II CONVEGNO REGIONALE ISDE FVG. Udine, 28 novembre 2009 Ecovigilanza nella prevenzione delle malattie attraverso la tutela dell ambiente

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1 II CONVEGNO REGIONALE ISDE FVG Udine, 28 novembre 2009 Ecovigilanza nella prevenzione delle malattie attraverso la tutela dell ambiente ECOFARMACOVIGILANZA Giampaolo Velo Università di Verona Unità di Farmacologia Medica WHO Reference Centre Centro di Farmacovigilanza della Regione Veneto

2 I firmly believe that if the whole materia medica, as used now, could be sunk to the bottom of the sea, it would be all the better for mankind - and all the worse for the fishes. Oliver Wendell Holmes (1860) Holmes OW. Collected Essays, Boston: Houghton Mifflin; 1891:

3 Workshop ECOPHARMACOLOGY June 9-10, 2006 Sala Terzian, Rettorato University of Verona, Italy Klaus Kümmerer Giampaolo Velo

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8 The Little Water Cycle Workshop Ecopharmcology, Verona 2006

9 CONSUMO DI FARMACI IN ITALIA. ESEMPI FARMACI Con Obbligo Di Ricetta Amoxicillina+Ac.clavulanico Acido acetilsalicilico Acetilcisteina Claritromicina Nimesulide CONSUMO nel tonnellate (t) 88 t 54 t 34 t 25 t FARMACI Senza Obbligo Di Ricetta Paracetamolo Ibuprofene Ketoprofene Diclofenac CONSUMO nel tonnellate (t) 52.2 t 31.3 t 24 t Considerando la totalità dei farmaci, sono migliaia di tonnellate!

10 N. di Sostanze Medicinali in Commercio in Italia nel Sostanze medicinali singole Associazioni di sostanze medicinali

11 N. di Confezioni di Specialità Medicinali in Commercio in Italia nel Confezioni monocomposte Confezioni policomposte

12 Prozac in the Thames. British Environment Agency, UK Cocaine in the Po river Istituto Mario Negri, Italy Antidepressants, antiepileptics and statins in Niagara river and Ontario lake.. Water Quality Centre, University of Ontario, Canada

13 (Pharmaceuticals and Personal Care Products)

14 Impact of waste pharmaceuticals Some drugs have been found in drinking water, which is a warning sign that the current handling of pharmaceuticals may lead to future health and environmental problems. There is positive evidence of an endocrine disruption effect on aquatic life with reports on the feminisation of male fish, notably the freshwater roach (Rutilus rutilus), causing intersex species or development of ova in the testes, where oestrogens (from HRT, oral contraceptive and endogenous human production) are present at the level of one part per billion. C. Richman and S. Castensson, Impact of waste pharmaceuticals, The Pharmaceutical Journal, 2008

15 Drug concentrations in the environment Wastewater Sewage Surface water (rivers, lakes) Drinking water Sea water ng/l ng/kg ng/l 1-10 ng/l ng/l

16 Spread of drugs in the environment The largest flow of drugs into the environment comes from people who are under medical treatment. Drugs are eliminated from the body either in unchanged form or as metabolites in faeces and urine and find their way to sewage treatment plants (STP).

17 Spread of drugs in the environment How drugs later behave in the environment and what happens in the long term will depend on their chemical and physical properties. Drugs and their metabolites may be divided roughly into three groups:

18 Spread of drugs in the acqueous face Drugs that break down rapidly will be found close to their sources and only if they have been released in large amounts. Acetylsalicylic acid is an example of such a drug. Drugs that are both water-soluble and stable will pass through a treatment plant more or less unchanged and be dispersed in the surrounding watercourse. Bezafibrate and other lipid-lowering drugs are examples of drugs of this kind. Drugs that are fat-soluble and stable will adsorb to a considerable extent to sludge particles through the sewage treatment process. Fluoroquinolones (a group of antibiotics) are examples of such drugs.

19 Principali farmaci presenti nelle acque di fiumi e laghi in Europa E. Zuccato et al. (2007) Ricerca&Pratica 23 pp 67-73

20 Spread of drugs in the drinking water The first pharmaceutical substance detected in drinking water was clofibric acid, found by a German research group in Berlin fifteen years ago (Stan, 1994). Since then several drugs (such as bezafibrate, phenazone and carbamazepine) have been found in drinking water in Germany (Ternes, 2001). Various types of antibiotics have also been detected in the USA (Ye et al., 2007).

21 Drugs in drinking water Compound Therapeutic group Maximum conc. (ng l -1 ) Country Reference Bezafibrate Lipid regulator 27 Germany Stumpf, 1996 Bleomycin Anti -neoplastic 13 UK Aherne, 1990 Clofibric acid Lipid regulator + UK Fielding, Germany Stumpf, Germany Stan, Germany Heberer, Italy Zuccato, 2000 Carbamazepine Anti -epileptic 24 Canada Tauber, USA Stachelberg, 2004 Diazepam Anxiolytic 10 UK Waggot, Italy Zuccato, 2000 Diclofenac NSAID 6 Germany Stumpf, 1996 Gemfibrozil Lipid regulator 70 Canada Tauber, 2003 Ibuprofen NSAID 3 Germany Stumpf, 1996 Phenazone NSAID 250 Germany Zuhlke, Germany Reddersen, 2002 Propyphenazone NSAID 80 Germany Zuhlke, Germany Reddersen, 2002 Tylosin Antibiotic 1.7 Italy Zuccato, 2000

22 When medicines are used or misused there can be some serious and damaging consequences to our global environment and ecosystem.

