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Published on: July 13, 2014
Species- and strain-dependent teratogenicity of methanol in rabbits and mice
J Nicole Sweeting1, Michelle Siu, Michael J Wiley
1Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Abstract:
Estimates of human risk for developmental toxicity of methanol (MeOH) are based on studies in rodents, which unlike humans use catalase to metabolize MeOH. Rabbits, like humans, may largely use alcohol dehydrogenase (ADH), and more accurately than rodents reflect primate MeOH and formic acid (FA) pharmacokinetic profiles. Here we show that New Zealand white rabbits and one strain of mouse (C3H) are resistant to MeOH teratogenicity, whereas C57BL/6J mice are susceptible. Neither rabbits nor mice were susceptible to the acute MeOH toxicity observed in humans. The strain-dependent teratological susceptibility in mice could not be explained by differences in MeOH or FA disposition, nor could the resistance of rabbits, which exhibited more prolonged FA accumulation, suggesting that different mechanisms underlie MeOH teratogenesis and the FA-mediated acute toxicity in humans. It is not clear if the human risk for MeOH developmental toxicity can be accurately estimated using sensitive rodent strains.
Insights
Methanol (MeOH) developmental toxicity risk in humans is unclear. Rabbits and some mice are resistant to MeOH teratogenicity, unlike susceptible mice, indicating complex toxicity mechanisms and questioning rodent models for human risk assessment.
Area of Science:
- Toxicology
- Pharmacokinetics
- Developmental Biology
Background:
- Human risk assessment for methanol (MeOH) developmental toxicity relies on rodent studies.
- Rodents metabolize MeOH using catalase, unlike humans who primarily use alcohol dehydrogenase (ADH).
- Rabbits, similar to humans, utilize ADH for MeOH metabolism, offering a potentially more accurate model.
Purpose of the Study:
- To investigate methanol (MeOH) teratogenicity and toxicity in rabbits and mice.
- To compare MeOH and formic acid (FA) pharmacokinetic profiles across species and strains.
- To evaluate the suitability of rodent models for estimating human developmental toxicity risk from MeOH.
Main Methods:
- Administration of methanol (MeOH) to New Zealand white rabbits and two mouse strains (C3H and C57BL/6J).
- Assessment of teratogenicity and acute toxicity.
- Pharmacokinetic analysis of MeOH and formic acid (FA) levels.
Main Results:
- Rabbits and C3H mice were resistant to MeOH teratogenicity; C57BL/6J mice were susceptible.
- No rabbits or mice exhibited acute MeOH toxicity seen in humans.
- Differences in MeOH/FA disposition did not explain strain-dependent teratogenicity in mice or rabbit resistance.
- Rabbits showed prolonged FA accumulation, suggesting distinct mechanisms for teratogenesis and acute toxicity.
Conclusions:
- Methanol teratogenesis mechanisms differ between species and strains, and from acute FA toxicity in humans.
- Rabbit and mouse models provide insights but do not fully replicate human MeOH developmental toxicity.
- The accuracy of using sensitive rodent strains to estimate human developmental risk from MeOH remains uncertain.
