Abstract
Human pharmaceuticals present in the environment have the potential to cause adverse effects on non-target organisms. The “read-across hypothesis” stipulates that pharmaceuticals will exhibit similar biological effects across species (e.g. human and fish) if the molecular target has been conserved and the effective drug concentrations are reached (Cmax). We tested this hypothesis by evaluating if ibuprofen, a non-selective inhibitor of prostaglandins and the cyclooxygenase (COX) enzyme, can mimic its primary effect in humans, on fish, at comparable plasma concentrations. The endpoints, prostaglandin E metabolite (PGEM) levels and the mRNA expression of COX (ptgs) gene, were measured in the gills of control and exposed fathead minnows (Pimephales promelas), using enzyme-immunoassay and quantitative real-time PCR (qPCR). Fish were exposed, for 24–72 h, to measured water concentrations of 9 (n = 12), 370 (n = 40) and 470 μg ibuprofen/L (n = 12). Water and blood plasma concentrations were determined using LC-MS/MS. Results showed that PGEM levels in fish exposed to 370 and 470 μg ibuprofen/L were significantly decreased compared to control fish, when mean plasma ibuprofen concentrations were 1.8–5.6-fold below the Cmax. The plasma ibuprofen concentrations and PGEM levels varied greatly between individuals. In fish exposed to 9 μg ibuprofen/L, when the mean plasma ibuprofen concentration was 224-fold below Cmax, no change in PGEM levels was observed. These data provide evidence for the read-across hypothesis, but suggest establishing a direct dose-response between internal plasma and PGEM is difficult, and would require significantly larger numbers of fish to overcome the inter-individual variation.
Highlights
Research Centre, Bracknell, Berkshire, RG42 6EY, UK. 2 Present address
Ibuprofen measurements in the water of solvent control (SC) tanks were below the Limit of Detection (LOD; 2.5 mg/L)
The reduced prostaglandin E metabolite (PGEM) levels were observed in fish with plasma ibuprofen concentrations spanning over 30-fold. These results demonstrate that ibuprofen can inhibit PGEM levels over a range of plasma concentrations, including concentrations up to 21fold below the lowest Cmax
Summary
A. Patel et al / Chemosphere 163 (2016) 592e600 base the ranking of pharmaceuticals on how close the plasma concentrations of wildlife, such as fish, are to the effective drug concentrations in humans, provided that the molecular drug target (i.e. receptor or enzyme) has been conserved: this is the basis of the read-across hypothesis (Huggett et al, 2003; Rand-Weaver et al, 2013; Tanoue et al, 2015). Little information is available to support the use of the read-across hypothesis to predict the environmental (e.g. river) concentrations of pharmaceuticals that will cause effects to fish. A recent publication (Margiotta-Casaluci et al, 2014) has shown that the anti-depressant fluoxetine affects behavior of fish only when their plasma concentration is within the human therapeutic range. To assess the robustness of the read-across hypothesis, we investigated the uptake of the human pharmaceutical ibuprofen by fish and the internal (blood plasma) concentrations required to elicit a mode-ofaction related effect
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