Methodological Aspects Concerning the Environmental Risk Assessment for Medicinal Products; Research Challenges

  • M. H. M. M. Montforts


Risk Assessment Drug Substance Methodological Aspect Environmental Risk Assessment Safety Testing 
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  1. Anonymous (1976) Council Directive 76/464/EEC of 4 May 1976 on pollution caused by certain dangerous substances discharged into the aquatic environment of the communityGoogle Scholar
  2. Anonymous (1979) Council Directive 80/68/EEC of 17 December 1979 on the protection of groundwater against pollution caused by certain dangerous substancesGoogle Scholar
  3. Anonymous (2001a) Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal productsGoogle Scholar
  4. Anonymous (2001b) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human useGoogle Scholar
  5. Abbas B, Kratz W (2000) Humanarzneimittel in der Umwelt. Erhebung von Humanarzneimittelmengen im Land Brandenburg 1999. Potsdam, Germany: Landes Umweltamt Brandenburg (LUA), Studien und Tagungsberichte Band 25Google Scholar
  6. Auteri D, Visentin S, Alberio P, Redolfi E, Azimonti G, Mangiarotti M, Maroni M (2002) Statistical evaluation of available ecotoxicology data on plant protection products and their metabolites. Milan, Italy: International Centre for Pesticides and Health Risk Prevention, SEEM project final reportGoogle Scholar
  7. Baart F, De Neeling AJ (2001) Antibioticagebruik buiten het ziekenhuis. Pharmaceutisch Weekblad 136:786–790Google Scholar
  8. Baillie TA, Cayen MN, Fouda H, Gerson RJ, Green JD, Grossman SJ, Klunk LJ, LeBlanc B, Perkins DG, Shipley LA (2002). Drug metabolites in safety testing. Toxicol Appl Pharm 182:188–196CrossRefGoogle Scholar
  9. Baillie TA, Cayen MN, Fouda H, Gerson RJ, Green JD, Grossman SJ, Klunk LJ, LeBlanc B, Perkins DG, Shipley LA (2003) Reply to the Letter to the Editor on Drug metabolites in safety testing. Toxicol Appl Pharm 190:93–94CrossRefGoogle Scholar
  10. Balcioglu IA, Ötker M (2003) Treatment of pharmaceutical wastewater containing antibiotics by O3 and O3/H2O2 processes. Chemosphere 50:85–95CrossRefGoogle Scholar
  11. Berard A, Benninghoff C (2001) Pollution-induced community tolerance (PICT) and seasonal variations in the sensitivity of phytoplankton to atrazine in nanocosms. Chemosphere 45:427–437CrossRefGoogle Scholar
  12. Berland BR, Maestrini SY (1969) Study of bacteria associated with marine algae in culture. II. Action of antibiotic substances. Mar Biol 3:334–335CrossRefGoogle Scholar
  13. Bertelsen SL, Hoffman AD, Gallinat CA, Elonen CM, Nichols JW (1998) Evaluation of log Kow and tissue lipid content as predictors of chemical partitioning to fish tissues. Environ Toxicol Chem 17:1447–1455CrossRefGoogle Scholar
  14. Blume RR, Younger RL, Aga A, Myers CJ (1976) Effects of residues of certain anthelmintics in bovine manure on Onthophagus gazella, a non-target organism. Southwest Entomol 1:100–103Google Scholar
  15. Boxall ABA, Fogg LA, Blackwell PA, Kay P, Pemberton EJ, Croxford A (2004) Veterinary medicines in the environment. Rev Environ Contam Toxicol 180:1–91CrossRefGoogle Scholar
  16. Brooks BW, Foran CM, Richards SM, Weston J, Turner PK, Stanley JK, Solomon KR, Slattery M, La Point TW (2003) Aquatic ecotoxicology of fluoxetine. Toxicol Lett 142:169–183CrossRefGoogle Scholar
  17. Brouwer WWM, Boesten JJTI, Linders JBHJ, Van der Linden AMA (1994). Dutch guidelines for laboratory studies on behaviour in soil and their evaluation. Pesticide Outlook October:23–28Google Scholar
