Biomedical Engineering Reference
In-Depth Information
rats at 1000 ppm methanol (NEDO, 1987) appear to be the most robust
and most sensitive effects.
While it is established that the toxic consequences of acute methanol
poisoning in adult humans arise from the action of formate, there is less
certainty on how the toxicological impacts of long-term exposure to
lower levels of methanol are brought about. Experiments carried out by
Dorman et al. (1995) indicate that formate is not the proximate
teratogen in pregnant CD-1 mice exposed to high concentrations of
methanol vapor. Little, if any, formate accumulated in the blood of mice
exposed to teratogenic concentrations of methanol, and treatment of
pregnant mice with a high oral dose of formate did not induce neural
tube closure defects. Finally, methanol, but not formate, induced neural
tube closure defects in mouse embryos in vitro at concentrations
comparable to the levels of methanol and formate detected in blood
after a teratogenic exposure. Harris and colleagues (Hansen et al., 2005;
Harris et al., 2003, 2004) concluded that the metabolite responsible for
the developmental toxicity of methanol may be formaldehyde rather
than the parent compound or formate. It was suggested that species
differences in the metabolism of methanol to formaldehyde and formic
acid by ADH1, ADH3, and catalase may contribute to differences in
species sensitivity to methanol teratogenicity. The finding that ADH3
activity (converting formaldehyde to formate) was lower in the mouse
VYS, and that inhibition of GSH synthesis increases the developmental
toxicity of methanol, are consistent with the greater sensitivity of the
mouse to the developmental toxicity of methanol. That formaldehyde
may be the proximate teratogen is further supported by the finding that
formaldehyde is embryotoxic to rat and mouse embryos in vitro at much
lower concentrations than is either methanol or formate (Hansen et al.,
2005).
While studies such as those by Harris et al. (Harris et al., 2003, 2004),
Hansen et al. (2005), and Dorman et al. (1994, 1995) strongly suggest
that formate is not the metabolite responsible for methanol's teratogenic
effects, there are still questions regarding the relative involvement of
methanol versus formaldehyde.
For further discussion of the role of metabolism in the teratogenicity
of methanol, see chapter 7.
