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Toxicological Sciences 53, 185-193 (2000)
Copyright © 2000 by the Society of Toxicology

Analysis of Respiratory Exchange of Methanol in the Lung of the Monkey Using a Physiological Model

Jeffrey W. Fisher*,1, David C. Dorman, Michelle A. Medinsky, Frank Welsch and Rory B. Conolly

Chemical Industry Institute of Toxicology, 6 Davis Drive, PO Box 12137, Research Triangle Park, North Carolina 27709 * Visiting scientist from the Toxicology Division, Wright-Patterson AFB, Ohio.

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.

Key Words: inhaled methanol; metabolism; physiologically based pharmacokinetic model; relative respiratory uptake (RRU); lung-only exposure system..


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[Abstract] [Full Text] [PDF]


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