  18. Cars O, Mölstad S, Melander A (2000) Large variation in antibiotic usage between European countries. 10th ECCMID Stockholm Poster no. 299Google Scholar
  19. Cleuvers M (2003) Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Toxicol Lett 142:185–194CrossRefGoogle Scholar
  20. Cramp S (1063) Toxic chemicals and birds of prey. Brit Birds 56:124–139Google Scholar
  21. Cranor CF (1997). The normative nature of risk assessment: features and possibilities. RISK Health Safety Environ 8:1–4Google Scholar
  22. CVMP (2004) Guideline on environmental impact assessment for veterinary medicinal products Phase II. EMEY, London, CVMP/VICH/790/03-FINALGoogle Scholar
  23. Daughton CG, Jones-Lepp TL (2001) Pharmaceuticals and personal care products in the environment: scientific and regulatory issues. American Chemical Society, Washington, DC (Symposium Series 791)Google Scholar
  24. De Greef J, De Nijs ACM (1990) Risk assessment of new chemical substances. Dilution factors of effluents in the Netherlands. RIVM, Bilthoven, The Netherlands (report 670208001)Google Scholar
  25. De Lange HJ, Noordoven W, Murk AJ, Lürling M, Peeters ETHM (2006) Behavioural responses of Gammarus pulex (Crustacea, Amphipoda) to low concentrations of pharmaceuticals. Aquat Toxicol 78:209–216CrossRefGoogle Scholar
  26. De Wolf W, Siebel-Sauer A, Lecloux A, Koch V, Holt M, Feijtel T, Comber M, Boeije G (2005) Mode of action and aquatic exposure thresholds of no concern. Environ Toxicol Chem 24:479–485CrossRefGoogle Scholar
  27. Dee DP (1994) Guidelines for documenting the validity of computational modelling software. IAHR/AIHR Delft, The NetherlandsGoogle Scholar
  28. Di Fabio U (1994) Das Arzneimittelrecht als Repräsentant der Risikoverwaltung. Die Verwaltung 27:345–360Google Scholar
  29. Di Guardo A, Calamari D, Benfenati E, Halling-Sørensen B, Zuccato E, Fanelli R (2001) Pharmaceuticals as environmental contaminants: modelling distribution and fate. In: Kümmerer K (ed) Pharmaceuticals in the environment, 1st edn. Springer-Verlag, Berlin, Germany, pp 91–102Google Scholar
  30. Dietrich DR (2002) Special Issue on pharmaceuticals in the environment. Toxicol Lett 131 EC (2001) Commission organises “name and shame” seminar on city sewage. gb/dg11en49.htm (Date of access 2003)Google Scholar
  31. EC (2003) Technical Guidance Document in Support of Commission Directive 93/67/EEC on Risk Assessment for New Notified Substances, Commission Regulation (EC) No 1488/94 on Risk Assessment for Existing Substances and Directive 98/8/EC concerning the placing of biocidal products on the market, Part II. Office for Official Publications of the European Communities, LuxembourgGoogle Scholar
  32. EC (2006) Survey on antibiotics used in crop protection. European Commission, Directorate-General Health and Consumer Protection, Brussels (SANCO/973/2000 rev 5 survey 2005)Google Scholar
  33. ECCO (2002) Guidance document on aquatic ecotoxicology; E1 - Plant health. Sanco/3268/2001 rev.4 (final) 17 October 2002 Brussels: DG Sanco, wrkdoc10_en.pdf Google Scholar
  34. EMEA (2006) Guideline on the environmental risk assessment of medicinal products for human use. EMEA, London (CHMP/SWP/4447/00)Google Scholar
  35. ESC (2001) Opinion of the Economic and Social Committee on Organised civil society and European governance: the Committee’s contribution to the drafting of the White Paper. Economic and Social Committee, Brussels (CES535/2001)Google Scholar
