1. Pharmaceuticals in water – including legislative aspects Nicole Adler, Anette Küster, Bettina Rechenberg German Federal Environment Agency (UBA) Copenhagen 6th of December 2010

2. Overview 1. 1. Pharmaceuticals in the environment 2. 2. Entry of human/veterinary pharmaceuticals into water 3. 3. Disposal of pharmaceuticals 4. 4. ERA in authorisation procedures 5. 5. Problem of “old” substances 6. 6. “Gaps” in regulation 7. 7. Ecopharmacovigilanz 8. 8. Production and consumption of pharmaceuticals 9. 9. Monitoring of pharmaceuticals 10. 10. Conclusions

3.  120 different pharmaceutical active substances and metabolites detected in surface waters  German rivers: single substances > 0.5 µg/l  German ground water: single substances > 0.5 µg/l  Leachate from waste dump: single substances > 100 µg/l  Environmental loads into surface waters: pharmaceuticals  plant protection products Source: BLAC report 2003 Foto: Simone Lehmann 1. Pharmaceuticals in the environment – an arising problem?

4.  EE2- hormone: effects < 1 ng/L fishes, measured environmental concentrations sometimes exceed this value  Fluoxetin – anti-depressant: delay of development in fishes and frogs in concentrations that were measured in sewage  Avermectins – parasiticides: inhibition of dung fauna organisms; highly toxic to invertebrates  Diclofenac - antiphlogistic: damages in kidneys in fishes after a long exposure =1 µg/L*, concentrations in sewage and STP effluents sometimes exceed this value * Schwaiger et al. 2004, Triebskorn et al. 2004 1. Pharmaceuticals in the environment – an arising problem?

5. 2. Entry of human pharmaceuticals into water excretion surface water ground water drinking water Incorrect disposal waste/ sewage system sewage sludge soil production

6. 2. Entry of veterinary pharmaceuticals into water direct entry entry via incorporation of slurry/manure ground water production drinking water

7. What can be done for reduction by authorities?   production setting quality standards for sewage, monitoring   excretion after ingestion, injection or infusion assessing potential environmental risk within authorization procedure, risk mitigation measures, risk triggered monitoring   disposal of unwanted or leftover pharmaceuticals organizing safe disposal 2. Entry of pharmaceuticals into water

8. Incorrect disposal waste/ sewage system   Improper disposal of unwanted and unused medications represents a significant source of pharmaceutical discharges into the environment   Sewage system is a main route of entry of unwanted or leftover pharmaceuticals   Disposal on household waste landfills without leachate collection represents a locally significant source 3. Disposal of pharmaceuticals

9. Incorrect disposal - Examples UK (Bound and Voulvoulis 2005)   63% of patients dispose pharmaceuticals via household waste   11% of patients empty them into sink or toilet   22% of patients return them to a pharmacy Germany (START 2008 www.start-project.de)   15.7% of patients dispose tablets via the toilet (1% always)   43.7% of patients dispose liquid medicinal products via drain/toilet (10% always)   approximately 10-20% of unused HMPs enter household waste   Berlin: 100 t unused pharmaceuticals per year were collected in pharmacies (wiss. Institut AOK, 2006) 3. Disposal of pharmaceuticals

10. Incorrect disposal - Regulation EC Directive 2004/27/EC – Article 127b requires : “Member States shall ensure that appropriate collection systems are in place for medicinal products that are unused or have expired.” Survey of the 27 EU member states and Norway in 2007 (Taylor and Poulmaire 2008, cited in Glassmeyer et al. 2009) : 20 nations have established a pharmaceutical waste collection scheme 11 of which are pharmacy-based collection systems 3. Disposal of pharmaceuticals

11. ERA regulated by Directives 2001/83/EC and 2001/82/EC (as amended in 2004) for human and veterinary pharmaceuticals within EU ERA carried out according to:   EU Human Guideline Phase I und II - 2006   Veterinary Guideline VICHPhase I2001 andPhase II2005 and supporting document 2007 4. ERA in authorisation procedures

12.   Assess potential risk for the environment on product level  prospective risk assessment before marketing   Directives require mitigation measures in case of risk for veterinary pharmaceuticals e.g. no access for treated animals to surface waters  if no practicable mitigation measures available – refusal of marketing authorisation possible after risk-benefit analysis for human pharmaceuticals e.g. disposal advices  availability of the medicine must not be reduced, environmental risks not included in risk/benefit analysis – marketing authorisation cannot be denied 4. ERA in authorisation procedures

13. Estimation of Exposure (Phase I) non-experimental calculation of predicted environmental concentration, identification of substances of concern Analysis of Fate (Phase II) experimental data on degradation, sorption and partitioning between octanol and water Analysis of Effects (Phase II) experimental data on effects on organisms in surface water, sediment,… (here only aquatic compartment) 4. ERA in authorisation procedures

14. Effect Assessment PNEC P redicted N o E ffect C oncentration Exposure assessment PEC P redicted E nvironmental C oncentration Riskquotient (RQ): PEC PNEC ≥ 1 ?  1 Risk for Environment granting of marketing authorisation with risk mitigation measurements or refusal of marketing authorisation (only possible vor VMPs) < 1 No risk for environment granting of marketing authorisation 4. ERA - Risk Characterisation

15. Assessment of the medicinal product Pharmaceuticals (HMPs) with identified Environmental Risk UBA results 2008-2009 Same situation for VMPs 4. ERA - Risk Characterisation

