ExITox – Explain Inhalation Toxicity

Development of an integrated testing strategy for the prediction of toxicity after repeated-dose inhalation exposure: a proof of concept.

A collaborative project funded by the German Federal Ministry of Education and Research (BMBF) in the funding program "e:ToP – Innovative Toxikologie zur Reduzierung von Tierversuchen"

Coordinator: The project is being coordinated by Dr. Sylvia Escher, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM. The 6 participants of the consortium are from Hannover, Freiburg, Göttingen, and Wolfenbüttel.

Contract period: November 1st, 2013 - October 31st, 2015

Grant no.: 031 A269 D

Summary: This project aims at developing an integrated testing strategy (ITS) for human health risk assessment of repeated-dose toxicity after inhalation exposure for the replacement of de-novo animal testing. In the pilot phase, chemicals with different modes of action will be selected and tested with human precision-cut lung slices (PCLS) and human pulmonary cell cultures in order to identify route-specific biomarkers. Genome-wide transcriptome analyses will be conducted in these models and evaluated using bioinformatics methods. These results will be complemented with data mining results and QSAR predictions. Furthermore, structurally related chemicals will be tested in addition to investigate the possibility of the test system to support read across. The outcome of this pilot project will be a proposal for an integrated testing strategy for respiratory toxicity. Further validation, e.g. testing of a broader spectrum of chemicals, is foreseen in a follow-up project. The proposed ITS, the developed methodologies on data sharing and data integration are not limited to the evaluation of transcriptome data, but allow proteome and metabolome data to be integrated in a follow-up project.

The Fraunhofer ITEM will contribute in-vivo data from the RepDose database and try to identify relevant target and source compounds for the read-across activity. Genome-wide transcriptome analyses and further mechanistic as well as functional data will be evaluated by using an ex-vivo model, human precision-cut lung slices, and relevant human pulmonary cell lines as an in-vitro model.

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