Tardif R, Laparé S, Krishnan K, Brodeur J
Département de médecine du travail et d'hygiène du milieu, Faculté de médecine, Université de Montréal, PQ, Canada.
Toxicol Appl Pharmacol. 1993 Jun;120(2):266-73. doi: 10.1006/taap.1993.1111.
The present study was undertaken to investigate the mechanism of toxicokinetic interaction between toluene (TOL) and m-xylene (XYL) in vivo in the male Sprague-Dawley rat by physiologically based toxicokinetic (PBTK) modeling. First, the metabolic constants (Vmax and Km) were determined for TOL and XYL individually by conducting a series of closed-chamber inhalation exposures of three rats to starting concentrations of 500 to 4000 ppm. The values of Km (TOL, 0.55 mg/liter; XYL, 0.20 mg/liter) and Vmax (TOL, 4.8 mg/hr/kg; XYL, 8.4 mg/hr/kg) were obtained following best visual fit of PBTK model simulations to experimental data. Then using the same experimental set-up, rats were exposed to three different mixtures of both solvents (500 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 500 ppm XYL). The data from the time course of chamber solvent concentrations were analyzed with a binary chemical mixture PBTK model that had four mechanistic hypotheses of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition) quantitatively defined in the liver compartment. The validity of the various model descriptions was verified with open-chamber inhalation exposure data on toxicokinetics of TOL and XYL. Overall, the results of this combined experimental and modeling approach are consistent with a competitive metabolic inhibition between XYL and TOL in the rat.
本研究旨在通过基于生理学的毒代动力学（PBTK）模型，研究雄性Sprague-Dawley大鼠体内甲苯（TOL）和间二甲苯（XYL）之间的毒代动力学相互作用机制。首先，通过对三只大鼠进行一系列封闭腔室吸入暴露，起始浓度为500至4000 ppm，分别测定TOL和XYL的代谢常数（Vmax和Km）。在PBTK模型模拟与实验数据进行最佳视觉拟合后，获得了Km值（TOL为0.55 mg/升；XYL为0.20 mg/升）和Vmax值（TOL为4.8 mg/小时/千克；XYL为8.4 mg/小时/千克）。然后，使用相同的实验装置，将大鼠暴露于两种溶剂的三种不同混合物中（500 ppm TOL + 1000 ppm XYL；1000 ppm TOL + 1000 ppm XYL；1000 ppm TOL + 500 ppm XYL）。利用肝脏隔室中定量定义的代谢相互作用的四种机制假设（即无相互作用、竞争性抑制、非竞争性抑制和反竞争性抑制）的二元化学混合物PBTK模型，分析了腔室溶剂浓度随时间变化的数据。通过TOL和XYL毒代动力学的开放腔室吸入暴露数据验证了各种模型描述的有效性。总体而言，这种实验与建模相结合方法的结果与大鼠体内XYL和TOL之间的竞争性代谢抑制一致。
