J. Verbr. Lebensm. 3 (2008): 351 – 358 1661-5751/08/040351-8 DOI 10.1007/s00003-008-0369-x © Birkhäuser Verlag, Basel, 2008
Journal für Verbraucherschutz und Lebensmittelsicherheit Journal of Consumer Protection and Food Safety
Maximum Residue Levels of Veterinary Medicines in Relation to Food Safety: European Community Legislation and Ethical Aspects A. Passantino1 and C. Russo2 1 Messina University, Department of Veterinary Public Health, Italy Doctor in Pharmacy, Post-graduate triennial specialization school of “Pharmacognosy”, Faculty of Pharmacy, University of Messina
2
Correspondence to: Prof. Dr. Annamaria Passantino, Department of Veterinary Public Health, Messina University, I-98168 Messina, Italy; Tel. +39 90-3503742; E-mail:
[email protected] Received: March 6, 2008; accepted: March 17, 2008 Online First 14 November 2008
Key words: Maximum residue level, veterinarian, farm animals, food safety, law, ethic. Abstract: Residues of veterinary medicinal products, as defined by the European Union, are “pharmacologically active substances (whether active principles, excipients or degradation products) and their metabolites which remain in foodstuffs obtained from animals to which the veterinary medicinal product in question has been administered”. The policy for Maximum Residue Limit (MRL) setting is focused on a high protection level for the consumer. MRL can be set when risk assessment shows no risk for the consumer. An MRL is the maximum concentration of residue following administration of a veterinary medicine which is legally permitted or acceptable in food under the laws of the EU. The responsibility for keeping residues under the MRL lies with veterinarians and farmers, using licensed animal medicines. Violative residues of veterinary medicines can occur as a result of improper use of a licensed product or through the illegal use of an unlicensed substance. Consequently, it became clear that prudent use of not only antimicrobials used for treatment and prevention of disease but also those used for growth promotion (e.g. b-agonists or steroid hormones) in farm animals is an integral part of good veterinary practice. In the following an overview of the European Community legislation on the studies required for residues is given. Ethical aspects are also considered. Zusammenfassung (Redaktion): Nach der Definition der EU sind Rückstände von Tierarzneimitteln pharmakologisch wirksame Substanzen und ihre Metabolite, die in von Tieren herrührenden Lebensmittel verbleiben, nachdem Tierärzte solche Tiere mit diesen Substanzen behandelt haben. Die Strategie für die Festsetzung von „Maximum Residue Limit“-Levels (MRL) ist ausgerichtet auf das hohe Schutzniveau der Verbraucher. MRL können festgesetzt werden, wenn sich aus der Risikobewertung keine Gefährdung der Verbraucher ergibt. Ein MRL ist die maxi-
male Konzentration eines Rückstandes im Lebensmittel, nachdem zuvor ein Tierarzneimittel verwendet worden ist, das gesetzlich zugelassen oder nach den EU-Gesetzen in Lebensmitteln akzeptiert ist. Die Verantwortung dafür, dass die MRL im Hinblick auf die Rückstände eingehalten werden, liegt bei den Tierärzten und Landwirten, wenn sie zugelassene Tierarzneimittel einsetzen. Unbeabsichtigte Tierarzneimittelrückstände können auftreten als Ergebnis unsachgemäßer Anwendung eines zugelassenen Produkts wie auch als Ergebnis des illegalen Einsatzes einer nicht zugelassenen Substanz. In der Konsequenz sollte es nachvollziehbar sein, dass nicht nur der umsichtige Einsatz von Antibiotioka zur Behandlung und Verhinderung von Krankheiten, sondern auch der Substanzen zur Wachstumssteuerung (e.g. b–Antagonisten und Steroide) in der landwirtschaftlichen Tierhaltung ein integraler Teil der Guten Tierärzlichen Praxis ist. Im folgenden Überblick über die EU-Gesetzgebung wird die aktuelle Situation im Hinblick auf die Rückstände von Tierarzneimitteln in Lebensmitteln dargestellt. Ethische Aspekte werden dabei einbezogen.
