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Journal ArticleDOI

Exposure to Drinking Water Trihalomethanes and Their Association with Low Birth Weight and Small for Gestational Age in Genetically Susceptible Women

06 Dec 2012-International Journal of Environmental Research and Public Health (Multidisciplinary Digital Publishing Institute (MDPI))-Vol. 9, Iss: 12, pp 4470-4485

TL;DR: It is suggested that THM internal dose may affect foetal growth and that maternal GSTM1 genotype modifies the THM exposure effects on LBW.

AbstractLittle is known about genetic susceptibility to individual trihalomethanes (THM) in relation to adverse pregnancy outcomes. We conducted a nested case-control study of 682 pregnant women in Kaunas (Lithuania) and, using individual information on drinking water, ingestion, showering and bathing, and uptake factors of THMs in blood, estimated an internal THM dose. We used logistic regression to evaluate the relationship between internal THM dose, birth outcomes and individual and joint (modifying) effects of metabolic gene polymorphisms. THM exposure during entire pregnancy and specific trimesters slightly increased low birth weight (LBW) risk. When considering both THM exposure and maternal genotypes, the largest associations were found for third trimester among total THM (TTHM) and chloroform-exposed women with the GSTM1–0 genotype (OR: 4.37; 95% CI: 1.36–14.08 and OR: 5.06; 95% CI: 1.50–17.05, respectively). A test of interaction between internal THM dose and GSTM1–0 genotype suggested a modifying effect of exposure to chloroform and bromodichloromethane on LBW risk. However, the effect on small for gestational age (SGA) was not statistically significant. These data suggest that THM internal dose may affect foetal growth and that maternal GSTM1 genotype modifies the THM exposure effects on LBW.

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Citations
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Journal ArticleDOI
TL;DR: Maternal genotypes for enzymes participating in metabolism of polycyclic aromatic hydrocarbons alter the association between cigarette smoking and birth weight, and this finding raises the question of whether metabolic genes interact with smoking.
Abstract: This study sought to clarify the relation, if any, between genetic susceptibility to cigarette smoke and adverse pregnancy outcomes. The working hypothesis was that the risk of reduced birth weight (or increased risk of low birth weight [LBW], <2500 g) is modified by maternal genetic susceptibility as defined by polymorphisms for two genes regulating the metabolism of polycyclic aromatic hydrocarbons, the most important carcinogens in tobacco smoke. A case-control study enlisted 741 women delivering live singleton infants, 567 had never smoked, whereas 174 had smoked at some time. The series included 207 preterm or LBW infants. All three possible genotypes for the CYP1A1 Mspl polymorphism (AA, homozygous wild type; Aa, heterozygous variant type; aa, homozygous variant type) were analyzed, as was the presence or absence of the GSTT1 deletion polymorphism. The mean birth weight in women who had smoked at some time in their lives was 280 g lower than for those who had never smoked, and the mean gestational age was 0.8 week shorter. The odds ratio (OR) for preterm birth was 1.8 in the smokers. Continuous smoking during pregnancy carried an OR for LBW of 2.1; the mean birth weight was reduced by 377 g compared with nonsmokers. When analyzing CYP1A1, the reduction in birth weight was 252 g for the AA genotype (OR, 1.3) and 520 g for the Aalaa genotype group (OR, 3.2). Birth weight was reduced by 285 g (OR, 1.7) when the GSTT1 was present and 642 g (OR, 3.5) when it was absent. Birth weights were most reduced, by a mean of 1285 g, in smoking mothers bearing the CYP1A1 Aalaa and GSTT1 absent genotypes. Similar effects were noted for gestational age. Genotype had no independent adverse effect on women who had never smoked. Comparable results emerged when allowing for maternal ethnicity. Maternal genotypes for enzymes participating in metabolism of polycyclic aromatic hydrocarbons alter the association between cigarette smoking and birth weight. This finding raises the question of whether metabolic genes interact with smoking, and it may in time help to identify high-risk women who might be persuaded not to smoke.

