Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys.
Large-scale use of methanol (MeOH) as an automotive fuel may increase exposure of the public to MeOH vapor, necessitating the need for additional data for an adequate human health risk assessment. Formate is accepted as the toxic metabolite of MeOH, its metabolism is folate-dependent, and potentially sensitive folate-deficient subpopulations (e.g., pregnant women) exist that may be at higher risk to low-level methanol exposure. This study determined the pharmacokinetics of [14C]MeOH and [14C]formate in normal and folate-deficient (FD) monkeys following inhalation of environmentally relevant concentrations of [14C]MeOH. Four normal adult female cynomolgus monkeys were anesthetized (isoflurane) and exposed by lung-only inhalation to 10, 45, 200, and 900 ppm [14C]MeOH for 2 hr. Monkeys were then placed on a FD diet until folate concentrations consistent with moderate deficiency (29-107 ng/ml) developed in red blood cells and then reexposed to 900 ppm (900-FD) for 2 hr. Average (+/- SD) end-of-exposure blood [14C]MeOH concentrations were 0.65 +/- 0.3, 3.0 +/- 0.8, 21 +/- 16, 106 +/- 84, and 211 +/- 71 microM, while average (+/- SD) peak blood [14C]formate concentrations were 0.07 +/- 0.02, 0.25 +/- 0.09, 2.3 +/- 2.9, 2.8 +/- 1.7, and 9.5 +/- 4.7 microM following MeOH inhalation at 10, 45, 200, 900, and 900-FD ppm, respectively. The blood concentration of [14C]MeOH-derived formate from all exposures was 10 to 1000 times lower than the endogenous blood formate concentration (0.1 to 0.2 mM) reported for monkeys. These results suggest that low-level exposure to MeOH would not result in elevated blood formate concentrations in humans under short-term exposure conditions.
Dorman
D C
DC
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Moss
O R
OR
Farris
G M
GM
Janszen
D
D
Bond
J A
JA
Medinsky
M A
MA
D000280:Administration, Inhalation; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002849:Chromatography, Gas; D004195:Disease Models, Animal; D004781:Environmental Exposure; D005260:Female; D005492:Folic Acid / Q000097:blood; D005494:Folic Acid Deficiency / Q000378:metabolism*; D005561:Formates / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D007553:Isotope Labeling; D008252:Macaca fascicularis; D000432:Methanol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D012119:Respiration / Q000187:drug effects; D012129:Respiratory Function Tests; D013057:Spectrum Analysis
D005561:Formates; C030544:formic acid; D002245:Carbon Dioxide; D005492:Folic Acid; D000432:Methanol