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Ecopharmacovigilance: why? Giampaolo Velo Clinical Pharmacology Unit Regional Pharmacovigilance Centre WHO Reference Centre University of Verona Italy Moving beyond Kyoto New York Times, July 1 2007 by Al Gore WE — the human species — have arrived at a moment of decision. It is unprecedented and even laughable for us to imagine that we could actually make a conscious choice as a species, but that is nevertheless the challenge that is before us. Our home — Earth — is in danger. What is at risk of being destroyed is not the planet itself, but the conditions that have made it hospitable for human beings. Workshop ECOPHARMACOLOGY June 9-10, 2006 “Sala Terzian”, Rettorato University of Verona, Italy Klaus Kümmerer Giampaolo Velo The “Little” Water Cycle Workshop Ecopharmcology, Verona 2006 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 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). 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: 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. 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 ten 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., 2004). 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, 1981 70 Germany Stumpf, 1996 165 Germany Stan, 1994 270 Germany Heberer, 1997 5 Italy Zuccato, 2000 24 Canada Tauber, 2003 258 USA Stachelberg, 2004 10 UK Waggot, 1981 23 Italy Zuccato, 2000 Carbamazepine Diazepam Anti -epileptic Anxiolytic Diclofenac NSAID 6 Germany Stumpf, 1996 Gemfibrozil Lipid regulator 70 Canada Tauber, 2003 Ibuprofen NSAID 3 Germany Stumpf, 1996 Phenazone NSAID 250 Germany Zuhlke, 2004 400 Germany Reddersen, 2002 80 Germany Zuhlke, 2004 120 Germany Reddersen, 2002 1.7 Italy Zuccato, 2000 Propyphenazone Tylosin NSAID Antibiotic Spread of drugs in the watercourses The majority of studies have been carried out in Europe and the amounts in the watercourses are about one-tenth of those found in treated sewage, i.e. 1–100 ng/L (Daughton and Ternes, 1999, Debska et al., 2004). Spread of drugs in the watercourses The following classes of drugs have been found: - Analgesic/anti-inflammatory agents (acetylsalicylic acid (and its metabolites), diclofenac, ibuprofen (and its metabolites), indometacin, ketoprofen, naproxen and phenazone) - Antibiotics (chloramphenicol, erythromycin, lincomycin, roxithromycin, fluoroquinolones, tetracyclines, sulphonamides and trimethoprim) - Hormone preparations (estradiol-17alfa, estradiol-17beta, ethinylestradiol, mestranol, 19-noretisterone, progesterone, testosterone and estriol) - Antihypertensive agents (beta-blockers: atenolol, metoprolol….) The city's sewers each day soaks up its citizens' routines, taking in a steady stream of products. Toothpaste and shampoo may be harmless enough, but the waste also collects a wide array of medicines people take. Most drugs are poorly absorbed and metabolized by the body, so it is not unusual that the majority of a drug would end up intact in the urine. Because all water goes through toilets at some point, these artificial compounds, some quite difficult to break down, can eventually find their way into the city's water supply—even bottled water. Nature Medicine 12, 376 - 377 (2006) Drugs down the drain Alan Dove Traces of prescription heart medications and caffeine have even found their way into the Atlantic Ocean. Nature Medicine 12, 376 - 377 (2006) Drugs down the drain Alan Dove When medicines are used or misused there can be some serious and damaging consequences to our global environment and ecosystem. The pharmaceutical chemicals in the environment can also affect man chronically, causing many unwanted interactions, compromising human responses to medicines, contributing to drug resistance More rational drug use could be very helpful for the patient and for the ecosystem Rational drug use no consumerism! Rational drug use sometimes rational drug use means… “no use” 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 unknowing consumption of unnecessary drugs 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. 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. Precautionary principle We should consider special populations, like infants and children, pregnant women…. type B reactions are dose/concentration independent…. Ecopharmacovigilance? Ecopharmacovigilance concerns the adverse events related to drugs within the ecosystem with all consequences in humans and other organisms in the environment 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? Environmental contamination pathways (Pharmaceuticals for human use) ADMINISTRATION to patients (treatment/prevention diseases) Excretion in urine/stool (parent compound, metabolites) Industrial pollution SEWAGE TREATMENT PLANT Treated water (containing pharmaceuticals) Rivers, Lakes E. Zuccato, ISOP 2007 Improper disposal Industrial pollution Sludge (containing pharmaceuticals) Ground water Pharmacology and Eco-Pharmacology Pharmacology (humans) one or only a few compounds at the same time stable Eco-pharmacology (environment) an unknown cocktail of different compounds administration aimed, on demand, controlled wanted effects/ side effects active, wanted effects, side effects metabolism/ biotransformation/ affected organisms one type of organism 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 number of compounds administered desirable physico-chemical properties readily (bio) degradable Kümmerer (Ed) Pharmaceuticals in the Environment, 2nd Ed. 2004, Kümmerer K & Velo G, Drug Safety, 2006 Some Data • Approx. 