Analysis of respiratory exchange of methanol in the lung of the monkey using a physiological model.
A physiologically based pharmacokinetic (PBPK) model was developed for the monkey, to account for fractional systemic uptake of inhaled methanol vapors in the lung. Fractional uptake of inhaled [14C]-methanol was estimated using unreported exhaled breath time course measurements of [14C]-methanol from the D.C. Dorman et al. (1994, Toxicol Appl Pharmacol. 128, 229-238) lung-only exposure study. The cumulative amount of [14C]-methanol exhaled was linear with respect to exposure duration (0.5 to 2 h) and concentration (10 to 900 ppm). The model estimated that forty to eighty-one percent of the of inhaled [14C]-methanol delivered to the lung was taken into systemic circulation in female Cynomolgus monkeys exposed for two h to 10-900 ppm of [14C]-methanol. There was no apparent trend between the percent of inhaled [14C]-methanol absorbed systemically and the [14C]-methanol exposure concentration. Model simulations were conducted using a single saturable Michaelis-Menten equation with Vmaxc, the metabolic capacity set to 15.54 mg/kg/h and Km, the affinity constant, to 0.66 mg/l. The [14C]-methanol blood concentrations were variable across [14C]-methanol exposure groups and the PBPK model tended to over-predict systemic clearance of [14C]-methanol. Accounting for fractional uptake of inhaled polar solvents is an important consideration for risk assessment of inhaled polar solvents.
Fisher
J W
JW
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Dorman
D C
DC
Medinsky
M A
MA
Welsch
F
F
Conolly
R B
RB
D000280:Administration, Inhalation; D000818:Animals; D005260:Female; D016014:Linear Models; D008168:Lung / Q000378:metabolism*; D008252:Macaca fascicularis; D000432:Methanol / Q000493:pharmacokinetics*; D008954:Models, Biological; D011659:Pulmonary Gas Exchange; D012997:Solvents / Q000493:pharmacokinetics*
D012997:Solvents; D000432:Methanol