23 The pharmaceutical chemicals in the environment can also affect man chronically, causing many unwanted interactions, compromising human responses to medicines, contributing to drug resistance

24 More rational drug use could be very helpful for the patient and for the ecosystem

25 Rational drug use no consumerism!

26 Rational drug use sometimes rational drug use means NO USE

27 Drugs can pollute our environment, water, animals, soil and plant life and can also have ongoing effects in humans, causing adverse effects and/or unwanted and unknown assumption of unnecessary drugs

28 Impact of waste pharmaceuticals Pharmaceutical micropollutants are detected at parts per trillion or parts per billion levels, far below their acute toxic levels. The effect of chronic exposure to these low levels of pollutants on humans remains unknown and arguments to apply the precautionary principle have been made as a reason for action into reducing the presence of pharmaceuticals in the environment. C. Richman and S. Castensson, Impact of waste pharmaceuticals, The Pharmaceutical Journal, 2008

29 Drug environmental concentrations are well below therapeutic levels,. we do not know the significance in humans of interactions between multiple drugs at low concentrations ingested over the whole lifespan. we must think and act on a precautionary basis.

30 Precautionary principle We should not deny risks simply because they are less than certain. On the contrary we should ensure that we know in advance the possible damages to human health and the environment, so that we can prevent them.

31 Precautionary principle We should consider special populations, like infants and children, pregnant women. type B reactions are dose/concentration independent.

32 ECOPHARMACOVIGILANCE Science and activities concerning detection, assessment, understanding and prevention of adverse effects or other problems related to the presence of Pharmaceuticals in the environment, which effect both human and other species.

33 ECOPHARMACOVIGILANCE It is a world in which we are all swimming but of which we know very little. For a better and safer use of drugs?

34 K. Kümmerer and GP Velo - Ecopharmacology Workshop, Verona 2006

35 Pharmacology and Eco-Pharmacology number of compounds administered desirable physico-chemical properties administration wanted effects/ side effects metabolism/ biotransformation/ affected organisms Pharmacology (humans) one or only a few compounds at the same time stable aimed, on demand, controlled active, wanted effects, side effects one type of organism Eco-pharmacology (environment) an unknown cocktail of different compounds readily (bio) degradable diffuse i.e. emissions of medical care units and the community wanted effects in humans are often most important side effects in the environment various types of organisms of different trophic levels Kümmerer (Ed) Pharmaceuticals in the Environment, 2nd Ed. 2004, Kümmerer K & Velo G, Drug Safety, 2006

36 SWEDISH MPA (MEDICAL PRODUCTS AGENCY) Environmental hazard and risk assessment 27 drugs were selected

37 Selected drugs Atenolol (β1-adrenergic blocking) Cyclofosfamide (Antineoplastic) Dextropropoxyphene (Analgesic) Diazepam (Tranquilizer) Diclofenac (Analgesic, Antiinflammatory, Antipyretic) Enalapril (ACE-inhibitor, Antihypertensive) Ethinyloestradiol (Oestrogen) Furosemid (Diuretic) Hydrochlorothiazide (Diuretic) Ibuprofen (Analgesic, Antiinflammatory, Antipyretic) Ifosfamide (Antineoplastic) Ketoprofen (Analgesic, Antiinflammatory, Antipyretic) Metformin (Antidiabetic) Metoprolol (β1-adrenergic blocking) Naproxen (Analgesic, Antiinflammatory, Antipyretic) Norethisterone (Progestin) Oestradiol (Oestrogen) Oestriol (Oestrogen) Oxazepam (Tranquilizer) Oxytetracycline (Antibiotic) Paracetamol (Analgesic, Antipyretic) Ranitidin (Gastric secretory inhibitor, H2-receptor antagonist) Salbutamol (Bronchodilator, β2- Sympathomimetic) Simvastatin (Antihyperlipidemic) Terbutalin (Antiasthmatic, β2- Sympathomimetic) Tetracycline (Antibiotic) Warfarin (Anticoagulant)

38 Conclusions of the Swedish study The risk for acute toxic effects in the environment is unlikely Chronic environmental toxic effects cannot be excluded due to the lack of chronic ecotoxicity data Reduction of potential environmental impact should be based on knowledge on chronic ecotoxic effects The environmental impact of drugs should be further studied and more attention is needed

39 Impact of Medications on Environment We have little knowledge of the effects that continuously supplied trace quantities of pharmaceuticals and other chemicals could have on our development, our ability to resist disease and our wellness in general. Therefore caution is advisable. Stockholm City Council, Enviromentally classified Pharmaceuticals, Stockholms laens landsting, 2008

40 Directive 2004/27/EC of the European Parliament and of the Council of the European Union Environmental risk assessment as part of a marketing authorization application.

