: These results add further evidence that disinfection by-products in drinking water may be a possible risk factor for proximal colon cancer in men. This observation was made at THM concentrations lower than those in most previous studies., (© The Author(s) 2023. Published by Oxford University Press.)

Numerous disinfection by-products (DBPs) are formed from reactions between disinfectants and organic/inorganic matter during water disinfection. More than seven hundred DBPs that have been identified in disinfected water, only a fraction of which are regulated by drinking water guidelines, including trihalomethanes, haloacetic acids, bromate, and chlorite. Toxicity assessments have demonstrated that the identified DBPs cannot fully explain the overall toxicity of disinfected water; therefore, the identification of unknown DBPs is an important prerequisite to obtain insights for understanding the adverse effects of drinking water disinfection. Herein, we review the progress in identification of unknown DBPs in the recent five years with classifications of halogenated or nonhalogenated, aliphatic or aromatic, followed by specific halogen groups. The concentration and toxicity data of newly identified DBPs are also included. According to the current advances and existing shortcomings, we envisioned future perspectives in this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Level of confidence in DBP identification based on the level system proposed by Schymanski et al. (2014) (Schymanski et al., 2014): Level 1: structure confirmed with a reference standard; Level 2: exact structure was proposed by different evidence; Level 3: candidate structural isomer exist but exact structure was not confirmed; Level 4: specific molecular formula was determined; Level 5: only exact mass (m/z) was measured while formula was not elucidated., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chlorination is widely used to disinfect drinking water to keep humans safe from microorganisms. During chlorination, chlorine and its compounds react with contaminants to form disinfection by-products (DBPs). Toxicological and epidemiological studies have demonstrated that trihalomethanes (THMs) are the most widely investigated DBPs in drinking water, and their exposure has been associated with some adverse health effects. However, studies about risk characteristics in this field are limited. We estimated the health risks of THMs exposure in drinking water through multi-pathways, and systematically analyzed the factors influencing health risks of THMs in Wuxi, China. A total of 488 drinking water samples were collected and analyzed for THMs from four water treatment utilities from 2008 to 2016 in Wuxi. And water exposure parameters were obtained from 602 participants by structured questionnaires. The median concentration of THMs ranged from 6.71 μg/L to 9.18 μg/L. The cumulative cancer risk of THMs exposure through multi-pathways was 1.26 × 10 -4 , and CHBr 2 Cl made the largest contribution to the total cancer risk (48.25%). The non-cancer risk of THMs exposure was 2.02 × 10 -1 . Health risks of the exposure to THMs in drinking water in summer were significantly higher than that in winter (P = 0.0003 for cancer risk, and P = 5.95 × 10 -7 for non-cancer risk). In our study, the average individual disability-adjusted life years (DALYs) lost was 1.27 × 10 -4 per person-year (ppy). This study attempted to use DALYs for risk assessment of THMs, which will provide useful information for risk comparison and prioritization of hazards in drinking water. This suggested that potential higher risk might exist, and possible measures could be considered to decrease the health risks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Nitrate and trihalomethanes (THMs) in drinking water are widespread and are potential human carcinogens., Objective: We evaluated the association between drinking-water exposure to nitrate and THMs and prostate cancer., Methods: During the period 2008-2013, 697 hospital-based incident prostate cancer cases (97 aggressive tumors) and 927 population-based controls were recruited in Spain, providing information on residential histories and type of water consumed. Average nitrate and THMs levels in drinking water were linked with lifetime water consumption to calculate waterborne ingestion. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using mixed models with recruitment area as random effect. Effect modification by tumor grade (Gleason score), age, education, lifestyle, and dietary factors was explored., Results: Mean ( ± standard deviation ) adult lifetime waterborne ingested nitrate (milligrams per day), brominated (Br)-THMs (micrograms per day), and chloroform (micrograms per day) were 11.5 ( ± 9.0 ), 20.7 ( ± 32.4 ), and 15.1 ( ± 14.7 ) in controls. Waterborne ingested nitrate > 13.8 vs. < 5.5 mg / d was associated with an OR of 1.74 (95% CI: 1.19, 2.54) overall, and 2.78 (95% CI: 1.23, 6.27) for tumors with Gleason scores ≥ 8 . Associations were higher in the youngest and those with lower intakes of fiber, fruit/vegetables, and vitamin C. Waterborne ingested THMs were not associated with prostate cancer. Residential tap water levels of Br-THMs and chloroform showed, respectively, inverse and positive associations with prostate cancer., Conclusions: Findings suggest long-term waterborne ingested nitrate could be a risk factor of prostate cancer, particularly for aggressive tumors. High intakes of fiber, fruit/vegetables and vitamin C may lower this risk. Association with residential levels but not ingested chloroform/Br-THM may suggest inhalation and dermal routes could be relevant for prostate cancer. https://doi.org/10.1289/EHP11391.

Boiling is a widely adopted household tap water treatment method because of its ability to inactivate chlorine-resistant pathogenic bacteria, and to reduce certain groups of disinfection byproducts (DBPs). From a more comprehensive point of view, this study revisited the effect of boiling on four groups of 17 aliphatic DBPs and six groups of 44 aromatic DBPs in both simulated chlorinated and chloraminated tap water samples, with a special focus on the changes of total organic halogen (TOX) and cytotoxicity. Results showed that the concentrations of aliphatic DBPs substantially decreased during boiling via volatilization (trihalomethanes and chloral hydrate) and hydrolysis (haloacetamides) in chlorinated and chloraminated tap water samples. The concentrations of aromatic DBPs during boiling generally followed an increasing trend due to decarboxylation of polycarboxylic precursors in chlorinated tap water samples, and showed a first increasing and then decreasing trend in chloraminated tap water samples. A sharp decreasing of TOX occurred in the heating process of tap water samples from room temperature to 100 °C, and a relatively gentle decreasing was kept in the prolonged boiling process till 5 min. The most abundant DBP group in the tap water samples without boiling was trihalomethanes, and was replaced by haloacetic acids with boiling for 5 min. Continuous boiling for 5 min substantially reduced the cytotoxicity of chlorinated and chloraminated water samples by 52.6% and 21.3%, respectively. Reduction of cytotoxicity matched well with the reduction of TOCl (r = 0.907, P < 0.01), TOBr (r = 0.885, P < 0.01) and TOX (r = 0.905, P < 0.01), suggesting that the cytotoxicity reduction during boiling was mainly ascribed to the reduction of halogenated DBPs. Therefore, boiling of tap water to 100 °C was strongly recommended to reduce the potential health risks induced by tap water ingestion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Disinfection byproducts (DBPs) in public water systems (PWS) are an unintended consequence resulting from reactions between mostly chlorine-based disinfectants and organic and inorganic compounds in source waters. Epidemiology studies have shown that exposure to DBP (specifically trihalomethanes) was associated with an increased risk of bladder cancer., Objective: Our goal was to characterize the relative differences in exposures and estimated potential bladder cancer risks for people served by different strata of PWS in the United States and to evaluate uncertainties associated with these estimates., Methods: We stratified PWS by source water type (surface vs. groundwater) and population served (large, medium, and small) and calculated population-weighted mean trihalomethane-4 (THM4) concentrations for each stratum. For each stratum, we calculated a population attributable risk (PAR) for bladder cancer using odds ratios derived from published pooled epidemiology estimates as a function of the mean THM4 concentration and the fraction of the total U.S. population served by each stratum of systems. We then applied the stratum-specific PARs to the total annual number of new bladder cancer cases in the U.S. population to estimate bladder cancer incidence in each stratum., Results: Our results show that approximately 8,000 of the 79,000 annual bladder cancer cases in the United States were potentially attributable to DBPs in drinking water systems. The estimated attributable cases vary based on source water type and system size. Approximately 74% of the estimated attributable cases were from surface water systems serving populations of > 10,000 people. We also identified several uncertainties that may affect the results from this study, primarily related to the use of THM4 as a surrogate measure for DBPs relevant to bladder cancer., Discussion: Despite significant reductions in exposure over the past several decades, our study suggests that ∼ 10 % of the bladder cancer cases in the United States may still be attributed to exposure to DBPs found in drinking water systems. https://doi.org/10.1289/EHP9985.

