Evaluation of Toxicological Interactions for the Dose-Response Assessment of Chemical Mixtures

General, Applied and Systems Toxicology Pub Date : 2009-12-15 DOI:10.1002/9780470744307.GAT009

K. Krishnan, S. Isukapalli, Jonathan W. Boyd

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Abstract

Dose-response assessment for chemical mixtures involves the characterization of the relationship between administered dose (or more appropriately target tissue dose) and tissue response, in order to facilitate the determination of safe exposure levels for humans. When interactions among chemicals occur, the consideration of mechanisms would be necessary for the conduct of scientifically sound dose-response assessment for mixtures. The present chapter focusses on the current approaches for evaluating toxicological interactions for the dose-response assessment of chemical mixtures. The approaches described in this chapter include: (i) interaction matrix method, (ii) interaction weighting ratio method and (iii) physiologically based pharmacokinetic (PBPK) modelling. The unique use of PBPK models in predicting the change in tissue dose of mixture components as a function of dose, route, exposure scenario and mixture complexity is highlighted. Finally, the interaction-based dose-response analysis of chemical mixtures is described, along with illustrative examples. Keywords: toxic interactions; PBPK modeling; chemical mixtures; interaction matrix; interaction weighting ratio; metabolic interactions

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化学混合物剂量-反应评价中毒理学相互作用的评价

化学混合物的剂量-反应评估包括确定给药剂量(或更适当的靶组织剂量)与组织反应之间的关系，以便于确定人类的安全暴露水平。当化学品之间发生相互作用时，有必要考虑各种机制，以便对混合物进行科学合理的剂量反应评估。本章的重点是目前评估化学混合物剂量-反应评估的毒理学相互作用的方法。本章描述的方法包括:(i)相互作用矩阵法，(ii)相互作用权重比法和(iii)基于生理的药代动力学(PBPK)建模。强调了PBPK模型在预测混合组分的组织剂量变化作为剂量、途径、暴露场景和混合物复杂性的函数方面的独特用途。最后，描述了化学混合物的基于相互作用的剂量-反应分析，并附有说明性的例子。关键词:毒性相互作用;PBPK模型;化学混合物;交互矩阵;相互作用权重比;代谢相互作用

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General, Applied and Systems Toxicology

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