Animal model for the study of methanol toxicity: comparison of folate-reduced rat responses with published monkey data.
We attempted to develop a rodent model that exhibits characteristics of human methanol toxicities such as acidosis and visual dysfunction, which are correlated with an accumulation of formate, a toxic metabolite of methanol. Initially three groups of Long-Evans rats with different levels of liver folate were prepared and examined for formate accumulation after methanol administration (3.5 g/kg). The folate-reduced (FR) rats prepared by feeding a folate-deficient diet with 1% succinylsulfathiazole yielded blood formate levels equivalent to those found in methanol-intoxicated humans and developed signs of the visual system toxicity (a manuscript on the latter aspect is in preparation). Responses of FR rats to a variety of methanol exposure scenarios were then investigated, and the results were compared with those reported in the literature for monkeys. Formate accumulation and/or lethality were used as toxic parameters for this comparative evaluation. In FR rats dosed orally with 3 g/kg, the blood formate concentration was 9.2 mmol/L at 24 h postadministration and increased to 15.6 mmol/L at 48 h. The same dose given to monkeys yielded a plateau of 7.4 mmol/L at 12 h after methanol administration, and stayed at this level for an additional 12 h. The area under the concentration vs. time curve for blood formate in FR rats was 2.5-fold greater than that in monkeys when 2.0 g/kg methanol was administered. After a 6-h exposure to 1200 ppm and 2000 ppm methanol, the blood formate concentrations in FR rats were increased by 370% and 636% above the endogenous level, respectively. However, blood formate did not accumulate above the endogenous level when monkeys were exposed to methanol up to 2000 ppm for 6 h. Under acute inhalation exposure conditions, FR rats exposed to 3000 ppm methanol, 20 h/d, could not survive more than 4 d. On the other hand, monkeys exposed to 3000 ppm, 21 h/d, out-lived 20 d. Moreover, monkeys survived for more than 4 d even after an exposure to 10,000 ppm. Thus, these results indicate that FR rats are more sensitive to methanol challenges than monkeys, and suggest that the FR rat could be a congruous animal model for evaluating the health effects of methanol in humans.
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Biomedical Science Department, General Motors North American Operations, Warren, Michigan 48090-9055.
Garner
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Terzo
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D000280:Administration, Inhalation; D000284:Administration, Oral; D000336:Aerosols; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005492:Folic Acid / Q000032:analysis; D005494:Folic Acid Deficiency / Q000378:metabolism*; D005561:Formates / Q000097:blood; D008099:Liver / Q000737:chemistry; D008253:Macaca mulatta; D008297:Male; D000432:Methanol / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D051381:Rats
D000336:Aerosols; D005561:Formates; C030544:formic acid; D005492:Folic Acid; D000432:Methanol