16.4.1 Human Health Hazards of Drug Residues

The human health hazards of drug residues can be classified as direct or indirect impacts [7]. Direct impacts are those that result more immediately and include toxic reactions that impact consumers directly, such as the clenbuterol exposure of 135 people in Spain in 1990 and similarly, 15 people in Italy in 1997 who consumed contaminated beef [8, 9]. Other examples of direct impacts include allergic/hypersensitivity reactions or bone marrow toxicity. Indirect impacts usually have negative effects over a longer time period and include carcinogenicity, mutagenicity, reproductive disorders, immunopathologic effects, and transfer of antibiotic‐resistant bacteria to the human population. The US FDA Center for Veterinary Medicine (CVM) assesses the risks of veterinary drugs on public health prior to granting approval [10–13]. However, when drugs are used in an extra‐label manner, these risk assessments have not been performed by a regulatory agency. A review of how risk assessment principles can be applied to evaluate the human health risks posed by different classes of drugs used in extra‐label manner has been published [11].

16.4.2 Regulatory Monitoring of Drug Residues in Animal Products

Monitoring of drug residues in food‐producing animals has been previously described [14]. In addition, regulatory systems for Europe, Australia, Canada, and Japan have also been reviewed [15].

In the United States, the primary mission of the National Residue Program (NRP) is to verify control of animal drug residues, pesticides, environmental contaminants, and any other chemical hazards in or on meat, poultry, or egg products. The principal agencies that work together to achieve the mission of the NRP include the Food Safety and Inspection Service (FSIS), the Environmental Protection Agency (EPA), and the FDA. Through the Federal Food, Drug and Cosmetic Act, the FDA is given the authority to establish drug tolerances (maximum permissible concentrations) that are published in Title 21 of the Code of Federal Regulations (CFR). Title 21 also contains tolerances set by the FDA for heavy metals, industrial chemicals, and pesticides that are no longer approved for use. The EPA is provided a similar responsibility for pesticide tolerances under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). The tolerances for pesticides are published in Title 40 of the CFR.

The USDA oversees the FSIS, an agency that is responsible for the analytical testing program for residues in domestic and imported meat, poultry, and egg products. In particular, the NRP Sampling Plan, known as the Blue Book, is developed yearly and made publicly available, whereas the Red Book contains NRP drug residue testing results from previous years. Both the Blue and Red Books are available online by linking to their URLs, which are listed in Table 16.1.

Game animals are classified as nonamenable species and undergo voluntary inspection by the FSIS in accordance with the Agriculture Marketing Act [2]. While the NRP Sampling Plan is targeted toward major food‐producing species, it can be used as a guide for potential residue testing of edible products derived from gamebirds. An inspector may sample products that, according to their professional judgment, warrant testing and include analysis for approved and unapproved drugs, pesticides, hormones, and environmental contaminants.

In contrast to federally inspected large‐scale commercial operations are the mid‐size, smaller scale, and individual producers that are involved with local sales. To the authors’ knowledge, there is minimal regulatory oversight for these operations; therefore, it is critical that the advising veterinarians take responsibility and educate their clients regarding best practices for avoiding drug residues.

16.5.1 Minor Use/Minor Species (MUMs) Animal Health Act

The MUMs Animal Health Act was passed in 2004. This legislation added new options for approving limited‐use drugs and provided a new mechanism to legally market some unapproved products. The intention of this legislation was to increase the number of FDA approvals for minor food animal species, such as gamebirds, and to provide sponsors with incentives to seek label claims for veterinary products that would have “minor uses” in major species of animals. “Minor use” is determined by frequency of use and geography. More specifically, minor use means that a drug can be used in a major species for an indication that occurs infrequently and in a small number of animals, or in a limited geographical area and in only a small number of animals annually.

The MUMs Animal Health Act modifies the Federal Food, Drug and Cosmetic Act to include conditional approval, designation, and indexing for veterinary drugs used in minor animal species [16]. Conditional approval and designation provide incentives to drug sponsors with the ultimate goal of drug approval. Drugs that are conditionally approved have shown a reasonable expectation of effectiveness, but the sponsor is granted up to 5 years to provide all the necessary data proving effectiveness. Conditionally approved drugs cannot be used in an extra‐label manner. Designation provides incentives for approvals, including grants to support the studies required for approval, and up to 7 years’ exclusive marketing rights by the sponsor. MUMs legislation also allows for medications to be categorized as “indexed” drugs. Indexed drugs have not undergone a formal drug approval process, but the designation allows drug companies to market and sell these medications for selected populations. Indexing is intended for drug treatment of diagnosed conditions in minor nonfood‐producing animal species, specifically targeting laboratory animals and zoological collection specimens. The purpose of indexing is to make products available that cannot meet requirements of the drug approval process as a result of a limited animal population and a wide variety of species. Indexed drugs may not be legally used in an extra‐label manner in food‐producing animals. More details regarding MUMS legislation have been previously described [17].

