A consistent approach for the application of pharmacokinetic modeling in cancer and noncancer risk assessment.
A consistent approach for the application of pharmacokinetic modeling in cancer and noncancer risk assessment.
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DOI：
10.1289/ehp.0211085
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发表时间：
2002-01
影响因子：
10.4
通讯作者：
Barton, Hugh A
中科院分区：
文献类型：
--
作者：
Clewell, Harvey J 3rd;Andersen, Melvin E;Barton, Hugh A
基于生理的药代动力学模型为提高跨剂量、物种和暴露途径的外推的可靠性提供了重要的能力，这些外推通常是化学风险评估中所需的，而不考虑所考虑的毒性终点。最近，监管机构使用的癌症和非癌症风险评估方法的协调越来越受到关注。尽管在这两个范例中应用药代动力学模型的具体细节可能不同，但有可能确定两个范例中共同的重要因素。这些要素在描述毒性发展的四部分框架上展开：a)暴露，b)组织剂量学/药代动力学，c)毒性过程/药效学，以及d)反应。中间两个组成部分构成了行动模式。特别是，本文描述的方法提供了一个通用模板，用于将药代动力学建模用于估计组织剂量学到化学风险评估中，无论是针对癌症还是非癌症终点。化学品风险评估通常取决于不同物种之间的比较，这些比较往往简化为反映差异的比率。在这篇文章中，我们描述了这一比率概念的用途，并讨论了与使用默认剂量学相比，基于药代动力学的方法的优势。
Physiologically based pharmacokinetic modeling provides important capabilities for improving the reliability of the extrapolations across dose, species, and exposure route that are generally required in chemical risk assessment regardless of the toxic end point being considered. Recently, there has been an increasing focus on harmonization of the cancer and noncancer risk assessment approaches used by regulatory agencies. Although the specific details of applying pharmacokinetic modeling within these two paradigms may differ, it is possible to identify important elements common to both. These elements expand on a four-part framework for describing the development of toxicity: a) exposure, b) tissue dosimetry/pharmacokinetics, c) toxicity process/pharmacodynamics, and d) response. The middle two components constitute the mode of action. In particular, the approach described in this paper provides a common template for incorporating pharmacokinetic modeling to estimate tissue dosimetry into chemical risk assessment, whether for cancer or noncancer end points. Chemical risk assessments typically depend upon comparisons across species that often simplify to ratios reflecting the differences. In this paper we describe the uses of this ratio concept and discuss the advantages of a pharmacokinetic-based approach as compared to the use of default dosimetry.