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Environmental Science and Pollution Research

, Volume 23, Issue 15, pp 14780–14790 | Cite as

Toxicity of the mixture of selected antineoplastic drugs against aquatic primary producers

  • Tina Elersek
  • Sara Milavec
  • Maša Korošec
  • Polona Brezovsek
  • Noelia Negreira
  • Bozo Zonja
  • Miren López de Alda
  • Damià Barceló
  • Ester Heath
  • Janez Ščančar
  • Metka Filipič
Fate and effects of the residues of anticancer drugs in the environment

Abstract

The residues of antineoplastic drugs are considered as new and emerging pollutants in aquatic environments. Recent experiments showed relatively high toxicity of 5-fluorouracil (5-FU), imatinib mesylate (IM), etoposide (ET) and cisplatin (CP) that are currently among most widely used antineoplastic drugs, against phytoplankton species. In this study, we investigated the toxic potential of the mixture of 5-FU + IM + ET against green alga Pseudokirchneriella subcapitata and cyanobacterium Synechococcus leopoliensis, and the stability and sorption of these drugs to algal cells. Toxic potential of the mixture was predicted by the concepts of ‘concentration addition’ and ‘independent action’ and compared to the experimentally determined toxicity. In both test species, the measured toxicity of the mixture was at effects concentrations EC10–EC50 higher than the predicted, whereas at higher effect concentration (EC90), it was lower. In general, P. subcapitata was more sensitive than S. leopoliensis. The stability studies of the tested drugs during the experiment showed that 5-FU, IM and CP are relatively stable, whereas in the cultures exposed to ET, two transformation products with the same mass as ET but different retention time were detected. The measurements of the cell-linked concentrations of the tested compounds after 72 h exposure indicated that except for CP (1.9 % of the initial concentration), these drugs are not adsorbed or absorbed by algal cells. The results of this study showed that in alga and cyanobacteria exposure to the mixture of 5-FU + ET + IM, in particular at low effect concentration range, caused additive or synergistic effect on growth inhibition, and they suggest that single compound toxicity data are not sufficient for the proper toxicity prediction for aquatic primary producers.

Keywords

Mixture toxicity Antineoplastics 5-fluorouracil Imatinib mesylate Etoposide Cisplatin Algae Cyanobacteria 

Notes

Acknowledgments

This study received funding from the Seventh Framework Programme FP7/2007-2013 under grant agreement No 265264 (CytoThreat). The authors would like to thank to Mihael Bricelj, Katja Kološa, Karmen Stanič and Kazimir Drašlar for their assistance at the experimental work.

