Evidence for Cross Species Extrapolation of Mammalian-Based High-Throughput Screening Assay Results

High-throughput
screening (HTS) and computational technologies
have emerged as important tools for chemical hazard identification.
The US Environmental Protection Agency (EPA) launched the Toxicity
ForeCaster (ToxCast) Program, which has screened thousands of chemicals
in hundreds of mammalian-based HTS assays for biological activity.
The data are being used to prioritize toxicity testing on those chemicals
likely to lead to adverse effects. To use HTS assays in predicting
hazard to both humans and wildlife, it is necessary to understand
how broadly these data may be extrapolated across species. The US
EPA Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS; https://seqapass.epa.gov/seqapass/) tool was used to assess conservation of the 484 protein targets
represented in the suite of ToxCast assays and other HTS assays. To
demonstrate the utility of the SeqAPASS data for guiding extrapolation,
case studies were developed which focused on targets of interest to
the US Endocrine Disruptor Screening Program and the Organisation
for Economic Cooperation and Development. These case studies provide
a line of evidence for conservation of endocrine targets across vertebrate
species, with few exceptions, and demonstrate the utility of SeqAPASS
for defining the taxonomic domain of applicability for HTS results
and identifying organisms for suitable follow-up toxicity tests.