Food animal production in Canada depends on drugs and other chemicals to protect the health and welfare of animals. Food animals may  also be exposed to environmental contaminants or possibly become the object of bioterrorism. To protect Canadian public health, the Canadian Food Inspection Agency (CFIA) screens for chemical and drug residues in foods of animal origin. But not all products are tested and detection programs are not available for all drugs and chemicals used in livestock production. To proactively reduce residues risks, veterinarians must provide producers with science-based withdrawal interval recommendations for extralabel drug use or chemical exposures.  Practitioners may lack information with which to make such recommendations. With financial support from the Agriculture and Agri-Food Canada’s Canadian Adaptation and Rural Development Fund (CARD Fund), veterinary medical and livestock producer groups, Canada joined a global food animal residue avoidance databank program known as gFARAD in the fall of 2002. Based at the Western College of Veterinary Medicine in Saskatoon, SK and the Faculté de médecine vétérinaire at St Hyacinthe, QC, the Canadian gFARAD provides information on residue avoidance to veterinarians.
 

Historical Background

The FARAD concept was established in 1982 as a cooperative project between four US veterinary colleges and the US Department of Agriculture’s Food Safety and Inspection Service as a way to reduce the rate of residue violations in animal products through education and information.¹ The founding philosophy of FARAD was that information about residue avoidance from all sources should be immediately available from a scientific source. The FARAD was developed to not only contain information related to approved animal drugs but to also include information on extralabel drug use and environmental toxins. For this "one-stop shopping" information service to work, the FARAD information was collated into a searchable computer database, with residue and pharmacokinetic data analyzed and interpreted by veterinary pharmacologists and toxicologists. Currently, the FARAD database includes over 1200 drugs and chemicals and over 20,000 pharmacokinetic records extracted from over 9000 citations. For 20 years, the US FARAD centers have been providing accurate and timely information to veterinarians to protect the US food supply.² 

The Global FARAD

For many years, the US FARAD centers provided limited consultation on residue avoidance to Canadian veterinarians. But with the disappearance of trade barriers, it was apparent that an international clearinghouse of residue information was needed. In 1998, 11 countries, including Canada, embraced the concept of  global FARAD centers with multinational cooperative sharing of data on food animal drugs and residue avoidance.² Member countries receive web-based access to the FARAD database along with customized software and technical training from the original US centers. In return, gFARAD members share all relevant drug and chemical information and tolerance data from their countries. This global partnership provides a web-accessible compendium of drug information and tolerance data, to which only member countries have access. This pooling of data greatly augments efforts to ensure that withdrawal recommendations and interspecies extrapolations are based on the best scientific information available. The gFARAD system also aids in harmonization of acceptable international standards of veterinary drug use. 
 

The Canadian gFARAD

With the development of the gFARAD system, the US FARAD centers discontinued consultations with Canadian veterinarians and limited residue avoidance information was provided by veterinary pharmacologists and toxicologists at Canadian veterinary colleges. In order to bring Canada into the gFARAD cooperative, Dr Tim Blackwell of the Ontario Ministry for Agriculture, Food and Rural Affairs and Dr Patricia Dowling of the Western College of Veterinary Medicine petitioned the federal CARD’s program for start up funding for a Canadian program. Dr Michèle Doucet of the Faculté de Médecine Vétérinaire joined in February 2000. In July of 2001, the Agriculture and Agri-Food Minister announced the funding of the Canadian gFARAD program. Canada now joins the United States, Great Britain, France, and Spain as a full gFARAD member country.

The Canadian gFARAD is composed of two regional centers: the Western College of Veterinary Medicine in the west and the Faculté de Médecine Vétérinaire in the east. The western gFARAD center is directed by Patricia Dowling, DVM, MS, a professor of clinical pharmacology and a diplomate of both the American College of Veterinary Internal Medicine and the American College of Veterinary Clinical Pharmacology. The western center is also supported by Chris Clark, VetMB, MVetSc, Barry Blakely, DVM, PhD and Mark Wickstrom, DVM, PhD of the Toxicology Centre. The eastern gFARAD center is directed by Michele Doucet, DMV, DVSc, associate professor of pharmacology and a diplomate of both the American College of Veterinary Internal Medicine and the American College of Veterinary Clinical Pharmacology. Sylvie Fortier, DMV, MSc is the CgFARAD administrator, who maintains the database, researches residue information and ensures the adequate follow-up of all inquiries. Graduate veterinary students also participate in the centers’ activities. 
 

