Drug and Chemical Residues in the Edible Tissues of Animals

Definition:

A residue of a parent drug or chemical and its metabolites may accumulate and be deposited or stored within the tissues or organs of an animal following the use of drugs or chemicals in the control and treatment of animal diseases or from the use of feed additive to promote growth and feed efficiency.

Residue may be intentional and unintentional

Intentional residue (direct additive): is a drug or chemical substance used for animals for the purposes of disease control or promotion of growth or intended to protect feed against the attack of infectious or parasitic diseases.

Unintentional residue (indirect additive, accidental): is a residue that occurs as an environmental contaminant or may be acquired at any phase in the production, processing or storage of feed.

Units of residues: Residual quantities of a drug or chemical and its derivatives are expressed in parts by weight such as: mg kg-1 or mg L-1 (i.e., ppm)

g kg-1 or g L-1 (i.e., ppb) ng kg-1 or ng L-1 (i.e., ppt) 2

Importance of residues

With the intensification in the production of animal proteins for human consumption, particularly with potential worldwide food shortages, the use of drugs in the diagnosis, prevention, control and treatment of animal diseases is increasingly and consequently the chance of presence of residues is also increased. These residues constitute a real hazard to human consumption if detected in their food. Also they are responsible for inducing untoward and toxic effects including:

1. Hypersensitivity or allergic reactions due to antibiotic

residues: of the antibiotics employed as feed additives or

in chemotherapy, penicillin and streptomycin and, to a

lesser extent, novobiocin and oleandomycin appear from

clinical usage in human beings to be more inclined to

produce hypersensitivity or allergenicity than others. The

principle way that penicillins may enter food for human

consumption is the use of intramammary infusion

preparations for treatment of bovine mastitis. Penicillins

may be ingested in milk that has not been discarded or

withheld from sale until free from antibiotic activity.

Novobiocin has important use in treatment of

staphylococcal infections that are resistant to other 3

antibiotics. Allergic reactions are likely to occur to

novobiocin in human beings.

2. Carcinogenic effect: produced by a substance having

carcinogenic or cancer-producing activity. There is good

evidence that a large number of molecules/cell are

required for a carcinogen to induce its effect. For example,

3x109 molecules/liver cell of aflatoxin in a single dose

produce hepato-carcinoma in the rat.

3. Mutagenic effect: the term mutagen is used to describe

those chemical agents that damage the genetic

components of a cell (DNA) inducing gene mutations or

chromosomal abrasions. Certain chemicals including

alkylating agents such as DNA analogues have been

shown to elicit mutagenic activity.

4. Teratogenic effect: the term teratogen applies to drug or

chemical agents that produce a toxic effect on the embryo

or fetus during a critical phase of the gestation period. As

a consequence, a congenital malformation that affects the

structural and functional integrity of the organ is produced.

Thalidomide and methallibure (anterior pituitary activator

or estrus cycle control) are well known examples resulted

in congenital malformation. Experimental methods used in 4

the detection of teratogenic agents involve the design of a

three-generation reproductive study (FDA).

5. Drug resistance and cross resistant: due to

development of resistant strains of bacteria and

consequently failure of antimicrobial therapy in human

beings.

Terminology used in residues:

Permissible limits of drug residues:

The permissible level of a residue is the quantity of the residue permitted when first offered for consumption. The assessment of this level is by the determination of the dose level showing no observable effect in at least two species of animals one of them is non-rodent.

No effect (observable) level:

It is the level of drug or chemical that produces no harmful effect (no change or effect on physiological activity, organ weight, body weight, and cellular structure and enzymatic activity of cells) when fed for 2 years to the most sensitive species.

Acceptable daily intake (ADI):

It is the amount of drug that could be consumed by adult person daily during his life span without any health disturbance. 5

ADI = 70/100 x No effect level

Where 70 = weight of adult person

100 = safety factor

Withdrawal time:

Refer to the interval from the time an animal is removed from medication until the permitted time of slaughter. This interval is not intended to safeguard the health of the animal but is required to minimize or prevent levels of drug residues in edible tissues for human consumption.

