A drug that isn’t approved for use in the food animal species treated has a tolerance of zero. And that zero is getting smaller as new detection technology is developed.
The FDA’s Center for Veterinary Medicine (CVM) sets slaughter withdrawal times for approved food animal drugs. Let’s discuss the work that goes into ensuring their safety. In short, this is the sequence: no observable effect level (NOEL), acceptable daily intake (ADI), safe concentration, tolerance and withdrawal time.
The first step in determining a drug’s withdrawal time is to determine its NOEL, which is the dose of the drug that results in no toxic effects in test animals. A safety factor is then applied, which may decrease the NOEL by up to a thousandfold.
For example, if tests indicate that 1 milligram (mg; 1,000 mg = 1 gram) of the drug per kilogram (kg, or 2.2 lbs.) of body weight is the NOEL, a thousandfold safety factor would drop that dose to 1 microgram (mcg)/kg (1 gram = 1 million mcg).
The NOEL is then multiplied by the average body weight of a human (60 kg for this purpose), resulting in the total ADI. ADI is the total dose of the drug that an average human could ingest on a daily basis for his or her entire life with no adverse effects. In our example, the ADI would be 60 mcg/day (1 x 60).
The ADI is then used to determine how much of the drug can be in each of the edible tissues, or the safe concentration. For this purpose, CVM considers that people will eat only one of the following edible tissues (and related quantity) as their main meal for the day — muscle (300g), liver (100g), kidney (50g) or fat (50g). In our example, safe concentration for muscle would be 0.2 mcg of drug per gram of tissue (60/300).
The safe concentration is for all residues of the drug, which may include multiple chemical metabolites due to the breakdown of the drug in the animal. The U.S. only tests the carcass for one of these compounds, known as the marker residue. The percentage of the safe concentration represented by the marker residue becomes the tolerance for the marker residue. For example, if the marker residue is the original drug molecule, and it constitutes 50% of the total residues, the tolerance in our example now becomes 0.1 mcg/gm for muscle (0.2 X 50%).
That was a lot of math and several million dollars’ worth of studies to get us to this point. The final step is a study where animals receive the drug and are then sacrificed at different time points to determine when the marker residue drops below the tolerance in the target tissue (the edible organ that maintains drug residues the longest, usually the kidney or liver).
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When the target tissue is below the tolerance, so are all the other tissues. Statistical methods are used to estimate the withdrawal time, so that only one in 1,000 animals would potentially have a marker residue concentration in the target tissue which would be above the tolerance.
This withdrawal timeonly applies when the drug is used according to label instructions. Changing the dose, route, volume per injection site or duration of treatment can drastically change the required withdrawal time of a drug.
If an animal is subjected to testing for residues and an amount is found in the target tissue which is above the tolerance (classified as a violative residue), the carcass will be condemned, and you will get to explain the occurrence to an FDA investigator. Violations may result in you being unable to sell animals until you have fixed the problem.
Any extralabel use requires a veterinarian to establish a new, prolonged withdrawal time. And, here’s the kicker — a drug that isn’t approved for use in the food animal species treated has a tolerance of zero. And that zero is growing increasingly smaller as more sensitive detection technology is developed.
Mike Apley, DVM, PhD, is a professor in clinical sciences at Kansas State University in Manhattan.
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