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The impact of exercise and intersubject variability on dose estimates for dichloromethane derived from a physiologically based pharmacokinetic model.
Fundam Appl Toxicol 1994 Jan; 22(1):20-25
The impact of exercise and intersubject variability on dose estimates for methylene-chloride (75092) derived from a physiologically based pharmacokinetic (PBPK) model was examined. A PBPK model of the human metabolism of methylene-chloride was modified to produce dose estimates for persons exposed to 25 parts per million methylene-chloride vapor under occupational conditions. The model had postulated that methylene-chloride was metabolized in the lung and liver and that its carcinogenicity was related to its being metabolized by glutathione-S-transferase (GST) in these tissues. The model included the lungs, liver, fat, and slowly and rapidly perfused tissues as the compartments of interest and had been developed for a 70 kilogram male at rest. It was modified by increasing alveolar ventilation, cardiac output, and blood flow to the tissue compartments to reflect the effects of light work, equivalent to 33.67 watts of exercise for 8 hours, and by varying the Michaelis constant (Km) and maximum velocity (Vmax) for the mixed-function-oxidase (MFO) pathway and the first order rate constant for the GST pathway to reflect interindividual variability. Variations in the Km and Vmax for the MFO pathway and the GST rate constant were obtained from measurements made in in-vitro studies of methylene-chloride metabolism in four human livers. These modifications produced increases in GST pathway doses for the liver and lung varying from 0 to 5.4 and 0 to 3.6 times those computed by the original model, respectively. The authors conclude that the modified model indicates that some occupationally exposed individuals may receive GST metabolized methylene-chloride doses that are several times larger than those predicted by the original model. The implications of this for methylene- chloride carcinogenicity depends on whether metabolism by the GST pathway is the only mechanism by which methylene-chloride exerts its carcinogenicity.
NIOSH-Author; Pharmacodynamics; Organic-solvents; Chloromethanes; Biotransformation; Mathematical-models; Physical-exercise; Risk-analysis; Liver-tissue; Chlorinated-hydrocarbons
Issue of Publication
Fundamental and Applied Toxicology
Page last reviewed: May 5, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division