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Evaluating Pharmacokinetic and Pharmacodynamic Interactions with Computational Models in Supporting Cumulative Risk Assessment
National Exposure Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, 109 T.W. Alexander Drive, Research Triangle Park, NC 27711, USA
Center for Human Health Assessment, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA
* Author to whom correspondence should be addressed.
Received: 22 April 2011; in revised form: 13 May 2011 / Accepted: 17 May 2011 / Published: 19 May 2011
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.
Keywords: pharmacokinetics; pharmacodynamics; mixture interactions; physiologically based pharmacokinetic/pharmacodynamic model
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Tan, Y.-M.; Clewell, H.; Campbell, J.; Andersen, M. Evaluating Pharmacokinetic and Pharmacodynamic Interactions with Computational Models in Supporting Cumulative Risk Assessment. Int. J. Environ. Res. Public Health 2011, 8, 1613-1630.
Tan Y-M, Clewell H, Campbell J, Andersen M. Evaluating Pharmacokinetic and Pharmacodynamic Interactions with Computational Models in Supporting Cumulative Risk Assessment. International Journal of Environmental Research and Public Health. 2011; 8(5):1613-1630.
Tan, Yu-Mei; Clewell, Harvey; Campbell, Jerry; Andersen, Melvin. 2011. "Evaluating Pharmacokinetic and Pharmacodynamic Interactions with Computational Models in Supporting Cumulative Risk Assessment." Int. J. Environ. Res. Public Health 8, no. 5: 1613-1630.