2
Food-Animal Production Practices and Drug Use

OVERVIEW

Food-animal production has intensified over the past 50 years. The number of livestock and poultry farms in the United States has decreased, but the density of animals on those farms has increased substantially. Production also has become more efficient; a greater quantity of commodities is produced by fewer animals. The increase in efficiency results from several factors, including preventive medicine, genetic selection, and improved nutrition and management. Veterinary medical care in food animals consists of the use of: (1) vaccines and prophylactic medication to prevent or minimize infection; (2) antibiotics and parasiticides to treat active infection or prevent disease onset in situations that induce high susceptibility; and (3) antibiotic drugs and hormones for production enhancement, growth promotion, and improved feed efficiency. This chapter provides a historical description of the major food-animal industries, the challenges faced by each that influence drug use today, and the types of drugs in use and the trends associated with food-animal production. It might appear that some of the data presented are unbalanced with regard to the quantity of information presented and the inferences made regarding health statistics and antibiotic drug use. The imbalance largely reflects the availability of data from quality-assurance programs and feeding and production records.

The structure of the major food-animal industries varies considerably, and this variation has an important influence on accountability (the recorded instances of use, duration, procurement records, containment, security, and appropriateness of use) for use of drugs and the ease of implementing quality-assur-



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The Use of Drugs in Food Animals: Benefits and Risks 2 Food-Animal Production Practices and Drug Use OVERVIEW Food-animal production has intensified over the past 50 years. The number of livestock and poultry farms in the United States has decreased, but the density of animals on those farms has increased substantially. Production also has become more efficient; a greater quantity of commodities is produced by fewer animals. The increase in efficiency results from several factors, including preventive medicine, genetic selection, and improved nutrition and management. Veterinary medical care in food animals consists of the use of: (1) vaccines and prophylactic medication to prevent or minimize infection; (2) antibiotics and parasiticides to treat active infection or prevent disease onset in situations that induce high susceptibility; and (3) antibiotic drugs and hormones for production enhancement, growth promotion, and improved feed efficiency. This chapter provides a historical description of the major food-animal industries, the challenges faced by each that influence drug use today, and the types of drugs in use and the trends associated with food-animal production. It might appear that some of the data presented are unbalanced with regard to the quantity of information presented and the inferences made regarding health statistics and antibiotic drug use. The imbalance largely reflects the availability of data from quality-assurance programs and feeding and production records. The structure of the major food-animal industries varies considerably, and this variation has an important influence on accountability (the recorded instances of use, duration, procurement records, containment, security, and appropriateness of use) for use of drugs and the ease of implementing quality-assur-

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The Use of Drugs in Food Animals: Benefits and Risks ance programs within individual industries. The structure of the industries also affects the ease of identifying the source of a problem (whether it is a pathogenic microorganism, a drug residue, or an antibiotic-resistant bacteria) and the ease with which consumer preferences flow back through the system to stimulate changes in the genetics and breeding of stock to produce the desired product. In all of the animal industries, antibiotic drugs are used for three primary reasons: (1) therapeutically, for treating existing disease conditions; (2) prophylactically, at subtherapeutic concentrations1; and (3) subtherapeutically for production enhancement (increased growth rate and efficiency of feed use). Therapeutic use generally occurs after diagnosis of a disease condition, and treatment is governed by the drug’s label instructions or in accordance with extra-label instructions provided by a veterinarian in the context of a valid and current veterinarian–client–patient relationship (VCPR). Subtherapeutic doses are used when pathogens are known to be present in the environment or when animals encounter a high-stress situation and are more susceptible to pathogens. Subtherapeutic doses are smaller than those required to treat established infections. They might also use compounds developed exclusively as production enhancers that have no therapeutic purpose. Although the U.S. Food and Drug Administration (FDA) defines subtherapeutic concentration as <200 g/t of feed, there is a wide range of concentrations below that for which different antibiotics are formulated into feeds and fed to different species. As summarized in Cromwell (1991), there are three mechanisms of action through which antibiotics appear to enhance growth and production. The first involves direct biochemical events that are affected by antibiotics: nitrogen excretion, efficiency of phosphorylation reactions in cells, and direct effects on protein synthesis. The second involves direct effects on metabolism, including the effects of antibiotics on the generation of essential vitamins and cofactors by intestinal microbes and the way that antibiotics affect the population of microbes that make these nutrients. In addition, the feeding of antibiotics is associated with decreases in gut mass, increased intestinal absorption of nutrients, and energy sparing. This results in a reduction in the nutrient cost for maintenance, so that a larger portion of consumed nutrients can be used for growth and production, thereby improving the efficiency of nutrient use for productive functions. The third proposed mechanism of action is eliminating subclinical populations of pathogenic microorganisms. The elimination of this route of metabolic drain allows more efficient use of nutrients for production. The goal of an efficient livestock operation is to maintain animals that are free of disease or injury, that gain weight well if they are intended for market, or that stay in optimal condition if they are kept as breeding stock. The producer 1   Antibiotics are used in food animals therapeutically to treat disease and sub-therapeutically (at <200 g/t of feed) to increase production performance, to increase efficiency in the use of feed for growth or output, and to modify the nutrient composition of an animal product.

