title: Evaluating pharmacokinetic and pharmacodynamic interactions with computational models in supporting cumulative risk assessment.
abstract: Simultaneous or sequential exposure to multiple chemicals may cause interactions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual chemicals. Such interactions can cause modification of the internal or target dose/response of one chemical in the mixture by other chemical(s), resulting in a change in the toxicity from that predicted from the summation of the effects of the single chemicals using dose additivity. In such cases, conducting quantitative cumulative risk assessment for chemicals present as a mixture is difficult. The uncertainties that arise from PK interactions can be addressed by developing physiologically based pharmacokinetic (PBPK) models to describe the disposition of chemical mixtures. Further, PK models can be developed to describe mechanisms of action and tissue responses. In this article, PBPK/PD modeling efforts conducted to investigate chemical interactions at the PK and PD levels are reviewed to demonstrate the use of this predictive modeling framework in assessing health risks associated with exposures to complex chemical mixtures.
authors.affiliation: National Exposure Research Laboratory, Office of Research and Development, US Environmental Protection Agency, 109 TW Alexander Drive, Research Triangle Park, NC 27711, USA.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Tan
authors.forename: Harvey
authors.initials: H
authors.lastname: Clewell
authors.forename: Jerry
authors.initials: J
authors.lastname: Campbell
authors.forename: Melvin
authors.initials: M
authors.lastname: Andersen
mesh_terms: D000818:Animals; D004347:Drug Interactions; D006801:Humans; D008956:Models, Chemical; D010599:Pharmacokinetics; D018570:Risk Assessment