Americans cherish the availability and affordability of a vast food supply. At the same time, we expect the foods we choose to buy and eat to be clean, fresh, and not contaminated with debris, chemicals, or organisms that cause sickness or discomfort. Many of our foods come from “food animals” or “food-producing” animals raised specifically to provide meat, milk, and eggs. These animals serve primarily as a rich source of protein and protein-related products, vitamins, and minerals, some of which are not readily available from nonanimal sources.
Food animals convert one form of nutrient (usually grain or lignocellulosic feed such as grass, hay, or silage) to another form that differs in amino acid content, nutrient composition, and general nutritional benefit. Chickens can be raised at remarkable rates of weight gain and great metabolic efficiency to yield lean white meat. Laying hens provide a useful protein source in the eggs they produce. It takes longer for a steer to mature to a size that is marketable for beef or for a cow to mature to the point of providing milk. However, ruminants are unique in the human food chain in that they convert low-quality protein and plant-derived feed that is fundamentally indigestible by humans into meat and milk that are readily used by humans. Similarly, swine, fish, and minor species contribute to the supply of available and affordable animal-derived food.
In current agricultural practice, raising animals for food depends heavily on the use of pharmacologically active compounds: drugs. The use of drugs in food animals is fundamental to animal health and well-being and to the economics of the industry. However, their use also is associated with human health effects. There are two sides to the issue of how drug use in food animals affects the health of humans: Reported benefits are derived largely from the maintenance of good
animal health and, therefore, the reduced chance that disease will spread to humans from animals. But drugs used in food-animal production and residues of those drugs could enter human food and increase the risk of ill-health in persons who consume products from treated animals. Moreover, the use of antibiotics in food animals could contribute to the emergence of antibiotic-resistant microorganisms in animals that could be transmitted to humans and result in infections that could be difficult to treat.
There are five major classes of drugs used in food animals:
topical antiseptics, bactericides, and fungicides used to treat skin or hoof infections, cuts, and abrasions;
ionophores, which alter stomach microorganisms to provide more favorable and efficient energy substrates from bacterial conversion of feeds and to impart some degree of protection against some parasites;
hormone and hormonelike production enhancers (anabolic hormones for meat production and bovine somatotropin for increased milk production in dairy cows);
antiparasite drugs; and
antibiotics used to control overt and occult disease and to promote growth.
There are also compounds used to modify gastrointestinal environments to reduce the likelihood of rumen foaming and bloat in cattle, organic and inorganic water treatments that reduce the chances of infection in aquaculture, and miscellaneous substances used with the advice of veterinarians to treat specific conditions. Noticeably absent from the list is a specific class of drugs for treating pain and discomfort in food animals.
In response to growing public concern over food safety in relation to the use of drugs in food animals, the U.S. Department of Agriculture (USDA) and the Center for Veterinary Medicine (CVM) of the Food and Drug Administration (FDA) asked the National Research Council to form a committee to examine and review the benefits and risks associated with drug use in the food-animal industry. The National Research Council assigned the task to the Board on Agriculture, which, through the Panel on Animal Health, Food Safety, and Public Health—a joint panel with the Institute of Medicine—convened the Committee on Drug Use in Food Animals. The committee was charged with reviewing, evaluating, and making recommendations related to the need for drugs and their availability and accountability in agriculture, the benefits and risks to human health and food safety associated with food-animal drugs, the development of food-animal drugs and the process of approval of their use, and the emerging trends in animal health care and the availability of alternative management practices for raising food animals. In particular, the sponsors stressed the importance of evaluating the class of drugs known as antibiotics.
The committee’s report summarizes the current state of the science concern-
ing the relationship between food-animal drug use and public health, reviews the rationale and process under which food-animal drugs are developed by industry and approved by the federal government for use, addresses alternative measures that might be considered in food-animal production strategies to lower use of and dependence on drugs—specifically antibiotics—and summarizes the basic strategies and practices used in modern animal production. Risks and benefits to human and animal health and to animal production economics and efficiency are identified but because quantitative information was insufficient or confounding, not objectively ranked.
THE COMMITTEE PROCESS
The committee reviewed the major classes of drugs used in food animals, focusing on the potential effect of drugs used both for human and for animal health. The committee conducted a review of the scientific literature; heard testimony on animal-drug-related issues; and reviewed federal regulations that provide guidelines and list mandatory practices for drug use, monitoring capabilities for drugs and residues in foods, veterinary oversight in prescription drug use, rates of violations, and instances of documented health problems. The committee concluded that most drugs used and most drug residues found in animal-derived foods pose a relatively low risk to the public so long as the drugs are used responsibly and in keeping with label instructions.
