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Prevalidation of the ex vivo model precision cut lung slices (PCLS) for the prediction of respiratory toxicology

: Sewald, Katherina; Lauenstein, Lan; Vogel, S.; Hess, A.; Schneider, X.; Martin, C.; Pirow, R.; Liebsch, M.; Landsiedel, R.; Braun, Armin

The Toxicologist 52 (2013), Nr.1, S.315, Abstract PS 1469
ISSN: 0731-9193
Society of Toxicology (Annual Meeting) <52, 2013, San Antonio/Tex.>
Zeitschriftenaufsatz, Konferenzbeitrag
Fraunhofer ITEM ()

Introduction: For acute inhalation toxicity studies, animals inhale chemicals. At the beginning it is difficult to estimate non-toxic doses for in vivo inhalation. In the context of REACH and the principle of 3Rs, there is a public demand for alternative methods. The goal of this BMBF-funded project is the pre-validation of PCLS as a suitable ex vivo alternative model to replace pre-studies of inhalation toxicology. The project is conducted in three independent laboratories. BfR provides support in biostatistics.
Methods: In all participating laboratories, PCLS were prepared and exposed to 5 concentrations of industrial chemicals in DMEM under standard culture conditions for 1 hour. After post-incubation, chemical-induced toxicity was assessed by LDH and WST-1 assay. In addition, PCLS protein content and pro-inflammatory cytokine IL-1alpha were measured by BCA assay and ELISA, respectively. For all endpoints a sigmoid dose-response model was fitted to the data and EC50 values were calculated. Test acceptance criteria were established for each endpoint.
Results: This study shows the results of the first 6 tested substances out of 20. In all laboratories, concentration dependent toxicity could be shown for aniline, glutaraldehyde, triton X-100 and paracetamol, but not for lactose and methyl methacrylate. EC50-values obtained for the WST-1, LDH and BCA data were very similar in all participating laboratories. No increase in IL-1alpha was observed for these chemicals.
Conclusion: Local respiratory toxicity induced by chemicals could be tested with comparable results in the PCLS model without in vivo experiments in three independent laboratories. The standardization of the PCLS method was successful and the reproducibility of the results is very promising after testing of the first 6 substances.