Pharmaceuticals in waters

1. Water Consulting Services Pharmaceuticals in waters Niina Vieno

2. Over 3000 chemicals are used in human and veterinary medicine Niina Vieno • Sources in the environment: • Wastewater treatment plants • Via human urine and feces (sewage) • Via disposal of old pharmaceuticals (in Finland 29 000 kg) • Hospitals • Pharmaceutical industry • Solid waste • For example, in Finland 32 000 kg of pharmaceuticals are incorrectly disposed via solid waste and end up in landfills

3. Harmful effects in the environment have been proven Niina Vieno 1 μg/l of diclofenac and propranolol induced: • Reduced growth • Reduced ability to attach to the underlying substrate • Bioconcentration into the mussel Source: Ericson et al. 2010, Aquat Toxicol. 99(2):223-31 Baltic Sea blue mussel Photo: www.blueoceans.org Unpublished data of Blue Mussels in the Gulf of Finland: • Low concentrations (< 10 ng/l) of pharmaceuticals induce stress in blue mussel.

4. Niina Vieno Zebrafish embryos: 30 ng/l concentration of diclofenac at 90-minute exposure has induced oxidative stress reduced ability to detoxify the reactive intermediates or to repair the resulting damage Photos: ehsc.oregonstate.edu & www.landesbioscience.com Source: Feito et al. 2012 Ecotoxicology. 21(1):289-96

5. Wild European perch: Antidepressant oxazepam has been noted to alter behavior and feeding rate of at concentrations measured in effluent- influenced surface waters. Source: Brodin et al. 2013, Science 339, 814- 815 Niina Vieno

6. Pharmaceuticals bioconcentrate in fish • Fish were caught from a Finnish lake that receives treated municipal wastewater via a small river. • Diclofenac, ibuprofen and naproxen were detected in bile samples of nearly all the fish • Concentrations in the lake were up to 300 ng/l (diclofenac) Niina Vieno Source: Brozinski et al. 2013, ES&T47, 342-348

7. 17α-ethinylestradiol (EE2) is an endocrine disruptor: there are effects already at a concentration of 0.1 ng/l Fathead minnow: • LOEC= 1 ng/l for: • plasma vitellogenin induction (measures estrogenic sensitivity) in both sexes • ultrastructural changes in the testes and livers • LOEC= 0.1 ng/l for: • significant increase in the mean number of eggs spawned per pair Source: Pawlowski et al. 2004. Ecotoxicol Environ Saf. 2004, (3):330-45. Niina Vieno

8. EU’s environmental legislation will consider pharmaceuticals for the first time ever in the revised Water Framework Directive Niina Vieno

9. Niina Vieno LIST OF PRIORITY SUBSTANCES AND PRIORITY HAZARDOUS SUBSTANCES Use of these compounds should be reduced or banned. Water Framework Directive (2000/60/EC) WATCH LIST OF EMERGING POLLUTANTS CURRENT SITUATION PROPOSAL (alongside the list of priority substances These compounds should be monitored -> can be classified as priority substance

10. Pharmaceuticals and hormones proposed to be added in the watch list Niina Vieno Compound CAS Use 17µ-ethinylestradiol 57-63-6 Contraceptive 17b-estradiol 50-28-2 Estrogen hormone Diclofenac 15307-79-6 Anti-inflammatory Ibuprofen 15687-27-1 Anti-inflammatory Carbamazepine 298-46-4 Antiepileptic Inclusion is confirmed!

11. Pharmaceuticals in the “watch list” means that member states shall: • monitore them in surface waters and report to European Commission (mandatory) • monitore them in wastewater effluents (voluntary) Niina Vieno

12. Classification of pharmaceuticals as HELCOM Core indicators • Diclofenac and EE2 has been suggested • Discussion also about addition of natural estrogens (E1, E2 and E3) and possibly complemented with an in vitro yeast assay. Niina Vieno

13. Occurrence of pharmaceuticals in wastewater depends on the consumption Niina Vieno 0 100 200 300 400 500 600 700 800 900 1000 Consumptionmg/inh/year Diclofenac 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 Consumptionmg/inh/year Ibuprofen Dnf Dnf Dnf= data not found

14. …next important thing is human metabolism Niina Vieno 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Excreted as parent compound

15. Niina Vieno Diclofenac-1- -o-acyl glucuronide (DCF-G) 4´-hydroxy-diclofenac (4´-OH-DCF) 5-hydroxy-diclofenac (5-OH-DCF) Diclofenac (DCF) 3´-hydroxy-diclofenac (3´-OH-DCF) 4´,5-dihydroxy-diclofenac (4´,5-OH-DCF) R, R´, R´´= not definitely identified ligands, presumably one per molecule About 1 % is excreted unchanged About 11 % is excreted conjugated 36 % 10%

