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95723 
Journal Article 
Developmental toxicity of methanol in rodents 
Dorman, DC; Welsch, F 
1996 
0 
CIIT Activities
ISSN: 8755-4259 
16 
2 
40360 
Methanol is a widely used commodity chemical that has also been proposed for large-scale use as an automotive fuel. Widespread use of methanol-based fuels would increase exposure of the general public to methanol vapors. Therefore additional data for an adequate human health risk assessment are needed, including information on pregnant women and potential health hazards to the unborn. In conventional bioassays with pregnant rats or mice, daily repeated inhalation exposure to high concentrations of methanol during major organogenesis causes developmental toxicity, including frank malformations at multiple sites. Mouse embryos display failure of the anterior neuropore to close (exencephaly) when dams inhale methanol concentrations of 10,000 ppm or greater oh gestation day 8 (GD 8; day of mating and copulation plug = GD 0). This malformation is the most obvious lesion observed in mice and rats. Studies examining the pathogenesis of methanol-induced exencephaly (15,000 ppm for 6 hours on both GD 7 and GD 8) in pregnant mice suggest that cells in the region of the paraxial mesoderm are damaged by methanol. Methanol-induced structural anomalies in offspring may be explained by toxic effects of the chemical on mesodermal and neural crest cells. Methanol is metabolized (by oxidation) to formate, which is of special significance for the severe acute systemic toxicity encountered in adult humans. Studies at the Chemical Industry Institute of Toxicology (CIIT) examined the role of formate in the development of methanol-induced exencephaly in CD-1 mice, and evaluations of formate were conducted in parallel on cultured mouse embryos. Pharmacokinetic analyses in pregnant mice suggest that exencephaly is directly related to high concentrations of the parent compound methanol in maternal blood and embryos rather than to the accumulation of formate. These observations lend a new perspective to risk assessment for humans following very low-level exposure to methanol by inhalation.