Bladder Cancer and Exposure to Water Disinfection By-Products through Ingestion, Bathing, Showering, and Swimming in Pools

Villanueva, Cristina M.; Cantor, Kenneth P.; Grimalt, Joan O.; Malats, Núria; Silverman, Debra T.; Tardón, Adonina; García-Closas, Reina; Serra, Consol; Carrato, Alfredo; Castaño‐Vinyals, Gemma; Marcos, Ricard; Rothman, Nathaniel; Real, Francisco X.; Dosemeci, Mustafa; Kogevinas, Manolis

doi:10.1093/aje/kwj364

Cited by 511 publications

(321 citation statements)

References 19 publications

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“…2,3 Experimental evidence has suggested that the mechanisms behind DBP carcinogenicity may partially be explained by epigenetic alterations that result from chronic cytotoxicity mediated by a mixture of oxidative metabolites release, reductive free radicals, and cell integrity disruption. 5,32 For non-genotoxic compounds, cycles of mitotic regeneration in response to cytotoxicity may produce cumulative epigenetic changes.…”

Section: Discussionmentioning

confidence: 99%

“…53 The pipeline used (adapted from RnBeads) 54 included the following steps: (1) loading raw intensity data (idat); 55 (2) prefiltering (removal of SNP-enriched probes, greedycut algorithm removal of unreliable measurements, and removal of predefined blacklisted probes-all crossreactive probes and polymorphisms as reported by Chen et al 51 ); (3) normalization (methylumi-noob for background correction 56 and dasen normalization 57 ); (4) quality control (detection and exclusion of technical failures during bisulfite conversion, hybridization, extension and staining, detection of potential sample mixups using the default 65 SNPs included in the array); (5) postfiltering (removal of non CpG probes, removal of sex chromosomes); (6) negative control batch effect correction 58 and surrogate variable analysis-sva multidimensional reduction adjusting for residual confounding; (7) visualization of the general unadjusted methylation profile. Once data were clean, the downstream data analysis was performed using b values.…”

Section: Bioinformatics and Statistical Analysismentioning

confidence: 99%

“…Trihalometanes (THMs) are one of the most abundant classes in chlorinated waters; in the past, Spain has shown high levels of THMs compared to Northern Europe. 1 Lifetime exposure to DBPs has been related to bladder cancer 2,3 and, possibly, colorectal cancer 4 in epidemiological studies. However, the mechanisms involved in these deleterious effects are not clear.…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation levels and long-term trihalomethane exposure in drinking water: an epigenome-wide association study

et al. 2015

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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 casecontrol study of colorectal cancer conducted in Barcelona, Spain, exposed to average lifetime THM levels 85 mg/L vs. >85 mg/L (N D 68 and N D 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 mg/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 (|Db| 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.

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Section: Discussionmentioning

confidence: 99%

Section: Bioinformatics and Statistical Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA methylation levels and long-term trihalomethane exposure in drinking water: an epigenome-wide association study

et al. 2015

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“…Recent modelling of THM uptake suggested that swimming may lead to the highest levels in the blood (Whitaker et al 2003). Uptake of DBPs through showering, bathing and swimming was associated with an increased risk of bladder cancer in a recent Spanish epidemiology study (Villanueva et al 2007).…”

Section: Introductionmentioning

confidence: 94%

The epidemiology and possible mechanisms of disinfection by-products in drinking water

Nieuwenhuijsen

Grellier

Smith

et al. 2009

Phil. Trans. R. Soc. A.