Ship ballast water can control the roll, trim, and draft of the ship, and thus ensuring the balance and stability of the ship in the course of sailing, and playing a vital role in the safe navigation of ships. The annual discharge of ship ballast water is very large in China. About three to five billion cubic meters of ship ballast water is discharged into offshore or inland waters every year. This water contains plankton, pathogens, and their larvae or spores. If not be handled appropriately, this will have a serious impact on the ecological environment of the discharge waters. Ballast water is usually treated by electrolysis before being discharged. Sodium hypochlorite can be generated, which can kill microorganisms; however, the by-products trihalomethanes (THMs) are cytotoxic and biotoxic. Studies have shown that THMs may cause fetal growth retardation, spontaneous abortion, or death. The concentration of THMs in drinking water is closely related to the risk of bladder cancer death. Hence, it is important to establish a method for the determination of THMs in ship ballast water. The four kinds of THMs are chloroform, dichlorobromomethane, chlorodibromomethane, and tribromomethane. At present, ship ballast water is mostly analyzed by gas chromatography (GC) using an electron capture detector (ECD) or by gas chromatography-mass spectrometry (GC-MS). Given the low boiling point of THMs, headspace injection and purge-and-trap can be used. Gas chromatography-negative chemical ionization-mass spectrometry (GC-NCI-MS), was adopted. NCI is a soft ionization technique that shows special response to compounds bearing electronegative elements or groups. THMs contain electronegative chlorine atoms and bromine atoms. Therefore, NCI is a good choice for their analysis. The samples were processed by the headspace injection technique. The NaCl content in 10 mL sample was optimized in headspace injection. The results showed that 3.0 g NaCl was the most suitable dosage. The analytes were separated on a DB-5MS UI capillary-column (30 m×0.25 mm×1.0 μm). The target compounds were quantified by using the external standard method in selected ion monitoring (SIM) mode. The four THMs were not only well separated but also showed a high response at 0.2 μg/L. The four THMs showed good linear relationships in the range of 0.2-50 μg/L, with correlation coefficients≥0.995. The limits of quantification (LOQs, S/N =10) were 0.1-0.2 μg/L, and the average recoveries of the four THMs were 90.3%-106.8% at the three spike levels of 0.2, 0.5, and 2.0 μg/L. The relative standard deviations were 1.4%-6.2%. The LOQs of the THMs in the GB/T 5750.8-2006 Standard Test Method of Drinking Water Organic Matter Index are 0.3-6.0 μg/L. It can be seen that the LOQs of the THMs are greatly reduced in this study. The proposed method is accurate, stable, and reliable, and it can be used for monitoring the four THMs in ship ballast water. The method was applied for the detection of 36 ship ballast water samples. In all cases, the detection rates of tribromomethane, chlorodibromomethane, dichlorobromomethane, and chloroform were 83.3%, 69.4%, 22.2%, and 19.4%, respectively. The detection values of tribromomethane, chlorodibromomethane, dichlorobromomethane, and chloroform were 34.25-221.5 μg/L, 3.52-41.87 μg/L, 1.52-8.56 μg/L, and 0.02-5.46 μg/L, respectively. Based on the analysis of several ship ballast water samples (electrolytic water), it was concluded that the greater the number of bromine atoms in the THMs, the higher are the detection rate and detection value in ship ballast water. Compared to chloroform, tribromomethane is more harmful to living beings. China has acceded to the International Convention on Ship Ballast Water and Sediment Control and Management. There is an urgent need to establish analysis methods with high sensitivity, good stability, and high accuracy in addition to determining standards and regulations for ship ballast water.

The present study aims to assess the probable lifetime cancer and non-cancer risks of exposure to the trihalomethanes in Egypt's drinking water through ingestion, dermal contact, and inhalation. A total of 1667 drinking water samples were collected from twenty-three Egyptian governorates over a three-years period. The concentrations of total trihalomethanes ranged between 29.07 and 86.01 μg/L and were always below the maximum contamination level recommended by the Egyptian standards (100 μg/L). Chloroform was the most prominent trihalomethanes species, while bromoform was rarely detected. The cancer risk study revealed that, among the investigated paths, inhalation poses the greatest risk. And bromodichloromethane had the highest impact to cancer (69%), followed by chlorodibromomethane (28%). Geographically, the highest cancer risk value was found in Matruh governorate (42.2 × 10 -6 ) and the lowest was in Minya governorate (1.0 × 10 -6 ). The cancer risk for the studied governorates, except Minya governorate, was higher than the level recommended by the USEPA (1.0 × 10 -6 ). Hazard index (HI) study revealed that the ingestion pathway caused higher HI values than the dermal pathway and that chloroform had the highest contribution to HI value. However, the values of HI were below unity in all studied governorates demonstrating that there would be negligible non-cancer risk., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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: 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 ( NO 3 -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 ≥ 95 th percentile. We also computed years of PWS use above one-half the U.S. maximum contaminant level ( >½  MCL ; 40 μ g / L TTHM; 30 μ g / L HAA5; 5 mg / L   NO 3 -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  NO 3 -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 μ g / L , HAA5 ≥ 49 μ g / L ) were associated with endometrial cancer risk (TTHM: HR 95 vsQ 1 = 2.19 , 95% CI: 1.41, 3.40; HAA5: HR 95 vsQ 1 = 1.84 , 95% CI: 1.19, 2.83; p trend < 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: HR 36 + vs 0 y = 1.61 , 95% CI: 1.18, 2.21; HAA5: HR 38 + vs 0 y = 1.85 , 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: HR Q 4 vsQ 1 = 2.12 , 95% CI: 1.17, 3.83; p -trend = 0.008 ) than for high-grade tumors (TTHM: HR Q 4 vsQ 1 = 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 NO 3 -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.

