VETERINARY DRUG RESIDUE IN LIVESTOCK FOOD PRODUCTS & ITS RISK FACTORS ON PUBLIC HEALTH

March 21, 2020

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Compiled & Shared By-Dr Rajesh kumar singh, Livestock consultant, Jamshedpur, Jharkhand,9431309542

rajeshsinghvet@gmail.com

The use of veterinary drugs in food-producing animals has the potential to generate residues in animal derived products (meat, milk, eggs and honey) and poses a health hazard to the consumer. The most likely reason for drug residues might be due to improper drug usage and failure to keep the withdrawal period. The major public health significances of drug residue are development of antimicrobial drug resistance, hypersensitivity reaction, carcinogenicity, mutagenicity, teratogenicity, and disruption of intestinal normal flora. The residual amount ingested is in small amounts and not necessarily toxic.

Veterinarians are not primarily concerned with the increase in production by treating the sick animals and poultry but their important job is to ensure quality (residue free) edible animal products such as milk, meat and eggs to the public. The implementations of WTO regulations demand that veterinarians working in food animal medicine should learn how to avoid drug/chemical residues in food animals and disseminate this information to the farmers to safeguard the health of general public. This issue is also of paramount importance for the veterinarians employed in pharmaceutical and regulatory sectors responsible for assessing the fate of drugs and chemicals that enter the human food chain via the edible products. It is also need of the day that environmentalists, toxicologists and non government organizations (NGO) should pay due attention towards this issue. This is necessary to conduct complete risk assessment, risk management, risk communication studies and implement certain legislative measures to safeguard the public health.

Veterinary drugs are critically needed to meet the
challenges of providing adequate amounts of food for the
growing world population. Drugs improve the rate of weight
gain, improve feed efficiency, or prevent and treat diseases in
food producing animals. However, the benefit of improved
productivity is not obtained without the risk associated with
residues that remain in the tissues of treated animals at the time
of slaughter or residues in animal derived products (meat, milk,
eggs and honey) that poses a health hazard to the customer.
There are many factors influencing the occurrence of residues
in animal products such as drug’s properties and their
pharmacokinetic characteristics, physicochemical or biological
reactions of animal body and processes on animal products.
The most likely reason as improper usage, extra-label or illegal
drug applications, long acting drugs and the most obvious is
failure to keep the withdrawal period.

History:

People concerns in the food safety has been shaken by
incident involving chemical contaminants. The 1962
publication of the book Silent spring by Rachel Carson drew
public attention to the dangers of pesticides in the environment
and in food. The association of diethylstilbestrol (DES) with
cancer in the daughters of women treated with this hormone
also raised questions about the safety of using DES as a growth
promoter in animals. In addition, there have been incidents of
illegal use of hormones in animal production, reports of drug

residues in milk, and considerable public debate about bovine somatotropin (BST) use in dairy cattle.

Incidence of veterinary drug residues—-

In many countries indiscriminate use of veterinary
drugs for animal diseases or as feed additives resulted in to
occurrence of drug residues in food products. Different studies
have been conducted by Babapour et al. (2012) in Iran reported
low level of heavy metals and gentian violet residue from
catfish. Other studies conducted in Nigeria also revealed the
detection of antimicrobial drug residues in commercial eggs
(Kehinde et al., 2012), in meat from slaughtered cattle (Ibrahim
et al., 2012). Furthermore, oxytetracycline and penicillin G
from milk (Desalegne et al., 2014), and tetracycline from cattle
beef (Addisalem et al., 2012) were detected in Ethiopia.
Currently, the joint FAO/WHO Expert Committee on Food
Additives (JECFA) has also reported various veterinary drugs
and other environmental substances residues food products
(JECFA, 2013).

Factors responsible for the development of drug residues in animal products:

Veterinary drug residues are one of the major problems for

food contamination. Veterinary drugs and

agricultural chemicals usage according to label directions will not result in residues at slaughter (Doyle, 2006). However, possible reasons for such residues include:

 Not following recommended label directions or dosage
(extra-label usage)

 Not adhering to recommended withdrawal times

 Administering too large a volume at a single injection site  Use of drug-contaminated equipment, or failure to properly
clean equipment used to mix or administer drugs
 Dosing, measuring, or mixing errors; allowing animals
access to spilled chemicals or medicated feeds

Animal effects- age, pregnancy, congenital, illness, allergies

 Chemical interactions between drugs

 Variations in water temperature for fish species  Environmental contamination

 Improper use of agricultural chemicals such as pesticides
(CFIA, 2014).

