Comparative physiology, pharmacology and toxicology of beta-blockers: mammals versus fish

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 ('beta-blockers') which are widely detected in surface waters. While reported concentrations of beta-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 beta-blockers, we can increasingly exploit the knowledge from molecular approaches to understand phenotypes and functions of adrenergic receptors in mammals versus fish. Some beta-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 beta-adrenergic receptors very similar to those present in mammals. Since we believe that any effects of beta-blockers in fish are most likely to be mediated via beta-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 beta-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 beta-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.