Animal model for the study of methanol toxicity: Comparison of folate-reduced rat responses with published monkey data

Journal Article · Sat Jan 01 04:00:00 EST 1994 · Journal of Toxicology and Environmental Health; (United States)

DOI:https://doi.org/10.1080/15287399409531827· OSTI ID:7033557

Lee, E W; Garner, C D; Terzo, T S ^[1]

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1. General Motors North American Operations, Warren, MI (United States)

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. 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. 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.

• OSTI ID: 7033557
• Journal Information: Journal of Toxicology and Environmental Health; (United States), Journal Name: Journal of Toxicology and Environmental Health; (United States) Vol. 41:1; ISSN 0098-4108; ISSN JTEHD6
• Country of Publication: United States
• Language: English

Related Subjects

550500 -- Metabolism
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALCOHOLS
ANIMALS
BIOLOGICAL ACCUMULATION
BIOLOGICAL MODELS
CARBOXYLIC ACID SALTS
COMPARATIVE EVALUATIONS
EVALUATION
FORMATES
HYDROXY COMPOUNDS
MAMMALS
METHANOL
MONKEYS
ORGANIC COMPOUNDS
PRIMATES
RATS
RODENTS
TOXICITY
VERTEBRATES