The Adverse Outcome Pathway concept is a mechanistically-based approach that has the potential to transform human and environmental safety assessment and reduce the reliance on animal models in this area. This concept links molecular initiating event(s) (MIE), caused by a chemical or drug interaction at a cellular level, with undesired (‘adverse’) effects in an organism or population, through a scientifically proven causal chain of key events. In vitro and in silico methods could be used in place of animal toxicity tests to determine whether a chemical or drug induces the key events within the biochemical pathway of interest, also known as an Adverse Outcome Pathway (AOP). Identification of hazardous compounds earlier in drug or product development will reduce the number of compounds that go on to further compulsory tests in animals. The Organisation for Economic Co-operation and Development (OECD), the global authority which supports government and industry efforts to manage risks posed by chemicals, has a programme dedicated to the development of AOPs, and published a descriptive document on the use of AOPs to predict skin sensitisation.
Our programme of work represents an opportunity to increase awareness of AOPs and encourage their use as part of a new approach to human and environmental safety assurance. Its aims are to:
- Increase the understanding of AOPs amongst the bioscience community, particularly in the UK;
- Engage a wide range of researchers, particularly those that may not be aware of AOPs or that their research may be relevant to AOPs;
- Bring together academic and industry researchers from different disciplines and regulators and encourage cross-sector collaboration;
- Translate knowledge of relevant disease and biological pathways and mechanisms of action to be part of this new approach to safety assessment;
- Equip a wide range of sectors and communities with unifying language, goals and applications.
We have set up an AOP Steering Group to support our programme of work in this area. This group brings together experts from companies and academia across the pharmaceutical, chemicals, consumer products and cosmetics sectors. The first group meeting was held in February 2014, and the group continues to inform the direction and scope of our AOP activities.
The key activities within the programme are:
- Launch of a resource webpage and regular AOP News bulletin for scientists and regulators interested in developing and applying the AOP concept.
- Survey to be carried out in to gauge awareness of mechanistic/pathways-based approaches within the UK scientific community.
- Development of an AOP in the field of cardiotoxicity, in collaboration EURL ECVAM and an expert working group.
- Two day workshop held in May 2014: 'Applying pathways-based approaches across the biosciences' and a follow up workshop in April 2016: 'Pathways-based approaches across the biosciences: Towards application in practice'.
- NC3Rs publications with experts in the field in Journal of Applied Toxicology : “Adverse Outcome Pathways can drive non-animal approaches for safety assessment” and Archives of Toxicology: "The future trajectory of adverse outcome pathways: a commentary".
Sewell F, Gellatly N, Beaumont M et al. (2018). The future trajectory of adverse outcome pathways: a commentary. Archives of Toxicology, 92(4):1657-1661. doi: 10.1007/s00204-018-2183-2
Poster presented at the NC3Rs Toxicology Showcase, September 2016: Application of the Adverse Outcome Pathway (AOP) approach for cardiotoxicity endpoints
Burden N, Sewell F, Andersen ME, Boobis A, Chipman JK, Cronin MT, Hutchinson TH, Kimber I, Whelan M (2015). Adverse Outcome Pathways can drive non-animal approaches for safety assessment. Journal of Applied Toxicology 35(9):971-975 doi: 10.1002/jat.3165
The NC3Rs hosted a one-day workshop in Central London on 28 April 2016 entitled 'Pathways-based approaches across the biosciences: Towards application in practice'. This brought together multi-disciplinary academic and industry researchers to share their knowledge and experiences in applying pathways-based approaches in practice. Widespread application of such approaches promises to improve safety assessment processes and reduce reliance on animal models.
The workshop was attended by expert scientists from academia, government and regulatory agencies and the chemicals, consumer products, and pharmaceutical industries.
The key objectives of the workshop were to:
- increase awareness among the scientific community of developments in the field;
- expand and consolidate the multidisciplinary community needed to accelerate the development and application of pathways-based approaches;
- 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 was chaired by Professor Ian Kimber OBE, Professor of Toxicology at the University of Manchester and covered 1) Case studies: practical applications of pathways-based approaches; 2) AOPs: perspectives for future development and application; 3) Next steps to enable wider application of pathways-based approaches; and 4) An interactive roundtable discussion entitled ‘The big conundrum – what constitutes validation?’.
The workshop report, including the agenda can be found here.
Presentations from the day can be accessed below.
- Dr Elisabet Berggren, European Commission Joint Research Centre, Italy
- Professor Alan Boobis OBE, Imperial College London, UK
- Dr Kevin Crofton, National Center for Computational Toxicology, EPA, USA
- Dr John Paul Gosling, University of Leeds, UK
- Dr Hennicke Kamp, BASF, Germany
- Dr Magdalini Sachana, OECD, France
- Dr James Sidaway, Phenotox, UK
- Dr Fiona Sewell, NC3Rs
- Dr Chantal Smulders, Shell, Netherlands and Dr Marjolein Wildwater, Universiteit Utrecht, Netherlands
- Dr Carl Westmoreland, Unilever, UK
- Dr James Wheeler, Dow AgroSciences, UK
- Professor Maurice Whelan, European Commission Joint Research Centre, Italy