Toxicokinetic modeling and its applications in chemical risk assessment
Toxicokinetic modeling and its applications in chemical risk assessment
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DOI：
10.1016/s0378-4274(02)00375-2
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发表时间：
2003-02-18
影响因子：
3.5
通讯作者：
Andersen, ME
中科院分区：
文献类型：
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作者：
Andersen, ME
近年来，基于生理学的药代动力学（PBPK）模型在风险评估中得到了广泛的应用，PBPK模型是研究外源性药物作用方式的重要工具。在这方面，对作用模式的研究提供了对作用位点/机制以及与毒性反应相关的异生素形式的深入了解。经验证的PBPK模型允许计算各种条件下（即低剂量下）不同动物种属和人群不同成员中外源性物质和代谢物的组织剂量。通过这种方式，这些PBPK模型支持作为当前风险评估方法重要组成部分的低剂量和物种间推断。PBPK模型有时被称为生理毒代动力学（PT）模型，以强调其与引起毒性反应的化合物的应用。药代动力学（PK）建模一般具有丰富的历史。基于数据的PK房室模型是在20世纪30年代开发的，当时只有原始工具可用于求解微分方程组。这些模型在20世纪60年代和70年代得到扩展，以适应剂量依赖性消除和流量限制代谢的新观察结果。清除概念的应用带来了许多关于药物在体内处置的新见解。在20世纪70年代，开发了PBPK/PT模型来评估具有职业重要性的挥发性化合物的代谢，并且首次将毒理学中的剂量依赖性过程包括在PBPK模型中，以评估代谢和消除过程的饱和导致非线性剂量反应关系的条件。在20世纪80年代，化学工程师和职业毒理学的见解被结合起来，开发PBPK/PT模型，以支持二氯甲烷和其他溶剂的风险评估。20世纪90年代见证了PBPK/PT模型的风险评估应用以及应用灵敏度和变异性方法来评估模型性能的爆炸性增长。详细检查的一些化合物包括丁二烯、苯乙烯、乙二醇醚、二恶英和有机酯/助剂。本文概述了PBPK/PT模型的历史，强调了PBPK/TK模型在健康风险评估中的最新应用，并讨论了现代使用这些建模方法提供的风险评估前景。(C)2002爱思唯尔科学爱尔兰有限公司保留所有权利。
In recent years physiologically based pharmacokinetic (PBPK) modeling has found frequent application in risk assessments where PBPK models serve as important adjuncts to studies on modes of action of xenobiotics. In this regard, studies on mode of action provide insight into both the sites/mechanisms of action and the form of the xenobiotic associated with toxic responses. Validated PBPK models permit calculation of tissue doses of xenobiotics and metabolites for a variety of conditions, i.e. at low-doses, in different animal species, and in different members of a human population. In this manner, these PBPK models support the low-dose and interspecies extrapolations that are important components of current risk assessment methodologies. PBPK models are sometimes referred to as physiological toxicokinetic (PT) models to emphasize their application with compounds causing toxic responses. Pharmacokinetic (PK) modeling in general has a rich history. Data-based PK compartmental models were developed in the 1930's when only primitive tools were available for solving sets of differential equations. These models were expanded in the 1960's and 1970's to accommodate new observations on dose-dependent elimination and flow-limited metabolism. The application of clearance concepts brought many new insights about the disposition of drugs in the body. In the 1970's PBPK/PT models were developed to evaluate metabolism of volatile compounds of occupational importance, and, for the first time, dose-dependent processes in toxicology were included in PBPK models in order to assess the conditions under which saturation of metabolic and elimination processes lead to non-linear dose response relationships. In the 1980's insights from chemical engineers and occupational toxicology were combined to develop PBPK/PT models to support risk assessment with methylene chloride and other solvents. The 1990's witnessed explosive growth in risk assessment applications of PBPK/PT models and in applying sensitivity and variability methods to evaluate model performance. Some of the compounds examined in detail include butadiene, styrene, glycol ethers, dioxins and organic esters/aids. This paper outlines the history of PBPK/PT modeling, emphasizes more recent applications of PBPK/TK models in health risk assessment, and discusses the risk assessment perspective provided by modern uses of these modeling approaches. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.