In developing countries, the evaluation of disinfection by-products in drinking water has been neglected because most water utility companies focus on microbial elimination. As a result, this study aimed at evaluating trihalomethane formation, the relation between water quality parameters and trihalomethane formation, and the estimation of the associated potential health risks in drinking water. The headspace purge and trap coupled with a gas chromatography-mass spectrometry technique was used to quantify trihalomethane. The concentrations of trihalomethane found in the water were within the National Water and Sewerage Corporation, World Health Organization guidelines, and the United States Environmental Protection Agency standards. Total organic carbon, ultraviolet absorbance at 254 nm, bromide concentration, and the temperature had a positive and significant correlation, pH had a positive but non-significant correlation, while the residual chlorine had a negative but significant correlation with trihalomethane formation. The potential health risk using the WHO index was 0.4, indicating no noncarcinogenic risk to human health in the study area. The lifetime carcinogenic risks of trihalomethane due to oral ingestion, dermal, and inhalation were 2.5×10 -5 , 9.1×10 -6 , and 8.3×10 -6 for females and 2.4×10 -5 , 1×10 -5 , and 7.9×10 -6 for males, and the values were within the USEPA acceptable low-risk range of 1×10 -6 -5 .

Background: Trihalomethanes (THMs) and nitrate are widespread chemicals in drinking water associated with colorectal cancer risk but mechanisms are not well understood., Objectives: We explored the association between exposure to THMs and nitrate in drinking water and inflammation markers, and the link with colorectal cancer risk., Methods: A subset of 198 colorectal cancer cases and 205 controls from the multicase-control study MCC-Spain were included. Average concentration of THMs (chloroform, bromodichloromethane, dibromochloromethane, bromoform) and nitrate in tap water at the residence was estimated from age 18 until 2 years before the interview ("long term") and for a recent period (3 years before diagnosis). Serum levels of EGF, eotaxin, G-CSF, IL-17E, IL-1rA, IL-8, IP-10, MDC, MPO, periostin, VEGF, and C-reactive protein (CRP) were measured. We estimated the linear association between inflammation markers and exposure among controls, and the odds ratio of colorectal cancer associated with THM and nitrate exposure, and inflammation markers. A mediation analysis was conducted to identify inflammation markers in the pathway between THM/nitrate exposure and colorectal cancer., Results: Serum concentrations of EGF, IL-8, IL-17E and eotaxin increased with recent residential levels of brominated THMs, chloroforom and/or total THM. No associations were observed for nitrate and for long-term residential THM levels. All residential exposures except chloroform were positively associated with colorectal cancer. Serum concentrations of VEGF and periostin were positively associated with colorectal cancer, while EGF was inversely associated. One protein-exposure combination (periostin-recent ingested brominated THMs) slightly mediated the association with colorectal cancer risk., Discussion: Results suggest that estimated THM exposure is involved in inflammation processes. However, the study design was limited to stablish etiologically relevant associations between the protein levels and colorectal cancer risk. The lack of association between nitrate exposure and inflammation markers suggests other biological mechanisms are involved in the link with colorectal cancer., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Brain tumours (BTs) are one of the most frequent tumour types in young people. We explored the association between tap water, exposure to trihalomethanes (THM) and nitrate and neuroepithelial BT risk in young people. Analysis of tap water consumption were based on 321 cases and 919 appendicitis controls (10-24 years old) from 6 of the 14 participating countries in the international MOBI-Kids case-control study (2010-2016). Available historical residential tap water concentrations of THMs and nitrate, available from 3 countries for 86 cases and 352 controls and 85 cases and 343 for nitrate, respectively, were modelled and combined with the study subjects' personal consumption patterns to estimate ingestion and residential exposure levels in the study population (both pre- and postnatal). The mean age of participants was 16.6 years old and 56% were male. The highest levels and widest ranges for THMs were found in Spain (residential and ingested) and Italy and in Korea for nitrate. There was no association between BT and the amount of tap water consumed and the showering/bathing frequency. Odds Ratios (ORs) for BT in relation to both pre- and postnatal residential and ingestion levels of THMs were systematically below 1 (OR = 0.37 (0.08-1.73)) for postnatal average residential THMs higher than 66 μg/L. For nitrate, all ORs were above 1 (OR = 1.80 (0.91-3.55)) for postnatal average residential nitrate levels higher than 8.5 mg/L, with a suggestion of a trend of increased risk of neuroepithelial BTs with increasing residential nitrate levels in tap water, which appeared stronger in early in life. This, to our knowledge, is the first study on this topic in young people. Further research is required to clarify the observed associations., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Drinking water chlorination by-products have been associated with adverse reproductive outcomes, although the findings for congenital malformations are still inconclusive., Objective: We conducted a nationwide register-based prospective study to assess whether first trimester maternal exposure to the four most common trihalomethanes [total trihalomethanes (TTHM)] via municipal drinking water was associated with risk of congenital malformation among newborns., Methods: We included all births during 2005-2015 (live and stillbirths) of mothers residing in Swedish localities having > 10,000 inhabitants, two or fewer operating water works, and sufficient municipal TTHM monitoring data. Individual maternal first trimester exposure was obtained by linking TTHM measurements to residential information, categorized into no chlorination and < 5 , 5-15, and > 15 μ g TTHM/L. We also made chlorination treatment-specific analyses (exclusive use of chloramine or hypochlorite). Outcomes and covariates were obtained via linkage to health care and administrative registers. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression., Results: Based on 623,468 births and a prevalence of congenital malformation of ∼ 2 cases/100 births, we observed associations between TTHM exposure in areas using chloramine and malformations of the nervous system ( OR = 1.82 ; 95% CI: 1.07, 3.12), urinary system ( OR = 2.06 ; 95% CI: 1.53, 2.78), genitals ( OR = 1.77 ; 95% CI: 1.38, 2.26), and limbs ( OR = 1.34 ; 95% CI: 1.10, 1.64), comparing the highest exposed category with the unexposed. No associations were observed in areas using exclusively hypochlorite as the primary water treatment method. By contrast, for malformations of the heart, a significant inverse association was observed only in areas using hypochlorite., Discussion: TTHM exposure was associated with the increased risk of malformations of the nervous system, urinary system, genitals, and limbs in areas exclusively using chloramine. An association between chloramine-related chlorination by-products and congenital malformations has not previously been highlighted and needs further attention. https://doi.org/10.1289/EHP9122.

