Putative adverse outcome pathways relevant to neurotoxicity

The limitations of current in vivo testing coupled with the paucity of data for thousands of chemicals in the human chemosphere has significantly stymied hazard identification and risk assessment needed to protect the developing and mature human nervous system. To address this problem, new biochemical and cellular assay systems as well as computational predictive methods are being developed to more efficiently generate, interpret and use new and existing data for improved chemical safety evaluation. 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). It has been developed to be used in human health risk assessment as it provides a tool for a knowledge-based safety assessment that relies on understanding toxicity, rather than simply observing its effects. The AOP approach describes a sequence of measurable key events (KEs) that link chemical exposure to an AO at the organism or population level. 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 functional changes in biological processes, that ultimate result in an AO manifest in individual organisms and populations. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central and peripheral nervous systems (CNS and PNS, respectively). 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. This lack of AOPs, and in particular the lack of MIEs, has made it difficult to evaluate the predictive ability of high-throughput chemical testing for neurotoxicity, which in turn has hampered discussion of how to use in vitro testing data for regulatory use. 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 complete, they serve as a basis for further research and identification of MIEs and KEs that could help prioritise alternative assay development needed to advance human health protection.

PRICE Anna;  CROFTON Kevin;  SACHANA Magdalini;  SHAFER Timothy;  BEHL Mamta;  FORSBY Anna;  HARGREAVES Alan;  LANDESMANN Brigitte;  LEIN Pamela J.;  LOUISSE Jochem;  MONNET-TSCHUDI Florianne;  PAINI Alicia;  ROLAKI Alexandra;  SCHRATTENHOLZ André;  SUÑOL Cristina;  VAN THRIEL Christoph;  WHELAN Maurice;  FRITSCHE Ellen; 

2015-03-30

INFORMA HEALTHCARE

JRC87463

1040-8444,   

http://informahealthcare.com/doi/abs/10.3109/10408444.2014.981331,    https://publications.jrc.ec.europa.eu/repository/handle/JRC87463,   

10.3109/10408444.2014.981331,