Biochemical effects of methyl chloride in relation to its tumorigenicity

The biochemical effects of methyl chloride were investigated in tissues of F-344 rats and B6C3F1 mice (both sexes). Activities of GST were 2-3 times higher in livers of male B6C3F1 mice, compared with those of female mice, and with rats of both sexes. In kidneys GST activities of (male) mice were about 7 times lower than those found in livers. The activity of FDH was higher in livers of mice (both sexes) than in those of rats. No obvious sex difference was found in livers of rats and mice with respect to FDH. In kidneys, however, (minor) differences in FDH activities occurred between male and female B6C3F1 mice (4.7 vs. 3.1 nmol/min per mg). Sex differences of FDH activity in kidneys were not observed in F-344 rats. The microsomal transformation (by cytochrome P-450) of methyl chloride and S-methyl-L-cysteine to formaldehyde in tissues of B6C3F1 mice occurred preferentially in the liver. More formaldehyde was produced in liver microsomes of male, compared to those of female mice. Kidney microsomes metabolized methyl chloride to formaldehyde much less than liver microsomes. After a single exposure of mice of both sexes to 1000 ppm methyl chloride no elevation in formaldehyde concentrations was observed in livers and kidneys ex vivo. The determination of DNA lesions, using the alkaline elution technique, revealed no DNA-protein crosslinks in kidneys of male B6C3F1 mice after exposure to methyl chloride (1000 ppm, 6 h day-1, 4 days) and gave only minor evidence of single-strand breaks. Lipid peroxidation (production of TBA reactive material), induced by single exposure to methyl chloride (1000 ppm, 6 h), was very pronounced in livers of male and female mice. Smaller increases in peroxidation were observed in the kidneys of exposed mice. The theory that renal tumors observed in male mice after chronic exposure of the test animals to high (1000 ppm) concentrations of methyl chloride, are evoked by intermediates and in situ produced formaldehyde is proven unlikely by our results.