Drinking water disinfection by-products (DBPs), including the ubiquitous trihalomethanes (THMs), are formed during the treatment of water with disinfectants (e.g., chlorine, chloramines) to produce and distribute potable water. Brominated THMs (Br-THMs) are activated to mutagens via glutathione S-transferase theta 1 (GSTT1); however, iodinated THMs (I-THMs) have never been evaluated for activation by GSTT1. Among the I-THMs, only triiodomethane (iodoform) has been tested previously for mutagenicity in Salmonella and was positive (in the absence of GSTT1) in three strains (TA98, TA100, and BA13), all of which have error-prone DNA repair (pKM101). We evaluated five I-THMs (chlorodiiodomethane, dichloroiodomethane, dibromoiodomethane, bromochloroiodomethane, and triiodomethane) for mutagenicity in Salmonella strain RSJ100, which expresses GSTT1, and its homologue TPT100, which does not; neither strain has pKM101. We also evaluated chlorodiiodo-, dichloroiodo-, and dibromoiodo-methanes in strain TA100 +/- rat liver S9 mix; TA100 has pKM101. None was mutagenic in any of the strains. The I-THMs were generally more cytotoxic than their brominated and chlorinated analogues but less cytotoxic than analogous trihalonitromethanes tested previously. All five I-THMs showed similar thresholds for cytotoxicity at ~2.5 μmoles/plate, possibly due to release of iodine, a well-known antimicrobial. Although none of these I-THMs was activated by GSTT1, iodoform appears to be the only I-THM that is mutagenic in Salmonella, only in strains deficient in nucleotide excision repair (uvrB) and having pKM101. Given that only iodoform is mutagenic among the I-THMs and is generally present at low concentrations in drinking water, the I-THMs likely play little role in the mutagenicity of drinking water., (© 2021 Wiley Periodicals LLC.)

Water disinfection, primarily by chlorination, is one of the greatest achievements of public health. However, more than half a century after its introduction, studies in the 1970s reported that (a) chlorine interacted with organic matter in the water to form disinfection by-products (DBPs); (b) two DBPs, chloroform and bromoform, both trihalomethanes (THMs), were rodent carcinogens; (c) three brominated THMs were mutagenic; in six studies chlorinated drinking waters in the United States and Canada were mutagenic; and (d) in one epidemiological study there was an association between bladder cancer mortality and THM exposure. This led the U.S. Environmental Protection Agency to issue its first DBP regulation in 1979. Forty years later, >600 DBPs have been characterized, 20/22 have been shown to be rodent carcinogens, >100 have been shown to be genotoxic, and 1000s of water samples have been found to be mutagenic. Data support a hypothesis that long-term dermal/inhalation exposure to certain levels of the three brominated THMs, as well as oral exposure to the haloacetic acids, combined with a specific genotype may increase the risk for bladder cancer for a small but significant population group. Improved water-treatment methods and stricter regulations have likely reduced such risks over the years, and further reductions in potential risk are anticipated with the application of advanced water-treatment methods and wider application of drinking water regulations. This 40-year research effort is a remarkable example of sustained cooperation between academic and government scientists, along with public/private water companies, to find answers to a pressing public health question., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Chlorination is globally used to produce of safe drinking water. Chlorination by-products are easily formed, and there are indications that these are associated with adverse reproductive outcomes., Objectives: We conducted a nationwide register-based prospective study to assess whether gestational exposure to the four most common chlorination by-products [total trihalomethanes (TTHMs)] via tap water was associated with risk of small for gestational age (SGA), preterm delivery, and very preterm delivery. To date, this is one of the largest studies assessing drinking water TTHM-associated adverse reproductive outcomes., Methods: We included all singleton births 2005-2015 (live and stillbirths) of mothers residing in Swedish localities having > 10,000 inhabitants, ≤ 2 operating waterworks, adequate information on chlorination treatment, and a sufficient number of routine TTHM measurements in tap water. Individual maternal second and third trimester exposure was obtained by linking TTHM measurements to residential history, categorized into no chlorination, < 5 , 5-15, and > 15 μ g TTHM/L. Outcomes and covariates were obtained via the linkage to Swedish health and administrative registers. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression using inverse probability weighting. We stratified the analyses by chlorination treatment (chloramine, hypochlorite)., Results: Based on approximately 500,000 births, we observed a TTHM dose-dependent association with increased risk of SGA, confined to treatment with hypochlorite, corresponding to a multivariable-adjusted OR = 1.20 (95% CI: 1.08, 1.33) comparing drinking water TTHM > 15 μ g to the unexposed. Similar results were obtained when, instead of unexposed, the lowest exposure category ( < 5 μ g / L TTHM) was used as reference. No clear associations were observed for preterm delivery and very preterm delivery., Discussion: Chlorination by-products exposure via drinking water was associated with increased risk of SGA in areas with hypochlorite treatment. https://doi.org/10.1289/EHP6012.

Health risk and burden of disease induced by exposure to trihalomethanes (THMs, four compounds) and haloacetic acids (HAAs, 5 compounds) from drinking water through ingestion, dermal absorption, and inhalation routes were assessed based on one-year water quality monitoring in four urban communities (Bandar Deylam, Borazjan, Bushehr, and Choghadak) of Bushehr Province, Iran. The total average concentrations of THMs and HAAs at all the communities level were determined to be 92.9 ± 43.7 and 70.6 ± 26.5 μg/L, respectively. The dominant components of the THMs and HAAs were determined to be tribromomethane (TBM, 41.6%) and monobromoacetic acid (MBAA, 60.8%), respectively. The average contributions of ingestion, dermal absorption, and inhalation routes in exposure to the chlorination by-products (CBPs) were respectively 65.0, 15.4, and 19.6%. The total average non-carcinogenic risk as the hazard index (HI) and incremental lifetime cancer risk (ILCR) of the CBPs at all the communities level were found to be 4.03 × 10 -1 and 3.16 × 10 -4 , respectively. The total attributable deaths, death rate (per 100,000 people), age-weighted disability-adjusted life years (DALYs), and age-weighted DALY rate for all ages both sexes combined at all the communities level were estimated to be 1.0 (uncertainty interval: UI 95% 0.3 to 2.8), 0.27 (0.08-0.75), 30.8 (11.3-100.1), and 8.1 (3.0-26.4), respectively. The average contribution of mortality (years of life lost due to premature mortality: YLLs) in the attributable burden of disease was 94.7% (94.4-95.6). Although in most of cases the average levels of the CBPs were in the permissible range of Iranian standards for drinking water quality, the average values of ILCRs as well as attributable burden of disease were not acceptable (the ILCRs were higher than the boundary limit of 10 -5 ); therefore, implementation of interventions for reducing exposure to CBPs through drinking water especially in Kowsar Dam Water Treatment Plant is strictly recommended., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The occurrence and transformation behaviors of disinfection byproducts (DBPs) were investigated in the finished water and tap water of 14 water treatment plants in rural areas of eastern China. Mammalian cell toxicity data from previous studies were used to evaluate the cytotoxicity of trihalomethanes (THMs), haloacetic acids (HAAs), haloacetonitriles (HANs), trichloronitromethane (TCNM) and the genotoxicity of HAAs, HANs and TCNM. Correlation analysis was conducted to identify the factors that might influence the variability of DBPs. The measured median values were 29.76 μg/L for THMs, 20.47 μg/L for HAAs, 3.98 μg/L for HANs, 0.76 μg/L for haloketones (HKs) and 0.03 μg/L for TCNM. The spatial variability analysis showed that the total concentrations of HAAs and HANs decreased during long hydraulic residence time (HRT) in seven drinking water distribution systems, which could result in reduced mammalian cell cytotoxicity and genotoxicity at consumers' taps. The concentrations of trihalogenated-DBPs were more stable than those of dihalogenated-DBPs and monohalogenated-DBPs during long HRT. Bromine acted as a more efficient substituting agent than chlorine for THMs and dihaloacetonitriles (DHANs) in actual drinking water. The dominant chlorinated-THMs and chlorinated-DHANs would transfer to brominated -THMs and brominated-DHANs when the concentration of bromide ion exceeds 450.67 and 610.25 μg/L, respectively. Correlation analysis indicated that particulate and soluble manganese (Mn) might play critical roles in promoting the production of DBPs in bulk water. Hydraulic disturbance could also result in secondary release of DBPs from loose deposits accumulated on distribution pipe walls., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chloroform and Bromoform are two abundant trihalomethanes found in Algerian drinking water. The investigation of the mutagenic hazard of these disinfection by-products was studied by Ames test as prokaryotic bioassay to show their mutagenic effects. For this, Salmonella typhimurium TA98 and TA100 strains were employed. Both chloroform and bromoform showed a direct mutagenic effect since the number of revertant colonies gradually increase in dose-dependent manner with all concentrations tested with the two bacterial strains and these were both in the absence and presence of S9 metabolic activation. The genotoxic hazard was also studied by random amplified polymorphic DNA test on the root cells of Allium cepa as eukaryotic bioassay. DNA extracted from the roots of the onion were incubated at different concentrations of chloroform and bromoform and then amplified by polymerase chain reaction. This was based on demonstrating a major effect of disappearance of bands compared to roots incubated in the negative control (distilled water). The results showed that these two compounds affected genomic DNA by breaks although by mutations.

