Pharmaceuticals as environmental pollutants – current situation and ongoing research Christina Rudén Royal Institute of Technology (KTH)

Christina Rudén Pharmaceuticals in the environment 1.General introduction 2.Ongoing research 3.Needs

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

Christina Rudén Pharmaceuticals in the aquatic environment 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, gram, 1 microgram = 0, gram)

Christina Rudén Pharmaceuticals are biologically active 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)

Christina Rudén Pharmacology vs. toxicology 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

Christina Rudén 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.

Christina Rudén 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. Mouse

Christina Rudén 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. Fish Frog

Christina Rudén 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. Water flea Fly Worm

Christina Rudén 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. Bacteria Plants Amoeba Yeast

Christina Rudén Current legislation 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)

Christina Rudén Pharmacology and ”toxicity” −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

Christina Rudén We need tests that cover pharmacological effects −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!

Christina Rudén Environmental Risk Assessment Comparison of (1) Water concentrations that is expected not to affect organisms, based on laboratory experiments (Predicted No Effect Concentration; PNEC) (2)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 )

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

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

Effluent water from 3 waste water treatment plants Exposure of fish

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

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

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

Results BCF-studies

Christina Rudén 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

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

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

The Stockholm Water project The introduction of full scale complementary treatment must be weighed against higher consumption of energy and resources For Sweden, the additional cost for extra treatment 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:

27 Thank you!