Andrew Cannavan, Seibersdorf, Austria
In recent years, the issue of veterinary drug residues in animal-derived foods has become increasingly important in many developing countries. Concerns over veterinary drug usage and residues are primarily related to food safety and the possibility of the development of antibiotic resistant pathogens, but the main impetus behind the increased interest of developing country governments is the need to meet requirements for international trade. Failure to do so can have devastating economic consequences. A recent example is the EU suspension of imports of products of animal origin from China in March 2002, a market worth €327.7 million in the year 2000 1. There is also growing public concern regarding drug residues in many developing countries. In a survey in Nigeria, for example, more than half of the respondents were concerned about residues in meat and favoured the introduction of legislation for residue prevention, including condemnation of contaminated meat2. Since the late 1990s, the Joint Food and Agriculture Organisation/International Atomic Energy Agency (FAO/IAEA) Division of Nuclear Techniques in Food and Agriculture has been active in assisting capacity-building for drug residue monitoring in various developing countries, through technical co-operation, technology transfer, co-ordinated research and other awareness-building and training activities.
Veterinary drug use and control in developing countries
The use and control of veterinary drugs in developing countries varies between and within regions. Many of the least developed countries lack the resources to assure food security and issues such as drug residues have a very low priority. However, as public awareness of food safety and quality issues grows, there is increased pressure on governments to address these issues even in low income countries. Many middle or high income developing countries already have accredited control systems in place, or are working towards that goal.
Antibiotics are widely used in developing countries, due in part to the high incidence of infectious diseases in many areas 3,4. Anthelmintics are also commonly used5 and there is widespread use of drugs that may not be relevant in the developed world, such as trypanocides in certain areas of sub-Saharan Africa6.
There is a trend toward increased consumption of meat and dairy products, especially poultry. It is estimated that the per capita consumption in developing countries of livestock products could rise by as much as 44% by 20307. To meet this demand, an increasing share of livestock production is by commercial enterprises and intensive or semi-intensive peri-urban production systems rather than traditional mixed farming systems, with a consequent increase in the use of compounds such as antibiotics, coccidiostats and growth promoting hormones.
Aquaculture has also exhibited a rapid growth worldwide in recent years, accounting for 26% of world fish production in 1999. About half of global aquaculture production is in developing countries, Asia providing about 89% of world production in 19997. Contamination of aquaculture products from Asia and Latin America with antibiotic residues has recently been the cause of international trade interventions leading to loss of revenue for the exporting countries.
Causes of residues
Where no regulatory legislation or mechanisms are in place for drug approval and use or for residues monitoring, the occurrence of residues is not surprising. Drugs, including unapproved and unregulated compounds that may have no ADI, can often be easily purchased from village shops and informal vendors 5,6,8. There may be no quality control of the substances supplied and concentrations and dosage rates may be incorrectly recorded 9. There is often a lack of veterinary advice regarding withdrawal periods and this may be compounded by illiteracy, rendering labelling and printed instructions for drugs of limited use. Drugs are frequently administered by unqualified farmers or para-veterinary field staff and extended usage or excessive or multiple dosage of the compounds are common. Treatment records are frequently poorly maintained or non-existent and individual animal identification and traceability is often impossible. For resource-poor farmers, a scarcity of meat and the fear of economic loss may prompt the slaughter of casualty animals for food. Educational programmes and awareness campaigns targeted at farmers and field workers on the correct and appropriate use of veterinary drugs can help avoid many of these scenarios. Such campaigns must take into account the socio-economic status of the farmers and the level of veterinary advice available to them in the field and should be included in the design of residue programmes.
Problems in implementation
The problems identified and solutions proposed for testing for veterinary drug residues in laboratories with limited capabilities and resources were summarised by Jeggo and Ferris10. The IAEA has current or completed veterinary drug residue projects in various countries, including Cyprus, The Dominican Republic, Jamaica, Malaysia, Malta, Mongolia, Morocco, Namibia, South Africa, Sri Lanka and Yemen. A general objective of all of these projects was to implement screening methodologies in a quality assured manner that would facilitate the implementation of an overall quality system with accreditation as an achievable future goal.
With limited resources and personnel it is impossible for laboratories in many countries to meet the criteria set out for confirmatory analysis in, for example, EU Commission Decision 2002/657/EC11. The goal is often to set up a quality-assured screening laboratory using techniques such as microbial inhibition tests and immunoassays. Certain countries, such as Thailand, where the export market is very important, have invested in LC-MSMS instrumentation and personnel. In certain countries in Latin America commercial laboratories are contracted by government to perform confirmatory analyses, and these laboratories may have advanced MS instrumentation. In other cases, confirmatory analyses may be performed using methods that may not meet the stringent identification criteria usually required for confirmatory analyses, but which may be sufficiently sensitive. Such testing should be acceptable to importing countries because any shortcomings in the methodology will compromise the producer rather than the consumer; false positive results are more likely to occur than false negatives. There is a need for the provision of affordable confirmatory services from advanced laboratories in the developed world.
The implementation of screening methods can also be problematic. Commercial immunoassay reagents such as enzyme conjugates can deteriorate during transport and storage, causing poor performance of the method. Such problems are being addressed under a FAO/IAEA research project in which several groups will study the problem and investigate reagent stabilisation. Immunoassay reagents have also been produced in several countries to develop in-house methods and ensure regional reagent supply.