Canadian gFARAD Services

The CgFARAD became operational on October 1, 2002. The centers provide expert-mediated decision support for any inquiry related to drug or chemical residues in food animals. Canadian gFARAD personnel also assist veterinarians or government agencies with inquiries related to animal exposures to environmental contamination. Extralabel drug withdrawal information is only provided to veterinarians authorized to practice in Canada because of their privilege and responsibility in using or prescribing drugs in an extralabel manner. The purpose of the CgFARAD is not to promote extralabel drug use, but to protect the food supply when it is necessary for veterinarians to use drugs in an extralabel manner. Accurate information regarding the health of the affected animals is critical in determining residue depletion. Because of the impact of physiology and disease on drug disposition, all CgFARAD personnel are veterinarians and neither the Canadian nor the US gFARAD publishes lists of extralabel drug withdrawal times. Because the CgFARAD withdrawal recommendation is not an official withdrawal time and is based on data that has not been reviewed nor approved by the Veterinary Drugs Directorate, responsibility for residue violations rests with the prescribing veterinarian. In the unfortunate event where a residue results from extralabel drug use, it is still advantageous for a veterinarian to have recommended a withdrawal interval that is based on the best scientific evidence available.

Requests to the CgFARAD can be submitted via the CgFARAD website (www.cgfarad.usask.ca). Practitioners are asked for their contact information and provincial license number. After the first inquiry, the database remembers the contact information, but it can be changed and the database keeps a historical record. A CgFARAD inquiry is considered a medical record and all personal information is kept confidential. If the inquiry is related to a licensed veterinary drug, the veterinarian can select the generic and corresponding trade name of the drug from a drop-down menu of entries from the Canadian Veterinary Compendium. For each specific drug, the veterinarian is directed to provide information regarding species, number of animals treated, dosage, route of administration, and disease. There is a box for additional information relevant to the situation. Requests are submitted directly to a secure SQL server at the University of Saskatchewan and stored in a temporary file. CgFARAD personnel review submissions for legitimacy and then transfer requests into the database. For requests involving chemicals or environmental contaminants or if the person making the request is not a veterinarian, the CgFARAD can be contacted by phone (1-866-CGFARAD) or email (cgfarad@umontreal.ca).

When a new request is submitted to the CgFARAD, Dr Sylvie Fortier conducts a systematic review of our database, other gFARAD databases and the available scientific literature for background information on the drug or chemical. The database is searchable by drug or chemical name, case number, province, veterinarian and species, so center personnel can easily review past inquires and update with new information. Dr Fortier then sends a report to Dr Dowling, Dr Clark or Dr Doucet for final analysis. The information is reviewed along with the Maximum Residue Limits (MRLs) in Canada,³ the acceptable daily intake and tolerance limits in other countries and the limits of detection of the CFIA. If depletion data are available, CgFARAD personnel conduct a pharmacokinetic analysis to determine the time at which the meat, milk, honey or egg concentration is expected to be undetectable.⁴ Additional time may be added to account for variables such as disease, which affect how individual animals eliminate the drug or chemical. In some situations, there simply is not enough data upon which to base a recommendation. In such cases, either the product should not be used in food animals or testing should be carried out to insure that products do not have detectable residues. The CgFARAD also provides information on rapid milk screening tests and laboratories available to carry out such testing.

When to call the CgFARAD

Most calls to the CgFARAD are for withdrawal recommendations for extralabel drug use. Veterinarians who intend to use a drug in an extralabel manner should contact the CgFARAD first to obtain advice on a safe withdrawal interval. If data is available, center personnel will provide science-based withdrawal recommendations or advise the practitioner that such information is not available and discourage the drug use. The practitioner will also be advised if the extralabel drug use is permitted in Canada but banned in other countries, such as the extralabel use of fluoroquinolones in the United States.⁵ CgFARAD personnel also assist in determining safe withdrawal times when animals are accidentally exposed to pesticides, heavy metals or other chemicals.

