Multi-scale modelling in toxicology : how to bridge the gaps between scales ?

The physiological functions of an organism coexist across several temporal and spatial orders of magnitude. Therefore, the toxic effects of a substance should be examined in all those scales. Understanding and integrating the information and dynamical behaviour in all these spatio-temporal scales is essential for developing a more coherent approach in toxicology. Multi-scale modelling has been developed as a computational approach to deal with this scale diversity and several techniques have been developed and applied with success to other fields. The main objective of this work is to study the feasibility of the application of these methodologies in toxicology to overcome the problems associated with the gaps between scales. This will allow to explore the continuum toxic effects and to establish an interface between different levels in terms of data and results transferability. We have developed a first case study with acetaminophen, in single and multiple dose situations (data from DETECTIVE), and with two species of interest, rats and humans. We have developed cell toxicokinetic/ toxicodynamic (TK/TD) models, TK/TD organ models and organism PBPK models. The coupling between the models allows performing in vitro in vivo extrapolation (IVIVE) producing estimated effects close to actual values. Furthermore, the differences relative to kinetics (metabolism in particular) explained a large part of interspecies differences. Additionally, with an in silico model of liver we couple the internal metabolism of the hepatocytes (NOTOX) with a simple 3D model of the liver and predict toxic effects distributed in space and time inside the organ