References

  1. Altenburger R, Greco WR (2009) Extrapolation concepts for dealing with multiple contamination in environmental risk assessment. Integr Environ Assess Manag 5:62–68Google Scholar
  2. Backhaus T, Karlsson M (2014) Screening level mixture risk assessment of pharmaceuticals in STP effluents. Water Res 49:157–165CrossRefGoogle Scholar
  3. Besse JP, Latour JF, Garric J (2012) Anticancer drugs in surface waters: what can we say about the occurrence and environmental significance of cytotoxic, cytostatic and endocrine therapy drugs? Environ Int 39:73–86Google Scholar
  4. Bliss CI (1939) The toxicity of poisons applied jointly. Ann Appl Biol 26:585–615CrossRefGoogle Scholar
  5. Booker V, Halsall C, Llewellyn N, Johnson A, Williams R (2014) Prioritising anticancer drugs for environmental monitoring and risk assessment purposes. Sci Total Environ 473–474:159–170CrossRefGoogle Scholar
  6. Brain RA, Johnson DJ, Richards SM, Hanson ML, Sanderson H, Lam MW, Young C, Mabury SA, Sibley PK, Solomon KR (2004) Microcosm evaluation of the effects of an eight pharmaceutical mixture to the aquatic macrophytes Lemna gibba and Myriophyllum sibiricum. Aquat Toxicol 70(1):23–40CrossRefGoogle Scholar
  7. Brezovsek P, Elersek T, Filipic M (2014) Toxicities of four anti-neoplastic drugs and their binary mixtures tested on the green alga Pseudokirchneriella subcapitata and the cyanobacterium Synechococcus leopoliensis. Water Res 52:168–177CrossRefGoogle Scholar
  8. Chou TC, Martin N (2007) CompuSyn software for drug combinations and for general dose effect analysis, and user’s guide. ComboSyn, Inc. Paramus, NJ. http://www.combosyn.com. Accessed 15 May 2014
  9. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationship: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55CrossRefGoogle Scholar
  10. Cleuvers M (2003) Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Toxicol Lett 142:185–194CrossRefGoogle Scholar
  11. Eitel A, Scherrer M, Kuemmerer K (2000) Handling cytostatic drugs: a practical guide. Bristol-Myers-Squibb, MünchenGoogle Scholar
  12. Elersek T (2012) The advantages of flow cytometry in comparison to fluorimetric measurement in algal toxicity test. Acta Biol Slov 55(2):3–11Google Scholar
  13. Fabarius A, Giehl M, Frank O, Duesberg P, Hochhaus A, Hehlmann R, Seifarth W (2005) Induction of centrosome and chromosome aberrations by imatinib in vitro. Leukemia 19:1573–1578CrossRefGoogle Scholar
  14. Fabarius A, Giehl M, Frank O, Spiess B, Zheng C, Muller MC, Weiss C, Duesberg P, Hehlmann R, Hochhaus A, Seifarth W (2007) Centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle defects and genetic instability. Br J Haematol 138:369–73CrossRefGoogle Scholar
  15. Faust M, Altenburger R, Backhaus T, Bodeker W, Scholze M, Grimme LH (2000) Predictive assessment of the aquatic toxicity of multiple chemical mixtures. J Environ Qual 29:1063–1068CrossRefGoogle Scholar
  16. Fava C, Rege-Cambrin G, Saglio G (2015) The choice of first-line chronic myelogenous leukemia treatment. Ann Hematol 94(2):S123–31CrossRefGoogle Scholar
  17. Fent K, Weston AA, Caminada D (2006) Ecotoxicology of human pharmaceuticals. Aquat Toxicol 76:122–159CrossRefGoogle Scholar
  18. Hagenbuch IM, Pinckney JL (2012) Toxic effect of the combined antibiotics ciprofloxacin, lincomycin, and tylosin on two species of marine diatoms. Water Res 46:5028–5036CrossRefGoogle Scholar
  19. Hernando MD, Mezcua M, Fernández-Alba AR, Barceló D (2006) Environmental risk assessment of pharmaceutical residues in wastewater effluents, surface waters and sediments. Talanta 69(2):334–342CrossRefGoogle Scholar
  20. Hughes SR, Kay P, Brown LE (2012) Global synthesis and critical evaluation of pharmaceutical data sets collected from river systems. Environ Sci Technol 47(2):661–677CrossRefGoogle Scholar
  21. Jia J, Zhu F, Ma X, Cao ZW, Li YX, Chen YZ (2009) Mechanisms of drug combinations: interaction and network perspectives. Nat Rev Drug Discov 8:111–128CrossRefGoogle Scholar
  22. Kosjek T, Heath E (2011) Occurrence, fate and determination of cytostatic pharmaceuticals in the environment. Trends Anal Chem 30(7):1065–1087CrossRefGoogle Scholar
  23. Kosjek T, Perko S, Žigon D, Heath E (2013) Fluorouracil in the environment: analysis, occurrence, degradation and transformation. J Chromatogr A 1290:62–72Google Scholar
  24. Kuemmerer K, Al-Ahmad A, Bertram B, Wießler M (2000) Biodegradability of antineoplastic compounds in screening tests: influence of glucosidation and of stereochemistry. Chemosphere 40(7):767–773CrossRefGoogle Scholar
