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In a mechanistic study Chellman et al. (1986) investigated the effects of GSH depletion on chloromethane toxicity to brain and kidney in male B6C3F1 mice exposed to 3091 mg/m³ 6 hours/day, 5 days/week for 2 weeks with and without daily pretreatment with 2 mmol L-BSO/kg. This dose of BSO depleted hepatic and renal GSH by 28% and 60%, respectively before exposure to chloromethane. No central nervous system toxicity as assessed by microscopic examination of the granule cell layer of the cerebellum occurred in BSO-pretreated mice. BSO pretreatment also inhibited the renal toxicity of chloromethane as measured by incorporation of [3H]thymidine into renal DNA, an indicator of cell regeneration after cortical necrosis (control 105 +/-10 dpm/µg DNA; chloromethane exposure 337 +/- 40 dpm/µg DNA; BSO pretreatment + chloromethane exposure 60 +/-15 dpm/µg DNA). The authors concluded, that GSH is an important component in the toxicity of chloromethane to multiple organ systems in B6C3F1 mice. Reaction of chloromethane with GSH appears to constitute a mechanism of toxication, contrary to the role usually proposed for GSH in detoxifying xenobiotics.

 

Jäger et al. (1988) performed a study to determine whether chloromethane induced renal tumors in male B6C3F1 mice was mediated by the metabolic intermediate, formaldehyde. DNA-lesions (crosslinks and single strand breaks), glutathione-S-transferase (GST), and formaldehyde dehydrogenase (FDH) activity were measured in Fischer 344 rats and B6C3F1 mice exposed to 2064 mg/m³ chloromethane for 6 days. It was shown that the tumour formation in male mice is not based on any obvious biochemical sex differences in enzymatic transformation with respect to FDH. Neither is the metabolically formed formaldehyde likely to be the effective carcinogen, because characteristic formaldehyde-induced genetic damage is not present. However, there was s significant species difference between mice and rats due to the higher activity of GST, especially in the kidneys. Mice seem to be more susceptible to the GSH-depleting effect of chloromethane.

Reference:

Jäger, R. et al. (1988) Biochemical effects of methyl chloride in relation to its tumorigenicity. Journal of cancer research and clinical oncology, 114(1):64-70 [as cited in: OECD SIDS, Chloromethane, 2004].