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| Levels of TCAA loading in blood and urinary excretion between Exposure Day 12 and 15 in five groups.
Source publication
Disinfection by-products (DBPs) in drinking water represent a public health issue and a challenge for epidemiology to provide evidence towards the causation of various hypothesized health effects. Validation of a biomarker of exposure to DBPs is a strategy to achieve progress which has been advocated. The objective of this study was to validate uri...
Citations
... Urinary TCAA has been validated as an optimal DBP biomarker for drinking tap water that has undergone chlorination (Parvez et al., 2019;Zeng et al., 2014;Zhang et al., 2009), with existing studies in humans suggesting that TCAA is poorly metabolized in vivo and mainly excreted unchanged in urine, with a half-life of approximately 2-4 days (IARC, 2018c). Approximately 75% of absorbed TCAA would be excreted as the parent compound in human urine (IARC, 2018c). ...
... Blood THM levels are generally more sensitive to low levels of exposure and can reflect an integrative measure of multiple exposure routes (Miles et al., 2002;Weisel et al., 1999), but they are easily influenced by recent water-use activities (Nuckols et al., 2005) and the collection of blood sample is invasive. Urinary HAAs such as TCAA have been reported to significantly link with ingestion of THMs and HAAs in drinking water (Costet et al., 2012;Wang et al., 2014;Zhang et al., 2009). Moreover, the collection of urine sample is non-invasive and enhances subject participation. ...
Disinfection byproducts (DBPs) are a class of ubiquitous chemicals in drinking water and inevitably result in widespread human exposures. Potentially adverse health effects of DBP exposures, including reproductive and developmental outcomes, have been increasing public concerns. Several reviews have focused on the adverse pregnancy outcomes of DBPs. This review summarized current evidence on male reproduction health upon exposure to DBPs from toxicological and epidemiological literature. Based on existing experimental studies, there are sufficient evidence showing that haloacetic acids (HAAs) are male reproductive toxicants, including reduced epididymal weight, decreased semen parameters and sperm protein 22, and declined testosterone levels. However, epidemiological evidence remains insufficient to support a link of DBP exposures with adverse male reproductive outcomes, despite that blood and urinary DBP biomarkers are associated with decreased semen quality. Eight potential mechanisms, including germ/somatic cell dysfunction, oxidative stress, genotoxicity, inflammation, endocrine hormones, folate metabolism, epigenetic alterations, and gut microbiota are likely involved in male reproductive toxicity of DBPs. We also identified knowledge gaps in toxicological and epidemiological studies to enhance future needs.
... THMs have been typically used as DBP markers for association analyses of human health effects, although one can argue that they might not necessarily be the causal agents [9]. Among the nonvolatile HAAs, trichloroacetic acid (TCAA) received increased attention as a proxy DBP biomarker due to significant correlations reported between TCAA concentrations in urine and ingested TCAA from drinking water [10][11][12][13]. However, there is limited knowledge about other urinary HAAs. ...
... Although the use of biomarkers to estimate exposure for etiologically relevant periods is hampered by the short half-life of DBPs, urinary TCAA has been used as a proxy DBP biomarker [12,13,51,52] given that half-life (2.1-6.3 days) is longer than consecutive exposure events. Due to its nonvolatile nature, urinary TCAA can potentially inform about the ingested DBP exposure. ...
... In this study, we evaluated the relationship between urinary TCAA and ingested TCAA calculated by self-reported at-home drinking water consumption questionnaire resulting in a statistically significant moderate (r = 0.48) correlation. This finding is directly in line with Smith et al. [13] that showed a significant moderate correlation (r = 0.50, p value=0.002) between ingested TCAA from home tap water and TCAA in urine as well as by Zhang et al. [12] showing a significant strong correlation (r = 0.66, p value < 0.001). ...
Background
Knowledge about human exposure and health effects associated with non-routinely monitored disinfection by-products (DBPs) in drinking water is sparse.
Objective
To provide insights to estimate exposure to regulated and non-regulated DBPs in drinking water.
Methods
We collected tap water from homes (N = 42), bottled water (N = 10), filtered tap water with domestic activated carbon jars (N = 6) and reverse osmosis (N = 5), and urine (N = 39) samples of participants from Barcelona, Spain. We analyzed 11 haloacetic acids (HAAs), 4 trihalomethanes (THMs), 4 haloacetonitriles (HANs), 2 haloketones, chlorate, chlorite, and trichloronitromethane in water and HAAs in urine samples. Personal information on water intake and socio-demographics was ascertained in the study population (N = 39) through questionnaires. Statistical models were developed based on THMs as explanatory variables using multivariate linear regression and machine learning techniques to predict non-regulated DBPs.
