Evidenced-Based Approaches to Support the Development of Endocrine-Mediated Adverse Outcome Pathways: Challenges and Opportunities

Karine Marie Laure Audouze*, Elias Zgheib, Khaled Abass, Asma H. Baig, Isabel Forner-Piquer, Henrik Holbech, Dries Knapen, Pim E. G. Leonards, Diana I. Lupu, Saranya Palaniswamy, Arja Rautio, Maria Sapounidou, Olwenn V Martin*


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A transformation of regulatory toxicology is underway to meet the demands of testing increasing numbers of chemicals whilst reducing reliance on in vivo models. This transformation requires a shift from chemical safety assessment largely based on direct empirical observation of apical toxicity outcomes in whole organisms to predictive approaches in which outcomes and risks are inferred from accumulated mechanistic understanding. In the last decade, Adverse Outcome Pathways (AOPs) (Ankley et al., 2010; Ankley and Edwards, 2018) have captured the attention of regulators and researchers alike as a systematic approach for organizing knowledge that may support such inferences (Wittwehr et al., 2017).

An AOP is a conceptual structured representation of existing toxicological knowledge describing the causally connected sequence of events, across different levels of biological organization, required to produce an adverse effect when an organism is exposed to a stressor. Specifically, AOPs depict a series of key events (KEs) linking a molecular initiating event (MIE, an interaction between a stressor (e.g., endogenous ligand, xenobiotic) and a biomolecule) to an adverse outcome (AO, at organism or population levels). The causal links between 2 KEs are referred to as key event relationships (KERs). AOPs provide a useful framework to connect mechanistic data to adverse effects on human health or wildlife populations as a basis for the identification of cell- or biochemical-based tests that could fit in Integrated Approaches to Testing and Assessment (IATAs), identifying KEs that could be targeted for the development of New Approach Methods (NAMs), as well as investigating similarities in mechanistic pathways between species.

AOPs are also particularly salient for identifying potential Endocrine Disruptors (EDs). Indeed, both the World Health Organization (WHO) and the International Programme on Chemical Safety (IPCS) definition and the scientific criteria adopted by the European Union in 2017 are articulated around three key requirements, namely; evidence of an adverse effect, evidence of an endocrine-mediated (EM) mode-of-action, and the plausibility of the causal relationship between the mode-of-action and adverse effect. Both the European Chemical Agency (ECHA) and European Food Safety Authority (EFSA) recommend that more EM AOPs be developed for substantiation of chemicals’ ED properties [European Chemical Agency (ECHA) et al., 2018]. Of the 370 AOPs currently included in the AOP-wiki (aopwiki.org), there are 80 EM AOPs (Table 1).
TidsskriftFrontiers in Toxicology
Antal sider10
StatusUdgivet - dec. 2021


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