Development of a data-driven approach to Adverse Outcome Pathway network generation: a case study on the EATS-modalities

Abstract

Adverse Outcome Pathways (AOPs) summarize mechanistic understanding of toxicological effects and have, for example, been highlighted as a promising tool to integrate data from novel in vitro and in silico methods into chemical risk assessments. Networks based on AOPs are considered the functional implementation of AOPs, as they are more representative of complex biology. At the same time, there are currently no harmonized approaches to generate AOP networks (AOPNs). Systematic strategies to identify relevant AOPs, and methods to extract and visualize data from the AOP-Wiki, are needed. The aim of this work was to develop a structured search strategy to identify relevant AOPs in the AOP-Wiki, and an automated data-driven workflow to generate AOPNs. The approach was applied on a case study to generate an AOPN focused on the Estrogen, Androgen, Thyroid, and Steroidogenesis (EATS) modalities. A search strategy was developed a priori with search terms based on effect parameters in the ECHA/EFSA Guidance Document on Identification of Endocrine Disruptors. Furthermore, manual curation of the data was performed by screening the contents of each pathway in the AOP-Wiki, excluding irrelevant AOPs. Data were downloaded from the Wiki, and a computational workflow was utilized to automatically process, filter, and format the data for visualization. This study presents an approach to structured searches of AOPs in the AOP-Wiki coupled to an automated data-driven workflow for generating AOPNs. In addition, the case study presented here provides a map of the contents of the AOP-Wiki related to the EATS-modalities, and a basis for further research, for example, on integrating mechanistic data from novel methods and exploring mechanism-based approaches to identify endocrine disruptors (EDs). The computational approach is freely available as an R-script, and currently allows for the (re)-generation and filtering of new AOP networks based on data from the AOP-Wiki and a list of relevant AOPs used for filtering.

Keywords: AOP; AOP network; EATS-modalities; ED assessment; computational; data-driven; endocrine disruptors.