The specific technical problems encountered in developing country laboratories can also impede the implementation of quality systems 12. These problems include difficulties with supply of laboratory materials, analytical standards and reference materials, sourcing of analytical equipment and availability of local servicing and consumables. Scientific literature is not readily available and methodologies may not be available in the local language. Poor laboratory conditions such as high temperatures, unstable power supplies and inadequate safety facilities can adversely affect performance. Measurements using national standards (e.g. calibration of instruments) may not be traceable to international base units.
It is difficult to recruit and retain specialised scientific staff in developing countries and there are few training opportunities. IAEA provides training through a number of mechanisms. Fellowships are arranged in established residues laboratories. Expert missions are also provided, the experts recruited being experienced scientists who can adapt the training to conditions in the counterpart laboratory and can provide a wider range of expertise than that requested if the need arises.
Contact with developing countries has often revealed a lack of knowledge on the procedures involved in the control of veterinary drug residues. Requests for IAEA assistance frequently focus on training in inappropriate technologies and fail to address aspects such as the need for national legislation, Good Veterinary Practice, regulation of drug use and the design of national plans. To address this problem, FAO/IAEA has implemented several awareness building and training exercises. A training course on screening and confirmatory methodologies for veterinary drug residues was presented in three different regions with participants from approximately 50 developing countries. A workshop for policy-makers, designed to provide and exchange information on the overall process of drug residues control was held in Vienna in October 2003. The workshop was attended by representatives from 34 developing countries. Recommendations drafted at the workshop can be found on the FAO/IAEA Animal Production & Health Section Website (http://www.iaea.org/programmes/nafa/d3/index.html) and will be circulated through Codex Alimentarius channels. Feedback from these activities indicated that further such training and awareness-building is required.
One of the most important aspects of these meetings was the opportunity for participants to establish networks of scientists and regulators from the developing and developed worlds. Where possible, consultants with broad international experience and with influence on the drafting of technical and regulatory guidelines were recruited. It is of key importance that the information flow is bilateral, so that the consultants from developed countries gain a better understanding of the problems and needs of the developing countries. It is hoped that this enhanced understanding will be improve the quality and applicability of future guidelines.
For countries wishing to trade with the EU, it is usually impossible with the resources available to test for the complete range of compounds set out in Council Directive 96/23/EC 13. An approach must be defined to prioritise these substances in the development of a National Plan. One possibility is that the focus should be on compounds that have caused most disruption in international trade, for example prohibited compounds such as nitrofuran metabolites and chloramphenicol.
There is also confusion concerning the lack of harmonisation with respect to aspects such as maximum residue limits (MRLs) and method validation. Developing countries exporting to the EU are required under Commission Decision 2001/487/EC 14 to comply with Directive 96/23/EC for residue plans and Council Regulation (EEC) No 2377/90 15 for MRLs. However, the EU sampling strategy and MRLs may differ from those set by Codex, which is intended to be used as a point of reference in trade disputes under the Sanitary and Phytosanitary Standards Agreement of the World Trade Organization 16. These differences can have a significant effect on developing country trade; for example, it is estimated 17 that if Codex MRLs were adopted for tetracyclines, global trade in beef would increase by over $3.2 billion.
There has been a trend away from the classical validation pathway involving interlaboratory studies towards single laboratory performance-based validation. The EU has adopted this approach in Decision 2002/657/EC and Codex guidelines are currently under revision. The prescriptive approach of the EU legislation and the clear instructions for validation may be easier to follow in a developing country situation, where the analysts often have limited experience in residues analysis, than the guidelines provided by, for example, Codex, which require more interpretation. For screening methods, validation guidelines are considered by many analysts to be insufficiently defined. There is a large area of overlap in the respective guidelines, but the use of different terminology and statistical approaches can confuse the analyst. The adoption in the EU of the terms "decision limit" (CCá) and "detection capability" (CCâ), though based on existing statistical approaches, initially appear to be new parameters which bear no relationship to the more familiar limits of detection and quantitation. The "minimum required performance level" (MRPL) for prohibited compounds introduced in Decision 2002/657/EC makes no apparent sense to a laboratory in an exporting third world country. Even if the MRPL can be achieved, there is no guarantee that products will be accepted for import, since the importing country may be able to achieve better sensitivity. In the training courses run by the Joint Division, considerable effort is made to fully explain these concepts.
The implementation of sampling regimes as outlined in Codex guidelines CAC/GL/16 1993 or the European Directive 96/23/EC can be difficult given the problems with animal identification and traceability and the lack of resources and infrastructure for sample collection and transport. There is often no legislation empowering regulators to implement sampling plans. In some instances, residues testing has been integrated into wider food safety mechanisms; for instance, in Sri Lanka, the major aquaculture producers have included sampling and testing of shrimps for antibiotic residues before processing as part of their HACCP plan. Such schemes protect the export market, help establish residue laboratories and encourage further development of residue plans.
Developing countries face many difficulties when planning to implement a residue control programme. However, with assistance from the developed world, the problems are not insurmountable. Several of the projects implemented by the IAEA have resulted in accredited (ISO/IEC 17025) screening laboratories and National Plans being put in place, with a consequent positive impact on food quality and the ability to participate in international trade. The ultimate outcome is an increase in foreign exchange and a contribution to the alleviation of poverty. The continuing development of international networks and collaboration between developed and developing countries must be actively promoted to progress towards the goal of a safe food supply.
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