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Environmental risk assessment of veterinary medicinal products in the EU—a regulatory perspective
Toxicology Letters 131 (2002) 117– 124 www.elsevier.com/locate/toxlet
Environmental risk assessment of veterinary medicinal products in the EU—a regulatory perspective Jan Koschorreck *, Claudia Koch, Ines Ro¨nnefahrt Umweltbundesamt, P.O. Box 330022, Berlin 14191, Germany Received 18 January 2002; received in revised form 6 February 2002; accepted 7 February 2002
Abstract The pharmacological nature of veterinary medicinal products, frequent application rates and use on a large scale for livestock production sensitizes regulation authorities for environmental concern. Consequently, in the European Union legal requirements plus guidance for an Environmental Risk Assessment of veterinary pharmaceuticals have been established. Applicants of new veterinary medicinal products have to provide an ecotoxicity report according to a guidance document which rests upon a logical, tiered approach with a cut-off trigger between a basic characterisation of the veterinary medicinal product and an in-depth assessment of its fate and ecotoxic effects. The outcome of this assessment is the establishment of the environmental risk that may arise from the use of the VMP under question. Contamination of the environment can be reduced by appropriate risk mitigation measures, e.g. limiting the application rate, the amount of contaminated manure being spread on agricultural lands or the access of treated pasture animals to surface waters. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Environmental risk assessment; Veterinary pharmaceuticals; EU
1. Introduction Veterinary pharmaceuticals are widely used across Europe to treat farm animals. After application to an animal, a veterinary medicinal product may be absorbed and partially metabolised before being excreted with urine and faeces. The resulting manure or slurry can then be released directly to the environment or collected and stored before being applied to land. Once * Corresponding author. Tel.: +49-30-890-3122; fax: + 4930-890-33900. E-mail address: [email protected] (J. Koschorreck).
released to land, the medicines and its metabolites may run off into surface waters or leach to groundwater where they may impact environmental as well as human health (Fig. 1). At present there are approximately 2700 veterinary medicinal products based on about 600 active ingredients on the German pharmaceutical market. Some veterinary drugs are used in large volumes of up to more than 50 tons per year in Germany, have widespread use, a specific mode of therapeutic/toxic action and may give rise to acute and chronic ecotoxic effects in the terrestrial and aquatic environment. Antibiotics and antiparasitics, which account for about 90% (BfT, 2000) of
0378-4274/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 4 2 7 4 ( 0 2 ) 0 0 0 4 7 - 4
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the veterinary medicinal products used in German livestock production are of key concern. Until now various drug residues have been detected in German soils and water bodies (Hamscher et al., 2000; Daughton and Ternes, 1999). Data on their environmental impact is scarce. Before any new veterinary pharmaceutical product can obtain marketing authorisation, a stringent review has to be carried out by national and/or European Union (EU) authorities to ensure its efficacy, quality and safety to public health as well as to the environment. The requirements for ecotoxicity testing were introduced into European legislation by Directive 81/851/EEC and Directive 81/852/EEC and have recently been codified in the new Directive 2001/82/EC (EC, 2001a). The European Agency for the Evaluation of Medicinal Products (EMEA) coordinates the existing scientific resources of the Member States
of the EU in order to evaluate and supervise medicinal products for both human and veterinary use throughout the entire EU. In 1998 the EMEA issued a note for guidance on ‘Environmental Risk Assessment for Veterinary Medicinal Products (VMP) other than GMO (genetically modified organism)-containing and immunological products’ (EMEA, 1998). The guidance rests upon a logical, tiered approach with a cut-off trigger between a basic characterisation of the veterinary medicinal product and an in-depth assessment of its fate and ecotoxic effects (Fig. 2). In order to facilitate authorization and to improve the availability of veterinary pharmaceuticals, harmonized technical requirements for veterinary product authorization are elaborated by a new international initiative, the International Co-operation on Harmonization of Technical Requirements for Authorization of Veterinary
Fig. 1. Entry of veterinary medicinal products (VMPs) into the environment.
J. Koschorreck et al. / Toxicology Letters 131 (2002) 117–124
119
Fig. 2. Environmental risk assessment of veterinary medicinal products (VMPs) — decision tree phase I and phase II tier A.
Medicinal Products (VICH). The VICH parties are the EU, USA and Japan. In addition, Australia and New Zealand joined in as observers. Each party has nominated a representative from the regulation authority and veterinary pharmaceutical industry. Once adopted, the VICH recommendations for a uniform environmental risk assessment for veterinary medicinal products will replace the present EMEA-guidance (EMEA, 1998). VICH Phase I guidance for environmental risk assessment has already been agreed on and implemented (VICH, 2000); phase II is expected to follow in 2003. To address specific testing requirements for genetically modified products, immunological VMPs and feed additives the EU provides guidance on the ‘Environmental risk assessment for immunological veterinary medicinal products’ (EMEA, 1997), ‘Guidance on data relating to the Environmental Risk Assessment for products containing or consisting of genetically modified organisms’ (EC, 2001b) and ‘Guidelines on the assessment of additives in animal nutrition’ (EC, 2001c). Each guidance relies on legislation of its own.
