Prediction and experimental validation of acute toxicity of β‐blockers in Ceriodaphnia dubia

Abstract

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.

Occurrence, ecotoxicological effects and risk assessment of antihypertensive pharmaceutical residues in the aquatic environment - A review

“…To our knowledge, only a few acute effects data are described in published papers for some antihypertensives such as acebutolol, betaxolol, oxprenolol, practolol and enalapril. For acebutolol and oxprenolol, results were available only for acute 48 h Ceriodaphnia dubia immobility tests, with EC 50 of 50.9 and 10.1 mg L À1 respectively (Fraysse and Garric, 2005). The authors classified oxprenolol as between toxic and harmful and acebutolol as harmful for aquatic organisms, according to European Union Directive 93/67/EEC (European Commission, 2003).…”

Beta-blockers in the environment: Part I. Mobility and hydrolysis study

“…In the case of the ionic strength sorption Kibbey et al (2007). b Fraysse and Garric (2005). c Huggett et al (2002).…”

Transcriptional Responses in Adult Zebrafish (Danio rerio) Exposed to Propranolol and Metoprolol

“…However, the difference in transcriptional patterns of b-AR genes between the two b-blockers may be due to receptor selectivity. Propranolol binds to any b-AR, while metoprolol has a higher affinity for the b1-AR (Fraysse and Garric 2005;Huggett et al 2003).…”

“…Since the discovery of propranolol in the 1960s, many b-blockers have emerged and more than 30 types are used clinically (Massarsky et al 2011;Owen et al 2007). Within the most commonly used b-blockers, propranolol and nadolol are non-specific antagonists that block both b1-and b2-receptors, while metoprolol and atenolol exhibit b1-receptors specificity (Fraysse and Garric 2005;Huggett et al 2003). Due to the high incidence of cardiovascular disease, the global market value of b-blockers rises substantially each year, and over the last decade the number of prescriptions written has doubled (Massarsky et al 2011).…”