In vitro assessment of the effect of methanol and the metabolite, formic acid, on embryonic development of the rat

Inhalation studies in rats have indicated that methanol is embryotoxic at levels that are only mildly maternally toxic. In the present study, the embryotoxicity of methanol and its metabolite, formic acid, was evaluated using rat embryo culture. The results showed that both methanol and formic acid have a concentration-dependent embryotoxic effect on the developing rat embryo in vitro. The no-effect concentration of methanol was 211.7 μmol/ml culture medium, while embryotoxicity was observed at 286.5 μmol/ml. The no-effect concentration of formic acid was 3.74 μmol/mm, while a concentration of 18.66 μmol/mm was associated with severe embryotoxicity. When embryos were grown in sera containing 18.66 μmol sodium formate/ml or in sera adjusted with hydrochloric acid to pH values similar to those achieved with formic acid, the results indicated that both low pH and formate contributed to the observed embryotoxicity of formic acid. When the level of methanol found to be embryotoxic in the present study is compared to blood levels in the human following controlled industrial exposure there appears to be a large margin of safety. However, plasma methanol levels are only one aspect of methanol toxicity in the human. Of greater significance is the formate level and the associated acidosis. However, it appears that embryotoxicity due to low pH or high formate levels would only occur after very severe methanol intoxication. Based on these in vitro studies, current industrial safety limits would appear to provide protection for the developing embryo.