Food Safety,antimicrobial Residues

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Vol. 22, No. 9 September 2000

Refereed Peer Review

FOCAL POINT ★Food animal producers and veterinarians share an interest in supplying packers with residuefree animals to maintain consumer and government confidence in the safety of food supplies.

KEY FACTS ■ Food animal producers and veterinarians need to assume responsibility for food safety. ■ Violative tissue residues of chemicals, antimicrobials, and other potential contaminants are a public health concern and the object of a national monitoring and surveillance program. ■ The education of anyone using animal health care products is a key to preventing violative tissue residues in meat, milk, and eggs. ■ Hazard analysis and critical control point plans followed by packers must address chemical hazards, such as violative tissue residues of animal health care products and other potential contaminants.

Food Safety: Antimicrobial Residues National Pork Producers Council Des Moines, Iowa

Paul Sundberg, DVM, PhD ABSTRACT: Animal health products are management tools used by food animal producers and veterinarians to provide for their animals’ health and welfare. These products can also help to minimize production costs and economically enhance production performance. To ensure public health, regulatory bodies have developed methods of determining the maximum concentration of compounds and chemical residues that are permissible in the food supply. In the United States, the National Residue Program samples and tests the nation’s production of meat, poultry, and eggs to ensure that these limits are not violated. Commodity organizations have developed quality-assurance programs on the safe use of animal health products. These programs serve as an on-farm precursor of the packer’s hazard analysis and critical control point plans addressing residue avoidance.

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or the food animal production industry to be successful and continue to grow, producers need to continually improve their ability to provide customers with safe products. Meat quality may vary according to various labels determined by consumers, such as tenderness, taste, or color. However, meat safety is legally determined by whether products comply with chemical and antimicrobial residue limits. Without a basic assurance of food safety, consumers lose confidence in the safety of food products.

MAXIMUM RESIDUE LIMIT Residue is any compound present in edible or target tissues of an animal, either from intentional or inadvertent introduction of the compound to the animal. Residue includes the compound itself, its metabolite, and other substances that form in or on food after introduction of the compound.1 The maximum residue limit (MRL) is the maximum concentration of a substance allowed in a particular tissue or commodity (e.g., meat, milk, or eggs). Historically, MRLs have been set using toxicologic research that provides a biologic no-observable-effect-level (NOEL) for each compound. The NOEL is used to mathematically determine an acceptable daily intake (ADI) for the compound. The ADI then serves as a basis for calculating the MRL in meat, milk, and eggs in such a manner that the ADI (using estimated daily human food intake of all these commodities) is not exceeded.2 In 1996, the U.S. FDA published a guideline for the microbiologic testing of antimicrobial drug residues in food: The agency considers safe to be that level of antimicrobial residues in food

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with no meaningful effect on the intestinal microflora of consumers.3 This guideline has led to an effort to evaluate in vitro and in vivo model systems that could be used to establish new ADIs and MRLs for some antimicrobial drug residues in foods. The Codex Alimentarius Commission, established in 1962, is the joint food standards program of the Food and Agriculture Organization (FAO) and the World Health Organization (WHO), both programs of the United Nations. The commission was established to help protect the health of consumers and facilitate fair trade by establishing international food standards, codes of practices, and other guidelines.4 Once they were developed, Codex standards (which include an MRL for particular veterinary drugs) are recommended to national governments by the FAO and WHO. Because these organizations cannot make appropriate rule- or law-making decisions, a Codex standard is not enforceable in a nation if it is not adopted by that nation. Although a country can establish its own MRL for a compound, if that MRL differs from the Codex standard with the intent of acting as a nontariff trade barrier and therefore cannot be scientifically defensible, the action may be brought before the World Trade Organization if the disputing countries are members. Therefore, despite attempts to harmonize food safety standards, the possibility of country-specific MRLs exists and can lead to confusion during international trading. For example, country A may set a withdrawal on a product or compound with the intent of complying with its particular MRL for that product in meat. Country B may have a lower, more stringent MRL on the same product in meat (perhaps even zero tolerance), which would mean the product would either have a longer withdrawal time or perhaps a prohibition on use. Thus even though the producers of country A follow their product’s labeled directions, their meat products may be condemned in country B for violating that country’s MRL. International standards agreed on by the Codex Alimentarius Commission have helped resolve some of these problems; however, the demands of the growing global market require additional standards. In the United States, three federal government agencies share responsibility for the regulation of pesticides, antimicrobials, and other chemicals used during food animal production. The Environmental Protection Agency approves the use of pesticides and sets tolerances if the use of that pesticide may result in residues in or on food.5 The FDA sets residue limits for animal drugs and environmental contaminants and enforces these and pesticide tolerances in domestically produced or imported foods that may be shipped in interstate commerce. The U.S. Department of Agriculture (USDA)