  36. Escher BI, Schwarzenbach RP, Westall JC (2000) Evaluation of liposome-water partitioning of organic acids and bases. 1. Development of a sorption model. Environ Sci Technol 34:3954–3961CrossRefGoogle Scholar
  37. Feldmann D, Niederland N, Reddersen K, Heberer Th (2002). Modulare Darstellung des Verhaltens und Verbleibs von Arzneimittelrückständen in Krankenhausabwasser. Versuchszeitraum 08. bis 15. April 2002. Zwischenbericht (Oktober 2002) an das Bundesministerium für Verteidigung (BMVg) vom 28.10.2002; Technische Universität, BerlinGoogle Scholar
  38. Fitzsimmons PN, Fernandez JD, Hoffman AD, Butterworth BC, Nichols JW (2001) Branchial elimination of superhydrophobic organic compounds by rainbow trout (Oncorhynchus mykiss). Aquat Toxicol 55:23–34CrossRefGoogle Scholar
  39. Fong PP (1998) Zebra mussel spawning is induced in low concentrations of putative serotonin reuptake inhibitors. Biol Bull 194:143–149CrossRefGoogle Scholar
  40. Forbes VE, Calow P (2002) Extrapolation in ecological risk assessment: balancing pragmatism and precaution in chemical controls legislation. BioScience 52:249–257CrossRefGoogle Scholar
  41. Halling-Sørensen B, Sengeløv G, Tjørnelund J (2002) Toxicity of tetracyclines and tetracycline degradation products to environmentally relevant bacteria, including selected tetracycline-resistant bacteria. Arch Environ Contam Toxicol 42:263–271CrossRefGoogle Scholar
  42. Hastings KL, El-Hage J, Jacobs A, Leighton J, Morse D, Osterberg RE (2003) Comment on: Drug metabolites in safety testing. Toxicol ApplPharm 190:91–92Google Scholar
  43. Henny CJ, Blus LJ, Kolbe EJ, Fitzner RE (1985) Organophosphate insecticide (famphur) topically applied to cattle kills magpies and hawks. J Wildlife Manage 49:648–658CrossRefGoogle Scholar
  44. Heyvaert V (1999) Coping with uncertainty. The regulation of chemicals in the European Union. European University Institute, Florence, ItalyGoogle Scholar
  45. Hill EF, Fleming WJ (1982) Anticholinesterase poisoning of birds: field monitoring and diagnosis of acute poisoning. Environ Toxicol Chem 1:27–38CrossRefGoogle Scholar
  46. Hill EF, Mendenhall VM (1980). Secondary poisoning of barn owls with famphur, an organophosphate insecticide. J Wildlife Manage 44:676–681CrossRefGoogle Scholar
  47. Huggett DB, Benson WH, Chipman K, Cook JC, Gray LE, Kinter LB, Meyerhoff RD, Trudeau VL (2005) Role of mammalian data in determining pharmaceutical responses in aquatic species. In: Williams RT (ed) Human pharmaceuticals. Assessing the impacts on aquatic ecosystems. SETAC, Pensacola, USA, pp 149–181Google Scholar
  48. Joerges C, Ladeur K, Vos E (1997) Integrating Scientific expertise into regulatory decision-making. Nomos, Baden-Baden, GermanyGoogle Scholar
  49. Johnston JJ, Savarie PJ, Primus TM, Eisemann JD, Hurley JC, Kohler DJ (2002) Risk assessment of an acetaminophen baiting program for chemical control of brown tree snakes on Guam: Evaluation of baits, snake residues, and potential primary and secondary hazards. Environ Sci Technol 36:3827–3833CrossRefGoogle Scholar
  50. Jørgensen SE, Halling-Sørensen B (2000) Special issue on pharmaceuticals in the environment. Chemosphere 40Google Scholar
  51. Koeman JH, Van Beusekom CF, De Goeij JJM (1972) Eggshell and population changes in the sparrowhawk (Accipiter nisus). TNO-nieuws 27:542–550Google Scholar
