Skip to main content

Advertisement

SpringerLink
Log in

Antineoplastic compounds in the environment—substances of special concern

  • Fate and effects of the residues of anticancer drugs in the environment
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

Antineoplastic drugs are important in the treatment of cancer. Some interact directly with the deoxyribonucleic acid (DNA) and are of utmost importance in terms of risk. As highly active compounds, antineoplastics and their metabolites are largely excreted into wastewater and are found in the aquatic environment up to the lower μg/L range. Their predicted environmental concentrations are often below the action limit set in the European Medicines Agency (EMA) guideline. An in-depth risk assessment regarding their presence and effects in the aquatic environment is often not performed, and there is a lack of knowledge. This study considered whether there is an underestimation of possible risks associated with the presence of antineoplastic drugs with regard to trigger value stated in the EMA and FDA guidelines. In a balance, we identified a total of 102 active pharmaceutical ingredients of the ATC-group L01 (antineoplastic agents), which are environmentally relevant. In Germany, 20.7 t of antineoplastic agents was consumed in 2012. The share of drugs with DNA-damaging properties increased within the last 6 years from 24 up to 67 %. Solely, capecitabine and 5-fluorouracil amount together 8 t—which corresponds to 39 % of the total antineoplastic consumption. Around 80 % of the total mass consumed could be attributed to prescriptions issued by office-based practitioners and is mostly excreted at home. Based on the different mode of actions, a case-by-case evaluation of the risk connected to their presence in the environment is recommended. DNA-damaging drugs should be assessed independently as no action limit can be assumed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Notes

  1. ATC: Anatomical Therapeutic Chemical/Defined Daily Dose Classification: Developed by 1976 European Pharmaceutical Market Research Association (EPhMRA), since 1990 used by the Collaborating Centre for Drug Statistics of the World Health Organization (WHO), group L: antineoplastic and immune modulating compounds.

  2. log Pow: calculated values from Drugbank and SciFinder (ALOGPS, ACD-labs and Chemaxon software). In case that an experimental and a calculated value are available the experimental one was used for selection.

References

  • Aga DS (2007) Fate of pharmaceuticals in the environment and in water treatment systems. CRC Press, Boca Raton

    Book  Google Scholar 

  • Aherne GW, Hardcastle A, Nield AH (1990) Cytotoxic drugs and the aquatic environment: estimation of bleomycin in river and water samples. J Pharm Pharmacol 42:741–742

    Article  CAS  Google Scholar 

  • Allwood M, Stanley A, Wright P (2002) The cytotoxics handbook. Radcliffe Medical Press, Oxford

    Google Scholar 

  • Bergmann A, Fohrmann R, Weber FA (2011) Arrangement of monitoring data to environmental concentrations of pharmaceuticals. Umweltbundesamt Berlin Texte 66/2011. https://www.umweltbundesamt.de/sites/default/files/medien/461/publikationen/4188.pdf. Accessed 25 Feb 2014 (in German)

  • 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 39:73–86

    Article  CAS  Google Scholar 

  • Booker V, Halsall C, Llewellyn N, Johnson A, Williams R (2014) Prioritizing anticancer drugs for environmental monitoring and risk assessment purposes. Sci Total Environ 473–474:159–170

    Article  Google Scholar 

  • Buerge IJ, Buser HR, Poiger T, Müller MD (2006) Occurrence and fate of the cytostatic drugs cyclophosphamide and ifosfamide in wastewater and surface waters. Environ Sci Technol 40:7242–7250

    Article  CAS  Google Scholar 

  • Calamari D, Zuccato E, Castiglioni S, Bagnati R, Fanelli R (2003) Strategic survey of therapeutic drugs in the rivers Po and lambro in Northern Italy. Environ Sci Technol 37:1241–1248

    Article  CAS  Google Scholar 

  • Cass Y, Musgrave CF (1992) Guidelines for the safe handling of excreta contaminated by cytotoxic agents. Am J Hosp Pharm 49:1957–1958

    CAS  Google Scholar 

  • Collier AC (2007) Pharmaceutical contaminants in potable water: potential concerns for pregnant women and children. EcoHealth 4:164–171

    Article  Google Scholar 

  • CSTEE (Committee on Toxicity, Ecotoxicity and the Environment of the EU) (2001) Opinion on: draft CPMP discussion paper on environmental risk assessment of medicinal products for human use. CCPM paper Rassess Hum Pharm 12062001/D(01):1–22. http://ec.europa.eu/health/archive/ph_risk/committees/sct/documents/out111_en.pdf. Accessed 26 Feb 2014

