Animal Pharm Reports
Veterinary Drug Residues and MRLs
Published November 2006
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CHAPTER 1 - MAJOR CAUSES
1.1 Introduction
Veterinary drug residues are defined as all pharmacologically active substances – including active principles, excipients or degradation products and their metabolites - which remain in food sourced from animals treated with the drug in question. A MRL refers to the maximum concentration of a drug that is legally permitted in food of animal origin. Residues in food from animals constitute a problem for all countries regardless of whether they are classified as developed, developing or underdeveloped.
An obvious enough point is that the reason for the existence of residues is the treatment (therapeutic, non-therapeutic and prophylactic) of food-producing animals. There are a number of scenarios where an unacceptable pharmaceutical residue is present in food. First, there is the situation where a sample contains a substance that is not authorised for use in a food-producing animal. Secondly, the residue may come from a permitted compound but the concentration found exceeds the legally authorised level (i.e. the MRL).
As to how the residues got there in the first place, animal husbandry techniques and supervision (or rather lack of) play a large role. One significant problem is the fact that, in some countries, controls are deficient when it comes to the sale and distribution of veterinary medicines. Drugs can also be dispensed and administered without veterinary supervision, leaving the path open to abuse and misuse.
Another cause is products not being used according to label instructions. Not only can this have ramifications for the treatment timeframe and withdrawal period but also the route of administration. People with insufficient training sometimes carry out the latter. The wrong equipment and techniques might be used to administer drugs. Also contaminated feed may result in residues in animal tissue. Contamination may happen when feed mills produce medicated alongside non-medicated feed and cross-contamination occurs.
Another, admittedly remoter, possibility is that the person, who administers the drug, is actually taking medication for an infection, for example, and this contaminates the animal being treated.
Intensive farming can make it difficult to control disease on a holding, making both therapeutic and prophylactic use of drugs a necessity. One example is in pig production – disease control of endemic conditions can be difficult where there are many pigs in one unit (Sørensen et al. 2006).
1.2 Withdrawal periods
A major cause of residues is not respecting withdrawal periods. This results in animals, which contain an unacceptable concentration of residues, being sent to slaughter. As to why such periods are not respected can be down to a number of factors. At the primary level, one reason could be a lack of knowledge. It could be that the farmer does not grasp the importance of waiting until chemical residues have depleted in an animal before sending it to the abattoir. Furthermore, the insufficient keeping of treatment records may mean that the medical treatment is not properly charted. This can lead to other problems such as exceeding the recommended dosage and extended use. The veterinarian also bears responsibility for ensuring that the treatment dosage and period are adhered to and for communicating such points clearly to holding staff.
As the Institute of Food Safety of Wageningen University points out, residues are not necessarily a problem per se. “If withdrawal periods are obeyed and residues are below the MRLs, there is no problem,” spokeswoman Jeannette Leenders said. She added that the use of drugs, like nitrofurans, or substances, such as hormones, is more problematic because they are legally used in some countries but not in others (see below).
1.3 Hygiene
Lack of on-farm hygiene can also contribute to residue occurrence by encouraging the spread of diseases requiring therapeutic treatment. Holdings may neither be large enough to house the number of animals they contain nor properly ventilated. There may be lapses in cleanliness as staff do not sanitise the facilities properly or the units might be difficult to clean because of poor design.
The personnel might also contribute to the spread of pathogens and bacteria by not observing personal hygiene, such as washing hands and changing clothing before entering controlled zones. Sometimes clean and soiled areas are not separated sufficiently and production zones might overlap. Different species are also kept together and sick animals are not separated from healthy ones, thus facilitating the spread of pathogenic agents and resistant bacteria (OIE, 2006).
Not cleaning equipment used for administering veterinary drugs properly can also lead to contamination. Residues may remain in the equipment, such as in syringes and buckets, leading to accidental contamination. Similarly in feed production, cross-contamination is a possibility during different stages of manufacture. The mixing of components may be uneven, the labelling of the finished product could be erroneous and mixers may contain traces of old feed. Unused feed is not cleared from feeding troughs and animals might be fed with feed unsuitable for their species.
1.4 Misuse
Drugs may be used to treat conditions and species for which they are not targeted; this increases the possibility of residues occurring. One reason for this practice is that there is a lack of medicines for minor uses and species. This is a result of certain formulations being authorised for some species and uses and not for others. Particularly affected by this are commodities such as honey, rabbit and game.
In the EU, legislation requires that the pharmaceutical company develops and validates a routine analytical method for an active substance. This is a problematic area, as both development and validation takes time, are expensive and reward laboratories rather than the company itself (Serratosa et al., 2006). This means that the industry is sometimes reluctant to fund studies into species for which the market is restricted as the costs outweigh the benefits. Consequently, some veterinary drugs used for minor species have no MRLs and their use is illegal.