There were, however, concerns about the effects of antibiotic use in food animals. Effects on human health were not related to food contamination from the use of antibiotics or from antibiotic residues. Rather, the concern was narrowed to the effect of antibiotic use on the emergence in food animals of populations of microorganisms that become resistant to the biochemical mechanism by which an antibiotic drug kills or severely restricts the proliferative capability of microorganisms. For example, a review of the scientific literature found that studies focused on antibiotic resistance in human health outnumber those related to drug and chemical residues by almost 10 to 1. In addition, there has been a notable increase in reported cases of human illness associated with antibiotic resistance and an increase in documented resistance patterns from veterinary microbiological surveillance data.
Based on that information, the committee decided to focus on the potential for antibiotic resistance as the main food-animal drug issue. The committee updated and consolidated the most recent findings and opinions that address the human health risk or shape perceptions of the risk. It also summarized the science behind the process by which bacteria become resistant to antibiotic drugs and the ramifications for animals and humans.
FOOD-ANIMAL DRUG USE
Intensive production practices in the modern farming industry have created a new set of management concerns and interactions. Animal-to-animal contact is often closer, less space is available, and preventive-health measures are much more important than are therapeutic ones. Antibiotic use with prescription or veterinary oversight is assumed to be, in general, highly accountable. As with many human drugs for which adequate directions can be written for the lay user, some food-animal drugs can be purchased over the counter without a prescription, usually from distributors of animal feed and other animal production supplies. Accountability of use is improved when producers follow industry quality-assurance guidelines and, with the assistance of veterinarians, document the instances of drug use and the practices associated with drug use.
Most drugs used in food animals have a specific purpose: to treat cuts and abrasions, to enhance growth, to fight parasites. Antibiotics are among the few classes of drugs used in food animals both therapeutically to treat disease and subtherapeutically to increase production performance, to increase efficiency of use of feed for growth or product output, and to modify the nutrient composition of an animal product. Therapeutic use generally occurs after diagnosis of disease, and treatment is governed by label instructions. Subtherapeutic use, defined in the United States as the use of an antibiotic as a feed additive at less than 200 g per ton of feed, delivers antibiotics that have therapeutic effects but at dosages below those required to treat established infections. In most cases, subtherapeutic drugs are given to animals in feed or water.
Antibiotics used to improve the health of animals can increase growth rates and thus offer an economic benefit. When antibiotics stabilize animal health, food animals are able to use nutrients for growth and production rather than to fight infection. Subtherapeutic drugs are used in a range of concentrations, which vary with the type of antibiotic, the food-animal species, and the purpose of treatment. The bacterial species affected also vary with the drug used, so the potential for drug use to affect resistance and human disease varies from drug to drug, from dose to dose, and from animal species to animal species.
There is substantial food-animal industry concern that the unavailability of approved antibiotics compromises food-animal production practices in the United States. Many producers believe that, without more antibiotic choices, current production capacity and economic return might not be maintained, animal well-being could decline, and human health could be affected. The human medical community has the same concern about the lack of development of newer antibiotics to treat antibiotic-resistant bacterial infection in people. The human health care community also calls the use of these drugs in food animals into question because of the possibility that drugs used in animals will become ineffective in treating human diseases as a result of drug resistance in pathogens.
APPROVAL AND OVERSIGHT OF FOOD-ANIMAL DRUGS
New developments and FDA regulations have begun to offset the perceived shortage of drug choices for veterinarians to treat food animal diseases and other problems. CVM has authority for approving new food-animal drugs and feed additives and for regulating, tracking, and monitoring their use and their residues. A considerable portion of the monitoring activity, particularly for detecting drug residue violations, is done by FDA in cooperation with the Food Safety Inspection Service of USDA. CVM’s mandate, through the Food, Drug and Cosmetic Act, is to make public health its paramount responsibility.
In the opinion of several organizations, regulatory decisions aimed at protecting people, animals, and the environment from harmful food-animal drugs have also produced delays in the approval of effective new drugs. The cost of production has increased for drug developers and frustration with the process has increased as communication between CVM and drug developers has become strained. Some organizations have used the term “crisis” to describe the present lack of choice of pharmaceuticals to administer to food animals when traditional therapies prove ineffective. The crisis reflects the fears inherent in conflicting concerns and the fears that arise when the choices and practices of one stakeholder are restricted by those of other stakeholders.
