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Application of a framework for extrapolating chemical effects across species in pathways controlled by estrogen receptor-á
Citation:
LaLone, C., M. Hornung, E. Gray, AND G. Ankley. Application of a framework for extrapolating chemical effects across species in pathways controlled by estrogen receptor-á. SETAC North America, Salt Lake City, UT, November 01 - 05, 2015.
Impact/Purpose:
not applicable
Description:
Cross-species extrapolation of toxicity data from limited surrogate test organisms to all wildlife with potential of chemical exposure remains a key challenge in ecological risk assessment. A number of factors affect extrapolation, including the chemical exposure, pharmacokinetics, life-stage, and pathway similarities/differences. Here we propose a framework using a tiered approach for species extrapolation that enables a transparent weight-of-evidence driven evaluation of pathway conservation (or lack thereof) in the context of adverse outcome pathways. Adverse outcome pathways describe the linkages from a molecular initiating event, defined as the chemical-biomolecule interaction, through subsequent key events leading to an adverse outcome of regulatory concern (e.g., mortality, reproductive dysfunction). Tier 1 of the extrapolation framework employs in silico evaluations of sequence and structural conservation of molecules (e.g., receptors, enzymes) associated with molecular initiating events or upstream key events. Such evaluations make use of available empirical and sequence data to assess taxonomic relevance. Tier 2 uses in vitro bioassays, such as enzyme inhibition/activation, competitive receptor binding, and transcriptional activation assays to explore functional conservation of pathways across taxa. Finally, Tier 3 provides a comparative analysis of in vivo responses between species utilizing well-established model organisms to assess departure from “normal” processes, identify indicators of molecular initiating events or key events, and measure apical responses to chemicals that describe the adverse outcome relevant to risk assessment. Together, knowledge assembled from each tier yields weight-of-evidence for defining the taxonomic domain of applicability associated with a biological pathway. Further in moving from Tier 1 approaches to Tier 3 approaches greater certainty can be incorporated in the extrapolation. This presentation will demonstrate application of the proposed framework relevant to extrapolation of pathways modulated via estrogen receptor-á, a prominent target of endocrine disrupting chemicals.