The Development and Use of Adverse Outcome Pathways in Mechanistic Toxicology

Abstract

Adverse Outcome Pathways (AOPs) offer a structured and mechanistic approach to understanding the toxicity of chemical substances, enabling a shift away from traditional animal-based testing methods. This thesis explores the historical development, conceptual structure, and practical applications of AOPs within the field of mechanistic toxicology. It outlines the emergence of AOPs in response to the ethical and scientific limitations of apical-endpoint testing and highlights the necessity of the paradigm shift in chemical safety assessment towards more rigorous, economical and sustainable methods such as new approach methodologies (NAMs) and integrated approaches to testing and assessment (IATAs).

The work also examines AOP development strategies, from manual curation to computational modelling, and the use of platforms like OECD-facilitated AOP-Wiki. Further, it considers the integration of omics data, artificial intelligence, and quantitative modelling (qAOPs) to enhance AOP utility in regulatory frameworks. Examples in related literature illustrate the use of AOPs in chemical prioritisation, biomarker discovery, nanomaterial assessment, and the development of predictive models. Ultimately, the thesis argues that AOPs are essential tools for enabling ethical, efficient, and scientifically robust chemical safety assessment, with significant potential to support the ongoing transformation of regulatory toxicology.