41 Directive 2004/27/EC of the European Parliament and of the Council of the European Union Article 8 (3): (ca) Evaluation of the potential environmental risks posed by the medicinal product. This impact shall be assessed and, on a case-by-case basis, specific arrangements to limit it shall be envisaged; (g) Reasons for any precautionary and safety measures to be taken for the storage of the medicinal product, its administration to patients and for the disposal of waste products, together with an indication of potential risks presented by medicinal product for the environment.

42 Impact of waste pharmaceuticals Erkki Liikanen, member of the European Commission responsible for enterprise, was quoted as saying: The possible effects of the use of medicinal products on the environment are important. The question needed to be addressed carefully as, at the end of the day, the availability of certain medicines was at stake. The compromise amendments, which require an environmental impact assessment and possible mitigating measures, but leave the criteria for granting the marketing authorisation untouched is to be seen as a well balanced solution. C. Richman and S. Castensson, Impact of waste pharmaceuticals, The Pharmaceutical Journal, 2008

43 Impact of waste pharmaceuticals For veterinary medicinal products a more straightforward approach is laid down in directive 2004/28/EC. This legislation forbids product authorisation when the environmental risk is unacceptable and the managing the risk is not possible. C. Richman and S. Castensson, Impact of waste pharmaceuticals, The Pharmaceutical Journal, 2008

44 Different approaches for the reduction of pharmaceuticals in the environment Short term approach: effluent treatment

45 Fate of pharmaceuticals in treatment plants (STPs) Amoxycillin Ciprofloxacin Enalapril Ibuprofen Ofloxacin Removal rate: 30-60% Atenolol Bezafibrate Clofibric acid Furosemide Diazepam Removal rate; 10-30% Carbamazepine Clarithromycin Erythromycin Estrone Lincomycin Spiramycin Removal rate: 0% Hydrochlorothiazide Ranitidine Sulphamethoxazole Removal rate: variable E. Zuccato, ISOP 2007

46 Pharmaceuticals in effluents (ng/l) of sewage treatment plants (nine plants), River Po (seven sites), and River Lambro ng/l STPs Lambro River Po River Median Maximum Median Ofloxacin Furosemide Atenolol Hydrochlorothiazide Carbamazepine Ranitidine Ciprofloxacin Nd Sulphamethoxazole Nd Nd Nd Ibuprofen Spiramycin Bezafibrate Erythromycin Lincomycin Clarithromycin Salbutamol Amoxycillin 4.7 Nd Nd Nd Cyclophosphamide 0.6 Nd Nd Nd Diazepam 0.0 Nd Nd Nd Enalapril Ethinylestradiol 0.0 Nd Nd Nd Methotrexate 0.0 Nd Nd Nd Omeprazole 0.0 Nd Nd Nd Zuccato et al, ESPR 2006

47 Different approaches for the reduction of the pharmaceuticals in the environment Mid term approach: Education training and creating public awareness. Rational drug use could be an important issue

48 Mid-term Risk Management: Information, Training, and Education Education and training (staff) Information of all involved people (pharmacists, doctors, patients, ) Pharmacovigilance has to inform doctors, pharmacists & consumers! K. Kümmerer and GP Velo - Ecopharmacology Workshop, Verona 2006

49 Different approaches for the reduction of the pharmaceuticals in the environment Long term approach: green pharmacy

50 What is Green Chemistry? Green chemistry is the design of chemical products and processes that reduce or eliminate the use and generation of hazardous substances Discovery and application of new chemistry/ technology leading to prevention/reduction of environmental, health and safety impacts at source J. H. Clark - Ecopharmacology Workshop, Verona 2006

51 Long Term Risk Management: Green Pharmacy New compounds are effective, efficient, and readily degradable in the environment identification (sub)structures essential for efficacy (bio)degradability

52 Modification of Structure Changes Properties OH Benzene: not biodegradable cancergenic, not bactericidal Phenol: readily biodgradable not concerogenic bactericidal K. Kümmerer - Ecopharmacology Workshop, Verona 2006

53 Green Chemistry for a healthier environment J. H. Clark - Ecopharmacology Workshop, Verona 2006

54 ACADEMIE NATIONALE DE PHARMACIE Medicaments et environnement Rapport Juin 2008

55 RECOMMANDATIONS LIMITER ET CONTRÔLER LES REJETS EVALUER LES RISQUES LIES AUX REJETS DEVELOPPER DES ACTIONS DE FORMATION ET D EDUCATION Academie Nationale de Pharmacie, Medicaments et environnement, Rapport Juin 2008

56 Meeting on Pharmaceuticals and Personal Care Products (PPCPs) in drinking water RECOMMENDATIONS: Enhanced preventive measures including rational drug use, education of prescribers and the public to reduce disposal and discharges to the environment will reduce human exposure Singapore, June WHO Meeting on PPCPs in drinking water

57 GP Velo, 7th ISoP Annual Meeting