A biologically based dynamic model for predicting the disposition of methanol and its metabolites in animals and humans

A multicompartment biologically based dynamic model was developed to descri be the time evolution of methanol and its metabolites in the whole body and in accessible biological matrices of rats, monkeys, and humans following d ifferent exposure scenarios. The dynamic of intercompartment exchanges was described mathematically by a mass balance differential equation system. Th e model's conceptual and functional representation was the same for rats, m onkeys, and humans, but relevant published data specific to the species of interest served to determine the critical parameters of the kinetics. Simul ations provided a close approximation to kinetic data available in the publ ished literature. The average pulmonary absorption fraction of methanol was estimated to be 0.60 in rats, 0.69 in monkeys, and 0.58-0.82 in human volu nteers. The corresponding average elimination half-life of absorbed methano l through metabolism to formaldehyde was estimated to be 1.3, 0.7-3.2, and 1.7 h. Saturation of methanol metabolism appeared to occur at a lower expos ure in rats than in monkeys and humans. Also, the main species difference i n the kinetics was attributed to a metabolism rate constant of whole body f ormaldehyde to formate estimated to be twice as high in rats as in monkeys. Inversely, in monkeys and in humans, a larger fraction of body burden of f ormaldehyde is rapidly transferred to a long-term component. The latter rep resents the formaldehyde that (directly or after oxidation to formate) bind s to various endogenous molecules or is taken up by the tetrahydrofolic-aci d-dependent one-carbon pathway to become the building block of synthetic pa thways. This model can be used to quantitatively relate methanol or its met abolites in biological matrices to the absorbed dose and tissue burden at a ny point in time in rats, monkeys, and humans for different exposures, thus reducing uncertainties in the dose-response relationship, and animal-to-hu man and exposure scenario comparisons. The model, adapted to kinetic data i n human volunteers exposed acutely to methanol vapors, predicts that 8-h in halation exposures ranging from 500 to 2000 ppm, without physical activitie s, are needed to increase concentrations of blood formate and urinary formi c acid above mean background values reported by various authors (4.9-10.3 a nd 6.3-13 mg/liter, respectively). This leaves blood and urinary methanol c oncentrations as the most sensitive biomarkers of absorbed methanol.