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The Use of Drugs in Food Animals: Benefits and Risks relies on many methods of disease prevention and treatment. The worst case is having diseased and injured animals deprived of therapeutic treatment. Such a situation results in needless pain and suffering and, in far too many cases, in death. Leaving sickness or injury untreated is the most expensive alternative for the owner and is certainly the least humane for the animal. The strategies for raising food animals are pertinent to the larger issue of human health effects from drug use in food animals. The intensiveness of farm production in this country has increased because of the advantages inherent in the use of drugs that prevent or control infection and promote growth in animals. Strong incentives for the use of these drugs exist to assure the public that only healthy animals enter the food chain and to maintain the profitability of the industry. A significant limit to animal production efficiency is any form of disease stress that animals might encounter in their production lives. Traditional growth promoters, such as the steroidal and nonsteroidal estrogenic agents, are less effective when used, because even low-grade disease affects general metabolism. For this reason, pharmacological strategies to prevent or treat animal diseases are used, and the drugs of choice for bacterial infections are antibiotics. Adequate use of antibiotics is necessary for several reasons. Improvements in feed efficiency reduce environmental pollution, for example, through reduced nitrogen and phosphorus losses in animal waste products. Illness in herds and flocks decreases production and nutritional use efficiency (Elsasser et al. 1995, 1997). Klasing and co-workers (1987) suggested that the antigenic challenge of the immune system in animals fighting off disease stress and illness causes repartitioning of nutrients away from growth and production to support the mechanisms that participate in restoring homeostasis and health. Repartitioning of nutrients is a process in which hormone and immune cytokines direct one type of cell to not take up and use a given nutrient and to spare the availability of that nutrient while facilitating other cells (e.g., immune function cells) in increasing their metabolism and uptake of nutrients (Elsasser et al. 1995). THE POULTRY INDUSTRY Originating in the 1700s, the U.S. poultry industry grew in size and genetic diversity as chickens were brought to North America on ships from Europe and Asia. In the 1870s, farmers began to select breeding stock, emphasizing specific traits pertaining to meat and egg production. Bugos (1992) outlined the evolution of the broiler and egg-layer industries and the breeding that propelled rapid advances in each. In 1928, before modern breeding began for broilers, the average broiler required 112 days and 22 kg of feed to reach a 1.7-kg market weight. By 1990, broilers required 42 days and less than 4 kg of feed to reach a market weight of 2.0 kg. Laying hens produced an average of 93 eggs per year in 1930, 174 eggs per year in 1950, and 252 eggs per year in 1993. Immediately after

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The Use of Drugs in Food Animals: Benefits and Risks World War II, the broiler industry was concentrated in the northeastern and the midwestern states. However, by 1991, 54 percent of broilers were produced in just four states: Arkansas (16 percent), Georgia (15 percent), Alabama (14 percent), and North Carolina (9 percent) (Knutson 1993). Broiler production in the United States increased from 1.6 billion birds in 1960 to 7.0 billion birds in 1994, a number that corresponds to 13.6 billion kg (30 billion lb) of meat with a value of $10 billion (FSIS 1994b). Annual per capita consumption of poultry meat (chicken and turkey) was projected to be 43 kg (94 lb) in 1995. Similarly, egg production in the United States has grown from 59 million eggs produced in 1950 to 70 million eggs produced in 1994, with average consumption projected to be 240 eggs per capita in 1995. Selective breeding has propelled the poultry industry and allowed the breeders to become relatively independent; at the same time, broiler, layer, and turkey industries have become integrated (Rogers 1993). An Integrated Industry Integration is defined as the unified control of several successive (vertical) or similar (horizontal) economic, especially industrial, processes formerly carried out independently. When that definition is applied to the various animal industries, it is notable that the poultry industry is vertically integrated with the exception of the primary breeders who produce the parent strains for commercial production. The swine industry is progressing rapidly toward complete vertical integration. The dairy industry, by its very nature, involves some degree of vertical integration, and the beef and sheep industries remain largely unintegrated. Some effort has been made, starting with the processors, to integrate beef cattle production, but in general the various segments of these industries continue to operate independently. In vertical integration, the integrator (the poultry company) buys the breeder’s eggs that become the parent stock of the broilers and delivers the hatched broiler chicks to others who are under contract to grow the birds, usually in floor pens with 10,000 to 20,000 birds per pen (Lasley 1983). Turkeys are bred and managed similarly to broilers, except that pens of 5,000 to 10,000 birds are more common (Lasley et al. 1983). The integrator maintains ownership of the birds, and supplies the feed and medication to the grower. Integrators also own their feed mills (to control costs and customize feed) where the grain can be purchased in bulk at cost savings to the grower–producer. In addition, integrators own the slaughter and processing facilities, and they generally market the finished product. Poultry diets, which constitute 68 percent of total production costs, consist of corn and soybean-meal mixtures with vitamins and minerals, and typically include two or three medications (North 1984). Starter, grower, finisher, and layer diets are designed to meet the needs of the birds in each phase of development.

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The Use of Drugs in Food Animals: Benefits and Risks Medications and vaccinations make up 2.16 percent of the total production costs (Agrimetrics Associates 1994). History and Trends in Drug Use The growth-enhancing effect of antibiotics was first demonstrated for poultry. Various nutritional studies in chicks showed that antibiotic-fermentation products influenced the growth of chicks (Moore et al. 1946; Stokstad et al. 1949). By 1951, the addition of growth-promoting antibiotics to feed had become standard practice (CAST 1981). The history of antibiotics, growth-promotion compounds, arsenical compounds, and coccidiostats has been reviewed (NAS 1969; Fagerberg and Quarles 1979; CAST 1981; IOM 1989). An earlier review of poultry experiments showed an important advantage in the use of low concentrations of various antibiotics (NAS 1969) that was evident in the superior growth of birds that received antibiotics. The majority of drug use in poultry management practice today is prophylactic, with the bulk of medications encompassing application of antiprotozoal compounds and antibiotic growth promoters. The poultry production system serves as an interface between animal and human health and affects the environment, so it is important to describe drug use in the context of the overall system as well as to define what process controls are in place to address the safety and quality of the products. In terms of the overall system, intensive management and confinement operations minimize some kinds of infection and facilitate control of others. For example, Salmonella gallinarum and Salmonella pullorum, which are spread congenitally through the fertilized egg, are controlled by using breeding birds that test negative. Tuberculosis has been virtually eliminated by culling from the flock birds that test positive. Calnek et al. (1991) assembled a comprehensive treatise on diseases of poultry. Vaccination of day-old chickens controls some viral infections, such as Newcastle and Marek’s diseases. Turkeys are routinely vaccinated against Newcastle (5 days of age) and hemorrhagic enteritis (2 to 3 weeks of age), and sometimes against erysipelas, Bordetella avium, cholera, and influenza, depending on local experience. Antibacterials and other chemicals are frequently used for controlling other infections such as coccidia, worms, fungi, ectoparasites, and several bacterial infections. In practice, broiler producers almost always include a coccidiostat (Table 2–1) in grower rations, as well as an arsenical, and an antibiotic (Table 2–2) for improved feed efficiency and body weight gains and for reduced morbidity and mortality. Control of coccidiosis is imperative with modern management systems for broilers and turkeys. Table 2–1 lists 20 coccidiostats labeled for use in broilers (Shepard et al. 1992), 11 of which also may be used in turkeys; only 2 are approved for layer chickens. The ionophores dominate the coccidiostats, but evolution of resistant coccidia has led many broiler producers to alternate

