Toxicogenomics Data for Chemical Safety Assessment and Development of New Approach Methodologies: An Adverse Outcome Pathway‐Based Approach. Issue 2 (7th December 2022)

• Record Type: Journal Article
• Authors: Saarimäki, Laura Aliisa; Morikka, Jack; Pavel, Alisa; Korpilähde, Seela; del Giudice, Giusy; Federico, Antonio; Fratello, Michele; Serra, Angela; Greco, Dario
• Is Part Of: Advanced science. Volume 10:Issue 2(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-07
• Subjects: adverse outcome pathways -- biomarkers -- new approach methodologies -- toxicogenomics; Science -- Periodicals; 505
• DOI: 10.1002/advs.202203984
• Languages: English
• ISSNs: 2198-3844

Abstract

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. Abstract : Comprehensive molecular annotation of adverse outcome pathways (AOPs) supports the development of new approach methodologies (NAMs) and the integration of toxicogenomic evidence into chemical safety assessment. Annotated AOPs can be used to interpret complex omics data, identify relevant biomarkers, and to gain information on potential systemic adverse outcomes with high in vitro to in vivo convergence.