W8 PM Ecotoxicology of Agrochemicals and Pharmaceuticals
Wednesday, 16 November 2005: 1:50 PM - 5:30 PM in 337-338

(ESC-1117-137295) Comparative ecotoxicological hazard assessment of beta-blockers and their human metabolites.

Escher, B¹, Bramaz, N¹, Richter, M¹, Lienert, J¹, ¹ EAWAG, Dübendorf, CH, Switzerland

ABSTRACT- A mode-of-action based screening test battery was used to analyze the non-target effects of the beta-blockers propranolol, metoprolol, and atenolol. The test battery consists of six tests and encompasses non-specific, receptor-mediated, and reactive modes of toxic action. It has earlier been used to assess a range of different drugs (Escher, B. I., Bramaz, N., Eggen, R. I. L., Richter, M. (2005), "In-vitro Assessment of Modes of Toxic Action of Pharmaceuticals in Aquatic Life", Environ. Sci. Technol., 39, 3090-3100). In all test systems, toxicity increased with hydrophobicity. Propranolol was more toxic than metoprolol, followed by atenolol. All beta-blockers were baseline toxicants in all test systems with the exception of the chlorophyll fluorescence test for inhibition of photosynthesis. In this test all investigated beta-blockers were about ten times more toxic than their baseline toxicity predictions. The human metabolites were included in the second part of the analysis. A model was developed using baseline QSAR and the QSAR for the chlorophyll fluorescence assay described above. The identity and fraction of human metabolites excreted in feces and urine were compiled from the literature and their ecotoxic potential predicted with these QSARs. The total toxic potential of the beta-blockers and their human metabolites were modeled under the following assumptions: (1) similar mode of action of parent drug and metabolite as worst case, and (2) baseline toxicity of the metabolites as realistic case, and consequently the concept of concentration addition to describe mixture effects. In general, human metabolism decreased the overall toxicity of beta-blockers with exception of the poorly metabolized atenolol. The proposed method is a simple approach to initial hazard assessment of pharmaceuticals and can guide higher tier testing. It can be applied to other classes of pollutants, e.g., biocides as well as environmental metabolites.

Key words: parmaceuticals, QSAR, hazard, mixtures