Withdrawal time intervals vary with each drug from a few hours to several days or months. 120 days is required following implantation of diethylstilbestrol (DES) before slaughtering for human consumption. Only

48 hours is required for withdrawal of melengestrol acetate (MGA) a synthetic hormonal agent used to prevent estrus in feedlot heifers prior to slaughter.

Tolerance level (maximum residue level):

It is the maximum level or concentration of a drug or chemical that is permitted in or on food at a specified time of slaughter and processing, storage and marketing of the feed up to the time of consumption by human beings.

Veterinary drugs of residual concerns 6

Antimicrobial agents: penicillins, streptomycin, polypeptides, macrolides, tetracyclines, chloramphenicol, sulphonamides and quinolones.

Antiparasitic agents: including anthelmintics, antipotozoal.

Insecticides: organophosphates, organochlorine etc.

Hormones and antihormones: estrogen, androgens, and corticoids.

Growth promoters and feed additives.

Methods used for detection of drug residues

For detection of drug residues in foodstuffs, specific chemical or biological

methods are applied according to the physico-chemical or biological

properties of the substance to be detected. For precise detection, sufficient

quantity of the samples are extracted using appropriate solvents, then

evaporated, concentrated and detected by one of the adopted methods as:

1. Microbiological assay (bioassay).

2. Thin layer chromatography (TLC).

3. Gas chromatography (GC).

4. High-pressure liquid chromatography (HPLC).

5. Mass spectrometry (MS).

6. Radio-immunoassay (RIA)

7. Atomic absorption spectrometry (AAS). 7

Effect of cooking and freezing upon tissue residues:

It is known that cooking degrades the tetracyclines in food products.

Streptomycin is unaffected when heated at 100 0C for 2 h. also chloramphenicol is also quite heat stable.

Decoquinate (anticoccidial), is resist 220 0C in chicken tissues and present in the upper layer of cooking juices. Fat drippings from cooked tissues contain concentrated levels of fat-soluble compounds such as insecticides.

Freezing will degrade penicillin in tissues but has little effect on the degradation of oxytetracycline and dihydrostreptomycin.

Excretory organs like kidney, liver expects to contain high levels of residues. 8

Control measures of drug residues

1- Legislation of authorization of veterinarians in supervising animal and poultry farms.

2- Confinement to the use of certain antibiotics as growth promoters as: virginiamycin, avoparcine, and zinc bacitracin.

Condemnation of meat, milk or eggs proved to be polluted with drug residues or chemical impurities beyond the permissible limits determined by the FDA.

3- Pre-slaughter detection of residues in abattoir in biological fluids

(urine, blood and saliva etc.)

4- Following the FDA instructions in using veterinary drugs as:

Contraindication of the use of certain antibiotics in milking cows and certain

coccidiostats in laying hens. 9

Follow the withdrawal times in using drugs for food producing animals or poultry.

Drug withdrawal times and tolerance levels of drugs commonly used in cattle.

Pre-slaughter times Discard times for Tolerance level

Drug (days) milk (hours) (ppm)

Ampicillin 6 24-48 0.01

Dihydrostreptomycin 30 48 Zero

Erythromycin 14 72 Zero

Oxytetracycline 28 96 0.1

Tetracycline Hcl 12 0.25

Tylosin 8 96 0.05-0.2

Sulfamethazine 10-21 96 0.1

Levamisole 7 Don’t use in dairy 0.1 10

Ivermectin 35 30 Zero

Thiabendazole 3 96 0.05-0.1

Estradiol (implants) 120 For beefing Zero

Drug withdrawal times and tolerance levels of drugs commonly used in chickens.

Pre-slaughter times Tolerance level (ppm) Drug (days)

Chlortetracycline 1 1-4

Dihydrostreptomycin 30 Zero

Erythromycin 1-2 0.025

Sulfadimethoxine 2 0.1

Lincospectin 6 ---

Sulfaquinoxalline 10 0.1 11

Clopidol 0-5 5-15

Robenidine 5 0.1

Monensin 3 0.05

Salinomycin 5 0.05

Nicarbazin 4 ---

Most of the above mentioned drugs are not used in egg-laying hens.