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The Use of Drugs in Food Animals: Benefits and Risks TABLE 2–1 Coccidiostats Approved for Use in Broilers (B), Turkeys (T), and Layers (L) Sulfonamides Ionophores Others Sulfachloropyrazine (B) Lasalocid (B) Amprolium (B, T) Sulfamethazine (B, T) Maduramycin (B) Arsanilate (B, T, L) Sulfadimethoxine (B, T) Monensin (B, T) Buquinolate (B, L) Sulfamyxin (B, T) Narasin (B, T) Clopindol (B, T) Sulfanitran (B) Salinomycin (B, T) Dequinate (B) Sulfaquinoxaline (B, T)   Nequinate (B)     Nicarbazin (B)     Robenidine (B)     Zoalene (B, T)   Source: Compiled from FDA Approved Animal Drug List (Green Book), 1998a, and Feed Additive Compendium, 1997. TABLE 2–2 Major Claims of Antibiotics Approved for Use in Chickens and Turkeys Compound Growth and Feed Efficiency Various Infections Bambermycin yes no Bacitracina yes yes Chlortetracycline yes yes Erythromycina no yes Gentamycin no yes Neomycin no yes Novobiocin no yes Oleandomycin yes yes Oxytetracyclinea no yes Penicillin yes yes Roxarsone yes yes Spectinomycin yes yes Streptomycin no yes Tetracycline no yes Tylosina yes yes Virginiamycin yes yes Fluoroquinolones no yes aAlso labeled for use in layer chickens. Source: Compiled from FDA Approved Animal Drug List (Green Book), 1998a, and Feed Additive Compendium, 1997.

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The Use of Drugs in Food Animals: Benefits and Risks coccidostats in “shuttle” programs. Several turkey farms now use a coccidiosis vaccine with good results. All of the antibiotics listed in Table 2–2 are marketed over the counter. Several of these antibacterials are labeled for use against some other specific infections, but some viral infections still periodically devastate the industry. For example, in extreme cases of avian influenza, houses can be depopulated and sanitized to eradicate the virus. Mycoplasma galisepticum and Mycoplasma synovia were ubiquitous and required prophylaxis in broilers, for example, with tylosin or oxytetracycline. On the other hand, mycoplasmas have been controlled in most turkey flocks by using breeders that test negative. According to Shepard et al. (1992), 16 antibiotics are approved for use in broilers or turkeys (Table 2–2), but only 4 of these may be used in layers. In addition, 2 arsenicals are approved for control of blackhead, 4 compounds are available for worms, and 1 fungicide is approved for broilers. There are three categories of antiprotozoal drugs: ionophores, sulfonamides, and other chemical compounds. They are routinely administered through feed. Some ionophores are not well absorbed across the intestinal wall or are not sufficiently toxic to dictate a withdrawal period and so they can legally be used until slaughter. (Withdrawal is the period required by law between the final administration of a drug and the time when the animal can be harvested for food. The withdrawal period allows drug residue concentrations to fall in the tissue or milk of treated animals to those considered nonthreatening to human health.) Chemical coccidiostats (e.g., amprolium, roxarsone) are most often used in broiler starter diets and traditionally have been followed by ionophores. Most chemical coccidiostats require withdrawal periods. Antiprotozoal drugs used to combat Histomonas infections in turkeys and pheasants are similar to the organic arsenical compounds used in broiler chickens. Nitrarsone (4-nitrophenyl arsenic acid) is the only compound approved to prevent histomoniasis and the subsequent sequella produced by the protozoa in combination with some bacteria. Two other compounds previously approved for this purpose, ipronidazole and furazolidone, were recently removed from the market. Furazolidone is a member of the nitrofuran family of compounds, which were removed from the market by the FDA’s Center for Veterinary Medicine because of their carcinogenic potential; however, similar compounds are still in use in human medicine today. The integration of the poultry industry facilitates tracing a potential residue in meat or eggs to its origin. The integrator companies have much to gain by avoiding altogether any hint of problems, such as drug residues in poultry foods. This constitutes a powerful motivation to control drug and chemical use.

