VETERINARY DRUG RESIDUES  IN FOOD ANIMALS AND THEIR POSSIBLE LINK TO ANTIMICROBIAL RESISTANCE

VETERINARY DRUG RESIDUES  IN FOOD ANIMALS AND THEIR POSSIBLE LINK TO ANTIMICROBIAL RESISTANCE

 

Antimicrobial resistance (AMR) is a major threat worldwide and more important in developing countries including in India where it is considered as emergence due to the burden of various infectious diseases, use of antibiotics and resulting occurrence of antimicrobial resistance (Laxminarayan et al., 2013, 2016). AMR along is becoming the reason of making victims of people more than the total victims of cancer and road accidents, and it is alarming that by 2050 this figures will be much more than 10 million than that of the present figure of 700,000 people losing the battle to AMR per year (O’Neill, 2016). While projecting disaster effect of AMR on economic point of view, it is suggested that AMR could alone diminish 2-3.5% of gross domestic product (GDP) equating a total value of USD100 trillion to the world (O’Neill, 2014). Indiscriminate in the form of overuse and misuse of antibiotics or other antimicrobial agents are the main contributing factor for the development of such high rates of resistance (WHO, 2014).The public health researchers all over the world have termed these resistant microorganisms as ‘nightmare bacteria’ that often called ‘pose a catastrophic threat’ to human beings.

The misuse of veterinary drugs in food-producing animals could result in deposition of drug residues in the tissues and organs. When the animal is slaughtered and processed into food, or when it produces eggs or milk, these residues enter the food chain. Veterinary drug residues are one of the important factors affecting the safety of animal-derived food. With improvements in living standards and growing demand for animal-derived food, veterinary drugs are commonly used in animal husbandry to prevent and treat animal diseases. However, improper use of veterinary drugs may cause various problems, such as drug resistance. Owing to this, international standards for limits of veterinary drug residues in animal-derived food have been established to ensure the quality and safety of agricultural products. It regulates the rational and scientific use of veterinary drugs in animal husbandry to prevent their residues from exceeding the enacted limits and causing hazards to human health. Back in May 2013, Macao government has promulgated the ‘Maximum Residue Limits of Veterinary Drugs in Food’ to control the maximum residue limits¹ of any drugs in the edible parts of food animals, including cattle, pigs, chickens, sheep, goats, horses, poultry, fish, shrimps, etc. A total of 18 veterinary drugs classified into 10 types of drugs are subject to be regulated.

The consumption of food containing excessive levels of veterinary drug residues, may have adverse effects on human health, such as allergies in some individuals. It can also potentially lead to the development of antimicrobial drug resistant microorganisms in humans. Antimicrobial resistance (AMR) is a serious threat to public health around the world as disease causing microbes can become resistant to antimicrobials. As a result, humans and food animals will have fewer and more limited treatment options when they are infected with antimicrobial resistant microorganisms. The World Health Organization (WHO) has identified AMR as one of the top 10 public health threats facing humanity, and launched the Global Action Plan on AMR in 2015, to spur global efforts.

Antibiotics are part of the veterinary drugs which are administered to food producing animals routinely for either treatment, prevention of disease or to modify physiological functions. However, such drugs leave behind residues in the organisms and these residues can make their way into the animal sourced products such as meat, milk, eggs and honey and from there they find their way into the human food chain. The most likely reason for drug residues is improper usage which could be over use of the drug or use of non-permitted antibiotics. Another reason could be the failure to maintain the withdrawal period in animals.

Uncontrolled presence of residues of antibiotics and other drugs in food, as a result of their use in food-producing animals, has the potential to pose a threat to human health and also lead to the development of antimicrobial resistance (AMR) among disease-causing bacteria.

The World Health Organisation has often laid emphasis on the issue of antimicrobial resistance brought on by rampant use of antibiotics on animals for therapeutic use. Misuse of antibiotics in veterinary practices and in agriculture is leading to the resistance issue. Unless residues in meat and meat products, chicken, milk etc. are controlled therapeutic use of veterinary drugs and antibiotics in meat and chicken will continue.

However, controlling veterinary drug residues in the food sector is challenging due to the large number of drugs administered to animals that are a food source, the diversity of the animals themselves as well as the different varieties of food products derived from the animals. There are more than 200 compounds from veterinary drugs that have been identified as posing a potential health risk for consumers. It is therefore, important for food producers and food manufacturers to fully understand regulatory standards relating to veterinary drugs, antibiotics and their residues in the food chain.