1. Introduction A wide range of veterinary medicinal products1 such as antibiotic is administered legitimately to farm animals to treat disease or prevent disease from spreading (EC, 2001a) and improve health in animals. As more antibiotics were discovered and introduced to veterinary clinical practice2, it be-
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A “medicinal product” is defined in article 1 of Directive 65/65/EEC as any substance or combination of substances presented for treating or preventing diseases in human beings or animals. The most commonly used antimicrobials in food-producing animals are the blactamas (i.e. amoxicillin, ampicillin, oxacillin, etc.), tetracyclines, aminoglycosides, lincosamides, macrolides, pleuromutilins and sulfonamides. In addition, quinolones have been available for more than 25 years. Antimicrobials are administered to animals by injections (intravenously, intramuscularly, or subcu-
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A. Passantino and C. Russo Tab. 1 Factors which may lead a veterinarian or animal owner to use unapproved drug products or improper use of a licensed product. No approved product is available to treat a specific condition or illness. An imported, unapproved product is cheaper than an approved product. Lack of understanding as to the difference between approved and unapproved products or a misunderstanding of policies and regulations related to these products. A drug may be on “back-order” and therefore, unavailable from the pharmaceutical industry when needed. The unapproved product may be imported with an animal (e.g. a show dog or race horse) that has been traveling outside the country and is returning.
came clear that choice among rational agents needed to be guided by the agreement of antibiotic policies or “ethical” measures. Prudent use of antimicrobial drugs is an integral part of good veterinary practices; it is an attitude to maximize therapeutic efficacy and minimize selection of resistant microorganisms. The importance of veterinary medicine and especially of antimicrobial agents is shown, not only as beneficial compounds for animal health and welfare but as risks as well, being potential sources of residues in food of animal origin, when after administration of drugs to the animals the withdrawal time3 in relation to the Maximum Residue Limit (MRL)4 is not taken into account. A number of possible adverse health effects of veterinary drug residues have been suggested: (a) allergic / toxic reactions to residues (Gomes and Demoly, 2001; Martinez, 2005; Raison-Peyron et al., 2001), (b) chronic toxic effects occurring with prolonged exposure to low levels of antibiotics, (c) development of antibiotic-resistant bacteria in treated animal and etc. On the basis of the considerations mentioned above, community legislation relating to veterinary medicines has a twofold aim: to guarantee a high level of safety and medicinal efficacy for the animal being treated, and to protect the health of the consumer of foods of animal origin. In the specific case of veterinary medicinal substances destined for food-producing animals, the safety assessment must also take account of an additional factor associated with the possible persistence of residues of medicinal products in the foodstuff and possible consequences for the consumer. To these ends the competent authorities establish a minimum
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4
taneously), orally in feed or water, topically on the skin and by intramammary and intrauterine infusions (Mitchell et al., 1998). Theoretically, all of these routes may lead to residues appearing in foods of animal origin such as milk, meat and eggs (Johnston, 1998). Use of animal medicines is strictly controlled by European law, and requires observance of the withdrawal period, defined in Directive 2001/82/EC as “the period necessary between the last administration of the veterinary medicinal product to animals under normal conditions of use and the production of foodstuffs from such animals to ensure that such foodstuffs do not contain residues in quantities in excess of the maximum residue limits laid down in application of Regulation (EEC) No 2377/90”. This is the time which passes between the last dose given to the animal and the time when the level of residues in the tissues (muscle, liver, kidney, skin/fat) or products (milk, eggs, honey) is lower than or equal to the MRL (Cholas, 1976; Nouws and Ziv, 1978; Jackson, 1980). Until the withdrawal period has elapsed, the animal or its products must not be used for human consumption. The withdrawal period is set out in the data sheet for the medicine and in the instructions for use which are part of the product packaging. Farmers are required by law to record all uses of animal medicines; it is therefore straightforward to ensure that withdrawal periods are observed. The notion of “maximal residue limit” (MRL) takes into account a combination of data of three different sources: toxicity studies in laboratory animals, tissular distribution of veterinary drugs in animal species producing food-stuffs and habits of consumption by human beings.