Canadian gFARAD: The First Year

Because of the obvious similarities between the two countries, we anticipated the Canadian gFARAD caseload to resemble the US caseload. However, just prior to our startup, the CFIA and the poultry industry developed a policy aimed at preventing drug residues from extralabel drug usage in poultry products. According to the policy, if extralabel drugs are used in a flock then such use must be declared in writing on a “flock sheet”. The flock sheet is to be sent ahead of the birds to the slaughter facility along with the veterinarian’s prescription for the extralabel drug use and a reference from the CgFARAD with a withdrawal recommendation. If there is no CgFARAD withdrawal recommendation, then the birds are subject to “hold and test” for the administered drug(s) at the producer’s expense. Therefore, as soon as the CgFARAD became operational, personnel were deluged with requests from poultry practitioners and it became apparent that the CgFARAD caseload would differ significantly from the US. Under the rules of the Animal Medicinal Drug Use Clarification Act in the United States, extralabel drug use is not permitted in feed.² In Canada, such use is permitted and the pharmaceutical companies have not had an incentive to seek label approvals for a number of drug and drug combinations routinely used in poultry production. So the CgFARAD personnel had to find residue depletion information for these drugs and drug combinations without assistance from the US center. It also was apparent that the relational database received from the US was not adequate for our needs, so information technology services at the University of Saskatchewan were contracted to make a database accessible from both CgFARAD centers that would allow practitioners to submit requests via the web. The new database became operational in October 2003 and has greatly increased efficiency and consistency in withdrawal recommendations.

The US gFARAD recently published a review of their caseload from 2000 to 2002.⁶ They received 1,145 inquires during that time period. In contrast, from October 1, 2002 until December 31, 2003, the CgFARAD received 970 inquiries for 1084 drugs (some requests involved more than one drug). The Canadian caseload by species is very different from the US caseload (Figure 1). In the US, the majority of inquiries relate to dairy cattle, followed by swine, and beef cattle.⁶ The CgFARAD caseload is lead by poultry as a group, followed by swine, dairy cattle and beef cattle. In the US, the majority of inquires were from the states with high dairy production (California, Ohio, Alabama, Wisconsin and Texas), while the CgFARAD inquires were predominantly from the poultry producing provinces of Ontario, Quebec and British Columbia (Figure 2). As a group, withdrawal recommendations were requested most frequently for antimicrobials in both countries. However, the single most frequently used drug used extralabel in Canada was the anthelmintic fenbendazole with 161 requests (Figure 3). In the US, the most frequent antimicrobials requests were for aminoglycosides, penicillins and tetracyclines.⁶ After fenbendazole, in Canada the most frequent requests were for bacitracin, ormetoprim/sulfadimethoxine, virginamycin and penicillin. After antimicrobials, in both countries common inquiries were for information on anti-inflammatory and analgesic drugs, anthelmintics and endectocides.⁶

The CFIA policy on extralabel drug use in poultry and the ability of Canadian veterinarians to prescribe extralabel drugs in feed and water are responsible for the request volume and predominantly avian caseload of the CgFARAD. The searchability of the database allows analysis of extralabel drug use that had not previously been possible. The widespread extralabel use of fenbendazole in poultry was unknown to the manufacturer and scientists at the CFIA’s Centre for Veterinary Drug Residues (CVDR). Fenbendazole is approved for use in the US for turkeys at a dose of 15 ppm in feed. It is not approved for any species of poultry in Canada, but requests have been received for turkeys, broilers, broiler breeders, layers and eggs with a wide variation in dosages prescribed, from 15 ppm to 110 ppm. When questioned about the dosages and withdrawal intervals previously followed by poultry veterinarians, a practitioner supplied the CgFARAD with a much-copied sheet of paper listing extralabel drug dosages and withdrawal times for meat and eggs for chickens, turkeys and ratites. This document contained no identifying information as to its source and CgFARAD has not been able to substantiate either the suggested dosages or withdrawal times from any of its global resources. The widespread acceptance of unreferenced material is concerning, and it highlights the benefits of a national database of withdrawal information. Every record in the CgFARAD database contains the information used to make the withdrawal recommendation and the identity of the person who answered the inquiry. As the database is relational, it is simple to review and update recommendations. The frequent use of fenbendazole clearly indicates the need for an approved product and appropriate dosage regimens in poultry and a surveillance program for residues. In this way, the CgFARAD serves as an independent, academic intermediary between the commodity groups and the federal agencies for veterinary drug use information.

