Mörk Anna-Karin, Jonsson Fredrik, Johanson Gunnar
Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.
Toxicol Appl Pharmacol. 2009 Nov 1;240(3):423-32. doi: 10.1016/j.taap.2009.07.033. Epub 2009 Aug 4.
The aim of this study was to derive improved estimates of population variability and uncertainty of physiologically based pharmacokinetic (PBPK) model parameters, especially of those related to the washin-washout behavior of polar volatile substances. This was done by optimizing a previously published washin-washout PBPK model for acetone in a Bayesian framework using Markov chain Monte Carlo simulation. The sensitivity of the model parameters was investigated by creating four different prior sets, where the uncertainty surrounding the population variability of the physiological model parameters was given values corresponding to coefficients of variation of 1%, 25%, 50%, and 100%, respectively. The PBPK model was calibrated to toxicokinetic data from 2 previous studies where 18 volunteers were exposed to 250-550 ppm of acetone at various levels of workload. The updated PBPK model provided a good description of the concentrations in arterial, venous, and exhaled air. The precision of most of the model parameter estimates was improved. New information was particularly gained on the population distribution of the parameters governing the washin-washout effect. The results presented herein provide a good starting point to estimate the target dose of acetone in the working and general populations for risk assessment purposes.
本研究的目的是对基于生理学的药代动力学（PBPK）模型参数的总体变异性和不确定性，尤其是与极性挥发性物质的吸入-呼出行为相关的参数，得出更准确的估计值。这是通过在贝叶斯框架下使用马尔可夫链蒙特卡罗模拟优化先前发表的丙酮吸入-呼出PBPK模型来实现的。通过创建四个不同的先验集来研究模型参数的敏感性，其中生理模型参数总体变异性的不确定性分别赋予对应于1%、25%、50%和100%变异系数的值。将PBPK模型校准至来自之前两项研究的毒代动力学数据，在这两项研究中，18名志愿者在不同工作负荷水平下暴露于250 - 550 ppm的丙酮中。更新后的PBPK模型很好地描述了动脉血、静脉血和呼出气体中的浓度。大多数模型参数估计的精度得到了提高。特别是在控制吸入-呼出效应的参数的总体分布方面获得了新信息。本文给出的结果为估计工作人群和普通人群中丙酮的目标剂量以进行风险评估提供了一个良好的起点。
