Benzalkonium Chloride and Anticancer Drugs in Binary Mixtures: Reproductive Toxicity and Genotoxicity in the Freshwater Crustacean Ceriodaphnia dubia

  • Chiara Russo
  • Michael Kundi
  • Margherita Lavorgna
  • Alfredo Parrella
  • Marina Isidori
Article

Abstract

Benzalkonium chloride (BAC) is a cationic surfactant commonly used as a disinfectant. Its ubiquitous nature is the result of high usage and frequent discharge into the environment and evidence of interaction with numerous contaminants, such as pharmaceutical active compound residues. Anticancer drugs, among these compounds, are able to exert eco-genotoxic effects at sub ng–µg/L. The purpose of this study was to assess the reproductive toxicity and the genotoxicity of 5-fluorouracil (5-FU), cisplatin (CDDP), etoposide (ET), and imatinib mesylate (IM)—binary mixtures combined with BAC in Ceriodaphnia dubia. The effects of the mixtures were assessed under the assumption of independent action in experiments that applied two effect levels. The type of interaction was not the same over the range of effect sizes. The combined action experiment on reproduction showed an antagonistic effect at higher effect levels for all binary combinations, except for BAC/IM, whereas independent action was observed in all mixtures at a low effect level. The results of binary combinations on genotoxicity showed antagonistic effects for BAC + ET and BAC + CDDP, whereas independence was expressed in BAC + IM and BAC + 5-FU. The antagonistic interactions still led to higher effects than those observed after single exposures at the same doses in most cases. The effects of mixtures of drugs should be taken into account for environmental risk assessment.

Notes

Acknowledgements

This work was financially supported by the EU through the EU FP7 Project CytoThreat (Fate and effects of cytostatic pharmaceuticals in the environment and the identification of biomarkers for an improved risk assessment on environmental exposure. Grant Agreement No. 265264).

Supplementary material

244_2017_473_MOESM1_ESM.docx (163 kb)
Supplementary material 1 (DOCX 163 kb)

