Applying pathways-based approaches across the biosciences
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 the first descriptive document on the use of AOPs, to predict skin sensitisation. The collaborative AOP-Wiki has been established as an interactive and virtual repository for AOP development. AOPs within the AOP-Wiki are living documents and are intended to be revised as and when new information becomes available. Some of the AOPs in the Wiki have undergone expert reviews and have been subsequently endorsed by the OECD.
Our programme was established to increase awareness of AOPs and encourage their use as part of a new approach to human and environmental safety assurance. It has aimed 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 set up an AOP Steering Group to support our programme of work in this area in 2014. This brought together experts from companies and academia across the pharmaceutical, chemicals, consumer products and cosmetics sectors.
The key activities achieved within the programme:
- Provision of a resource webpage and regular AOP News bulletin for scientists and regulators interested in developing and applying the AOP concept.Survey conducted to gauge awareness of mechanistic/pathways-based approaches within the UK scientific community.
- Development of AOPs in the field of cardiotoxicity, in collaboration with EURL ECVAM and an expert working group. We provided funding via a strategic grant to Dr Luigi Margiotta-Casaluci who identified multiple pathways of cardiotoxicity linked to blockade of L-type calcium channels.
- 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".
- Margiotta-Casaluci L et al. (2019) Development of an adverse outcome pathway (AOP) for cardiotoxicity mediated by the blockade of L-type calcium channels. Journal of Pharmacological and Toxicological Methods 99:106595. doi: /10.1016/j.vascn.2019.05.102
- Sewell F 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
- Burden N et al. (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
- Poster presented at the NC3Rs Toxicology Showcase, September 2016: Application of the AOP Approach for Cardiotoxicity Poster Toxicology Showcase.
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 is available for download:
In December 2018 we jointly hosted with Unilever a two day workshop in central London. The workshop brought together academic and industry researchers across multiple disciplines to share their knowledge and experiences in applying non-animal methods for decision-making in safety assessment. It was well attended with over 90 delegates and speakers from industry (including those working on agrochemicals, industrial chemicals, pharmaceuticals, and consumer products), academia and regulatory agencies from 14 countries.
The objectives of the workshop were to:
- Showcase how non-animal approaches (i.e. in vitro and in silico) are currently being used to enable and improve decision-making for chemical safety assessment, including the use of AOPs/mechanistic approaches and incorporation of exposure science.
- Increase awareness and acceptance of non-animal approaches to accelerate their uptake to support decision-making, particularly in a regulatory setting.
- Identify scientific gaps that if addressed could have a significant impact on the application and uptake of non-animal approaches.
- Encourage collaboration between sectors, to share knowledge and ‘lessons learned’ to maximise the impact of non-animal approaches and to improve safety and efficacy decision-making.
The workshop was chaired by Professor Ian Kimber OBE, Professor of Toxicology at the University of Manchester. Discussions focused on what is needed to give ‘comfort’ and confidence in these new approaches to make decisions for safety assessment.
Past editions of our AOP News bulletin are available to download below as PDFs.
- A public health/regulatory perspective: Dr Nicole Kleinstreuer, NICEATM
- AOP Spotlight: Interview with Dr Luigi Margiotta-Casaluci, Brunel University
- Ask the experts: Scientists consider what is needed to increase the value of AOPs in toxicology
- Latest publications and event highlights
- 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 Wednesday 26 April 2017
- Information about our session at EUROTOX 2017 on non-animal approaches for assessing cardiotoxicity
- NC3Rs survey - summary of preliminary results
- The NC3Rs/ECVAM cardiotoxicity AOP workstream
- An industrial chemicals company perspective on AOPs: Dr Chantal Smulders, Shell
- AOP spotlight: Protein alkylation leading to liver fibrosis
- Latest news including events
- Ask an expert – Drs João Barroso and Silvia Casati, European Commission Joint Research Centre, answer your AOP question
- A summary of the recent NC3Rs AOP workshop including a link to the workshop report and presentations
- An agrochemical industry perspective on AOPs by Dr Tina Mehta, Dow AgroSciences
- Feature articles on EU-ToxRisk and Determining the level of confidence in an AOP
- Latest news including publication highlights and events
- Ask an expert – Professor Maurice Whelan, European Commission Joint Research Centre, answers your AOP question
- Details of the NC3Rs workshop 'Pathways-based approaches across the biosciences: Towards application in practice' to be held in April 2016
- A pharmaceutical company perspective on AOPs by Maria Beaumont and James Louttit, GlaxoSmithKline
- AOP Spotlight including interviews with Dan Villeneuve, US EPA and James Wheeler, Dow AgroSciences
- Latest news, publications, opportunities and events
- AOP Resources: links and information
- An industry perspective: 3Rs opportunities - Carl Westmoreland, Unilever
- OECD AOP training: feedback from Anna Bottomley, NC3Rs
- Latest AOP news: publications, opportunities and events