title: Bacterial and mammalian-cell genotoxicity of mixtures of chlorohydroxyfuranones, by-products of water chlorination.
abstract: The genotoxic responses of mixtures of four chlorohydroxyfuranones (CHFs), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), 3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA), 3-chloro- 4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF) and 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF), were compared with the genotoxicity of the individual compounds. Genotoxicity was evaluated in the Salmonella reversion assay (Ames test), the in vitro Chinese hamster ovary (CHO) cell Hprt mutation assay, and in the CHO chromosome aberration test. When tested individually, the concentrations of the chemicals that were chosen for the mixtures induced no or only a modest increase in the genotoxic effects, and caused little or no cytotoxicity. In the Ames test, the genotoxic responses caused by the mixtures of CHFs did not follow simple additivity. Synergism was observed with strains TA97 and TA98, and antagonism with strain TA100. In the CHO/Hprt mutation assay, the mutagenic response of the mixtures was inconsistent, with near additivity seen with a mixture of CHFs that resulted in 12% cell survival. In contrast, the four CHFs together consistently caused more structural chromosome damage (mainly chromatid-type breaks and exchanges) compared to the sum of net effects of the four CHFs tested alone. Also, a potentiating effect was consistently seen for the cytotoxicity of the CHF mixtures both in the CHO/Hprt mutation assay and the chromosome aberration test. The present results indicate that the genotoxic effects of CHF mixtures can be greater than additive. Such effects may be worth considering in the cancer risk assessment of chlorinated drinking water.
authors.affiliation: Laboratory of Toxicology, National Public Health Institute, Kuopio, Finland. Jorma.Maki-Paakkanen@ktl.fi
authors.forename: Jorma
authors.initials: J
authors.lastname: Mäki-Paakkanen
authors.forename: Hannu
authors.initials: H
authors.lastname: Komulainen
authors.forename: Leif
authors.initials: L
authors.lastname: Kronberg
mesh_terms: D000818:Animals; D016466:CHO Cells; D002869:Chromosome Aberrations / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D004347:Drug Interactions; D005387:Finland; D005663:Furans / Q000737:chemistry / Q000633:toxicity*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests; D012044:Regression Analysis; D012486:Salmonella typhimurium; D018508:Water Purification / Q000379:methods
chemical_list: D005663:Furans; C101818:3-chloro-4-methyl-5-hydroxy-2(5H)-furanone; C092013:3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone; C067157:3,4-(dichloro)-5-hydroxy-2(5H)-furanone; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; D007041:Hypoxanthine Phosphoribosyltransferase