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New frontiers in toxicology: Predictive tools for cross species extrapolation
Citation:
Vliet, S. New frontiers in toxicology: Predictive tools for cross species extrapolation. Univ. of Cincinnati Dept of Environmental and Public Health Sciences Webinar, Duluth, MN, September 02, 2020. https://doi.org/10.23645/epacomptox.12869543
Impact/Purpose:
With efforts to reduce the use of animals in chemical safety assessments and the need to continue to protect human health and species in the environment, new non-animal testing methods are being developed and vetted. A number of these new approaches utilize bioinformatic techniques, which are computer-driven methods that allow for rapid, in-depth, exploration of biological data to understand species similarities and differences that can aid in understanding chemical susceptibility across species, and thus assist with efforts in extrapolating available toxicity knowledge from tested species to untested species. This presentation aims to describe advances in predictive toxicology for extrapolating toxicity knowledge from one tested species to hundreds of untested species using computational methods
Description:
Cell-based high-throughput screening (HTS) and computational technologies are being applied as tools for toxicity testing in the 21st century. The U.S. Environmental Protection Agency (EPA) embraced these technologies and created the ToxCast Program in 2007, which has served as a screening and prioritization tool for thousands of chemicals. The rapid and automated screening methods take advantage of hundreds of (primarily) mammalian-based HTS assays for identifying biological activity suggestive of potential toxic effects. The data can aid in identifying chemicals that are most likely to impact biological pathways that lead to adverse health effects. To realize the full potential of the ToxCast data for predicting adverse effects to both humans and wildlife, it is necessary to understand how broadly these data may plausibly be extrapolated across species. Therefore, the U.S. EPA Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool was used to evaluate conservation of the 460 protein targets represented in the ToxCast assay suite. The SeqAPASS query sequence was selected based on the model organism used in the ToxCast assay (e.g., human, cattle, chimpanzee, guinea pig, rabbit, rat, mouse, pig, or sheep). Similarity of primary amino acid sequences and sequences from appropriate functional domains were compared across species to understand conservation of each assay target across taxa. To demonstrate application of the SeqAPASS data for extrapolation of ToxCast targets, case studies were developed that focus on the extrapolation of targets being evaluated as part of the Endocrine Disruptor Screening Program, including the androgen receptor, enzymes involved in steroidogenesis, and proteins in thyroid axis function. These case studies demonstrate the utility of SeqAPASS for informing the extrapolation of HTS data and identification of model organisms likely to be suitable for follow-up or complementary in vivo toxicity tests.
