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Improving toxicity extrapolation using molecular sequence similarity: A case study of pyrethroids and the sodium ion channel
Citation:
Willming, M., C. LaLone, AND M. Barron. Improving toxicity extrapolation using molecular sequence similarity: A case study of pyrethroids and the sodium ion channel. SETAC North America 37th Annual Meeting, Orlando, FL, November 06 - 10, 2016.
Impact/Purpose:
This abstract summarizes research on relationships between organismal sensitivity and molecular similarity. It is important because it is a proof of concept of how two EPA tools, Web-ICE and SeqAPASS can be integrated to support improved toxicity extrapolation.
Description:
A significant challenge in ecotoxicology has been determining chemical hazards to species with limited or no toxicity data. Currently, extrapolation tools like U.S. EPA’s Web-based Interspecies Correlation Estimation (Web-ICE; www3.epa.gov/webice) models categorize toxicity estimation between the surrogate and predicted species by broad taxonomic groups. Toxicity predictions between more distantly related taxa have greater uncertainty, thus identifying variations in sensitivity across taxonomic levels may improve extrapolation. Because species sensitivity is a function of phylogenetic relatedness, understanding conservation of a chemical’s molecular target can likely inform cross-species predictions of sensitivity based on whole organism toxicity data. EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS; https://seqapass.epa.gov/seqapass/) tool can be used to determine cross-species molecular target similarity by comparing protein sequences to a known susceptible query species. The goal of this work was to explore the relationship between sequence similarity of key functional domains of the voltage-gated sodium channel, derived from SeqAPASS, and curated, mode of action specific, acute toxicity data for pyrethroids to improve correlation based toxicity extrapolation. Sequence similarity was determined at the species, genus, and family level to identify variability in sensitivity at each taxonomic level. These analyses showed that species sensitivity to pyrethroids was correlated with the sodium channel gate and ion transport domains across taxa. These results will be used to improve cross-taxa toxicity extrapolation models and reduce uncertainty in predictions by grouping species with similar molecular target sequences and chemicals with the same molecular initiating event.