MacDonald A J, Rostami-Hodjegan A, Tucker G T, Linkens D A
Section of Molecular Pharmacology and Pharmacogenetics, Clinical Sciences Division, The University of Sheffield, Sheffield S10 2JF, UK.
Regul Toxicol Pharmacol. 2002 Apr;35(2 Pt 1):165-76. doi: 10.1006/rtph.2001.1507.
The effect of acute ethanol-mediated inhibition of m-xylene metabolism on central nervous system (CNS) depression in the human worker population was investigated using physiologically based pharmacokinetic (PBPK) models and probabilistic random (Monte Carlo) sampling. PBPK models of inhaled m-xylene and orally ingested ethanol were developed and combined by a competitive enzyme (CYP2E1) inhibition model. Human interindividual variability was modeled by combining estimated statistical distributions of model parameters with the deterministic PBPK models and multiple random or Monte Carlo simulations. A simple threshold pharmacodynamic model was obtained by simulating m-xylene kinetics in human studies where CNS effects were observed and assigning the peak venous blood m-xylene concentration (C(V,max)) as the dose surrogate of toxicity. Probabilistic estimates of an individual experiencing CNS disturbances given exposure to the current UK occupational exposure standard (100 ppm time-weighted average over 8 h), with and without ethanol ingestion, were obtained. The probability of experiencing CNS effects given this scenario increases markedly and nonlinearly with ethanol dose. As CYP2E1-mediated metabolism of other occupationally relevant organic compounds may be inhibited by ethanol, simulation studies of this type should have an increasingly significant role in the chemical toxicity risk assessment.
利用基于生理学的药代动力学（PBPK）模型和概率随机（蒙特卡洛）抽样，研究了急性乙醇介导的间二甲苯代谢抑制对人类劳动者群体中枢神经系统（CNS）抑制的影响。通过竞争性酶（CYP2E1）抑制模型，开发并结合了吸入间二甲苯和口服乙醇的PBPK模型。通过将模型参数的估计统计分布与确定性PBPK模型以及多次随机或蒙特卡洛模拟相结合，对人类个体间变异性进行建模。通过模拟人类研究中间二甲苯动力学并将静脉血中间二甲苯峰值浓度（C(V,max)）指定为毒性剂量替代物，获得了一个简单的阈值药效学模型。得出了在接触当前英国职业接触标准（8小时内时间加权平均浓度为100 ppm）的情况下，无论是否摄入乙醇，个体出现中枢神经系统紊乱的概率估计值。在这种情况下，出现中枢神经系统效应的概率随乙醇剂量显著且非线性增加。由于乙醇可能会抑制CYP2E1介导的其他职业相关有机化合物的代谢，这类模拟研究在化学毒性风险评估中应发挥越来越重要的作用。
