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Review
. 2015 Jan;45(1):83-91.
doi: 10.3109/10408444.2014.981331.

Putative adverse outcome pathways relevant to neurotoxicity

Anna Bal-Price  1 , Kevin M Crofton, Magdalini Sachana, Timothy J Shafer, Mamta Behl, Anna Forsby, Alan Hargreaves, Brigitte Landesmann, Pamela J Lein, Jochem Louisse, Florianne Monnet-Tschudi, Alicia Paini, Alexandra Rolaki, André Schrattenholz, Cristina Suñol, Christoph van Thriel, Maurice Whelan, Ellen Fritsche
Affiliations
Review

Putative adverse outcome pathways relevant to neurotoxicity

Anna Bal-Price et al. Crit Rev Toxicol. 2015 Jan.

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.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Relationships between the uncertainty in AOP models, the data and resources needed to develop the models and the regulatory domains of applicability.
See this image and copyright information in PMC

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