1.5 Veterinarian
The veterinarian can also wittingly or unwittingly play a role in causing residues. At the onset, an inaccurate diagnosis may compromise treatment. Also too many products may be prescribed, leading to the risk of cumulative residues. Another potential problem is that the veterinarian supplies a quantity of drugs in excess of what is required immediately. This may result in incorrect use or deterioration as the products are stockpiled and used after their expiry date. Such a stockpile may lead the farmer to use the medication if the condition arises once more without consulting a vet.
1.6 Risky residues
Some residues of certain drugs are thought to pose a health risk to human consumers of treated food-producing animals. Others are detrimental to animal health as well as welfare. The latter is a guiding principle of EU law – the bloc recognises that animals are sentient beings, whose well-being must be taken into account when formulating legislation . Furthermore, Directive 98/58/EC says: “no other substance, with the exception of those given for therapeutic or prophylactic purposes, shall be administered to an animal unless it has been demonstrated by scientific studies of animal welfare or established experience that the effect of the substances is not detrimental to the health or welfare of the animal.”
1.6.1 Hormonal growth promoters
For some farmers, the use of growth-promoting hormones might prove tempting. In animal husbandry, such use can increase milk yields and meat production. However, consuming meat or milk containing hormonal residues is thought to involve certain hazards. These include fertility problems and interruption of sexual development. The use of hormonal growth promoters is banned in the EU but it is estimated that 10 per cent of animals in the European bloc are treated illegally with these substances. However, only between 0.2 and 0.3 per cent of sampled animals are found to be non-compliant when tested in laboratories as part of a surveillance programme, according to the EU-wide BioCop project (see chapter on detection and technology).
Specifically, it is prohibited in the EU to use testosterone, 17-beta oestradiol, progesterone, zeranol, trenbolone acetate and melengestrol acetate as growth promoters in food animals. However, oestradiol, testosterone, progesterone and their derivatives may be used for reproduction and therapeutic use only when administered by veterinarians to non-food animals. However, many of the same hormones may be used as growth promoters in food animals in the US . The result was that meat imports from countries in which the use of those hormones for growth promotion was acceptable could not be sold in the EU. These countries included Canada and the US, which imposed trade sanctions on the EU in the form of increased tariffs on certain goods.
In 1998, the WTO found the EU’s ban on hormonal growth promoters in breach of its obligations under the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS) (see chapter on International Food Safety and the Codex Alimentarius). The international organisation concluded that the scientific evidence the EU had based the ban on was too general. The EU consequently conducted more specific studies into the risk, which considered 17-beta oestradiol a carcinogen. New legislation was introduced, restricting the scope of its therapeutic and reproduction uses. As far as the other hormones (testosterone, progesterone, trenbolone acetate, zeranol and melengestrol acetate) were concerned, a provisional prohibition was put into place. The reason given was that the current state of knowledge makes it difficult to quantify the degree of risk hormone-treated food animals pose to consumers.
1.6.2 Beta-agonists
Beta-agonists can be used in growth promotion, a practice, which is banned in the EU. They generally induce cardiac stimulation and systemic vasodilation (Serratosa et al., 2006). They also relax the bronchial smooth muscle, stimulate glycogenolysis in the liver and encourage the release of renin in the kidney. Muscular hypertrophy is induced by administering doses larger than therapeutic ones, which results in a reduction in muscular degradation and fat synthesis. Consequently, the carcass’ proportion of muscle is increased as the ratio of muscle to fat is decreased.
1.6.3 Bovine somatotrophin
Bovine somatotrophin (BST) is a protein hormone, which increases milk yield in dairy cows by 10 to 15 per cent (Serratosa et al., 2006). During lactation, BST has the effect of utilising body fat as energy diverting feed energy away from tissue synthesis and towards milk production. However, studies by the EU concluded that BST should be used, as it was not a treatment for disease. On the contrary, the committee found that it could cause disease, such increasing the risk of clinical mastitis and the incidence of foot and leg disorders, as well as adversely affecting reproduction and inducing severe reactions at injection sites.
BST’s use was consequently banned in the EU. It has also been found that cows treated with BST have much higher levels of insulin-like growth factor 1 (IGF 1) in their milk than untreated animals. As to whether there is a link between IGF 1 and breast and prostrate cancer, the EU recommended further studies.
1.6.4 Penicillins
The most commonly used penicillins in veterinary medicine are benzylpenicillin, amoxicillin and ampicillin (Bishop, 1998; Wright and Wilkowske, 1991). They are generally non-toxic when used to treat animals and humans. However, they may also elicit allergic reactions ranging from skin rashes to anaphylaxis (Idsoe et al., 1968) in humans. At one point, it was estimated that penicillins were behind 75 per cent of deaths from anaphylaxis in the United States (Delage and Irey, 1972).
