Effects and Risks of Pharmaceuticals in the Environment

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Effects and Risks of Pharmaceuticals in the Environment Dissertation Thesis in Environmental Chemistry Effects and Risks of Pharmaceuticals in the Environment Radka Zounková 2010 Masaryk University, Faculty of Science, RECETOX – Research Centre for Toxic Compounds in the Environment Brno, Czech Republic Supervisor: Assoc. Prof. Blahoslav Maršálek, Ph.D. Supervisor – specialist: Assoc. Prof. LudˇekBláha, Ph.D. Bibliographic identification Author: Radka Zounková Title of dissertation: Effects and Risks of Pharmaceuti- cals in the Environment Title of dissertation (in Czech): Úˇcinkya rizika léˇcivv životním prostˇredí Ph.D. study program: Chemistry Specialization: Environmental Chemistry Supervisor: Assoc. Prof. Blahoslav Maršálek, Ph.D. Supervisor - specialist: Assoc. Prof. LudˇekBláha, Ph.D. Year of defence: 2010 Keywords: pharmaceuticals, metabolites, eco- toxicity, genotoxicity, ecotoxico- logical bioassays, risk assessment Keywords (in Czech): léˇciva, metabolity, ekotoxicita, genotoxicita, ekotoxikologické biotesty, analýza rizik ⃝c Radka Zounková, Masaryk University, 2010 Acknowledgements I would like to thank my supervisor Assoc. Prof. Blahoslav Maršálek, Ph.D. and especially my supervisor - specialist Assoc. Prof. LudˇekBláha, Ph.D. for all the support, advice, motivation and help during my Ph.D. studies. Thanks belong also to Mgr. Klára Hilscherová, Ph.D. for her help at the beginning of my work. I would like to express my gratitude to my colleagues and friends from the RECETOX for their help, advice, and answers to my questions, as well as my colleagues from IHU in Aachen and AQUAbase project-mates for the opportunity to work in such an inspiring and motivating environment. Further I would like to thank Ondráš Pˇribyla,without whom this dis- sertation would have never been written, my sister Danka, Jakub Mareˇcek, and Petr Tobola, without whom this dissertation would have never looked like it does. Last but not least, I wish to thank to the FRVŠ fund of the Ministry of Education, Youth and Sports and the Marie-Curie Actions Programme of the European Commission for their financial support. Abstract Pharmaceuticals, diagnostics, and other products of the pharmaceutical in- dustry are widely perceived as helpful. However, when enter the envi- ronment, it may not be so. On the contrary, they may have effects as any other chemical compounds polluting the environment. Pharmaceuticals have been developed to have specific effects on living organisms, i.e. hu- mans or animals. As pollutants, they may well affect the environment in similar, but often unforeseen ways. The presented work describes using of classic aquatic bioassays and genotoxicity assays in order to evaluate the risks associated with two groups of pharmaceuticals – veterinary antimicrobials and cytostatics (antineoplas- tics), and their metabolites. Antimicrobials are used in the treatment of in- fectious diseases. They aim at killing or controlling growth of bacteria and other micro organisms. Cytostatics are used in cancer treatment. They tar- get rapidly growing eukaryotic cells, which form tumours. Both groups of pharmaceuticals can thus affect the growth and metabolism of cells, which form all the living organisms. These effects may manifest on different levels of ecosystem. This thesis investigates acute and chronic effects – immobi- lisation, growth inhibition, inhibition of reproduction – and genotoxicity. Within the frame of the three studies, bioassays involving representatives of all main trophic levels of an ecosystem – producers, consumers, and de- composers – were used. Genotoxicity was studied using both prokaryotic and eukaryotic models. Cytostatics are entering the environment in relatively small amounts mainly as more or less changed metabolic products of oncological patients. Some cytostatics, indeed, do not undergo any metabolic reactions at all. With respect to their high toxicity and the mode of action targeted on DNA, they are considered one of the priority groups of pharmaceuticals as far as the effects on ecosystem are concerned. 