The disinfection of drinking water is a major public health achievement; however, an unintended consequence of disinfection is the generation of disinfection by-products (DBPs). Many of the identified DBPs exhibit in vitro and in vivo toxicity, generate a diversity of adverse biological effects, and may be hazards to the public health and the environment. Only a few DBPs are regulated by several national and international agencies and it is not clear if these regulated DBPs are the forcing agents that drive the observed toxicity and their associated health effects. In this study, we combine analytical chemical and biological data to resolve the forcing agents associated with mammalian cell cytotoxicity of drinking water samples from three cities. These data suggest that the trihalomethanes (THMs) and haloacetic acids may be a small component of the overall cytotoxicity of the organic material isolated from disinfected drinking water. Chemical classes of nitrogen-containing DBPs, such as the haloacetonitriles and haloacetamides, appear to be the major forcing agents of toxicity in these samples. These findings may have important implications for the design of epidemiological studies that primarily rely on the levels of THMs to define DBP exposure among populations. The TIC-Tox approach constitutes a beginning step in the process of identifying the forcing agents of toxicity in disinfected water., (Copyright © 2017. Published by Elsevier B.V.)

Background: We examined the association between exposure during pregnancy to trihalomethanes, the most common water disinfection by-products, and birth outcomes in a European cohort study (Health Impacts of Long-Term Exposure to Disinfection By-Products in Drinking Water). We took into account exposure through different water uses, measures of water toxicity, and genetic susceptibility., Methods: We enrolled 14,005 mothers (2002-2010) and their children from France, Greece, Lithuania, Spain, and the UK. Information on lifestyle- and water-related activities was recorded. We ascertained residential concentrations of trihalomethanes through regulatory records and ad hoc sampling campaigns and estimated route-specific trihalomethane uptake by trimester and for whole pregnancy. We examined single nucleotide polymorphisms and copy number variants in disinfection by-product metabolizing genes in nested case-control studies., Results: Average levels of trihalomethanes ranged from around 10 μg/L to above the regulatory limits in the EU of 100 μg/L between centers. There was no association between birth weight and total trihalomethane exposure during pregnancy (β = 2.2 g in birth weight per 10 μg/L of trihalomethane, 95% confidence interval = 3.3, 7.6). Birth weight was not associated with exposure through different routes or with specific trihalomethane species. Exposure to trihalomethanes was not associated with low birth weight (odds ratio [OR] per 10 μg/L = 1.02, 95% confidence interval = 0.95, 1.10), small-for-gestational age (OR = 0.99, 0.94, 1.03) and preterm births (OR = 0.98, 0.9, 1.05). We found no gene-environment interactions for mother or child polymorphisms in relation to preterm birth or small-for-gestational age., Conclusions: In this large European study, we found no association between birth outcomes and trihalomethane exposures during pregnancy in the total population or in potentially genetically susceptible subgroups. (See video abstract at http://links.lww.com/EDE/B104.).

Background: Evidence for a relationship between trihalomethane (THM) or haloacetic acid (HAA) exposure and adverse fetal growth is inconsistent. Disinfection by-products exist as complex mixtures in water supplies, but THMs and HAAs have typically been examined separately., Objectives: We investigated joint exposure at the individual level to THMs and HAAs in relation to birth weight in the multi-ethnic Born in Bradford birth cohort., Methods: Pregnant women reported their water consumption and activities via questionnaire. These data were combined with area-level THM and HAA concentrations to estimate integrated uptake of THMs into blood and HAA ingestion, accounting for boiling/filtering. We examined the relationship between THM and HAA exposures and birth weight of up to 7,438 singleton term babies using multiple linear regression, stratified by ethnicity., Results: Among Pakistani-origin infants, mean birth weight was significantly lower in association with the highest versus lowest tertiles of integrated THM uptake (e.g., -53.7 g; 95% CI: -89.9, -17.5 for ≥ 1.82 vs. < 1.05 μg/day of total THM) and there were significant trends (p < 0.01) across increasing tertiles, but there were no associations among white British infants. Neither ingestion of HAAs alone or jointly with THMs was associated with birth weight. Estimated THM uptake via showering, bathing, and swimming was significantly associated with lower birth weight in Pakistani-origin infants, when adjusting for THM and HAA ingestion via water consumption., Conclusions: To our knowledge, this is the largest DBP and fetal growth study to date with individual water use data, and the first to examine individual-level estimates of joint THM-HAA exposure. Our findings demonstrate associations between THM, but not HAA, exposure during pregnancy and reduced birth weight, but suggest this differs by ethnicity. This study suggests that THMs are not acting as a proxy for HAAs, or vice-versa., Citation: Smith RB, Edwards SC, Best N, Wright J, Nieuwenhuijsen MJ, Toledano MB. 2016. Birth weight, ethnicity, and exposure to trihalomethanes and haloacetic acids in drinking water during pregnancy in the Born in Bradford cohort. Environ Health Perspect 124:681-689; http://dx.doi.org/10.1289/ehp.1409480.

