title: Glutathione S-transferase-mediated mutagenicity of trihalomethanes in Salmonella typhimurium: contrasting results with bromodichloromethane off chloroform.
abstract: Trihalomethanes (THMs) are the most prevalent disinfection by-products identified in chlorinated drinking water. Among the THMs, chloroform (CHCl3) generally occurs at the highest concentration in finished water, but the concentrations of each of the brominated THMs (CHBrCl2, CHBr2Cl, and CHBr3) can exceed that of CHCl3. Each of these four THMs was carcinogenic in rodents in chronic oral dosing studies. This study assessed THM mutagenicity in a strain of Salmonella typhimurium TA1535 that was transfected with rat theta-class glutathione S-transferase T1-1 (+GST). The +GST strain and its nontransfected parent strain (-GST) were employed in a plate-incorporation assay and exposed for 24 hr to the vapor of individual THMs at concentrations up to 25,600 ppm in sealed Tedlar bags. Base-substitution revertants were produced in the +GST strain in a dose-dependent fashion by CHBrCl2 but not by CHCl3. At 4800 ppm CHBrCl2, which produced a calculated agar concentration of 0.67 mM, there were 419 +/- 75 revertants per plate compared to a spontaneous level of 23 +/- 5. CHCl3 produced a doubling of revertants only at the two highest concentrations tested (19,200 and 25,600 ppm). These results indicate that bromination of THMs confers the capability for theta-class GST-mediated transformation to mutagenic intermediates at low substrate concentrations, suggesting the possibility of a similar activation route in humans. Further, the very low affinity of the GSH-dependent pathway for CHCl3 demonstrates that different THMs can induce adverse effects via different mechanisms, indicating that risk evaluations of THMs should not treat members of this class as if they shared a common mode of action.
authors.affiliation: Experimental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. pegram.rex@epamail.epa.gov
authors.forename: R A
authors.initials: RA
authors.lastname: Pegram
authors.forename: M E
authors.initials: ME
authors.lastname: Andersen
authors.forename: S H
authors.initials: SH
authors.lastname: Warren
authors.forename: T M
authors.initials: TM
authors.lastname: Ross
authors.forename: L D
authors.initials: LD
authors.lastname: Claxton
mesh_terms: D000818:Animals; D002725:Chloroform / Q000633:toxicity*; D005982:Glutathione Transferase / Q000378:metabolism*; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D012486:Salmonella typhimurium / Q000235:genetics*; D022882:Trihalomethanes
chemical_list: D006846:Hydrocarbons, Halogenated; D009153:Mutagens; D022882:Trihalomethanes; C025191:bromodichloromethane; D002725:Chloroform; D005982:Glutathione Transferase