Department of Environmental Science, Institute for Water and Wetland Research, Faculty of Science, Radboud University Nijmegen, PO Box 9010, 6500 GL Nijmegen, The Netherlands.
Toxicol Lett. 2012 Oct 17;214(2):154-65. doi: 10.1016/j.toxlet.2012.08.016. Epub 2012 Aug 27.
Parameter uncertainty and interindividual variability in the predictions of a generic human physiologically based pharmacokinetic (PBPK) model were separated by means of nested Monte Carlo simulations. Separate information on uncertainty and variability can help decision makers to identify whether they should focus on identification of sensitive individuals rather than on additional research to obtain more accurate estimates for particular parameters. In this study, the concentration of acetone in human blood was simulated during and after 4h of exposure to 2-propanol via air. It was shown that the influence of interindividual variability and uncertainty varies over time, from the uptake phase, via a steady-state phase, into the elimination phase. During the uptake phase, interindividual variability played a significant role in the predicted variation of acetone concentrations in blood, with variability up to a factor of 2-3 (90th/10th percentile ratio). After exposure ceased, the parameter uncertainty increased up to a factor of 100 after 16h, whereas variability remained unchanged. Parameter importance analysis indicated that variability in human physiology had the largest influence on predicted acetone concentrations in blood during exposure. Uncertainty in the metabolic rate of acetone was most important after the exposure had ceased and overruled variability.
通过嵌套式蒙特卡罗模拟，将通用人体生理药代动力学（PBPK）模型预测中的参数不确定性和个体间变异性分离开来。关于不确定性和变异性的单独信息可以帮助决策者确定他们是否应该专注于识别敏感个体，而不是进行额外的研究以获得特定参数的更准确估计。在这项研究中，通过空气暴露于异丙醇 4 小时期间和之后，模拟了人血液中丙酮的浓度。结果表明，个体间变异性和不确定性的影响随时间变化，从吸收阶段，经过稳态阶段，进入消除阶段。在吸收阶段，个体间变异性在血液中丙酮浓度的预测变化中起着重要作用，变异性高达 2-3 倍（90 百分位/10 百分位比）。暴露停止后，16 小时后参数不确定性增加了 100 倍，而变异性保持不变。参数重要性分析表明，在暴露期间，人体生理学的变异性对血液中预测的丙酮浓度影响最大。丙酮代谢率的不确定性在暴露停止后最为重要，并且超过了变异性。
