Generalized concentration addition predicts joint effects of aryl hydrocarbon receptor agonists with partial agonists and cCompetitive antagonists


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dc.contributor.author Howard, Gregory J.
dc.contributor.author Schlezinger, Jennifer J.
dc.contributor.author Hahn, Mark E.
dc.contributor.author Webster, Thomas F.
dc.date.accessioned 2010-06-08T15:08:45Z
dc.date.available 2010-06-08T15:08:45Z
dc.date.issued 2009-12-22
dc.identifier.citation Environmental Health Perspectives 118 (2010): 666-672 en_US
dc.identifier.uri http://hdl.handle.net/1912/3603
dc.description This paper is not subject to U.S. copyright. The definitive version was published in Environmental Health Perspectives 118 (2010): 666-672, doi:10.1289/ehp.0901312. en_US
dc.description.abstract Background: Predicting the expected outcome of a combination exposure is critical to risk -assessment. The toxic equivalency factor (TEF) approach used for analyzing joint effects of dioxin-like chemicals is a special case of the method of concentration addition. However, the TEF method assumes that individual agents are full aryl hydrocarbon receptor (AhR) agonists with parallel dose–response curves, whereas many mixtures include partial agonists. Objectives: We assessed the ability of generalized concentration addition (GCA) to predict effects of combinations of full AhR agonists with partial agonists or competitive antagonists. Methods: We measured activation of AhR-dependent gene expression in H1G1.1c3 cells after application of binary combinations of AhR ligands. A full agonist (2,3,7,8-tetrachlorodibenzo-p--dioxin or 2,3,7,8-tetrachlorodibenzofuran) was combined with either a full agonist (3,3´,4,4´,5-penta-chloro-biphenyl), a partial agonist (2,3,3´,4,4´-pentachlorobiphenyl or galangin), or an antagonist (3,3´-diindolylmethane). Combination effects were modeled by the TEF and GCA approaches, and goodness of fit of the modeled response surface to the experimental data was assessed using a nonparametric statistical test. Results: The GCA and TEF models fit the experimental data equally well for a mixture of two full agonists. In all other cases, GCA fit the experimental data significantly better than the TEF model. Conclusions: The TEF model overpredicts effects of AhR ligands at the highest concentration combinations. At lower concentrations, the difference between GCA and TEF approaches depends on the efficacy of the partial agonist. GCA represents a more accurate definition of additivity for mixtures that include partial agonist or competitive antagonist ligands. en_US
dc.description.sponsorship J.J.S., M.E.H., and T.F.W. were supported by Superfund Research Program grant P42ES007381. G.J.H. was supported by U.S. Environmental Protection Agency STAR Fellowship FP-91636701. en_US
dc.format.mimetype application/pdf
dc.language.iso en_US en_US
dc.publisher National Institute of Environmental Health Sciences en_US
dc.relation.uri http://dx.doi.org/10.1289/ehp.0901312
dc.subject Additivity en_US
dc.subject AhR en_US
dc.subject Aryl hydrocarbon receptor en_US
dc.subject Concentration addition en_US
dc.subject Interaction en_US
dc.subject Mixtures en_US
dc.subject TEF en_US
dc.title Generalized concentration addition predicts joint effects of aryl hydrocarbon receptor agonists with partial agonists and cCompetitive antagonists en_US
dc.type Article en_US
dc.identifier.doi 10.1289/ehp.0901312

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