  25. Lenz K, Mahnik SN, Weissenbacher N, Mader RM, Krenn P, Hann S, Koellensperger G, Uhl M, Knasmueller S, Ferk F, Bursch W, Fuerhacker M (2007) Monitoring, removal and risk assessment of cytostatic drugs in hospital wastewater. Water Sci Technol 56(12):141–149CrossRefGoogle Scholar
  26. Loewe S, Muischnek H (1926) Ueber kombinationswirkungen. 1. Mitteilung: Hilfsmittel der fragestellung. Schmiedeb. Arch Exp Pathol Pharmakol 114:313–326CrossRefGoogle Scholar
  27. Magnusson M, Heimann K, Quayle P, Negri AP (2010) Additive toxicity of herbicide mixtures and comparative sensitivity of tropical benthic microalgae. Mar Pollut Bull 60(11):1978–1987CrossRefGoogle Scholar
  28. Mahnik SN, Rizovski B, Fuerhacker M, Mader RM (2004) Determination of 5-fluorouracil in hospital effluents. Anal Bioanal Chem 380:31–35CrossRefGoogle Scholar
  29. Martín J, Camacho-Muñoz D, Santos JL, Aparicio I, Alonso E (2014) Occurrence and ecotoxicological risk assessment of 14 cytostatic drugs in wastewater. Water Air Soil Pollut 225:10Google Scholar
  30. Misik M, Pichler C, Rainer B, Filipic M, Nersesyan A, Knasmueller S (2014) Acute toxic and genotoxic activities of widely used cytostatic drugs in higher plants: possible impact on the environment. Environ Res 135:196–203CrossRefGoogle Scholar
  31. Negreira N, Mastroianni N, Lopez de Alda M, Barcelo D (2013) Multianalyte determination of 24 cytostatics and metabolites by liquid chromatography-electrospray-tandem mass spectrometry and study of their stability and optimum storage conditions in aqueous solution. Talanta 116:290–299CrossRefGoogle Scholar
  32. Negreira N, Lopez de Alda M, Barcelo D (2014a) Study of the stability of 26 cytostatic drugs and metabolites in wastewater under different conditions. Sci Total Environ 482(3):389–398CrossRefGoogle Scholar
  33. Negreira N, Lopez de Alda M, Barceló D (2014b) Cytostatic drugs and metabolites in municipal and hospital wastewaters in Spain: filtration, occurrence, and environmental risk. Sci Total Environ 497–498:68–77CrossRefGoogle Scholar
  34. OECD TG 201 (2011) Organisation for Economic Co-operation and Development (OECD) Guidelines for the Testing of Chemicals, Section 2: Effects on Biotic Systems Test No. 201: Freshwater Alga and Cyanobacteria, Growth Inhibition Test OECD. OECD PublishingGoogle Scholar
  35. Parrella A, Lavorgna M, Criscuolo E, Russo C, Fiumano V, Isidori M (2014) Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans. Chemosphere 115:59–66CrossRefGoogle Scholar
  36. Pfleeger T, McFarlane JC, Sherman R, Volk G (1991) A short-term bioassay for whole plant toxicity. In: Gorsuch JW et al. (ed) Plant for toxicity assessment Vol 2 ASTM publ. 04-011150-16. American society of testing and materials, West Conshohocken, 355–364Google Scholar
  37. Pomati F, Orlandi C, Clerici M, Luciani F, Zuccato E (2008) Effects and interactions in an environmentally relevant mixture of pharmaceuticals. Toxicol Sci 102(1):129–137CrossRefGoogle Scholar
  38. Rodriguez-Mozaz S, Howard SW (2010) Meeting report: pharmaceuticals in water—an interdisciplinary approach to a public health challenge. Environ Health Perspect 118(7):1016–1020CrossRefGoogle Scholar
  39. Silva E, Rajapakse N, Kortenkamp A (2002) Something from “nothing” - eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol 36:1751–1756CrossRefGoogle Scholar
  40. Simpson SL, Roland MGE, Stauber JL, Batley GE (2003) Effect of declining toxicant concentrations on algal bioassay endpoints. Environ Toxicol Chem 22:2073–2079CrossRefGoogle Scholar
  41. Sumpter JP, Johnson AC, Williams RJ, Kortenkamp A, Scholze M (2006) Modeling effects of mixtures of endocrine disrupting chemicals at the river catchment scale. Environ Sci Technol 40(17):5478–5489CrossRefGoogle Scholar
  42. Xie H (2012) Occurrence, ecotoxicology, and treatment of anticancer agents as water contaminants. J Environ Anal Toxicol S2:1–11Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Tina Elersek
    • 1
  • Sara Milavec
    • 1
  • Maša Korošec
    • 1
  • Polona Brezovsek
    • 1
    • 2
  • Noelia Negreira
    • 3
  • Bozo Zonja
    • 3
  • Miren López de Alda
    • 3
  • Damià Barceló
    • 3
  • Ester Heath
    • 4
  • Janez Ščančar
    • 4
  • Metka Filipič
    • 1
  1. 1.Department of Genetic Toxicology and Cancer BiologyNational Institute of BiologyLjubljanaSlovenia
  2. 2.Ecological Engineering InstituteMariborSlovenia
  3. 3.Water and Soil Quality Research Group, Department of Environmental ChemistryInstitute of Environmental Assessment and Water ResearchBarcelonaSpain
  4. 4.Jožef Stefan InstituteLjubljanaSlovenia

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