Pharmaceuticals as environmental pollutants – current situation and ongoing research Christina Rudén Royal Institute of

1. Pharmaceuticals as environmental pollutants – current situation and ongoing research Christina Rudén Royal Institute of Technology (KTH) cr@infra.kth.se

2. General introduction Ongoing research Needs Pharmaceuticals in the environment

3. General: Large and increasing usage (high volume substances) Large and increasing use of pharmaceutials Human Pharmaceuticals Via sewage treatment plants to the aquatic environment Veterinary Drugs From treated animals to the terrestrial environment

4. Active pharmaceutical ingredients are in general stabile molecules; Many pass through sewage treatment plants Little less than 200 active pharmaceutical ingredients have been identified in effluents from sewage treatment plants and surface waters In general in very low concentrations: nano- to micrograms per litre water (1 nanogram = 0,000 000 001 gram, 1 microgram = 0,000 001 gram) Pharmaceuticals in the aquatic environment

5. Pharmaceuticals are carefully designed to be safe for the treated patient But: they are also designed to specifically and potently interact with biological molecules i.e. have an effect at low concentrations Each pharmaceutical has a more or less specific drug target (mode-of-action) Pharmaceuticals are biologically active

6. A drug-target can be a biological receptor, e.g. an enzyme, an ion channel, or a transport protein Pharmaceuticals are designed to interact with its target and have as few other, side-effects as possible Drug targets are well conserved through the evolution of species, i.e. they occur in many different species Pharmacology vs. toxicology

7. Evolutionary conservation of drug targets Gunnarsson, L., Jauhiainen, A., Kristiansson, E., Nerman, O., Larsson, D.G.J. (2008). Evolutionary Conservation of Human Drug Targets in Organisms used for Environmental Risk Assessments. Environmental Science and Technology, 42 (15), 5807–5813.

8. Evolutionary conservation of drug targets Mouse Gunnarsson, L., Jauhiainen, A., Kristiansson, E., Nerman, O., Larsson, D.G.J. (2008). Evolutionary Conservation of Human Drug Targets in Organisms used for Environmental Risk Assessments. Environmental Science and Technology, 42 (15), 5807–5813.

9. Evolutionary conservation of drug targets Fish Frog Gunnarsson, L., Jauhiainen, A., Kristiansson, E., Nerman, O., Larsson, D.G.J. (2008). Evolutionary Conservation of Human Drug Targets in Organisms used for Environmental Risk Assessments. Environmental Science and Technology, 42 (15), 5807–5813.

10. Evolutionary conservation of drug targets Water flea Fly Worm Gunnarsson, L., Jauhiainen, A., Kristiansson, E., Nerman, O., Larsson, D.G.J. (2008). Evolutionary Conservation of Human Drug Targets in Organisms used for Environmental Risk Assessments. Environmental Science and Technology, 42 (15), 5807–5813.

11. Evolutionary conservation of drug targets Bacteria Plants Amoeba Yeast Gunnarsson, L., Jauhiainen, A., Kristiansson, E., Nerman, O., Larsson, D.G.J. (2008). Evolutionary Conservation of Human Drug Targets in Organisms used for Environmental Risk Assessments. Environmental Science and Technology, 42 (15), 5807–5813.

12. EMEA requires environmental risk assessment for new registrations. The Technical Guidelines are from 2006 Based on data from standardized toxicity tests developed to identify unspecific toxicity (Industrial chemicals / effects on survival and reproduction) Current legislation

13. Example: Pharmaceuticals designed to treat depression will affect the central nervous system (uptake of signal substances in nerve synapses) The pharmaceutical can affect the fish nervous system Altered behavior caused by antidepressants has been observed in laboratory studies Altered behavior will reduce survival in the environment The regulatory standard tests will not cover such an effect Pharmacology and ”toxicity”

14. Pharmaceuticals that affect: The nervous system – behavioral tests (fish) Metabolising enzymes – enzyme induction assays (fish) Estrogenic effects -- vitellogenin (fish) Androgenic effects – Colour change and development (Guppy) No regulatory standards! We need tests that cover pharmacological effects

15. Comparison of Water concentrations that is expected not to affect organisms, based on laboratory experiments (Predicted No Effect Concentration; PNEC) Water concentrations predicted (or measured) in the environment (Predicted Environmental Concentration; PEC) PEC/PNEC is a risk ratio (if >1 then the exposure is of concern ) Environmental Risk Assessment

16. Bioconcentration of 18 human pharmaceuticals into blood plasma of fish exposed to treated sewage effluents Jerker Fick, Richard H. Lindberg, Mats Tysklind Department of Chemistry, Umeå University, Sweden Björn Arvidsson Swedish Defence Research Agency Jari Parkkonen and D. G. Joakim Larsson University of Gothenburg

17. Three Swedish Sewage Treatment plants • Juvenile fish (Rainbow trout) • 2 Weeks exposure to 100% treated effluent

18. Effluent water from 3 waste water treatment plants Exposure of fish

19. Effluent water from 3 waste water treatment plants Exposure of fish Concentration of pharmaceuticals in fish plasma

20. Effluent water from 3 waste water treatment plants Exposure of fish Human therapeutic blood plasma conc Concentration of pharmaceuticals in fish plasma

21. Effluent water from 3 waste water treatment plants Exposure of fish Human therapeutic blood plasma conc = Effect Ratio Concentration of pharmaceuticals in fish plasma The lower the effect ratio the higher probability of an effect

22. Beclometasone Beclometasone Levonorgestrel Levonorgestrel Haloperidol Risperidone Risperidone Cilazapril Cilazapril Verapamil Verapamil Ketoprofen Ketoprofen Diltiazem Diltiazem Meclozine Meclozine Safety factor Safety factor Memantine Memantine Sertraline Sertraline Diclofenac Diclofenac Tramadol Tramadol Orphenadrine Orphenadrine Ibuprofen Ibuprofen Oxazepam Oxazepam Naproxen Naproxen Carbamazepine Carbamazepine 0.01 0.01 0.1 0.1 1 1 10 10 100 100 1000 1000 10000 10000 Effect ratio Effect ratio Results BCF-studies

23. More research about exposures and effects More relevant test methods (Standardisation? Regulatory acceptance?) Improved European legislation Waste water treatment that removes chemicals Other actions towards (up-stream) risk management? Needs

24. The Stockholm Water project Main results: Modern operating WWTPs do not remove all pharmaceuticals (APIs) Persistent and water soluble APIs are present in the receiving waters of the Stockholm WWTP effluents 13 of 82 APIs are found also in drinking water, however at low concentrations (~1 ng/L) “Pharmaceuticals -occurrence in the water environment, preventive measures, and possible treatment methods” A four-year project funded by the City of Stockholm, run by Stockholm Water Company

25. The Stockholm Water project Sludge from WWTPs contains low levels of some APIs Through upstream source control, a minor part of the APIs can be prevented from reaching the sewers Additional treatment with low dose ozone or activated carbon reduces the APIs in waste water without causing negative effects on the aquatic environment Membrane methods such as reversed osmosis also work well but at higher energy costs Biological treatment or UV/hydrogen peroxide will not be sufficient

26. The Stockholm Water project • The introduction of full scale complementary treatment must be weighed against higher consumption ofenergy and resources • For Sweden, the additional cost for extratreatment would amount to € 20 - € 150 per person and year • The techniques do not have any effect on the WWTP sludge quality • Await research results on aquatic effects before a decision is taken to add new treatment to WWTPs! For more information: Cajsa.wahlberg@stockholmvatten.se

27. Thank you!