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

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Serval ID
serval:BIB_20415
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A biologically based dynamic model for predicting the disposition of methanol and its metabolites in animals and humans
Journal
Toxicological Sciences
Author(s)
Bouchard M., Brunet R.C., Droz P.O., Carrier G.
ISSN
1096-6080
Publication state
Published
Issued date
2001
Peer-reviewed
Oui
Volume
64
Number
2
Pages
169-184
Language
english
Notes
Publication types: Comparative Study ; Journal Article - Publication Status: ppublish
Abstract
A multicompartment biologically based dynamic model was developed to describe the time evolution of methanol and its metabolites in the whole body and in accessible biological matrices of rats, monkeys, and humans following different exposure scenarios. The dynamic of intercompartment exchanges was described mathematically by a mass balance differential equation system. The model's conceptual and functional representation was the same for rats, monkeys, and humans, but relevant published data specific to the species of interest served to determine the critical parameters of the kinetics. Simulations provided a close approximation to kinetic data available in the published 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 volunteers. The corresponding average elimination half-life of absorbed methanol 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 exposure in rats than in monkeys and humans. Also, the main species difference in the kinetics was attributed to a metabolism rate constant of whole body formaldehyde 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 formaldehyde is rapidly transferred to a long-term component. The latter represents the formaldehyde that (directly or after oxidation to formate) binds to various endogenous molecules or is taken up by the tetrahydrofolic-acid-dependent one-carbon pathway to become the building block of synthetic pathways. This model can be used to quantitatively relate methanol or its metabolites in biological matrices to the absorbed dose and tissue burden at any point in time in rats, monkeys, and humans for different exposures, thus reducing uncertainties in the dose-response relationship, and animal-to-human and exposure scenario comparisons. The model, adapted to kinetic data in human volunteers exposed acutely to methanol vapors, predicts that 8-h inhalation exposures ranging from 500 to 2000 ppm, without physical activities, are needed to increase concentrations of blood formate and urinary formic acid above mean background values reported by various authors (4.9-10.3 and 6.3-13 mg/liter, respectively). This leaves blood and urinary methanol concentrations as the most sensitive biomarkers of absorbed methanol.
Keywords
Air Pollutants, Occupational, Air Pollution, Animals, Female, Formaldehyde, Formic Acids, Humans, Inhalation Exposure, Lung, Macaca fascicularis, Male, Methanol, Models, Biological, Pulmonary Ventilation, Rats, Rats, Inbred F344
Pubmed
Web of science
Open Access
Yes
Create date
19/11/2007 13:15
Last modification date
25/09/2019 7:08
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