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Food Safety Inspection Service (FSIS) is responsible for ensuring that USDA-inspected meat and poultry products are safe, wholesome, and free of adulterating residues and are accurately labeled.6

NATIONAL RESIDUE PROGRAM The USDA FSIS National Residue Program (NRP) is a multicomponent analytic testing program for residues in domestic and imported meat, poultry, and egg products. The program uses a variety of sampling plans to verify that slaughter establishments are fulfilling their responsibilities in preventing violative residues and develops national data on chemical residues to support risk assessment, enforcement, and educational activities. The range of chemical compounds is comprehensive in scope and includes approved and unapproved pharmaceutical drugs and pesticides known or suspected to be present in food animals in the United States and in countries exporting products to this country.7 Because thousands of chemicals and compounds worldwide are used in food animal production, it is impractical if not impossible for the FSIS to test for every one. Each year, an agency surveillance advisory team convenes to identify and discuss compounds of potential public health concern. An interagency residue prioritization committee then meets to allocate resources to test for compounds that are of greatest concern and to develop a statistically based residue monitoring plan that provides defined levels of assurance of detecting residue violations in meat, poultry, and eggs.7 Thus the list of prioritized compounds of concern is updated and may change on at least an annual basis. Although special projects are possible, NRP plant procedures can be divided into two activities: monitoring and surveillance. Monitoring information is obtained through a statistically based random selection of specimens of normal-appearing tissue from inspectionpassed carcasses (healthy animals). Generally, for a specific slaughter class or compound pair, the number of randomly chosen specimens (300) provides a 95% probability of detecting at least one violation when 1% of the animal population is violative.8 Surveillance or enforcement testing consists of the analysis of specimens obtained from individual animals or lots based on clinical signs, herd history, or postmortem findings. This testing detects individual animals with violative tissue residue, is emphasized in high prevalence populations, and may also be used to follow up on producers who have had previous residue violations when marketing animals. The testing frequency is based on decisions by program employees using regional guidelines or direct observations.8

MAXIMUM RESIDUE LIMITS ■ MULTICOMPONENT TESTING PROGRAM ■ MONITORING AND SURVEILLANCE

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In-Plant Screening Tests ■ SOS (Sulfa-On-Site): This test is used in approximately 50 of the largest swineslaughtering facilities to check swine urine for sulfonamide residues. ■ CAST (Calf Antibiotic and Sulfonamide Test): This tissue microbial inhibition test is used on veal calves weighing less than 150 pounds or younger than 3 weeks of age. Cultures with inhibition zones greater than 18 mm are sent to a laboratory for confirmation. ■ STOP (Swab Test On Premises): This microbial inhibition test is used on kidney tissue to detect antibiotics and sulfonamides. ■ FAST (Fast Antimicrobial Screen Test): A faster replacement of the CAST and STOP tests, it screens kidney and liver tissue in virtually all the larger bovine-slaughtering plants.