Veterinary drugs are regulated at the national level or internationally through global food standards organizations. International Organisations such as Codex Alimentarius lay down maximum residual limits (MRL) for such residues in different animal products. While most veterinary drugs are regulated based on maximum residue limits, there are others that are banned for human consumption in food. In India, the Food Safety and Standards Authority of India (FSSAI) publishes regulations laying down such limits to be followed by food producers in India.

The Food Safety and Standards (Contaminants, Toxins, and Residues) Second Amendment Regulation, 2018 mentions the tolerance limit of antibiotics and pharmacology active substances in foods of animal origin, like meat/meat products, poultry, fish, and milk. In the second amendment the FSSAI has provided new tolerance limits for 103 antibiotics and veterinary drugs in meat/meat products (including poultry and fish) and milk. Among the new provisions, tolerance limits for 76 antibiotics (These are either prohibited or not-intended for use in food-producing animals) have been specified at 0.01 mg/kg of the listed food and largely reflects the level of detection of such antibiotics/drugs by existing method of analysis.

There were also revisions to the prohibited list of antibiotics and veterinary drugs applicable to meat and meat products, and poultry and eggs, seafood including shrimps, prawns or any variety of fish and fishery products. The Extraneous Maximum Residue Limit of 0.001 mg/kg will be applicable except for Chloramphenicol for which it will be 0.0003 mg/Kg. This means that mere detection of these antibiotics in foods is unacceptable from the food safety point of view. The revised or new provisions pertaining to the tolerance limits of antibiotics and veterinary drugs were amended by FSSAI so that they could be in alignment with the international best practices. They are intended to address the food safety concerns in foods of animal origin, whether consumed domestically or in the countries of export.

The need for the food industry to monitor veterinary substances in a wide range of food products through reliable analytical solutions cannot be overlooked as residues have the potential to pose a health risk to consumers. Another reason to monitor these residues is that the international market will accept only those foods that are safe. Indian processed foods will not be able to compete unless the standards for veterinary drug residues is in keeping with international standards. Analysis of animal sourced foods, therefore, needs to be thorough, using approved methods of analysis accepted worldwide.

At the same time it is also necessary to educate and train dairy and poultry farmers and bee keepers in the latest standards of animal husbandry procedures.  They also need to maintain high level of quality control to keep antibiotic residues within permissible limits and avoid contaminating the food chain as that can have wide ranging effects on the health of the people. All animal farmers need to be careful and must administer antibiotics only under prescribed conditions and in front of the veterinarians. It is also necessary that appropriate tool kits are available at the field level for effective monitoring of residue limits, particularly in the case of milk which is often the main diet of infants. Over the counter sales of such antibiotics should be discouraged and food producers must ensure that they

• follow the recommended label directions or dosage
• adhere to recommended withdrawal period
• not administer a large volume at a single injection site
• make sure equipment is cleaned properly and free of drug-contaminants
• prevent animals from having access to veterinary drugs when not required

The antibiotics nowadays used for improved performance in growth especially in broilers and fatteners. They may produce improved growth rate because of thinning of mucous membrane of the gut, facilitating better absorption, altering gut motility to enhance better assimilation, producing favorable conditions to beneficial microbes in the gut of animal by destroying harmful bacteria and partitioning proteins to muscle accretion by suppressing monokines. Antibiotics also favour growth by decreasing degree of activity of the immune system, reduced waste of nutrients and reduce toxin formation. In most of the cases only young growing animals and poultry are responsive to antibiotic mediated growth promotion.

Antibiotics in Therapeutics

Indiscriminating use of antibiotics in all cases of pyrexia, inflammation, wounds and viral diseases have widespread residual effects on edible tissues. The use of antibiotics only in specific conditions is justified because the roll of microbial agents is mainly to kill the rapidly dividing invading cells Antibiotics in Prophylaxis Animals and poultry are receiving sub therapeutic levels of antibiotics to prevent possible infection. But the antibiotics are specific to their spectrum of activity only in the active multiplying stage of bacteria. But it will not provide overall protection. Only in certain cases like dry cow therapy and surgical procedures are wanting of antibiotic prophylaxis.

