Tardif R, Laparé S, Charest-Tardif G, Brodeur J, Krishnan K
Département de médecine du travail et d'hygiène du milieu, Faculté de médecine, Université de Montréal, Québec, Canada.
Risk Anal. 1995 Jun;15(3):335-42. doi: 10.1111/j.1539-6924.1995.tb00326.x.
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.
在大鼠体内建立并验证的甲苯（TOL）和二甲苯（XYL）混合物的基于生理的药代动力学（PBPK）模型，被用于预测TOL/XYL混合物在人体中的摄取和处置动力学。通过用人体的生理参数和血-气分配系数替代大鼠的相应参数，基于体重0.75对肝脏代谢的最大速度进行缩放，并保持所有其他模型参数不随物种变化，从而实现了这一目标。基于在大鼠中阐明的相互作用的定量生化机制（即竞争性代谢抑制）建立的人体TOL/XYL混合物PBPK模型，充分模拟了人体联合暴露期间TOL和XYL的动力学。使用该PBPK模型进行的模拟表明，同时暴露于仍在TOL（50 ppm）和XYL（100 ppm）当前阈限值范围内的浓度8小时，不会导致显著的药代动力学干扰，这意味着在联合暴露期间，关于工人接触这些溶剂的生物监测数据不会受到影响。
