title: Defining the chronic impacts of atenolol on embryo-larval development and reproduction in the fathead minnow (Pimephales promelas).
abstract: Atenolol is a beta-adrenergic receptor antagonist ('beta-blocker') widely used for the treatment of angina, glaucoma, high blood pressure and other related conditions. Since atenolol is not appreciably metabolized in humans, the parent compound is the predominant excretory product, and has been detected in sewage effluent discharges and surface waters. Consequently, atenolol has been chosen as a reference pharmaceutical for a European Union-funded research consortium, known as ERAPharm (http://www.erapharm.org), which focused on the fate and effects of pharmaceuticals in the environment. Here, we present data generated within this project from studies assessing population-relevant effects in a freshwater fish species. Using fathead minnows (Pimephales promelas) as a standard OECD test species, embryo-larval development (early life stage or ELS) and short-term (21 d) adult reproduction studies were undertaken. In the ELS study, the 4d embryo NOEC(hatching) and LOEC(hatching) values were 10 and >10mg/L, respectively, and after 28 d, NOEC(growth) and LOEC(growth) values were 3.2 and 10mg/L, respectively (arithmetic mean measured atenolol concentrations were >90% of these nominal values). In the short-term reproduction study, NOEC(reproduction) and LOEC(reproduction) values were 10 and >10mg/L, respectively (mean measured concentrations were 77-96% of nominal values), while the most sensitive endpoint was an increase in male fish condition index, giving NOEC(condition index) and LOEC(condition index) values of 1.0 and 3.2mg/L, respectively. The corresponding measured plasma concentration of atenolol in these fish was 0.0518 mg/L. These data collectively suggest that atenolol has low chronic toxicity to fish under the conditions described, particularly considering the low environmental concentrations reported. These data also allowed the assessment of two theoretical approaches proposed as predictors of the environmental impact of human pharmaceuticals: the Huggett 'mammalian-fish leverage model'; and the acute:chronic ratio (ACR). The Huggett model gave a measured human: fish effect ratio (ER) of 19.3 for atenolol, which compared well with the predicted ER of 40.98. Moreover, for an ER of 19.3, the model suggests that chronic testing may be warranted, and from our resultant effects data, atenolol does not cause significant chronic effects in fathead minnow at environmentally realistic concentrations. The calculated ACR for atenolol is >31.25, which is far lower than that of 17 alpha-ethinylestradiol and other potent steroidal oestrogens, thus further supporting the observed low toxicity. The data produced for atenolol here fit well with both approaches, but also highlight the importance of generating 'real' experimental data with which to calibrate and validate such models.
authors.affiliation: AstraZeneca Global Safety, Health and Environment, Brixham Environmental Laboratory, Freshwater Quarry, Brixham, Devon TQ5 8BA, United Kingdom. matthew.winter@astrazeneca.com
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Winter
authors.forename: Adam D
authors.initials: AD
authors.lastname: Lillicrap
authors.forename: John E
authors.initials: JE
authors.lastname: Caunter
authors.forename: Christian
authors.initials: C
authors.lastname: Schaffner
authors.forename: Alfredo C
authors.initials: AC
authors.lastname: Alder
authors.forename: Maria
authors.initials: M
authors.lastname: Ramil
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ternes
authors.forename: Emma
authors.initials: E
authors.lastname: Giltrow
authors.forename: John P
authors.initials: JP
authors.lastname: Sumpter
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hutchinson
mesh_terms: D000818:Animals; D001262:Atenolol / Q000032:analysis / Q000633:toxicity*; D001835:Body Weight; D003530:Cyprinidae / Q000196:embryology / Q000502:physiology*; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D005260:Female; D008297:Male; D008954:Models, Biological; D011897:Random Allocation; D012098:Reproduction / Q000187:drug effects*; D014867:Water / Q000032:analysis; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D014874:Water Pollutants, Chemical; D014867:Water; D001262:Atenolol