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

Monika Gajewska 1 Alexandre Pery 2 Céline Brochot 2 Florence Anna Zeman 2 Juan G. Diaz 3 Joachim Bucher 3 Klaus Mauch 3 José-Manuel Zaldivar 1
1 Institute for Health and Consumer Protection
2 INERIS - Institut National de l'Environnement Industriel et des Risques
3 Insilico Biotechnology AG
Abstract : 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
Keywords : TOXICOLOGIE METHODES ALTERNATIVES IN VITRO PBPK
Document type :
Conference papers
Complete list of metadatas
https://hal-ineris.archives-ouvertes.fr/ineris-00970934
Contributor : Gestionnaire Civs <>
Submitted on : Wednesday, April 2, 2014 - 3:58:38 PM
Last modification on : Wednesday, April 2, 2014 - 3:58:38 PM

Identifiers

  • HAL Id : ineris-00970934, version 1
  • INERIS : EN-2012-007

Collections

INERIS

Citation

Monika Gajewska, Alexandre Pery, Céline Brochot, Florence Anna Zeman, Juan G. Diaz, et al.. Multi-scale modelling in toxicology : how to bridge the gaps between scales ?. 2. Annual meeting - SEURAT-1 "Towards the replacement of in vivo repeated dose systemic toxicity testing", Feb 2012, Lisbonne, Portugal. ⟨ineris-00970934⟩

Export

BibTeX TEI DC DCterms EndNote

Share

Metrics

Record views

180

Contact

support.ccsd.cnrs.fr
hal.support@ccsd.cnrs.fr
Logo CCSD