Bottom-up physiologically-based biokinetic modelling as an alternative to animal testing_suppl

James Chan

doi:10.14573/altex.1812051s

Abstract

Bottom-up physiologically-based biokinetic modelling as an alternative to animal testing_suppl

Highlights

The replacement, refinement, and reduction of animal use in research (3R) was first established in 1959 (Russell and Burch, 1959), with growing efforts in recent times to establish alternatives to animal testing in the risk assessment of xenobiotics (Chapman et al, 2013; Paini et al, 2017)
By leveraging recent developments in transporter kinetics and quantitative proteomics that were not available at the time of development of the published models, we demonstrate the utility of mechanistic scaling factors for in vivo extrapolation (IVIVE) via bottom-up physiologically-based biokinetic (PBK) modeling
Building upon the work by Lundquist, Vildhede and colleagues, we show that the key to greater accuracy in IVIVE of transporters lies in the use of quantitative proteomics to account for differential expression of transporters in in vitro systems compared with isolated hepatocytes and liver tissue (Kimoto et al, 2012; Lundquist et al, 2014; Vildhede et al, 2015, 2018)

Summary

Introduction

The replacement, refinement, and reduction of animal use in research (3R) was first established in 1959 (Russell and Burch, 1959), with growing efforts in recent times to establish alternatives to animal testing in the risk assessment of xenobiotics (Chapman et al, 2013; Paini et al, 2017). In 2006, the REACH Regulation implemented in the EU demanded that testing on animals be done only as a last resort (EU, 2006). Under the EU Cosmetics Regulation (EU, 2009; Creton et al, 2009), a complete ban on testing of cosmetic products and ingredients in animals in the EU was imposed in 2013. The current strategies to extrapolate toxicity testing results obtained with animals to humans struggle with predictivity and, in some cases, lack physiological relevance for humans (Blaauboer and Andersen, 2007). There is a acute need, especially in the area of biokinetics, for viable alternatives to animal testing in risk assessment

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Discussion

Conclusion