waiting time to be observed by the animal’s owner when appropriate to the proper use of a veterinary medicinal product. This waiting time corresponds to the period during which the foodstuffs produced by the animal in question may not be marketed for human consumption. It is determined by reference in particular to the rapidity with which the active substances of the product are eliminated, to the point below which the residues present in the foodstuffs produced by the animal can be regarded as no longer representing a risk to the consumer. These thresholds are defined as Maximum Residue Levels (MRLs). For banned compounds there is a zero-tolerance for residues, on the grounds that no safe MRL can be should not occur. In establishing MRLs for residues of veterinary medicinal products in foodstuffs of animal origin, it is necessary to specify the animal species in which the residues may be present, the levels at which they may be present in each of the relevant tissues obtained from the treated animal (target tissue) as well as the nature of the residue that is relevant for the monitoring of residues (marker residue). In the case of veterinary medicinal products intended for use in lactating animals MRLs must be established for milk.
2. Violative veterinary drug residues5 Italy has banned the use of certain antibiotics or growth promoting agents (e.g. steroid hormones) from use in food producing animals. If a compound is banned from use in these animals, contamination of animal feed should not occur. The most likely cause of violative drug residues is the failure to observe withdrawal times (Paige and Kent, 1987; van Dresser and Wilke, 1989; Guest and Paige, 1991; Paige, 1994). Violative residues of veterinary medicines can occur as a result of improper use of a licensed product (Tab. 1) or through the illegal use6 of an unlicensed substance (Papich et al., 1993; Kaneene and Miller, 1997; Higgins et al., 1999). Nevertheless, violative veterinary drug residues do not necessarily mean that abuse occurred (Kennedy et al., 2000). 5
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Regulation 2377/90/ECC, art. 2, point a, states that residues of veterinary medicinal products are “pharmacologically active substances (whether active principles, excipients or degradation products) and their metabolites which remain in foodstuffs obtained from animals to which the veterinary medicinal product in question has been administered”. Illegal use or treatment is defined Directive 96/23/EC as the “use of unauthorised substances or products or the use of substances or products authorised under Community legislation for purposes or under conditions other than those laid down in Community legislation or, where appropriate, in the various national legislations”.
MRLs and food safety: law and ethic
In fact they can occur by a variety of routes: i) contamination of animal feedingstuffs7 (Kennedy et al., 2000; Lynas et al., 1998), ii) environmental contamination (i.e. exposure of wild marine species, residues arising from ingestion of naturally occurring toxins, contamination of soils and freshwater systems) (Björklund, et al., 1990; Capone et al., 1996; Coyne et al., 1997; Erasmuson et al., 1994; Ervik et al., 1994; Kennedy et al., 1995; Kennedy et al., 1998; Le Bris et al., 1995; Migliore et al., 1996; Muller et al., 1998) and iii) animal to animal transfer of drug via ingestion of faeces and/or urine (Mc Caughey et al., 1990). Generally, rational use of drugs should be based on the knowledge of each agent, its indications and correct dosage.
