Species comparison of rat and human precision-cut lung slices as an alternative in risk assessment based on read-across approach

Question: Human risk assessment of chemicals is currently based on the evaluation of in vivo animal studies. The use of high animal numbers and the suffering of animals in experiments such as repeated dose toxicity studies (RDT) demand for alternative test approaches. One alternative approach currently used in human risk assessment is read-across (RAX). In a RAX approach toxicity data of one or several tested source compound(s) are used to predict the toxicity of ""similar"" non-tested target compound(s). Similar compounds shall share structural- and physico-chemical proper-ties as well as a similar mode of action. This study was designed to evaluate the use of data from ex vivo experiments such as rator human precision-cut lung slices (PCLS). Three RAX-categories were tested, namely vicinal halogenides, naphthalene derivatives and vinyl esters. Each RAX category was selected based on shared structural properties and similar toxicological effects in RDT studies extracted from the FhG RepDose database (www.fraunhofer-repdose.de). Methods: Exposure of rat and human PCLS was performed on three days for three hours daily. The cytotoxicity of chemicals was assessed by LDH and WST-1 assay. Ex vivo IC50 values were calculated by sigmoidal curve fitting. These values were correlated to the LD50 values. Results: At least one substance in each category showed cyto-toxic effects in dose dependent manner. Linear regression analysis of public available in vivo LD50 values to the obtained ex vivo IC50values showed good linear correlation. Vicinal halogenides and naphthalene derivatives were less toxic in human lung sections compared to rat sections, where as the vinyl esters showed the comparable cytotoxicity in both species. Thus only one substance group showed similar cytotoxicity in both tested species, whereas two other groups reveal interspecies and metabolism diversity based on cytotoxicity endpoint. Conclusion: This first evaluation of rat and human and PCLs show that ex vivo chemical testing in human lung sections result in a promising approach for toxicity screening as no human in vivo reference data exist.