Mutagenic potency of chlorofuranones and related compounds in salmonella

Abstract

One of the mutagenic byproducts associated with chlorinated humic waters and kraft pulp bleaching effluents was recently identified as 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone. This compound and several related chlorofuranones and precursors were synthesized and evaluated for direct-acting mutagenicity in Salmonella typhimurium tester strain TA100. Mutagenicity was greatest for 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone, its 5-methoxy derivative, and the precursor in their synthesis, 3-(dichloromethyl)-2,4,4-trichloro-2-butenoic acid. Several of the compounds were tested in the presence of added rat liver homogenate S9 fraction, and in all cases mutagenicity was substantially reduced. An important structural feature which may govern the mutagenic response in these instances appears to be the cis arrangement of CHCl2 and Cl substituents on a carbon-carbon double bond. These compounds may also be transformed in vitro to the same acyclic chlorine substituted alpha, beta-unsaturated aldehyde derivative, which is proposed to be the agent responsible for the observed mutagenicity.

Lack of Modification by Environmental Estrogenic Compounds of Thyroid Carcinogenesis in Ovariectomized Rats Pretreated with N‐bis(2‐hydroxypropyl)nitrosamine (DHPN)

“…MX formed during chlorination of drinking water is a very potent bacterial mutagen 56) and a mammalian cell clastogen, 57) and tumor-promoting effects have been reported. 14,15,58) A recent carcinogenicity study using rats showed MX to be definitely carcinogenic, in a dosedependant manner, when given in drinking water at doses of 5.9, 18.7 and 70.0 ppm for 104 weeks.…”

Mutation spectra of the drinking water mutagen 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF) in Salmonella TA100 and TA104: Comparison to MX

“…MX is the most prominent representative of a larger class of halogenated oxobutenoic acids (or halogenated hydroxyfuranones), a number of which have been detected in chlorinated drinking water [Richardson, 1998] and studied for mutagenicity [Ishiguro, 1988;Tikkanen and Kronberg, 1990;Fekadu et al, 1994;Franzén et al, 1998]. The structurally related mutagen 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF) has been found at concentrations similar to or greater than that of MX [Smeds et al, 1997;Kronberg and Franzén, 1993].…”

MX, a by‐product of water chlorination, lacks in vivo genotoxicity in gpt delta mice but inhibits gap junctional intercellular communication in rat WB cells

“…1), a by-product resulting from organic acid reactions during chlorine disinfection, has been isolated and identified as a nonvolatile compound in drinking water from several countries, including Finland [Hemming et al, 1986], the United States [Meier et al, 1987 a,b], England [Horth et al, 1989], and Japan [Suzuki and Nakanishi, 1990]. MX is strongly mutagenic in Salmonella typhimurium without metabolic activation [Ishiguro et al, 1988], and a Finnish group demonstrated the carcinogenicity of MX in the liver, thyroid gland, and lung of rats [Komulainen et al, 1997]. In addition, it has been reported that MX enhances replicative DNA synthesis and increases ornithine decarboxylase activity in the glandular stomach of rats when administered by gastric intubation at extremely high doses (10-60 mg/kg body weight) [Furihata et al, 1992].…”