3. EU legislation: an overview The basic Directives of European legislation on veterinary medicinal products have been frequently and substantially amended over time. Very recently in the interests of clarity these Directives have been codified by assembling them in a single text (EC, 2001). Therefore only a very brief overview of the original legislation will be presented here in order that the way in which regulation has been developed may be understood. The basic rules governing the marketing of veterinary medicinal products within the European Union is contained in the codified Directive adopted by the European Parliament and the Council in 2001, Directive 2001/82/EC (EC, 2001)8. Furthermore, Regulation No 2309/93/ECC (ECC, 1993) lays down a Community procedure for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products. In order to protect the health of the consumer of foodstuffs of animal origin, one of the most important principles laid down in the legislation is that foodstuffs obtained from animals treated with veterinary medicinal products must not contain residues of the medicine or its metabolites which might constitute a health hazard for the consumer. Consecutively to facilitate the uniform application of this principle throughout the European Union, and in order to ensure that differences in the assessment of the effects of residues by Member States do not create barriers to the free movement of foodstuffs of animal origin, on 26 June 1990 the Council adopted Regulation No 2377/90/EEC9 (EEC, 1990) laying down a Community procedure for the establishment of maximum residue limits (MRLs) for veterinary medicinal products in foodstuffs of animal origin including meat of mammals,
poultry, fish, milk, eggs or honey10. This Regulation has subsequently been amended to introduce values of MRLs for substances used in veterinary medicinal products in the annexes to the Regulation and to adapt the legislation to technical progress and amendments to the regulatory procedures. Rules on food control in general can be found in a variety of Community legislative acts and is at this time under consideration (Proposal for a Regulation of the European Parliament and of the Council on official feed and food controls)11. Additionally Directive 96/23/EC (‘Residue Control Directive’) (EC, 1996b) contains specific requirements, in particular for the control of pharmacologically active substances that may be used as veterinary medicinal products in food producing animals12. This includes primarily sampling and investigation procedures, requirements on the documentation of use, indication for sanctions in case of noncompliance, requirements for targeted investigations and for the establishment and reporting of monitoring programmes. Moreover Directive 96/22/EC (EC, 1996a), as amended by Directive 2003/74/EC (EC, 2003a) prohibits the use of certain substances for specific purposes in food producing animals and Decision 1999/879/EC prohibits the use of bovine somatotropin for animal health reasons (EC, 1999). Together, these Directives describe how to investigate and detect substances in animals, feedingstuffs and animal products (Serratosa et al., 2006). The evaluation of the safety of residues is based on the determination of the acceptable daily intake (ADI) on which in turn maximum residues limits (MRL) is based. The ADI is an estimate of the residue, expressed in term of mg or mg per kg bodyweight, which can be ingested daily over a lifetime with a health risk to the consumer (EC, 2003b). According to Regulation No. 2377/90, a maximum residue limit (MRL) is defined as: “the maximum concentration of residue resulting from the use of a veterinary medicinal product […] which may be accepted by the Union to be legally permitted or recognized as acceptable in or on a food”13 and allocated to individual food commodities. It is based on the type and amount of residue considered to be without any toxicological hazard for human health as expressed by the ADI, or on the basis of a temporary ADI that utilizes an additional safety factor. In calculating an MRL, the ADI, the residue depletion patterns of a compound in the edible tissues of a particular foodproducing animal and the theoretical food intakes are taken into account. Once the process of safety evaluation is complete and MRLs have been derived for a particular substance, consideration is given to the likely level of residue which may be expected to remain after the use of the substance in accor10
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Contamination of animal feedingstuffs with a variety of compounds also occurs. The significance of this contamination depends on the pharmacodynamics of the compound and the species affected (McEvoy, 2002). It should be noted that Directive 2001/82/EC has recently been amended by Directive 2004/28/EC, published in OJ L 136, 30. 4. 2004, pp. 58 – 84. It is amended by Commission Regulation (EC) No. 1873/2003 of 24 October 2003 amending Annex II to Council Regulation (EEC) No 2377/90 laying down a Community procedure for the establishment of maximum residue limits of veterinary medicinal products in foodstuffs of animal origin. OJ L 275, 25. 10. 2003, pp. 9 – 11.
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The maximum residue limits established in Regulation 2377/90 are the point of reference for residue control of food of animal origin. Food that contains residues non-compliant with the limits established in regulation is considered unfit for human consumption. Available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=COM:2003:0052:FIN:IT:PDF The main purpose of Directive 96/23/EC is to provide an effective and uniform system for the monitoring and control of illegal substances or incorrect use of authorised substances in animal products intended for human consumption. This definition is the same as that adopted by the FAO/WHO Codex Alimentarius Committee for Residues of Veterinary Drugs in Foods.