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The Use of Drugs in Food Animals: Benefits and Risks Routes of Drug Administration Feed Several diet formulations are typically fed to poultry from hatching to market. Prestarter and starter diets are fed to broilers for up to 19 days after hatching. These diets might contain up to three drug components: (1) a prophylactic coccidiostat, (2) a growth-promoter antibiotic, and (3) an organic arsenical compound that has both growth promoter and coccidiostat activity. A battery of grower diets are fed for the next 8 to 12 days to maintain the metabolic requirements of these fast-growing birds, and withdrawal diets of one or two types are fed in the remaining days before market. Thus, the diets used in each phase are progressively reduced in drug use and cost. To comply with FDA-mandated drug-withdrawal periods, organic arsenical compounds are not used in withdrawal diets. Most poultry operations routinely monitor withdrawal feed to ensure compliance, for several reasons. First and foremost, monitoring reduces any potential risk that drug residues will remain in tissues, and second, the difference in cost between withdrawal diets and grower diets is substantial. The cost differences might exceed $20/t; if grower feed were fed in place of withdrawal feed, the cost of gain would increase. The industry has adopted what is known as a “two-bin system” for most broiler houses. This system places two bulk tanks at each grower’s house and eliminates mixing of withdrawal feed with other types. Further monitoring by tissue analyses is done before slaughter. Fat and other samples are tested for residues of pesticides, herbicides, and heavy metals. One-Day-of-Age Injection Two drugs are currently approved (ceftiofur sodium and gentamicin sulfate) for one-day-of-age injection of chicks. Neither drug is absorbed gastrointestinally. Both have been used to protect the poult or chick from injection-site abscesses after vaccination for Marek’s disease. Because mass incubation and hatching techniques create significant challenges with aerosols of various genera of Enterobacteriaceae, one-day-of-age injections can be used to improve early viability. Water Medication Sick poultry are generally medicated through drinking-water systems. Systemic or intestinal medication can be given that way, and the industry has learned how to achieve and maintain therapeutic concentrations of drugs by studying the actual water use for each class of poultry, and accounting for the age of the birds and the environmental temperature. Although the actual overall water-soluble

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The Use of Drugs in Food Animals: Benefits and Risks systemic use of drugs in poultry is declining, a recently approved therapeutic-concentration fluoroquinolone antibiotic may now be administered to poultry via drinking water. Summaries of drug use in poultry from 1989 to 1994 are presented in Tables 2–3, 2–4, and 2–5. The amount of antibiotics administered to poultry, especially the amount administered in medicated feeds, declined for the following reasons: use of preventive medicine, including implementation of biosecurity procedures, vaccination, genetic selection, and eradication of various pathogens, resulting in specific-pathogen-free stocks; reduction in the number of available efficacious compounds for treating respiratory diseases caused by Escherichia coli and Pasteurella multocida, and for treating other infections such as those caused by Staphylococcus aureus; efforts to control cost, including improving environmental conditions and culling unhealthy birds; concentration and focus on residue avoidance; and innovation on the part of manufacturers of vaccines and biological agents to rapidly meet the demands of industry when exotic diseases occur. These reasons notwithstanding, there is cause for concern in the poultry industry. In recent years only one new systemic antibiotic, a fluoroquinolone, has been approved for treatment of diseases caused in poultry by E. coli. The use of that antibiotic is being criticized because its effectiveness as a last line of defense in human antibiotic therapy might be undermined by further FDA approval and use in animals. The removal of the nitrofurans from the market further complicated the situation. When exotic or variant respiratory viruses emerge in an area, septicemic E. coli infections cause excessive mortality if no treatment is initiated. In the past, vaccine strategies were developed and implemented to prevent the spread of the newly emerged virus and to decrease the stresses on poultry that facilitate opportunistic secondary bacterial infection such as occurs with E. coli. TABLE 2–3 Cost of Drug and Vaccine Use in Broilers from 1989 to 1994 Treatment 1989 1990 1991 1992 1993 1994 Vaccine (¢/broiler) 0.14 0.15 0.14 0.14 0.13 0.14 Direct medication (¢/broiler) 0.09 0.09 0.07 0.06 0.05 0.06 Feed medication (¢/broiler) 0.58 0.68 0.60 0.56 0.56 0.52 Total (¢/broiler) 0.81 0.92 0.81 0.76 0.74 0.72 Diseased or condemned (%) 1.01 0.96 0.80 0.85 0.67 0.81   Source: Agrimetrics Associates, Inc., 1994.

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The Use of Drugs in Food Animals: Benefits and Risks TABLE 2–4 Turkey Medication and Vaccine Cost Analysis Treatment 1st Half 1989 1990 1991 1992 1993 1994 Confined hens   Feed medication ($/t of feed) 2.91 2.93 3.14 3.09 3.171 3.22 Feed conversion (lb feed/lb weight gain) 2.401 2.400 2.380 2.448 2.471 2.397 Field medication and vaccine ($/lb) 0.0038 0.0032 0.0035 0.0034 0.0031 0.0035 Feed medication ($/lb) 0.0035 0.0035 0.0037 0.0038 0.0039 0.0039 Confined toms   Feed medication ($/t of feed) 2.62 2.85 1.64 3.17 3.21 3.03 Feed conversion (lb feed/lb weight gain) 2.686 2.660 2.582 2.579 2.583 2.667 Field medication and vaccine ($/lb) 0.0043 0.0039 0.0035 0.0036 0.0034 0.0035 Feed medication ($/lb) 0.0035 0.0038 0.0021 0.0041 0.0041 0.0040   Source: Agrimetrics Associates, Inc., 1994.

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The Use of Drugs in Food Animals: Benefits and Risks TABLE 2–5 Cost of Medication and Vaccination Used for Turkeys and Broilers in the United States   Medicationa Vaccinationb Target Use Total Live Cost (¢/lb live weight) Cost (¢/lb live weight) Percentage of Total Live Cost Cost (¢/lb live weight) Percentage of Total Live Cost Hen turkey 32 0.165 0.52 0.083 0.26 Tom turkey 26 0.231 0.64 0.116 0.32 Broiler —c 0.060 0.22 0.140 0.50 aWater-soluble medication only, excluding feed-grade drugs. bVaccines and vaccine stabilizers. cTotal live cost for chicken amounts to 28 ¢/lb live weight. Source: Agrimetrics Associates, Inc., 1994.