2. The principles of an environmental risk assessment for veterinary medicinal products Phase I of the environmental risk assessment for a VMP starts with questions on the physical and chemical properties of the VMP, its use, dose route, frequency of dosing, animal husbandry and routes of excretion into the environment. It is assumed that VMPs with limited use and limited environmental exposure will have limited environmental effects and thus stop in Phase I. Phase I also identifies VMPs that require a more extensive environmental risk assessment under Phase II. Major routes of introduction of a VMP are: Pasture animals directly excrete residues and/ or metabolites of VMPs onto grassland or into adjacent surface waters. Contaminated manure and slurry from treated animals is spread on agricultural lands. Dips, pour-on formulations, etc. may run off after topical application of antiparasitics. Fish medicines are directly introduced into aquaculture water bodies.
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J. Koschorreck et al. / Toxicology Letters 131 (2002) 117–124
At the end of Phase I, the concentration of a VMP in the relevant environmental matrice is predicted using a uniform approach developed by Montfort (Montfort et al., 1999). The predicted environmental concentration PEC is based on worst case assumptions, e.g. highest number of animals treated, highest dose, no degradation. If the predicted concentration exceeds 100 mg/kg in arable soils or grassland or if more than 1 mg/l of the VMP is released from aquaculture facilities into the environmental the risk assessment proceeds to Phase II. Due to their insecticidal nature all endo- as well as ectoparasitics intended for use on pasture animals advance to the phase II pasture section where special regard is given to the protection of dung fauna. Some VMPs that might otherwise stop in Phase I may need additional environmental information to address particular concerns associated with their activity and use. Once a VMP has reached Phase II its predicted environmental concentration (PEC) is compared with its lowest effective concentration from standard ecotoxicity tests in soil and/or water to assess a probable environmental risk. After the toxic potential of the substance or its metabolites is assessed, the value is multiplied by an appropriate safety factor to create a predicted no effects concentration (PNEC). If the ratio of the predicted concentration to the predicted no effects concentration is greater than 1, further and more detailed studies on fate and effects of the VMPs have to be performed in order to refine the PEC as well as the PNEC. A decline of the expected environmental concentration is a function of hydrolysis, photolysis (chemical transformation) and biodegradation (mineralisation and biotransformation) of a VMP in the environment. The results from a short-term laboratory base set of ecotoxicity tests may be refined by long-term, semi-field or field data. At the end of the Phase II assessment, a VMP may not be expected to cause a significant harm to the environment or, if the PEC/PNEC ratio remains greater than 1, a risk to the environment is assumed. In the latter case, risk mitigation measures have to be linked with the authorisation for use of the product. Risk may be mitigated with restricted application rates of the veterinary medicinal product, restricted access to surface wa-
ters for the target animals on pasture, prolonged storage time for manure (in order to extend the degradation time of the VMP), limitations in the amounts of manure being spread or extensive monitoring of fate and effects after authorisation. In order to illustrate the above processes, three environmental risk assessments from veterinary medicinal products authorization procedures carried out by the German Federal Environmental Agency since 1998 are presented in the following section.
2.1. En6ironmental risk assessment for a benzimidazole helmintic This orally applied veterinary medicinal product belongs to the chemical class of benzimidazoles and is used for the treatment of sheep and cattle harboring mixed age liver fluke. Benzimidazole and sulfon/sulfoxidmetabolites are excreted with dung on grassland from treated pasture animals or spread with manure from treated intensively reared animals on agricultural land. Contamination of the aquatic environment occurs via direct entry from treated pasture animals and run-off from manured arable lands. The predicted environmental concentration of the parent compound and its metabolites in soil or grassland is below the threshold trigger of 100 mg/kg (Table 1). However, the VICH guidance (VICH, 2000) takes the insecticidal properties of veterinary endo- and ectoparasitics and the environmental risks of their use on pasture animals into account and leads antiparasiticidal veterinary medicinal products straight to a Phase II in-depth environmental risk assessment. After fast primary degradation of the parent compound in soil, persistent bound metabolites are generated. The aquatic studies demonstrate that the benzimidazole has no effects on higher plants, earthworms and dung fauna but is highly toxic to daphnids and fish (Table 2). An assessment factor of 100 lowers the predicted no effects concentration of the benzimaidazole for fish to 1 mg/l. Predicted environmental concentrations for both surfacewater scenarios assuming run-off from manured lands and direct entry from pastured animals were considerably higher than 1
J. Koschorreck et al. / Toxicology Letters 131 (2002) 117–124
mg/L and thus environmental concerns needed to be addressed. In order to protect the aquatic environment, risk mitigation measures for the use of the veterinary medicinal product were imposed by use of the following label: ‘‘Access of medicated livestock to open waters must be prevented. A safety distance of 10 m to open waters must be kept when spreading manure on agricultural land.’’