One patient, who was sensitive to penicillin, suffered anaphylactic shock after eating steak (Schwartz and Sher, 1984). Within 20 minutes of consumption, they developed generalised pruritis, found it hard to swallow and speak and experienced dyspnoea. Testing of the meat revealed that it contained penicillin. Another patient experienced penicillin-induced anaphylaxis after imbibing a soft drink (Wicher and Reisman, 1980), which did indeed contain the substance but whose origin remains shrouded in mystery.
However, the likelihood of adverse reactions to penicillin residues in food is thought to be low, due to factors like the low density of antigenic determinants, dosage and oral intake (Dewdney et al., 1991). Indeed, it has been suggested that, in general, allergy to antimicrobial residues in food is “exceedingly rare” (Dayan, 1993).
When it came to setting an MRL for benzylpenicillin, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) decided that the Acceptable Daily Intake (ADI) should be below 30 µg (JECFA, 1991a). The EU MRLs for the substance follow those of the Codex and apply to all food animals.
Table 1.1: Benzylpenicillin MRLs as set in Codex Alimentarius
| Species | Matrix | MRL (µg/kg) |
| Cattle | Liver | 50 |
| | Muscle | 50 |
| | Kidney | 50 |
| | Milk (/l) | 4 |
| Pig | Muscle | 50 |
| | Kidney | 50 |
| | Liver | 50 |
1.6.5 Cephalosporins
Cefalonium, cefalexin, cefuroxime, ceftiofur, cefquinome, cefoperazone, cefazolin, cefapirin and cefacetrile are examples of cephalosporins used to treat food-producing animls. This group is chemically related to pencillins. In general, cephalosporins can be neurotoxic but only in circumstances where large doses are directly applied to the brain surface in both animals and humans.
This form of administration and dosage is particularly harmful to patients with kidney problems (Fekety, 1990; Norrby, 1987; Schliamser et al., 1991; Thompson and Jacobs, 1993; Weiss et al., 1974). Cephalosporins can also induce skin rashes, contact dermatitis and epidermal necrolysis, like pencillin, but severe reactions such as anaphylaxis are seldom (Woodward, 2004). When establishing ADI for ceftiofur at 0-0.05 mg/kg bodyweight, JECFA used the microbiological end-points (JECFA, 1996a). The EU MRLs for ceftiofur mirror those of the Codex and apply to bovines and pigs.
Table 1.2: Ceftiofur MRLs as set in Codex Alimentarius
| Species | Matrix | MRL (µg/kg) |
| Cattle | Muscle | 1000 |
| | Liver | 2000 |
| | Kidney | 6000 |
| | Fat | 2000 |
| | Milk (/l) | 100 |
| Pig | Muscle | 1000 |
| | Liver | 2000 |
| | Kidney | 6000 |
| | Fat | 2000 |
1.7 Selected macrolide antibiotics
1.7.1 Spiramycin
There is not much data available on the use of spiramycin in humans, but it is clear that it does not result in as severe reactions as pencillins (Woodward, 2004). However, there are some reports that the substance affects the emptying and filling of the stomach and can result in an ulcerated oesophagus (Perreard and Klotz, 1989; Qin et al., 1987). Adverse effects in humans are generally nausea, vomiting and allergic reactions (Galland et al., 1987). Exposure during the course of work is known to have resulted in dermatitis and bronchial asthma (Davis and Pepys, 1975; Moscato et al., 1984: Paggiaro et al., 1979; Veien et al., 1980, 1983).
JECFA established the ADI for spiramycin on the basis of effects on gastrointestinal flora (which were studied in the most sensitive studies). It was set at 0-0.05 mg/kg bodyweight (JECFA, 1991b).
The EU MRLs for spiramycin are broadly in line with those of the Codex. The differences are:
• Bovines (liver) – 300 µg/kg;
• Pigs (muscle) – 250 µg/kg;
• Pigs (liver) – 2000 µg/kg;
• Pigs (kidney) – 1000 µg/kg; and
• Chicken (liver) – 400 µg/kg.
