| Autor: |
Zobl W; Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany., Bitsch A; Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany., Blum J; University of Konstanz, Konstanz, Germany., Boei JJWA; Leiden University Medical Center, Leiden, The Netherlands., Capinha L; Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Carta G; Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Castell J; Instituto de Investigación Sanitaria La Fe, CIBEREHD, CIBERBBN, Valencia, Spain., Davoli E; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Drake C; Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany., Fisher CP; Certara - Simcyp Division, Sheffield, United Kingdom., Heldring MM; Leiden University, Leiden Academic Centre for Drug Research, Leiden, The Netherlands., Islam B; Certara - Simcyp Division, Sheffield, United Kingdom., Jennings P; Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Leist M; University of Konstanz, Konstanz, Germany., Pellegrino-Coppola D; Leiden University, Leiden Academic Centre for Drug Research, Leiden, The Netherlands., Schimming JP; Leiden University, Leiden Academic Centre for Drug Research, Leiden, The Netherlands., Snijders KE; Leiden University, Leiden Academic Centre for Drug Research, Leiden, The Netherlands., Tolosa L; Instituto de Investigación Sanitaria La Fe, CIBEREHD, CIBERBBN, Valencia, Spain., van de Water B; Leiden University, Leiden Academic Centre for Drug Research, Leiden, The Netherlands., van Vugt-Lussenburg BMA; BioDetection Systems, Amsterdam, The Netherlands., Walker P; Cyprotex Discovery Ltd UK, Macclesfield, United Kingdom., Wehr MM; Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany., Wijaya LS, Escher SE |
| Abstrakt: |
Hazard assessment requires toxicity tests to allow deriving protective points of departure (PoDs) for risk assessment irrespective of a compound’s mode of action (MoA). The scope of in vitro test batteries (ivTB) needed to assess systemic toxicity is still unclear. We explored the protectiveness regarding systemic toxicity of an ivTB with a scope that was guided by previous findings from rodent studies, where examining six main targets, including liver and kidney, was sufficient to predict the guideline scope-based PoD with high probability. The ivTB comprises human in vitro models representing liver, kidney, lung, and the neuronal system covering transcriptome, mitochondrial dysfunction, and neuronal outgrowth. Additionally, 32 CALUXR- and 10 HepG2 BAC-GFP reporters cover a broad range of disturbance mechanisms. Eight compounds were chosen for causing adverse effects such as immunotoxicity or anemia in vivo, i.e., effects not directly covered by assays in the ivTB. PoDs derived from the ivTB and from oral repeated dose studies in rodents were extrapolated to maximum unbound plasma concentrations for comparison. The ivTB-based PoDs were one to five orders of magnitude lower than in vivo PoDs for six of eight compounds, implying that they were protective. The extent of in vitro response varied across test compounds. Especially for hematotoxic substances, the ivTB showed either no response or only cytotoxicity. Assays better capturing this type of hazard would be needed to complement the ivTB. This study highlights the potentially broad applicability of ivTBs for deriving protective PoDs of compounds with unknown MoA. |
