Toxicogenomics Data for Chemical Safety Assessment and Development of New Approach Methodologies: An Adverse Outcome Pathway-Based Approach

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    Abstract

    Mechanistic toxicology provides a powerful approach to inform on the safety of chemicals and the development of safe-by-design compounds. Although toxicogenomics supports mechanistic evaluation of chemical exposures, its implementation into the regulatory framework is hindered by uncertainties in the analysis and interpretation of such data. The use of mechanistic evidence through the adverse outcome pathway (AOP) concept is promoted for the development of new approach methodologies (NAMs) that can reduce animal experimentation. However, to unleash the full potential of AOPs and build confidence into toxicogenomics, robust associations between AOPs and patterns of molecular alteration need to be established. Systematic curation of molecular events to AOPs will create the much-needed link between toxicogenomics and systemic mechanisms depicted by the AOPs. This, in turn, will introduce novel ways of benefitting from the AOPs, including predictive models and targeted assays, while also reducing the need for multiple testing strategies. Hence, a multi-step strategy to annotate AOPs is developed, and the resulting associations are applied to successfully highlight relevant adverse outcomes for chemical exposures with strong in vitro and in vivo convergence, supporting chemical grouping and other data-driven approaches. Finally, a panel of AOP-derived in vitro biomarkers for pulmonary fibrosis (PF) is identified and experimentally validated.

    Original languageEnglish
    Article number2203984
    JournalAdvanced science
    Volume10
    Issue number2
    Early online date7 Dec 2022
    DOIs
    Publication statusPublished - 13 Jan 2023
    Publication typeA1 Journal article-refereed

    Keywords

    • adverse outcome pathways
    • biomarkers
    • new approach methodologies
    • toxicogenomics

    Publication forum classification

    • Publication forum level 1

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • General Chemical Engineering
    • General Materials Science
    • Biochemistry, Genetics and Molecular Biology (miscellaneous)
    • General Engineering
    • General Physics and Astronomy

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