Bois F Y, Zeise L, Tozer T N
Department of Pharmacy, University of California, San Francisco 94143-0446.
Toxicol Appl Pharmacol. 1990 Feb;102(2):300-15. doi: 10.1016/0041-008x(90)90029-t.
Pharmacokinetic analyses have recently been incorporated in risk assessments, with resultant risks sometimes lower and associated "allowable" exposures higher, than would have been otherwise calculated. Predictions of coupled pharmacokinetic and multistage models, as used for regulatory purposes, are evaluated here for tetrachloroethylene carcinogenicity in mice, rats, and humans. Precision is studied by treating parameters as random variables and determining the range of risk estimates once parameter uncertainties are considered via Monte Carlo simulations. The methods developed in this study are of interest for any similar application. The resultant median risk estimate for humans exposed continuously to 1 ng/liter of tetrachloroethylene in the air is 1.6 per million and 5, 25, 75, and 95 percentiles are 0, 0.04, 2.8, and 6.8 per million. Sensitivity of the pharmacokinetic model predictions to its parameters is assessed by analyzing the results of the Monte Carlo simulations. The kinetic parameters defining the metabolic rate are the most important for the case studied.
药代动力学分析最近已被纳入风险评估中，其结果是，与原本计算的结果相比，有时风险更低，而相关的“可允许”暴露量更高。本文对用于监管目的的药代动力学和多阶段模型的耦合预测进行了评估，以研究四氯乙烯对小鼠、大鼠和人类的致癌性。通过将参数视为随机变量，并在通过蒙特卡罗模拟考虑参数不确定性后确定风险估计范围，来研究精度。本研究中开发的方法对于任何类似应用都具有重要意义。对于持续暴露于空气中1纳克/升四氯乙烯的人群，所得的中位风险估计值为百万分之1.6，第5、25、75和95百分位数分别为百万分之0、0.04、2.8和6.8。通过分析蒙特卡罗模拟的结果，评估药代动力学模型预测对其参数的敏感性。在所研究的案例中，定义代谢率的动力学参数最为重要。
