Mutagenicity of three disinfection by-products: di- and trichloroacetic acid and chloral hydrate in L5178Y/TK+/− −3.7.2C mouse lymphoma cells

There is limited information on the prevalence of the potent mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in U.S. water supplies. We measured MX concentrations and mutagenic activity in tap water samples from 36 surface water systems throughout Massachusetts. We found MX levels much higher (up to 80 ng/L) than previously reported in the United States. We also evaluated the role of water treatment on mutagenic activity and disinfection by-product formation. After adjusting for other covariates, chloramination and filtration were the most important treatment options for reducing mutagenic activity and disinfection by-product formation. Multiple chlorine application (before and after filtration) was associated with increased mutagenicity. Chlorine dose, pH, and total organic carbon were also associated with mutagenicity, MX, and total trihalomethane (TTHM) concentration. Seasonal variation was evident for MX and mutagenic activity, with higher levels occurring in the spring compared to the fall. In contrast, TTHM concentrations were greater in the fall.

Section: Resultsmentioning

confidence: 99%

“…The haloacetic acids are the most prevalent nonvolatile compounds (12), but they have been shown to be weak mutagens (13)(14)(15). MX has been shown to be one of the most potent bacterial mutagens tested (16).…”

mentioning

confidence: 99%

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and mutagenic activity in Massachusetts drinking water.

Wright

Schwartz

Vartiainen

et al. 2002

“…As a consequence, these data imply that either the initiated cells promoted by TCA to hepatocellular carcinomas are susceptible to this clastogenic result spontaneously (something that is known to happen both clinically and experimentally) or that TCA could be acting as a tumor progressor. The very weak activity of TCA to act as a clastogen provides some basis for the former hypothesis (115).…”

Section: Hepatocarcinogenicity Of Tnichloroacetatementioning

confidence: 99%

Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.

Bull

2000

127

Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute-chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH and TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concentrations of TCA in blood required to induce liver cancer approach the mM range. Concentrations of DCA in blood associated with carcinogenesis are in the sub-pM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA and/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPARa) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPARa that are observed in rodents. This may be attributed to lower levels of expressed PPARax in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA and TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis. Key words: chloral hydrate, dichloroacetate, liver tumors, mode of action, trichloroacetate, trichloroethylene. -Environ Health Perspect 108(suppl 2):241-259 (2000). http.//ehpnetl.niehs.nih.gov/docs/2000/suppl-2/24 1-259bull/abstract. html

“…To address these questions, histopathologic analysis was conducted for livers and hepatic lesions arising in B6C3F 1 male mice receiving DCA doses as low as 0.05 g/L for 100 weeks, and DCA at 0.5, 1.0, 2.0, and 3.5 g/L for between 26 and 100 weeks (DeAngelo et al 1999). Nongenotoxic versus potential genotoxic effects of DCA can be separated based on low dose (0.05-1.0 g/L) or low concentrations, where genotoxicity has not been demonstrated, versus high dose (2-3.5 g/L) or high concentrations, where gene mutations and clastogenesis has been observed in several test systems (Chang et al 1992;DeMarini et al 1994;Ferreia-Gonzalez et al 1995;Fuscoe et al 1995;Harrington-Brock et al 1998;Leavitt et al 1997) (Table 8). This analysis suggested a model for DCA-induced carcinogenesis, involving three lesion sequences, that lends itself to testing by mathematical means (Rabinowitz et al 2000(Rabinowitz et al , 2001.…”

Section: Discussionmentioning

confidence: 99%

“…At the highest concentrations tested, 3.5-5 g/L DCA, there were no differences between strains or sexes in the CA multiplicity respective of the spontaneous tumor background rate (DeAngelo 2000b;DeAngelo et al , 1999. Although high concentrations (> 2 g/L) of DCA induced gene mutations and chromosomal damage (clastogenesis) in several in vivo and in vitro test systems (DeMarini et al 1994;Fuscoe et al 1995;Harrington-Brock et al 1998;Leavitt et al 1997), the role of genotoxicity in the DCA-induced carcinogenic process in vivo has not been clearly defined (Chang et al 1992;Fox et al 1996;Giller et al 1997;Kopfler et al 1985).…”

mentioning

confidence: 97%

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

Carter

Deddens

et al. 2003

Dichloroacetic acid (DCA) is carcinogenic to the B6C3F(1) mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in drinking water, reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer. In this study we determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05-3.5 g/L) for 26-100 weeks. Lesions were classified as foci of cellular alteration smaller than one liver lobule (altered hepatic foci; AHF), foci of cellular alteration larger than one liver lobule (large foci of cellular alteration; LFCA), adenomas (ADs), or carcinomas (CAs). Histopathologic analysis of 598 premalignant lesions revealed that (a)) each lesion class had a predominant phenotype; (b)) AHF, LFCA, and AD demonstrated neoplastic progression with time; and (c)) independent of DCA dose and length of exposure effects, some toxic/adaptive changes in non-involved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3F(1) mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Because all classes of premalignant lesions and CAs were found at both lower and higher doses, these data are consistent with the conclusion that nongenotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.