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OF MICE, MEN, MONKEYS AND METABOLISM: AN UPDATE ON THE DEVELOPMENTAL TOXICITY OF METHANOL
Citation:
ROGERS, J. M. OF MICE, MEN, MONKEYS AND METABOLISM: AN UPDATE ON THE DEVELOPMENTAL TOXICITY OF METHANOL. Presented at Teratology Society Meeting, Tucson, AZ, June 24 - 29, 2006.
Description:
With a world production ca. 30 million tons per year, methanol is a solvent, is used to produce formaldehyde, MTBE, and acetic acid, is a component of aspartame, and has been proposed as an alternate vehicle fuel. Methanol occurs naturally in plants and animals. It is sequentially oxidized to formaldehyde, formate and carbon dioxide, but the enzymology differs among species. In primates, oxidation of formate to carbon dioxide is rate-limiting. Formate accumulates above saturating dosages and is the proximate toxicant for blindness and death from acute methanol poisonings. Oxidation of formate in rodents is rapid and it does not accumulate. Further, in primates, methanol oxidation is primarily catalyzed by alcohol dehydrogenase (ADH), while in rodents catalase is the primary enzyme. The developmental toxicity of inhaled methanol has been studied in monkeys, rats and mice. Methanol causes visceral and skeletal malformations in rats and mice, including cervical ribs. In CD-1 mice, methanol causes cleft palate and exencephaly, while in C57BL/6J mice exposed intraperitoneally, methanol causes holoprosencephaly similar to that produced by ethanol. We reported a NOAEL of 1000 ppm methanol for 7 hr/d in CD-1 mice, with increased incidence of cervical rib at 2000 ppm. Cervical ribs and other malformations of the cervical vertebrae indicated posteriorization; e.g., tuberculae anterior normally found on C6 were observed on C5. The mouse model for human developmental toxicity of methanol is contentious because of the differences in formate oxidation. However, human exposures to environmental methanol are unlikely to produce blood levels saturating this pathway, so formate buildup would be unlikely; indeed, monkeys exposed to 2000 ppm showed no formate accumulation. Thus, methanol rather than formate may be the proximate toxicant in humans, and in the mouse higher exposures of methanol can be studied without formate accumulation. Oxidation of methanol by catalase in mice vs. ADH in humans may also be important. These studies will be discussed in the context of a risk assessment of developmental toxicity of methanol in humans. This abstract does not reflect EPA policy.