CVM has responded to industry concerns and to the enactment of new laws by reorganizing many of its operations and streamlining procedures to expedite drug approval even as it continues to meet the federal mandate to protect the public health. When no approved drug is available or when higher-than-approved dosages of approved drugs are needed, veterinarians must use their professional judgment regarding the benefits and risks to sick animals associated with extra-label use of drugs. Extra-label use for analgesic purposes is common because few animal-specific drugs have been approved for the relief of pain and suffering. Extra-label use also is common in the therapeutic treatment of minor species (goats, deer, llamas, fish, exotic pets) of food and companion animals of which the per capita use or consumption is relatively low; drugs approved for common food-animal species are typically used.
Legislative reform occurred in 1996 with the passage of the Animal Medicinal Drug Use Clarification Act (AMDUCA). AMDUCA legalized some aspects of extra-label drug use by giving veterinarians latitude in prescribing drugs for nonapproved species or dosages. Extra-label drug use is allowed only when a well-defined veterinarian–client–patient relationship is established, when drug use is accurately documented, and when accountability is ensured. A national database called the Food Animal Residue Avoidance Databank (FARAD) provides a valid and needed reference for practicing veterinarians with regard to the implementation and success of AMDUCA. Through FARAD, veterinarians can obtain information on specific veterinary and nonveterinary drugs for treating sick animals and recommend appropriate dosing and withdrawal times.
A second law aimed at streamlining the approval process is the Animal Drug Availability Act (ADAA), which was also signed into law in 1996. ADAA was developed to remove barriers in the drug approval process by reducing the stringency of requirements for proof of efficacy, by making clear early in the process which data CVM would require for approval, and by providing more flexible labeling to permit a range of dosages within a given species. Final FDA regulations based on ADAA are anticipated to be available by 1999.
There is still a need in the food-animal industry for FDA to approve more drugs for specific uses, but progress has been made in legalizing the use of medications for food animals under the guidance of veterinarians.
MONITORING OF DRUG RESIDUES
Drug residues in animal-derived food products are an important consideration for consumers. Residues of drugs used in the food-animal industry threaten human health by being acutely or cumulatively allergenic, toxic, mutagenic, teratogenic, or carcinogenic. There is inconclusive evidence that antibiotic residues transferred to humans through food might set up a biological milieu that favors the emergence of microbial strains within a host.
The processes for identifying drug residues and stopping their entry into the food chain were evaluated by the committee on the basis of drug-residue-screening data. There is always a need to increase the specificity and accuracy of screening and testing, and increased research in this regard would facilitate improvements in the monitoring process. Erring on the conservative side, regulatory agencies do find some degree of false-positive drug residue infractions. Food-animal producers generally use drugs responsibly and in keeping with manufacturers’ labels. In the view of the committee, residue-monitoring procedures must be and are deployed effectively to protect consumers against possible adverse effects of ingesting small or trace amounts of drug residues. With an effective monitoring and enforcement system in place, an efficient and accountable regulatory system is freer to provide more rapid approvals and greater availability of drugs. However, only the legal use of food-animal drugs can be accounted for; with the availability of some food-animal drugs as over-the-counter preparations, prescription drug use offers the greatest accountability. (Illegal drug use in food animals and its inherent problems were largely outside the charge to this committee.) To judge by the few detected incidents of illegal drug residues in milk, eggs, or meat, the health risk posed by drug residues in foods is minimal and specific.
RESISTANCE TO ANTIBIOTIC DRUGS
With an effective residue-monitoring system in place, the dominant issue in the use of drugs in food animals is the microbial acquisition of resistance to
antibiotics. This issue dominates both the drug approval process and the risk–benefit aspect of drug use in food animals, and therefore it was central to the committee’s response to its charge.
Microorganisms can mutate to develop or acquire resistance to antibiotic drugs. Several questions determine whether this resistance will result in an increased hazard for humans: First, is the microorganism zoonotic; that is, can it cause a human disease by moving from the animal to a human? Second, are there missteps in the normal safety procedures for processing and handling animal-derived foods that are intended to reduce the risk of transmission of zoonotic microorganisms to humans, whether they are resistant to antibiotics or not? Third, if transmitted to humans from an animal source, is the microorganism more virulent than in its less-antibiotic-resistant form? Fourth, if the microorganism is zoonotic, is the zoonosis treatable with other antibiotics? Finally, are there enough new antibiotics in development to substitute for antibiotics to which microorganisms have become resistant? How these questions are answered determines the extent of hazard to humans.