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The Use of Drugs in Food Animals: Benefits and Risks As with other food-animal industries, aquaculture is becoming a more concentrated industry of fewer but much larger farms. The vast majority of fish-farming enterprises in the United States where medications might be used are pond-like or tank structures, rather than open-water habitats, such as oceans and lakes. In contrast, some countries like Norway utilize natural structures, such as the fjords for salmon farming, and there are concerns about the wastes collecting in fjord bottoms. In the United States, approximately 158,800 acres of ponds were devoted to catfish production in 1995, but the number of farms decreased. Tilapia production in the United States has focused on the live-fish market, because import requirements and high costs restrict live-fish import. This market continues to expand, however, and production of tilapia in tank systems for processed products is likely to grow. Aquaculture encompasses production of various sizes and types of fish. Brood fish are kept to produce the fertilized eggs that go to hatcheries. Food-size fish include (1) small fish, weighing 0.34 to 0.7 kg (0.75 to 1.5 lb); (2) medium fish, weighing 0.7 to 1.4 kg (1.5 to 3 lb); and (3) large fish, weighing more than 1.4 kg (3 lb). Large stocker fish weigh from 82 to 341 kg (180 to 750 lb) per 1,000 fish, and small stocker fish weigh from 27 kg to 82 kg (60 to 180 lb) per 1,000 fish. Fingerlings or fry fish weigh 27 kg (60 lb) per 1,000 fish. The use of antibiotics and drugs in the fish industry is complicated because of the need to administer the compounds, for the most part, directly into the water in which the fish swim. The safety of aquatic food products, the integrity of the environment, the safety of target animals, and the safety of persons who administer various compounds are important issues that have an effect on drug use in the aquaculture industry. As with other food-animal industries, industry-developed and industry-directed aquaculture quality-assurance programs are preferred to monitor compounds that come into contact with food fish. Compounds commonly used in the aquaculture industry that might be considered a potential threat to food safety and consumer health include animal drugs and veterinary biologics, pesticides, disinfectants, and water-treatment compounds. New animal drugs that are added to aquaculture feed are subject to FDA approval and must be specifically approved for use in aquaculture feed. These drugs must be mixed in feed at concentrations that are specified in FDA medicated-feed regulations. Water treatments used in aquaculture include chemicals that are applied directly to water for control of algae or water-borne parasites. The selection of the federal agency that will have jurisdiction over a particular chemical depends on the intended use of the product in the water. Chemical residues in fish can occur from improper use or application of water treatments to improve fish health or improper use of products to control weeds or water quality. New animal drugs approved by FDA for use in the aquaculture industry appear in Table 2–15. There are several unapproved compounds of low regula-

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The Use of Drugs in Food Animals: Benefits and Risks TABLE 2–15 FDA-Approved New Drugs for Use in Aquaculture Drug Active Ingredient Indication Species Finquel, MS-222 Tricaine methanesulfonate Sedation/anesthesia Fish (Ictaluridae, Salmonidae, Esocidae, Percidae), other aquatic poikilotherms Formalin-F; Paracid-F; Parasite-S Formalin Control protozoa and monogenetic trematodes (Icthyopthirius, Chilodonella, Costia, Scyphidia, Epistylis, Trichodina spp. and Cleidodiscus, Gyrodactylus, Dactylogyrus spp.) Salmonids, catfish, largemouth bass, bluegill     Control fungi of the family Saprolegniaceae Salmodi and esocid eggs Parasite-S Formalin Control protozoan parasites (Bodo spp., Epistylis spp., and Zoothamnium spp.) Panaeid shrimp Romet-30 Sulfadimethoxine and ormetoprim Control furunculosis (Aeromonas salmonicida) Salmonids     Control enteric septicemia (Edwardsiella ictaluri) Catfish Terramycin Oxytetracycline monoalkyl trimethyl ammonium Mark skeletal tissue Control ulcer disease, furunculosis, bacterial hemorrhagic septicemia, and pseudomonas disease (Hemophilus piscium, Aeromonas salmonicida, Aeromonoas liquefaciens, Pseudomonas) Pacific salmon Salmonids     Control bacterial hemorrhagic septicemia and pseudomonas disease Catfish     Control gaffkemia (Aerococcus viridans) Lobster   Source: Adapted from Drugs Approved for Use in Aquaculture, Center for Veterinary Medicine, U.S. Food and Drug Administration, Revised June, 1995; http://www.fda.gov:80/cvm/fda/infores/other/aqua/appendixa.html

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The Use of Drugs in Food Animals: Benefits and Risks tory priority to FDA. FDA’s enforcement position on the use of these substances is not one of approval or affirmation of their safety. QUALITY-ASSURANCE PROGRAMS AND ANIMAL HEALTH MAINTENANCE Animal health products must be handled and administered properly if producers are to maintain public trust and be competitive in U.S. and world markets. Important objectives to producers are reducing the risk of drug residues in food products, and, ultimately, eliminating irresponsible drug use, so that public perceptions of poor drug management are changed with the result that consumer confidence increases. Food-animal producers know that the profitability of the production facility is directly linked to not only the quality and efficiency of animal management but also to the perceptions of the public regarding the industry and the overall appeal of the product. Stresses on animals must be managed and minimized, so that the animal can achieve its genetic potential for growth and productive metabolism rather than expend energy fighting disease. Quality-assurance programs in the food-animal industry focus on helping producers supply products that are as free as possible of microbiological hazards, and drug and chemical residues. The consumer is presented with products obtained from animals that received proper care. All major livestock-producer groups have initiated quality-assurance programs to address their responsibilities in producing safe, wholesome products. Among such groups are the National Pork Producers Council (NPPC), the National Cattlemen’s Beef Association, the National Milk Producers Federation, the American Sheep Industry Association, the American Veal Association, the National Broiler Council, the National Turkey Federation, the United Egg Producers, the Catfish Farmers of America, the National Aquaculture Association, and the U.S. Trout Farmers Association. The following sections describe the quality-assurance programs initiated by the National Broiler Council, the National Turkey Federation, NPPC, the National Cattlemen’s Beef Association, and the National Milk Producers Federation. Poultry Quality-Assurance Programs In the United States, with the help of various public and private institutions and the implementation of the National Poultry Improvement Plan (NPIP) of 1935 and the National Turkey Improvement Plan of 1943, the poultry industry has been able either to eradicate or to minimize disease exposure. That undertaking has improved profitability and expanded the industry. The eradication of various diseases caused by Mycoplasma gallisepticum, Mycoplasma synoviae, Mycoplasma meleagridis, Salmonella pullorum, and Sal-

