In the latest issue (a special edition) of AOP News:
- A ‘News Flash’ highlighting our recently launched strategic award for development of the AOP ‘L-type Ca2+ channel block leading to heart failure’ – deadline for applications via Je-S is Wendesday 26 April 2017
- Information about our session at EUROTOX 2017 on non-animal approaches for assessing cardiotoxicity
To access the previous editions of AOP News, click here.
In September 2016 Dr Helen Prior gave poster and platform presentations at the Safety Pharmacology Society Annual Meeting in Vancouver on the joint NC3Rs/EURL ECVAM project 'Application of the Adverse Outcome Pathway (AOP) approach for cardiotoxicity endpoints'. Download the poster here.
We hosted a workshop in April 2016 entitled ‘Pathways-based approaches across the biosciences: Towards application in practice’. The main aim of this workshop was encourage the transition towards application of the knowledge within established AOPs for product development and/or regulatory safety assessment, to ensure that the 3Rs benefits of utilising mechanistic approaches are maximised. The workshop report can be found here. Further information and speaker presentations can be found here.
On this page:
- An introduction to the AOP concept
- Why develop and apply AOPs for safety assessment?
- An example AOP
- Useful resources and links
In recent years, there has been increasing interest from the academic and industry sectors in using cell-based and computational approaches to investigate how pharmaceuticals and environmental chemicals interact with biological systems, to help predict whether they are harmful to humans and/or the environment. The vision for the future is that such approaches could be used to determine whether a chemical or drug of interest causes the critical (or ‘key’) events within the biochemical pathways known to result in adverse outcomes in organisms or populations. Advances in this area could enable the prediction of an adverse outcome within an organism in the absence of animal studies.
Such a scenario will be dependent on:
a) the key events of the pathways being categorically linked to each other and the adverse outcome in question;
b) the appropriate tools being available to assess the propensity for chemicals to induce the key events.
The biochemical pathways that will need to be developed and used can be described as ‘Adverse Outcome Pathways’ (AOPs), and can be visualised as:
To enable the wider application of such a mechanistic approach to product development and routine safety assessment, a framework has been established by the OECD (Organisation for Economic Co-operation and Development) to standardise the integration and organisation of the large amount of data available on different and interconnected AOPs. The framework offers a means to i) share information on a large scale; ii) better substantiate the links between pathway components and between pathways to establish networks; and iii) bring the necessary scientific disciplines together. The ultimate aim of the framework is to build sufficient confidence in the AOPs, so that adverse outcomes can be predicted through generation of the relevant mechanistic information, and practically applied in the safety assessment.
There is potential for the knowledge gained through the development of AOPs to be utilised in both early screening (i.e. for compound prioritisation) and regulatory risk assessment. The intended use for a specific AOP will determine the level of detail it captures, for example for regulatory purposes there will need to be a higher level of confidence in the linkages within the pathway and fewer data gaps than if it were used for screening purposes.
The diagram below summarises the new opportunities, as well as scientific and 3Rs benefits offered by the AOP framework. For example, the identification of data gaps within pathways could accelerate the development of in vitro and in silico techniques, and confidence may be increased in the use of non-traditional methods if they are routinely used to assess the occurrence of key events; these factors may ultimately result in a reduced reliance on the need for animal toxicity tests. For more detailed information, please refer to this recent NC3Rs publication.
The most well-developed AOP to date is entitled 'Skin Sensitisation Initiated by Covalent Binding to Proteins'. The scientific evidence for this AOP was published in 2012 by the OECD. This AOP is summarised as eleven steps, which include four key events. Several non-animal test methods have been developed to predict skin sensitisation potential by measuring the impact of known chemical sensitisers on some of these key events (reviewed in Adler et al., 2011 or Reisinger et al., 2015). Work is currently ongoing to apply the mechanistic understanding captured in the Skin Sensitisation AOP to develop new, non-animal chemical hazard and risk assessment approaches (e.g. Maxwell et al., 2014) that can weight and combine non-animal data to replace the need for new animal test data. A summary diagram of this AOP can be seen below.
Thank you to Gavin Maxwell (Unilever) for his help with this section and for supplying the figure.
Adler et al. (2011) Alternative (non-animal) methods for cosmetics testing: current status and future projects. Archives of Toxicology 85(5):367-485.
Maxwell et al. (2014) Applying the skin sensitisation adverse outcome pathway (AOP) to quantitative risk assessment. Toxicology in Vitro 28(1):8-12.
Reisinger et al. (2015) Systematic evaluation of non-animal test methods for skin sensitisation safety assessment. Toxicology in Vitro 29(1):259-270.
|NC3Rs office led programme: Applying pathways-based approaches across the biosciences|
|NC3Rs open access publication: Adverse Outcome Pathways can drive non-animal approaches for safety assessment|
|Human Toxicology Project consortium’s AOP workshop presentations: AOPs 101 and AOPs 201|
In 2012, the OECD launched a programme of work which now serves as the central framework for AOP development. As part of this programme the OECD is participating in a collaborative effort to develop a web-based platform, known as the AOP Knowledgebase (AOP-KB), where 'authors' of an AOP can enter information pertinent to the pathway of interest. The first AOP-KB module is the AOP Wiki which has been designed as an interactive and virtual repository for AOP development. All stakeholders from academia, governmental agencies and industry are invited to use the Wiki either as a source of information, or as active contributors posting comments and content. This expert contribution from third-parties is strongly encouraged to maximise the benefits of crowd sourcing. AOPs within the AOP Wiki are living documents and are intended to be revised as and when new information becomes available. Ultimately, some of the AOPs in the Wiki will be subject to expert reviews and subsequently published by the OECD. Further modules within the AOP-KB, designed to facilitate the collaborative development and utilisation of AOPs, will be made available for use in the future.
Go to the OECD’s AOP webpage
Go to the AOP Wiki