  • Daughton CG, Ternes TA (1999) Pharmaceuticals and personal care products in the environment: agents of subtle change? Environ Health Perspect 107:907–938

    Article  CAS  Google Scholar 

  • Dieter HH (2014) Health related guide values for drinking-water since 1993 as guidance to assess presence of new analytes in drinking-water. Int J Hyg Environ Health 217:117–132

    Article  CAS  Google Scholar 

  • Dieter HH, Mückter H (2007) Assessment of so called organic trace compounds in drinking water from the regulatory, health and aesthetic-quality points of view, with special consideration given to pharmaceuticals. Bundesgesundheitsbl Gesundheitsforsch Gesundheitsschutz 50:322–331 (in German)

    Article  CAS  Google Scholar 

  • DoH (Department of Health) (2004) Variations in usage of cancer drugs approved by NICE. Report of the review undertaken by the National Cancer Director. London: Department of Health

  • EC (European Commission) (2011) Commission regulation (EU) No 253/2011 of 15 March 2011 amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annex XIII. Official Journal of the European Union L69/7–12. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:069:0007:0012:en:PDF. Accessed 24 Feb 2014

  • EEC (European Economic Community) (1967) Council Directive 67/548/EEC of 27 June 1967 on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances (67/548/EEC). http://eur-lex.europa.eu/smartapi/cgi/sga_doc?smartapi!celexplus!prod!CELEXnumdoc&numdoc=31967L0548&lg=en. Accessed 15 Mar 2014

  • Eitel A, Scherrer M, Kümmerer K (1999) Handling cytostatic drugs: a practical guide. Bristol-Myers Squibb, München

    Google Scholar 

  • EMA (European Medicines Agency) (2006) Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. Doc. Ref. EMEA/CHMP/SWP/4447/00 corr 1 London 1 June 2006. London 1 June 2006. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/WC500003978.pdf. Accessed 24 Feb 2014

  • EMA (European Medicines Agency) (2011) Questions and answers on ‘Guideline on the environmental risk assessment of medicinal products for human use’. EMA/CHMP/SWP/44609/2010. London 17 March 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/04/WC500105107.pdf. Accessed 24 Feb 2014

  • FDA (Food and Drug Administration) (1998) Guidance for industry: environmental assessment of human drug and biologics applications. U.S. Department of Health and Human Services. CMC 6 Revision 1. Food and Drug Administration Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER): July 1998. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070561.pdf. Accessed 30 July 2013

  • Ferguson LR, Denny WA (1995) Anticancer drugs: an underestimated risk or an underutilized resource in mutagenesis? Mutat Res Fundam Mol Mech 331:1–26

    Article  CAS  Google Scholar 

  • Ferrando-Climent L, Rodriguez-Mozaz S, Barceló D (2013) Development of a UPLC-MS/MS method for the determination of ten anticancer drugs in hospital and urban wastewaters, and its application for the screening of human metabolites assisted by information-dependent acquisition tool (IDA) in sewage samples. Anal Bioanal Chem 405:5937–5952

    Article  CAS  Google Scholar 

  • Gómez-Canela C, Cortés-Francisco N, Oliva X, Pujol C, Ventura F, Lacorte S, Caixach J (2012) Occurrence of cyclophosphamide and epirubicin in wastewaters by direct injection analysis-liquid chromatography-high-resolution mass spectrometry. Environ Sci Pollut Res 19:3210–3218

    Article  Google Scholar 

  • Harris J, Dodds LJ (1985) Handling waste from patients receiving cytotoxic drugs. Pharm J 7:289–291

    Google Scholar 

  • Health Canada (2004) Progress report on cancer control in Canada. Health Canada, Ottawa

    Google Scholar 

  • Heberer T (2002) Occurrence, fate, and removal of pharmaceutical residues in the aquatic environment: a review of recent research data. Toxicol Lett 131:5–17

    Article  CAS  Google Scholar 

  • IMS Health AG (2012) MIDAS database. Frankfurt/Main, Germany

  • Johnson AC, Jürgens MD, Williams RJ, Kümmere K, Kortenkamp A, Sumpter JP (2008) Do cytotoxic chemotherapy drugs discharged into rivers pose a risk to the environment and human health? An overview and UK case study. J Hydrol 348:167–175