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dance with good veterinary practice, and to the availability of analytical detection methods suitable for use for routine monitoring purposes. The MRLs may be further reduced to take account of these factors (EC, 2003b). In the EU, MRLs based on microbiological effects have been set for e.g. cephalexin, CTC, doxicycline, EF, erythromycin, florfenicol, gentamicin, kanamycin, lincomycin, marbofloxacin, nafcillin, novobiocin, OTC, pirlimycin, sarafloxacin, spiramycin and tetracycline (EMEA, 2004). An ADI not based on microbiological effects has been set only for a few antimicrobials, e.g. for danofloxacin, difloxacin, dihydrostreptomycin (DHS), neomycin, streptomycin and tiamulin. MRLs for penicillins are based on immunological effects and on the sensitivity of bacteria used in the dairy industry. In Europe, a prescribing ‘cascade’14 has been established to guide veterinarians in their decision-making process. For foodproducing animals, extralabel use is restricted to medicines with pharmacologically active ingredients that are included in Annex I, II or III of Regulation (EEC) No. 2377/90 (Gehring et al., 2006). Annex I of the regulation includes substances for which final MRLs have been established, and Annex II contains the lists of substances for which it is not necessary for the protection of public health to establish MRL values. Annex III includes substances with provisional MRLs15. Annex IV includes substances for which no MRL can be established because residues of these substances, at whatever limit, in foodstuffs of animal origin constitute a hazard to the health of the consumer. So, their use is prohibited for production animals. The European’ approaches limit extralabel use to veterinarians within the context of a valid client-veterinarian relationship and aim to decrease risk by limiting the extralabel use of drugs in food-producing animals to those for which adequate information pertaining to food safety was available. The European approach does this by limiting extralabel use to those drugs for which an MRL has been established by the regulatory authorities (Gehring et al., 2006). Commission Decision 2002/657/EC (EC, 2002) introduced Minimum Required Performance limits (MRPLs) intended to promote harmonised implementation of Directive 96/23/EC for substances for which no permitted limit has been established. In contrast to MRLs, MRPLs are control tools based on expert advice on feasibility of controls, an ‘other legitimate factor’ in risk analysis (see Article 6 of Regulation 2002/178/EC ‘Food Law’).
help ensure there are morally acceptable, the necessary principles and tools are provided by professional ethics. Veterinarians are professionals who must make decisions that influence the fate of animals and effects the live of the people. In particular, they aim to safeguard and improve the welfare and moral status of animals (Passantino, 2007; van Vlissingen, 2001). They also have to address issues of public interest, such as public health. The central role they play in decision-making implies considerable collective and individual responsibility16. Every veterinarian has the obligation to uphold the trust invested in the profession by adhering to the profession’s Ethical Code (EC). EC is essential characteristic of a profession and serves three main functions: • • •
a code communicates to the public and to the members of the profession the ideals of the profession; a code is a general guide for professional ethical conduct17; a code provides standards of acceptable conduct that allow the professional to implement disciplinary procedures against those who fall below the standards.
In Veterinary Medicine, as in other professional fields, ECs provide the basic set of notions without which it would be impossible to practice with professional dignity, competence, correctness and diligence (Passantino, 2007). This model of behaviour, with regard to veterinarians, was codified in Italy, on April 03rd, 1993 and modified 17th December, 2006. The Italian Ethical Codes (IEC) places equal emphasis on professional obligations for protecting animal health, relief of animal suffering, conservation of animal resources, and promoting public health, as do similar oaths from other countries. Veterinarians will be forced to prioritize among these obligations even though they have no desire to act in a manner that is harmful to the public, their patients, or their clients. Because of the potential impact of veterinary medicinal products on foodstuffs of animal origin and on the environment, the problem of availability of medicines must be considered a real public health problem in every sense: human health, food safety, animal health and environmental protection. In fact, theoretically, when no MRLs have been fixed, there should be no residue in foodstuffs of animal origin. However, some sick animals have to be treated and a lack of medicines for the species and the disease in question can lead to uncontrolled practices.