Results
Chlorate, THMs, HAAs, and HANs were quantified in 98–100% tap water samples with median concentration of 214, 42, 18, and 3.2 μg/L, respectively. Multivariate linear regression models had similar or higher goodness of fit (R2) compared to machine learning models. Multivariate linear models for dichloro-, trichloro-, and bromodichloroacetic acid, dichloroacetonitrile, bromochloroacetonitrile, dibromoacetonitrile, trichloropropnanone, and chlorite showed good predictive ability (R² = 0.8–0.9) as 80–90% of total variance could be explained by THM concentrations. Activated carbon filters reduced DBP concentrations to a variable extent (27–80%), and reverse osmosis reduced DBP concentrations ≥98%. Only chlorate was detected in bottled water samples (N = 3), with median = 13.0 µg/L. Creatinine-adjusted trichloroacetic acid was the most frequently detected HAA in urine samples (69.2%), and moderately correlated with estimated drinking water intake (r = 0.48).
Significance
Findings provide valuable insights for DBP exposure assessment in epidemiological studies. Validation of predictive models in a larger number of samples and replication in different settings is warranted.
Impact statement
Our study focused on assessing and describing the occurrence of several classes of DBPs in drinking water and developing exposure models of good predictive ability for non-regulated DBPs.
... Disinfection byproducts (DBPs) are widespread water contaminants formed when oxidizing disinfectants react with organic matter in raw water. 1 More than 700 DBPs have been identified to date, among which haloacetic acids (HAAs) are the leading species of nonvolatile DBPs. 2 Exposure to HAAs occurs mainly through ingestion of water. Consequently, the concentrations of trichloroacetic acid (TCAA) in urine, valid biomarkers that reflect ingestion of HAAs in chlorinated drinking water, 3 are detectable in more than three-quarters of adults, children, and pregnant women from many countries, including China. 4,5 Given the cytotoxicity, carcinogenicity, genotoxicity, and reproductive toxicity of HAAs, 6,7 the maximum contaminant level (MCL) for TCAA has been regulated to 100 μg/L by the Chinese drinking water standard. ...
... (Wang et al., 2014). The high within-individual variability of blood THMs and urinary HAAs is not unexpected given their rapid elimination half-lives (1-65 days for THMs; 2-60 min for DCAA; and 1.2-6 days for TCAA) (Fakour and Lo, 2018;Zhang et al., 2009b), as well as the temporal variability in water supply systems and episodic nature of daily wateruse activities. The within-women variability of blood THMs and urinary HAAs could be further enhanced during pregnancy because of the changing physiological status that may affect DBP metabolism. ...
... DCAA and TCAA are both nonvolatile and have low dermal permeability, making ingestion the dominant route of exposure (Savitz, 2012). Many studies have revealed an exposure-response relationship between urinary TCAA excretion and the amount of TCAA ingestion (Froese et al., 2002;Kim et al., 1999;Weisel et al., 1999;Zhang et al., 2009b). Therefore, it is not surprising that we found higher urinary TCAA concentrations among women who used chlorinated water and ingested larger amounts of unfiltered tap water in the previous week. ...
Blood trihalomethanes (THMs) and urinary haloacetic acids (HAAs) are the leading candidate biomarkers for disinfection byproduct (DBP) exposure. However, no studies have assessed the exposure profiles, temporal variability, and potential predictors of these biomarkers during pregnancy. Here we collected blood (n=4304) and urine samples (n=4165) from 1760 Chinese pregnant women during early, mid-, and late pregnancy, which were separately analyzed for 4 THMs and 2 HAAs. We calculated the intraclass correlation coefficients (ICCs) to assess the variability of these biomarkers and estimated their correlations with sociodemographic, water-use behavioral, dietary and sample collection factors using mixed models. The median concentrations of TCM, BDCM, Br-THMs [sum of BDCM, dibromochloromethane (DBCM), bromoform (TBM)], total THMs (TTHMs, sum of TCM and Br-THMs), DCAA and TCAA in the water distribution system were 4.2 μg/L, 1.7 μg/L, 2.9 μg/L, 7.1 μg/L, 3.4 μg/L and 8.2 μg/L, respectively. Chloroform (TCM), bromodichloromethane (BDCM), dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) were detected in >75% of the biospecimens. Repeated measurements of blood TCM, BDCM, Br-THMs and TTHMs and urinary DCAA and TCAA uniformly exhibited high variability (ICCs=0.01–0.13); the use of a single measurement to classify gestational average exposure resulted in a high degree of exposure misclassification. The sampling season was a strong predictor of all analyzed DBPs. Additionally, we detected a positive association of blood TCM and BDCM with household income, urinary DCAA with age, and urinary TCAA with tap water usage, education level and amount of tap water consumed. Inverse associations were found between blood BDCM and vegetable consumption, and between blood Br-THM and TTHM and time interval since the last bathing/showering. Afternoon samples had lower DCAA concentrations than did early morning samples. Our results indicate that blood THM and urinary HAA concentrations vary greatly over the course of pregnancy and are affected by sampling season, time of day of blood/urine collection, sociodemographic factors, recent water-use activities and dietary intake.
