Battelle, Pacific Northwest Division, Richland, WA 99352, USA.
Regul Toxicol Pharmacol. 2011 Oct;61(1):82-92. doi: 10.1016/j.yrtph.2011.06.004. Epub 2011 Jun 22.
Probabilistic models of interindividual variation in exposure and response were linked to create a source-to-outcome population model. This model was used to investigate cholinesterase inhibition from dietary exposures to an insecticide (chlorpyrifos) in populations of adults and 3 year old children. A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was used to calculate the variation in sensitivity occurring from interindividual variability in physiology, metabolism, and physical activity levels. A dietary intake model characterizes the variation in dietary insecticide exposures and variation in anthropometry in the populations. Published equations were used to describe the necessary physiology for each simulated individual based on the anthropometry from the dietary intake model. The model of the interindividual variation in response to chlorpyrifos was developed by performing a sensitivity analysis on the PBPK/PD model to determine the parameters that drive variation in pharmacodynamics outcomes (brain and red blood cell acetylcholinesterase inhibition). Distributions of interindividual variation were developed for parameters with the largest impact; the probabilistic model sampled from these distributions. The impact of age and interindividual variation on sensitivity at the doses that occur from dietary exposures, typically orders of magnitude lower than exposures assessed in toxicological studies, was assessed using the source-to-outcome model. The resulting simulations demonstrated that metabolic detoxification capacity was sufficient to prevent significant brain and red blood cell acetylcholinesterase inhibition, even in individuals with the lowest detoxification potential. Age-specific pharmacokinetic and pharmacodynamic parameters did not predict differences in susceptibility between adults and children. In the future, the approach of this case study could be used to assess the risks from low level exposures to other chemicals.
建立了个体间暴露和反应差异的概率模型，以构建源至结局的人群模型。该模型用于研究成人和 3 岁儿童人群中因食用杀虫剂（毒死蜱）而引起的胆碱酯酶抑制情况。利用生理相关的药代动力学和药效动力学（PBPK/PD）模型，计算了由于生理、代谢和体力活动水平的个体差异而导致的敏感性变化。饮食摄入模型用于描述人群中饮食中杀虫剂暴露的差异和人体测量学的差异。利用发表的方程，根据饮食摄入模型中的人体测量学信息，为每个模拟个体描述必要的生理学特征。通过对 PBPK/PD 模型进行敏感性分析，确定了影响药效动力学结果（脑和红细胞乙酰胆碱酯酶抑制）的参数，从而建立了对毒死蜱反应的个体间差异模型。为具有最大影响的参数开发了个体间变异分布；概率模型从这些分布中进行采样。使用源至结局模型评估了年龄和个体间变异对饮食暴露剂量下敏感性的影响，饮食暴露剂量通常比毒理学研究中评估的暴露剂量低几个数量级。结果表明，即使在解毒能力最低的个体中，代谢解毒能力也足以防止脑和红细胞乙酰胆碱酯酶抑制的显著增加。年龄特异性药代动力学和药效动力学参数并不能预测成人和儿童之间的敏感性差异。在未来，该案例研究的方法可以用于评估低水平暴露于其他化学物质的风险。
