Adverse Outcome Pathways: An industry perspective on the 3Rs opportunities

In 2014 the NC3Rs launched a programme of work to support the wide-scale development and application of pathways-based approaches, with the aim of improving the science of human and environmental safety assessment and ultimately reducing the reliance on animal toxicity testing.

As part of this initiative, we have launched a new resource page, and “Adverse Outcome Pathway (AOP) News”, a regular periodical for scientists across academia and industry, as well as risk assessors and regulators who are interested in the application of pathways-based approaches.

Featured here is an extract from the first issue of AOP News, in which Carl Westmoreland (pictured), from Unilever, offers an industry perceptive on the use of the AOP framework.

Click here to visit the Pathways-based Approaches resource page.

An industry perspective: chemicals

Safety assessors, such as those in industry and in regulatory agencies worldwide, have traditionally determined acceptable (i.e. ‘safe’) levels of exposure to new chemicals by combining toxicology data from experimental animals with predicted levels of exposure in humans and environmental species.  The role of animal testing in safety assessment is increasingly questioned and there are currently several activities on-going globally looking at opportunities to reduce, refine and replace animal use in this area.

Knowledge of the pathways which eventually lead to toxicity could enable safety assessments in the future to be conducted based on mechanistic understanding and ‘Twenty First Century’ science, ultimately replacing the need for toxicology tests in animals. The AOP framework enables experimental in vitro data or in silico predictions associated with key events in a toxicity pathway to be generated on a new chemical. This information can be integrated in a transparent and mechanistic way, with biological knowledge of the pathways to inform decisions on the safety of the chemical. 

The aim of the AOP approach is to provide a toolbox of predictive, robust in vitro assays, in combination with in silico predictions.  The toolbox can be used to assess the critical mechanistic steps involved in the induction of an adverse outcome rather than the toxicity effects themselves. This will reduce the reliance on whole animal testing for hazard assessment.

For AOPs to be of use in the future for conducting safety assessments without using animals, it is clear that (eco)toxicological risk assessment processes and associated regulations will need to evolve to embrace this new science. Many technical challenges still remain to be solved before this vision is realised. Central to these challenges is the need for AOPs to produce a quantitative output (i.e. dose-response information to provide a quantifiable link between the key events and the adverse outcome).  Only if risk assessors can have confidence in the dose response predictions of AOPs, can this information be used for determining acceptable levels of exposure by combining it with predicted levels of exposure to those chemicals in humans and environmental species. An important aspect of this integration is the fundamental role of mathematical modelling in simulating underlying chemical and biological processes, to provide context to the experimental data and to explicitly capture uncertainties when determining acceptable levels of exposure to new chemicals.

Carl Westmoreland, Unilever

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