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.

Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: Example lists and criteria for their selection and use_suppl

“…The feasibility and utility of such tests is based on the measurement of cellular perturbations relevant to neurodevelopment in humans (Bal-Price et al, 2015b;Kadereit et al, 2012;Lein et al, 2005). The predictive power of these assays will depend on the strength of association between the test endpoints assessed and the neurodevelopmental impairment observed in exposed human populations (or representative mammalian animal models).…”

“…Vice versa, negative controls should not be identified as hits, or they would be classified as false positives. Thus, a set of control compounds would be useful to evaluate an IATA approach (Bal-Price et al, 2015b;Rovida et al, 2015), and at the same time they would be useful in guiding the establishment of a test battery and for identifying data gaps to be filled using tests of higher sensitivity for specific compounds.…”

“…Because cell-based assays that replicate these fundamental neurodevelopmental processes integrate effects across multiple molecular targets and mechanisms of action, and simple organism-based models additionally integrate effects across multiple cell types and organ systems, these alternative models can "cast a wide net" for detecting chemicals that act through diverse, and potentially unknown, MIE. Multiple such assays have been developed, e.g., using combinations of human neural cell types, or model organisms like zebrafish, and work with such methods is ongoing to clarify which of the perturbations that are observed show sufficient sensitivity and specificity to be used for predictions of human adverse effects (Bal-Price et al, 2015b, 2012Crofton et al, 2011Crofton et al, , 2012Smirnova et al, 2014;). …”

“…Quantitative descriptions of the network of cellular events that decide the eventual cell fate are the focus of the "pathways-of-toxicity" approach (Bouhifd et al, 2015;Hartung and McBride, 2011; a cascade of key events (KE) leading to an AO (Bal-Price et al, 2015b; Leist et al, 2014). For example, the binding of domoic acid to the glutamate receptor can result in a series of events that result in seizures and memory loss (Bal-Price et al, 2015b;Leist et al, 2014;Watanabe et al, 2011). In the case of chemicals that cause DNT, most AOPs lack sufficient quantitative features (i.e., quantifiable key event relationships (KER), such as activation thresholds and quantitative time-concentration-effect relationships) to allow specific associations between the MIE and toxicity manifested at higher levels of biological organization.…”

Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling

“…Such approaches might allow the detection of key events of AOPs, definition of biomarkers (Kuegler et al, 2010) or delineation of an entire MoA/AOP (Bal Price et al, 2015b). On this basis relevant assays could be combined into to a more efficient test battery (Piersma, 2014;Piersma et al, 2013;Zimmer et al, 2014).…”