Pharmacokinetics of methanol and formate in female cynomolgus monkeys exposed to methanol vapors.
The 1990 Clean Air Act Amendments contain mandates for reduced automotive emissions and add new requirements for the use of alternative fuels such as methanol to reduce certain automotive pollutants. Methanol is acutely toxic in humans at relatively low doses, and the potential for exposure to methanol will be increased if it is used in automotive fuel. Formate is the metabolite responsible for neurotoxic effects of acute methanol exposure. Since formate metabolism is dependent on folate, potentially sensitive folate-deficient subpopulations, such as pregnant women, may accumulate formate and be at higher risk from low-level methanol exposure. Our objective was to determine the pharmacokinetics of 14C-methanol and 14C-formate in normal and folate-deficient monkeys after exposure to 14C-methanol vapors at environmentally relevant concentrations: below the threshold limit value (TLV), at the TLV of 200 parts per million (ppm), and above the TLV. Four normal adult female cynomolgus monkeys were individually anesthetized with isoflurane, and each was exposed by endotracheal intubation to 10, 45, 200, or 900 ppm 14C-methanol for 2 hours. Concentrations of the inhaled and exhaled 14C-methanol, blood concentrations of 14C-methanol and 14C-formate, exhaled 14C-carbon dioxide (14CO2), and respiratory parameters were measured during exposure. After exposure, 14C-methanol and 14CO2 exhaled, 14C-methanol and 14C-formate excreted in urine, and 14C-methanol and 14C-formate in blood were quantified. The amounts of exhaled 14C-methanol and 14CO2, blood concentrations of 14C-methanol and 14C-formate, and 14C-methanol and 14C-formate excreted in urine were linearly related to methanol exposure concentration. For all exposures, blood concentrations of 14C-methanol-derived formate were 10 to 1000 times lower than endogenous blood formate concentrations (100 to 200 mM) reported for monkeys and were several orders of magnitude lower than levels of formate known to be toxic. Since the metabolism of formate in primates depends on the availability of tetrahydrofolate, the same four monkeys were next placed on a folate-deficient diet until folate concentrations in red blood cells consistent with moderate folate deficiency (29 to 107 ng/mL) were achieved. Monkeys were then reexposed to the highest exposure concentration, 900 ppm 14C-methanol, for a similar 2-hour period, and again the pharmacokinetic data described above were obtained. Even with a reduced folate status, monkeys exposed to 900 ppm methanol for 2 hours had peak concentrations of methanol-derived formate that were well below the endogenous levels of formate. Although these results represent only a single exposure and therefore preclude broad generalizations, they do suggest the body contains sufficient folate stores to effectively detoxify small doses of methanol-derived formate from exogenous sources, such as those that might occur during normal use of automotive fuel.
Medinsky
M A
MA
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709-2137, USA.
Dorman
D C
DC
Bond
J A
JA
Moss
O R
OR
Janszen
D B
DB
Everitt
J I
JI
D000328:Adult; D000393:Air Pollutants / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005494:Folic Acid Deficiency / Q000150:complications; D005561:Formates / Q000378:metabolism; D006490:Hemostatics / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D000432:Methanol / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D011897:Random Allocation; D012044:Regression Analysis; D015656:Respiratory Mechanics / Q000187:drug effects
D000393:Air Pollutants; D005561:Formates; D006490:Hemostatics; C030544:formic acid; D000432:Methanol