Mechanisms of carcinogenicity of methyl halides.

Methyl chloride, bromide, and iodide are used as methylating agents. These compounds are mutagenic in short-term tests and do not require activation by exogenous S9 mix. In DNA-binding studies performed in rats and mice, 14C-labeled methyl chloride was given by inhalation, and methylation of DNA bases was examined. The compound did not lead to specific DNA adducts. In particular, methylation of DNA bases was not observed. In contrast, methyl bromide and methyl iodide, upon oral and inhalation administration to rats and mice, caused systemic DNA methylation. Specifically, 3-methyl-adenine, 7-methyl-guanine, and O6-methyl-guanine were formed. Long-term inhalation bioassays have been performed in rats and mice with methyl chloride and methyl bromide. Methyl chloride induced renal tumors, but only in male mice at the highest concentration tested (1000 ppm). Under these special conditions, a number of secondary effects occur subsequent to glutathione depletion in the target tissue, resulting in DNA damage (DNA-protein cross-links and probably DNA single-strand breaks). The particular coincidence of secondary high-dose effects precludes a risk extrapolation to man. Methyl bromide did not induce tumors in rats and mice when administered by inhalation. However, experimental data point to a possible local carcinogenic effect on the rat forestomach when the compound is given by gavage. A factor that accounts for the discrepancy between systemic DNA methylation and apparent noncarcinogenicity upon inhalation might be the preference of 7-N over O6 methylation of guanine. An extrapolation of the negative rodent inhalation bioassay of methyl bromide to man might be problematic because rodents metabolize methyl bromide very quickly whereas in humans there is a particular subpopulation that only poorly metabolizes the compound ("nonconjugators"). Such individuals can be characterized by incubation of erythrocytes with methyl chloride or methyl bromide and measurement of the substrate decline. Methyl iodide has been tested, with positive outcome, in early carcinogenicity bioassays not based on modern methodology. However, these results, along with the proven systemic methylating potency of methyl iodide, argue in favor of a carcinogenic effect of the compound.