A quantitative AOP of mitochondrial toxicity based on data from three cell lines
Toxicology in Vitro, vol. 81, pp. 105345
Abstract
Adverse Outcome Pathways (AOPs) are increasingly used to support the integration of in vitro data in hazard assessment for chemicals. Quantitative AOPs (qAOPs) use mathematical models to describe the relationship between key events (KEs). In this paper, data obtained in three cell lines, LHUMES, HepG2 and RPTEC/TERT1, using similar experimental protocols, was used to calibrate a qAOP of mitochondrial toxicity for two chemicals, rotenone and deguelin. The objectives were to determine whether the same qAOP could be used for the three cell types, and to test chemical-independence by cross-validation with a dataset obtained on eight other chemicals in LHUMES cells. Repeating the calibration approach for both chemicals in three cell lines highlighted various practical difficulties. Even when the same readouts of KEs are measured, the mathematical functions used to describe the key event relationships may not be the same. Cross-validation in LHUMES cells was attempted by estimating chemical-specific potency at the molecular initiating events and using the rest of the calibrated qAOP to predict downstream KEs: toxicity of azoxystrobin, carboxine, mepronil and thifluzamide was underestimated. Selection of most relevant readouts and accurate characterization of the molecular initiating event for cross-validation are critical when designing in vitro experiments targeted at calibrating qAOPs.
Authors 9
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Cléo Tebby corresponding
Institut national de l'environnement industriel et des risques
Affiliation as printed
Experimental Toxicology and Modeling (TEAM) Unit, Ineris, rue Jacques Taffanel, 60550 Verneuil-en-Halatte, France. Electronic address: cleo.tebby@ineris.fr
Experimental Toxicology and Modeling (TEAM) Unit, Ineris, rue Jacques Taffanel, 60550 Verneuil-en-Halatte, France
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Université de Technologie de Compiègne · Institut national de l'environnement industriel et des risques · Laboratoire de mathématiques appliquées de Compiègne
Affiliation as printed
Experimental Toxicology and Modeling (TEAM) Unit, Ineris, rue Jacques Taffanel, 60550 Verneuil-en-Halatte, France; Applied Mathematics Laboratory (LMAC EA 2222), Université Technologique de Compiègne (UTC), 57 avenue de Landshut, 60203 Compiègne Cedex, France
Applied Mathematics Laboratory (LMAC EA 2222), Université Technologique de Compiègne (UTC), 57 avenue de Landshut, 60203 Compiègne Cedex, France
Experimental Toxicology and Modeling (TEAM) Unit, Ineris, rue Jacques Taffanel, 60550 Verneuil-en-Halatte, France
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Affiliation as printed
In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Universitaetsstr. 10, 78464, Konstanz, Germany; Cooperative Doctorate College InViTe, University of Konstanz, Konstanz, Germany
Cooperative Doctorate College InViTe, University of Konstanz, Konstanz, Germany
In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Universitaetsstr. 10, 78464, Konstanz, Germany
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Affiliation as printed
Division of Molecular and Computational Toxicology, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Wanda van der Stel Aachen Division of Drug Discovery and Safety Leiden Academic Centre of Drug Research
Affiliation as printed
Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, the Netherlands
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Affiliation as printed
In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Universitaetsstr. 10, 78464, Konstanz, Germany
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Affiliation as printed
Division of Molecular and Computational Toxicology, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Bob van de Water Aachen Division of Drug Discovery and Safety Leiden Academic Centre of Drug Research
Affiliation as printed
Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, the Netherlands
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Institut national de l'environnement industriel et des risques · Simcyp (United Kingdom)
Affiliation as printed
Experimental Toxicology and Modeling (TEAM) Unit, Ineris, rue Jacques Taffanel, 60550 Verneuil-en-Halatte, France; Certara, Simcyp, Sheffield, United Kingdom
Certara, Simcyp, Sheffield, United Kingdom
Experimental Toxicology and Modeling (TEAM) Unit, Ineris, rue Jacques Taffanel, 60550 Verneuil-en-Halatte, France
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