  52. Kümmerer K (2001) Pharmaceuticals in the environment, 1st edn. Springer-Verlag, BerlinGoogle Scholar
  53. Kümmerer K, Al-Ahmad A, Mersch-Sundermann V (2000) Biodegradability of some antibiotics, elimination of the genotoxicity and affection of wastewater bacteria in a simple test. Chemosphere 40: 701–710CrossRefGoogle Scholar
  54. Länge R, Dietrich D (2002) Environmental risk assessment of pharmaceutical drug substances – conceptual considerations. Toxicol Lett 131:97–104CrossRefGoogle Scholar
  55. Ludke JL, Locke LN (1976) Case report – Duck deaths from accidental ingestion of anthelmintic. Avian Dis 20:607–608CrossRefGoogle Scholar
  56. Manten A (1971) De betekenis van antibiotica in het milieu. Ned Tijdschr Geneesk 115:1844–1848Google Scholar
  57. McVeigh K, O’Brien D, Skelton J (1997) Sheep dip disposal: no room for complacency. Soil Association, Bristol, UKGoogle Scholar
  58. Mendenhall VM, Pank LF (1980) Secondary poisoning of owls by anticoagulant rodenticides. Wildl Soc Bull 8:311–315Google Scholar
  59. Montforts M, Spindler P, Taylor D, Williams R (2007) Guest Editorial: DIA/HESI/SAPS Conference on Environmental Risk Assessment of Human Medicines (Stockholm, May 22-23, 2006). Drug Inf Assoc J 41:129–131Google Scholar
  60. Montforts MHMM (2001) Regulatory and methodological aspects concerning the risk assessment of medicinal products. In: Kümmerer K (ed) Pharmaceuticals in the environment, 1st edn. Springer- Verlag, Berlin, pp 159–174Google Scholar
  61. Montforts MHMM (2004) Methodological aspects concerning the environmental risk assessment for medicinal products – research challenges. In: Kümmerer K (ed) Pharmaceuticals in the environment, 2nd edn. Springer-Verlag, Berlin, pp 439–462Google Scholar
  62. Montforts MHMM (2005) The trigger values in the environmental risk assessment for (veterinary) medicines in the European Union: a critical appraisal. RIVM, Bilthoven, The Netherlands (report 601500002/2005)Google Scholar
  63. Montforts MHMM (2007) Will risk assessment help risk management? In: Capri E, Karpouzas D (eds) Pesticide Risk Assessment in Rice Paddies, Theory and Practice. Elsevier, Amsterdam, pp 45–58CrossRefGoogle Scholar
  64. Montforts MHMM, De Knecht JA (2002) European medicines and feed additives regulation are not in compliance with environmental legislation and policy. Toxicol Lett 131:125–136CrossRefGoogle Scholar
  65. Montforts MHMM, Van Rijswick HFMW, Freriks AA, Keessen A, Wuijts S (2006) De relatie tussen productregistratie en waterkwaliteitsregelgeving: geneesmiddelen, diergeneesmiddelen, en veevoederadditieven. RIVM, Bilthoven, The Netherlands (report 601500003/2006)Google Scholar
  66. Montforts MHMM, Brandt I, Hutchinson TH (2007) Summary of Workshop on Environmental Assessment of Human Medicines: Development and Use of Aquatic Toxicity Data. Drug Inf Assoc J 41:203–210Google Scholar
  67. Notenboom J, Verschoor A, Van der Linden AMA, Van de Plassche E, Reuther C (1999) Pesticides in groundwater: occurrence and ecological impacts. RIVM, Bilthoven, The Netherlands (report 601506002)Google Scholar
  68. NW4 (1998) Fourth Action Plan Water Management. Ministry of Traffic and Public Works, The NetherlandsGoogle Scholar
  69. Oaks JL, Gilbert M, Virani MZ, Watson RT, Meteyer CU, Rideout BA, Shivaprasad HL, Ahmed S, Chaudry MJI, Arshad M, Mahmood S, Ali A, Khan AA (2004) Diclofenac residues as the cause of vulture population decline in Pakistan. Nature 427:630–633CrossRefGoogle Scholar