2.2. En6ironmental risk assessment for a mastitis teat dip Mastitis is a frequently occurring inflammation of the mammary gland of dairy cows usually caused by bacterial infection of udder tissues. Since a certain level of mastitis remains in all dairy herds, an effective mastitis control program includes routine teat dipping. Teat dips remove milk residues and kill organisms on the teat at the time of dipping and also leave a residual film of sanitizer on the teat between milkings. The pharmacologically active substance of the mastitis dip is an antimicrobial iodine complex in an excess of nonylphenol ethoxylates (NPEs), the carrier substance. Application is done via dipping the teats of 30 dairy cows into a dip cup of 250 ml dipping solution. After the defined number of
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animals have been treated, the iodine is spent and the remaining solution is usually poured away into manure. When manure from dairy cows is spread on arable land, residues of the veterinary medicinal product, e.g. nonylphenol ethoxylates (NPE), enter the environment. We decided to focus the environmental risk assessment on NPE leftovers in dip cups and not on the fate of residues of the mastitis dip on teats. The NPE carrier substance rapidly forms nonylphenol (NP) as degradation product which in turn is persistent and moderately to highly toxic to soil and aquatic organisms. The predicted environmental concentration of NPE in soil and grassland exceeds the trigger of 100 mg/kg (Table 1) leading to an in-depth environmental risk assessment according to the VICH-guidance. Sufficient data on fate and effects (Table 2) were found in the nonylphenol dossier of the EU existing chemicals program (EC, 2001d): Nonylphenol is persistent in both soil and water. It is not toxic to higher plants, moderately toxic to earthworms and highly toxic to aquatic organisms. Estrogenic effects and bioaccumulation are observed in fish. The comparison of the predicted environmental concentration of nonylphenol in soil and surface water (PECaquatic) with the toxic potential of the substance multiplied by an assessment factor of 100 revealed no concern for the environment. Nevertheless, the authorization for the mastitis dip was granted on condition of a
Table 1 Environmental fate data Substance
PECsoil (mg/kg) PECwater (mg/l) DT50 soil DT50 water Koc log Kow BCF in fish a
Nonylphenol (Dairy cows)
Macrolide (Chickens)
Benzimidazole (Cattle)
134a B0.01c 300 days 150 days \20000 4.5 1280
892 6.1b \60 days n.a.d 8200 −003 n.a.d
66 18.4c 15 days n.a.d n.a.d 6.2 n.a.d
Nonylphenol ethoxylates. Ground water. c Surfacewater. d Not available. b
J. Koschorreck et al. / Toxicology Letters 131 (2002) 117–124
122 Table 2 Ecotoxic effect data Species
Terrestrial path Plant Earthworm Dung beetle Aquatic path Green algae Daphnid Fish
Substance Nonylphenol
Macrolide
Benzimidazole
Mg/kg EC50:1000 (21 days) LC5013.7 (21 days) n.a.b Mg/l EC50:0.056c (72 h) EC50:0.085 (48 h) NOEC:0.024 (21 days) LC50:0.128 (96 h) NOEC: 0.007 (33 days)
Mg/kg EC50:116 (21 days) NOEC:30 LC50:\918 (28 days) n.a.b Mg/l EC50:0.16c (96 h) EC50:57 (48 h) LC50:851 (96 h)
Mg/kg EC50:\4000a LC50:\1000 LC50:\10 Mg/l EC50:26 (72 h) EC50:0.23 (24 h) EC50:0.13 (96 h)
a
Mg/ha. Not available. c Biomass. b
precautionary risk mitigation measure in order to prevent dispensable environmental contamination via waste disposal: ‘Residuals of the VMP and leftovers from dip cup must be collected and thereafter disposed with hazardous waste. The VMP must not get into the environment’. The risk mitigation measure was expanded to all NPE-containing teat dips on the German market and it was pointed out to the veterinary pharmaceutical industry that alternative products (e.g. PVP– Iodine) are favored from an environmental point of view. This was done in line with the opinion of the Commission of the European Union on the use of nonylphenol and nonylphenol ethoxylates in teat dips or other veterinary medicinal products concluding that marketing restrictions to minimize risks to the environment should be considered (EC, 2001e).
2.3. En6ironmental risk assessment for a macrolide antibiotic This veterinary medicinal product is administered with food and used for the treatment of chicken, pig and calf respiratory diseases. Due to poor transformation in the target animal considerable amounts of the unchanged active ingredient are excreted. The resulting predicted environmental concentration lies well above the trigger value of 100 mg/kg soil leading to an in-depth environmental risk assessment in phase II.
