PharmaceuticalsPharmaceuticals asas EnvironmentalEnvironmental Contaminants:Contaminants: anan OverviewOverview ofof thethe ScienceScience Christian G. Daughton, Ph.D. Chief, Environmental Chemistry Branch Environmental Sciences Division National Exposure Research Laboratory Office of Research and Development Environmental Protection Agency Las Vegas, Nevada 89119 [email protected] Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Why and how do drugs contaminate the environment? What might it all mean? How do we prevent it? Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada This talk presents only a cursory overview of some of the many science issues surrounding the topic of pharmaceuticals as environmental contaminants Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada A Clarification We sometimes loosely (but incorrectly) refer to drugs, medicines, medications, or pharmaceuticals as being the substances that contaminant the environment. The actual environmental contaminants, however, are the active pharmaceutical ingredients – APIs. These terms are all often used interchangeably Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Office of Research and Development Available: http://www.epa.gov/nerlesd1/chemistry/pharma/image/drawing.pdfNational Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada TheThe ChemicalChemical UniverseUniverse We live in a chemical sea of continually changing composition – comprising both anthropogenic and naturally occurring chemical stressors. Unlike biota, chemical pollutants have no boundaries in their global distribution – “everything is everywhere,” only the concentrations vary. TheThe ChemicalChemical UniverseUniverse The KNOWN Universe As of August 2002009,9, over 49 million organic and inorganic substances had been assigned CAS RNs. (indexe(indexedd by the American Chemical Society's Chemical Abstracts Service in their CAS Registry; excluding bio-sequences such as proteins and nucleotides: http://www.cas.org/expertise/cascontent/registry/regsys.html) Ø Of these millions of known chemicals, nearly 35 million were commercially available. Ø Of these, fewer than a quarter million (249,000) are inventoried or regulated by numerous government bodies worldwide - - representing about 0.7% of those that are commercially available or roughly 0.5% of the known universe of chemicals. Ø Approximately 12,000 new substances are added each day. TheThe ChemicalChemical UniverseUniverse The largest virtual chemical database yet reported comprises small drug-like molecules - - a total of over 977,000,000 structures (Blum and Reymond, 2009). Restricted to organic molecules containing fewer than 14 atoms of C, N, O, and S (and limited types of Cl-substituted molecules). Excluded likely substituents such as F, Br, I, P, Si, metals, and most Cl. Database represents the enormously large numbers of chemicals that could possibly be synthesized just from a very limited spectrum of types of elements and numbers of atoms. Blum, L. C., and J.-L. Reymond. 2009. 970 Million Druglike Small Molecules for Virtual Screening in the Chemical Universe Database GDB-13. J. Am. Chem. Soc. 131 (25):8732-8733. TheThe UniverseUniverse ofof CommercialCommercial APIsAPIs § Over 21,000 formulated drug products (ingredients, strengths, and form) § Over 1,460 FDA-approved small-molecule APIs (molecularly distinct); oral >800, parenteral >420; topical >270 § Over 3,200 experimental drugs Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, et al. "DrugBank: a knowledgebase for drugs, drug actions and drug targets." Nucl Acids Res 2008, 36(suppl_1):D901-906; doi:10.1093/nar/gkm958. DrugBank PharmaBroswe web page: http://www.drugbank.ca/pharmabrowse#mainB. ALIMENTARY Dolasetron VITAMINS Calcium Chloride Amiloride Felodipine Flucytosine Fluocinolone Acetonide Tioconazole Terazosin TRACT AND Granisetron Paricalcitol Cyclothiazide Nitrendipine Miconazole Triamcinolone Ketoconazole Calcium Chloride METABOLISM Ondansetron Vitamin D4 CARDIOVASCULAR Furosemide Perhexiline Econazole Flumethasone Pivalate Miconazole Finasteride STOMATOLOGICAL LAXATIVES (Dihydrotachysterol) SYSTEM CARDIAC Eplerenone Nifedipine Sertaconazole Hydrocortisone Econazole PREPARATIONS Lactulose THERAPY Hydroflumethiazide Bepridil Ciclopirox Mometasone Candicidin SYSTEMIC Doxycycline Magnesium Sulfate MINERAL Phentermine Indapamide AGENTS ACTING ON Hydrocortamate Ciclopirox HORMONAL Clotrimazole Mannitol SUPPLEMENTS Dofetilide Chlorothiazide THE RENIN- PREPARATIONS FOR