    Article  CAS  Google Scholar 

  • Johnson AC, Sumpter J, Dumont E, Oldenkamp R (2013) Predicting concentrations of the cytostatic drugs cyclophosphamide, carboplatin, 5-fluorouracil and capecitabine throughout the sewage effluents and surface waters of Europe. Environ Toxicol Chem 32:1954–1961

    Article  CAS  Google Scholar 

  • Kosjek T, Heath E (2011) Occurrence, fate and determination of cytostatic pharmaceuticals in the environment. TrAC 30:1065–1087

    CAS  Google Scholar 

  • Kümmerer K, Al-Ahmad A (2010) Estimation of the cancer risk to humans from cyclophoshamide and ifosfamide excreta emitted into surface water via hospital effluents. Environ Sci Pollut Res 17:486–496

    Article  Google Scholar 

  • Kümmerer K, Schuster A, Haiß A, Günther A, Jacobs J, Mohring S, Hamscher G, Simon D (2009) Environmental risk assessment for antineoplastic compounds. Umweltbundesamt Berlin FB 001256, Texte 06/09. http://www.umweltbundesamt.de/publikationen/umweltrisikobewertung-von-zytostatika. Accessed 25 Feb 2014 (in German)

  • Kümmerer K, Steger-Hartmann T, Meyer M (1997) Biodegradability of the anti-tumour agent ifosfamide and its occurrence in hospital effluents and communal sewage. Water Res 31:2705–2710

    Article  Google Scholar 

  • Kümmerer K (2001) Drugs, diagnostic agents and disinfectants in waste water and water—a review. Chemosphere 45:957–969

    Article  Google Scholar 

  • Kümmerer K (2008) Pharmaceuticals in the environment. Sources, fate, effects and risks, 3rd edn. Springer, Heidelberg

    Google Scholar 

  • Kümmerer K (2009) The presence of pharmaceuticals in the environment due to human use—present knowledge and future challenges. J Environ Manag 90:2354–2366

    Article  Google Scholar 

  • Llewellyn N, Lloyd P, Jürgens MD, Johnson AC (2011) Determination of cyclophosphamide and ifosfamide in sewage effluent by stable isotope-dilution liquid chromatography-tandem mass spectrometry. J Chromatogr A 121:8519–85288

    Article  Google Scholar 

  • Micromedex (1997) Micromedex Medizinisches Informationssystem. Micromedex Inc.

  • Mosby (2009) Mosby’s medical dictionary, 8th ed. Elsevier. http://medical-dictionary.thefreedictionary.com/Antineoplastic+agents. Accessed 9 Mar 2013

  • Negreira N, López de Alda M, Barceló D (2013) On-line solid phase extraction-liquid chromatography-tandem mass spectrometry for the determination of 17 cytostatics and metabolites in waste, surface and ground water samples. J Chromatogr A 1280:64–74

    Article  CAS  Google Scholar 

  • Richardson ML, Bowron JM (1985) The fate of pharmaceutical chemicals in the aquatic environment. J Pharm Pharmacol 37:1–12

    Article  CAS  Google Scholar 

  • Rowney NC, Johnson AC, Williams RJ (2009) Cytotoxic drugs in drinking water. A prediction and risk assessment exercise for the Thames catchment in the United Kingdom. Environ Toxicol Chem 28:2733–2743

    Article  CAS  Google Scholar 

  • Sattelberger R (1999) Residues of pharmaceuticals in the environment. Umweltbundesamt Wien, Report No. 162 (in German)

  • Schulman LJ, Sargent EV, Naumann BD, Faria EC, Dolan DG, Wargo JP (2002) A human health risk assessment of pharmaceuticals in the aquatic environment. Hum Ecol Risk Assess 8:657–680

    Article  CAS  Google Scholar 

  • Segen JC (2002) The concise dictionary of modern medicine. McGraw-Hill, New York

    Google Scholar 

  • Seira J, Claparols C, Joannis-Cassan C, Albasi C, Montréjaud-Vignoles M, Sablayrolles C (2013) Optimization of pressurized liquid extraction using a multivariate chemometric approach for the determination of anticancer drugs in sludge by ultra high performance liquid chromatography-tandem mass spectrometry. J Chromatogr A 1283:27–38

    Article  CAS  Google Scholar 

  • Steger-Hartmann T, Kümmerer K, Hartmann A (1997) Biological degradation of cyclophosphamide and its occurrence in sewage water. Ecotoxicol Environ Saf 36:174–179