According to the first steps of EMEA Phase II guidance (Fig. 2), the acute toxicity of the macrolide antibiotic to microorganisms, earthworms and plants is assessed. High toxic activity of the macrolide antibiotic against microorganisms on agar plates was demonstrated. Essentially less toxic effects are indicated in soil testing systems what can be explained by the strong adsorption capacity of the veterinary pharmaceutical in soil (Koc 8000–36000 depending on soil type). No acute toxic effects to earthworms and higher plants are observed. Despite a high predicted environmental concentration (892 mg/kg) the PEC/ PNEC ratio of below 1 indicates that the VMP does not pose a risk to soil organisms. Due to physico-chemical parameters the macrolide will not enter surfacewater in relevant concentrations and a risk to aquatic organisms is considered to be unlikely. A worst case assumption (concentration porewater= concentration groundwater) predicted a contamination of groundwater with the veterinary medicinal substance. However, the PECgw/PNEC approach with acute daphnid toxicity data did not reveal a risk to groundwater organisms. The outcome of the environmental risk assessment on the basis of the EMEA-guidance does not require risk mitigation measures. An improvement of the guidance paper might be necessary for a more expedient assessment of substances with both slow degradation rates and antimicrobial
J. Koschorreck et al. / Toxicology Letters 131 (2002) 117–124
activity. Complex microbial communities should be safeguarded by appropriate long-term tests in the environmental risk assessment. In light of antibiotic resistance and multiresistant pathogens, such testing may not only benefit environmental standards in modern agricultural systems but also help the evaluation of emerging risks to public health.
3. Outlook Environmental Risk Assessment as part of the authorisation routine has identified mitigation measures that are able to reduce contamination to acceptable levels. However, experience with the EMEA-Guidance has raised a number of critical questions: What is the outcome of a risk assessment for substances with long persistence but low ecotoxicity, e.g. antimicrobials? To what extent should fate and effects of metabolites be assessed? How do we deal with parent compounds and/ or its metabolites reaching groundwater? What are the appropriate testing guidelines for assessing toxicity to microorganisms? What are suitable triggers for conducting longterm effect studies in view of the fact that a majority of VMPs being applied more than once a year? Most ectoparasitics are also used as plant protection products or biocides. How can experience from e.g. pesticide regulation, be incorporated into the VICH-guidance? Should fate and effects testing of a VMP in the surface water matrice be triggered (e.g. by sorption characteristics) or be assessed as a basic principle? Should entry into the environment via waste disposal (e.g. mastitis dip leftovers, organophosphate or pyrethroid ear tags) be part of the guidance paper? Finally, a remaining general question is whether the precautionary principle of the ERA aims at sustaining the function of agricultural systems or at the protection of the environment.
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The VICH Phase II guidance is currently being developed and is expected to be implemented in 2003. A draft guidance paper reflecting the outline at this stage will be submitted to all interested parties in the EU for a 6 month public consultation period in the second half of 2002. The Umweltbundesamt would like to encourage interested parties (stakeholders, academics, and nongovernmental organisations) to contribute critical remarks and suggestions for improvement of the guidance document. References BfT, 2000. Bund fu¨ r Tiermedizin, BfT Special. Nr.20. Daughton, C.G., Ternes, T., 1999. Pharmaceuticals and personal care products in the environment. Agents of subtle change? Environ. Health Perspect. 107, 907 – 938. EC, 2001a. Directive 2001/82/EC of the European Parliament and of the Council of 6th November 2001 on the Community code relating to veterinary medicinal products. Official Journal of the European Community, L 311. EC, 2001b. EC Enterprise Directorate General, 2001. Notice to applicants: Vol 6B Presentation and content of the dossier Part II G and H: Guidance on data relating to the Environmental Risk Assessment for products containing or consisting of genetically modified organisms. EC, 2001c. EC Health and Consumer Protection Directorate General, 2001. Guidelines on the assessment of additives in animal nutrition: Additives other than micro-organisms and enzymes. EC, 2001d. European Union Risk Assessment Report, 4Nonylphenol (branched) and nonylphenol, Final report, April 2001. EC, 2001d. Empfehlung der Europa¨ ischen Kommission vom 07.11.2001 u¨ ber die Ergebnisse der Risikobewertung und u¨ ber die Risikobegrenzungsstrategie fu¨ r die Stoffe: AcrylAldehyd; Dimethylsulfat; Nonylphenol; Phenol 4-Nonyl-, verzweigt; tert-Butylmethylether. (2001/838/EC), Amtsblatt 04.12.2001. EMEA, 1997. Environmental risk assessment for immunological veterinary medicinal products. London, UK: European Agency for the Evaluation of Medicinal Products. Rapport nr. EMEA/CVMP/074/95. EMEA, 1998. Note for Guidance: Environmental risk assessment for veterinary medicinal products other than GMOcontaining and immunological products. London, UK: European Agency for the Evaluation of Medicinal Products. Rapport nr. EMEA/CVMP/055/96. Hamscher, G. Sczesny S., Abu-Quare A., Ho¨ per H., Nau H., 2000. Stoffe mit pharmakologischer Wirkung einschließlich hormonell aktiver Substanzen in der Umwelt: Erster Nachweis von Tetracyclinen in
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gu¨ llegedu¨ ngten Bo¨ den. Deutsche Tiera¨ rztliche Wochenschrift, 8/2000, 323 – 325. Montfort, M.H.M.M., Kalf, F.K., van Vlaardingen, P.L.A., Linders, J.B.H.J, 1999. The exposure assessment for veterinary medicinal products. The Science of the Total Environment, 225, 119 –133.
VICH, 2000. CVMP/VICH Topic GL6 (Ecotoxicity Phase I) Step 7 Guideline on Environmental Impact Assessment (EIAs) for Veterinary Medicinal Products — Phase I. London, UK: European Agency for the Evaluation of Medicinal Products. Rapport No. CVMP/ VICH/592/98.