39 citations


Journal ArticleDOI
TL;DR: The findings demonstrate associations between THM, but not HAA, exposure during pregnancy and reduced birth weight, but suggest this differs by ethnicity, and suggest that THMs are not acting as a proxy for HAAs, or vice-versa.
Abstract: This research was funded by HiWATE (Health Impacts of Long-Term Exposure to Disinfection By-products in Drinking Water in Europe) (EU 6th Framework Programme contract no Food-CT-2006-036224), the Joint Environment & Human Health Programme (NERC grant NE/ E008844/1), an Economic and Social Research Council studentship (PTA-031-2006-00544 to RBS), an MRC Capacity Building Studentship 2010-2013 to SCE, and a Research Training support stipend (SCE) The MRC-PHE Centre for Environment and Health is funded by the UK Medical Research Council and Public Health England

29 citations


Journal ArticleDOI
TL;DR: A new comprehensive bioanalytical method has been developed that can quantify mixtures of organic halogenated compounds, including DBPs, in human urine as total organic chlorine (TOCl), total organic bromine (TOBr), and total organic iodine (TOI).
Abstract: Disinfection by-products (DBPs) are a complex mixture of compounds unintentionally formed as a result of disinfection processes used to treat drinking water. Effects of long-term exposure to DBPs are mostly unknown and were the subject of recent epidemiological studies. However, most bioanalytical methods focus on a select few DBPs. In this study, a new comprehensive bioanalytical method has been developed that can quantify mixtures of organic halogenated compounds, including DBPs, in human urine as total organic chlorine (TOCl), total organic bromine (TOBr), and total organic iodine (TOI). The optimized method consists of urine dilution, adsorption to activated carbon, pyrolysis of activated carbon, absorption of gases in an aqueous solution, and halide analysis with ion chromatography and inductively coupled plasma-mass spectrometry. Spike recoveries for TOCl, TOBr, and TOI measurements ranged between 78% and 99%. Average TOCl, TOBr, and TOI concentrations in five urine samples from volunteers who consumed tap water were 1850, 82, and 21.0μg/L as X-, respectively. Volunteers who consumed spring water (control) had TOCl, TOBr, and TOI average concentrations in urine of 1090, 88, and 10.3μg/L as X-, respectively. TOCl and TOI in the urine samples from tap water consumers were higher than the control. However, TOBr was slightly lower in tap water urine samples compared to mineral water urine samples, indicating other sources of environmental exposure other than drinking water. A larger sample population that consumes tap water from different cities and mineral water is needed to determine TOCl, TOBr, and TOI exposure from drinking water.

28 citations


Additional excerpts

  • ...…birth outcomes (Swan et al., 1998; Waller et al., 1998; Nieuwenhuijsen et al., 2000, 2013; Villanueva et al., 2004, 2007; IARC, 2004; Bove et al., 2007; Costet et al., 2011; Grazuleviciene et al., 2011, 2013; Danileviciute et al., 2012; Jeong et al., 2012; Righi et al., 2012; Smith et al., 2016)....

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Journal ArticleDOI
TL;DR: The study results provide no evidence of an increased risk of TLBW, SGA, and preterm delivery at the relatively low concentrations of TTHMs in Taiwan's drinking water.
Abstract: Chlorination has been the major strategy for disinfection of drinking water in Taiwan. Recently there has been interest in the relationship between by-products of disinfection of drinking water and pregnancy outcomes including low birth weight and preterm delivery. We performed a study to examine the effects of exposure to total trihalomethanes (TTHMs) on the risk of term low birth weight (TLBW), small for gestational age (SGA), and preterm delivery in Taiwan. TTHMs data were available for 65 municipalities in Taiwan. The study population comprised 90,848 women residing in the 65 municipalities who had a first parity singleton birth between January 1, 2000 and December 31, 2002, and for which complete information on maternal age, education, gestational age, birth weight, and sex of the baby were available. Maternal TTHMs exposure was estimated from the TTHMs concentration for the municipality of residence at birth. The study results provide no evidence of an increased risk of TLBW, SGA, and preterm delivery at the relatively low concentrations of TTHMs in Taiwan's drinking water.

25 citations


Journal ArticleDOI
TL;DR: There was no association between birth outcomes and trihalomethane exposures during pregnancy in the total population or in potentially genetically susceptible subgroups in this large European study.
Abstract: 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.)

