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ToxCast results to identify chemical hazards across species
Citation:
LaLone, C., Dan Villeneuve, J. Doering, B. Blackwell, T. Transue, C. Simmons, J. Swintek, S. Degitz, A. Williams, AND G. Ankley. ToxCast results to identify chemical hazards across species. SETAC North America, Sacramento, CA, November 02 - 08, 2018.
Impact/Purpose:
Increasingly cell-based screening methods are being used to identify chemicals that may adversely affect human health and the environment. Typically, these methods use mammalian-cells from humans or rodents. Therefore, it is of interest to understand how broadly the results from such assays may be extrapolated to other species, including non-mammalian species (e.g., birds, fish, frogs, insects, plants). Here we applied a web-based computational approach to species extrapolation, the US EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS; https://seqapass.epa.gov/seqapass/), to begin to understand whether chemicals of interest identified from such mammalian cell-based assays may be extrapolated to other species. Specific examples were developed that focus on a variety of chemical targets to demonstrate the utility of the SeqAPASS tool for addressing such challenges in species extrapolation.
Description:
The US Environmental Protection Agency’s (EPA) Toxicity Forcaster (ToxCastTM), is a suite of rapid high-throughput screening (HTS) assays used to evaluate chemical safety. Thousands of chemicals have been screened in these HTS assays that cover broad biological space. However, the assays utilized in ToxCast are primarily mammalian-based assays (e.g., human, rat, mouse) as the original intent was to utilize the results to prioritize chemicals based on potential impacts to human health. Recognizing the wealth of information that is available through ToxCast screening results, it is important to consider the utility of these data in understanding chemical effects across species. Therefore, to expand the utility of these data the US EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS; https://seqapass.epa.gov/seqapass/) tool was employed to evaluate how well the protein targets used in the ToxCast Assays are conserved across species. For extrapolation of ToxCast results the SeqAPASS tool evaluates protein similarity between protein sequence from the model organism used in the HTS assay and all species with sequence information available, making a prediction of which species are likely similar enough to have the protein target available for a chemical to act upon. This initial understanding of whether the chemical target is available in other species can provide the foundation for extrapolating ToxCast results across species and further identifying where extrapolation is not practical. All 484 ToxCast assays associated with a protein sequence were evaluated with SeqAPASS and made publicly available both through ToxCast and the US EPA’s CompTox Chemistry Dashboard (https://comptox.epa.gov/dashboard). Four case studies were developed to describe the SeqAPASS results for ToxCast assay target families including G-protein-coupled receptors, DNA-binding proteins, esterases, and growth factors. These SeqAPASS case studies demonstrate how broadly the HTS assay results can be extrapolated beyond the model organism to understand potential chemical hazard.