Academic journal article Environmental Health Perspectives

Generalized Concentration Addition Predicts Joint Effects of Aryl Hydrocarbon Receptor Agonists with Partial Agonists and Competitive Antagonists

Academic journal article Environmental Health Perspectives

Generalized Concentration Addition Predicts Joint Effects of Aryl Hydrocarbon Receptor Agonists with Partial Agonists and Competitive Antagonists

Article excerpt

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 HlGl.lc3 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-chlorobiphenyl), 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 non-parametric 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.

Key WORDS: additivity, AhR, aryl hydrocarbon receptor, concentration addition, interaction, mixtures, TEF. Environ Health Perspect 118:666-672 (2010). doi:10.1289/ehp.0901312 [Online 22 December 2009]


Dioxin-like compounds [e.g., non-ortho-substituted polychlorinated biphenyls (PCBs), chlorinated dibenzo-p-dioxins, and chlorinated dibenzofurans] rank among the highest-priority environmental toxicants at Superfund sites (Agency for Toxic Substances and Disease Registry 2007). Because these compounds occur most commonly as complex mixtures, methods to predict the expected outcome of combination exposures are critical both to risk assessment and to an accurate judgment of whether mixture effects are additive, synergistic, or antagonistic.

A rigorous approach is to first define a model, sometimes called the null model, for the expected additive (i.e., noninteractive) effects of a combination. Mixture effects above or below those predicted can then be thought of as synergy or antagonism with respect to the null model (Kortenkamp 2007; U.S. Environmental Protection Agency 2000). Choice of the null model is crucial. An inappropriate null model for a mixture can greatly underestimate the additive (noninteractive) effects of mixtures, as was demonstrated dramatically in an experiment measuring activation of the estrogen receptor by a mixture of environmental estrogenic agents (Silva et al. 2002). Although the concentration of each individual agent was below its no observed effect concentration or effective concentration causing 1% of maximal response, the total effect of the mixture was many times greater than that predicted by a simple sum of the individual effects, a null model sometimes called effect summation. It is easy to show that the effect summation model is appropriate only for agents with linear dose-response curves (Berenbaum 1989).

Combination effects of estrogenic agents in the Silva experiment (Silva et al. 2002) were, however, accurately predicted by the null model of concentration addition (CA). CA assumes that one agent can be substituted for another in proportion to their relative potencies; it is usually thought to apply to agents that work by similar mechanisms and is not limited to linear dose-response curves (Kortenkamp 2007). …

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