Uptake of propranolol, a cardiovascular pharmaceutical, from water into fish plasma and its effects on growth and organ biometry

Pharmaceuticals in the environment (PIE) are of importance since these compounds are designed to affect biological receptors/enzymes that are often conserved across vertebrate families. Across-species extrapolation of these therapeutic targets suggests potential for impacting amphibia and fish in the aquatic environment. Due to the scarcity of relevant ecotoxicological data, the long-tem impact of PIE remains a research question. Efficient use of mammalian data has been proposed to better understand and predict the potential for a given pharmaceutical to impact the environment. Using a model cardiovascular pharmaceutical (propranolol, a non-specific beta(1)/beta(2)-adrenergic antagonist), the hypothesis that mammalian data can be used to predict toxicity in fish was tested. Rainbow trout (Oncorhynchus mykiss (Walbaum)) have beta-adrenergic signalling mechanisms analogous to human cardiovascular receptors that respond to pharmacological doses of agonists and antagonists. Trout absorbed propranolol from water such that after 40 days of exposure, the linear relationship was [plasma] = 0.59[water] (it = 31, r = 0.96). Growth rate was affected only at very high aqueous concentrations (10-day (NOEC)-N-growth = 1.0 and (LOEC)-L-growth = 10 mg/l). Growth recovered with time (40-day (NOEC)-N-growth = 10 mg/l), suggesting possible adaptation to the pharmaceutical, although the internal plasma concentration in trout exposed to 10 mg propranolol/l of water was higher than the mammalian therapeutic plasma concentration. Additional endpoints suggested subtle changes of liver and heart size at much lower concentrations may have occurred, although these were not concentration-related. There was, however, a dose-dependent effect upon overall body condition. The trout plasma concentrations at these effective aqueous concentrations fell within the range of mammalian effective plasma concentrations, supporting the potential for developing 'read-across' from mammalian pharmacology safety data to fish ecotoxicology. Despite these effects at relatively high concentrations, propranolol is not expected to pose a risk to fish at the concentrations considered to be present in the aquatic environment. (C) 2009 Elsevier B.V. All rights reserved.