IN-PLANT TESTS Rapid screening tests are used in packing plants to detect the presence of antimicrobial residue. Because they are screening tests only, laboratory confirmation of violations is required. USDA FSIS confirms samples that test positive by using a bioassay procedure for antibiotic residue detection and quantification9 (see InPlant Screening Tests). Compounds tested during 1997 (the most current year for which statistics have been compiled and published) included antibiotics (chlortetracycline, erythromycin, gentamicin, neomycin, oxytetracycline, penicillin, streptomycin, tetracycline, and tylosin), sulfonamides (sulfachlorpyridazine, sulfadimethoxine, sulfamethazine, and sulfathiozole), arsenicals, chlorinated hydrocarbons and chlorinated organophosphates, halofuginone, ivermectin, carbadox, and clenbuterol. The results are reported in the FSIS Domestic Residue Data Book by compound for each class of animal. Of the 26,626 total monitoring analyses made, 72 showed violative concentrations of residues (20 sulfonamides, 32 antibiotics, 9 chlorinated hydrocarbons and chlorinated organophosphates, 6 ivermectin, and 5 arsenic).8 RESIDUE AVOIDANCE The goal of residue avoidance is not necessarily the absence of residues. Rather, it is the avoidance of viola-

Producers’ Responsibilities for Animal Health Care Products ■ Identify and track animals to which drugs were administered. ■ Maintain a system of medication and treatment records that, at a minimum, identify the animal(s) treated, date(s) of treatment, drug(s) administered, who administered the drug(s), amount administered, and withdrawal time before slaughter. ■ Properly store, label, and keep an account of all drug products and medicated feeds. ■ Obtain and use veterinary prescription drugs only through a licensed veterinarian based on a valid veterinarian–client–patient relationship. ■ Educate all employees and family members involved in treating, hauling, and selling the animals on proper administration techniques, observance of withdrawal times, and methods to avoid marketing adulterated products for human food.

tive concentrations of residues, which may include total absence. Some minute level of residue may be acceptable if scientific data show there is no risk to consumers through the food supply (i.e., residues below the MRL for that compound). For example, in 1997 only 101 (1%) of 7732 monitoring samples from all slaughter classes had nonviolative but detectable residues of antibiotics.8 This concept is easily misunderstood by consumers and is important to understand because of each country’s right to set its own MRLs as long as they are scientifically defensible and do not violate international trading agreements.

By Food Animal Producers In 1993, the FDA published its Compliance Policy Guide (CPG), which provides regulatory guidance to its inspectors for the development of cases resulting from the use of animal drugs contrary to label directions and resulting in violative tissue residue concentrations.10 CPG 7125.37, Proper Drug Use and Residue Avoidance by Non-Veterinarians, outlines the producers’ responsibilities when using animal health care products (see Producers’ Responsibilities for Animal Health Care Products). Following these guidelines ensures that food-producing animals are free of violative antimicro-

