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

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