    Article  CAS  Google Scholar 

  • Steger-Hartmann T, Kümmerer K, Schecker J (1996) Trace analysis of the antineoplastics ifosfamide and cyclophosphamide in sewage water by two-step solid-phase extraction and gas chromatography–mass spectrometry. J Chromatogr A 726:179–184

    Article  CAS  Google Scholar 

  • Stewart BW, Wild CP (2014) World cancer report 2014. IARC Non Serial publication. WHO Press

  • Straub JO (2010) Protein and peptide therapeuticals: an example of benign by nature active pharmaceutical ingredients. In: Kümmerer K, Hempel M (eds) Green and sustainable pharmacy. Springer, Heidelberg, pp 127–134

    Chapter  Google Scholar 

  • Sweetman SC (2009) Martindale: the complete drug reference, 36th edn. Pharmaceutical Press, London

    Google Scholar 

  • TRG 905 (technical rule for hazardous materials 905) (2008) Directory of carcinogenic, mutagenic or reproduction toxic materials. http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/pdf/TRGS-905.pdf?__blob=publicationFile&v=3. Accessed 15 Mar 2014 (in German)

  • Umweltbundesamt (2003) Assessment of the presence partially or not valueable materials in the drinking water from health view. Recommendation of the federal environment office after hearing of the drinking water commission of the federal environment office. Bundesgesundheitsbl Gesundheitsforsch Gesundheitsschutz 46:249–251 (in German)

    Article  Google Scholar 

  • Van der Aa M, Kommer G (2010) Forecast of pharmaceutical consumption in the Netherlands using demographic projections. In: Kümmerer K, Hempel M (eds) Green and sustainable pharmacy. Springer, Heidelberg, pp 201–210

    Google Scholar 

  • Varadhachary GR, Hoff PM (2005) Front-line therapy for advanced colorectal cancer: emphasis on chemotherapy. Semin Oncol 32:40–42

    Article  Google Scholar 

  • Webb S, Ternes T, Gibert M, Olejniczak K (2003) Indirect human exposure to pharmaceuticals via drinking water. Toxicol Lett 142:157–167

    Article  CAS  Google Scholar 

  • Williams RT (2005) Human pharmaceuticals: assessing the impacts on aquatic ecosystems. SETAC PRESS, Pensacola

    Google Scholar 

  • Zhang J, Chang VWC, Giannis A, Wang JY (2013) Removal of cytostatic drugs from aquatic environment: a review. Sci Total Environ 445–446:281–298

    Article  Google Scholar 

  • Zuccato E, Calamari D, Natangelo M, Fanelli R (2000) Presence of therapeutic drugs in the environment. Lancet 355:1789–1790

    Article  CAS  Google Scholar 

  • Zuccato E, Castiglioni S, Fanelli R (2005) Identification of the pharmaceuticals for human use contaminating the Italian aquatic environment. J Hazard Mater 122:205–209

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was funded by the German Federal Environmental Agency (Umweltbundesamt), Grant No. 360 14 004. The authors thank Anita Günther and Johanna Jacobs for their help and Gerd Hamscher and Sigrun Mohring (University of Gießen, Germany) for providing information on the use of antineoplastic drugs in veterinary pharmacy and the treatment of pets as well as for valuable discussions and Hermann Dieter for valuable discussions and reading of the manuscript.

Author information

Authors and Affiliations

  1. Institute of Sustainable and Environmental Chemistry, Leuphana University Lüneburg, Scharnhorststraße1, 21335, Lüneburg, Germany

    Klaus Kümmerer & Annette Haiß

  2. Department of Environmental Health Sciences, University Medical Centre Freiburg, Breisacher Str. 115B, 79106, Freiburg, Germany

    Armin Schuster

  3. Federal Environment Agency, Pharmaceuticals, Washing and Cleansing Agents, Wörlitzer Platz 1, 06844, Dessau, Germany

    Arne Hein & Ina Ebert

Authors
  1. Klaus Kümmerer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annette Haiß
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Armin Schuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arne Hein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ina Ebert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Klaus Kümmerer.

Additional information

Responsible editor: Roland Kallenborn

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kümmerer, K., Haiß, A., Schuster, A. et al. Antineoplastic compounds in the environment—substances of special concern. Environ Sci Pollut Res 23, 14791–14804 (2016). https://doi.org/10.1007/s11356-014-3902-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-014-3902-8

Keywords

Search

Navigation