Animal factors:———-

a) Age and species of animal:

Weaning status and the age of the animal affect drug
disposition. For instance, the study conducted on comparisons
of the pharmacokinetics of norfloxacin nicotinate between
weaning and unweaned calves revealed that total body
clearance time was increased in weaned calves, possibly due to
increased weight from the presence of rumen fluid (Gips and
Soback, 1996). Elimination half-life of apramycin is longer in
calves than in adult cattle, possibly due to the immaturity of the
drug clearance system (Kaneene and Miller, 1996). It has been
reported that there is an extensive species variation among
animals in their general ability to excrete drugs in the bile;
example, chicken are characterized as good biliary excretes,
whereas sheep and rabbit are characterized as moderate and
poor excretes (Riviere et al., 1991).

b) Disease status animal:

The disease status of an animal can affect the
pharmacokinetics of drugs administered, which can influence
the potential for residues (Boothe and Reevers, 2012). This can
occur either when the disease affects the metabolic system (and
consequently drug metabolism), or when the presence of
infection and/or inflammation causes the drug to accumulate in
affected tissues. For example, cattle with acutely inflamed
mastitis quarters, apramycin penetrates these areas of the body,
and concentrations of the drug have been observed at ten times
over the level recorded from cows without mastitis. Ketoprofen
levels in milk increase during clinical mastitis. In calves with
experimentally induced fascioliasis, the elimination half-life of

antipyrine was increased. The proposed mechanisms for these changes were the changes in liver function by fascioliasis, which changed the processing of drugs through the liver (Korsrud et al., 1993).

Extra-label drug use (ELU):

Extra-label Drug Use (ELU) refers to the use of an approved drug in a manner that is not in accordance with the approved label directions.

 ELU occurs when a drug only approved for human use is
used in animals

 When a drug approved for one species of animal is used in
another

 When a drug is used to treat a condition for which it was
not approved

 The use of drugs at levels in excess of recommended
dosages

For instances, the use of phenobarbital (a drug only
approved for humans) to treat epilepsy in dogs and cats and the
use of enrofloxacin solution as a topical ear medication (only
approved for use as an injection) are the common ELU in

veterinary medicine (Gillian, 2003). The families

of drugs and substances currently prohibited for ELU in all
food producing animals are chloramphenicol, clenbuterol,

diethylstilbestrol (DES), dimetridazole, ipronidazole,

furazolidone, nitrofurazone, sulfonamide drugs in lactating

dairy cattle (CFR, 2006).

Improper withdrawal time———-

It is the interval necessary between the last drug
administration to the animals and the time when treated animal
can be slaughtered for the production of safe foodstuffs
(Kaneene and Miller, 1997). The withdrawal time (clearance
period) is the time for the residue of toxicological concern to
reach a safe concentration as defined by the tolerance.
Depending on the drug product, dosage form and route of administration, the withdrawal time may vary from a few hours to several days or weeks.

Potential effect of veterinary drug residues on public health—-

The major public health significances of drug residue
are    development    of    antimicrobial    drug    resistance,
hypersensitivity   reaction,   carcinogenicity,   mutagenicity,
teratogenicity   and   disruption   of   intestinal   normal   flora.
Rationally, there is no product from treated animal should be
consumed unless the entire drug administered has been
eliminated. This is called zero tolerance, where this concept is
in fact equivalent to the idea of total absence of residual
amounts. However, because of the improvement of analytical
techniques value of zero tolerance became smaller and smaller
that depicts parts per million (ppm), parts per billion (ppb) and
parts per trillion (ppt) concentration.

Development of drug resistance—-

Resistant microorganism can get access to human,
either through direct contact or indirectly via milk, meat, and or
egg. The use of antibiotic in livestock production has been
associated with the development of human antibiotic resistance
(Landers et al., 2012). The animal fed with the low
prophylactic level of antibiotic may develop bacteria evolving
resistance to this antibiotic during the preparation or
consumption of food of animal origin. Human being obtains
drug resistant bacteria such as Salmonella, Campylobacter, and
Staphylococcus from food of animal origin (Chang et al.,
2012).

Drug hypersensitivity reaction——

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 (About 10% of the
human population is hypersensitive), but in animals the extent of hypersensitive to the drug is not well known. Certain macrolides may also be responsible for liver injuries, caused by a specific allergic response to macrolide modified hepatic cells (Darwish et al., 2013).

Carcinogenic effect——

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.

Mutagenic effect——-

Several chemicals, including alkalizing agents and
analogous of DNA bases, have been shown to elicit mutagenic
activity. It has a potential hazard to the human population by
production of gene mutagen or chromosome breakage that may
have adversely affects human fertility (Foster and Beecroft,
2014).

