The read-across hypothesis and environmental risk assessment of pharmaceuticals

This article is made available through the Brunel Open Access Publishing Fund. Copyright © 2013 American Chemical Society.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.BBSRC Industrial Partnership Award BB/ I00646X/1 and BBSRC Industrial CASE Partnership Studentship BB/I53257X/1 with AstraZeneca Safety Health and Environment Research Programme

Testing the “read-across hypothesis” by investigating the effects of ibuprofen on fish

Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.chemosphere.2016.08.041Human 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 to 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.This work was supported by Biotechnology and Biological Sci- ences Research Council (BBSRC) Industrial CASE Partnership Stu- dentship BB/I53257X/1 with AstraZeneca Safety Health and Environment Research Programme

Indistinguishable gene expression between healthy eyes and eyes with unilateral exfoliative glaucoma

Marcelo Ayala,1–3 Filip Cuklev41Eye Department, Skaraborg Hospital, Skövde, Sweden; 2Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; 3Karolinska Institute, Solna, Sweden; 4TATAA Biocenter, Gothenburg, SwedenBackground: Glaucoma is an optic neuropathy associated with visual field loss. There are different types of glaucoma, among them exfoliative glaucoma. Glaucoma can present as unilateral or bilateral. The present study aimed to show the association between gene expression and exfoliation in unilateral glaucoma cases.Methods: Included patients were suffering from exfoliative glaucoma in one eye, meanwhile the other eye was healthy and used as a control. Lens capsule and conjunctival biopsies were taken from both eyes. Gene expression was analyzed.Results: Both groups were completely different at baseline regarding intraocular pressure, visual acuity before the operation, visual field damage, optic nerve damage, etc. As for gene expression, the only significant difference was found in CYP1B1 from lens capsules. None of the other genes studied showed differential expression in either lens capsules or conjunctival biopsies.Conclusion: No difference in gene expression was found between eyes with and without exfoliative glaucoma. Exfoliative glaucoma seems to be a bilateral disease, though the phenotype is not always clinically present.Keywords: exfoliation, glaucoma, gene expression, unilatera

Does ketoprofen or diclofenac pose the lowest risk to fish?

Ketoprofen and diclofenac are non-steroidal anti-inflammatory drugs (NSAIDs) often used for similar indications, and both are frequently found in surface waters. Diclofenac affects organ histology and gene expression in fish at around 1 mu g/L. Here, we exposed rainbow trout to ketoprofen (1, 10 and 100 mu g/L) to investigate if this alternative causes less risk for pharmacological responses in fish. The bioconcentration factor from water to fish blood plasma wa

Impact of pollution on rivers in Montenegro: Ecotoxicological perspective

Montenegrin surface water and groundwater are important for the Balkan Peninsula since they are connected by the transboundary Dinaric Karst Aquifer System with the waters of additional five countries. The pollution from the surface water can rapidly infiltrate in aquifer and endanger this sensible ecosystem and the health of humans through drinking water supply. This chapter gives insights in the pressures of pollution on Montenegrin waters and in a limited literature data regarding freshwater ecotoxicological studies in Montenegro. Also, this chapter provides new ecotoxicological data obtained during survey in 2019, with a focus on the sites which are identified as hotspots of fecal pollution. The highest responses of biomarkers which indicate embryotoxic, genotoxic, and phytotoxic effects in zebrafish embryo test and in roots of Allium cepa were obtained at Ćehotina – downstream of Pljevlja. Similar results were detected at the site downstream Mojkovac at Tara, yet this site is affected by different type of pollution. Genotoxic endpoints in zebrafish stressed out sites on Morača and Lim rivers which are under pressures of fecal pollution. The data in this chapter provides an insight into current status obtained by the ex situ bioassays and indicates need for more comprehensive in situ assessment