Environmental risk assessment of veterinary medicinal products in the EU—a regulatory perspective Jan Koschorreck *, Claudia Koch, Ines Ro¨nnefahrt Umweltbundesamt, P.O. Box 330022, Berlin 14191, Germany Received 18 January 2002; received in revised form 6 February 2002; accepted 7 February 2002
Abstract The pharmacological nature of veterinary medicinal products, frequent application rates and use on a large scale for livestock production sensitizes regulation authorities for environmental concern. Consequently, in the European Union legal requirements plus guidance for an Environmental Risk Assessment of veterinary pharmaceuticals have been established. Applicants of new veterinary medicinal products have to provide an ecotoxicity report according to a guidance document which rests upon a logical, tiered approach with a cut-off trigger between a basic characterisation of the veterinary medicinal product and an in-depth assessment of its fate and ecotoxic effects. The outcome of this assessment is the establishment of the environmental risk that may arise from the use of the VMP under question. Contamination of the environment can be reduced by appropriate risk mitigation measures, e.g. limiting the application rate, the amount of contaminated manure being spread on agricultural lands or the access of treated pasture animals to surface waters. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Environmental risk assessment; Veterinary pharmaceuticals; EU
1. Introduction Veterinary pharmaceuticals are widely used across Europe to treat farm animals. After application to an animal, a veterinary medicinal product may be absorbed and partially metabolised before being excreted with urine and faeces. The resulting manure or slurry can then be released directly to the environment or collected and stored before being applied to land. Once * Corresponding author. Tel.: +49-30-890-3122; fax: + 4930-890-33900. E-mail address: [email protected] (J. Koschorreck).
released to land, the medicines and its metabolites may run off into surface waters or leach to groundwater where they may impact environmental as well as human health (Fig. 1). At present there are approximately 2700 veterinary medicinal products based on about 600 active ingredients on the German pharmaceutical market. Some veterinary drugs are used in large volumes of up to more than 50 tons per year in Germany, have widespread use, a specific mode of therapeutic/toxic action and may give rise to acute and chronic ecotoxic effects in the terrestrial and aquatic environment. Antibiotics and antiparasitics, which account for about 90% (BfT, 2000) of
0378-4274/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 4 2 7 4 ( 0 2 ) 0 0 0 4 7 - 4
118
J. Koschorreck et al. / Toxicology Letters 131 (2002) 117–124
the veterinary medicinal products used in German livestock production are of key concern. Until now various drug residues have been detected in German soils and water bodies (Hamscher et al., 2000; Daughton and Ternes, 1999). Data on their environmental impact is scarce. Before any new veterinary pharmaceutical product can obtain marketing authorisation, a stringent review has to be carried out by national and/or European Union (EU) authorities to ensure its efficacy, quality and safety to public health as well as to the environment. The requirements for ecotoxicity testing were introduced into European legislation by Directive 81/851/EEC and Directive 81/852/EEC and have recently been codified in the new Directive 2001/82/EC (EC, 2001a). The European Agency for the Evaluation of Medicinal Products (EMEA) coordinates the existing scientific resources of the Member States
of the EU in order to evaluate and supervise medicinal products for both human and veterinary use throughout the entire EU. In 1998 the EMEA issued a note for guidance on ‘Environmental Risk Assessment for Veterinary Medicinal Products (VMP) other than GMO (genetically modified organism)-containing and immunological products’ (EMEA, 1998). The guidance rests upon a logical, tiered approach with a cut-off trigger between a basic characterisation of the veterinary medicinal product and an in-depth assessment of its fate and ecotoxic effects (Fig. 2). In order to facilitate authorization and to improve the availability of veterinary pharmaceuticals, harmonized technical requirements for veterinary product authorization are elaborated by a new international initiative, the International Co-operation on Harmonization of Technical Requirements for Authorization of Veterinary
Fig. 1. Entry of veterinary medicinal products (VMPs) into the environment.
J. Koschorreck et al. / Toxicology Letters 131 (2002) 117–124
119
Fig. 2. Environmental risk assessment of veterinary medicinal products (VMPs) — decision tree phase I and phase II tier A.
Medicinal Products (VICH). The VICH parties are the EU, USA and Japan. In addition, Australia and New Zealand joined in as observers. Each party has nominated a representative from the regulation authority and veterinary pharmaceutical industry. Once adopted, the VICH recommendations for a uniform environmental risk assessment for veterinary medicinal products will replace the present EMEA-guidance (EMEA, 1998). VICH Phase I guidance for environmental risk assessment has already been agreed on and implemented (VICH, 2000); phase II is expected to follow in 2003. To address specific testing requirements for genetically modified products, immunological VMPs and feed additives the EU provides guidance on the ‘Environmental risk assessment for immunological veterinary medicinal products’ (EMEA, 1997), ‘Guidance on data relating to the Environmental Risk Assessment for products containing or consisting of genetically modified organisms’ (EC, 2001b) and ‘Guidelines on the assessment of additives in animal nutrition’ (EC, 2001c). Each guidance relies on legislation of its own.
