The Health Effects Institute

Synopsis
Research Report Number 73

Developmental Neurotoxicity of Inhaled Methanol in Rats

Bernard Weiss, Sander Stern, Sidney C. Soderholm, Christopher Cox, Archana Sharma, Geoffrey B. Inglis, Ray Preston, Marlene Balys, Kenneth R. Reuhl, and Robert Gelein
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, and Department of Pharmacology and Toxicology, Rutgers University College of Pharmacy, Piscataway, NJ

BACKGROUND

Methanol was designated a "clean alternative fuel" by the Clean Air Act Amendments of 1990. The use of methanol as an alternative motor vehicle fuel could have important remedial effects on air pollution by decreasing hydrocarbon emissions and thereby potentially reducing atmospheric ozone concentrations. As a result, its use could help address the continued inability to meet air quality standards in many urban areas of the United States.

If methanol is used as an alternative motor vehicle fuel, humans will be exposed to relatively low levels of methanol vapors through inhalation. Although methanol is clearly poisonous when ingested at high levels, it is not known whether it would pose health risks when inhalated at low levels. Observations of methanol's effects on pregnant rodents suggest the potential for methanol vapors to have adverse effects on the fetus. To determine whether exposure to methanol vapors may influence development of the nervous system, HEI funded the study described by Dr. Weiss and his colleagues, which examined the effects of prenatal and early postnatal inhalation of methanol on selected measures of neurobehavior in rats.

APPROACH

Dr. Weiss and his colleagues conducted a controlled series of experiments in which they exposed pregnant rats and their newborn offspring to 4,500 parts per million (ppm) methanol by inhalation, and then submitted them to tests of behavioral function.

RESULTS AND IMPLICATIONS

Exposure to 4,500 ppm methanol vapors did not affect the amount of time it took newborn rats to attach to their mothers' nipples (sucking test) or their ability to be trained to avoid specific odors (conditioned olfactory aversion test); however, methanol-exposed newborns were less active on postnatal day 18 and more active on postnatal day 25 than control newborns (motor activity test). The lack of effect of methanol on suckling contrasted with what the investigators had observed in an earlier study in which high doses of methanol were administered via drinking water. In adult rats that had been exposed to methanol in utero and as newborns, small effects were observed in tests of coordination on a running wheel and persistance in obtaining food rewards for this activity (fixed-ratio wheel-running test), but only when the genders were analyzed separately. In addition, when adult rats were trained to press levers in a specific sequence to obtain food rewards (stochastic spatial discrimination test), there were some relatively subtle performance differences in their rates of adjustment to a new pattern of lever-pressing; specifically, after extended training the control animals performed better than the methanol-treated animals on the second of two lever-press sequence patterns.

The HEI Review Committee noted that the investigators conducted many tests and found only isolated positive results that were small and variable. Because no compensation was made for multiple testing, care must be taken not to ascribe too much significance to these results. This is particularly true in light of the fact that the methanol exposure level investigated in this study (4,500 ppm) was appreciably higher than the ambient exposures predicted for 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). Overall, the investigators' results point to the neurobehavioral measures that should be studied when evaluating the potential neurologic effects of inhaled methanol exposures.

Developmental Neurotoxicity of Methanol Exposure by Inhalation in Rats

TABLE OF CONTENTS

Investigators' Report
Bernard Weiss, Sander Stern, Sidney C. Soderholm, Christopher Cox, Archana Sharma, Geoffrey B. Inglis, Ray Preston, Marlene Balys, Kenneth R. Reuhl, and Robert Gelein

Commentary
Health Review Committee

CODE: WEISS73

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