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The Use of Drugs in Food Animals: Benefits and Risks monella gallinarum; velogenic Newcastle disease; and highly pathogenic avian influenza could not have been accomplished without the NPIP system. The goal of the National Turkey Federation’s Chemical Residue Avoidance Program is to ensure that the tissue of turkeys produced and slaughtered in the United States will not contain any chemical residues and will meet or exceed all tolerance and action levels for known harmful residues as established by the federal regulatory agencies (the U.S. Environmental Protection Agency, FDA, and the USDA Food Safety and Inspection Service [FSIS]). The National Broiler Council’s recommended Good Manufacturing Practices address every quality-control point in the production and processing of broiler chickens to enhance product quality and consumer protection. The procedures are drawn from quality-control programs throughout the broiler industry, from the scientific literature, and from existing regulatory documents. In production, recommended practices include: maintaining proper facility standards, providing growers with pesticide information, including pesticide-use statements in grower contracts, and enforcing biosecurity programs. Regarding animal health care, the following practices are recommended: ensuring that pharmaceutical laws and regulations are followed (only FDA-approved pharmaceuticals and regimens are to be used), and enforcing company standards for pharmaceutical use. In breeder operations, standards are to be maintained for feeds and animal health. In addition, procedures to control poultry-borne and egg-borne pathogens and diseases should be a routine part of breeder-monitoring programs. Hatchery recommendations address sanitation and microbiological controls, which continue through the growing period, transport, slaughter, and processing. Testing for microbiological quality, pesticide and chemical residues in feed ingredients is recommended for feed preparation during the growing period. Maintaining records of feed distribution and pharmaceutical inventories, and ensuring that FDA regulations are adhered to, are important aspects of good poultry management practice. Pork Quality-Assurance Programs In June 1989, NPPC introduced a management education program called the Pork Quality Assurance (PQA) program. It was designed to help producers avoid violative drug residues, improve management practices, reduce production costs, and increase awareness of food safety concerns. The PQA program emphasizes

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The Use of Drugs in Food Animals: Benefits and Risks good management practices in the handling and use of animal health products and encourages producers to review their herds’ health programs annually. The program provides information covering the following topics: food safety and the pork industry, products used today, routes of administration, on-farm feed preparation, minimum withdrawal times, current regulatory system, and on-farm testing. The PQA program (NPPC 1997) was developed by NPPC to institute safety, uniformity, and consistency in the production of pork. The program refers to three achievement levels in the quality-assurance certification process. Levels I and II are self-instructional and self-paced reading from a booklet obtainable from NPPC. All producers are encouraged to learn and implement the 10 “good production practices” defined in the booklet. Producers can achieve Level III through a professional consultation, which takes them step-by-step through the design of a herd health program. For producers this 10-step program is developed around the appropriate uses of medications and the need for accountability. The plan results in an understanding of the need for the oversight of the veterinarian and in written accounts of animal-by-animal drug use. Level III of the PQA program applies principles from the Hazard Analysis and Critical Control Points (HACCP) to the production of pork. The HACCP involves determining where problems could develop and establishing procedures to monitor those problems. To complete Level III, a producer must annually perform the following 10 critical control points: Establish an efficient and effective herd health-management plan. Establish a valid veterinarian, client, and patient relationship. Store all drugs correctly. Use only FDA-approved over-the-counter or prescription drugs with professional assistance. Administer all injectable drugs and oral medications properly. Follow label instructions for use of feed additives. Maintain proper treatment records and adequate identification of all treated animals. Use drug-residue tests when appropriate. Implement employee and family awareness of proper drug use. Complete quality-assurance checklist annually. In the implementation of the PQA program, extensive cooperation has been

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The Use of Drugs in Food Animals: Benefits and Risks received from veterinarians, packers, media, agriculture teachers, FDA, FSIS, extension personnel, feed manufacturers, and pharmaceutical companies. Producer response to the PQA program has been favorable. As of July 1, 1995, approximately 32,000 pork producers who provide 63 percent of the market hogs in the United States were enrolled in the program. Thirty percent of U.S. pork is from producers who have completed the program and an even larger percentage comes from producers who have implemented some aspects of the program. According to the 1993 nationwide monitoring program administered by FSIS, violative residues for sulfamethazine and antibiotics in market hogs have decreased (FSIS 1993c). The violation rate for sulfamethazine has continued to remain low in recent years. FSIS has congratulated NPPC for its work in reducing the violation rate and has encouraged the NPPC membership to continue to follow the recommendations in the PQA program to avoid illegal residues. To continue reducing violative drug residue rates and reach the industry goal of no violative residues, NPPC urges all producers to enroll in and complete the PQA program. In addition to its Compliance Policy Guides directed toward use of animal health products by veterinarians, FDA has issued a Compliance Policy Guide on Proper Drug Use and Residue Avoidance by NonVeterinarians. The objective of this guide is to ensure proper use of animal health products in food-producing animals when administered by producers. The guide describes the records FDA inspectors would ask to see when doing on-farm investigations after a violative drug residue has been discovered. The guide addresses identification of treated animals; maintenance of treatment records; storage, labeling, and accounting of medications; use of prescription products only through a valid VCPR; and education of employees and family members. The PQA program provides a means for producers to comply with the FDA guide. Dairy Quality-Assurance Programs To ensure that only the highest quality dairy foods and residue-free products reach the consumer, two important documents have been developed. The first was the Grade A Pasteurized Milk Ordinance, also known as the FDA PMO (FDA 1995b). The premise of the original PMO, developed in 1924, was that effective public-health control of milk-borne diseases required the application of sanitation measures through the production, handling, pasteurization, and distribution of milk and milk products. The second document was the Milk and Dairy Beef Residue Prevention Protocol (Boeckman and Carlson 1995), which addresses the need to market residue-free milk and dairy beef. That 10-point plan for the Milk and Dairy Beef Quality Assurance Program was developed by the National Milk Producers Federation and the American Veterinary Medical Association (AVMA). Both organizations emphasized that the plan would require cooperation and communica-

