Mutagenic and lethal effects of halogenated methanes in the Ara test of Salmonella typhimurium: quantitative relationship with chemical reactivity.

The mutagenic and lethal effects of nine halogenated methanes (CCl4, carbon tetrachloride; CHCl3, chloroform; CH2Cl2, dichloromethane; CBr4, carbon tetrachloride; CHBr3, bromoform; CH2Br2, dibromomethane; CI4, carbon tetraiodide; CHI3, iodoform; and CH2I2, diiodomethane) have been investigated with the Ara forward-mutation assay of Salmonella typhimurium. Five substances (CH2Cl2, CBr4, CH2Br2, CHI3 and CH2I2) gave clear mutagenic responses. In all these cases the mutagenicity diminished in the presence of mammalian metabolic activation (S9 mixture). Two halomethanes (CCl4 and CHBr3) were classified as 'questionable' mutagens since they did not double the spontaneous value although a dose-response curve was obtained. All halomethanes tested exerted a lethal effect. A high concordance was found between lethality and chemical reactivity, as expected from the type and number of halogenated substituents. Compounds with equal numbers of substituents were lethal in the order I > Br > Cl. Additionally, the lethality of compounds with identical halogen substituents increased by successive halogenations. No such concordances were observed with respect to mutagenic activity. Structure-activity quantitative relationships were investigated by using the previously reported values of the polarographic half-wave reduction potential (-E1/2), a physicochemical parameter related to the energy required to put an electron into the lowest unoccupied molecular orbital. The lethality, quantified as LD37, correlated highly with the -E1/2 values for the nine halogenated compounds (r = -0.955 P < 0.001). These data suggest that halomethanes which are reduced easily will induce higher lethality than those with low reduction potential, in agreement with the predicted effects on lipid peroxidation and hepatotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)