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Evaluation of the scientific underpinnings for identifying estrogenic chemicals in non-mammalian taxa using mammalian test systems
Citation:
Ankley, G., C. LaLone, E. Gray, Dan Villeneuve, AND M. Hornung. Evaluation of the scientific underpinnings for identifying estrogenic chemicals in non-mammalian taxa using mammalian test systems. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 35(11):2806-2816, (2016).
Impact/Purpose:
A major challenge in chemical risk assessment is extrapolation of toxicity data from tested to untested species. Successful cross-species extrapolation involves understanding similarities and differences in toxicokinetic and toxicodynamic processes among species. In this paper we consider the toxicodynamic challenge, and propose a hierarchal framework, based on the adverse outcome pathway (AOP) concept, to transparently and systematically assess cross-species conservation of biological pathways that could be perturbed by toxic chemicals. The approach features consideration of computational, in vitro and in vivo evidence to assess molecular initiating and intermediate key events of an AOP in a systematic, comparative manner. To demonstrate practical application of the framework, we consider an assessment question arising from the legislatively-mandated USEPA endocrine disruptor screening program, which involves the degree to which data generated using mammalian systems can be translated to non-mammalian species. Specifically, there is a need to define cross-species conservation of pathways controlled by activation of estrogen receptor-á (ERá), as a basis for using mammalian (primarily human) high-throughput (HTP) in vitro data to prioritize subsequent testing to assess human health and ecological risks of estrogenic chemicals. Based on a weight-of-evidence analysis enabled by the hierarchal framework, chemicals identified as estrogenic using mammalian HTP data also should be categorized as high priority in terms of possible risks to non-mammalian vertebrates.
Description:
A major challenge in chemical risk assessment is extrapolation of toxicity data from tested to untested species. Successful cross-species extrapolation involves understanding similarities and differences in toxicokinetic and toxicodynamic processes among species. Herein we consider the toxicodynamic challenge, and propose a hierarchal framework, based on the adverse outcome pathway (AOP) concept, to transparently and systematically assess cross-species conservation of biological pathways that could be perturbed by toxic chemicals. The approach features consideration of computational, in vitro and in vivo evidence to assess molecular initiating and intermediate key events of an AOP in a systematic, comparative manner. To demonstrate practical application of the framework, we consider an assessment question arising from the legislatively-mandated USEPA endocrine disruptor screening program, which involves the degree to which data generated using mammalian systems can be translated to non-mammalian species. Specifically, there is a need to define cross-species conservation of pathways controlled by activation of estrogen receptor-á (ERá), as a basis for using mammalian (primarily human) high-throughput (HTP) in vitro data to prioritize subsequent testing to assess human health and ecological risks of estrogenic chemicals. The initial phase of our analysis revealed good structural conservation the ERá across vertebrate species in terms of amino acid sequence of the primary structure and ligand binding domain, as well as key residues known to be involved in ligand binding and co-activator recruitment. Comparative evaluation of functional aspects of the ERá based on in vitro chemical-receptor binding and transcriptional activation also revealed strong cross-species conservation, particularly for moderate to high affinity ligands. Finally, consideration of in vivo data involving perturbation of pathways known to be controlled by ERá signaling also indicated consistent conservation among vertebrate species. Based on a weight-of-evidence analysis enabled by the hierarchal framework, chemicals identified as estrogenic using mammalian HTP data also should be categorized as high priority in terms of possible risks to non-mammalian vertebrates.