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The Use of Drugs in Food Animals: Benefits and Risks tion between dairy farmers and veterinarians, so that the industry could remain active in preventing drug residues in milk and beef. In the plan’s guidelines, the producer is viewed as providing a safe product, and the consumer as benefiting by drinking uncontaminated milk. The 10-point plan has been adopted as part of the PMO by individual states, and it is mandatory for all producers after one contaminated load of milk is detected. An extremely important aspect of quality-assurance programs is the establishment of a valid VCPR. This relationship ensures that farm animals receiving antibiotics will be withheld from the food chain until drug concentrations are below those permitted by FDA. Both the producer and the veterinarian must work closely with quality-assurance program coordinators and extension personnel to ensure that the drug-avoidance programs are followed. The 10-point quality assurance plan deals specifically with the drug-residue issue and for milk and dairy beef production includes: 1) Practicing healthy-herd management. Investments in disease prevention are more cost-effective than is disease treatment. Some examples include proper milking management versus treatment of clinical mastitis, good hoof care and trimming versus treatment of foot infections, calving cows in a sanitary location versus treatment of uterine infection, and proper vaccination versus treatment. Producers are encouraged to practice herd health management by consulting with licensed veterinarians and other related professionals. 2) Establishing a valid VCPR. AVMA (1998) defines a VCPR as follows: An appropriate veterinarian/client/patient relationship is characterized by these attributes: (1) [t]he veterinarian has assumed the responsibility for making medical judgments regarding the health of the animal(s) and the need for medical treatment, and the client (owner or other caretaker) has agreed to follow the instructions of the veterinarian; and when (2) [t]here is sufficient knowledge of the animal(s) by the veterinarian to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s). This means that the veterinarian has recently seen and is personally acquainted with the keeping and care of the animal(s) by virtue of an examination of the animal(s) and/or by medically appropriate and timely visits to the premises where the animal(s) are kept; and when (3) [t]he veterinarian is readily available, or has arranged for emergency coverage, for follow-up in the event of adverse reactions or failure of the treatment regimen. (Pp. 49–50) A valid VCPR is mandatory if drugs are to be used for reasons different from those stated on the label; this is called an extra-label use. Dairy farmers need the benefit of a valid VCPR to make sure they are following the veterinarian’s instructions properly.

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The Use of Drugs in Food Animals: Benefits and Risks 3) Using only FDA-approved over-the-counter or prescription drugs with a veterinarian’s guidance. FDA-approved drugs have been tested extensively to show that they perform consistently according to the manufacturer’s claims and that they cause no harm to the animal when administered according to the label. As a result, dairy farmers will reduce the risk of violative drug residues in the milk and meat of animals receiving drugs and protect their market by supplying safe and wholesome milk and meat. FDA-approved over-the-counter drugs are those that can be purchased anywhere without a veterinarian’s prescription or supervision. Drugs are labeled for over-the-counter sale when instructions that are adequate for a layperson can be printed on the label, including the package insert. 4) Ensuring that all drugs have labels that comply with state or federal labeling requirements. Because dairy farmers are ultimately responsible for any drug residues, they should be careful to follow drug label instructions. They should not be concerned about the accuracy of a label, because the manufacturer must meet all the requirements to get the drug approved, and veterinarians are responsible for all labels of drugs they prescribe for their clients’ animals. 5) Storing all drugs correctly. All medications for cattle must be properly stored, so that they will not come into contact with milk or the milking equipment. Topical antiseptics, wound dressings, vaccines, and other biological products and vitamins or mineral products are generally exempt from labeling and storage requirements. However, some states might have specific storage regulations. 6) Administering all drugs properly and identifying all treated animals. The best way for dairy farmers to avoid problems associated with this critical control point is simply to follow the drug’s label and package insert, and to identify each animal that receives the drug at the time it is administered. Immediate identification of the animal will greatly reduce the risk of putting adulterated or contaminated milk into a tank or sending an animal with tissue residues to slaughter. 7) Maintaining and using proper treatment records on all treated animals. Dairy farmers must identify treated animals with a paint stick, leg bands, hock markers, neck strap, numbered ear tags, or other marking devices. Proper identification is crucial for keeping violative drug residues out of milk and meat. Equally important is maintaining a record of all treated animals. The records should be accessible to everyone who works with the animals. The records need to be used to ensure that cull cows, dairy beef, steers, or calves whose markings have worn off are not sold before the withholding time has expired. The records also should be permanent, so the veterinarian can refer to them to prescribe effective therapy and to serve as protection in case of a regulatory follow-up. 8) Using drug-residue screening tests. New technology has made it possible to conduct milk, urine, and blood tests that are easy to use on the farm. Many of these tests are as sensitive as those done at milk or slaughter plants. On-farm testing gives dairy farmers an additional way to avoid violative drug residues in

