Comparative ecotoxicological hazard assessment of beta-blockers and their human metabolites using a mode-of-action-based test battery and a QSAR approach.
We analyzed nontarget effects of the beta-blockers propranolol, metoprolol, and atenolol with a screening test battery encompassing nonspecific, receptor-mediated, and reactive modes of toxic action. All beta-blockers were baseline toxicants and showed no specific effects on energy transduction nor endocrine activity in the yeast estrogen and androgen screen, and no reactive toxicity toward proteins and DNA. However, in a phytotoxicity assay based on the inhibition of the photosynthesis efficiency in green algae, all beta-blockers were 10 times more toxic than their modeled baseline toxicity. Baseline- and phytotoxicity effects increased with hydrophobicity. The beta-blockers showed concentration addition in mixture experiments, indicating a mutual specific nontarget effect on algae. Using literature data and quantitative structure-activity relationships (QSAR), we modeled the total toxic potential of mixtures of the beta-blockers and their associated human metabolites for the phytotoxicity endpoint with two scenarios. The realistic scenario (I) assumes that the metabolites lose their specific activity and act as baseline toxicants. In the worst-case scenario (II) the metabolites exhibitthe same specific mode of action as their parent drug. For scenario (II), metabolism hardly affected the overall toxicity of atenolol and metoprolol, whereas propranolol's hazard potential decreased significantly. In scenario (I), metabolism reduced the apparent EC50 of the mixture of parent drug and metabolite even further. 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 to environmental transformation products of pollutants.
Escher
Beate I
BI
Department of Environmental Toxicology, Department of Urban Water Management, Swiss Federal Institute of Aquatic Science and Technology (Eawag), CH-8600 Dübendorf, Switzerland. escher@eawag.ch
Bramaz
Nadine
N
Richter
Manuela
M
Lienert
Judit
J
D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000633:toxicity*; D001262:Atenolol / Q000633:toxicity; D000460:Chlorophyta / Q000187:drug effects*; D023381:Endpoint Determination; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D008790:Metoprolol / Q000633:toxicity; D010788:Photosynthesis / Q000187:drug effects*; D011433:Propranolol / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D000319:Adrenergic beta-Antagonists; D008081:Liposomes; D014874:Water Pollutants, Chemical; D001262:Atenolol; D011433:Propranolol; D008790:Metoprolol