4. How can we make ethical decisions? 16
Ethics is concerned with how we should decide what is morally or wrong right. It is a specific discipline which attempts to analyse the concepts and principles used to justify a moral choices and actions in particular situations. Therefore, being a professional entails making decisions of consequence and to
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See the following paragraph no. 4. Based on the list of molecules in Annexes I, II and III of the MRLs regulation, table 2 shows the main shortage medicines identified by species.
Important issues such as food safety, zoonotic disease and public health, prevention of the dissemination of antibiotic resistance, protection of the health of the nations animals (companion and production) as a whole, and contribution to the advancement of veterinary science requires the balancing of the interests of the patient (animal), the client (owner) and the public (society). A loss of the concept of a fiduciary responsibility to society in professional practice can lead toward adoption of a business ethic model and away from the more traditional professional roles. Cfr. Rollin, B. E. “An Introduction to Veterinary Medical Ethics – Theory and Cases”, 2nd ed. Blackwell Publishing, Ames, Iowa, USA, 2006. Codes of ethics for veterinarians focus mainly on professional conduct in relation to colleagues and clients, such as advertising and the adoption of one anothers clients. Meanwhile, the interests of animals are considered implicit rather than being discussed explicitly.
MRLs and food safety: law and ethic
On the one hand, these could involve the use of a medicine intended for another species, off-label and in a more or less approximate fashion, due to the lack of specific information. On the other hand, these could involve the illegal use of raw materials resulting in public health problems (residues, environmental contamination). The veterinarians must prioritize the prescription of a veterinary medicinal product authorized for an animal of the species concerned and for the therapeutic indication involved or a medicated feedstuff manufactured from an authorized medicated premix which meets the same conditions. If no suitable veterinary medicinal product benefiting from a marketing authorization, a temporary authorization of use or a registration is available, the veterinarians may morally prescribe the following medicinal products: a) a veterinary medicinal product authorized for animals of another species with the same therapeutic indication or for animals of the same species for a different therapeutic indication or a medicated feedstuff manufactured from an authorized medicated pre-mix meeting the same conditions; b) if the medicinal product described in a) is not available, a veterinary medicinal product authorized for animals of another species for a different therapeutic indication or a medicated feedstuff manufactured from an authorized medicated pre-mix meeting the same conditions; c) if the medicinal products mentioned in a) and b) are not available, a medicine authorized for human use; d) if the medicinal products mentioned in a), b) and c) are not available, a magistral veterinary preparation. The medicines mentioned above, must be administered either by the veterinarian or, under his personal responsibility, by the holder of the animals, in compliance with the veterinarian’s instructions. When the veterinarian prescribes a medicinal product for administration to animals whose meat or products are intended for human consumption, the pharmacologically active substances which it contains must be listed in one of Annexes I, II and III of Council Regulation (EEC) No. 2377/90. The veterinarian must fix the applicable withdrawal period which may not be less than the minimum set for the foodstuff of animal origin concerned. This option of using the “cascade” approach18 should be considered as a prudent decision-making help for the veteri-
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The unique role of veterinarians is recognised in the so-called Cascade provision of both the EU Directive and national legislation. This provision, which is intended as being exceptional, allows veterinarians where it is necessary in order to avoid unacceptable suffering and where no suitable product exists for the treatment of an animal, to prescribe medicines off-label within very strict limitations. These limitations include the restriction that the medicine must be administered by the veterinarians or given under his/her direct personal responsibility; that an MRL must be established for the active substance(s) in the medicine; that the use of the product is confined to a single animal or to a small number of animals on a particular holding and that the Veterinarians specifies an appropriate withdrawal period for the slaughter of treated animals or for the production of milk, eggs or honey.
