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Cited by 101Animal testing and alternativesCarcinogens and Genotoxicity AssessmentEnvironmental Toxicology and Ecotoxicology

Considerations for strategic use of high-throughput transcriptomics chemical screening data in regulatory decisions

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Harrill, Joshua, Shah, Imran, Setzer, R. Woodrow, Haggard, Derik, Auerbach, Scott, Judson, Richard, Thomas, Russell S.·2019·Current Opinion in Toxicology
DOI 10.1016/j.cotox.2019.05.004PMC PMC6733036
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Abstract

Recently, numerous organizations, including governmental regulatory agencies in the U.S. and abroad, have proposed using data from New Approach Methodologies (NAMs) for augmenting and increasing the pace of chemical assessments. NAMs are broadly defined as any technology, methodology, approach or combination thereof that can be used to provide information on chemical hazard and risk assessment that avoids the use of intact animals. High-throughput transcriptomics (HTTr) is a type of NAM that uses gene expression profiling as an endpoint for rapidly evaluating the effects of large numbers of chemicals on in vitro cell culture systems. As compared to targeted high-throughput screening (HTS) approaches that measure the effect of chemical X on target Y, HTTr is a non-targeted approach that allows researchers to more broadly characterize the integrated response of an intact biological system to chemicals that may affect a specific biological target or many biological targets under a defined set of treatment conditions (time, concentration, etc.). HTTr screening performed in concentration-response mode can provide potency estimates for the concentrations of chemicals that produce perturbations in cellular response pathways. Here, we discuss study design considerations for HTTr concentration-response screening and present a framework for the use of HTTr-based biological pathway-altering concentrations (BPACs) in a screening-level, risk-based chemical prioritization approach. The framework involves concentration-response modeling of HTTr data, mapping gene level responses to biological pathways, determination of BPACs, in vitro-to-in vivo extrapolation (IVIVE) and comparison to human exposure predictions.

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  • High-throughput screening techniques that can generate large amounts of data are now common in many fields of biology.

    “High-throughput screening techniques that can generate large amounts of data are now common in many fields of biology”

    From WILDS: A Benchmark of in-the-Wild Distribution Shifts (2020) · cites this paper as Harrill et al., 2019

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Authors
Harrill, J., Shah, I., Setzer, R. W., Haggard, D., Auerbach, S., Judson, R., & Thomas, R. S.
Affiliations
  • Environmental Protection Agency (US)
  • Oak Ridge Institute for Science and Education (US)
  • National Institutes of Health (US)
Corresponding author
Harrill, Joshua
ORCID
Venue
Current Opinion in Toxicology
Publisher
Elsevier BV
Published
2019-06
Volume
15
Pages
64-75
ISSN
2468-2020 (ISSN-L)
DOI
10.1016/j.cotox.2019.05.004
PMC
PMC6733036
OpenAlex
W2944913941
Cited by
101
References
3
Citations by year
2026: 6 · 2025: 14 · 2024: 25 · 2023: 13 · 2022: 19 · 2021: 12 · 2020: 10 · 2019: 2
FWCI
2.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Toxicology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Environmental Protection Agency
  • Office of Research and Development
Topics
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Environmental Toxicology and Ecotoxicology
Keywords
high-throughput transcriptomics, compound screening, new approach methodologies, chemical prioritization, gene expression profiling, in vitro-in vivo extrapolation, chemical risk assessment, regulatory decision-making, research design

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