2. The principles of an environmental risk assessment for veterinary medicinal products Phase I of the environmental risk assessment for a VMP starts with questions on the physical and chemical properties of the VMP, its use, dose route, frequency of dosing, animal husbandry and routes of excretion into the environment. It is assumed that VMPs with limited use and limited environmental exposure will have limited environmental effects and thus stop in Phase I. Phase I also identifies VMPs that require a more extensive environmental risk assessment under Phase II. Major routes of introduction of a VMP are: Pasture animals directly excrete residues and/ or metabolites of VMPs onto grassland or into adjacent surface waters. Contaminated manure and slurry from treated animals is spread on agricultural lands. Dips, pour-on formulations, etc. may run off after topical application of antiparasitics. Fish medicines are directly introduced into aquaculture water bodies.
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J. Koschorreck et al. / Toxicology Letters 131 (2002) 117–124
At the end of Phase I, the concentration of a VMP in the relevant environmental matrice is predicted using a uniform approach developed by Montfort (Montfort et al., 1999). The predicted environmental concentration PEC is based on worst case assumptions, e.g. highest number of animals treated, highest dose, no degradation. If the predicted concentration exceeds 100 mg/kg in arable soils or grassland or if more than 1 mg/l of the VMP is released from aquaculture facilities into the environmental the risk assessment proceeds to Phase II. Due to their insecticidal nature all endo- as well as ectoparasitics intended for use on pasture animals advance to the phase II pasture section where special regard is given to the protection of dung fauna. Some VMPs that might otherwise stop in Phase I may need additional environmental information to address particular concerns associated with their activity and use. Once a VMP has reached Phase II its predicted environmental concentration (PEC) is compared with its lowest effective concentration from standard ecotoxicity tests in soil and/or water to assess a probable environmental risk. After the toxic potential of the substance or its metabolites is assessed, the value is multiplied by an appropriate safety factor to create a predicted no effects concentration (PNEC). If the ratio of the predicted concentration to the predicted no effects concentration is greater than 1, further and more detailed studies on fate and effects of the VMPs have to be performed in order to refine the PEC as well as the PNEC. A decline of the expected environmental concentration is a function of hydrolysis, photolysis (chemical transformation) and biodegradation (mineralisation and biotransformation) of a VMP in the environment. The results from a short-term laboratory base set of ecotoxicity tests may be refined by long-term, semi-field or field data. At the end of the Phase II assessment, a VMP may not be expected to cause a significant harm to the environment or, if the PEC/PNEC ratio remains greater than 1, a risk to the environment is assumed. In the latter case, risk mitigation measures have to be linked with the authorisation for use of the product. Risk may be mitigated with restricted application rates of the veterinary medicinal product, restricted access to surface wa-
ters for the target animals on pasture, prolonged storage time for manure (in order to extend the degradation time of the VMP), limitations in the amounts of manure being spread or extensive monitoring of fate and effects after authorisation. In order to illustrate the above processes, three environmental risk assessments from veterinary medicinal products authorization procedures carried out by the German Federal Environmental Agency since 1998 are presented in the following section.
2.1. En6ironmental risk assessment for a benzimidazole helmintic This orally applied veterinary medicinal product belongs to the chemical class of benzimidazoles and is used for the treatment of sheep and cattle harboring mixed age liver fluke. Benzimidazole and sulfon/sulfoxidmetabolites are excreted with dung on grassland from treated pasture animals or spread with manure from treated intensively reared animals on agricultural land. Contamination of the aquatic environment occurs via direct entry from treated pasture animals and run-off from manured arable lands. The predicted environmental concentration of the parent compound and its metabolites in soil or grassland is below the threshold trigger of 100 mg/kg (Table 1). However, the VICH guidance (VICH, 2000) takes the insecticidal properties of veterinary endo- and ectoparasitics and the environmental risks of their use on pasture animals into account and leads antiparasiticidal veterinary medicinal products straight to a Phase II in-depth environmental risk assessment. After fast primary degradation of the parent compound in soil, persistent bound metabolites are generated. The aquatic studies demonstrate that the benzimidazole has no effects on higher plants, earthworms and dung fauna but is highly toxic to daphnids and fish (Table 2). An assessment factor of 100 lowers the predicted no effects concentration of the benzimaidazole for fish to 1 mg/l. Predicted environmental concentrations for both surfacewater scenarios assuming run-off from manured lands and direct entry from pastured animals were considerably higher than 1
J. Koschorreck et al. / Toxicology Letters 131 (2002) 117–124
mg/L and thus environmental concerns needed to be addressed. In order to protect the aquatic environment, risk mitigation measures for the use of the veterinary medicinal product were imposed by use of the following label: ‘‘Access of medicated livestock to open waters must be prevented. A safety distance of 10 m to open waters must be kept when spreading manure on agricultural land.’’