Veterinary drug residues can be found in animal food products such as meat, eggs and milk, when poor practices are adopted when rearing food animals. The residues can be of the drug itself or metabolites formed when these drugs are broken down in animals. Some contributing factors to veterinary drug residues in food include:

• Usage of antibiotics when it is not necessary (e.g. on healthy animals)
• Not following manufacturer’s instructions (e.g. administering wrong dosage, route, or types of veterinary drugs)
• Administering banned drugs which are harmful to humans
• Not adhering to withdrawal periods (time taken for a drug to be broken down in animal tissue to a safe, acceptable level) prior to slaughter
• Cross contamination of animal feed and water with drugs 

 

Miscellaneous use of Antibiotics

Antimicrobials are used either directly or indirectly during the production processing and storage of milk and milk products. Direct contamination of milk may occur from air and water during processing, storage and transportation. Besides feed given to animals is also source of indirect contamination. Man will be the ultimate consumer of these antibiotic residues. There are some causes of miscellaneous use like lack of awareness, lack of extension activities, inadequate literature supplied by manufacturers, lack of safer drugs and exploitation of more production and profit from animals. FDA prohibits the extra label use of chloramphenicol, furazolidone, nitrofurazone, sulphonamide drugs, and flouroquinolones in lactating animals.

 

Techniques used for Detection and Analysis of Drug Residues –

 

 ELISA – HPLC – Liquid chromatography – Gas chromatography – Paper chromatography.

 

Pathological Effects produced by Antibiotic Residues in Food

– Transfer of antibiotic resistant bacteria to the human. – Immunopathological effects – Autoimmunity – Carcinogenicity (Sulphamethazine, Oxytetracycline, Furazolidone) – Mutagenicity – Nephropathy (Gentamicin) – Hepatotoxicity – Reproductive disorders – Bone marrow toxicity (Chloramphenicol) – Allergy (Penicillin).

 

Causes for occurrence of antimicrobial residues ———–

Poor treatment records, poor management, difficulty to identify treated animals, lack of guidance on withdrawal periods, off-label use of antimicrobial, failure to notice drug withdrawal period, accessibility of antimicrobials to laymen, extended usage or unnecessary dosages of antimicrobials, absence or lack of enforcement of restrictive legislation to use antimicrobials, lack of consumer awareness about the magnitude of human health hazards associated with antimicrobial residues consumption through meat and meat products are some of the primary reasons for incidence of antimicrobial residues in meat and meat products.

Major list of antibiotic & veterinary drugs that been regulated under FSSAI regulation:

The MRL differ from matrix to matrix

S. No.	Name of the antibiotics and veterinary drugs	S. No.	Name of the antibiotics and veterinary drugs	S. No.	Name of the antibiotics and veterinary drugs
1	Chloroform	38	Moxidectin	75	Magnesium Hypophosphite
2	Chloropromazine	39	Sulphaquinoxaline	76	Meloxicam
3	Colchicine	40	Sulfadimidine	77	Mepyramine
4	Dapsone	41	Tilmicosin	78	Methyl Hydroxybenzoate
5	Diethylstibestrol	42	Tylosin	79	Nandrolone Laurate
6	Glycopeptides	43	Tyvalosin Tartrate	80	Niclosamide
7	Stilbenes and other steroids	44		81	Nimesulide
8	Crystal Violet	45	Acepromazine	82	Nitroscanate
9	Malachite Green	46	Albendazole	83	Nitroxynil
10	Ampicillin	47	Amitraz	84	Oxybendazole
11	Cloxacillin	48	Aspirin	85	Febantel/Fenbendazole/Oxyf endazole
12	Colistin	49	Buqarvaquone	86	Oxyclozanide
13	Dihydrostreptomycin Streptomycin	50	Buserelin	87	Parbendazole
14	Chlortetracycline/Oxytetracy cline/Tetracycline	51	Butafosfane	88	Pentobarbitone
15	Erythromycin	52	Butaphosphan	89	Praziquantel
16	Flumequine	53	Calcium Borogluconate	90	Pregnant Mare Serum Gonadotrophin
17	Lincomycin	54	Calcium Magnesium Borogluconate	91	Proligestone
18	Neomycin	55	Carboprost tromethamine	92	Promazine Hydrochloride
19	Salinomycicin	56	Cefquinone Sulphate	93	Propofol
20	Spectinomycin	57	Chloral hydrate	94	Prosolvin
21	Sulphadiazine	58	Closprostenol Sodium	95	Rafoxanide
22	Sulphathiazole Sodium	59	Closantel	96	Semduramycin
23	Trimethoprim	60	Clenbutrol (Broncopulmin powder)	97	Sulpha Chloropyrazine Sodium
24	Sulfadiazine	61	Diethylcarbamazine	98	Suramin
25	Sulfanilamide	62	Dinitolmide	99	Thiabendazole
26	Sulfaguanidine	63	Doramectin	100	Tiamulin Hydrogen Fumarate
27	Amprolium	64	Dexcloprostenolum	101	Totrazuril
28	Apramycin	65	Flunixin Meglumine	102	Triclabendazole
29	Ceftiofur	66	Halofuginone	103	Xylazine
30	Cephapirine	67	Haloxon	104	Clorsulon
31	Clopidol	68	Ivermectin	105	Diminazene
32	Danofloxacin	69	Kaolin	106	Hydrocortisone
33	Enrofloxacin	70	Ketamine hydrochloride	107	Phenazone
34	Ethopabate	71	Levamisole	108	Quinapyramine
35	Flavophospholipol (Flavomycin)	72	Lithium Antimony Thiomalate	109	Cefphactril
36	Nicarbazin	73	Luprostiol	110	Chlorpyridazine
37	Monensin	74	Madramicin	111	Tiaprost Trometamol

