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.