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Risk assessment of inhalable read-across chemicals with different mode of action showed great differences in cytotoxicity in rat and human precision-cut lung slices

: Danov, Olga

The Toxicologist 54 (2015), Nr.1, S.400, Abstract PS 1868
ISSN: 0731-9193
Society of Toxicology (Annual Meeting) <54, 2015, San Diego/Calif.>
Fraunhofer ITEM ()

Toxicity of chemicals is traditionally assessed using animal studies. For reasons of ethics, economy and legislation predictive alternatives have to be used, whenever possible. Nevertheless, the development of alternatives to animal testing has lagged behind. One alternative in risk assessment of chemicals is read-across. Here, toxicity data of a tested compound is used to predict the toxicity of a "similar" non-tested compound. As one of the main routes of exposure to chemicals is the inhalation route, our project combines the read-across approach with genomic data of in vitro and ex vivo respiratory assays. First, we selected three categories of chemicals (vicinale halogenide, aromates, and ester) and defined one lead compound and two read-across in each category. Categories were chosen based on potentially different mode of action. Secondly, repeated exposure of chemicals was performed on three days for three hours daily in rat and human precision-cut lung slices (PCLS). The cytotoxicity of chemicals was assessed in PCLS by LDH and WST-1 assay. At least one substance in each category showed cytotoxic effect in dose dependent manner. The chemicals did not show increased sensitivity upon repeated exposure. Human PCLS were less sensitive to chemicals compared to rat PCLS maybe due to differences in metabolic activity. This study shows differences of rodent and human metabolism. Although toxicity profiling is based on rodent exposure data, species diversity can be studied ex vivo for better predictively in human. Moreover, results of the project will be used to evaluate the read-across approach based on the tested chemicals.