Veterinary Drug Residues in Food Animal Products, Its Risk Factors and Potential Effects on Public Health

~Dr. Snigdha Hazarika…

Human health is related directly to the environment [1], and in particular the nature and quality of the food [2]. Quality of food from animal products is widely concerning public health agencies around the world since veterinary drugs have played an important role in the field of animal husbandry and agro-industry [3]. Veterinary drugs or veterinary medicinal products are critically needed to meet the challenges of providing adequate amounts of food for the growing world population [4] as drugs improve the rate of weight gain, improve feed efficiency, or prevent and treat diseases in food producing animals [4, 5]. Antibacterial drugs and hormonal growth promoters are the main veterinary medicinal products that potentially contaminate foods of animal origin [6]. The use of veterinary drugs in food-producing animals has the potential to generate residues in animal derived products and poses a health hazard to the consumer.
Residues, as defined by the European Union (EU) and the Centre of Veterinary Medicine, an agency under the Food and Drug Administration (FDA/CVM) in the USA are ‘pharmacologically active substances and their metabolites which remain in foodstuff obtained from animals to which the veterinary medicinal products in question has been administered” [7]. Under normal physiological condition, following administration of a drug to an animal, most drugs are metabolized in order to facilitate elimination, and to a large extent detoxification as well. In general, most of the parent product and its metabolites are excreted in urine and a lesser extent via faeces [8]. However, these substances may also be found in milk and eggs, and in the meat [9]. This review provides an overview of the risk factors for development of drug residues, their global incidence rates and public health significance.
Potential effects of veterinary drug residues on public health:
Drug low level contamination generally may not generate a violation problem on public health. However, extensive use of drugs may increase the risk of an adverse effect of residues on the customer including the occurrence of antibiotic resistance [10,11] and hypersensitivity reaction [11]. Therefore, prudent use of drugs in the manner of preventing feed contamination is necessary [12].
Development of drug resistance:
Human health can either affect through residues of drugs in food of animal origin, which may cause direct side effects [10], or indirectly, through selection of antibiotic resistance determinants that may spread human pathogen [11,13,14]. Resistant microorganism can get access to human, either through direct contact [13] or indirectly via milk, meat, and or egg. As the bacteria of animal origin, they may either colonize human endogenous flora or superimpose and additional load to the reservoir of resistance genes already present in man. The potential for animal to human transfer of resistance is existed. Clearly, the use of antibiotic in livestock production has been associated with the development of human antibiotic resistance [13,14]. It has been documented that human develop drug resistant bacteria such as Salmonella, Campylobacter, and Staphylococcus from food of animal origin [13]. Examples of drugs that have been shown to cause the growth of resistant bacteria in food of animal are fluoroquinolones and avaoparin. The resistance of microorganisms, arising from sub-therapeutic uses of penicillin, tetracyclines, and sulfa drugs; in agriculture is suggested by the WHO to be a high priority issue [15].
Drug hypersensitivity reaction:
Drug hypersensitivity is defined as an immune mediated response to a drug agent in a sensitized patient, and drug allergy is restricted to a reaction mediated by IgE. Allergic reactions to drugs may include anaphylaxis, serum sickness, cutaneous reaction, a delayed hypersensitivity response to drugs appear to be more commonly associated with the antibiotics, especially of penicillin [16].
Carcinogenic effect:
The term carcinogen refers to an effect produced by a substance having carcinogenic activity [17] considerable confusion has existed because a carcinogen applies to substances that are so varied in their qualitative and quantitative characteristics. The potential hazard of carcinogenic residues is related to their interaction or covalently binding to various intracellular components such as proteins, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), glycogen, phospholipids, and glutathione [18].
Mutagenic effect:
The term mutagen is used to describe chemical or physical agents that can cause a mutation in a DNA molecule or damage the genetic component of a cell or organisms. Several chemicals, including alkalizing agents and analogous of DNA bases, have been shown to elicit mutagenic activity [19]. There has been increasing concern that drugs as well as environmental chemicals may pose a potential hazard to the human population by production of gene mutagen or chromosome breakage [20] that may have adversely affects human fertility [21].
Teratogenic effect:
The term teratogen applies to drug or chemical agent that produces a toxic effect on the embryo or fetus during a critical phase of gestation. Consequently, a congenital malformation that affects the structural and functional integrity of the organism is produced. The well-known thalidomide incident involving a number of children in Europe was a direct testimony to the hazard that may occur when such agent is administered during pregnancy [20]. Of the anthelmintics, benzimidazole is embryo toxic and teratogenic when given during early stage of pregnancy because of the anthelminthic activity of the drug [18,22]. In addition to embryo toxicity including teratogenicity, the benzimidazole drug of oxfendazole, has also exhibited a mutagenic effect [22].
Disruption of Normal Intestinal Flora:
The bacteria that usually live in the intestine acts as a barrier to prevent incoming pathogen from being established and causing diseases. Antibiotics may reduce the total number of the bacteria or selectively kill some important species. The broad-spectrum antimicrobials may adversely affect a wide range of intestinal flora and consequently cause gastrointestinal disturbance [23]. For example, use of drugs like, flunixin, streptomycin [24], and tylosin in animals, and also use of vancomycin, nitroimidazole, and metronidazole in humans [23] are known for this effect.

