The Health Effects Institute

Research Report Number 77

Metabolic Studies in Monkeys Exposed to Methanol Vapors

Michele A. Medinsky, David C. Dorman, James A. Bond, Owen R. Moss, Derek B. Janszen, and Jeffrey I. Everitt
Chemical Industry Institute of Toxicology, Research Triangle Park, NC


In an effort to improve air quality and decrease dependence on petroleum, the U.S. government has encouraged the development of alternative fuels, one of which is methanol. Although the proposed use of methanol as an alternative motor vehicle fuel should decrease air pollution by reducing carbon monoxide and hydrocarbon emissions, expanding its use will increase emissions of other pollutants, especially formaldehyde and methanol vapors.

Methanol is a natural constituent of plant and animal tissues and some foods, but can be highly poisonous when ingested (for example, as wood alcohol). The well-recognized symptoms of methanol poisoning (nervous system dysfunction, damage to the visual system, and even death) are thought to be due to the buildup of formate, a metabolite produced when methanol is broken down by the body. In small amounts, formate is essential for DNA and protein synthesis; however, excess blood levels are highly toxic. Converting formate to nontoxic substances requires adequate stores of one form of the vitamin folic acid, and proceeds efficiently as long as the body's metabolic systems are not overwhelmed by excess methanol. Most analysts think that inhaling low concentrations of methanol is not a risk factor for healthy people. However, there is concern about potentially susceptible populations, especially those who might be deficient in folic acid. These include pregnant women, the developing fetus, and patients with alcoholism and other chronically debilitating illnesses. The HEI funded this study to determine how rapidly formate is formed and removed in monkeys after they have been exposed to methanol vapors, and whether monkeys that are deficient in folic acid accumulate more formate than normal animals. Monkeys were used in this study because rodents are not susceptible to methanol-induced poisoning.


Dr. Medinsky and colleagues of the Chemical Industry Institute of Toxicology exposed female cynomolgus monkeys to environmentally relevant concentrations (10, 45, or 200 parts per million [ppm]) of methanol vapors and to one high dose (900 ppm) for two hours. The methanol was administered while the animals were under general anesthesia. They also exposed monkeys that had been fed a diet deficient in folic acid to the highest methanol concentration. In order to increase the sensitivity of their measurements, and to differentiate between the formate that naturally occurs in the body (endogenous formate) and that which results from methanol exposure, the investigators used methanol tagged with radiolabeled carbon.


Blood levels of radiolabeled methanol increased in a dose-dependent manner in monkeys exposed for two hours to methanol vapors. The blood levels of formate also increased; however, the levels of formate derived from the radiolabeled methanol were 10 to 1000 times lower than endogenous blood formate levels reported from other research, and much lower than the levels known to be toxic. Even monkeys that had moderate folic acid deficiency and were exposed to 900 ppm methanol had peak concentrations of methanol-derived formate that were only one percent of the background levels. Because the exposure conditions used in this study are not the same as those experienced by people, the absolute blood methanol and formate levels cannot be directly extrapolated to humans.

Nevertheless, this report provides reassuring data that single exposures to methanol vapors are unlikely to produce hazardous increases in blood methanol or formate concentrations in the general population or even in individuals with moderate folic acid deficiency. However, some workers, such as garage mechanics, tunnel workers, and underground parking lot attendants, who could be exposed to levels of methanol vapors higher than 200 ppm for longer than two hours, and fetuses, whose development can be affected by methanol exposure and folic acid deficiency, could still be at risk. Further research using animals with more pronounced folate deficiency and longer exposures is critical for any risk assessment of methanol.

Pharmacokinetics of Methanol and Formate in Female Cynomolgus Monkeys Exposed to Methanol Vapors


Investigators' Report
Michele A. Medinsky, David C. Forman, James A. Bond, Owen R. Moss, Derek B. Janszen, and Jeffrey I. Everitt

Health Review Committee


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