Hazard Identification

What are antibiotics?

The term 'antibiotics' is now used to describe a broad and diverse range of chemical compounds that destroy, or limit, the growth of microorganisms. Antibiotics may have activity against bacteria, fungi, or protozoa, though not viruses, and are used widely as veterinary drugs in food animals by the farming industry. There are many classes of compound with antibiotic properties, but some of the major groups in use are the ß-lactams (including the penicillins), macrolides, ionophores, quinolones, lincosamides and tetracyclines.

Antibiotics may be administered to food animals for two reasons. They may be used, at relatively high doses, as therapeutic agents to treat clinical infections, or they may be administered at low, sub-therapeutic doses as 'growth promoters'. The use of antibiotic growth promoters in intensive livestock farming has been shown to be an effective means of increasing the growth rate of food animals and improving the quality of meat by raising the protein content. It is not entirely clear how this effect is achieved, but it seems likely that antibiotic growth promoters in animal feed suppress some of the bacteria in the gut and allow more of the energy in the feed to be diverted to the growth of the animal. A further benefit of antibiotic growth promoters is said to be improved control of disease caused by bacterial pathogens, including Salmonella and Campylobacter, in intensively reared livestock.

The use of antibiotics in food animals has both direct and indirect implications for food safety. Some antibiotics and their metabolites may be toxic to humans, or may cause serious reactions in sensitive individuals (e.g. penicillins). Therefore antibiotic and antibiotic metabolite residues in meat, milk and other animal products may be a direct risk to human health. However, many experts currently consider that the development of antibiotic resistance in pathogenic bacteria that can cause disease in animals and humans (zoonoses) is a much more serious potential threat to human health, and the use of antibiotic growth promoters is widely thought to have contributed to reported increases in the prevalence of antibiotic resistance. The farming industry is a significant consumer of antibiotics, and it has been estimated that as much as 60--80% of antibiotics produced in the United States are administered in feed to healthy livestock at non-therapeutic levels. Many of these antibiotics are closely related to compounds that are administered to humans in clinical settings, and include tetracyclines, macrolides, streptogramins, and fluoroquinolones.

Occurrence in foods

Antibiotic residues are most likely to be found in foods of animal origin, such as meat, poultry, fish, eggs and honey. They are usually present as a result of the use of therapeutic veterinary drugs to control infection and disease in food animals. Antibiotics are frequently used to treat mastitis in cows, and therefore antibiotic residues may be present in milk. Antibiotic residues in milk can pose significant problems to the dairy industry, as many of the antibiotics used may inhibit the starter cultures used in cheese and yoghurt production.

The use of antibiotic growth promoters in animals is unlikely to give rise to detectable residues in meat and other animal products unless they have been administered at levels much higher than are permitted.

The use of veterinary drugs for therapeutic use is highly regulated within the EU and in the US, and only certain drugs that have met stringent safety requirements are permitted (see Control Options). However, residues of antibiotics not authorised for food use may sometimes be found in certain foods. An example of this is the occasional detection of chloramphenicol residues in honey imported from China. Chloramphenicol is suspected of involvement in a form of anaemia in humans and is banned from food animal use worldwide. Nitrofurans are also banned from food use in most of the world, but have been regularly detected in poultry and farmed crustaceans imported from East Asia and South America.

It is difficult to estimate current dietary intake of antibiotic residues from animal-derived products, but it is likely to be very low.

Hazard Characterisation

Effects on health

The control of veterinary medicines in the EU and the USA is sufficiently strict that potentially toxic antibiotic residues are now very unlikely to be found in commercially produced animal products. Furthermore, most of the permitted antibiotics used are not considered to present a risk to human health at the levels likely to be found in meat, fish, milk, or eggs. However, there are still some concerns over the possible presence of penicillin and its derivatives. A number of individuals are sensitive to penicillins, and exhibit an immunopathogenic response that can be life threatening. This makes it essential that MRLs for this class of drugs are strictly adhered to. In addition, some hypersensitive individuals may develop a reaction to low-levels of tetracyclines, also used in veterinary medicine.

Of much more concern is the possible role of antibiotic growth promoters in the development of antibiotic resistance in zoonotic bacterial pathogens. There is now considerable evidence that the use of medically important antibiotics as growth promoters in food animals may have contributed significantly to a reported rise in antibiotic resistance in several pathogenic bacterial species that cause zoonotic infections, notably Salmonella enterica serotypes, Campylobacter jejuni, Escherichia coli and enterococci. For example, Salmonella Typhimurium definitive phage type (DT) 104 is a strain first isolated in the UK in 1988. At that time it already showed resistance to ampicillin, tetracycline and other antibiotics, but since 1988 it has spread all over the world and is often isolated from food animals. Many isolates are now resistant to other antibiotics, including fluoroquinolones, some of which have been used as growth promoters. Human infections caused by these bacteria now have very limited treatment options. The prevalence of fluoroquinolone-resistant Campylobacter in poultry is also increasing, especially in countries that permit the use of these antibiotics as growth promoters. The incidence of human infections caused by these pathogens is reported to be rising, especially in the USA.

