Aquatic Toxicology 82 (2007) 145–162 Review Comparative physiology, pharmacology and toxicology of -blockers: Mammals versus fish Stewart F. Owen a,c , Emma Giltrow a , Duane B. Huggett b , Thomas H. Hutchinson c,∗ , JoAnne Saye d , Matthew J. Winter c , John P. Sumpter a a Institute for the Environment, Brunel University, Uxbridge, Middlesex UB8 3PH, UK b Global Research and Development, Groton Laboratories, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA c AstraZeneca Global Safety, Health & Environment, Brixham Environmental Laboratory, Devon TQ5 8BA, UK d AstraZeneca Pharmaceuticals US, 1800 Concord Pike, Wilmington, DE 19850, USA Received 15 May 2006; received in revised form 26 January 2007; accepted 12 February 2007 Abstract On the premise that human medicines may potentially induce similar pharmacological and toxicological profiles in fish and other lower vertebrates, we have applied this comparative approach to beta-adrenergic receptor antagonists (‘-blockers’) which are widely detected in surface waters. While reported concentrations of -blockers are typically in the low ng/L range, data are needed to define whether this contamination poses any long-term threat to fish or other aquatic organisms. We argue that gathering experimental data in fish for these compounds may be done more efficiently by considering mammalian toxicology data. Extensive mammalian pharmacological and toxicological studies are central to development of medicines and these can provide valuable information to guide ecotoxicological studies. For -blockers, we can increasingly exploit the knowledge from molecular approaches to understand phenotypes and functions of adrenergic receptors in mammals versus fish. Some -adrenergic receptors have been characterised in fish using both traditional molecular cloning methods, or via mining of genomic sequences from various organisms. These approaches demonstrate that fish have -adrenergic receptors very similar to those present in mammals. Since we believe that any effects of -blockers in fish are most likely to be mediated via -adrenergic receptors, it is the physiological processes regulated by these receptors that are most likely to be affected. Thus, cardiovascular dysfunction is one possible consequence of exposure of fish to these compounds, leading to impaired fitness (e.g. reduced growth and fecundity). More broadly, conceptual mathematical models suggest it might be possible to predict plasma concentrations of -blockers in fish from mammals, although these models cannot be regarded as reliable until thoroughly validated. Experimental data are therefore urgently needed to define plasma levels and metabolism of -blockers compared in fish with mammals. Finally, accurate citation of CAS numbers is essential for pharmaceuticals in order to compare nominal concentration data in terms of either the drug free base or the drug salt complex. © 2007 Published by Elsevier B.V. Keywords: Pharmaceuticals; Drugs; Cardiovascular; Ecotoxicology; Aquatic; Water Contents 1. Introduction ............................................................................................................ 146 2. The adrenergic system in fish ............................................................................................. 147 3. The Physiological function of the adrenergic system in fish .................................................................. 148 4. Biochemistry of the beta-adrenergic receptor ............................................................................... 149 5. Xenobiotic uptake and metabolism ........................................................................................ 153 6. Possible effects of beta-blockers—physiology .............................................................................. 154 6.1. Effects of -blockers in humans .................................................................................... 154 6.2. Potential effects of -blockers on fish ............................................................................... 155 ∗ Corresponding author. Tel.: +44 1803 882882. E-mail address: tom.hutchinson@astrazeneca.com (T.H. Hutchinson). 0166-445X/$ – see front matter © 2007 Published by Elsevier B.V. doi:10.1016/j.aquatox.2007.02.007