Interesting Cases from the CgFARAD Files

Dipyrone in Swine and Cattle

The CgFARAD received inquiries regarding dipyrone administered intramuscularly as an anti-inflammatory drug in swine and cattle. It is banned for use in food animals in the US and any animal treated with dipyrone can never enter the US food chain.^5,7 Dipyrone has historically been used in humans and animals as an antipyretic, anti-inflammatory, and analgesic. However, its use is associated with serious toxic effects in humans, including dose-independent teratogenicity, reduced clotting times and a potentially fatal agranulocytosis.⁵ Because of these concerns, the US Food and Drug Administration (FDA) removed approval for all dipyrone-containing human medical products in 1977. Dipyrone products labeled for  horses and small animals continued to be sold in the US, even though they had never been formally approved by the FDA. Extralabel drug use surveys indicated that dipyrone was being used in food animals. This use, along with the lack, animal safety, residue, and efficacy data and the lack of an assay method for residues caused the FDA to ban the sale of all dipyrone products in 1995 in the US.⁷ However, it continues to be sold labeled for use in horses and dogs in Canada. Any use of dipyrone in food animals in the US receives the same regulatory priority as chloramphenicol and clenbuterol.⁵ The analytical chemists from the CVDR recently developed an accurate detection method with an extremely low detection limit.⁸ In the part of the project involving residues, it was apparent that intramscular injection of dipyrone is highly irritating to muscle tissues and its use is not consistent with beef and pork quality assurance guidelines (Figure 4). Since a depletion study was not performed, there is still no information on which to base a withdrawal recommendation for food animals in Canada. The CgFARAD has played a vital role in bringing these issues to the attention of bovine and swine practitioners and decreasing this unacceptable extralabel drug use.

Swine and Cattle exposed to Chemical and Environmental Contaminants

The Canadian gFARAD was contacted in two cases where cattle and feeder pigs were accidentally fed seed grain treated withTerbufos, an organophosphate pesticide. In both cases the intoxication was identified following the acute deaths of a number of animals in the herd. The question was when (if ever) would the surviving animals be fit for human consumption. As terbufos is a licensed pesticide, it has been extensively tested and its toxicity and disposition are well defined. The US gFARAD shared with us a Joint Expert Committee on Food Additives (JEFCA) report on terbufos in food animals. While terbufos is highly toxic, it is also rapidly metabolized and eliminated. In sublethal doses, residues are undetectable 24 hours after exposure. So the CgFARAD was able to assure the parties involved in these cases that the surviving cattle and swine were fit for human consumption at their regular marketing times.

In another case, the CgFARAD was consulted on a group of cows and calves exposed to a natural gas desiccant product in water due to containment system overflow from heavy rains. The product contained a number of compounds that are known carcinogens, initiators of aplastic anemia and which can cause blindness. We consulted with Jim E. Riviere, D.V.M., Ph.D., who is a director of the US gFARAD as well as the director of Center for Chemical Toxicology Research and Pharmacokinetics at North Carolina State University and concluded that the exposed animals should never be used for human consumption.

Dexamethasone and Flumethasone in Swine and Cattle

The CgFARAD has received inquires regarding dexamethasone in swine and cattle. Dexamethasone products in Canada and the US were approved for use in food animals many years ago without withdrawal recommendations on their labels. Lack of a label withdrawal time is often interpreted by practitioners as a “zero” withdrawal. However, there is no legal MRL for dexamethasone in meat or milk in Canada.³ The European Union considers dexamethasone residues a high priority in food animals as they are synergistic with illegal growth promoters such as beta-agonists or anabolic steroids.^9-11 Product withdrawal times in Europe range from 14 days to 2 months. In a recent analytical methodology study, dexamethasone concentrations in calf liver were as high as 15 times the European MRL 72 hours after injection.⁹ As this was not a depletion study, the CgFARD does not have depletion data with which to predict a suitable meat withdrawal interval. If administration is declared, the CFIA is now subjecting treated animals to “hold and test” at the producer’s expense. For milk, the US and Canadian gFARAD’s have found data to support a 48 hr withdrawal interval when dosed at 0.06 mg/kg IM.¹²

A similar situation exists for flumethasone in dairy cattle. Flumethasone is not labeled for use in food animals in the US, while the Canadian label states that it is indicated for the treatment of ketosis and milk fever in cattle, it does not specifically indicate lactating dairy cattle. While there is a 4 day meat withdrawal time on the flumethasone label, there is no recommendation for a milk withdrawal time, and there are no Canadian MRLs for meat or milk.³ When flumethasone is dosed to dairy cattle at 0.014 mg/kg, the US and Canadian gFARAD’s have found data to support a 48 hr milk withdrawal interval.¹²

Conclusions

Consumers are increasingly demanding a safe food supply and food animal veterinarians have an important role in this process. To avoid politically-mandated, top-driven regulation of food animal production, veterinarians must work with producers in on-farm food safety programs using the best available information. The number of inquiries received by the US and Canadian gFARAD centers indicates the need for expert-mediated advice on residue avoidance issues. The CgFARAD database is now easily accessible to Canadian veterinarians and the data can be used to identify trends in drug usage and the pharmaceutical needs of the commodity groups.  The centralized database provides an accurate historical record and national consistency on withdrawal recommendations. International cooperation facilitates the gFARAD model in other countries for the global enhancement of food safety and animal welfare.

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