Cigarette smoke and cigarette smoke condensate induce cell injury and early biomarkers of inflammation in human and rodent Precision-Cut Lung Slices

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. This can be done by grouping of chemicals to reduce in vivo studies. Therefore, read-across (RAX) approach is purposed to reduce animal numbers as 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 properties as well as a similar mode of action. RAX approach can be used for filling data gaps in human risk assessment. This study was designed to evaluate the use of data from ex vivo experiments such as rat or 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 FhGRepDose database (http://www.fraunhofer-repdose.de). Repeated chemical 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 public available in vivo LD50 values. Cytotoxic effect was assessed in dose dependent manner. Vicinal halogenides and naphthalene derivatives were less toxic in human lung sections compared to rat sections, whereas the vinyl esters showed the comparable cytotoxicity in both species. Linear regression analysis of public available LD50 values to the obtained ex vivo IC50 values showed good linear correlation. Thus only one substance group showed similar cytotoxicity in both tested species, whereas two other groups revealed interspecies diversity based on cytotoxicity endpoint. This first evaluation of rat and human and PCLS show that ex vivo chemical testing inhuman lung sections result in a promising approach for toxicity profiling as no human in vivo reference data exist