16. Sewage concentrations follow consumption pattern Niina Vieno 0 100 200 300 400 500 600 700 800 900 1000 Consumptionmg/inh/year Diclofenac consumption 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 Concentration,g/l Diclofenac, max influent concentration Dnf Dnf Dnf Dnf Dnf= data not found

17. Niina Vieno 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 Consumptionmg/inh/year Ibuprofen 0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 Concentration,g/l Ibuprofen, influent concentration

18. Sewage concentrations can easily be estimated by calculations Niina Vieno Ccalc = A ´ P ´ e% ´10 365 ´ Q A= consumption of a pharmaceutical (as grams per inhabitant per year) P= number of inhabitants serviced by the sewage treatment plant e%= the percentage of pharmaceuticals excreted unmetabolized Q= influent flow rate of the sewage treatment plant (m3/d) Concentration of a pharmaceutical in influent of a sewage treatment plant in g/l:

19. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Sewageconcentration,g/l Calculated Measured Calculated values are often lower because deconjugation is not considered in the equation. Niina Vieno 10 % excreted unchanged 60 % excreted as glucuronides 10 % excreted unchanged 70 % excreted as glucuronides

20. Niina Vieno Concentrations in Finnish sewage (n= 13-21) 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Concentration,g/l

21. Concentrations in Finnish sewage Niina Vieno 0 5 10 15 20 25 30 35 Naproxen Ibuprofen Concentration,g/l

22. In comparison: Black wastewater Niina Vieno PAR TRI TC MET DOX PRO CBZ CET IBP DCF g/L 0 50 100 150 200 250 300 BW UASB PN AMX >1000 g/L DOX PRO CBZ CET g/L 0 1 2 3 4 5 6 7 BW= Black water UASB= Upflow Anaerobic Sludge Blanket PN= Partial nitritation AMX= Anammox PAR= paracetamol TRI= trimethoprim TC= tetracycline MET= metoprolol DOX= doxycycline PRO= propranolol CBZ= carbamazepine CET= cetirizine IBP= ibuprofen DCF= diclofenac Source: De Graaff et al. 2011. Water Research, 45(1), 375-383.

23. Elimination in wastewater treatment • In conventional treatment plants, elimination of pharmaceuticals from the water phase occurs: • Via sorption to sludge • Via biodegradation/biotransformation • Compounds do not evaporate Niina Vieno

24. Sorption= Absorption + Adsorption Niina Vieno SLUDGE FLOC CELL Hydrophobic compound Hydrophilic, ionic, compound Absorption Adsorption - desorption SLUDGE FLOC CELL

25. Sorption can be estimated by Kd value • Sorption of a compound to sludge can be considered negligible when • Kd value is < 500 L/kgSS (i.e. logKd < 2.7) Niina Vieno Kd = concentration in the solid phase concentration in the aqueous phase

26. logKd (primary sludge) logKd (activated sludge) Ciprofloxacin 4.3 Norfloxacin 4.2 Sulfamethoxazole 2.05 – 2.6 Carbamazepine < 1.3 0.09 Diclofenac 2.3 – 2.7 1.2 – 2.1 Ibuprofen <1.3 0.85 Naproxen 2.34 Atenolol 1.6 Metoprolol 0.5 Sotalol 1.6 Niina Vieno

27. Biodegradation: direct- or cometabolism • Direct metabolisation= bacteria use the compound as their primary carbon source • Cometabolisation= bacteria break down or partially convert the compound but do not use it as the primary carbon source Niina Vieno

28. Pharmaceuticals are primarily degraded cometabolically • Bacteria secrete enzymes to break down large organic molecules into monomers that are small enough to be ingested. • The enzymes have the potential to degrade or to transform small organic pollutant molecules present in wastewater. Niina Vieno

29. • E Coli secrete -glucuronidase enzyme • It is capable to deconjugate the -glucuronated pharmaceuticals excreted by the human body. • Ammonia monooxygenase (AMO) is secreted by autotrophic ammonia oxidizing bacteria during the oxidation of ammonium to hydroxylamine in aerobic nitrification. Niina Vieno

30. Deconjugation of diclofenac b-O-acyl glucuronide can occur in wastewater treatment plant • In microbiological degradation tests: • DCF-G has been noted to deconjugate to form equimolar DCF within 7 d of incubation. • Reaction rate constant were 0.28 d-1 in the inoculum and 0.12 d-1 under sterile conditions. • This suggests that abiotic hydrolysis occurs but the reaction is enhanced by micro-organisms. Niina Vieno Source: Lee et al. 2012, Chemosphere, 87, 969-974

31. Biodegradation varies greatly between pharmaceuticals • Ibuprofen is highly biodegradable at any process configurations • Diclofenac and carbamazepine are hardly biodegradable • Suggestions that process parameters such as increase of solids retention time or applying membrane bioreactor could enhance biodegradation. Niina Vieno