16. Top 10 HMP - measured surface water concentrations in Germany 2001 BLAC-Report 2003 5. Problem of “old” substances Active ingredient Annual consumption (kg/a) Max. measured Concentration ( µ g/L) Measured in Ground / Drinking Water Carbamazepine87,604.91.81+ Metoprolol92,974.41.8+ Iopamidol42,994.41.0+ Sotalol26,649.20.95+ Diatrizoic acid60,686.80.95+ Clarithromycin7,159.10.95+ Phenazone24,843.20.84+ Diclofenac85,800.70.47+ Sulfamethoxazole53,600.30.38+ Bezafibrate33,475.60.35+ Not a single ERA available! Same situation for VMPs

17. UBA proposes a program for substances that are already on the market for years but have no environmental risk assessment:   Prioritization of substances of concern   Monographic system for „old“ HMPs and VMPs   Data Sharing (COM; EMA; EEA and Member States) 5. Problem of “old” substances

18. Example VMP - Toltrazuril Coccidiostatic Infection of protozoa (Coccidiosis) Environmental Risk Assessment Broiler: PECgw = 1.33 µg/l (Focus) Toltrazuril-sulfone = Metabolite = organohalogen compound Risk for groundwater ! because of the persistency (dt50 = 472d) and the mobility of Toltrazuril-sulfone 6. “Gaps” in regulation

19. ANNEX VIII INDICATIVE LIST OF THE MAIN POLLUTANTS 1. Organohalogen compounds and substances which may form such compounds in the aquatic environment. 2. Organophosphorous compounds. 3. Organotin compounds… DIRECTIVE 2000/60/EC establishing a framework for Community action in the field of water policy DIRECTIVE 2006/118/EC on the protection of groundwater against pollution and deterioration Article 6 1. (a) all measures necessary to prevent inputs into groundwater of any hazardous substances… In identifying such substances, Member States shall in particular take account of hazardous substances belonging to the families or groups of pollutants referred to in points 1 to 6 of Annex VIII to Directive 2000/ 60/EC… 6. “Gaps” in regulation

20. “no input into groundwater” can be interpreted as input < 0.1 µg/l DIRECTIVE 2006/118/EC on the protection of groundwater against pollution and deterioration ANNEX I GROUNDWATER QUALITY STANDARDS Pollutant Quality standards Nitrates 50 mg/l Active substances in pesticides, including their relevant 0.1 µg/l metabolites, degradation and reaction products (1) 0.5 µg/l (total) (2) (1) ‘Pesticides’ means plant protection products and biocidal products as defined in Article 2 of Directive 91/414/EEC and in Article 2 of Directive 98/8/EC, respectively. (2) ‘Total’ means the sum of all individual pesticides detected and quantified in the monitoring procedure, including their relevant metabolites, degradation and reaction products. 6. “Gaps” in regulation Pharmaceuticals should be clearly mentioned

21. Decision of CVMP (EMEA): Authorization without special measures (CVMP used ADI for ground water risk assessment ) UBA proposal: Monitoring of groundwater New Environmental Risk Assessment after 5 years Example VMP - Toltrazuril 6. “Gaps” in regulation 0.1 µg/l limit from veterinary ERA guideline not applied

22. Potential risk for human health through environmental pathway?   PHARMAS: detailed assessment of risks for ground and drinking water to be included in the ERA guidelines for HMPs and VMPs EU Project PHARMAS starts in January 2011 “Ecological and human health risk assessments of antibiotics and anticancer drugs found in the environment” 6. “Gaps” in regulation

23. Definition Ecopharmacovigilance: Collection of unexpected side effects in environment after authorisation and monitoring of concentration in environment VMPs: implemented in the legislation but not used in practice HMPs: not implemented in the current legislation 7. Ecopharmacovigilanz

24. Revision of EU Directive and Regulation for human pharmaceuticals - Released by the Commission in November 2008   Recital 2 a (new) 2a) The pollution of waters and soils with pharmaceutical residues is an emerging environmental problem and an emerging public health concern. Measures should be taken to monitor and evaluate adverse environmental effects of medicinal products, including those which impact on public health. The Commission should, based on data received from the Agency, the Environment Agency, and Member States, produce a report on the scale of the problem, along with an assessment on whether amendments to EU legislation on medicinal products or other relevant EU legislation are required. Results of the Pharmaceutical Package EU Commission has to collect and evaluate monitoring data and write a report on the results 7. Ecopharmacovigilanz

25. 8. Production and consumption of pharmaceuticals

26. Production data:   Unknown for HMPs and VMPs (production is not regulated) Consumption data:   Data for HMP are comercially available (IMS)   Nearly no data for VMP are exisiting for Europe (IFAH EU) German government will start programm in 2011 to collect data for the use of Antibiotics in animal production Entry of pharmaceuticals through production is not regulated

27. Monitoring of surface waters: Data from production, consumption and incorrect disposal: Problem:   No standardized monitoring programs for pharmaceuticals in the EU Member States   Very few quality standards in WFD for pharmaceuticals EU: Ibuprofen, Diclofenac, 17 alpha-Ethinylestradiol, 17 beta-Estradiol under discussion for list of priority substances Germany: Carbamazepine, Diclofenac, Sulfamethoxazole under discussion for national quality standards 9. Monitoring of pharmaceuticals

28. UBA proposes: Report of production data from industry Report of detailed sales/consumption data Monitoring of pharmaceuticals in surface waters – setting quality standards for pharmaceuticals in WFD

29. 10. Conclusions For the sustainable use of pharmaceuticals authorities should:   assess the potential environmental risk of existing (old) substances e.g. by Monographic systems, identify critical substances   find a harmonized approach for the assessment of hazardous pharmaceuticals entering ground and drinking water   establish systematic monitoring programs for pharmaceuticals and set quality standards for wastewater, surface water, drinking water, etc.   establish safe collection systems for unused pharmaceuticals   make “all” existent data available and evaluate it in order to protect environmental and human health   development of a life-cycle-assessment for pharmaceuticals (production + consumption)

30. nicole.adler@uba.de Any Questions?