March 2, 2017 by Louise Youngs
Non-animal approaches can provide useful information on the mechanism of action, informing substance evaluation and product development. However, the regulatory applicability of these approaches is typically limited, as the relevance of in vitro concentrations to in vivo exposure, is often not considered. Held at the Royal College of Obstetrics and Gynaecology (London, UK), the NC3Rs and Unilever held a workshop on ‘Applying exposure science to increase the safety of non-animal data in efficacy and safety testing’ in February 2017.
Collating a community of scientists working in the area of exposure-driven safety and efficacy assessment, the workshop aimed to increase awareness and confidence in the application of exposure-driven approaches to the 3Rs (Replacement, Reduction, Refinement). Following an introduction from Professor Alan Boobis (Imperial College London, UK) and Dr Natalie Burden (NC3Rs, UK), Dr Bette Meek (University of Ottawa, Canada) introduced the concept of Adverse Outcome Pathways (AOPs), which address chemically agnostic biological pathways within target tissues. The need for AOPs to consider chemical space, metabolism and toxicokinetics, was highlighted, suggesting that an ‘aggregate exposure pathway’ is required for regulatory applicability.
In an engaging and provocative presentation, Dr Justin Teeguarden (Pacific North West National Library, US) discussed the importance and of exposure science in toxicity testing. Reporting upon a series of National Academy of Sciences reports (2007-2017), the need to move away from the ‘axis of ignorance’, to enable the integration of toxicology and exposure data was highlighted. Teeguarden suggested that the current emphasis on detecting potential hazard, rather than the exposure and potential risk was nonsensical, as in vitro tests are inaccurate if nominal media concentrations are not proportional to cell concentrations in vivo.
Further complicating our understanding of the relevance of in vitro concentrations, Professor Steve Charlton (University of Nottingham, UK) introduced the topic of ‘micro pharmacokinetics’ and drug re-binding, using a novel approach using time resolved fluorescence resonance energy transfer (FRET) capable of simultaneously measuring the kinetics of hundreds of compounds. Dr Iain Gardner (Certara, UK) also outlined the use of population-based physiologically based PK/PD simulators.
Professor Gareth Jenkins (Swansea University, UK) outlined the development of chronic and passive dosing systems for in vitro for genotoxicity assessment, suggesting that more sophisticated in vitro exposure scenarios may refine in vitro to in vivo extrapolation (IVIVE). In a passionate follow-up, Dr Steve Webb (Liverpool John Moores University, UK) discussed the applicability of mathematics in IVIVE and predicting systemic toxicity. To close the day, breakout sessions explored the current status of exposure science and barriers to uptake.
Overall, the presentation highlighted the need for the development of quantifiable networks of AOPs, with an increased understanding of the biological mechanisms, which are often ill-defined. Quantification of Key Event Relationships (KER) was identified as a basis for developing predictive ‘response-response’ models, which may ultimately result in adversity. Transparency and consistency were identified as essential, in order to overcome the challenges and barriers to regulatory acceptance of exposure-driven approaches.
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