The committee’s findings on antibiotic resistance for food animals are as follows:
Use of antibiotics increases the risk of emergence of microorganisms that are resistant to specific, and perhaps other, antibiotics. Development of this kind of resistance is not restricted to antibiotic use in food animals; it is far more prevalent because of misuses in human medicine. Issues concerning antibiotic use in food animals and humans should be coordinated—with regard to use patterns, resistance trends, surveillance data, and recommendations for use—in a partnership of regulatory agencies, pharmaceutical companies, the food-animal industry, and animal and human health care professionals.
The emergence of resistance in bacteria in animals that receive antibiotics is related to the concentrations of the drugs to which bacteria are exposed and also to the duration of treatment or exposure. There are no clear definitions of the duration or dosage at which resistance develops. The FDA definitions of therapeutic and subtherapeutic uses of animal antibiotics are oversimplified; this is important because the extent of drug use affects the propensity for resistance. Generalized assumptions and conclusions pertaining to the risk posed by therapeutic or subtherapeutic use are also oversimplified in evaluations of the human health risk associated with antibiotic use in food animals. Resistance emergence should be classified with regard to each antibiotic used, the concentration and dosage administered, the blood and tissue concentrations attained, the bacterial species or strain affected, and the animal species in which the drug is used. A specific data-driven link should be available to substantiate that the use of an antibiotic at a particular dosage not only promotes resistance but also poses a disease threat to other animals or humans. The definition of resistance is central
to documenting changes in patterns and magnitudes of resistance emergence associated with the use of antibiotics in food-animal production.
A link can be demonstrated between the use of antibiotics in food animals, the development of resistant microorganisms in those animals, and the zoonotic spread of pathogens to humans. The incidence of the spread of human disease in that way is historically very low, but data are seriously inadequate to ascertain whether the incidence is changing. It is difficult to establish whether resistance detection has increased because more antibiotics are needed in food animals or because of the perpetuation of resistant species in food animals, the environment, or other reservoirs. Furthermore, care should be used in evaluating the likelihood of disease spread of this kind because disease incidence is not uniform throughout the human population. Infants, the elderly, and the immunocompromised constitute population groups at greater-than-average risk for infection. Farm workers and pharmaceutical technicians who work with antibiotic compounds, feeds, feed premixes, and concentrates, and people who work with sick and therapeutically treated animals also could be at greater risk for clinical resistance. Resistance in bacteria in farm workers might arise either from contracting an infection with resistant bacteria from a treated animal or from developing resistance in an endogenous pathogen through increased exposure to the food-animal drug.
A major impediment to determining the effect of antibiotic use in food animals on human health risk is the complexity of food-animal drug treatment and subsequent food-processing and handling interactions. Data suggest that most human disease scenarios associated with food-animal pathogens are related to enteric diseases contracted principally through consumption of pathogen-contaminated foods. The initial event that facilitated the emergence of an antibioticresistant microorganism might have been the use of an antibiotic on a farm. Postfarm food processing, storage, and improper handling and cooking are major contributors to the chain of events that allows the pathogen to contaminate the product, proliferate on or in the food, and attain the large numbers that cause disease.
Substantial information gaps contribute to the difficulty of assessing the effect of antibiotic use in food animals on human health. First, it is unclear that the observed or perceived increases in transference of antibiotic resistance to humans are associated with the use of antibiotics in the food-animal industry. Second, there are no scientific data on resistance emergence and pathogen transfer in situations in which a therapeutic drug intervention is prescribed during subtherapeutic drug use for growth promotion that began in the absence of disease and when no prior disease state existed. Third, there are only sparse data to relate the dosages of a drug necessary to foster resistance to those dosages used and the observed degree of resistance. Fourth, antibiotic use is an integral part of the food-production system in the United States, and it is effective in enhancing growth. Fifth, the detection of antibiotic-resistant microorganisms in treated
animals does not automatically imply the presence of disease; many drug-resistant bacteria are not pathogens. Sixth, human oral antibiotic use might predispose some parts of the population to increased susceptibility to enteric clinical infection with food-animal enteric pathogens; there are few data for assessing how genes that code for resistance in bacteria move among and between bacterial species, and there is no concrete information on whether or how nonpathogenic bacteria exposed to antibiotics participate in the resistance emergence phenomenon. Finally, although conservative measures in the food-animal drug approval process might be prudent, until these questions are answered definitely, the quest for new antibiotics for use in food animals must continue. Mechanisms must be instituted to increase research funding to discover new mechanisms of antibiotic drug action; to increase and expedite FDA approvals of new drugs; to provide base funding for the aspects of long-term experimental resistance emergence research and surveillance research that are not likely to be funded by short-term competitive grants; and to develop more precise, accurate, and rapid tests of microbial, pathogenic, and antibiotic-resistant organisms for monitoring purposes.