Clocortolone Clindamycin PREPARATIONS, Triamcinolone Calcium Acetate Midodrine Bumetanide ANGIOTENSIN TREATMENT OF Prednisolone OTHER EXCL. SEX Epinephrine ANTIDIARRHEALS, Magnesium Sulfate Milrinone Hydrochlorothiazide SYSTEM WOUNDS AND Methylprednisolone GYNECOLOGICALS HORMONES AND Amphotericin B INTESTINAL Potassium Chloride Ranolazine Trichlormethiazide Valsartan ULCERS Clobetasol Cabergoline INSULINS Hydrocortisone ANTIINFLAMMATO Calcium Chloride Disopyramide Ramipril Isosorbide Dinitrate Fluocinonide Carboprost PITUITARY AND Tetracycline RY/ANTIINFECTIVE Lidocaine PERIPHERAL Remikiren Prednicarbate Tromethamine HYPOTHALAMIC Natamycin AGENTS ANABOLIC AGENTS Ibutilide Fumarate VASODILATORS Olmesartan Medoxomil ANTIPRURITICS, Budesonide Lisuride HORMONES AND Chlorhexidine Beclomethasone FOR SYSTEMIC USE Mexiletine Phentolamine Fosinopril INCL. Dexamethasone Naproxen ANALOGUES Metronidazole Betamethasone Oxandrolone Phenylephrine Nicergoline Trandolapril ANTIHISTAMINES, Ritodrine Gonadorelin Aspirin Vancomycin Nandrolone Digoxin Tolazoline Benazepril ANESTHETICS, ETC. ANTISEPTICS AND Dinoprostone Nafarelin Neomycin Guanidine Acetyldigitoxin Pentoxifylline Enalapril Lidocaine DISINFECTANTS Ibuprofen Carbetocin Minocycline Prednisone OTHER Metaraminol Phenoxybenzamine Losartan Procaine Hexachlorophene Dinoprost Amlexanox Nystatin ALIMENTARY Adenosine Ergoloid mesylate Moexipril Tripelennamine Chlorhexidine Tromethamine CORTICOSTEROIDS Miconazole Amphotericin B TRACT AND Epinephrine Lisinopril Oxybuprocaine Ethanol Bromocriptine FOR SYSTEMIC USE Dexamethasone Hydrocortisone METABOLISM Methoxamine VASOPROTECTIVES Perindopril Promethazine Proflavine Betamethasone Hydrocortamate PRODUCTS Nitroglycerin Lidocaine Candesartan Diphenhydramine SEX HORMONES Triamcinolone DRUGS FOR ACID Polymyxin B Sulfate Nitisinone Alprostadil Fluorometholone Eprosartan Benzocaine MEDICATED AND MODULATORS Prednisone RELATED Sulfasalazine Miglustat Fenoldopam Betamethasone Quinapril Bromodiphenhydramine DRESSINGS OF THE GENITAL Fludrocortisone DISORDERS Natamycin L-Carnitine Dobutamine Sodium Tetradecyl Telmisartan Trimeprazine -approvedFramycetin SYSTEM APIsHydrocortisone Pantoprazole Loperamide Cysteamine Isosorbide Dinitrate Sulfate Irbesartan Chlorhexidine Diethylstilbestrol Prednisolone Omeprazole Prednisolone Quinidine Fluocinolone Acetonide Captopril ANTIPSORIATICS Chlorotrianisene Rimexolone Sucralfate Neomycin BLOOD AND BLOOD Levosimendan Flumethasone Pivalate Acitretin ANTI-ACNE Conjugated Estrogens Methylprednisolone Lansoprazole Balsalazide FORMING ORGANS Dopamine Pentosan Polysulfate LIPID MODIFYING Methoxsalen PREPARATIONS Etonogestrel Trilostane Cimetidine Diphenoxylate ANTITHROMBOTIC Isosorbide Mononitrate Procaine AGENTS Tazarotene Erythromycin Desogestrel Dexamethasone Nizatidine Streptomycin AGENTS Procainamide Hydrocortisone Pravastatin Etretinate Adapalene Megestrol Pirenzepine Miconazole Ticlopidine Ibuprofen Hydrocortamate Lovastatin Fluorometholone Levonorgestrel THYROID THERAPY Homatropine Kanamycin Argatroban Tocainide Prednisolone Colestipol ANTIBIOTICS AND Chloramphenicol Dydrogesterone Liothyronine Methylbromide Rifaximin Treprostinil Deslanoside Ethanol Cerivastatin CHEMOTHERAPEUTI Azelaic Acid Progesterone Carbimazole Esomeprazole Budesonide Phenindione Arbutamine Fluocinonide Dextrothyroxine CS FOR Prednisolone Raloxifene Levothyroxine Ranitidine Fondaparinux sodium Amiodarone Benzocaine Clofibrate DERMATOLOGICAL Methylprednisolone Norgestrel Propylthiouracil Famotidine ANTIOBESITY Warfarin Bretylium Heparin Simvastatin USE Isotretinoin Medroxyprogesterone Misoprostol PREPARATIONS, Clopidogrel Propafenone Dexamethasone Colesevelam Idoxuridine Clindamycin Testosterone CALCIUM Rabeprazole EXCL. DIET Tirofiban Flecainide Ezetimibe Sulfanilamide Dexamethasone Estrone HOMEOSTASIS PRODUCTS Aspirin Encainide BETA BLOCKING Fenofibrate Penciclovir Estradiol Cinacalcet DRUGS FOR Phentermine Phenprocoumon AGENTS Atorvastatin>1,460 Sulfadiazine OTHER Mifepristone FUNCTIONAL Fenfluramine Dipyridamole ANTIHYPERTENSIV Esmolol Fluvastatin Mupirocin DERMATOLOGICAL Clomifene ANTIINFECTIVES GASTROINTESTINA Mazindol Iloprost ES Betaxolol Rosuvastatin Chloramphenicol PREPARATIONS Dienestrol FOR SYSTEMIC USE L DISORDERS Diethylpropion Heparin Reserpine Metoprolol Gemfibrozil Amikacin Pimecrolimus Norgestimate ANTIBACTERIALS Oxyphenonium Orlistat Enoxaparin Bethanidine Atenolol Sulfamethizole Minoxidil Ethinyl Estradiol FOR SYSTEMIC USE Oxyphencyclimine