32. Example for diclofenac Niina Vieno 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Conventional activated sludge Activated sludge with biological nutrient removal Membrane bioreactor 35 % 29% 54%

33. Pharmaceuticals degrade to metabolites and complete mineralization is rare Niina Vieno DICLOFENAC

34. Removal rates are often calculated from influent and effluent concentrations • In Finnish sewage treatment plants Niina Vieno Compound Removal rate (%) Ciprofloxacin 84 % Carbamazepine -121 % Diclofenac 17 % Ibuprofen 95 % Ketoprofen 81 % Naproxen 91 % Atenolol 60 % Metoprolol 17 %

35. Example of mass flow analysis of diclofenac in Finland Niina Vieno PRETREATMENT ACTIVATED SLUDGE 324 kg 305 kg 19 kg (6 %) 270 kg (83 %) 4 kg (1 %) 31 kg (10 %) Sludge Sludge Biodegradation or -transformation ENVIRONMENT Yearly discharge to sewer ca. 60 mg/inh Evaporation 0 %

36. Elimination can be enhanced by tertiary treatment • Oxidation techniques • Ozonation, O3/UVA/TiO2 • Fenton treatment • UV based technologies • Catalytical techniques • Nanocatalysts • Photoelectrocatalysis Niina Vieno • Adsorption and filtration techniques • Sand filtration • Ultra and nanofiltration • Reverse and forward osmosis • Innovative sorbents • Other techniques • Electrochemical incineration • Sonolysis and ultrasound • Irradiation techniques • Liquid-core microcapsules

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39. Formation of oxidation products needs to be considered Niina Vieno DICLOFENAC DICLOFENAC-2,5-IMINOQUINONE Rate constant with O3 is about 5 % of that of diclofenac Reaction with O3 Source: Sein et al. 2008, ES&T, 42, 6656-6662

40. Niina Vieno Removal from aqueous phase is usually incomplete and pharmaceutical residues remain in the effluents Treated wastewater from Finnish WWTPs (n= 13-21) 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Concentration,g/l

41. In comparison: Antibiotic ciprofloxacin in treated wastewater in India Finland: Max 0.13 g/l (i.e. 0.00013 mg/l) Niina Vieno Patancheru/ India: 31 000 g/l (i.e. 31 mg/l) Defined daily dose for ciprofloxacin is 500–1000 mg.

42. Niina Vieno 42 Rivers carry a significant load of the pharmaceutical residues River Aura empties into the Baltic Sea at Turku, Finland. Example: River Aura Distance from Aura WWTP (km) c (ng/l)

43. Concentrations in Finnish rivers (n= 64) Niina Vieno 0 20 40 60 80 100 120 140 Concentration,ng/l

44. Niina Vieno Marine environment is the final sink for pharmaceuticals Photo: www.helcom.fi

45. Niina Vieno Source: E-PRTR (European Pollutant and Transfer Register) -> Waste and waste water management

46. Measurement data in the Baltic Sea is scarce Niina Vieno Compound Therapeutic use Max concentrations as ng/l Germany Stockholm Helsinki Bezafibrate Lipid regulator 0.3 Carbamazepine Antiepileptic 6.8 Detected Clofibric acid Metabolite of fibrates (lipid regulators) 0.4 Diclofenac Anti-inflammatory 0.4 Detected Gemfibrozil Lipid regulator 0.1 Ibuprofen Anti-inflammatory 0.1 Detected Naproxen Anti-inflammatory 0.5 Detected Oxazepam Antidepressive 20 Propyphenazone Analgesic 0.2

47. Niina Vieno EE2 (i.e. 17α-ethinylestradiol) is the most potent out of estrogens Source: Hazardous Substances in the Baltic Sea. Baltic Sea Environment Proceedings No. 120 B. Available at: www.helcom.fi EE2: 2.1– 17.9 ng/l EE2: Up to 14.1 ng/l EE2: Up to 3.9 ng/l EE2: 1.6–3.0 ng/l EE2: 1.7–3.2 ng/l

48. Most problematic are those pharmaceuticals that are not eliminated in the WWTP or in the environment Niina Vieno IBUPROFEN Breaks down easily by biotransformation Only a small fraction enters the environment CARBAMAZEPINE Is persistent in waste water treatment Is persistent in the environment and is detected also in ground w.aters

49. Whose responsibility it is to reduce the environmental load of pharmaceuticals? Niina Vieno PHARMACEU- TICAL INDUSTRY WASTEWATER TREATMENT PLANTS EVERYONE TOGETHER! AUTHORITIES DOCTORS & CONSUMERS

50. Niina Vieno Contact information Niina Vieno puh. 050 5448431 niina.vieno@envieno.com www.vesiuutisvuoto.fi

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