Biomedical Engineering Reference
In-Depth Information
within the body, as well as elimination from it, will likely play a critical
role in linking the relevant toxicity data to methanol exposure in the
context of quantitative dose-response modeling.
Inhaled methanol vapors are absorbed readily by both primates and
rodents. The primary metabolic pathway is oxidation to formaldehyde
by alcohol dehydrogenase (in primates) or catalase (in rodents), with
further rapid metabolism to formic acid by formaldehyde
dehydrogenase (Mannering and Parks, 1975; Makar and Tephly,
1977). Formic acid is then further oxidized to carbon dioxide by a
folate-dependent enzymatic pathway. In humans, the latter step
becomes rate limiting at sufficiently high blood methanol levels,
leading to metabolic acidosis, with the classic symptoms of methanol
poisoning, for example, visual impairment, blindness, and death, as
sequelae (McMartin et al., 1975, 1977; Tephly et al., 1979; Noker and
Tephly, 1980). In contrast, for rodents, it is the first metabolic step,
namely, oxidation of methanol to formaldehyde by catalase, which is
rate limiting at high blood methanol levels (Tephly et al., 1979). The
result is disproportionately large increases in rodent blood methanol
levels with increasing methanol exposure (Clary, 2003).
The National Toxicology Program's Center for the Evaluation of
Risks to Human Reproduction (NCERHR) completed a comprehensive
review of the reproductive and developmental toxicity of methanol
(CERHR, 2002). The CERHR Expert Panel report concluded that
“developmental toxicity was the most sensitive endpoint of concern
with respect to evaluating the risk to reproduction posed by methanol
exposure in humans,” and it identified the Rogers et al. (1993) study as a
“critical study for the assessment of developmental toxicity.” This study
found dose-related increases in the frequency of cervical rib malfor-
mations among mouse pups whose dams had been exposed to airborne
methanol concentrations of 0, 1000, 2000, 5000, or 15,000 ppm for
7 hours per day during a 10-day temporal window comprising gestation
days 6 through 15. Of particular interest is the fact that Rogers et al.
measured maternal blood methanol concentrations in a subset of the
pregnant dams at the end of their 7-hour exposure periods on gestation
days 6, 10, and 15, so these internal exposure data permit a quantitative
dose-response assessment of developmental
toxicity using blood