narian when the therapeutic indications as defined by the Marketing Authorization are not in place. He / she must also comply with a withdrawal period which must not be less than the standard withdrawal period fixed by the European legislation. This approach does not in any sense constitute a long term solution to the problem of availability of veterinary medicines. Moreover, it also places the full burden of responsibility for the use of an off-label medicine, when there is no authorized medicine available for the target species, on the veterinarian, particularly as regards insurance. In conclusion, the veterinarians and the food producers have the moral and legal obligation to guarantee the safety of product. If insufficient care results in an unsafe product which causes harm, the producer could be held to be morally culpable and legally accountable. This is an approach to the principle of responsibility. Therefore, the moral responsibility of the producer can only be to ensure that all reasonable care is taken in the light of current knowledge. This in turn implies that the principles of transparency and openness are closely linked to that of responsibility. Liability is a more specific legal concept involving the possibility for producers to be forced to answer and compensate for negative consequences of their activities on consumers’ health. Veterinarians are ethically obliged to continue to limit consumer exposure to pharmacologically active substances intended to be used in veterinary medicinal products for food producing animals and residues thereof in foodstuffs of animal origin. Therefore it is necessary that the legislator: i) simplifies the existing legislation by enhancing readability of the provisions on established MRLs for the end-users (i.e. animal health professionals, control competent authorities in Member states and third countries); ii) improves availability of veterinary medicinal products for food producing animals in order to ensure animal health and welfare and avoid illegal use of substances; iii) provides clear references for the control of residues of pharmacologically active substances in foodstuffs to improve consumer health protection and the functioning of the Single Market; iv) clarifies the Community procedures establishing Maximum Residues Limits (MRLs) by ensuring consistency with international standards. In fact, the compilation of all substances and their MRL related provisions in one Commission regulation replacing the existing four annexes would improve the readability and comprehension, in particular if sorted to the alphabet. Veterinarians should have access to a unique document collating all the necessary information on all substances evaluated as they are allowed to use in exceptional circumstances products for a food producing species without an explicit authorization of this product (article 11 of Directive 2001/82/EC). Thereby simplification would help to improve availability of veterinary medicine for certain animal species or conditions.
5. Consequences of current availability crisis The lack of suitably authorized veterinary medicinal products is a problem both of animal welfare and of public health.
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A. Passantino and C. Russo Tab. 2 Examples of shortage medicines identified by species. Species Disease
Permitted treatment
Turkey Histomoniasis
None: the only effective molecules are listed in Annex IV None
Alternative Possible solutions For curing: Metronidazole? For prevention: nitarsone (feed additive)
None with MA indications None Xylazine Ketamine
None None None
Oxyclozanide Vaccine (anatoxin D and C)* Tiletamine+Zolazepam, Romifidine
Cattle
Rumen fluke Botulism Anaesthesia
Goats
Mastitis None Parasite infestation Benzimidazoles Q Fever Inactivated vaccine
None Absence None
Cloxacillin, Nafcillin, Cefazolin, Spiramycin Levamisole, Pyrantel, Eprinomectin Live vaccine**
Nosemosis1 American foulbrood
None None
None None
Fumagilin Oxytetracycline
Rabbits Mange
None***
None
Amitraz, Avermectins, etc.
Pigs
Azaperone, Ketamine, Sodium thiopental
None
Tiletamine+Zolazepam, Acepromazine, Xylazine
Bees
Anaesthesia
*Currently available in South Africa. ** A vaccine of this type is currently marketed in Hungary. *** Carbaryl but only in pet rabbit. Nosemosis of honey bees is a notifiable disease, it is included on the B list of the OIE.
