The Health Effects Institute


Synopsis
Research Report Number 74

Methanol Distribution in NonPregnant and Pregnant Rodents

Gary M. Pollack and Kim L. R. Brouwer
University of North Carolina at Chapel Hill


BACKGROUND

Many urban locales remain unable to meet federal air quality standards for ozone, in part because motor vehicles produce large amounts of ozone-forming hydrocarbons. The Clean Alternative Fuels Program was initiated in the 1980s to encourage the development of new fuels; in 1990, methanol was designated as a clean alternative fuel by the Clean Air Act Amendments. The proposed use of methanol as an alternative motor vehicle fuel could have remedial effects on pollution by decreasing some hydrocarbon emissions and thereby potentially reducing atmospheric ozone concentrations. As a result, its use could help address the continued inability of many urban areas of the United States to meet air quality standards.

If methanol is used as an alternative fuel, humans will be exposed to increased levels of methanol vapors in evaporative and tailpipe emissions. Although methanol is clearly poisonous when ingested at relatively high levels, projections suggest that humans who inhale the low concentrations of methanol vapors expected to be emitted from motor vehicles will experience little risk of toxicity. However, inhaling low levels of methanol vapors could pose health risks for potentially susceptible populations. Because of the known effects of ethanol on developing fetuses, this population is one that is considered to be potentially susceptible to the neurotoxic effects of methanol. In fact, some animal studies have shown that exposure to high concentrations of methanol (5,000 to 20,000 ppm) can have negative effects on fetal development. In order to evaluate the possible risks of methanol exposure for developing fetuses, the HEI funded a study described in this report that was designed to determine the relationship between methanol exposure and its uptake into and elimination from the blood of nonpregnant and pregnant rodents. Because fetal toxicity cannot be studied directly in humans, the information obtained in this study will be helpful for extrapolating the effects seen in rodents to those anticipated in humans who are exposed to low environmental levels of methanol and for assessing the consequential risks associated with exposure.


APPROACH

Drs. Pollack and Brouwer exposed rats and mice at several different stages of gestation to methanol intravenously or orally (doses ranged from 100 mg/kg of body weight to 2,500 mg/kg) or by inhalation (1,000 to 20,000 ppm for 8 hours). They measured blood, urine, and amniotic fluid concentrations of methanol and used the data to develop a model of methanol distribution in rodents. It should be noted that the lowest inhalation exposure used in this study (1,000 ppm for 8 hours) was significantly higher than those predicted for ambient exposures resulting from the use of methanol fuels (1 to 10 ppm in typical traffic situations, and as high as 200 ppm in a worst-case scenario such as a malfunctioning vehicle in an enclosed garage).


RESULTS AND IMPLICATIONS

During the inhalation exposures, the investigators found that the rate of methanol accumulation in the mouse was two to three times greater than in the rat. This was true in spite of fact that the mouse eliminates methanol from its bloodstream twice as fast as the rat. The investigators hyothesized that this difference between rats and mice was due to more rapid breathing in the mouse, and to the apparently complete absorption of methanol in the nasal cavity of this rodent species. They also found that the uptake and elimination of methanol was virtually unaffected by pregnancy, and that fetal methanol concentrations were approximately the same as in the mother.

Using their results, the investigators constructed a model that describes the uptake and elimination of methanol in rats and mice. This a critical step in being able to make the interspecies extrapolations necessary for risk assessment. However, the differences seen between these two closely related species indicate that the use of this rodent model to extrapolate to humans could be difficult. As a result, the usefulness of the pharmacokinetic model developed for high-level exposures in rodents may be limited when predicting the effects of the lower ambient exposures on humans. Therefore, validation of this model at lower exposure levels is needed.


Maternal-Fetal Pharmacokinetics of Methanol

TABLE OF CONTENTS

Investigators' Report
Gary M. Pollack and Kim L.R. Brouwer

Commentary
Health Review Committee

CODE: POLLACK74

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