PARENT SESSION

1F - QSAR
Poster Hall
8:30 AM - Tuesday, 29 April 2003
Chair: Schüürmann, G.¹, ¹
Co-chair: Verhaar, H.J.M.², Cronin, M.³, ^{2 3}

(TUP/57) Bacterial Biosensors for Mode of Toxic Action Classification and as Tool in Hazard Assessment.

Harder, Angela^{1, 2}, Landini, Paolo¹, Tobler, Nicole, Schwarzenbach, Rene^{1, 2, 3}, Escher, Beate¹, ¹ EAWAG Swiss Federal Institute for Environmental Science and Technology, Duebendorf, Switzerland² ETH Swiss Federal Institute of Technology, Safety and Environmental Technology Group, Zuerich, Switzerland³ ETH Swiss Federal Institute of Technology, Environmental Organic Chemistry, Zuerich, Switzerland

ABSTRACT- Predictive ecotoxicological risk assessment is based on the correct assignment of a chemical towards the relevant mode of toxic action (MOA). The group of unspecific reactive chemicals comprises a large set of structurally diverse substances that are 10 to 10000 times more toxic than their theoretical baseline toxicity. The excess toxicity of reactive chemicals is believed to be caused by alkylation of essential cellular biomolecules such as DNA and proteins. In order to distinguish between different modes of action, the reactivity of electrophilic pollutants towards different biological target sites, i.e. the tripeptide glutathione (GSH) and DNA, was evaluated using a set of E.coli biosensors that vary in susceptibility towards reactive compounds due to lack of GSH synthesis or DNA repair systems. The test set of electrophiles comprised reactive organochlorines, epoxides, and compounds with activated double bonds Some of these compounds reacted specifically with either GSH (glutathione initiated toxicity) or DNA (DNA damage) and for others both mechanisms are contributing to overall toxicity (unspecific reactivity). For chemicals with a specific reactive MOA, the reaction rate constants to either GSH or the DNA base 2′-deoxyguanosine served to set up mode of toxic action specific quantitative structure-activity relationships (QSAR). Since assignment to a MOA class is neither directly correlated to the electrophilic moiety nor to the magnitude of the reaction rate constant, these QSARs are not suitable as predictive tool in hazard assessment. However, the proposed set of biosensors proved to be sufficient to clearly classify the MOA and to provide at the same time EC50-values as descriptors for QSARs of acute toxicity towards higher organisms.

Key words: biosensor, electrophiles, mode of toxic action, classification