2.2. En6ironmental risk assessment for a mastitis teat dip Mastitis is a frequently occurring inflammation of the mammary gland of dairy cows usually caused by bacterial infection of udder tissues. Since a certain level of mastitis remains in all dairy herds, an effective mastitis control program includes routine teat dipping. Teat dips remove milk residues and kill organisms on the teat at the time of dipping and also leave a residual film of sanitizer on the teat between milkings. The pharmacologically active substance of the mastitis dip is an antimicrobial iodine complex in an excess of nonylphenol ethoxylates (NPEs), the carrier substance. Application is done via dipping the teats of 30 dairy cows into a dip cup of 250 ml dipping solution. After the defined number of
121
animals have been treated, the iodine is spent and the remaining solution is usually poured away into manure. When manure from dairy cows is spread on arable land, residues of the veterinary medicinal product, e.g. nonylphenol ethoxylates (NPE), enter the environment. We decided to focus the environmental risk assessment on NPE leftovers in dip cups and not on the fate of residues of the mastitis dip on teats. The NPE carrier substance rapidly forms nonylphenol (NP) as degradation product which in turn is persistent and moderately to highly toxic to soil and aquatic organisms. The predicted environmental concentration of NPE in soil and grassland exceeds the trigger of 100 mg/kg (Table 1) leading to an in-depth environmental risk assessment according to the VICH-guidance. Sufficient data on fate and effects (Table 2) were found in the nonylphenol dossier of the EU existing chemicals program (EC, 2001d): Nonylphenol is persistent in both soil and water. It is not toxic to higher plants, moderately toxic to earthworms and highly toxic to aquatic organisms. Estrogenic effects and bioaccumulation are observed in fish. The comparison of the predicted environmental concentration of nonylphenol in soil and surface water (PECaquatic) with the toxic potential of the substance multiplied by an assessment factor of 100 revealed no concern for the environment. Nevertheless, the authorization for the mastitis dip was granted on condition of a
Table 1 Environmental fate data Substance
PECsoil (mg/kg) PECwater (mg/l) DT50 soil DT50 water Koc log Kow BCF in fish a
Nonylphenol (Dairy cows)
Macrolide (Chickens)
Benzimidazole (Cattle)
134a B0.01c 300 days 150 days \20000 4.5 1280
892 6.1b \60 days n.a.d 8200 −003 n.a.d
66 18.4c 15 days n.a.d n.a.d 6.2 n.a.d
Nonylphenol ethoxylates. Ground water. c Surfacewater. d Not available. b
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122 Table 2 Ecotoxic effect data Species
Terrestrial path Plant Earthworm Dung beetle Aquatic path Green algae Daphnid Fish
Substance Nonylphenol
Macrolide
Benzimidazole
Mg/kg EC50:1000 (21 days) LC5013.7 (21 days) n.a.b Mg/l EC50:0.056c (72 h) EC50:0.085 (48 h) NOEC:0.024 (21 days) LC50:0.128 (96 h) NOEC: 0.007 (33 days)
Mg/kg EC50:116 (21 days) NOEC:30 LC50:\918 (28 days) n.a.b Mg/l EC50:0.16c (96 h) EC50:57 (48 h) LC50:851 (96 h)
Mg/kg EC50:\4000a LC50:\1000 LC50:\10 Mg/l EC50:26 (72 h) EC50:0.23 (24 h) EC50:0.13 (96 h)
a
Mg/ha. Not available. c Biomass. b
precautionary risk mitigation measure in order to prevent dispensable environmental contamination via waste disposal: ‘Residuals of the VMP and leftovers from dip cup must be collected and thereafter disposed with hazardous waste. The VMP must not get into the environment’. The risk mitigation measure was expanded to all NPE-containing teat dips on the German market and it was pointed out to the veterinary pharmaceutical industry that alternative products (e.g. PVP– Iodine) are favored from an environmental point of view. This was done in line with the opinion of the Commission of the European Union on the use of nonylphenol and nonylphenol ethoxylates in teat dips or other veterinary medicinal products concluding that marketing restrictions to minimize risks to the environment should be considered (EC, 2001e).
2.3. En6ironmental risk assessment for a macrolide antibiotic This veterinary medicinal product is administered with food and used for the treatment of chicken, pig and calf respiratory diseases. Due to poor transformation in the target animal considerable amounts of the unchanged active ingredient are excreted. The resulting predicted environmental concentration lies well above the trigger value of 100 mg/kg soil leading to an in-depth environmental risk assessment in phase II.
According to the first steps of EMEA Phase II guidance (Fig. 2), the acute toxicity of the macrolide antibiotic to microorganisms, earthworms and plants is assessed. High toxic activity of the macrolide antibiotic against microorganisms on agar plates was demonstrated. Essentially less toxic effects are indicated in soil testing systems what can be explained by the strong adsorption capacity of the veterinary pharmaceutical in soil (Koc 8000–36000 depending on soil type). No acute toxic effects to earthworms and higher plants are observed. Despite a high predicted environmental concentration (892 mg/kg) the PEC/ PNEC ratio of below 1 indicates that the VMP does not pose a risk to soil organisms. Due to physico-chemical parameters the macrolide will not enter surfacewater in relevant concentrations and a risk to aquatic organisms is considered to be unlikely. A worst case assumption (concentration porewater= concentration groundwater) predicted a contamination of groundwater with the veterinary medicinal substance. However, the PECgw/PNEC approach with acute daphnid toxicity data did not reveal a risk to groundwater organisms. The outcome of the environmental risk assessment on the basis of the EMEA-guidance does not require risk mitigation measures. An improvement of the guidance paper might be necessary for a more expedient assessment of substances with both slow degradation rates and antimicrobial
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activity. Complex microbial communities should be safeguarded by appropriate long-term tests in the environmental risk assessment. In light of antibiotic resistance and multiresistant pathogens, such testing may not only benefit environmental standards in modern agricultural systems but also help the evaluation of emerging risks to public health.
