Physiologically-based pharmacokinetic modeling of a mixture of toluene and xylene in humans.
A physiologically-based pharmacokinetic (PBPK) model for a mixture of toluene (TOL) and xylene (XYL), developed and validated in the rat, was used to predict the uptake and disposition kinetics of TOL/XYL mixture in humans. This was accomplished by substituting the rat physiological parameters and the blood:air partition coefficient with those of humans, scaling the maximal velocity for hepatic metabolism on the basis of body weight0.75, and keeping all other model parameters species-invariant. The human TOL/XYL mixture PBPK model, developed based on the quantitative biochemical mechanism of interaction elucidated in the rat (i.e., competitive metabolic inhibition), simulated adequately the kinetics of TOL and XYL during combined exposures in humans. The simulations with this PBPK model indicate that an eight hour co-exposure to concentrations that remain within the current threshold limit values of TOL (50 ppm) and XYL (100 ppm) would not result in significant pharmacokinetic interferences, thus implying that data on biological monitoring of worker exposure to these solvents would be unaffected during co-exposures.
Tardif
R
R
Département de médecine du travail et d'hygiène du milieu, Faculté de médecine, Université de Montréal, Québec, Canada.
Laparé
S
S
Charest-Tardif
G
G
Brodeur
J
J
Krishnan
K
K
D000818:Animals; D001835:Body Weight; D003198:Computer Simulation; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008452:Maximum Allowable Concentration; D008954:Models, Biological; D008956:Models, Chemical; D016273:Occupational Exposure; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D051381:Rats; D014050:Toluene / Q000097:blood / Q000493:pharmacokinetics*; D014992:Xylenes / Q000097:blood / Q000493:pharmacokinetics*
D014992:Xylenes; D014050:Toluene; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating