Abstract
Pharmaceuticals in the environment have received increased attention over the past decade, as they are ubiquitous in rivers and waterways. Concentrations are in sub-ng to low μg/L, well below acute toxic levels, but there are uncertainties regarding the effects of chronic exposures and there is a need to prioritise which pharmaceuticals may be of concern. The read-across hypothesis stipulates that a drug will have an effect in non-target organisms only if the molecular targets such as receptors and enzymes have been conserved, resulting in a (specific) pharmacological effect only if plasma concentrations are similar to human therapeutic concentrations. If this holds true for different classes of pharmaceuticals, it should be possible to predict the potential environmental impact from information obtained during the drug development process. This paper critically reviews the evidence for read-across, and finds that few studies include plasma concentrations and mode of action based effects. Thus, despite a large number of apparently relevant papers and a general acceptance of the hypothesis, there is an absence of documented evidence. There is a need for large-scale studies to generate robust data for testing the read-across hypothesis and developing predictive models, the only feasible approach to protecting the environment.
Highlights
The issue of pharmaceuticals in the environment has come to the fore in recent years with the realization that these drugs, designed to act at specific mammalian targets, may have effects in non-target organisms provided that the molecular target is conserved
The hypothesis presumes that a specific interaction between a drug and a target will result in a pharmacological response before a toxicological one, and will require a plasma concentration similar to that necessary to see a pharmacological effect in humans
This concept is not new; the well-established use of rodents in the drug development process relies on the similarity of drug targets and physiology with humans
Summary
General use, and many of these have been detected in surface waters and sewage treatment work effluents.[12−14] aquatic organisms may be continually exposed to a cocktail of drugs, in contrast to the transient nature of human drug exposure. This review will provide a critical commentary of the extent to which these studies, mostly concerned with human pharmaceuticals, have validated the read-across hypothesis in general, and the Fish Plasma Model in particular. The evolutionary conservation of the primary drug target is a prerequisite for the read-across hypothesis, and the key paper by Gunnarsson et al.[16] demonstrated the power of in silico analysis in this regard They looked at 1318 human drug targets across 16 species, and found 86% to be conserved in zebrafish, 61% in Daphnia pulex (water flea) and 35% in Chlamydomonas reinhardtii (green algae), indicating the potential for lower vertebrates, and even invertebrates and plants, to respond to pharmaceuticals present in the environment. The biochemical, metabolic and cell signaling pathways are often better understood in invertebrates such as Drosophila and
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