129

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This paper summarizes the epidemiological evidence for adverse health effects associated with disinfection by-products (DBPs) in drinking water and describes the potential mechanism of action.There appears to be good epidemiological evidence for a relationship between exposure to DBPs, as measured by trihalomethanes (THMs), in drinking water and bladder cancer, but the evidence for other cancers including colorectal cancer is inconclusive and inconsistent. There appears to be some evidence for an association between exposure to DBPs, specifically THMs, and little for gestational age/intrauterine growth retardation and, to a lesser extent, pre-term delivery, but evidence for relationships with other outcomes such as low birth weight, stillbirth, congenital anomalies and semen quality is inconclusive and inconsistent. Major limitations in exposure assessment, small sample sizes and potential biases may account for the inconclusive and inconsistent results in epidemiological studies. Moreover, most studies have focused on total THMs as the exposure metric, whereas other DBPs appear to be more toxic than the THMs, albeit generally occurring at lower levels in the water.The mechanisms through which DBPs may cause adverse health effects including cancer and adverse reproductive effects have not been well investigated. Several mechanisms have been suggested, including genotoxicity, oxidative stress, disruption of folate metabolism, disruption of the synthesis and/or secretion of placental syncytiotrophoblast-derived chorionic gonadotropin and lowering of testosterone levels, but further work is required in this area.

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“…Several epidemiological studies suggest a link between consumption of chlorinated drinking water and reproductive and developmental outcomes, such as increased spontaneous abortions and intrauterine growth retardation [10][11][12][13][14], and bladder and gastrointestinal tract cancers [15][16][17][18][19][20][21]. At present, which by-products in chlorinated drinking water could be responsible for increasing cancer risk in human beings is not well established, because the potential synergistic interactions of chlorinated by-products and their role in the molecular mechanisms of carcinogenesis are still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Modulation of cytochrome P450 and induction of DNA damage in Cyprinus carpio exposed in situ to surface water treated with chlorine or alternative disinfectants in different seasons

Canistro

Melega

Ranieri

et al. 2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Epidemiological studies have shown an association between consumption of disinfected drinking water and adverse health outcomes. The chemicals used to disinfect water react with occurring organic matter and anthropogenic contaminants in the source water, resulting in the formation of disinfection byproducts (DBPs). The observations that some DBPs are carcinogenic in animal models have raised public concern over the possible adverse health effects for humans. Here, the modulation of liver cytochrome P450-linked monooxygenases (MFO) and the genotoxic effects in erythrocytes of Cyprinus carpio fish exposed in situ to surface drinking water in the presence of disinfectants, such as sodium hypochlorite (NaClO), chlorine dioxide (ClO 2 ) and peracetic acid (PAA), were investigated in winter and summer. A complex induction/suppression pattern of CYP-associated MFOs in winter was observed for all disinfectants. For example, a 3.4-to 15-fold increase was recorded of the CYP2B1/2-linked dealkylation of penthoxyresorufin with NaClO (10 days) and PAA (20 days). In contrast, ClO 2 generated the most notable inactivation, the CYP2E1-supported hydroxylation of p-nitrophenol being decreased up to 71% after 10 days' treatment. In summer, the degree of modulation was modest, with the exception of CYP3A1/2 and CYP1A1 supported MFOs (62% loss after 20 days PAA).The micronucleus (MN) induction in fish circulating erythrocytes was also analysed as an endpoint of genotoxic potential in the same fish population. Significant increases of MN induction were detected at the latest sampling time on fish exposed to surface water treated with chlorinate-disinfectants, both in winter (NaClO) and summer (NaClO and ClO 2 ), while no effect was observed in fish exposed to PAA-treated water.These results show that water disinfection may be responsible for harmful outcomes in terms of MFO perturbation and DNA damage; if extrapolated to humans, they ultimately offer a possible rationale for the increased urinary cancer risk recorded in regular drinking water consumers.

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Bladder Cancer and Exposure to Water Disinfection By-Products through Ingestion, Bathing, Showering, and Swimming in Pools

Cited by 511 publications

References 19 publications

DNA methylation levels and long-term trihalomethane exposure in drinking water: an epigenome-wide association study

DNA methylation levels and long-term trihalomethane exposure in drinking water: an epigenome-wide association study

The epidemiology and possible mechanisms of disinfection by-products in drinking water

Modulation of cytochrome P450 and induction of DNA damage in Cyprinus carpio exposed in situ to surface water treated with chlorine or alternative disinfectants in different seasons

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