Background: Previous studies have suggested that elevated exposure to disinfection by-products (DBPs) in drinking water during gestation may result in adverse birth outcomes. However, the findings of these studies remain inconclusive., Objective: The purpose of our study was to examine the association between blood biomarkers of late pregnancy exposure to trihalomethanes (THMs) in drinking water and fetal growth and gestational age., Methods: We recruited 1,184 pregnant women between 2011 and 2013 in Wuhan and Xiaogan City, Hubei, China. Maternal blood THM concentrations, including chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM), were measured as exposure biomarkers during late pregnancy. We estimated associations with gestational age and fetal growth indicators [birth weight, birth length, and small for gestational age (SGA)]., Results: Total THMs (TTHMs; sum of TCM, BDCM, DBCM, and TBM) were associated with lower mean birth weight (-60.9 g; 95% CI: -116.2, -5.6 for the highest vs. lowest tertile; p for trend = 0.03), and BDCM and DBCM exposures were associated with smaller birth length (e.g., -0.20 cm; 95% CI: -0.37, -0.04 for the highest vs. lowest tertile of DBCM; p for trend = 0.02). SGA was increased in association with the second and third tertiles of TTHMs (OR = 2.91; 95% CI: 1.32, 6.42 and OR = 2.25; 95% CI: 1.01, 5.03; p for trend = 0.08)., Conclusions: Our results suggested that elevated maternal THM exposure may adversely affect fetal growth., Citation: Cao WC, Zeng Q, Luo Y, Chen HX, Miao DY, Li L, Cheng YH, Li M, Wang F, You L, Wang YX, Yang P, Lu WQ. 2016. Blood biomarkers of late pregnancy exposure to trihalomethanes in drinking water and fetal growth measures and gestational age in a Chinese cohort. Environ Health Perspect 124:536-541; http://dx.doi.org/10.1289/ehp.1409234.

In order to investigate the risk of trihalomethane formation potential (THMFP) in finished waters as drinking water sources, 70 samples, 114 samples, and 70 samples were collected in November 2013, April 2014 and July 2014, respectively from different locations in the Beijiang River and the Pearl River. After filtration by 0.45 μm filter membrane, a total of 254 samples were chlorinated using Uniform Formation Condition (UFC) method for determining their THM Formation Potential (THMFP). The cancer risk and non-cancer risk of THMs were estimated using USEPA risk assessment model while dominant factors for total risk potential were estimated using sensitivity analysis. Among four THM species, chloroform( CF) was the highest ranging from 101.92-2 590.85 μg x L(-1), followed by bromodichloromethane (BDCM), dibromochloromethane (DBCM) and bromoform (BF). Chloroform, the major THMs speciation, accounted for 96.17% of total THMs. Non-cancer and cancer risk from ingesting THMs was estimated. The result indicated that non-cancer risk of THMs level ranged from 2.03 x 10(-7) to 1.00 x 10(-5) and was not more than 1.0 x 10(-5), the minimum or negligible non-cancer risk level defined by the USEPA. The average cancer risk of THMs was 2.91 x 10(-4) for male and 3.30 x 10(-4) for female in the two rivers, respectively, exceeding the minimum or negligible risk level defined by the USEPA (1. 0 x 10 ~6). The difference of cancer risk between the two rivers was that BDCM ranging from 2.50 x 10(-5) to 6.37 x 10(-4) was approximately twice that of CF in Beijing River. BDCM played an important role in the total risk in the Beijiang River while CF played an important role in the total risk in the Pearl River, Guangzhou. Sensitivity analysis showed that CF played an important role in the estimation of total risk potential, and that the direct utilization of water sources from Beijiang River and the Pearl River Guangzhou is dangerous, thus pretreatment is necessary before chlorination.

This study aimed to compare the toxicity reduction performance of conventional drinking water treatment (CT) and a treatment (NT) with quaternized magnetic microspheres (NDMP) based on chemical analyses. Fluorescence excitation-emission-matrix combined with parallel factor analysis identified four components in source water of different rivers or lake, and the abundance of each component differed greatly among the different samples. Compared with the CT, the NT evidently reduced the concentrations of dissolved organic carbon, adsorbable organic halogens (AOX), bromide and disinfection by-products. Toxicological evaluation indicated that the NT completely eliminated the cytotoxicity, and greatly reduced the genotoxicity and oxidative stress of all raw water. In contrast, the CT increased the cytotoxicity of Taihu Lake and the Zhongshan River water, genotoxicity of Taihu Lake and the Mangshe River water, as well as the levels of superoxide dismutase and malondialdehyde of the Mangshe River water. Correlation analysis indicated that the AOX of the treated samples was significantly correlated with the genotoxicity and glutathione concentration, but exhibited no correlation with either of them for all the samples. As it can effectively reduce pollutant levels and the toxicities of drinking water, NDMP might be widely used for drinking water treatment in future., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The lifetime cancer risk and the hazard index of trihalomethanes (THMs) through oral ingestion, dermal absorption, and inhalation exposure from supply water of five WTPs were analysed. THMs concentration varied from plant to plant and was found to be in the range of 274-511µg/l, which is much higher than the prescribed USEPA standards of 80µg/l. Chloroform was the most dominant THM followed by bromodichloromethane (BDCM), and dibromochloromethane (DBCM). Cancer risk analysis through multi-pathways exposure reveals that residents had a higher cancer risk through oral ingestion than other two routes of exposure. The lifetime cancer risks of THMs from supply water were 100 times higher than prescribed USEPA guidelines. The higher cancer risk found for Indian context than those reported for other countries like USA, UK, Japan, Australia, is mainly due to the higher concentration level of THMs, water intake and average body weight. The study also revealed that amongst different THMs, chloroform is the major THMs causing cancer risk through both oral and dermal route of exposure whereas in case of inhalation it was mainly because of BDCM. Average lifetime cancer risk analysis indicated that females are more prone to cancer risk than males. Oral ingestion is a major route indicating the potential impact of non-cancer risk while it was insignificant through dermal exposure. Sensitivity analysis of THMs revealed that chloroform is the predominant parameter followed by body weight and exposure duration influencing cancer risk., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This study reports the baseline data of chlorination disinfection by-products such as trihalomethanes (THMs) and their associated health risks in the water distribution network of Islamabad and Rawalpindi, Pakistan. THM monitoring was carried out at 30 different sampling sites across the twin cities for 6 months. The average concentration of total trihalomethanes (TTHMs) and chloroform ranged between 575 and 595 μg/L which exceeded the permissible US (80 μg/L) and EU (100 μg/L) limits. Chloroform was one of the major contributors to the TTHMs concentration (>85%). The occurrence of THMs was found in the following order: chloroform, bromodichloromethane > dibromochloromethane > bromoform. Lifetime cancer risk assessment of THMs for both males and females was carried out using prediction models via different exposure routes (ingestion, inhalation, and dermal). Total lifetime cancer risk assessment for different exposure routes (ingestion, inhalation, and skin) was carried out. The highest cancer risk expected from THMs seems to be from the inhalation route followed by ingestion and dermal contacts. The average lifetime cancer risk for males and females was found to be 0.51 × 10⁻³ and 1.22 × 10⁻³, respectively. The expected number of cancer risks per year could reach two to three cases for each city.