16.5.2 Animal Medicinal Drug Use Clarification Act (AMDUCA) 1994

The AMDUCA 1994 made ELDU of FDA‐approved medications by veterinarians in the United States legal. “Extra‐label use” is defined in the CFR as: “Actual use or intended use of a drug in an animal in a manner that is not in accordance with the approved labeling. This includes, but is not limited to, use in species not listed in the labeling, use for indications (disease and other conditions) not listed in the labeling, use at dosage levels, frequencies, or routes of administration other than those stated in the labeling, and deviation from labeled withdrawal time based on these different uses” [18].

The requirements of the AMDUCA are listed in Table 16.2. Key points within the AMDUCA include the following. (i) ELDU can only occur on the order of a veterinarian within the context of a veterinarian–client–patient relationship (VCPR); (ii) ELDU must be limited to a therapeutic purpose to treat a sick or dying animal; (iii) ELDU in food‐producing animals requires that no violative residues occur; (iv) certain compounds are prohibited from ELDU. The American Veterinary Medical Association (AVMA) has defined what constitutes a legal VCPR and the website address for this definition is included in Table 16.1. The AMDUCA stipulates that ELDU only applies to FDA‐approved human and veterinary medications. It does not legalize the extra‐label use of EPA‐regulated pesticides or USDA‐regulated biologics.

As all FDA‐approved veterinary products are assigned either a new animal drug application (NADA) or an abbreviated new animal drug applications (ANADA) number, if a veterinary product does not have a NADA or ANADA number, its use is most likely not AMDUCA compliant in an extra‐label manner. In addition, drugs that are approved for humans have new drug application (NDA) numbers for pioneer drugs or abbreviated new drug application (ANDA) numbers for generic medications. Approval status of both animal and human drugs can be found on the FDA‐CVM and FDA websites respectively. The website URLs are included in Table 16.1.

16.5.3 Compliance Policy Guide (CPG) 615.115 Extra‐Label Use of Medicated Feeds for Minor Species

Extra‐label use of medicated feed or drugs used extra‐label in or on feed are prohibited by the AMDUCA. However, for some minor food‐producing species, medicating via the feed might be essential. Therefore, the CPG 615.115 was created to allow veterinarians to prescribe FDA‐approved medicated feeds to be fed to minor food‐producing animals in an extra‐label manner. In 2016, the CPG was updated to include specifics on veterinary feed directives (VFDs) and to allow the nutritional content to be adjusted [19]. For the “minor” poultry species, such as pheasants and quail, medicated feeds that are approved for major species (turkeys or chickens) can be used under the supervision of a veterinarian. The CPG does not make it legal to use medicated feed for these minor poultry species. However, it does give field investigators “regulatory discretion,” and if all the CPG requirements are followed correctly, field investigators do not have to take any action against the producer or veterinarian.

When medicated feeds are being used under the auspices of the CPG, the other requirements of the AMDUCA need to be met. Additional stipulations for the ELDU of medicated feed in minor species include the following.

1. A written recommendation that includes the medical rationale and dated within 3 months prior to use is required. The producer and veterinarian must keep copies of the written recommendation that must be available in the case of a FDA inspection.
   
2. A medicated feed to be used in a minor food‐producing species must be approved in a similar food‐producing species. Only medicated feeds approved for use in avian species can be used extra‐label in a minor poultry species.
   
3. Extra‐label use is limited to farmed or confined minor species. Treatment of unconfined wildlife is not permitted under the CPG.

16.6.1 Prohibition of Extra‐Label Drug Use of Cephalosporins in Major Food‐Producing Animals

On 5 April 2012, prohibition of the extra‐label use of cephalosporins in major food‐producing animal species, including turkeys, took effect. The FDA enacted this prohibition because of concerns for increasing bacterial resistance to cephalosporins, many of which are used for treating humans. At the time that this chapter was written, there was only one cephalosporin that was approved for poultry, ceftiofur sodium. Ceftiofur sodium is labeled for use in day‐old chicks and turkey poults for control of early mortality associated with Escherichia coli infections. From a legal standpoint, ceftiofur sodium can only be used in an extra‐label manner in the aforementioned species/class for a different indication. In other words, the label dose, administration route, treatment duration, and species (in this case, day‐old chicks and turkey poults) must all be on‐label. In ovo administration would be deemed prohibited. When this chapter was written, the minor food‐producing poultry species (ducks, geese, etc.) were excluded from this ban; thus cephalosporins may continue to be used responsibly in an extra‐label manner.