Simultaneous or sequential exposure to multiple chemicals may cause\r\ninteractions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual\r\nchemicals. Such interactions can cause modification of the internal or target dose/response\r\nof one chemical in the mixture by other chemical(s), resulting in a change in the toxicity\r\nfrom that predicted from the summation of the effects of the single chemicals using dose\r\nadditivity. In such cases, conducting quantitative cumulative risk assessment for chemicals\r\npresent as a mixture is difficult. The uncertainties that arise from PK interactions can be\r\naddressed by developing physiologically based pharmacokinetic (PBPK) models to\r\ndescribe the disposition of chemical mixtures. Further, PK models can be developed to\r\ndescribe mechanisms of action and tissue responses. In this article, PBPK/PD modeling\r\nefforts conducted to investigate chemical interactions at the PK and PD levels are reviewed\r\nto demonstrate the use of this predictive modeling framework in assessing health risks\r\nassociated with exposures to complex chemical mixtures.
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