title: Environmental risk assessment of human pharmaceuticals in the European Union: A case study with the β-blocker atenolol.
abstract: β-Adrenergic receptor blockers (β-blockers) are applied to treat high blood pressure, ischemic heart disease, and heart rhythm disturbances. Due to their widespread use and limited human metabolism, β-blockers are widely detected in sewage effluents and surface waters. β-Adrenergic receptors have been characterized in fish and other aquatic animals, so it can be expected that physiological processes regulated by these receptors in wild animals may be affected by the presence of β-blockers. Because ecotoxicological data on β-blockers are scarce, it was decided to choose the β-blocker atenolol as a case study pharmaceutical within the project ERAPharm. A starting point for the assessment of potential environmental risks was the European guideline on the environmental risk assessment of medicinal products for human use. In Phase I of the risk assessment, the initial predicted environmental concentration (PEC) of atenolol in surface water (500 ng L−1) exceeded the action limit of 10 ng L−1. Thus, a Phase II risk assessment was conducted showing acceptable risks for surface water, for groundwater, and for aquatic microorganisms. Furthermore, atenolol showed a low potential for bioaccumulation as indicated by its low lipophilicity (log KOW = 0.16), a low potential for exposure of the terrestrial compartment via sludge (log KOC = 2.17), and a low affinity for sorption to the sediment. Thus, the risk assessment according to Phase II-Tier A did not reveal any unacceptable risk for atenolol. Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm. A 2-generation reproduction test with the waterflea Daphnia magna resulted in the most sensitive no-observed-effect concentration (NOEC) of 1.8 mg L−1. However, even with this NOEC, a risk quotient of 0.003 was calculated, which is still well below the risk threshold limit of 1. Additional studies confirm the outcome of the environmental risk assessment according to EMEA/CHMP (2006). However, atenolol should not be considered as representative for other β-blockers, such as metoprolol, oxprenolol, and propranolol, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies.
authors.affiliation: German Federal Environment Agency (UBA), Wörlitzer Platz 1, 06813 Dessau, Germany. anette.kuester@uba.de
authors.forename: Anette
authors.initials: A
authors.lastname: Küster
authors.forename: Alfredo C
authors.initials: AC
authors.lastname: Alder
authors.forename: Beate I
authors.initials: BI
authors.lastname: Escher
authors.forename: Karen
authors.initials: K
authors.lastname: Duis
authors.forename: Kathrin
authors.initials: K
authors.lastname: Fenner
authors.forename: Jeanne
authors.initials: J
authors.lastname: Garric
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hutchinson
authors.forename: David R
authors.initials: DR
authors.lastname: Lapen
authors.forename: Alexandre
authors.initials: A
authors.lastname: Péry
authors.forename: Jörg
authors.initials: J
authors.lastname: Römbke
authors.forename: Jason
authors.initials: J
authors.lastname: Snape
authors.forename: Thomas
authors.initials: T
authors.lastname: Ternes
authors.forename: Ed
authors.initials: E
authors.lastname: Topp
authors.forename: Anne
authors.initials: A
authors.lastname: Wehrhan
authors.forename: Thomas
authors.initials: T
authors.lastname: Knacker
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000032:analysis* / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001262:Atenolol / Q000032:analysis* / Q000737:chemistry / Q000633:toxicity*; D055598:Chemical Phenomena; D054750:Ecotoxicology; D004784:Environmental Monitoring; D004785:Environmental Pollutants / Q000032:analysis* / Q000633:toxicity; D005062:European Union; D017408:Guidelines as Topic; D006801:Humans; D008962:Models, Theoretical; D018570:Risk Assessment / Q000379:methods*; D014867:Water / Q000737:chemistry
chemical_list: D000319:Adrenergic beta-Antagonists; D004785:Environmental Pollutants; D014867:Water; D001262:Atenolol