Animal Health and Welfare: In some European countries, including Italy, the lack of authorized products carries legal consequences for veterinarians who may consider using unlicensed medicines in order to treat disease present in animals in this country. This has led to a legitimate concern among veterinarians faced with situations where there is no authorized veterinary medicine available. Farmers too may face problems in releasing the produce of such animals into the food chain. Problems of animal welfare include the unnecessary suffering of animals either through lack of pain relief or lack of suitable disease treatment. Public Health: Problems of public health could potentially arise either through the inability to control zoonotic disease in animals or in their produce or through the use of unlicensed medicines (off-label use of medicines licensed for use in humans or in another animal species or use of illegal medicines) with consequential risks of exposure of consumers to potentially harmful drug residues. There is also a risk that public confidence in the whole regulatory and monitoring systems may be undermined through the lack of authorized medicines. Professional Judgement: Any occupation or profession that is highly regulated in relation to the usage of medicines, where illegal use could lead to the loss of livelihoods, will be very compliant. Every animal circumstance and therapeutic need is unlikely to be covered. The exercise of professional judgement and experience may carry risks in the interpretation of the Cascade, or mean that only supportive therapy is provided. The animal medicines regulatory requirements may compete with animal welfare needs. The effect of this situation is to place significant personal responsibility on individual veterinary practitioners and the result of a wrong judgement call will have serious implications for him/her. In effect it would appear
that the veterinary practitioner rather than the pharmaceutical companies carries the greatest therapeutic responsibility.
6. Considerations Precaution is the policy underlying risk evaluation and management through the establishment of MRLs aimed at determining a waiting period for veterinary medicinals (i.e. antibacterial) in animal farms. This policy of precaution has developed in parallel with the rising level of scientific and consumer requirements aimed at guaranteeing the quality and safety of pharmaceutical products. Originally, the determination of MRLs did not depend on a specific approach related to each animal species concerned. Studies of comparative metabolism and pharmacokinetics currently result in residue risk evaluations base on the animal species concerned. For numerous active substances, MRLs, under Council Regulation 2377/90 (ECC, 1990) and successive amendments, have been determined only for a limited number of animal species. Consequently, only a very small number of MRLs exist for certain species (bees and fish, but also goats, sheep, laying hens, horses and others). Whose problem is it? Veterinarians and farmers (responsible for the animals’ health and welfare) are the first to be concerned by the lack of available medical products. Frequently, for lack of a treatment, they will have no alternative but to administer active substances available only outside the legal framework, without any approved indication of dosage or of the need to observe a waiting time. These substances are thus used without known therapeutic efficacy and without any safety evaluation for the final consumer of the foodstuffs concerned.
MRLs and food safety: law and ethic
This conduct is forced upon the persons concerned by two factors: unwillingness to allow sick animals to suffer, and / or unwillingness to accept the large potential economic costs of the animal’s sickness. The sudden reduction in the available therapeutic armoury has thus resulted in a significant risk of more widespread illegal and unmonitored use of active substances. These seems to be a need for a broad review of all aspects of the problem of availability, and for a coherent set of measures aimed at improving the availability of certain therapeutic substances for species and indications which are of little economic interest. To this end, the European Commission has two objectives: - to enhance pharmaceutical firms’ interest in certain market segments by making the investments required prior to marketing more attractive, by adapting as far as possible the system of marketing authorisation to the particularities of the animal health sector whilst maintaining the high level of consumer health protection. The costs and constraints of developing a veterinary medicinal product should not be a barrier to innovation or to making available to stock raisers and the profession the products necessary to maintain their animals’ health; - to permit and, if possible, facilitate the veterinary use of medicinal products not available in the Member State concerned but authorised elsewhere in the Community.
7. Conclusion Food quality and safety are essential concerns in our society. As regards foodstuffs of animal origin, veterinary medicinal products constitute an essential tool for controlling animal health and thereby ensuring quality and productivity. In addition, veterinary medicinal products are intended to maintain animals in good health, thereby contributing to animal welfare. The possible presence of residues in products of animal origin or in the environment requires a rigorous assessment of the safety of these products and control of their manufacture, marketing and use. To meet these objectives, legislation has been put in place which requires a marketing authorisation to be obtained for all veterinary medicinal products. On the basis of these considerations, the Authors trust that the prospects opened by short (MRL extrapolation) and medium term measures (revision of existing legal instruments) will reverse the current trend and also facilitate the sustainable development of new therapies for species and indications which are currently ignored by the veterinary pharmaceutical industry.
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