Prediction and experimental validation of acute toxicity of beta-blockers in Ceriodaphnia dubia.
Acute toxicity of beta-adrenoceptor blockers (beta-blockers) was studied with beta-blockers as single compounds or in mixture using the standardized acute 2-d Ceriodaphnia dubia immobility test. The tested compounds were selected according to their selectivity for the beta1-adrenoceptor, with three beta1-selective blockers (acebutolol, atenolol, and metoprolol) and three non-beta1-selective blockers (nadolol, oxprenolol, and propranolol). The acute toxicity (median effective concentration) of the six single compounds ranged from 1.4 mg/L for propranolol to 163 mg/L for nadolol. According to European Union directive 93/67EEC, these values range from toxic for aquatic organisms to nonclassified. The more toxic compounds, propranolol and oxprenolol, are both characterized by a membrane-stabilizing activity, a strong affinity for the beta1-adrenoceptor, and a high octanol-water partition coefficient (log Kow). The property of beta-receptor selectivity seems not to be involved in the observed acute toxicity of the single compounds for C. dubia. Nevertheless, the toxicity of the selected compounds in mixture can be defined according to the beta1-selectivity. Two main joint effects have been detected: An independent action for the beta1-selective blockers, and an additive effect when either the nonselective beta1-selective blockers or the six compounds are tested together. The concentration addition model seems to be appropriate, providing a reasonable worst-case estimation of beta-blocker mixture toxicity for regulatory purposes.
Fraysse
Benoit
B
Laboratoire d'ecotoxicologie, CEMAGREF, 3bis quai Chauveau, 69336 Lyon, CP 220, Cedex 09, France.
Garric
Jeanne
J
D000319:Adrenergic beta-Antagonists / Q000633:toxicity*; D000818:Animals; D033361:Cladocera; D005544:Forecasting; D007928:Lethal Dose 50; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D013329:Structure-Activity Relationship; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1; D014874:Water Pollutants, Chemical