21 citations


References
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Journal ArticleDOI
TL;DR: The brominated DBPs were the most genotoxic of all but have not been tested for carcinogenicity and highlighted the emerging importance of dermal/inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer.
Abstract: Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter, anthropogenic contaminants, bromide, and iodide during the production of drinking water. Here we review 30 years of research on the occurrence, genotoxicity, and carcinogenicity of 85 DBPs, 11 of which are currently regulated by the U.S., and 74 of which are considered emerging DBPs due to their moderate occurrence levels and/or toxicological properties. These 74 include halonitromethanes, iodo-acids and other unregulated halo-acids, iodo-trihalomethanes (THMs), and other unregulated halomethanes, halofuranones (MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] and brominated MX DBPs), haloamides, haloacetonitriles, tribromopyrrole, aldehydes, and N-nitrosodimethylamine (NDMA) and other nitrosamines. Alternative disinfection practices result in drinking water from which extracted organic material is less mutagenic than extracts of chlorinated water. However, the levels of many emerging DBPs are increased by alternative disinfectants (primarily ozone or chloramines) compared to chlorination, and many emerging DBPs are more genotoxic than some of the regulated DBPs. Our analysis identified three categories of DBPs of particular interest. Category 1 contains eight DBPs with some or all of the toxicologic characteristics of human carcinogens: four regulated (bromodichloromethane, dichloroacetic acid, dibromoacetic acid, and bromate) and four unregulated DBPs (formaldehyde, acetaldehyde, MX, and NDMA). Categories 2 and 3 contain 43 emerging DBPs that are present at moderate levels (sub- to low-mug/L): category 2 contains 29 of these that are genotoxic (including chloral hydrate and chloroacetaldehyde, which are also a rodent carcinogens); category 3 contains the remaining 14 for which little or no toxicological data are available. In general, the brominated DBPs are both more genotoxic and carcinogenic than are chlorinated compounds, and iodinated DBPs were the most genotoxic of all but have not been tested for carcinogenicity. There were toxicological data gaps for even some of the 11 regulated DBPs, as well as for most of the 74 emerging DBPs. A systematic assessment of DBPs for genotoxicity has been performed for approximately 60 DBPs for DNA damage in mammalian cells and 16 for mutagenicity in Salmonella. A recent epidemiologic study found that much of the risk for bladder cancer associated with drinking water was associated with three factors: THM levels, showering/bathing/swimming (i.e., dermal/inhalation exposure), and genotype (having the GSTT1-1 gene). This finding, along with mechanistic studies, highlights the emerging importance of dermal/inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer. More than 50% of the total organic halogen (TOX) formed by chlorination and more than 50% of the assimilable organic carbon (AOC) formed by ozonation has not been identified chemically. The potential interactions among the 600 identified DBPs in the complex mixture of drinking water to which we are exposed by various routes is not reflected in any of the toxicology studies of individual DBPs. The categories of DBPs described here, the identified data gaps, and the emerging role of dermal/inhalation exposure provide guidance for drinking water and public health research.

2,287 citations


Journal ArticleDOI
TL;DR: Two supergene families encode proteins with glutathione S-transferase (GST) activity that detoxify a variety of electrophilic compounds, including oxidized lipid, DNA and catechol products generated by reactive oxygen species-induced damage to intracellular molecules.
Abstract: Two supergene families encode proteins with glutathione S-transferase (GST) activity: the family of soluble enzymes comprises at least 16 genes; the separate family of microsomal enzymes comprises at

881 citations


"Exposure to Drinking Water Trihalom..." refers background in this paper

  • ...The metabolism of environmental toxicants includes the several allelic variants of the polymorphic GST group whose show impaired enzyme activities and increase the susceptibility to both environmental xenobiotics and adverse birth outcomes [31,32]....

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  • ...It is possible that GST induction represents part of an adaptive response mechanism to chemical stress [31], therefore genetic polymorphism of GSTM1 and GSTT1 may modify the oxidative stress caused by maternal exposure to THM and lead to adverse pregnancy outcomes....