 

Major list of antibiotic & veterinary drugs that Eurofins analyze:

S. No.	Name of the antibiotics and veterinary drugs	S. No.	Name of the antibiotics and veterinary drugs
1	Dapsone	28	Danofloxacin
2	Glycopeptides	29	Enrofloxacin
3	Stilbenes and other steroids	30	Ethopabate
4	Crystal Violet	31	Flavophospholipol (Flavomycin)
5	Malachite Green	32	Nicarbazin
6	Ampicillin	33	Monensin
7	Cloxacillin	34	Moxidectin
8	Colistin	35	Sulphaquinoxaline
9	Dihydrostreptomycin Streptomycin	36	Sulfadimidine
10	Chlortetracycline/Oxytetracy cline/Tetracycline	37	Tilmicosin
11	Erythromycin	38	Tylosin
12	Flumequine	39	Albendazole
13	Lincomycin	40	Amitraz
14	Neomycin	41	Cefquinone Sulphate
15	Salinomycicin	42	Doramectin
16	Spectinomycin	43	Ivermectin
17	Sulphadiazine	44	Niclosamide
18	Sulphathiazole Sodium	45	Febantel/Fenbendazole/Oxyf endazole
19	Trimethoprim	46	Oxyclozanide
20	Sulfadiazine	47	Parbendazole
21	Sulfanilamide	48	Praziquantel
22	Sulfaguanidine	49	Proligestone
23	Amprolium	50	Semduramycin
24	Apramycin	51	Thiabendazole
25	Ceftiofur	52	Totrazuril
26	Cephapirine	53	Triclabendazole
27	Clopidol	54	Cefphactril

 

 

Maximum Residues Limit (MRL) (ug/kg) for veterinary residues-

 

ANTIBIOTIC             MRL

Benzyl penicillin     4

Ampicillin       4

Amoxycillin       4

Oxacillin      30

Cloxacillin      30

Dicloxacillin      30

Tetracycline      100

Oxytetracycline      100

Chlortetracycline      100

Streptomycin      200

Dihydrostreptomycine      200

Gentamycine      200

Neomycin      100

Sulphonamides     100

Trimethoprime      50

Spiramycin      200

Tylosine     50

Erythromycine     40

Quinalones      75

Polymyxine       50

Ceftiofur      100

Cefquinome      20

Nitrofurans     0

Nitromidazoles     0

Other chemotherapeutics (Chloramphenicol, Novobiocine)   0

 

Residues Prevention –

The first step in residue prevention is to make individuals and organizations aware of the problem through education by veterinary personnel, organizations, and literatures and governmental agencies. – Rapid screening procedures for the analysis of antibiotic residues and instant grading and prohibition of food containing antibiotics more than MRL. – Processing of milk help for the inactivation of antibiotics. Refrigeration causes disappearance of penicillin. In pasteurization most of antibiotics will loose activity. – Use of activated charcoal, resin and UV irradiation also help for antibiotic inactivation. – Irrational use of antibiotics in field veterinary practices should be avoided. – Development of simple and economic field test to identify drug residue in edible animal products. – Ethno-veterinary practices may be promoted Nation wide monitoring and periodic surveillance of microbial residue in edible tissues and milk.