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The Use of Drugs in Food Animals: Benefits and Risks meat and milk. The key is to match the drug administered with the correct drug test at the desired level of sensitivity. 9) Implementing employee and family awareness of proper drug use to avoid marketing adulterated products. Many cases of adulterated meat or milk occur because one person treats the animals and someone else takes care of the milking or decides to sell the animals. If different individuals are carrying out those tasks, it is important that the critical control points of the quality-assurance program be explained to everyone involved with the animals. 10) Performing the 10-point Milk and Dairy Beef Residue Prevention Protocol annually. Producers need to go through these 10 points with their veterinarians at least once a year. Conditions on the farm change; new employees are hired and different drugs are used because of a change in herd health. In addition, new drugs or screening tests come onto the market. These factors make it worthwhile for producers to review the plan with their veterinarians and farm staff a minimum of once each year. Voluntary implementation of the 10-point plan has met with varied success. Even highlighting the incentive of reduced costs associated with a herd health program and the reduced need for drugs has not been completely effective. The Implementation and Communication Subcommittee of the Drug Residue Committee (Buntain et al. 1993) reviewed the quality-assurance initiatives and suggested that insurance companies sponsor premium reductions or price breaks on liability insurance for voluntary participants. Another suggestion was for milk processors and cooperatives to include plan participation in their requirements for quality bonuses. The cooperatives and processors could then use the information as a marketing advantage and advertise that a high percentage of their producers participated in the residue-prevention program. Another possible incentive mentioned was to have voluntary implementation of the 10-point plan defer the penalty of a first violation under the PMO. Suggestion was also made for veterinarians to go through the 10-point plan at no charge to producers who implement the plan voluntarily. Although the incentive of reduced costs associated with a sound herd health program has not enticed a majority of producers to adopt the 10-point plan voluntarily, it still should be a major focus of preventive herd health management. The resulting decrease in disease and increase in production also would lead to a decrease in finding violative drug residues. Residue avoidance would be best served by encouraging and emphasizing the need for on-farm treatment records. The use of treatment records as a source of residue information for withholding milk and meat from the market is obvious. Establishing drug use patterns from treatment records on each farm also would provide a basis for discussing changes in or alternatives to current drug use. This information could provide opportunities for educating producers about better management alternatives in certain stages of the production cycle.

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The Use of Drugs in Food Animals: Benefits and Risks Continuing-education programs on current and changing regulations are necessary for inspector, veterinarian, and producer groups. A centralized task force, perhaps encompassing extension personnel, would be helpful in gathering and reviewing the educational, labeling, and form material available, and distributing the most up-to-date information to producers. Along with details on changing regulations, information needs to be made available on sources such as Food Animal Residual Avoidance Databank (FARAD) project for determining withholding times of extra-label drugs, on drugs prohibited from use in food animals, on the liability associated with drug labeling and signing the 10-point plan, and on the definition of a valid VCPR. The relationship and importance of FARAD to drug use policy in the United States is further detailed in Chapter 3. Beef Quality-Assurance Program In 1996, the beef industry initiated the Beef Quality Assurance (BQA) program, a voluntary initiative designed by producers for producers (NCBA 1997). Because of the tremendous diversity across the United States in the beef cattle industry, the BQA program is implemented state by state. Although the National Cattlemen’s Beef Association provides technical support and national leadership to beef cattle producers, the administration and implementation of the BQA program are carried out by state cattle affiliates and state beef councils, with the assistance of practicing veterinarians. The BQA program is designed to educate and train beef cattle owners, their employees, and their veterinarians on the day-to-day management practices that influence the safety, wholesomeness, and quality of beef. Subjects emphasized through producer and veterinarian seminars, workshops, and chute-side demonstrations are (1) the importance of proper and safe animal drug use; (2) adherence to product label withdrawal periods; and (3) record-keeping relative to animal product use, drug inventories, and animal treatment regimens. The program teaches testing procedures for sampling and analyzing feed and feed ingredients for potential chemical and pesticide residues at the farm or feedlot. Through the BQA program, residue drug violations for feedlot cattle essentially have been reduced to zero, as reported by the USDA Residue Monitoring Program (FSIS 1994b). In the past few years, the BQA program has launched an aggressive effort designed to eliminate injection site tissue damage resulting from intramuscular administration of animal health products. Educational efforts regarding injection site awareness have resulted in a significant reduction in tissue quality defects. The success of these efforts demonstrates the ability of the BQA program to create an effective and responsive network of cattlemen and veterinarians. The BQA initiative is structured to reach all segments of beef cattle production, including cow and calf, stocker, backgrounding, and feedlot operations. To date, 42 states sponsor aggressive BQA programs. These states produce more

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The Use of Drugs in Food Animals: Benefits and Risks than 98 percent of the feedlot cattle and account for more than 95 percent of the cow and calf producers in the United States. More recently, the state BQA programs have implemented producer BQA certification programs. The certification procedure requires a specified amount of structured quality-assurance training and the verification of quality-assurance practices implemented in the actual operation. It is expected that the momentum for quality-assurance certification will increase throughout the industry. Finally, the BQA program is prepared to launch a major quality-assurance initiative for cull dairy and beef cows. Violative drug residues in cull dairy and beef cows remain a major concern for the industry. The industry’s BQA program is an effective producer network for addressing product safety concerns now and in the future. However, on-farm food safety interventions must develop around sound science if these efforts are to be effective and further enhance the safety of beef and beef products. SUMMARY OF FINDINGS Across all major species of animals used in food production, the development of intensive production practices has changed the way animals are exposed to pathogens in their environment. All species, including fish, derive some benefit from the use of antibiotics to treat active infections, prevent disease outbreaks, or modify their internal environment for faster growth with the use of less feed. Because animals typically are raised in close proximity to one another, the emergence of disease in one animal can result in the rapid infection of many more in a short time, underscoring the need to use subtherapeutic concentrations of antibiotics. Animal producers must adhere to strict guidelines on antibiotic use to ensure that drug residues are not carried over into the human food chain. As such, medication is halted before slaughter to curb the inappropriate introduction of drugs and their residues into the human food chain. Opportunities exist with the use of HAACP quality-assurance programs to modify production and animal-handling strategies, to minimize the incidence and management of disease, and to control the misuse of drugs and pharmaceuticals that could allow drug residues to enter the food chain or for disease pathogens to pose a risk to human health.