Applying exposure science to increase the utility of non-animal data in efficacy and safety testing

Many of the non-animal approaches currently available can provide useful information on how drugs and chemicals exert intended or toxic effects, which can be used to inform decision-making in product development programmes. However, the utility of data from these approaches can be limited, as the extent of exposure to the chemical or drug of interest is often not taken into account within the model system, nor is the relationship between the concentrations used related to what might be encountered by humans or the environment. For example, it is not always clear how the doses tested in in vitro assays relate to concentrations that humans or environmental species would be exposed to in real life situations.  Also, it can be difficult to determine how much of the chemical applied to the model system reaches the site of biological action (i.e., measured versus nominal or applied concentrations). This can affect interpretation of the phamacological or toxicological data. Consideration of exposure is necessary to ensure that non-animal approaches generate relevant data which answers the scientific questions. The data generated from non-animal studies that consider exposure will therefore be more useful for decision-making purposes, and support a reduction in the current reliance on data from animal tests.

The potential 3Rs benefits of applying exposure science were highlighted in 2014 at an NC3Rs-hosted expert cross-sector workshop [3]. Subsequent discussions within an NC3Rs-led expert cross-sector working group took place in 2016. These resulted in the recommendation that a multi-disciplinary workshop be held to explore the barriers and potential solutions for utilising exposure-driven approaches more widely, to support the use of non-animal data in efficacy and safety testing. 

In collaboration with Unilever, we hosted a two-day workshop in central London in February 2017: 'Applying exposure science to increase the utility of non-animal data in efficacy and safety testing'.

The meeting brought together academic and industry researchers across multiple disciplines to share their knowledge and experiences in applying exposure science to increase the utility of in vitro and in silico data for decision-making, efficacy and safety assessment.  The workshop was attended by 83 expert scientists from academia, government and regulatory agencies and the (agro)chemicals, consumer products, and pharmaceutical industries.

The key objectives of the workshop were to:

• Increase awareness and build confidence in the application of exposure-driven approaches to support decision-making based on data from non-animal approaches across sectors;
• Build a community of scientists working in the area of exposure-driven safety assessment;
• Identify gaps and challenge areas that need to be addressed to advance the application of exposure science capability;
• Develop and publish guidance to facilitate the use and wider acceptance of exposure-driven non-animal approaches to inform and improve safety and efficacy decision-making.

The workshop was chaired by Professor Alan Boobis OBE, Imperial College London and showcased new exposure-based approaches which aim to increase the physiological relevance of in vitro assays and computational models, and understanding of human-relevant exposures.  For example, the use of physiologically-based pharmacokinetic (PBPK) mathematical models to predict levels of systemic exposure in humans as well as methods to quantify exposure-response relationships to improve in vitro to in vivo extrapolation.  Discussions centred on how confidence can be built in these new approaches to enable their wider use and acceptance in practice.

A workshop report and publication summarising the discussions are available [1, 2].