The increasing prevalence of antibiotic resistance in zoonotic pathogens is now a global problem and many experts believe that the practice of using antibiotic growth promoters in food animals must be banned worldwide as it is in the EU. There are fears that, unless action is taken, antibiotics will soon no longer be effective as a treatment for many bacterial infections in animals and humans.

Sources

It is now thought that all antibiotic residues found in food are present as the result of being administered to animals for therapeutic reasons, or as growth promoters. There is little or no evidence to support suggestions that some antibiotics, such as chloramphenicol, can be produced naturally by microbial action in the soil.

Stability in foods

Many studies have been carried out investigating the effects of processing on the stability of antibiotic residues in food, with very variable results reflecting the wide range of chemical compounds concerned. For example, the penicillins and tetracyclines are known to be heat-sensitive and may degrade during cooking or canning processes, although the degree of degradation is variable and depends often on the nature of the food containing the residues. In addition, the implications of this to food safety are uncertain, since the nature of the degradation products is unknown in most cases. It is possible that some degradation products may be more toxic than the antibiotic from which they are derived.

Control Options

Control of antibiotic residues in food is focused on the strict regulation of the veterinary medicines administered to food animals.

Primary production

To safeguard human health, maximum residue limits (MRLs) at the time of slaughter can be determined for veterinary medicines in order to set permissible limits for antibiotic residues in foods. The limits depend on the toxicity of the drug in question. Establishing an MRL also requires the setting of a minimum withdrawal period. This is the time that passes between the last dose administered to the animal and the time when the level of residues in the tissues, milk or eggs are lower than, or equal to, the MRL. Neither the animal not its products can be used for human consumption until the withdrawal period has elapsed. The withdrawal period is set out in the data sheet for the medicine and on the product packaging instructions. In the EU, only those drugs with established MRLs are permitted for use in food animals. MRLs are set with very large safety margins. For example, the calculation of the MRL value is based on the acceptable daily intake (ADI) for the drug in question. The calculation of the ADI includes an extremely large safety factor, and the MRL calculation assumes an average daily intake of 500g of meat, 1.5 litres of milk, 2 eggs and 20 g of honey.

A full list of all permitted medicines and their established MRLs can be accessed on the European Medicines Agency web site at: http://www.emea.europa.eu/htms/vet/mrls/mrlop.htm

The use of sub-therapeutic doses of antibiotics as growth promoters was banned in the EU from 1 January 2006 (Regulation (EC) No.1831/2003). It is still permissible to add coccidiostats and histomonostats (used to control protozoa), but their use as feed additives will be banned in the EU by 2009. The addition of sub-therapeutic levels of antibiotics to animal feeds is currently still permitted in the United States and in other important meat producing countries.

The effectiveness of all these controls is closely monitored in the EU by the use of extensive surveillance programmes.

Alternatives to antibiotic growth promoters

A number of alternatives to the use of antibiotics as growth promoters in food animals have been suggested. These include the addition of digestive enzymes to animal feed to help break down certain feed components, the addition of probiotic microbes to animal feed, and the introduction of more effective infection controls, such as improved biosecurity measures.

In Sweden, where the use of antibiotic growth promoters was banned as long ago as 1985, it has been demonstrated that antibiotics are not necessary to produce healthy food animals in modern farming systems if accommodation, husbandry practices and feed quality are of a sufficiently high standard. However, Swedish production costs are still higher than those of other countries.

Legislation

EU

Information on legislation regarding MRLs for antibiotic residues and residues of other medicinally acceptable veterinary drugs for food-producing animals can be found on the European Medicines Agency web site at: http://emea.europa.eu/htms/vet/mrls/mrlfaq.htm

Specific legislation that relates to the establishment of MRLs in the European Union is laid out in the following Regulations and amendments:

• Council Regulation (EEC) No 2377/90 of 26 June 1990 laying down a Community procedure for the establishment of maximum residue limits of veterinary medicinal products in foodstuffs of animal origin.

The Regulation has subsequently been amended by:

• Commission Regulation (EEC) No 762/92

• Council Regulation (EC) 434/97

• Council Regulation (EC) No 1308/1999

US Legislation

Maximum tolerance levels for residues of animal drugs in food have also been laid down by the United States Food and Drug Administration. These levels can be accessed on the Internet at the following link:

http://www.access.gpo.gov/nara/cfr/waisidx_02/21cfr556_02.html

Sources of Further Information

Published

Moats W.A.
The effects of processing on veterinary residues in foods.
Advances in Experimental Medicine and Biology, 1999, 459, 233-241

Long A.R., Barker S.A.
Antibiotics in foods of animal origin.
Encyclopaedia of Food Science and Technology, (1991), Vol. 1 (Y.H. Hui, ed.) Wiley Intersciences, John Wiley and Sons, p.59

On the web

The UK Veterinary Medicines Directorate
http://www.vmd.gov.uk/

The European Medicines Agency
http://emea.europa.eu/

FDA Center for Veterinary Medicine
http://www.fda.gov/cvm/antimicrobial.html

Antibiotic growth promoters in food animals
http://www.fao.org/docrep/article/agrippa/555_en.htm