Citation

Spinu N, Bal-Price A, Cronin MTD, Enoch SJ, Madden JC, Worth AP. Arch. Toxicol. 2019; ePub(ePub): ePub.

Affiliation

European Commission, Joint Research Centre (JRC), Ispra, Italy. andrew.worth@ec.europa.eu.

Copyright

(Copyright © 2019, Holtzbrinck Springer Nature Publishing Group)

DOI

10.1007/s00204-019-02551-1

PMID

31444508

Abstract

An adverse outcome pathway (AOP) network is an attempt to represent the complexity of systems toxicology. This study illustrates how an AOP network can be derived and analysed in terms of its topological features to guide research and support chemical risk assessment. A four-step workflow describing general design principles and applied design principles was established and implemented. An AOP network linking nine linear AOPs was mapped and made available in AOPXplorer. The resultant AOP network was modelled and analysed in terms of its topological features, including level of degree, eccentricity and betweenness centrality. Several well-connected KEs were identified, and cell injury/death was established as the most hyperlinked KE across the network. The derived network expands the utility of linear AOPs to better understand signalling pathways involved in developmental and adult/ageing neurotoxicity. The results provide a solid basis to guide the development of in vitro test method batteries, as well as further quantitative modelling of key events (KEs) and key event relationships (KERs) in the AOP network, with an eventual aim to support hazard characterisation and chemical risk assessment.

Language: en

Keywords

Adverse outcome pathway; Network analytics; Network development; Neurotoxicity; Predictive toxicology