Field testing of a fish bioconcentration model proposed for risk assessment of human pharmaceutical residues in aquatic environments Jeffrey N. Brown†, Nicklas Paxéus*, Lars Förlin‡ and D.G. Joakim Larsson† † Institute for Neuroscience and Physiology, the Sahlgrenska Academy at Göteborg University, Sweden. * Environmental Chemistry, Gryaab AB, Göteborg. ‡ Department of Zoology, Göteborg University. Email: firstname.lastname@example.org Introduction A theoretical Fish Plasma Model (Fig. 1) has been proposed by Huggett et al.1 to assess the probability of a specific target interaction of pharmaceuticals in fish given that the drug target is conserved. A specific target interaction would not necessarily imply any adverse effects in aquatic organisms, but it would suggest a strong possibility and guide further testing. As a part of the model, a QSAR developed for hydrophobic organic pollutants is used to calculate fish bioconcentration but this QSAR is largely untested for pharmaceuticals, particularly in complex environmental exposure scenarios. To test the bioconcentration QSAR of the Fish Plasma Model using fish exposed to diluted sewage effluents. Fish exposure via water
• BCFs varied considerably between sites which could not be attributed to QSAR calculates differences in effluent bioconcentration concentrations, pH, temperatures or Gryaab STP exposure time. Gråbo STP Human therapeutic plasma Fish steady state plasma Spenshult STP
• Modelled BCFs were accurate for concentration giving known concentration (FssPC) effects (H PC) some drugs and sites but were rather far away for others. Reasons may be: (1) the QSAR does not take into Effect Ratio (ER) = H PC / F PC account special characteristics of pharmaceuticals; (2) active excretion Low ER = likely pharmaceutical target interaction and metabolism may lower plasma levels; (3) actual drug bioavailability High ER = target interaction less likely may be significantly lower through Fig. 1. The Fish Plasma Model1 utilises potency data gathered partitioning to colloids and particles. during pharmaceuticals efficacy and safety testing. If the level Naproxen toprofen
• Ibuprofen bioconcentrated greatly in fish blood plasma is near or greater than the human above model predictions. therapeutic plasma level pharmacological effects are
Max estimated BCF. Analyte not detected so plasma concentration set at 3
ng/ml detection limit to estimate maximal BCFs.
Experimental: Gryaab STP
• Juvenile rainbow trout (O. mykiss) were exposed in cages and tanks
Gråbo STP Risk Assessment Spenshult STP
• The lower the ER, the greater are
• Blood plasma was SPE extracted, derivatised and GC/MS analysed
the risks for pharmacological
for 4 non-steroidal anti-inflammatory drugs and the lipid regulator
effects in fish. The risk is highest for the undiluted Gryaab effluent, particularly for ibuprofen, diclofenac and gemfibrozil.
• Diclofenac presents the highest risk at all sites. fibrozil Ibuprofen Naproxen
• Naproxen presents little risk. Diclofenac Ketoprofen
Minimum estimated ER based on detection limit of 3 ng/ml plasma
Conclusions 1. Pharmaceuticals bioconcentrated from sewage effluents in to fish blood. 2. Significant differences in bioconcentration between sites shows the importance of field studies. 3. Diclofenac appears to present the highest risk for pharmacological effects in fish. 4. The Fish Plasma Model shows promising results but further refinement of the bioconcentration QSAR and validation of the model are necessary. REFERENCES
1 Huggett, D. B., Cook, J. C., Ericson, J. F. and Williams, R. T. (2003). A theoretical model for utilizing mammalian pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fish. Human and Ecological Risk Assessment, 9, 1789-1799.
2 Brown, J.N., Paxéus, N., Förlin, L. and Larsson, D.G.J. (2007). Variations in bioconcentration of human pharmaceuticals from sewage into fish blood plasma. Environmental Toxicology and Pharmacology, published online ahead of print June 2007, doi:10.1016/j.etap.2007.06.005.
We are pleased to publish an offering from our sister publication The Primary Care Companion to The Journal of Clinical Psychiatry about a topic of high importance to all physicians. This special commentary is Larry Culpepper. M.D.; Jonathan R. T. Davidson, M.D.; the first independent project undertaken by Allen J. Dietrich, M.D.; Wayne K. Goodman, M.D.; Kurt Kroenke, M.D.; and Tho
Testimonial by Dr Anil Kumar (Swami Shantananda) M.D., D.C.H. Kriyayoga Research Institute, Jhunsi, Allahabad, U.P., India I , a U.S. citizen and a medical doctor, has specialized in the care of children and young adults for the last 38 years. After practicing modern medicine mostly in the United States of America and also in England and India, I have returned to India