  70. OECD (2004) The Assessment of Persistency and Bioaccumulation in the Pesticide Registration Frameworks within the OECD Region. OECD, Paris (OECD Series on Pesticides 25)Google Scholar
  71. Patten DK, Wolf D, Kunkle WE, Douglass LW (1980) Effect of antibiotics in beef cattle feces on nitrogen and carbon mineralisation in soil and on plant growth and composition. J Environ Qual 9:167–172CrossRefGoogle Scholar
  72. Pro J, Ortiz JA, Boleas S, Fernández C, Carbonell G, Tarazona JV (2003) Effect assessment of antimicrobial pharmaceuticals in the aquatic plant Lemna minor. Bull Environ Contam Toxicol 70:290–295CrossRefGoogle Scholar
  73. Purdom CE, Hardiman PA, Bye VJ, Eno NC, Tyler CR, Sumpter JP (1994) Estrogenic effects of effluents from sewage treatment works. Chem Ecol 8:275–285CrossRefGoogle Scholar
  74. Resseler H, Shäfer H, Görlitz G, Hermann M, Hosang J, Kloskowski R, Marx R, Sarafin R, Stein B, Winkler R (1997) Recommendations for conducting simulation calculations for the registration procedure. Nachrichtenblatt des Deutschen Pflanzenschutzdienstes 49:305–309Google Scholar
  75. Roex EWM, Traas TP, Slooff W (2001) Ecotoxicological hazard assessment of genotoxic substances. RIVM, Bilthoven, The Netherlands (report 601503022)Google Scholar
  76. Roij ThAJM, De Vries PHU (1980) Milieutoxicologische aspecten van het gebruik van veevoederadditieven en therapeutica. Persistentie in dierlijke excreta en milieu. Ministry of Environment, The Hague, The Netherlands (Reeks Bodembescherming nr. 4)Google Scholar
  77. Römbke J, Knacker T, Stahlschmidt-Allner P (1996) Umweltprobleme durch Arzneimittel – Literaturstudie. Umweltbundesamt, BerlinGoogle Scholar
  78. Rurainski RD, Theiss HJ, Zimmermann W (1977) Über das Vorkommen von natürlichen und synthetischen Östrogenen im Trinkwasser. gwf Wasser Abwasser 118:288–291Google Scholar
  79. Schowanek D, Webb S (2002) Exposure simulation for pharmaceuticals in European surface waters with GREAT-ER. Toxicol Lett 131:39–50CrossRefGoogle Scholar
  80. SCP (1999) Opinion of the Scientific Committee on Plants on the Draft Guidance Document on Aquatic Ecotoxicology (DG VI 8075/VI/97-Rev.4 of 18.12.1998). SCP/GUIDE/023 – FinalGoogle Scholar
  81. Sinclair CJ, Boxall ABA (2002) Assessment of the environmental properties and effects of pesticide transformation products. Cranfield Centre for Ecochemistry, Silsoe, UK, report to DEFRA No: PN-0930Google Scholar
  82. Smith DA, Obach RS (2005) Seeing through the MIST: abundance versus percentage. Commentary on Metabolites in safety testing. Drug Metab Disp 33:1409–1417CrossRefGoogle Scholar
  83. Soulides DA, Pinck LA, Allison FE (1962) Antibiotics in soils: V. Stability and release of soil adsorbed antibiotics. Soil Sci 94:239–244CrossRefGoogle Scholar
  84. Spindler P, Montforts M, Olejniczak K, Koschorreck J, Vidal J-M, Johansson A-K, Stemplewski H, Virtanen V, Rönnefahrt I, Kristensen S, Van der Laan J-W (2007) Environmental Assessment for Human Medicines in the European Union. Drug Inf Assoc J 41:149-154Google Scholar
  85. Staeb JA, Tiesnitsch J, Schrap SM, Rijs GBJ (2004) Screening of human and veterinary pharmaceuticals in surface waters in the Netherlands using LC/MS/MS. RIZA, Lelystad, The Netherlands (poster)Google Scholar
  86. Tabak HH, Bunch RL (1970) Steroid hormones as water pollutants. I. Metabolism of natural and synthetic ovulation-inhibiting hormones by microorganisms of activated sludge and primary settler sewage. Dev Ind Microbiol 11:367–376Google Scholar
