Development of Adverse Outcome Pathways relevant for the identification of substances having endocrine disruptors properties

This report is the outcome of an EFSA procurement (NP/EFSA/PREV/2020/01) which aims at contributing to the development of adverse outcome pathways (AOPs) to be integrated in a network addressing uterine adenocarcinoma in mammals. The outcome is intended to support the identification of substances with endocrine disruptor mode of action. For this specific purpose, an evidence-based approach methodology was adopted. Available evidence was systematically mapped from the literature to identify Molecular Initiating Events (MIEs) and Key Events (KEs) linked to adverse outcome (AO) “uterine endometrioid adenocarcinoma” independently from prototypical stressors, by means of: 1. a priori defined search strategies initially addressing the AO and biologically plausible MIEs, 2. application of machine learning technique (Topic modelling) that automatically analyzes text data to identify biologically plausible KERs, 3. systematic literature review and critical appraisal of prioritized evidence, taking into account human, in vivo and in vitro studies. Estradiol and tamoxifen, two recognized human risk factors for endometrioid adenocarcinoma, were used as tool chemical compounds to empirically support the response and temporal concordance of the identified key event relationships (KERs). All evidence has been then integrated by means of the AOP conceptual network. An evidence-based AOP starting from activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma via epigenetic modulation was postulated.