In this study, a battery of genotoxicity assays for monitoring drinking water was performed to assess the quality of the water resulting from the treatment plants. Five different types of samples were collected: raw water (P1), treated after pre-chlorination (P2), treated after decantation (P3), treated post-chlorination (P4), and consumers' taps (P5-P12). This study aims to evaluate the formation/occurrence of mutagenic and/or genotoxic compounds in surface drinking waters treated with chlorine disinfectant, during four seasonal experiments: summer, autumn, winter, and spring between 2012 and 2013 by bacterial reverse mutation assay in both Salmonella typhimurium TA98 and TA100 strains with or without metabolic activation system (S9 mix) and Allium cepa root meristematic cells, respectively. All of water samples, except at P1, P2, and P5 in summer; P1 in autumn; and P1 and P3-P12 in spring without S9 mix, and at P1 and P2 in summer and P6 and P8-P12 in spring with S9 mix, were found to be mutagenic in S. typhimurium TA98. However, only P11 and P12 in winter were found to be mutagenic for TA100 without S9 mix. The tested preparations in Allium anaphase-telophase test revealed a significant decrease in mitotic index (MI) and a simultaneous increase in chromosome aberrations (CAs) compared to the control. The bridge, stickiness, vagrant chromosomes, and disturbed chromosome aberrations were observed in anaphase-telophase cells. Physicochemical analysis, trihalomethanes (THMs), romoform (CHBr3), chloroform (CHCl3), bromodichloromethane (CHBrCl2), and dibromochloromethane (CHBr2Cl) levels in water samples were also determined. The results show also that this short-term battery tests are applicable in the routine monitoring of drinking water quality before and after distribution.

Trihalomethanes (THM) are undesired disinfection byproducts (DBPs) formed during water treatment. Mice exposed to DBPs showed global DNA hypomethylation and c-myc and c-jun gene-specific hypomethylation, while evidence of epigenetic effects in humans is scarce. We explored the association between lifetime THM exposure and DNA methylation through an epigenome-wide association study. We selected 138 population-based controls from a case-control study of colorectal cancer conducted in Barcelona, Spain, exposed to average lifetime THM levels ≤85 μg/L vs. >85 μg/L (N = 68 and N = 70, respectively). Mean age of participants was 70 years, and 54% were male. Average lifetime THM level in the exposure groups was 64 and 130 µg/L, respectively. DNA was extracted from whole blood and was bisulphite converted to measure DNA methylation levels using the Illumina HumanMethylation450 BeadChip. Data preprocessing was performed using RnBeads. Methylation was compared between exposure groups using empirical Bayes moderated linear regression for CpG sites and Gaussian kernel for CpG regions. ConsensusPathDB was used for gene set enrichment. Statistically significant differences in methylation between exposure groups was found in 140 CpG sites and 30 gene-related regions, after false discovery rate <0.05 and adjustment for age, sex, methylation first principal component, and blood cell proportion. The annotated genes were localized to several cancer pathways. Among them, 29 CpGs had methylation levels associated with THM levels (|Δβ|≥0.05) located in 11 genes associated with cancer in other studies. Our results suggest that THM exposure may affect DNA methylation in genes related to tumors, including colorectal and bladder cancers. Future confirmation studies are required.

Background: Drinking water disinfection by-products (DBPs) are generated by the chemical disinfection of water and may pose hazards to public health. Two major classes of DBPs are found in finished drinking water: haloacetic acids (HAAs) and trihalomethanes (THMs). HAAs are formed following disinfection with chlorine, which reacts with iodide and bromide in the water. Previously the HAAs were shown to be cytotoxic, genotoxic, mutagenic, teratogenic and carcinogenic., Objectives: To determine the effect of HAAs in human somatic and germ cells and whether oxidative stress is involved in genotoxic action. In the present study both somatic and germ cells have been examined as peripheral blood lymphocytes and sperm., Methods: The effects of three HAA compounds: iodoacetic acid (IAA), bromoacetic acid (BAA) and chloroacetic acid (CAA) were investigated. After determining appropriate concentration responses, oxygen radical involvement with the antioxidants, butylated hydroxanisole (BHA) and the enzyme catalase, were investigated in the single cell gel electrophoresis (Comet) assay under alkaline conditions, >pH 13 and the micronucleus assay., Results: In the Comet assay, BHA and catalase were able to reduce DNA damage in each cell type compared to HAA alone. In the micronucleus assay, micronuclei (MNi) were found in peripheral lymphocytes exposed to all three HAAs and catalase and BHA were in general, able to reduce MNi induction, suggesting oxygen radicals play a role in both assays., Conclusion: These observations are of concern to public health since both human somatic and germ cells show similar genotoxic responses., (Copyright © 2014. Published by Elsevier B.V.)

Cylindrospermopsin (CYN) is an alkaloid commonly produced by some cyanobacteria that has been implicated in outbreaks of human illness. The aim of this study was to investigate the genotoxicity of Cylindrospermopsis raciborskii cellular content (including CYN) and its byproducts resulting from chlorination during water treatment. DNA damage in blood and liver cells was analysed by the comet assay and micronucleus test (MN). Mice were injected intraperitoneally with the following treatments: (a) physiological saline, (b) treated water, (c) treated water plus C. raciborskii extract (CYN producer strain, CYPO-011 K), (d) C. raciborskii extract (CYN producer strain, CYPO-011 K), (e) C. raciborskii extract (CYN non producer strain), and (f) treated water plus C. raciborskii extract (CYN non producer strain) extract. After 48 h, samples were taken to perform tests (blood and liver cells to the comet assay and bone marrow to MN test). The CYPO-011 K had a genotoxic and mutagenic effects on liver and bone marrow cells. The group that received chlorine-treated water plus CYPO-011 K also exhibited genotoxic effects in the liver, as well as in the blood, and a mutagenic effect in blood marrow cells. The results emphasise the need of improving CYN monitoring in waters bodies in order to reduce the risk of human exposure.

Disinfection by-products (DBPs) arise when natural organic matter in source water reacts with disinfectants used in the water treatment process. Studies have suggested an association between DBPs and birth defects. Neural tube defects (NTDs) in embryos of untreated control mice were first observed in-house in May 2006 and have continued to date. The source of the NTD-inducing agent was previously determined to be a component of drinking water. Tap water samples from a variety of sources were analyzed for trihalomethanes (THMs) to determine if they were causing the malformations. NTDs were observed in CD-1 mice provided with treated and untreated surface water. Occurrence of NTDs varied by water source and treatment regimens. THMs were detected in tap water derived from surface water but not detected in tap water derived from a groundwater source. THMs were absent in untreated river water and laboratory purified waters, yet the percentage of NTDs in untreated river water were similar to the treated water counterpart. These findings indicate that THMs were not the primary cause of NTDs in the mice since the occurrence of NTDs was unrelated to drinking water disinfection.

