Assessing the Relevance of Toxcast High-Throughput Screening for Informing Toxicity Testing

Assessing the Relevance of ToxCast High-Throughput Screening for Informing Toxicity Testing

Barbara A. Wetmore, Michael B. Black, Melvin E. Andersen, and Bethany Parks.ScitoVation.

The release of the 2007 National Research Council Report, “Toxicity Testing in the 21st Century,” and the subsequent development of the ToxCast research program has led to the implementation and utilization of in vitro and high-throughput screening strategies to inform prioritization and toxicity testing strategies in the chemical risk management arena. Inthefirstphaseofthe ToxCastand Tox21 programs,hundredsofin vitroassayswereused toscreena library ofagriculturaland industrialchemicalstoidentify cellularpathwaysandprocessesperturbedby these chemicals. Although millions ofdatapoints have been collected bythe NationalToxicology Program (NTP)andU.S.EnvironmentalProtectionAgency(EPA)onthecellularperturbationsofthese commoditychemicals, appropriate interpretation of the screening data requires scientists to: 1) frame the data in terms of anticipated real-world exposures and 2)recognize that, currently, it is difficult to determine which in vitro activities are indicative of an adverse outcome rather than a transient perturbation to which humans can adapt. Bioactivity assessments across fruits and vegetables provide useful data to underscore the need to consider context for the ToxCast in vitro bioactivity data and to guide in vitro data interpretation.

ScitoVationhas generated data on organically grown fruit and vegetable juices across various ToxCast platforms (e.g., ACEA, Attagene, BioSeek, NCGC (Tox21), Novascreen [now Perkin Elmer]). Analysis of these results are underway, with initial efforts focused on the BioMap Profiling platform (BioSeek) that utilizes a range of primary cell models that probe ~80 endpoints and cell-based assays designed to assess nuclear receptor activation (Attagene, Tox21-NCGC platforms).

Implications:Despiteacknowledgement that the ToxCastassaysetswere originally designed toprobebiologicalactivities rather than adverse effects,misunderstanding persists that ToxCastbioactivity indicatestoxicity.Bygenerating bioactivityprofilesofnaturalproducts, this effort provides an opportunity to redirect discussion to consider appropriate interpretation of the ToxCast assay datasets and design considerations as the next generation of in vitro tools are developed. Further,direct comparison of bioactivity potencies of fruit and vegetable juices to chemical oral equivalents provides anexposurecontexttothe data,shiftingthediscussionawayfromhazard andtoward riskrelevancy.

Collaborations: U.S. Environmental Protection Agency (EPA) National Center for Computational Toxicology; National Toxicology Program

Keywords:Tox21, ToxCast, high-throughputscreening, in vitro assays, naturalproducts, bioactivity

Projectstartandend dates:January2015 – December, 2016

References:

National Research Council. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press, 2007.

Peer-reviewed publication(s):

AssessingBioactivity-Exposure Profiles of Fruits and Vegetables in the

ToxCast BioMAP Profiling System. Barbara A. Wetmore, Bethany Parks, Keith Houck, Michael B. Black, Richard S. Judson, Russell S. Thomas, and Melvin E. Andersen. In preparation.

Abstractrevision date:February2016

This abstract was prepared by the principal investigator for the project. Please see for more information about the LRI.