Teratogenic effect————

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. Benzimidazole is embryo toxic and teratogenic
when given during early stage of pregnancy because of the
anthelminthic activity of the drug. In addition to embryo
toxicity including teratogenicity, the oxfendazole has also
exhibited a mutagenic effect (El-Makawy et al., 2006).

Disruption of normal intestinal flora———-

The bacteria that usually live in the intestine acts as a
barrier to prevent incoming pathogen 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. For
example, flunixin, streptomycin and tylosin in animals, and
also use of vancomycin, nitroimidazole and metronidazole in
humans are known for this effect (Cotter et al., 2012).

Safety evaluation for veterinary drug Residues 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. 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]. (CFR, 2006).

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).

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.
Withdrawal times are determined in edible, target tissues by
FDA/CVM during the drug approval process. These target
tissues are most commonly the liver or kidney. On the other
hand, for the drugs for which a muscle tolerance has been established, even if a violative residue is found in the kidney or
liver a violative residue is not found in the muscle, the carcass
would not need to be discarded. Table 1 gives MRLs set for
milk from cows.

Table 1: Maximum Residues Limit (MRL) (ug/kg) for

veterinary drug residues.

Antibiotic	MRL (ug/kg)	Antibiotic	MRL (ug/kg)
Benzyl penicillin & Ampicillin	4	Neomycin	100
Amoxycillin	4	Sulphonamides	100
Oxacillin	30	Trimethoprime	50
Cloxacillin	30	Spiramycin	200
Dicloxacillin	30	Tylosine	50
Tetracycline	100	Erythromycine	40
Oxytetracycline	100	Quinalones	75
Chlortetracycline	100	Polymyxine	50
Streptomycin	200	Ceftiofur	100
Dihydrostreptomycine	200	Cefquinome	20
Gentamicine	200

Table 2: Drug with drawl period to prevent veterinary drug

residues.

Antibiotic in Lactating cattle	Route of Administration	Withdrawal Times
Antibiotic in Lactating cattle	Route of Administration	Milk (Hour)	Meat (Day)
Amoxicillin	Intramammary	60	12
Amoxicillin	Injectable	96	25
Ampicillin	Injectable	48	6
Cefapirin	Intramammary	96	4
Cloxacillin	Intramammary	48	10
Erythromycin	Injectable	—	14
Erythromycin	Intramammary	36	14
Novobiocin	Intramammary	72	15
Penicillin-G	Intramammary	72	15
	Injectable	48	10

Prophylaxis measured to avoid drug residues in food
products

Pharmacological principles:———-

Most pharmacokinetic parameters have been determined in
healthy animals. Yet diseased animals would be expected to
altered physiology. The half-life will increase if CL is reduced
due to an increased Vd. This would result in increased
elimination a half-life by a factor of six. Doubling dose of the
drug should only prolong the approved withdrawal time by one
half-life; however, doubling the half-life as a result of the
disease would double the necessary withdrawal time
pathophysiologic states.

The residue prevention strategy which include the followings:

 Herd health management; all food animals should be
maintained in a clean and healthy environment whenever
possible.

 Read the label and administer the drug properly.

 Pay attention to withdrawal times and prevent extra-label drug
use

 Mark and identify all treated cows.

 Keep a written record of all treatments, including date of
treatment, diagnosis

 Discard milk from all four quarters of a treated cow.

 Do not exceed recommended dose levels and do not combine
several antibiotics.

 Prevent careless use of pesticides and insecticides, as well as
cleansing and sanitizing agents.

 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.

 Development of simple and economic field test to identify
drug residue in edible animal products.

 Ethno-veterinary practices may be promoted.

Conclusion:

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. The most likely reason
for drug residues may result from human management, such as
improper usage, including extra-label or illegal drug
applications, failure to keep the withdrawal period, including
using overdose and long-acting drugs. There is also limited
information on the magnitude of veterinary drug residue
worldwide. Hence, an extensive work has to be carried out to
prevent the occurrence of residues and specified time period is
strictly followed for withdrawal of medication from food of
animal origin prior to ready for human consumption. Veterinarians must be well aware of the importance of drug/chemical residues in the food animals and their possible risk to the general public. They must have updated information about the proper withdrawal times of all the drugs/chemicals used in their areas of practice. They must extend this information to the livestock and poultry farmers for the production of residue free edible animal products like milk, meet and eggs. For residue analysis, trained manpower are needed. In this regard, the availability of sensitive equipment and modern analytical techniques are of paramount importance.