EU-ToxRisk

The project

The vision of EU-ToxRisk is to drive the required paradigm shift in toxicological testing away from ‘black box’ animal testing towards a toxicological assessment based on a comprehensive mechanistic understanding. EU-ToxRisk will integrate advancements in cell biology, omics technologies, systems biology and computational modelling to define the complex chains of events that link chemical exposure to toxic outcome.

In the framework of this project the TEAM unit:

• • Develops quantitative models describing Adverse Outcome Pathways and QSAR models for the prediction of initiating events that trigger these pathways.

  • Explores and evaluates the possibilities offered by the concept of “biological read-across”

Contributions

TEAM has contributed to the following tasks:

• qAOPs of renal toxicity,

• qAOPs mitochondrial toxicity in neural (LHUMES), hepatic (HepG2 and renal (RPTEC) cells,

• qAOPs of hepatic steatosis,

• toxicokinetic modelling in zebrafish embryo,

• QSAR modelling of qAOP related endpoints.

Publications

Ségolène Siméon, Rémy Beaudouin, Katharina Brotzmann, Thomas Braunbeck, Frédéric Y. Bois. Multistate models of developmental toxicity: Application to valproic acid-induced malformations in the zebrafish embryo. Toxicology and Applied Pharmacology, Volume 414, 2021, 115424, https://doi.org/10.1016/j.taap.2021.115424.

Siméon S, Brotzmann K, Fisher C, Gardner I, Silvester S, Maclennan R, Walker P, Braunbeck T, Bois FY. Development of a generic zebrafish embryo PBPK model and application to the developmental toxicity assessment of valproic acid analogs. Reproductive Toxicology 93 (2020) 219–229

Fisher C, Siméon S, Jamei M, Gardner I, Bois FY. VIVD: virtual in vitro distribution model for the mechanistic prediction of intracellular concentrations of chemicals in in vitro toxicity assays. Toxicology in Vitro. Volume 58, August 2019, Pages 42-50

Zgheib E, Gao W, Limonciel A, Aladjov H, Yang H, Tebby C, Gayraud G, Jennings P, Sachana M, Beltman JB, Bois FY. Application of three approaches for quantitative AOP development to renal toxicity. Computational Toxicology, Volume 11, August 2019, Pages 1-13.

Gadaleta D, Manganelli S, Roncaglioni A, Toma C, Benfenati E, Mombelli E. QSAR modeling of ToxCast assays Relevant to the Molecular Initiating Events of AOPs Leading to Hepatic Steatosis. J Chem Inf Model. 2018, 58 (8), pp 1501–1517

Elias Zgheib, Alice Limonciel, Xiaoqi Jiang, Anja Wilmes, Steven Wink, Bob van de Water, Annette Kopp-Schneider, Frederic Y Bois, Paul Jennings. Identification of Nrf2, AhR and ATF4 pathway cross-talks from toxicogenomic data. Frontiers in Genetics, section Toxicogenomics. doi.org/10.3389/fgene.2018.00429

Alejandro Aguayo Orozco, Frederic Y Bois, Søren Brunak, Olivier Taboureau. Analysis of Time-series Gene Expression Data to Explore Mechanisms of Chemical-Induced Hepatic Steatosis Toxicity. Frontiers in Genetics, section Toxicogenomics. doi.org/10.3389/fgene.2018.00396.

Marcel Leist, Ahmed Ghallab, Rabea Graepel, Rosemarie Marchan, Reham Hassan, Susanne Hougaard Bennekou, Alice Limonciel, Mathieu Vinken, Stefan Schildknecht, Tanja Waldmann, Erik Danen, Ben van Ravenzwaay, Hennicke Kamp, Iain Gardner, Patricio Godoy, Frederic Y. Bois, Albert Braeuning, Raymond Reif, Franz Oesch, Dirk Drasdo, Stefan Höhme, Michael Schwarz, Thomas Hartung, Thomas Braunbeck, Joost Beltman, Harry Vrieling, Ferran Sanz, Anna Forsby, Domenico Gadaleta, Ciarán Fisher, Jens Kelm, David Fluri, Gerhard Ecker, Barbara Zdrazil, Andrea Terron, Paul Jennings, Bart van der Burg, Steven Dooley, Annemarie H. Meijer, Egon Willighagen, Marvin Martens, Chris Evelo, Enrico Mombelli, Olivier Taboureau, Alberto Mantovani, Barry Hardy, Bjorn Koch, Sylvia Escher, Christoph van Thriel, Cristina Cadenas, D. Kroese, Bob van de Water, Jan G. Hengstler. 2017. Adverse outcome pathways: opportunities, limitations and open questions. Archives of Toxicology, Volume 91, Issue 11, pp 3477–3505.