Safety Evaluation for VMPs Residue
Acceptable daily intake (ADI):
It is the amount of a substance that can be ingested daily over a lifetime without appreciable health risk. Calculation of ADI is based on an array of toxicological safety evaluation that takes into acute and long-term exposure to the drug and its potential impact [25]. If the drug is not a carcinogen, the no observed effect level (NOEL) of the most sensitive effect in the most sensitive species divided by a safety factor is used to determine an ADI for drug residues. The FDA will calculate the safe concentration for each edible tissue using the ADI, the weight in kg of an average adult (60 kg), and the amount of the product eaten per day in grams as follows.
Safe concentration=[ADI (µg/kg/day) x 60 kg] /[Grams consumed/day].
Maximum residue limit (MRL):
It is defined as the maximum concentration of a residue, resulting from the registered use of an agricultural or veterinary chemical, which is recommended to be legally permitted or recognized as acceptable in or on a food, agricultural commodity, or animal feed. The concentration is expressed in milligrams per kilogram of the commodity (or milligrams per liter the case of a liquid commodity) [26].
Calculating withdrawal time:
The withdrawal period or the milk discards time is the interval between the time of the last administration of a veterinary drug and the time when the animal can be safely slaughtered for food or the milk can be safely consumed. The withdrawal period is determined when the tolerance limit on the residue concentration is at or below the permissible concentration. A tolerance limit provides an interval within which a given percentile of the population lies, with a given confidence that the interval does contain that percentile of the population [27].
Control and preventive measures:
In general, the residue control strategy is based on a two-step approach: (1) the detection of residues using sensitive tests with a low rate of false negatives; (2) followed by confirmation, requiring quantification against the MRL and identification with a low rate of false positives [28]. Hence, the residue prevention strategy is based on preventing entry of violative residues in meat or milk intended for human consumption by proper drug use guide developed for use by both veterinarians and food animal (dairy and beef) producers include the following:
1. Herd health management; all food animals should be maintained in a clean and healthy environment whenever possible. Drug residues are best avoided by implementing management practice (good nutritional to meet growth, maintenance and lactation needs) and herd health program that keep animals healthy and producing efficiently;
2. Use of approved drugs; dairy and beef producers should not use or store un- approved drugs, special mixes, or products within adequate labels as unapproved drugs have no data regarding efficacy, safety, or withholding time. The herd veterinarian should be certain that ELU involves only approving products;
3. Establishment of valid veterinarian-client-patient relationship; the use of prescription drug and the ELU necessitate a veterinary-client- patient relationship, which is established hence a veterinarian is closely with the owner in health management of the herd;
4. Proper drug administration and identification of treated animals; before administering or dispensing drugs one has to: know the drugs approved for all classes of cattle on the farm and be familiar with approved dosage, route of administration, and withholding time;
5. Proper maintenance of treatment records and identification of treated animals; institute a workable health record for each animal to record all health related events, including administration of medication. Record the identification of all animals in the permanent health record book; and
6. Creating awareness of proper drug use, and methods to avoid marketing adulterated products principally educational, total residue avoidance program is based upon the objective of improving the livestock producer’s management and quality control of marketing animals with emphasis on avoidance of drug residues [29].
Conclusion and Recommendations:
The use of veterinary drugs in food-producing animals has the potential to generate residues in animal derived products and poses a health hazard to the consumer. Veterinarians are facing a dramatic change in attitude and behaviours concerning drug residues because of the therapeutic and prophylactic use of drugs. Until recently, veterinarians did not pay sufficient attention to ensuring that the producers adhered strictly to the withdrawal period for milk, meat, and egg from animals treated with a variety of drugs. The most likely reason for drug residues may result from human management, such as improper usage, including extra-label or illegal drug applications. However, the most obvious reason for unacceptable residues might be due to failure to keep to the withdrawal period, including using overdose and long-acting drugs. Therefore, veterinarians should pay sufficient attention regarding use of veterinary medicinal products in food producing animals.
References:
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27. Food and Drug administration Center for Veterinary Medicine (FDA-CVM) (2006) Guidance for approval of a withdrawal period. In: Contains-Binding Recommendations: Guidance for Industry- General Principles for evaluating the safety of compounds used in food-producing animals. U.S. Department of Health and Human Services.
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29. Scippo ML, Degand G, Duyckaerts A, Maghuin-Rogister G, Delahaut P (1994) Control of the illegal administration of natural steroid hormones in the plasma of bulls and heifers.Analyst 119: 2639-2644.

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Author: Dr. S. Hazarika, Dept. Of Pharmacology, L.C.V.Sc.


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