Quantitative AOPs

Data generated by alternative methods or in vivo testing can be integrated in quantitative Adverse Outcome Pathways (qAOPs). These can provide dose-time-response predictions which are more valuable than qualitative AOPs. METO works on adapting mechanistic or statistical models to qAOP modeling, as part of the EUToxRisk project.

We collaborate with research teams that can produce in vitro experimental data quantifying dose-response relationships for Molecular Initiating Events and Key Events (KEs).

Recently, within the EU-ToxRisk project we have investigated three approaches to qAOP building in the example of chronic kidney disease (CDK): empirical dose-response modeling, Bayesian network (BN) calibration, and systems biology (SB) modeling (Zgheib et al., 2019).

Currently, also within EU-ToxRisk, we are investigating bayesian network calibration and chemical independence with the example of mitochondrial toxicity in three cell lines.

References

• • Battistoni M, Di Renzo F, Menegola E, Bois FY. Quantitative AOP based teratogenicity prediction for mixtures of azole fungicides. Computational Toxicology. Volume 11, August 2019, Pages 72-81.

  • 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.

  • 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.

Eurotox 2017 talk