Putative adverse outcome pathways relevant to neurotoxicity

Abstract

The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways.

Keywords:

• adverse outcome pathway
• in vitro testing
• key events
• molecular initiating event
• pathways of neurotoxicity
• predictive toxicology

Acknowledgments

The EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) together with the Safety Evaluation Ultimately Replacing Animal Testing (SEURAT-1) consortium organized a workshop (March 2013, Ispra) on Adverse Outcome Pathways (AOP) Relevant to Neurotoxicity, in context of the SEURAT-1 research initiative (Safety Evaluation Ultimately Replacing Animal Testing— see www.seurat-1.eu). The work of all workshop participants greatly contributed to this manuscript. In addition to the authors, the final version of this manuscript was reviewed following the internal procedures of the US EPA, the US National Institute of Environmental Health Sciences and the European Commission's Joint Research Centre. We thank Sharon Munn (EURL ECVAM), William Mundy, and Mary Gilbert (US EPA) and Kristen Ryan (US NTP/NIEHS) for critically reading the manuscript and providing valuable comments.

Declaration of interest

The employment affiliation of the authors is shown on the cover page. The authors have sole responsibility for the writing and content of this paper. The contributing authors were participants of the workshop organized by the EURL ECVAM. The external workshop participants were invited on the basis of a survey performed by EURL ECVAM neurotoxicity experts of the latest literature to identify those with specific expertise in the relevant research fields. The workshop organization was financially supported by the European Commission, including the cost of travelling and per diem of all invited external experts. The strategy for preparing the report, the literature selected for review, the conclusions drawn and the recommendations made are exclusively the collective scientific output of the workshop participants and do not necessarily represent the views of the participants’ employers.

Supplementary material available online

Appendix: Examples of the putative AOPs for neurotoxicity