Generalized Concentration Addition Modeling Predicts Mixture Effects of Environmental PPAR{gamma} Agonists

The vast array of potential environmental toxicant combinations necessitates the development of efficient strategies for predicting toxic effects of mixtures. Current practices emphasize the use of concentration addition to predict joint effects of endocrine disrupting chemicals in coexposures. Generalized concentration addition (GCA) is one such method for predicting joint effects of coexposures to chemicals and has the advantage of allowing for mixture components to have differences in efficacy (ie, dose-response curve maxima). Peroxisome proliferator–activated receptor gamma (PPAR) is a nuclear receptor that plays a central role in regulating lipid homeostasis, insulin sensitivity, and bone quality and is the target of an increasing number of environmental toxicants. Here, we tested the applicability of GCA in predicting mixture effects of therapeutic (rosiglitazone and nonthiazolidinedione partial agonist) and environmental PPAR ligands (phthalate compounds identified using EPA’s ToxCast database). Transcriptional activation of human PPAR1 by individual compounds and mixtures was assessed using a peroxisome proliferator response element-driven luciferase reporter. Using individual dose-response parameters and GCA, we generated predictions of PPAR activation by the mixtures, and we compared these predictions with the empirical data. At high concentrations, GCA provided a better estimation of the experimental response compared with 3 alternative models: toxic eq...

Source: Toxicological Sciences - August 30, 2016 Category: Toxicology Authors: Watt, J., Webster, T. F., Schlezinger, J. J. Tags: Predicting Mixture Effects of PPAR[gamma ] Agonists Source Type: research