 

Effects on human health

Clenbuterol is used to induce weight gain in food animals. It can cause various health concerns for humans. Consumption exceeding the MRL can lead to “mild” effects such as hospitalisation with reversible symptoms of increased heart rate, muscular tremors, headache, nausea, fever, and chills.It has to be noted, however, that people who are sensitive to this drug could be far more severely affected by clenbuterol residues in food than the general population.

Ractopamine is a more controversial drug as its use is permitted in food production in some countries like the US and Canada, but the European Union, China, Taiwan and over 100 other countries have banned its use.

The European Union Food Safety Authority has conducted studies into the effect on humans and results stated that the drugs can cause a range of side effects including: tachycardia (fast heart rate, over 100 beats per minute), vasodilation, skeletal muscle tremor, nervousness, metabolic disturbances such as hyperglycaemia and hypokalaemia.

Because of these possible side effects, the EU has rejected the MRL proposed by the UN’s Joint FAO/WHO Expert Committee on Food Additives and said there is no current way of calculating a safe ractopamine residue limit for human consumption with the studies that have been conducted.

Phenylbutazone, commonly known as bute, has potentially more serious implications on human health than clenbuterol and ractopamine. Bute was originally used as a treatment for rheumatoid arthritis in humans in the 1950s but was removed as a result of its effects on human health.

Bute has been linked with the development of blood disorders, including aplastic anaemia, leukopaenia, agranulocytosis and thrombocytopaenia. It has also been known to be a carcinogen in rats but has not been conclusively proven to have this effect in humans.

Whilst the presence of antibiotics in the food system is a major threat to damaging human health, this is no longer the only issue. Recently, the chief medical officer of England, Dame Sally Davies, has raised awareness of the issue of antibiotic resistance and the serious threat it poses to the future of human medical care.

With an increased level of antibiotics used in food production, human consumption of regular antibiotics is increasing. This means that when producers do not meet MRLs, humans are consuming levels of antibiotics when they are not needed, causing an antibiotic resistance. Recent media have highlighted that this can lead to antibiotics losing effectiveness at treating infections.

Without antibiotics available to treat infections, having simple surgery could become a life-threatening procedure. This antibiotic resistance has the potential to be a lot more dangerous than simply being exposed to adverse side effects of the antimicrobial drugs.

Impact of antimicrobial residues on human health———

Incidence of antimicrobials residues in foods creates a significant health risk because of the augmented microbial resistance noticed in recent years (Butaye et al., 2001) . Drug low-level contamination normally may not create a ruin problem on public health. However, widespread use of drugs might upsurge the risk of an adverse effect of residues on the customer including the occurrence of antibiotic resistance and hypersensitivity reaction. Therefore, judicious use of drugs in the manner of preventing feed contamination is necessary.

Why are veterinary drugs used?

For raising livestock and poultry in an intensive capacity, the feeding management and excreta treatment can be centralised to increase efficiency. However, high-density feeding inevitably accelerates the spread of epidemic diseases in livestock and affects their growth. Animals, like humans, suffer from sickness and require proper treatment. Veterinary drugs are used for therapeutic, prophylactic and diagnostic purposes in food animals.

What are the veterinary drug residues in food?

Veterinary drug residues refer to any drugs or relevant substances which remain in the edible parts of food animals after treatment. Although veterinary drugs break down into other substances over time, it may leave residues in the animal body. These residues can be the veterinary drug itself or the products of decomposition. The amount and property of the residues as well as the time required for decomposition vary across different veterinary drugs. Consumption of food containing excessive veterinary drug residues over extended periods may result in acute or chronic poisoning. In mild cases, the symptoms are allergic reactions and headache. Chronic poisoning can cause damage to the liver, kidneys and nervous system.

Should veterinary drugs be completely banned from the use in food animals?

The veterinary drugs in the regulation include antibiotics, antimicrobials, anthelmintic and β2-adrenergic agonists (commonly known as leanness-enhancing agents), which are used to stabilise and improve the quantity and quality of food animals, promote their health and growth, as well as increase production efficiency. Proper and correct use of veterinary drugs in appropriate dosage has positive effects.

 

DR A. KUMAR,IVRI

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