Acute methanol toxicity in minipigs.
The pig has been proposed as a potential animal model for methanol-induced neuro-ocular toxicosis in humans because of its low liver tetrahydrofolate levels and slower rate of formate metabolism compared to those of humans. To examine the validity of this animal model, 12 4-month-old female minipigs (minipig YU) were given a single oral dose of water or methanol at 1.0, 2.5, or 5.0 g/kg body wt by gavage (n = 3 pigs/dose). Dose-dependent signs of acute methanol intoxication, which included mild CNS depression, tremors, ataxia, and recumbency, developed within 0.5 to 2.0 hr, and resolved by 52 hr. Average maximum methanol concentrations in plasma, of 3100 +/- 700 (SD), 6200 +/- 2300, and 15,200 +/- 900 micrograms/ml were reached within 0.5 to 4 hr following methanol administration in animals given 1.0, 2.5, or 5.0 g methanol/kg, respectively. The mean initial elimination half-lives of methanol were 9.0 +/- 1.6, 22.4 +/- 6.1, and 18.9 +/- 4.3 hr, for 1, 2.5, and 5.0 g/kg doses, respectively. In 3 minipigs, a transient increase in plasma formate concentration (1.74-3.40 mEq/liter vs control = 0.5 +/- 0.3 mEq/liter) occurred 4 to 30 hr following methanol administration. Methanol- and formate-dosed pigs did not develop optic nerve lesions, toxicologically significant formate accumulation, or metabolic acidosis. Based on results following a single dose, female minipigs do not appear to be overtly sensitive to methanol and thus may not be a suitable animal model for acute methanol-induced neuro-ocular toxicosis.
Chemical Industry Institute of Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27709.
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Dorman
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JA
Dye
M P
MP
Nassise
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J
Ekuta
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Bolon
M A
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Medinsky
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001784:Blood Gas Analysis; D004305:Dose-Response Relationship, Drug; D005128:Eye Diseases / Q000139:chemically induced; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005561:Formates / Q000493:pharmacokinetics / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000432:Methanol / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D009422:Nervous System Diseases / Q000139:chemically induced; D013552:Swine; D013556:Swine, Miniature
D005561:Formates; D005492:Folic Acid; D000432:Methanol