Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action

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Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action

Escher, Sylvia E. (författare): Fraunhofer Institute for Toxicology and Experimental Medicine, Chemical Safety and Toxicology, Germany

Aguayo-Orozco, Alejandro (författare): Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark

Benfenati, Emilio (författare): Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy

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Bitsch, Annette (författare): Fraunhofer Institute for Toxicology and Experimental Medicine, Chemical Safety and Toxicology, Germany

Braunbeck, Thomas (författare): Aquatic Ecology and Toxicology Group, Center for Organismal Studies, University of Heidelberg, Heidelberg, Germany

Brotzmann, Katharina (författare): Aquatic Ecology and Toxicology Group, Center for Organismal Studies, University of Heidelberg, Heidelberg, Germany

Bois, Frederic (författare): Certara UK Ltd, Simcyp Division, Sheffield, United Kingdom

van der Burg, Bart (författare): BioDetection Systems, Amsterdam, the Netherlands

Castel, Jose (författare): Instituto de Investigación Sanitaria La Fe, Valencia, Spain

Exner, Thomas (författare): Edelweiss Connect GmbH, Basel, Switzerland

Gadaleta, Domenico (författare): Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy

Gardner, Iain (författare): Certara UK Ltd, Simcyp Division, Sheffield, United Kingdom

Goldmann, Daria (författare): University of Vienna, Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Vienna, Austria

Hatley, Oliver (författare): Certara UK Ltd, Simcyp Division, Sheffield, United Kingdom

Golbamaki, Nazanin (författare): Lhasa Limited, Leeds, United Kingdom

Graepel, Rabea (författare): Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

Jennings, Paul (författare): Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

Limonciel, Alice (författare): Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

Long, Anthony (författare): Lhasa Limited, Leeds, United Kingdom

Maclennan, Richard (författare): Cyprotex, Cheshire, United Kingdom

Mombelli, Enrico (författare): Instituto de Investigación Sanitaria La Fe, Valencia, Spain

Norinder, Ulf, 1956- (författare): Örebro universitet,Institutionen för naturvetenskap och teknik,MTM Research Centre

Jain, Sankalp (författare): University of Vienna, Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Vienna, Austria

Capinha, Liliana Santos (författare): Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

Taboureau, Olivier T. (författare): Université de Paris, France

Tolosa, Laia (författare): Instituto de Investigación Sanitaria La Fe, Valencia, Spain

Vrijenhoek, Nanette G. (författare): Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

van Vugt-Lussenburg, Barbara M. A. (författare): BioDetection Systems, Amsterdam, the Netherlands

Walker, Paul (författare): Cyprotex, Cheshire, United Kingdom

van de Water, Bob (författare): Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

Wehr, Matthias (författare): Fraunhofer Institute for Toxicology and Experimental Medicine, Chemical Safety and Toxicology, Germany

White, Andrew (författare): Unilever Safety and Environmental Assurance Centre, Sharnbrook, Bedfordshire, United Kingdom

Zdrazil, Barbara (författare): University of Vienna, Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Vienna, Austria

Fisher, Ciarán (författare): Certara UK Ltd, Simcyp Division, Sheffield, United Kingdom

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Elsevier, 2022
2022
Engelska.
Ingår i: Toxicology in Vitro. - : Elsevier. - 0887-2333 .- 1879-3177. ; 79

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://doi.org/10.1...; https://urn.kb.se/re...; https://doi.org/10.1...; visa färre...

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Read-across approaches often remain inconclusive as they do not provide sufficient evidence on a common mode of action across the category members. This read-across case study on thirteen, structurally similar, branched aliphatic carboxylic acids investigates the concept of using human-based new approach methods, such as in vitro and in silico models, to demonstrate biological similarity.Five out of the thirteen analogues have preclinical in vivo studies. Three out of them induced lipid accumulation or hypertrophy in preclinical studies with repeated exposure, which leads to the read-across hypothesis that the analogues can potentially induce hepatic steatosis.To confirm the selection of analogues, the expression patterns of the induced differentially expressed genes (DEGs) were analysed in a human liver model. With increasing dose, the expression pattern within the tested analogues got more similar, which serves as a first indication of a common mode of action and suggests differences in the potency of the analogues.Hepatic steatosis is a well-known adverse outcome, for which over 55 adverse outcome pathways have been identified. The resulting adverse outcome pathway (AOP) network, comprised a total 43 MIEs/KEs and enabled the design of an in vitro testing battery. From the AOP network, ten MIEs, early and late KEs were tested to systematically investigate a common mode of action among the grouped compounds.The targeted testing of AOP specific MIE/KEs shows that biological activity in the category decreases with side chain length. A similar trend was evident in measuring liver alterations in zebra fish embryos. However, activation of single MIEs or early KEs at in vivo relevant doses did not necessarily progress to the late KE “lipid accumulation”. KEs not related to the read-across hypothesis, testing for example general mitochondrial stress responses in liver cells, showed no trend or biological similarity.Testing scope is a key issue in the design of in vitro test batteries. The Dempster-Shafer decision theory predicted those analogues with in vivo reference data correctly using one human liver model or the CALUX reporter assays.The case study shows that the read-across hypothesis is the key element to designing the testing strategy. In the case of a good mechanistic understanding, an AOP facilitates the selection of reliable human in vitro models to demonstrate a common mode of action. Testing DEGs, MIEs and early KEs served to show biological similarity, whereas the late KEs become important for confirmation, as progression from MIEs to AO is not always guaranteed.

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Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action

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