You are here:
Leveraging in vitro Transcriptomic Points of Departure in Chemical Safety Evaluation (WC12)
Citation:
Everett, L., D. Haggard, J. Fredenburg, F. Harris, J. Rogers, J. Bundy, R. Judson, I. Shah, K. Paul-Friedman, AND J. Harrill. Leveraging in vitro Transcriptomic Points of Departure in Chemical Safety Evaluation (WC12). 12th World Congress on Alternatives and Animal Use in the Life Sciences (WC12), Niagara Falls, Ontario, CANADA, August 27 - 31, 2023. https://doi.org/10.23645/epacomptox.24036711.v1
Impact/Purpose:
Invited presentation to the WC12 session entitled “Tipping Point in Omics: Transcriptomic Points of Departure (tPODs) and QIVIVE in Regulatory Decision-Making” by the session co-organizer, Anthony Reardon (HealthCanada). This session is part of the 21st Century Predictive Toxicology track within the WC12 conference on Alternatives and Animal Use in the Life Sciences. The topic we were specifically invited to submit an abstract for was “Application of transcriptomic points of departure in vitro and high throughput screening at the EPA”. The goal of this presentation will be to share our recent progress on building confidence in the use of transcriptomic points of departure (tPODs) for use in tiered testing strategies and other regulatory use cases. Logan Everett will be the presenting author.
Description:
Recent technological advancements and decreasing costs have made it feasible to profile all protein-coding genes across thousands of samples with high-throughput transcriptomics (HTTr), allowing for broad evaluation of many target pathways and modes of action in a single screening assay. Researchers at EPA have applied this method to chemical screening studies of over 1,000 chemicals using multiple in vitro cell culture models to generate data that can be used for both hazard prediction and potency estimation, thereby informing risk assessments and prioritizing chemicals for further testing. Assessing the reliability and reproducibility of in vitro HTTr screening methods is critical to their utility and adoption in regulatory applications. While the individual gene measurements in transcriptomics assays may have lower signal-to-noise compared to targeted assays, our analyses have shown that leveraging coordinated changes across biologically-related gene sets (e.g. pathways) often yields more accurate potency estimates compared to concentration-response modeling of individual genes. Advanced analysis methods are also needed to link gene expression changes to relevant chemical targets in order to predict organism-level hazards. We have developed novel methods to predict primary molecular targets based on HTTr data, which can then be linked to specific hazards and used to prioritize orthogonal follow-up testing with targeted assays. Overall, our work has shown that HTTr applied to in vitro cell lines provides a scalable and reliable toxicological screening method with potential utility to multiple use cases and regulatory contexts. This abstract does not necessarily reflect US EPA policy.
URLs/Downloads:
DOI: Leveraging in vitro Transcriptomic Points of Departure in Chemical Safety Evaluation (WC12)
EVERETT_WC12_AUG_2023_FINAL.PDF (PDF, NA pp, 2485.921 KB, about PDF)