This study aims at monitoring and risk assessment of trihalomethanes (THMs) such as chloroform, bromodichloromethane, dibromochloromethane and bromoform, in the drinking water supplies of Rawalpindi and Islamabad. THMs were monitored at twenty locations in these twin cities using solid phase micro extraction-gas chromatography (SPME-GC). Total concentration of THMs was ranged between 21 and 373μg/L, whereas both cities had an average total THMs concentration of 142 and 260μg/L, respectively. Chloroform was found as one the major contributor to the THMs concentration (>85%). The occurrence of THMs followed the given order: chloroform, bromodichloromethane>dibromochloromethane>bromoform. Lifetime cancer risk assessment of THMs was carried out using prediction models via different exposure routes (ingestion, inhalation and dermal). An average lifetime cancer risk was found to be 0.74×10(-4) and 1.24×10(-4) for Rawalpindi and Islamabad, respectively. The number of expected cancer cases per year could reach two cases for each city. Hazard index values were found below unity for both the cities implying that there would be no considerable non-cancer risk. Oral ingestion was found to be one of the main routes of exposure for both types of risk which was followed by inhalation and dermal routes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: Congenital anomalies have been inconsistently associated with maternal crude estimated exposure to drinking water trihalomethane (THM). We investigated the relationship between individual THM uptake during the first trimester of pregnancy and congenital anomalies., Methods: We estimated maternal THM uptake for 3074 live births using residential tap water concentrations, drinking water ingestion, showering and bathing, and uptake factors of THM in the blood. Multiple logistic regression was used to investigate the association of THM exposure with congenital anomalies., Results: We observed no statistically significant relationships between congenital anomalies and the total THM internal dose. We found little indication of a dose-response relationship for brominated THM and congenital heart anomalies. The relationship was statistically significant for bromodichloromethane (BDCM) (OR=2.16, 95% CI 1.05 to 4.46, highest vs lowest tertile) during the first month of pregnancy. During the first trimester of pregnancy, the probability of developing heart anomalies increased for every 0.1 μg/d increase in the BDCM and for every 0.01 μg/d increase in the internal dibromochloromethane (DBCM) dose (OR 1.70, 95% CI 1.09 to 2.66, and OR 1.25, 95% CI 1.01 to 1.54, respectively). A dose-response relationship was evident for musculoskeletal anomalies and DBCM exposure during the first and second months of pregnancy, while BDCM exposure tended to increase the risk of urogenital anomalies., Conclusions: This study shows some evidence for an association between the internal dose of THM and the risk of congenital anomalies. In particular, increased prenatal exposure to brominated THM might increase the risk of congenital heart and musculoskeletal anomalies.

Disinfection byproducts were measured in the finished drinking water from ten water treatment plants in three Chinese cities - Guangzhou, Foshan and Zhuhai. A total of 155 water samples were collected in 2011 and 2012. The median (range) of trihalomethane (THM) and haloacetic acid (HAA) levels were 17.7 (0.7-62.7) μg/L and 8.6 (0.3-81.3) μg/L, respectively. Chloroform, dichloroacetic acid and trichloroacetic acid were the dominant species observed in Guangzhou and Foshan water, while brominated THMs predominated in water from Zhuhai. Haloacetonitriles, haloketones, chloral hydrate and trichloronitromethane were usually detected at levels ranging from unquantifiable (<0.2μg/L) to 12.2μg/L (choral hydrate). THMs and HAAs showed clear seasonal variations with the total concentrations higher in winter than in summer. Correlations among DBP levels varied, with the strongest linear correlation observed between chloroform and chloral hydrate levels (R(2)=0.77). The risk of cancer from ingestion, inhalation and dermal contact exposure to THMs was estimated. CHCl2Br contributed the highest percentage of the cancer risk from ingestion pathway and CHCl3 contributed the highest of cancer risk from inhalation pathway., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The objectives of this study were to (1) examine the relationship between total trihalomethanes (TTHM) levels in public water supplies and risk of esophageal cancer occurrence and (2) determine whether calcium (Ca) and magnesium (Mg) levels in drinking water modify the effects of TTHM on risk to develop esophageal cancer. A matched case-control study was used to investigate the relationship between the risk of death attributed to esophageal cancer and exposure to TTHM in drinking water in 53 municipalities in Taiwan. All esophageal cancer deaths in the 53 municipalities from 2006 through 2010 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to the cancer cases by gender, year of birth, and year of death. Each matched control was selected randomly from the set of possible controls for each cancer case. Data on TTHM levels in drinking water were collected from Taiwan Environmental Protection Administration. Information on the levels of Ca and Mg in drinking water was obtained from the Taiwan Water Supply Corporation. The municipality of residence for cancer cases and controls was presumed to be the source of the subject's TTHM, Ca, and Mg exposure via drinking water. Relative to individuals whose TTHM exposure level <4.9 ppb, the adjusted odds ratio (OR) with 95% confidence interval (CI) for esophageal cancer was 1.02 (0.84-1.23) for individuals who resided in municipalities served by drinking water with a TTHM exposure ≥4.9 ppb. There was evidence of an interaction between drinking-water TTHM levels and low Ca and Mg intake. Our findings showed that the correlation between TTHM exposure and risk of esophageal cancer development was influenced by Ca and Mg levels in drinking water. This is the first study to report effect modification by Ca and Mg intake from drinking water on the correlation between TTHM exposure and risk of esophageal cancer occurrence. Increased knowledge of the interaction between Ca, Mg, and TTHM in reducing risk of esophageal cancer development will aid in public policymaking and standard setting for drinking water.

Background: Epidemiological evidence of an association between disinfection by-products (DBPs) exposure via drinking water and reproductive outcomes is still inconclusive., Objective: The aim of this study was to investigate the association between trihalomethanes (THMs), chlorite and chlorate exposure and congenital anomalies., Methods: A case-control study was carried out in Emilia-Romagna Region (Italy). Data on 1917 different congenital anomalies (neural tube, cardiac, diaphragm and abdominal wall, oesophagus, cleft lip and palate, respiratory, urinary tract and chromosomal anomalies) observed in the period 2002-2005 were extracted from the Regional Malformation Registry. Four controls (newborns without anomalies) were randomly selected form the Regional Birth Register and frequency matched to cases according to pregnancy period. The network supplying water during the first trimester of pregnancy was identified on the basis of mother's address: DBPs data, technical and structural information were linked to each subject., Results: Overall, THMs exposure was very low (mean: 3.8±3.6 μg/l), and no risk excess was observed. Chlorite and chlorate values were fairly high (mean: 427±184 μg/l and 283±79 μg/l, respectively). Women exposed to chlorite level >700 μg/l were at higher risk of newborns with renal defects (OR: 3.30; 95% IC: 1.35-8.09), abdominal wall defects (OR: 6.88; 95% IC: 1.67-28.33) and cleft palate (OR: 4.1; 95% IC: 0.98-16.8); women exposed to chlorate level >200 μg/l were at higher risk of newborns with obstructive urinary defects (OR: 2.88; 95% IC: 1.09-7.63), cleft palate (OR: 9.60; 95% IC:1.04-88.9) and spina bifida (OR: 4.94; 95% IC:1.10-22)., Conclusions: This was the first study showing an excess risk of different congenital anomalies related to chlorite and chlorate exposure via drinking water: further research is needed to confirm the observed relationships in large datasets, specifically for chlorate, an unregulated DBP., (Copyright © 2012 Elsevier Inc. All rights reserved.)