References

  1. Alblas J, Corven EJ, Hordijk PL, Milliganl G, Moolenaarll WH (1993) Gi-mediated activation of the p21ras-mitogen-activated protein kinase pathway by a2-adrenergic receptors expressed in fibroblasts. J Biol Chem 268(30):22235–22238Google Scholar
  2. Bliss CI (1939) The toxicity of poisons applied jointly. Ann Appl Biol 26(3):585–615CrossRefGoogle Scholar
  3. Brezovšek P, Eleršek T, Filipič 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
  4. Chang C, Zhang AQ, Kagan DB, Liu H, Hutnik CM (2015) Mechanisms of benzalkonium chloride toxicity in a human trabecular meshwork cell line and the protective role of preservative-free tafluprost. Clin Exp Ophthalmol 43(2):164–172CrossRefGoogle Scholar
  5. Clouzeau C, Godefroy D, Riancho L, Rostène W, Baudouin C, Brignole-Baudouin F (2012) Hyperosmolarity potentiates toxic effects of benzalkonium chloride on conjunctival epithelial cells in vitro. Mol Vis 18:851–863Google Scholar
  6. Ermler S, Scholze M, Kortenkamp A (2014) Genotoxic mixtures and dissimilar action: concepts for prediction and assessment. Arch Toxicol 88:799–814Google Scholar
  7. Fabarius A, Giehl M, Frank O et al (2007) Centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle defects and genetic instability. Br J Haematol 138(3):369–373CrossRefGoogle Scholar
  8. Ferk F, Mišík M, Hoelzl C et al (2007) Benzalkonium chloride (BAC) and dimethyldioctadecyl-ammonium bromide (DDAB), two common quaternary ammonium compounds, cause genotoxic effects in mammalian and plant cells at environmentally relevant concentrations. Mutagenesis 22(6):363–370CrossRefGoogle Scholar
  9. Gajski G, Gerić M, Žegura B et al (2015) Genotoxic potential of selected cytostatic drugs in human and zebrafish cells. Environ Sci Pollut Res 23(15):14739–14750CrossRefGoogle Scholar
  10. Ge F, Xu Y, Zhu R, Yu F, Zhu M, Wong M (2010) Joint action of binary mixtures of cetyltrimethyl ammonium chloride and aromatic hydrocarbons on Chlorella vulgaris. Ecotox Environ Safe 73:1689–1695CrossRefGoogle Scholar
  11. Greco CC (1996) Heavy metal removal system containing clay, quaternary ammonium compound, and mercaptan. US Pat 5:521–526Google Scholar
  12. Guo Y, Satpathy M, Wilson G, Srinivas SP (2007) Benzalkonium chloride induces dephosphorylation of myosin light chain in cultured corneal epithelial cells. Invest Ophthalmol Vis Sci 48(5):2001–2008CrossRefGoogle Scholar
  13. ISO 20665 (2008) Water quality-determination of chronic toxicity to Ceriodaphnia dubia in 7 days-population growth inhibition test. International Organization for Standardization, GenevaGoogle Scholar
  14. Ivanković T, Hrenović J (2010) Surfactants in the environment. Arh Hig Rada Toksikol 61(1):95–110Google Scholar
  15. Kovács R, Csenki Z, Bakosa K et al (2015) Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish (Danio rerio) two-generation study. Water Res 77:201–212CrossRefGoogle Scholar
  16. Kreuzinger N, Fuerhacker M, Scharf S, Uhl M, Gans O, Grillitsch B (2007) Methodological approach towards the environmental significance of uncharacterized substances—quaternary ammonium compounds as an example. Desalination 215(1–3):209–222CrossRefGoogle Scholar
  17. Kundi M, Parrella A, Lavorgna M, Criscuolo E, Russo C, Isidori M (2015) Prediction and assessment of ecogenotoxicity of antineoplastic drugs in binary mixtures. Environ Sci Pollut Res 23(15):14771–14779CrossRefGoogle Scholar
  18. Lavorgna M, Russo C, D’Abrosca B, Parrella A, Isidori M (2016) Toxicity and genotoxicity of the quaternary ammonium compound benzalkonium chloride (BAC) using Daphnia magna and Ceriodaphnia dubia as model systems. Environ Pollut 210:34–39CrossRefGoogle Scholar
  19. Li MH (2012) Survival, mobility, and membrane-bound enzyme activities of freshwater planarian, Dugesia japonica, exposed to synthetic and natural surfactants. Environ Toxicol Chem 31(4):843–850CrossRefGoogle Scholar
  20. Liversidge GG, Liversidge E, Sarpotdar PP (1996) Surface modified anticancer nanoparticles. US Pat 5:494–683Google Scholar
  21. Loewe S, Muischnek H (1926) Über Kombinationswirkungen Mitteilung: Hilfsmittel der Fragestellung. Naunyn-Schmiedebergs Arch Pharmakol Exp Pathol 114(5):313–326CrossRefGoogle Scholar
  22. Mahnik SN, Lenz K, Weissenbacher N, Mader RM, Fuerhacker M (2007) Fate of 5-fluorouracil, doxorubicin, epirubicin, and daunorubicin in hospital wastewater and their elimination by activated sludge and treatment in a membrane-bio-reactor system. Chemosphere 66:30–37CrossRefGoogle Scholar
  23. Martínez-Carballo E, Sitka A, González-Barreiro C et al (2007) Determination of selected quaternary ammonium compounds by liquid chromatography with mass spectrometry. Part I. Application to surface, waste and indirect discharge water samples in Austria. Environ Pollut 145:489–496CrossRefGoogle Scholar
  24. Mater N, Geret F, Castillo L, Faucet-Marquis V, Albasi C, Pfohl-Leszkowicz A (2014) In vitro tests aiding ecological risk assessment of ciprofloxacin, tamoxifen and cyclophosphamide in range of concentrations released in hospital wastewater and surface water. Environ Int 63:191–200CrossRefGoogle Scholar
  25. Mišík 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
  26. Olkowska E, Ruman M, Polkowska Ż (2014) Occurrence of surface active agents in the environment. J Anal Met Chem.  https://doi.org/10.1155/2014/769708 Google Scholar
  27. Parrella A, Kundi M, Lavorgna M, Criscuolo E, Russo C, Isidori M (2014a) Toxicity of exposure to binary mixtures of four anti-neoplastic drugs in Daphnia magna and Ceriodaphnia dubia. Aquat Toxicol 157:41–46CrossRefGoogle Scholar
  28. Parrella A, Lavorgna M, Criscuolo E, Russo C, Fiumano V, Isidori M (2014b) Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans. Chemosphere 115:59–66CrossRefGoogle Scholar
  29. Parrella A, Lavorgna M, Criscuolo E, Russo C, Isidori M (2014c) Estrogenic activity and cytotoxicity of six anticancer drugs detected in water systems. Sci Total Environ 485:216–222CrossRefGoogle Scholar
  30. Parrella A, Lavorgna M, Criscuolo E, Russo C, Isidori M (2015) Eco-genotoxicity of six anticancer drugs using comet assay in daphnids. J Hazard Mater 286:573–580CrossRefGoogle Scholar
  31. Sánchez-Fortún S, Llorente MT, Castaño A (2005) Genotoxic effects of selected biocides on RTG-2 fish cells by means of a modified Fast Micromethod Assay. Aquat Toxicol 73:55–64CrossRefGoogle Scholar
  32. Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175(1):184–191CrossRefGoogle Scholar
  33. Statsoft Inc. (2011) STATISTICA (data analysis software system), ver. 10.0. Statsoft Inc., TulsaGoogle Scholar
  34. Sütterlin H, Alexy R, Kümmerer K (2008) The toxicity of the quaternary ammonium compound benzalkonium chloride alone and in mixtures with other anionic compounds to bacteria in test systems with Vibrio fischeri and Pseudomonas putida. Ecotox Environ Safe 71:498–505CrossRefGoogle Scholar
  35. Tice RR, Agurell E, Anderson D et al (2009) Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35(3):206–221CrossRefGoogle Scholar
  36. Trevisan A, Borella-Venturini M, Di Marco L et al (2004) Erythrocyte aminolevulinic acid dehydratase inhibition by cis-platin. Toxicol Lett 152(2):105–110Google Scholar
  37. Yoshida M, Yoshida H, Kitaichi K et al (2001) Adrenomedullin and proadrenomedullin N-terminal 20 peptide induce histamine release from rat peritoneal mast cell. Regul Pept 101(1–3):163–168CrossRefGoogle Scholar
  38. Zhang C, Tezel U, Li K et al (2011) Evaluation and modeling of benzalkonium chloride inhibition and biodegradation in activated sludge. Water Res 45:1238–1246CrossRefGoogle Scholar
  39. Zhang C, Cui F, Zeng G et al (2015) Quaternary ammonium compounds (QACs): a review on occurrence, fate and toxicity in the environment. Sci Total Environ 518:352–362CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Chiara Russo
    • 1
  • Michael Kundi
    • 2
  • Margherita Lavorgna
    • 1
  • Alfredo Parrella
    • 1
  • Marina Isidori
    • 1
  1. 1.Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e FarmaceuticheUniversità della Campania “Luigi Vanvitelli”CasertaItaly
  2. 2.Center for Public Health, Institute of Environmental HealthMedical University of ViennaViennaAustria

Personalised recommendations