Prediction and experimental validation of acute toxicity of β-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 beta(1)-adrenoceptor, with three beta(1)-selective blockers (acebutolol, atenolol, and metoprolol) and three non-beta(1)-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 beta(1)-adrenoceptor, and a high octanol-water partition coefficient (log K,,). The property of P-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 beta(1)-selectivity. Two main joint effects have been detected: An independent action for the beta(1)-selective blockers, and an additive effect when either the nonselective beta(1)-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.