BIOASSAY PROCEDURES ■ ACCEPTABLE RESIDUE LEVELS ■ INSPECTION GUIDELINES

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bial and chemical residues and that they leave for the packing plant. 10 Good Production Practices for these animal health care prodThese screening tests are generalQuality-Assured Pork Production ucts will continue to be available ly available in multiple test kits to the producer for use when that are economical enough to be Food Safety needed. used for both spot-testing indi1. Identify and track all treated animals. In 1996, the USDA published vidual shipments of animals and the Final Rule on Pathogen Reducperiodic testing of animals and/ 2. Maintain medication and treatment tion: Hazard Analysis and Critical or feeds to verify their complirecords. Control Point (HACCP) Systems. ance with the production sys3. Properly store, label, and account for all HACCP is designed to prevent tem’s plan for antimicrobial use drug products and medicated feed. food safety problems resulting and residue avoidance. Although 4. Obtain and use veterinary prescription from microbial, chemical, or physthese tests are useful for some andrugs only based on a valid ical hazards in food instead of retimicrobials, many of those used veterinarian–client–patient relationship. lying on finding them after they in modern production systems 5. Educate all employees and family happen. Although HACCP does do not have a specific ELISAmembers on proper administration not remove or diminish the regubased on-farm test. Continuing techniques and withdrawal times. latory authority of the FSIS, it research and product developdoes increase the responsibility of ment are needed to supply food 6. Use drug residue tests when appropriate. the packing plant to ensure that animal producers with economitheir products are not adulterated cal on-farm testing alternatives. Efficient Production of a Quality Product by the presence of residues above 7. Establish an efficient and effective herd By Food Animal permitted levels when they enter health management plan. Practitioners commerce. Because violative an8. Provide proper swine care. Food animal veterinarians are timicrobial and chemical residues 9. Follow appropriate on-farm feed qualified to offer drug use and cannot be removed from the meat processing and commercial feed residue avoidance advice to proonce the animal is processed, proprocessor procedures. ducers. Thus practitioners serve ducers are responsible for supplyas key educators in the coming packers with animals that are 10. Complete the quality-assurance checklist modities’ quality-assurance profree from this HACCP-identified annually, and become recertified every grams. Regardless of whether hazard. 2 years. they share legal responsibility for Beef, veal, milk and dairy beef, residue avoidance from the aniand pork quality-assurance promal drugs they use, dispense, or prescribe, veterinarians grams involve good production and management pracmust maintain their professional knowledge of pharmatices that serve as the on-farm precursor to the packers’ cology, anatomy, and physiology to be credible, expert residue avoidance HACCP plans. These programs are sources of information. designed to provide the educational opportunity needThe Federal Food, Drug, and Cosmetic Act (FD&C ed for producers to understand each of the CPG Act) was amended in 1968 to create the mechanism for 7125.37 points and implement them into their producthe approval of animal drugs. This amendment restricttion systems. Although an individual commodity’s ed the use of animal drugs to only the species and usage quality-assurance program has specific practices that specified on the label. Strict interpretation of the apply to their production systems, they each generally FD&C Act, however, would have made it impossible to follow similar outlines to the Level III section of the provide proper veterinary care in the food animal inNational Pork Producers Council’s Pork Quality Assurdustry. ance Program and pork production’s 10 Good ProducThe FDA recognized the dilemma for veterinarians tion Practices11 (see 10 Good Production Practices for Quality-Assured Pork Production). They mimic the created by this 1968 amendment. Through two ComCPG 7125.37 and also offer a review of management pliance Policy Guides, the FDA adopted a policy of not practices that help minimize antimicrobial use during ordinarily penalizing veterinarians who prescribe drugs production. in an extralabel manner, providing the veterinarian makes a professional judgment that the health of the By On-Farm Testing animals to be treated is “immediately threatened and Multiple companies offer ELISAs for on-farm testing suffering or death would result from failure to treat the of the presence of antimicrobials in animals before affected animals.” In addition, criteria regarding diagQUALITY-ASSURANCE PROGRAMS ■ SPOT-TESTING SHIPMENTS ■ EXTRALABEL DRUG USE

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nostic needs, product selection, animal identification, and safe product use must be met.10 An important distinction needs to be made when it comes to using products off-label (in a manner not described on the label). Off-label use by producers on their own initiative is illegal, and producers who do so are subject to regulatory enforcement action by the FDA. Extralabel use refers to the off-label recommendations for use of a drug by a veterinarian under the conditions described in the FDA policy guide and in accordance with the Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994. AMDUCA codified the ability of herd veterinarians to use their professional judgment and, when necessary, prescribe drugs in an extralabel manner. However, for drugs administered in the feed, there is no provision for extralabel uses by either veterinarians or producers. Extralabel use of drugs by food animal veterinarians means that they accept additional responsibilities regarding the avoidance of violative tissue residues that could result from that use. The AVMA published its Extra-Label Drug Use Algorithm that helps practitioners decide when extralabel use in food-producing animals is permitted according to the AMDUCA regulations.12 Stipulations for such use include accepting added responsibility for food safety, establishing extended withdrawal times, maintaining required records, and labeling the extralabel use drugs appropriately.