... Only a few studies have measured urinary excretion of HAAs [39][40][41][42][43]. Moreover, studies on interand intra-individual exposure variability and sensitivity to exposure routes are limited. ...
... TCAA is frequently detected in urine because of its long half-life (1-6 days) [42,43], and reported as a biomarker of HAAs, but its interindividual and intra-individual variability is not fully known in humans. A few studies measured urinary HAAs in swimmers and pool workers, as well as in people after domestic activities (e.g., showering, bathing, and washing dishes and clothes), which essentially captured high exposure events, but did not capture baseline exposure levels [40,41]. Also, relying on TCAA as the only HAA biomarker may not represent cumulative exposure of all individual HAAs. ...
... This study frequently detected both urinary MCAA and TCAA (Tables 2 and 3). Although urinary TCAA is being used as a biomarker of HAAs [41], the use of urinary MCAA as a possible biomarker has never been explored. The frequent detection rate of urinary MCAA (44%) and moderate correlation between urinary MCAA and TCAA (r = 0.45; p = 0.04) in this study suggest that MCAA along with TCAA may be used as potential biomarkers of HAA exposure. ...
Disinfected water is the major source of haloacetic acids (HAAs) in humans, but their inter- and intra-individual variability for exposure and risk assessment applications is under-researched. Thus, we measured HAAs in cross-sectional and longitudinal urine and water specimens from 17 individuals. Five regulated HAAs—mono, di, and trichloroacetic acid (MCAA, DCAA, and TCAA) and mono- and dibromoacetic acid (MBAA and DBAA)—and one unregulated HAA—bromochloroacetic acid (BCAA)—were measured. Urinary DCAA, MBAA, DBAA, and BCAA levels were always below the limits of detection (LOD). Measured levels and interindividual variability of urinary MCAA were higher than urinary TCAA. Longitudinal urinary specimens showed MCAA levels peaked in after-shower specimens, while TCAA levels remain unchanged. Correlation between urinary MCAA and TCAA was moderate but statistically significant. The prevalence of MCAA and TCAA in urine suggest they can be considered as biomarkers of HAA. Peak urinary MCAA in post-shower specimens suggest MCAA captures short-term exposure via dermal and/or inhalation, while urinary TCAA captures long-term exposure via ingestion. However, further research is warranted in a large pool of participants to test the reliability of MCAA as exposure biomarker.
... Uses of the monitoring DBP concentrations in drinking water as surrogates of exposures result in a lack of reliable exposure assessment that has been considered as the main limitation in previous human studies (Arbuckle et al., 2002). Blood THMs and urinary trichloroacetic acid (TCAA) have been considered as valid biomarkers of DBP exposure to enhance exposure assessment (Miles et al., 2002;Zhang et al., 2009). Recent studies utilized these biomarkers and found that maternal exposure to drinking water DBPs during pregnancy is related to fetal growth restriction, low birth weight, and small for gestational age Costet et al., 2012;Zhou et al., 2012). ...
... Blood THM concentrations can accurately represent the integrative exposures from various routes (Miles et al., 2002;Rivera-Nunez et al., 2012). Urinary TCAA concentration is significantly related to its exposure through ingestion of chlorinated drinking water (Bader et al., 2004;Zhang et al., 2009). We found no evidence of an association between maternal urinary TCAA and DNA methylation. ...