Table 1.3: Spiramycin MRLs as set in Codex Alimentarius
| Species | Matrix | MRL (µg/kg) |
| Cattle | Liver | 600 |
| | Muscle | 200 |
| | Kidney | 300 |
| | Fat | 300 |
| | Milk (/l) | 200 |
| Pig | Muscle | 200 |
| | Liver | 600 |
| | Fat | 300 |
| | Kidney | 300 |
| Chicken | Muscle | 200 |
| | Kidney | 800 |
| | Liver | 600 |
| | Fat | 300 |
1.7.2 Tilmicosin
This substance appears to be more toxic than spiramycin when administered orally to mammalian species. However, toxicity was only this high when the substance was given to fasted animals. Reports of adverse reactions due to occupational exposure are few and far between but there have been cases of workers who accidently injected themselves with tilmicosin. Many resulted in minor local effects (McGuigan, 1994), but more significant adverse reactions involving the heart were reported in those who had been injected with higher doses. Chest pains, electrocardiographic abnormalities and intraventricular conduction delays were among them (Crown and Smith, 1999; von Essen et al., 2003). Deaths resulting from accidental intravenous injections have also occurred (Kuffner and Dart, 1996; von Essen et al., 2003).
The Codex is silent on MRLs for tilmicosin in poultry, unlike the EU. The following is applicable:
• Muscle – 75 µg/kg;
• Fat – 75 µg/kg;
• Liver - 1000 µg/kg; and
• Kidney – 250 µg/kg.
The EU also has set tilmicosin MRLs for all other food animals. These are:
• 50 µg/kg generally;
• Liver and kidney – 1000 µg/kg; and
• Milk – 50 µg/kg.
Table 1.4: Tilmicosin MRLs as set in Codex Alimentarius
| Species | Matrix | MRL (µg/kg) |
| Cattle | Liver | 1000 |
| | Muscle | 100 |
| | Kidney | 300 |
| | Fat | 100 |
| Pig | Liver | 1500 |
| | Muscle | 100 |
| | Kidney | 1000 |
| | Fat | 100 |
| Sheep | Muscle | 100 |
| | Liver | 1000 |
| | Kidney | 300 |
| | Fat | 100 |
| | Milk (/l) | 50 |
1.8 Aminoglycosides
Neomycin, streptomycin, gentamicin and dihydrostreptomycin, kanamycin and aminosidine are examples of aminoglycosides that are used in veterinary medicine. The most severe adverse effects caused by this group of chemicals are ototoxicity and nephrotoxicity in both animals and humans.
Table 1.5: Neomycin MRLs as set in Codex Alimentarius
| Species | Matrix | MRL (µg/kg) |
| Cattle | Muscle | 500 |
| | Liver | 500 |
| | Kidney | 10000 |
| | Fat | 500 |
| | Milk (/l) | 1500 |
| Pig/Sheep/Goat/Chicken | Muscle | 500 |
| | Liver | 500 |
| | Fat | 500 |
| | Kidney | 10000 |
1.8.1 Adverse effects
Between 10 and 25 per cent of patients taking aminoglycosides for more than a few days will develop mild renal impairment. Longer exposure or high doses will result in cellular necrosis of the proximal tubules (Chambers and Sande, 1996; Fillastre et al., 1989) but effects are usually reversible. Contact dermatitis can also occur after treatment with neomycin (Goh, 1989). Hearing loss has also been reported in humans and ototoxicity has affected children whose mothers took streptomycin and dihydrostreptomycin while pregnant (Davis, 1991; Erlanson and Lundgren, 1964; Matz, 1993, Robinson and Cambon, 1964).
Table 1.6: Gentamicin MRLs as set in Codex Alimentarius
| Species | Matrix | MRL (µg/kg) |
| Cattle | Muscle | 100 |
| | Liver | 2000 |
| | Kidney | 5000 |
| | Fat | 100 |
| | Milk (/l) | 200 |
| Pig | Muscle | 100 |
| | Liver | 2000 |
| | Kidney | 5000 |
| | Fat | 100 |
JECFA established the ADIs for gentamicin and neomycin on the bases of toxicology, microbiology and ototoxicity (JECFA 1995a). This was 0-0.02 mg/kg bodyweight for gentamicin and 0-0.06 mg/kg bodyweight for neomycin.
The EU MRLs for streptomycin are generally lower for all species than the Codex ones. For bovines and ovines, the limits are 500 μg/kg for muscle, fat and liver, 1000 μg/kg for the kidney and 200 μg/kg for milk. These limits (apart from milk, of course) also apply to pigs. The EU has not set an MRL for gentamicin.
Table 1.7: Dihydrostreptomycin/Streptomycin MRLs as set in Codex Alimentarius
| Species | Matrix | MRL (µg/kg) |
| Cattle | Muscle | 600 |
| | Liver | 600 |
| | Kidney | 1000 |
| | Fat | 600 |
| | Milk (/l) | 200 |
| Pig | Kidney | 1000 |
| | Liver | 600 |
| | Muscle | 600 |
| | Fat | 600 |
| Sheep | Muscle | 600 |
| | Liver | 600 |
| | Kidney | 1000 |
| | Fat | 600 |
| | Milk (/l) | 200 |
| Chicken | Muscle | 600 |
| | Liver | 600 |
| | Kidney |