100,000 chemicals on the market in the EU • World wide: several 100,000 tons of pharmaceuticals used: anti-inflammatory, lipid lowering agents, pain killers, antibiotics, anti-depressants, anti-inflammatory, anti-neoplastics, … Doctors fear drug pollution poses risk to fish, people Jim Ritter, Suntimes Chicago The Americal Medical Association is considering resolutions calling on the Environmental Protection Agency to conduct comprehensive studies on the topic “It is a huge , huge issue for us in the future…” AMA, from Chicago Meeting, June 12, 2006 The Swedish Government commission the MPA (Medical Products Agency) to: • investigate environmental effects of pharmaceuticals. • present proposals on measures to reduce environmental effects of the products, nationally as well as within the EU. • investigate how information about content and quantities of chemical substances in these products can be improved and made more easily available. • investigate the possibilities to introduce environmental classification of pharmaceutical products on a national basis. MPA Environmental hazard and risk assessment • 27 drugs were selected 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, β2Sympathomimetic) Simvastatin (Antihyperlipidemic) Terbutalin (Antiasthmatic, β2Sympathomimetic) Tetracycline (Antibiotic) Warfarin (Anticoagulant) 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 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. 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”. Different approaches for the reduction of the pharmaceuticals in the environment Short term approach: effluent treatment Fate of pharmaceuticals in treatment plants (STPs) Removal efficiencies in the STPs analyzed 39% Total loads (g/d/1000 inhabitants) 5,0 64% 31% 4,5 4,0 3,5 0% 0% 3,0 STPs influent STPs effluent 2,5 2,0 16% 31% 1,5 1,0 0,5 0,0 Naples Latina Cagliari Cuneo Varese Lago STPs analyzed E. Zuccato, ISOP 2007 Va Olona winter Va Olona summer Fate of pharmaceuticals in treatment plants (STPs) Amoxycillin Ciprofloxacin Enalapril Ibuprofen Ofloxacin Carbamazepine Clarithromycin Erythromycin Estrone Lincomycin Spiramycin Removal rate: 30-60% Atenolol Bezafibrate Clofibric acid Furosemide Diazepam Removal rate; 10-30% Removal rate: 0% E. Zuccato, ISOP 2007 Hydrochlorothiazide Ranitidine Sulphamethoxazole Removal rate: variable Pharmaceuticals in effluents of urban sewage treatment plants in Italy (Median values of 9 STPs) E. Zuccato, ISOP 2007 Pharmaceuticals in effluents of sewage treatment plants (nine plants), River Po (median and maximum, seven site), and River Lambro (ng/L) ng/L STPs Lambro River Ofloxacin Furosemide Atenolol Hydrochlorothiazide Carbamazepine Ranitidine Ciprofloxacin Sulphamethoxazole Ibuprofen Spiramycin Bezafibrate Erythromycin Lincomycin Clarithromycin Salbutamol Amoxycillin Cyclophosphamide Diazepam Enalapril Ethinylestradiol Methotrexate Omeprazole Median 600.0 585.0 466.0 439.1 291.1 288.2 251.0 127.2 121.2 75.0 54.8 47.4 30.5 18.1 8.7 4.7 0.6 0.0 0.0 0.0 0.0 0.0 306.1 254.7 241.0 255.8 175.3 38.5 14.4 Nd 20.0 74.2 57.2 4.5 24.4 8.3 2.5 Nd Nd Nd 0.5 Nd Nd Nd Po River Maximum 37.0 67.2 41.7 24.4 34.2 4 26.2 Nd 17.4 43.8 2.7 15.9 248.9 20.3 1.7 Nd Nd Nd 0.1 Nd Nd Nd Median 33.1 3.5 17.2 4.6 23.1 1.3 Nd Nd 13.0 9.8 1.9 3.2 32.6 1.6 1.1 Nd Nd Nd 0.1 Nd Nd Nd Refined list of priority pharmaceuticals for monitoring ecotoxicology and removal studies Zuccato et al, ESPR 2006 Pharmaceuticals : concentrations in the environment • • • • • Wastewater : 100-1000 ng/L Sewage : 100-1000 ng/kg Surface water (rivers, lakes) : 10-100 ng/L Drinking water : 1-10 ng/L Sea water : 0.1-1 ng/L 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 Mid-term Risk Management: Information, Training, and Education • Education and training (staff) • Information of all involved people (pharmacists, doctors, patients,…) Pharmacovigilance has tohas inform and pharmacists! even Santa Claus todoctors train his staff Different approaches for the reduction of the pharmaceuticals in the environment Long term approach: green pharmacy Green Drugs Readily degradable in the Environment No Exposition No Effects, no Risk ! 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 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 Modification of Structure Changes Properties OH Benzene: not biodegradable cancergenic, not bactericidal Phenol: readily biodgradable not concerogenic bactericidal Green Chemistry for a healthier environment GP Velo, 7th ISoP Annual Meeting Bye-bye Au revoir (zai jian) Ciao