THE FUTURE What the NRP of the future will look like because of HACCP is yet to be determined. Additional responsibilities borne by packers could mean additional responsibilities transferred to producers and veterinarians. Packer HACCP plans must address the chemical food safety hazard of violative tissue residues. Because FSIS will continue to conduct a comprehensive residue detection program, there will be increased pressure on packing plants to verify that their products are not adulterated by residues because such a violation might be an indication of an HACCP plan failure and could lead to regulatory action against the plant (in addition to the animal supplier). Repeated residue violations could indicate an HACCP system failure that could result in suspension or withdrawal of FSIS inspection.13 If that becomes the case, packers might resort to any of several options for ensuring that incoming animals do not bear violative residues13: • Rejecting animals assessed to be at risk for having violative residues • Specifying the management conditions necessary for animals to be processed for human consumption • Purchasing from producer-suppliers that have imple-

mented proper animal drug and pesticide use procedures, which may include periodically visiting producer-suppliers or requiring third-party verification of implementation of the procedures • Requiring written assurances from producer-suppliers that all animals meet the plant’s contract specifications • Periodically using analytical tissue residue tests to verify that the supplier information is correct Although each of these options has specific drawbacks and caveats for packers, they also have the potential to impact the economic viability of producers. Discussions among government regulatory agencies, packers, and food animal producers will need to ensure that each understands their respective responsibilities and the implications of their actions and policies. It is imperative that producers and their veterinarians use animal health products safely, according to labeled directions unless indicated by the stipulations of AMDUCA, and only when needed so that packers can continue to have confidence that they are purchasing only safe, residue-free animals.

REFERENCES 1. Domestic Residue Data Book—National Residue Program 1996. Washington, DC, USDA-FSIS, Office of Public Health and Science, 1996. 2. Fernandez AH: Human Food Safety of Tetracyclines—Expert Review. Washington, DC, HHS-FDA, Center for Veterinary Medicine, 997. 3. Microbiological Testing of Antimicrobial Drug Residues in Food, guideline #52, docket #93D–0398. Washington, DC, HHS-FDA, 1996. 4. Codex Alimentarius Backgrounder. Washington, DC, USDAFSIS, Congressional and Public Affairs Staff, 1999. 5. Food and Drug Administration Pesticide Program—Residue Monitoring 1998. Washington, DC, HHS-FDA, 1998. 6. Domestic Residue Data Book—National Residue Program 1996. Washington, DC, USDA-FSIS, Office of Public Health and Science, 1996. 7. 1999 National Residue Program—Blue Book. Washington, DC, USDA-FSIS, Office of Public Health and Science, Chemistry and Toxicology Division, Emerging Issues Branch, 1999. 8. Domestic Residue Data Book—National Residue Program 1997. Washington, DC, USDA-FSIS, Office of Public Health and Science, 1997. 9. Microbiology Laboratory Guidebook, ed 3, vol 1 and 2. Washington, DC, USDA-FSIS, Office of Public Health and Science, Microbiology Division, 1998. 10. Compliance Policy Guides. Washington, DC, HHS-FDA, Public Health Service, Office of Regulatory Affairs, Office of Enforcement, Division of Compliance, 1995.

OFF-LABEL DRUG USE ■ DRUG-USE ALGORITHM ■ ECONOMIC IMPACT

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11. Pork Quality Assurance Program™. Des Moines, IA, National Pork Producers Council, 1997. 12. Extralabel drug use (ELDU), AMDUCA guidance brochure. JAVMA 212(4):suppl, 1998. 13. Stephan GE: How the residue monitoring program will change. Proc 1998 Allen D. Leman Swine Conf:197–201, 1998.

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About the Author Dr. Sundberg is Assistant Vice President, Veterinary Issues, National Pork Producers Council in Des Moines, Iowa. He is a Diplomate of the American College of Veterinary Preventive Medicine.