  87. Tabak HH, Bloomhuff RN, Bunch RL (1981) Steroid hormones as water pollutants II. Studies on the persistence and stability of natural urinary and synthetic ovulation-inhibiting hormones in untreated and treated wastewaters. Dev Ind Microbiol 22:497–519Google Scholar
  88. Tarazona JV, Hund K, Jager T, S-Salonen M, Soares AMVM, Skaare JU, Vigui M (2002) Standardizing chemical risk assessment, at last. Nature 415:14CrossRefGoogle Scholar
  89. Ternes TA (1999) Special Issue on pharmaceuticals in the environment. Sci Total Environ 225Google Scholar
  90. Thorpe KL, Hutchinson TH, Hetheridge MJ, Scholze M, Sumpter JP, Tyler CR (2001) Assessing the biological potency of binary mixtures of environmental estrogens using vitellogenin induction in juvenile rainbow trout (Oncorhynchus mykiss). Environ Sci Technol 35:2476–2481CrossRefGoogle Scholar
  91. Tolls J, Bodo K, De Felip E, Dujardin R, Kim YH, Moeller-Jensen L, Mullee D, Nakajima A, Paschke A, Pawliczek J-B, Schneider J, Tadeo J-L, Tognucci AC, Webb J, Zwijzen AC (2003) Slow-stirring method for determining the n-octanol/water partition coefficient (pow) for highly hydrophobic chemicals: performance evaluation in a ring test. Environ Toxicol Chem 22:1051–1057CrossRefGoogle Scholar
  92. Uffink GJM, Van der Linden AMA (1998) Dilution of pesticides in groundwater during advective dispersive transport. RIVM, Bilthoven, The Netherlands (report 716601002)Google Scholar
  93. Vaclavik E, Halling-Sørensen B, Ingerslev F (2004) Evaluation of manometric respiration tests to assess the effects of veterinary antibiotics in soil. Chemosphere 56:667–676CrossRefGoogle Scholar
  94. Van der Linden AMA, Van Beek CGEM, Boesten JJTI, Leistra M, Meinardi CR, Puijker LM (1999) Beoordeling van het gedrag van bestrijdingsmiddelen in de verzadigde zone van de bodem. RIVM, Bilthoven, The Netherlands (report 715801005)Google Scholar
  95. Van Rijswick HFMW (2001) De kwaliteit van water (The quality of water). Utrecht University, Utrecht, The NetherlandsGoogle Scholar
  96. Vethaak AD, Rijs GBJ, Schrap SM, Ruiter H, Gerritsen A, Lahr J (2002) Estrogens and xeno-estrogens in the aquatic environment of The Netherlands: occurrence, potency and biological effects. RIZA/RIKZ, Lelystad, The Hague, The Netherlands (report 2002.001)Google Scholar
  97. VICH (2000) Environmental impact assessment (EIAs) for veterinary medicinal products (VMPs) – Phase I. CVMP/VICH, London (CVMP/VICH/592/98-final)Google Scholar
  98. Winkler R (2001a) Exposit 1.1. Umweltbundesamt, BerlinGoogle Scholar
  99. Winkler R (2001b) Konzept zur Bewertung des Eintrags von Pflanzenschutzmitteln in Oberflächen- und Grundwasser unter besonderer Berücksichtigung des Oberflächenabflusses (Dokumentation zum Modell EXPOSIT). Umweltbundesamt, Berlin, 27.09.2001Google Scholar
  100. WRc-NSF (2001) VetPec. Veterinary Medicines Directorate, UKGoogle Scholar
  101. Würgler FE, Kramers PGN (1992) Environmental effects of genotoxins (eco-genotoxicology). Mutagenesis 7:321–327CrossRefGoogle Scholar
  102. Zondek B, Sulman F (1943) Inactivation of estrone and diethylstilbestrol by microorganisms. Endocrinology 33:204–208CrossRefGoogle Scholar

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Authors and Affiliations

  • M. H. M. M. Montforts
    • 1
  1. 1.National Institute for Public Health and the EnvironmentExpertise Centre for SubstancesThe Netherlands

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