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Journal ArticleDOI
09 Jan 2002-JAMA
TL;DR: In this study, maternal CYP1A1 and GSTT1 genotypes modified the association between maternal cigarette smoking and infant birth weight, suggesting an interaction between metabolic genes and cigarette smoking.
Abstract: ContextLittle is known about genetic susceptibility to cigarette smoke in relation to adverse pregnancy outcomes.ObjectiveTo investigate whether the association between maternal cigarette smoking and infant birth weight differs by polymorphisms of 2 maternal metabolic genes: CYP1A1 and GSTT1.Design, Setting, and ParticipantsCase-control study conducted in 1998-2000 among 741 mothers (174 ever smokers and 567 never smokers) who delivered singleton live births at Boston Medical Center. A total of 207 cases were preterm or low-birth-weight infants and 534 were non–low-birth-weight, full-term infants (control).Main Outcome MeasureBirth weight, gestation, fetal growth by smoking status and CYP1A1 MspI (AA vs Aa and aa, where Aa and aa were combined because of small numbers of aa and similar results), and GSTT1 (present vs absent) genotypes.ResultsWithout consideration of genotype, continuous maternal smoking during pregnancy was associated with a mean reduction of 377 g (SE, 89 g) in birth weight (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.7). When CYP1A1 genotype was considered, the estimated reduction in birth weight was 252 g (SE, 111 g) for the AA genotype group (n = 75; OR, 1.3; 95% CI, 0.6-2.6), but was 520 g (SE, 124 g) for the Aa/aa genotype group (n = 43 for Aa, n = 6 for aa; OR, 3.2; 95% CI, 1.6-6.4). When GSTT1 genotype was considered, the estimated reduction in birth weight was 285 g (SE, 99 g) (OR, 1.7; 95% CI, 0.9-3.2) and 642 g (SE, 154 g) (OR, 3.5; 95% CI, 1.5-8.3) for the present and absent genotype groups, respectively. When both CYP1A1 and GSTT1 genotypes were considered, the greatest reduction in birth weight was found among smoking mothers with the CYP1A1 Aa/aa and GSTT1 absent genotypes (−1285 g; SE, 234 g; P<.001). Among never smokers, genotype did not independently confer an adverse effect. A similar pattern emerged in analyses stratified by maternal ethnicity and in analyses for gestation.ConclusionsIn our study, maternal CYP1A1 and GSTT1 genotypes modified the association between maternal cigarette smoking and infant birth weight, suggesting an interaction between metabolic genes and cigarette smoking.

551 citations


Journal ArticleDOI
TL;DR: To identify the specific components that may be of aetiological concern and hence to fit the most appropriate exposure model with which to investigate human exposure to chlorinated DBPs, further detailed toxicological assessments of the mixture of byproducts commonly found in drinking water are also needed.
Abstract: Objectives and methods—Chlorination has been the major disinfectant process for domestic drinking water for many years. Concern about the potential health eVects of the byproducts of chlorination has prompted the investigation of the possible association between exposure to these byproducts and incidence of human cancer, and more recently, with adverse reproductive outcomes. This paper evaluates both the toxicological and epidemiological data involving chlorination disinfection byproducts (DBPs) and adverse reproductive outcomes, and makes

549 citations


Journal ArticleDOI
TL;DR: The effects of public drinking water contamination on birth outcomes were evaluated in an area of northern New Jersey and it cannot resolve whether the drinking water contaminants caused the adverse birth outcomes; therefore, these findings should be followed up utilizing available drinkingWater contamination databases.
Abstract: The effects of public drinking water contamination on birth outcomes were evaluated in an area of northern New Jersey. After excluding plural births and chromosomal defects, 80,938 live births and 594 fetal deaths that occurred during the period 1985-1988 were studied. Information on birth outcome status and maternal risk factors was obtained from vital records and the New Jersey Birth Defects Registry. Monthly exposures during pregnancy were estimated for all births using tap water sample data. Odds ratios of > or = 1.50 were found for the following: total trihalomethanes with small for gestational age, central nervous system defects, oral cleft defects, and major cardiac defects; carbon tetrachloride with term low birth weight, small for gestational age, very low birth weight, total surveillance birth defects, central nervous system defects, neural tube defects, and oral cleft defects; trichloroethylene with central nervous system defects, neural tube defects, and oral cleft defects; tetrachloroethylene with oral cleft defects; total dichloroethylenes with central nervous system defects and oral cleft defects; benzene with neural tube defects and major cardiac defects; and 1,2-dichloroethane with major cardiac defects. Total trihalomethane levels > 100 ppb reduced birth weight among term births by 70.4 g. By itself, this study cannot resolve whether the drinking water contaminants caused the adverse birth outcomes; therefore, these findings should be followed up utilizing available drinking water contamination databases.

386 citations