Maternal exposure to drinking water disinfection by-products (DBPs) during pregnancy has been related to adverse birth outcomes. While experimental studies have shown that exposure to DBPs induce DNA hypomethylation, evidence from humans is limited. This study aimed to examine whether prenatal exposure to drinking water DBPs was associated with DNA methylation in cord blood. Maternal biomarkers of exposure to drinking water DBPs including blood trihalomethanes [THMs, including chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM)] and urinary trichloroacetic acid (TCAA) were measured during late pregnancy. DNA methylation in Alu and long interspersed nucleotide element-1 (LINE-1) repetitive elements from cord blood samples (n = 115) was measured by pyrosequencing. We used multivariable linear regression to estimate the associations of DNA methylation in cord blood with maternal blood THMs and urinary TCAA. We found no statistically significant association between urinary TCAA and DNA methylation. However, we found that blood TBM was associated with decreased Alu methylation (− 0.39%; 95% CI: − 0.83%, 0.05% for the highest versus lowest exposure group; p for trend = 0.08) and decreased LINE-1 methylation (− 1.27%; 95% CI: − 2.91%, 0.36% for the highest versus lowest exposure group; p for trend = 0.06). Our results suggest that prenatal exposure to drinking water TBM is associated with DNA hypomethylation in cord blood. However, further studies are needed to confirm our findings.
... conclusion: Our findings suggest that exposure to drinking-water DBPs may contribute to decreased semen quality in humans. (Calafat et al. 2003;Froese et al. 2002;Kim et al. 1999;Zhang et al. 2009b). ...
... Moreover, the collection of urine samples is noninvasive and thus feasible for large-scale epidemiological studies. Previous studies have reported that urinary TCAA could be a valid biomarker of DBP ingestion (e.g., HAAs) through chlorinated drinking water (Calafat et al. 2003;Froese et al. 2002;Kim et al. 1999;Zhang et al. 2009b). A recent study has found that urinary TCAA concentrations were significantly associated with THM ingestion (total THMs and all individual THMs except bromoform) (Costet et al. 2012). ...
Exposure to disinfection by-products (DBPs) has been demonstrated to impair male reproductive health in animals, but human evidence is limited and inconsistent.
To examine the association between exposure to drinking water DBPs and semen quality in a Chinese population.
We recruited 2,009 men seeking semen analysis from the Reproductive Center of Tongji Hospital in Wuhan, China between April 2011 and May 2012. Each man provided a semen sample and a urine sample. Semen samples were analyzed for sperm concentration, sperm motility, and sperm count. As a biomarker of exposure to drinking water DBPs, trichloroacetic acid (TCAA) was measured in urine samples.
The mean (median) urinary TCAA concentration was 9.58 (7.97) μg/L (interquartile range, 6.01 to 10.96 μg/L). Compared to men with urine TCAA in the lowest quartile, increased adjusted ORs were estimated for below-reference sperm concentration in men with TCAA in the second and fourth quartile (OR = 1.79; 95% CI: 1.19, 2.69 and OR = 1.51; 95% CI: 0.98, 2.31, respectively), for below-reference sperm motility in men with TCAA in the second and third quartile (OR = 1.46; 95% CI: 1.12, 1.90 and OR = 1.30; 95% CI: 1.00, 1.70, respectively), and for below-reference sperm count in men with TCAA in the second quartile (OR 1.62; 95% CI: 1.04, 2.55). Non-monotonic associations with TCAA quartiles were also estimated for semen parameters modeled as continuous outcomes, though significant negative associations were estimated for all quartiles above the reference level for sperm motility.
Our findings suggest that exposure to drinking water DBPs may contribute to decreased semen quality in humans.
... HAAs are non-volatile and the predominant route for exposure is ingestion; with no significant contribution from inhalation and dermal absorption (Xu et al., 2002; Xu and Weisel 2003 ). TCAA is one of the most common HAAs found in chlorinated drinking water, and urinary TCAA has been validated as a biomarker for measuring TCAA exposure by ingestion of drinking water (Zhang et al., 2009). Incorporation of biomarkers into exposure assessment in epidemiological studies examining DBPs and fetal growth outcomes has occurred only recently, with two studies using urinary TCAA biomarkers (Costet et al., 2012; Zhou et al., 2012). ...