5-fluorouracil can be highlighted as the most toxic compound, but most tested compounds showed significant effects in all bioassays used. 5-fluorouracil and doxorubicin exhibited the highest genotoxicity, but significant genotoxicity of all tested compounds except cyclophosphamide was confirmed. The human metabolites of cyto- statics elicited generally lower or no toxicity in tested concentrations. Only the metabolite of 5-fluorouracil reached values comparable with the toxicity of the less toxic parent compounds. Veterinary antimicrobials enter the environment in considerably higher amounts than cytostatics. This is true especially for substances used for prevention and treatment of fish infections in aquacultures. Results of the complex assessment confirmed that these compounds may have severe ef- fects in aquatic ecosystems. Both compounds tested – oxytetracycine and flumequine – elicited significant effects in most tests. Flumequine elicited markedly higher toxicity in the tests with D. magna and genotoxicity. Risk assessment based on the results of the present dissertation seems to indicate significant risks for both veterinary antimicrobials and highly toxic cytostatic compounds. In summary, this work contributes to the environmental research of pharmaceuticals as an example of micropollutants with a specific mode of action. Compounds used in high quantities may represent a significant risk for the environment, especially when considering their potential long-term effects. Abstrakt (abstract in Czech) Léky, diagnostické látky a další produkty farmaceutického pr ˚umyslujsou vˇetšinouchápány jako látky zdraví prospˇešné,v životním prostˇredítomu tak však není. Naopak, mohou p ˚usobitjako jakékoli jiné chemické látky, které životní prostˇredízneˇciš´tují. Prvotním úˇcelemlék ˚uje definovaným zp ˚usobemp ˚usobitna živý organismus – tedy ˇclovˇekanebo zvíˇre.Problém je však v tom, že podobný nebo jiný úˇcinekmohou mít léky i poté, co se dostanou do životmího prostˇredí. Pˇredkládanápráce popisuje použití klasických ekotoxikologických bio- test ˚ua test ˚ugenotoxicity pro hodnocení úˇcink˚ua rizik dvou skupin lék ˚u– veterinárních antibiotik a cytostatik – a jejich metabolit ˚uv životním prostˇre- dí. Antibiotika se používají k léˇcbˇeinfekˇcníchonemocnˇení,jejich úˇcinekje zamˇeˇrenna mikroorganismy, pˇredevšímbakterie, a to tak, že jejich r ˚ust omezují nebo je zabíjejí. Cytostatika se používají k léˇcbˇerakoviny, jejich úˇcinekje zamˇeˇrenna rychle rostoucí eukaryotické buˇnky, z nichž jsou tvoˇre- ny nádory. Obˇedvˇeskupiny léˇcivtedy mohou ovlivˇnovatr ˚usta metabo- lické pochody bunˇek,z kterých jsou tvoˇrenyvšechny živé organismy, a tento úˇcinekse m ˚užeprojevit na r ˚uznýchúrovních ekosystému. Použité metody zahrnují studium akutních i chronických úˇcink˚u– imobilizaci, in- hibici r ˚ustu,inhibici reprodukce – a genotoxicity. V rámci tˇrístudií byly použity testy zahrnují zástupce všech trofických úrovní ekosystému – pro- ducenty, konzumenty i destruenty. Genotoxicita byla studována na proka- ryotickém i eukaryotickém modelu. Cytostatika se do životního prostˇredídostávají v relativnˇemalém množ- ství, a to pˇrevážnˇejako více ˇcíménˇezpracované produkty metabolismu onkologických pacient ˚u;nˇekterácytostatika ovšem nepodstupují metabo- lické reakce v ˚ubec. Vzhledem k vysoké toxicitˇea mechanismu úˇcinku, který je cílen na DNA, jsou považována za jednu z prioritních skupin léˇciv co se týˇcep ˚usobenína ekosystém. Témˇeˇrvšechny testované látky vyka- zovaly významné úˇcinkyve všech použitých testech. Za nejtoxiˇctˇejšílátku m ˚užemeoznaˇcit5-fluorouracil. Výsledky test ˚ugenotoxicity potvrdily výz- namnou genotoxicitu u všech testovaných látek kromˇecyklofosfamidu. Nej- vyšší genotoxicitu prokázaly 5-fluorouracil a doxorubicin. Testované hu- mánní metabolity cytostatik vykazovaly všeobecnˇenižší nebo žádnou toxi- citu v testovaných koncentracích. Pouze metabolit 5-fluorouracilu dosaho- val hodnot srovnatelných s toxicitou ménˇetoxických p ˚uvodníchlátek. Veterinární antibiotika ˇciantimikrobní látky se dostávají do životního prostˇredív ˇrádovˇevˇetšíchmnožstvích. Zvláštˇelátky používané v aqua- kulturách pro prevenci a léˇceníinfekcí ryb jsou aplikovány v podstatných množstvích pˇrímodo vody – pˇredevšímjako medikované krmné smˇesi. Výsledky komplexního testování potvrdily, že tyto látky mohou mít zá- važné úˇcinkyve vodních ekosystémech. Obˇetestované antimikrobní látky používané v aquakulturách – oxytetracyklin a flumequin – vykazovaly výz- namné úˇcinkytémˇeˇrve všech použitých testech. Flumequin vykazoval výraznˇevyšší toxicitu v testech s D. magna a genotoxicitu. Výpoˇctya odhady koeficientu rizika založené na výsledcích pˇredklá- dané práce naznaˇcujívýznamné riziko pro veterinární antibiotika i cyto- statika. Pˇredkládanápráce pˇrispívásvými výsledky k výzkumu farmak jakožto mikropolutant ˚use specifickým mechanismem úˇcinku.Takové látky používané ve velkých množstvích mohou pˇredstavovatvýznamné riziko pro životní prostˇredízejména vzhledem ke svým možným dlouhodobým úˇcink˚um. List of abbreviations 5-FU 5-fluorouracil ADaM Aachener Daphnien Medium AF assessment factor APCI atmospheric pressure chemical ionization araU uracil-1-β-D-arabinofuranoside – metabolite of cytara- bine ATC Anatomical-Therapeutic-Chemical classification CAS chemical abstract service CIS cisplatin CNI Czech Normalisation Institute CP cyclophosphamide CYT cytarabine DAD diode array detector dFdU 2’,2’-difluorodeoxyuridine – metabolite of gemcitabine DHF dihydrofolic acid DIN Deutsches Institut
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