3. Outlook Environmental Risk Assessment as part of the authorisation routine has identified mitigation measures that are able to reduce contamination to acceptable levels. However, experience with the EMEA-Guidance has raised a number of critical questions: What is the outcome of a risk assessment for substances with long persistence but low ecotoxicity, e.g. antimicrobials? To what extent should fate and effects of metabolites be assessed? How do we deal with parent compounds and/ or its metabolites reaching groundwater? What are the appropriate testing guidelines for assessing toxicity to microorganisms? What are suitable triggers for conducting longterm effect studies in view of the fact that a majority of VMPs being applied more than once a year? Most ectoparasitics are also used as plant protection products or biocides. How can experience from e.g. pesticide regulation, be incorporated into the VICH-guidance? Should fate and effects testing of a VMP in the surface water matrice be triggered (e.g. by sorption characteristics) or be assessed as a basic principle? Should entry into the environment via waste disposal (e.g. mastitis dip leftovers, organophosphate or pyrethroid ear tags) be part of the guidance paper? Finally, a remaining general question is whether the precautionary principle of the ERA aims at sustaining the function of agricultural systems or at the protection of the environment.
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The VICH Phase II guidance is currently being developed and is expected to be implemented in 2003. A draft guidance paper reflecting the outline at this stage will be submitted to all interested parties in the EU for a 6 month public consultation period in the second half of 2002. The Umweltbundesamt would like to encourage interested parties (stakeholders, academics, and nongovernmental organisations) to contribute critical remarks and suggestions for improvement of the guidance document. References BfT, 2000. Bund fu¨ r Tiermedizin, BfT Special. Nr.20. Daughton, C.G., Ternes, T., 1999. Pharmaceuticals and personal care products in the environment. Agents of subtle change? Environ. Health Perspect. 107, 907 – 938. EC, 2001a. Directive 2001/82/EC of the European Parliament and of the Council of 6th November 2001 on the Community code relating to veterinary medicinal products. Official Journal of the European Community, L 311. EC, 2001b. EC Enterprise Directorate General, 2001. Notice to applicants: Vol 6B Presentation and content of the dossier Part II G and H: Guidance on data relating to the Environmental Risk Assessment for products containing or consisting of genetically modified organisms. EC, 2001c. EC Health and Consumer Protection Directorate General, 2001. Guidelines on the assessment of additives in animal nutrition: Additives other than micro-organisms and enzymes. EC, 2001d. European Union Risk Assessment Report, 4Nonylphenol (branched) and nonylphenol, Final report, April 2001. EC, 2001d. Empfehlung der Europa¨ ischen Kommission vom 07.11.2001 u¨ ber die Ergebnisse der Risikobewertung und u¨ ber die Risikobegrenzungsstrategie fu¨ r die Stoffe: AcrylAldehyd; Dimethylsulfat; Nonylphenol; Phenol 4-Nonyl-, verzweigt; tert-Butylmethylether. (2001/838/EC), Amtsblatt 04.12.2001. EMEA, 1997. Environmental risk assessment for immunological veterinary medicinal products. London, UK: European Agency for the Evaluation of Medicinal Products. Rapport nr. EMEA/CVMP/074/95. EMEA, 1998. Note for Guidance: Environmental risk assessment for veterinary medicinal products other than GMOcontaining and immunological products. London, UK: European Agency for the Evaluation of Medicinal Products. Rapport nr. EMEA/CVMP/055/96. Hamscher, G. Sczesny S., Abu-Quare A., Ho¨ per H., Nau H., 2000. Stoffe mit pharmakologischer Wirkung einschließlich hormonell aktiver Substanzen in der Umwelt: Erster Nachweis von Tetracyclinen in
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gu¨ llegedu¨ ngten Bo¨ den. Deutsche Tiera¨ rztliche Wochenschrift, 8/2000, 323 – 325. Montfort, M.H.M.M., Kalf, F.K., van Vlaardingen, P.L.A., Linders, J.B.H.J, 1999. The exposure assessment for veterinary medicinal products. The Science of the Total Environment, 225, 119 –133.
VICH, 2000. CVMP/VICH Topic GL6 (Ecotoxicity Phase I) Step 7 Guideline on Environmental Impact Assessment (EIAs) for Veterinary Medicinal Products — Phase I. London, UK: European Agency for the Evaluation of Medicinal Products. Rapport No. CVMP/ VICH/592/98.