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Molecular Mechanisms by Which Chlorinated Water Causes Bladder Cancer
Citation:
Pegram, R., E. Kenyon, Steve Simmons, D. DeMarini, B. Chorley, A. Teal, AND T. Ross. Molecular Mechanisms by Which Chlorinated Water Causes Bladder Cancer. 48th Annual Meeting of the Environmental Mutagenesis and Genomics Society, Raleigh, North Carolina, September 09 - 13, 2017.
Impact/Purpose:
Exposure to drinking water disinfection byproducts (DBPs) has been consistently associated with an increased risk for cancer of the urinary bladder in numerous epidemiology studies conducted over the last 30+ years. Work conducted at EPA and the National Cancer Institute (NIH) has implicated two prevalent classes of DBPs as potential causative agents of this increased risk. This presentation will describe our mechanistic hypothesis that addresses the etiology of DBP-associated bladder cancer and supporting data from studies of DBP epidemiology, exposure route-dependent pharmacokinetics, biotransformation, and genotoxicity. These findings may impact DBP risk assessment, future reviews of current drinking water regulations and approaches for water treatment. The results are of interest to the Office of Water.
Description:
Epidemiology studies have consistently found that greater exposure to drinking water disinfection byproducts (DBPs) is associated with an increased risk for urinary bladder cancer. In our earlier work, we found that the polymorphically-expressed xenobiotic metabolizing enzyme, glutathione S-transferase theta (GSTT1) activates the prevalent DBPs, brominated trihalomethanes (BrTHMs), to mutagenic intermediates. Subsequently, Cantor et al. (Environ. Health Perspect. 118: 1545, 2010) evaluated the impact of GSTT1 genotype and reported that the increased bladder cancer risk was dependent upon the presence of GSTT1. Moreover, the risk was 6-fold higher for people with susceptible genotypes for both GSTT1 and GSTZ1 (an enzyme that metabolizes haloacetic acids (HAAs), another prevalent DBP class). We have now developed a mechanistic hypothesis addressing the etiology of DBP-associated bladder cancer. The hypothesis synthesizes results from studies of DBP epidemiology, exposure route-dependent pharmacokinetics, biotransformation, and genotoxicity. Key elements suggesting a role for BrTHMs include: blood levels of BrTHMs are much higher following dermal/inhalation exposure compared to oral exposure; bladder urothelium is exposed via blood and urine, and urine THM levels can exceed blood levels; GSTT1 activity is present in human urothelial cells, but the primary competing BrTHM biotransformation pathway (CYP2E1) may be very low in the urinary tract; and GSTT1-mediated genotoxicity of BrTHMs has been demonstrated in human urothelial cells. In addition, HAAs may contribute directly or indirectly to mutagenic events in bladder cells. Together, these findings support the biological plausibility of a role for these prevalent DBPs in bladder carcinogenesis. (This abstract does not reflect EPA policy).