RECENT DEVELOPMENTS IN METHANOL TOXICITY

The disposition of methanol and its putative toxic metabolite formate has been studied in humans, non-human primates, and rodents after expo sure to high, neurotoxic doses. The rate at which rodents detoxify for mate is more rapid than that of primates. Formate, an endogenous biolo gical substrate, is detoxified by metabolism to CO2 via a tetrahydrofo late-(THF) dependent pathway. Species with high hepatic THF levels, su ch as rodents, are less sensitive to the neurotoxic effects of large m ethanol doses compared with species with low THF levels, such as prima tes. Data on the capacity of primates to detoxify formate derived from inhalation of low levels of methanol are critical for assessing human risk from methanol fuels. Female cynomolgus monkeys exposed to low co ncentrations of [C-14]methanol (10-200 ppm) for 2 h have blood levels of methanol-derived formate that are 100- to 1000-fold lower than endo genous levels of formate. Healthy human volunteers exposed at rest or during exercise to 200 ppm methanol for 6 h or exposed to 20 mg/kg ora lly have elevated blood levels of methanol, but blood formate concentr ations are not significantly increased above endogenous concentrations . Deficiencies in THF may prolong blood levels of formate and increase the likelihood of toxic effects. Limited studies in non-human primate s with low THF levels exposed to 900 ppm methanol for 2 h have shown t hat concentrations of methanol-derived formate in blood remain below e ndogenous levels. Thus human populations may not be at added risk of n eurotoxic effects resulting from exposure to low levels of methanol.