Alternatives to antibiotic use for maintaining animal health and productivity—such as new vaccination techniques, improved animal nutrition, and genetic strategies—must be sought. Existing alternatives should be implemented in a practical manner so that the appropriate uses of antibiotics and their effectiveness are maintained. Furthermore, risk factors in the development of resistance other than antibiotic use need to be better understood through increased research.
The committee concludes that the use of drugs in the food-animal production industry is not without some problems and concerns, but it does not appear to constitute an immediate public health concern; additional data might alter this conclusion. The greatest concern is associated with the use of antibiotics in food animals in such a way that there is a potential for antibiotic resistance to develop in or be transferred to pathogens that can cause disease in humans. This report acknowledges that there is a link between the use of antibiotics in food animals, the development of bacterial resistance to these drugs, and human disease—although the incidence of such disease is very low. A substantial change in the human health risk posed by antibiotic use would affect not only how animal drugs are reviewed, approved, and used, but also how food animals are produced. It should be noted that antibiotics are still effective for their intended purposes at the recommended dosages.
Bacterial resistance to antibiotics will be the most important motivating factor in the development of new drugs to fight infections and in the modification of processes by which drugs are approved. Regulatory agency approval practices have improved in recent years and continue to do so. Reasonable balance in accountability, oversight, and veterinarians’ access to alternative drugs has in-
creased with the passage of ADAA and AMDUCA. However, those are only temporary solutions to a continuing problem. Unless new antibiotics become available, even the extra-label use of antibiotics is expected to become ineffective. There is a great need to understand better both the magnitude of the risk and the options available to minimize the risk while maintaining the benefits these drugs confer on agriculture. Constant vigilance in monitoring trends in antibiotic resistance in farm animals and humans is strongly encouraged.
New antibiotic drugs are needed to combat emerging animal diseases that do not respond to traditional drugs and so threaten public confidence in animal agriculture and human medicine. Professionals in human health care should be concerned that they do not have enough specialty antibiotics to treat resistant and emerging infections in humans, as should veterinarians. The question is, should newly discovered medications be held in reserve for human or animal use only? Antibiotics should be available to treat specific human and animal diseases with proper accountability and oversight of the drugs used.
Information gaps hinder the decision- and policy-making processes for regulatory approval and antibiotic use in food animals. A data-driven scientific consensus on the human health risk posed by antibiotic use in food animals is lacking.
Development, Approval, and Availability of Food-Animal Drugs
The committee recommends that the Center for Veterinary Medicine continue procedural reform to expedite the drug approval review process and broaden its perspective on efficacy and risk assessment to encompass review of data on products already approved and used elsewhere in the world.
The committee recommends that, to improve drug availability, worldwide harmonization of requirements for drug development and review be considered and further enhanced among the federal agencies that are responsible for ensuring the safety of the food supply.
The committee recommends that the Center for Veterinary Medicine base drug use guidelines on maximal safe dosage regimens for specific food animals, consider greater emphasis on the pharmacokinetics of drug elimination from tissues that are consumed in large quantity, and set drug withdrawal times accordingly.
The committee recommends increased funding for basic research that explores and discovers new or novel antibiotics and mechanisms of their action, including the development of more rapid and wide-screen diagnostics to improve the tracking of emerging antibiotic resistance and zoonotic disease.
Resistance to Antibiotic Drugs
The committee recommends establishment of integrated national databases to support a rational, visible, science-driven decision-making process and policy development for regulatory approval and use of antibiotics in food animals, which would ensure the effectiveness of these drugs and the safety of foods of animal origin.
The committee recommends that further development and use of antibiotics in both human medicine and food-animal practices have oversight by an interdisciplinary panel of experts composed of representatives of the veterinary and animal health industry, the human medicine community, consumer advocacy, the animal production industry, research, epidemiology, and the regulatory agencies.
Alternatives to Drug Use in Food Animals
The committee recommends increased public- and private-sector research on the effect of nutrition and management practices on immune function and disease resistance in all species of food animals.
The committee recommends increased public- and private-sector research on strategies for the development of new vaccination techniques, on a better understanding of the biochemical basis of antibody production, and on genetic selection and molecular genetic engineering for disease resistance.