PHYSIOLOGICALLY-BASED MODELING OF THE TOXICOKINETIC INTERACTION BETWEEN TOLUENE AND M-XYLENE IN THE RAT
PHYSIOLOGICALLY-BASED MODELING OF THE TOXICOKINETIC INTERACTION BETWEEN TOLUENE AND M-XYLENE IN THE RAT
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DOI：
10.1006/taap.1993.1111
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发表时间：
1993-06-01
影响因子：
3.8
通讯作者：
BRODEUR, J
中科院分区：
文献类型：
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作者：
TARDIF, R;LAPARE, S;BRODEUR, J
采用基于生理的毒物动力学（PBTK）模型研究了雄性Sprague-Dawley大鼠体内甲苯（TOL）和间二甲苯（XYL）相互作用的毒性动力学机制。首先，通过对3只大鼠进行一系列闭室吸入暴露，分别测定TOL和XYL的代谢常数（Vmaxand Km），起始浓度为500至4000 ppm。将PBTK模型模拟与实验数据进行最佳视觉拟合，得到Km（TOL, 0.55 mg/l； XYL, 0.20mg/l）和Vmax（TOL, 4.8 mg/hr/kg； XYL, 8.4 mg/hr/kg）值。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）。用二元化学混合物PBTK模型分析了腔室溶剂浓度的时间过程数据，该模型有四种机制假设，即在肝室中定量定义的代谢相互作用（即无相互作用、竞争性抑制、非竞争性抑制和非竞争性抑制）。各种模型描述的有效性通过TOL和XYL的开室吸入暴露数据得到验证。总的来说，这种结合实验和建模方法的结果与XYL和TOL在大鼠中的竞争性代谢抑制一致。
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 (Vmaxand 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, 0.20mg/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.