Reproductive and offspring developmental effects following maternal inhalation exposure to methanol in nonhuman primates.

INTRODUCTION In an effort to improve air quality and decrease dependence on petroleum, the federal government, industry, and other groups have encouraged development of alternative fuels such as methanol to substitute for gasoline or diesel fuel. Methanol is also a candidate to provide the hydrogen for fuel cells, which are being developed for a variety of power sources (including motor vehicle engines). Before people are exposed to increased concentrations of methanol, the potential health effects of such exposures require study. Methanol, a simple alcohol containing one carbon atom, occurs naturally in plants and animals and participates in human metabolism. People regularly consume low doses of methanol in fruits, vegetables, and fermented beverages as well as soft drinks and foods sweetened with aspartame (which breaks down to methanol in the gastrointestinal tract). Despite its ubiquitous presence, methanol can be highly toxic if sufficient quantities are consumed. Ingestion of methanol (usually in the form of wood alcohol or tainted alcoholic beverages) can result in metabolic acidosis, blindness, and even death. Although the body has the capacity to metabolize the low doses of methanol to which people are regularly exposed, it cannot handle high doses because too much methanol overwhelms the body's ability to remove a toxic metabolite (formate). When formate accumulates, methanol poisoning occurs. One factor that regulates the rate at which formate is removed is the liver level of a derivative of the vitamin folic acid. People who are deficient in folic acid (including 15% to 30% of pregnant women) may be particularly susceptible to the toxic effects of methanol. If methanol were to be widely adopted as a fuel, environmental exposures would increase through ingestion of contaminated drinking water, inhalation of vapors from evaporative and other emissions, and dermal contact. Current concentrations of methanol in ambient air are very low, 1 to 30 parts per billion (ppb). If all motor vehicles in the United States were converted to 100% methanol fuel, methanol levels in ambient air are estimated to increase approximately 1,000-fold (to 1 to 10 ppm in cities) and in a worst-case situation could occasionally reach concentrations as high as 200 ppm in enclosed spaces (HEI 1987). Inhaling these concentrations of methanol for short periods of time is not predicted to affect formate production and thus should not present a health risk. However, little is known about the consequences of long-term inhalation of methanol vapors, especially in susceptible populations of pregnant women and developing fetuses. HEI, therefore, developed a research program to address this information gap. APPROACH Dr. Thomas Burbacher and colleagues of the University of Washington studied the effects of long-term exposure to methanol vapors on metabolism and reproduction in adult female monkeys (Macaca fascicularis) and developmental effects in their offspring, who were exposed prenatally to methanol. The investigators exposed adult female monkeys (11 to 12 animals/group) to one of four concentrations of methanol vapors (0, 200, 600, and 1,800 ppm) for 2.5 hours a day, seven days a week during the following periods: (1) before breeding, (2) during breeding, and (3) during pregnancy. They collected blood from the adults at regular intervals to monitor methanol levels (which served as a marker of internal dose) and formate concentrations. They also conducted pharmacokinetic studies to determine whether methanol disposition (which includes absorption, distribution, metabolism, and excretion) was altered as a result of repeated methanol exposures and to assess pregnancy-related changes. Because high doses of methanol damage the central nervous system, the infants (8 to 9 animals/group) were examined at regular intervals during the first nine months of life to assess their growth and neurobehavioral development. RESULTS Exposure to methanol vapors did n