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Pre-validation of the ex vivo model precision cut lung slices (PCLuS) for the prediction of respiratory toxicology

: Hess, A.; Lauenstein, Lan; Schneider, X.; Vogel, S.; Ma-Hock, L.; Kolle, S.; Martin, C.; Pirow, R.; Steinfath, M.; Liebsch, M.; Landsiedel, R.; Braun, Armin; Sewald, Katherina

Naunyn-Schmiedebergs archives of pharmacology 386 (2013), Supplement 1, S.S34
ISSN: 0028-1298
ISSN: 1432-1912
Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (Annual Meeting) <79, 2013, Halle/Saale>
Zeitschriftenaufsatz, Konferenzbeitrag
Fraunhofer ITEM ()

Information requirement on acute inhalation toxicity study is mandatory for substances in different regulatory contexts. There is a demand for alternative methods according to the principles of the 3Rs (reduction, refinement and replacement). Precision cut lung slices (PCLuS) is an ex vivo model currently pre-validated in a BMBF-funded projects. It can be used as screening method and to aid the selection of starting concentrations for acute inhalation studies. The project is conducted in three independent laboratories (Fraunhofer ITEM, BASF SE, RWTH Aachen; BfR (Bundesinstitut für Risikobewertung) provides biostatistics support.
In all participating laboratories, PCLuS were prepared and exposed to 5 concentrations of industrial chemicals under standardized culture conditions for 1 hour. Afterwards, the medium containing test substance was replaced by fresh medium and the PCLuS was incubated for further 23 hours. Chemical-induced toxicity was assessed by LDH and WST-1 assay. In addition, protein content of the PCLuS and pro-inflammatory cytokine IL-1alpha (intra- and extracellular) 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.
The results of the first 6 test substances out of 20 are presented here: In all laboratories, concentration-related 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 aboratories. No increase in IL-1alpha was observed for these chemicals at all tested concentrations.
The standardization of the PCLuS method was successful and the reproducibility of the results is very promising after testing of the first 6 substances.
This study was supported by the German BMBF [project number 0315720 A-C]