... Participants collected a first morning urine (FMU) sample (Urine 1) three days after tap sampling to account for approximate TCAA half-life when comparing tap water and urine TCAA concentrations. Urinary TCAA measured in FMU samples has been validated as a biomarker for TCAA exposure by ingestion of drinking water, in a controlled direct exposure experiment in humans which demonstrated urinary TCAA concentration reflected TCAA ingestion (μg/day) (Zhang et al., 2009). Diary 1 recorded the same water exposures as the baseline questionnaire (daily intake at home, work/study and elsewhere of tap water, bottled water, tea, coffee and squash/cordial measured in mugs/glasses; water filtering habits; and daily frequency and duration of showering, bathing and swimming), additional tap water intakes and water-related activities, and potential DBP exposure modifiers (e.g. ...
... We observed that creatinine-adjusted urinary TCAA generally demonstrated weaker correlation with volume of tap water intake and TCAA ingestion than (unadjusted) urinary TCAA, although differences were often not statistically significant. This differs from the study by Zhang et al. which found similar correlations between TCAA ingestion and both creatinine-adjusted and unadjusted urinary TCAA (Zhang et al., 2009). The utility of using creatinine to account for diuresis depends on the analyte of interest being excreted in the same way as creatinine and for highly water soluble compounds like TCAA this is not always the case. ...
Disinfection by-product (DBP) exposure during pregnancy may be related to reduced fetal growth, but the evidence is inconclusive and improved DBP exposure assessment is required. The authors conducted a nested exposure study on a subset (n=39) of pregnant women in the Born in Bradford cohort to assess validity of TCAA exposure assessment based on tap water sampling and self-reported water-use; water-use questionnaire validity; and use of a one-time urinary TCAA biomarker. TCAA levels in urine and home tap water supply were quantified, and water use was measured via a questionnaire and 7-day diary, at 28 weeks gestation. Diary and urine measures were repeated later in pregnancy (n=14). TCAA level in home tap water supply was not correlated with urinary TCAA (0.18, P=0.29). Cold unfiltered tap water intake at home measured by questionnaire was correlated with urinary TCAA (0.44, P=0.007), but correlation was stronger still for cold unfiltered tap water intake reported over the 3 days prior to urine sampling (0.60, P<0.001). For unemployed women TCAA ingestion at home, derived from tap water sampling and self-reported water-use, correlated strongly with urinary TCAA (0.78, P<0.001), but for employed women the correlation was weak (0.31, P=0.20). Results suggest individual tap water intake is most influential in determining TCAA exposure variability in this cohort, and that TCAA ingestion at home is a valid proxy for TCAA exposure for unemployed women but less satisfactory for employed women.
... Held to the criteria indicated above, the answer is a resounding ''no,'' but there is an empirical basis for optimism that it could become a useful tool for epidemiologic studies. Urinary TCAA has been shown to be responsive to contaminant levels and volume of water consumption (12). It is stable, passing into the urine unmetabolized, and is not readily degraded through the collection and storage process (12). ...
... Urinary TCAA has been shown to be responsive to contaminant levels and volume of water consumption (12). It is stable, passing into the urine unmetabolized, and is not readily degraded through the collection and storage process (12). The elimination half-life of TCAA is in the range of 2-6 days (13), sufficient to provide meaningful information based on urinary concentration. ...
... The range of chemicals for which urinary TCAA may be an effective proxy is unknown, as well as whether its value as a proxy for chemicals other than TCAA itself varies by location. The needed number of samples, the requirement for urine specimens to be collected first thing in the morning, and other important logistical issues for field studies have yet to be worked out, but there is encouraging quantitative evidence of the potential value of this biomarker under optimal conditions (11,12), a necessary starting point. ...
Studies of the relation between exposure to drinking water disinfection by-products and pregnancy outcomes have been limited by the complexity of the exposure itself (consisting of hundreds of different chemicals), the diverse pathways contributing to exposure, and the difficulty in assessing behavioral determinants of exposure. Therefore, exposure biomarkers offer great promise of enhancing exposure assessment, the limiting factor in the quality and conclusiveness of epidemiologic studies. However, there are significant conceptual and logistical challenges in developing biomarkers for the various constituents of concern that are sensitive to typical variation in exposure, reflective of the time periods of interest, not susceptible to interference from exposures other than water, not subject to reverse causality by correlates of adverse pregnancy outcomes, reflective of the chemicals of interest, and feasible for large-scale epidemiologic studies. Urinary trichloroacetic acid has been the leading candidate exposure biomarker for over a decade, and the first attempt to incorporate it into an epidemiologic study (Am J Epidemiol. 2012;175(4):263-275) is notable-the considerable limitations notwithstanding. In future efforts, investigators need to combine biomarker development with substantive epidemiologic studies to improve on this initial effort and prepare for more definitive research.
