The United States Department of Agriculture’s (USDA’s) Food Safety and Inspection Service (FSIS) recently validated its testing methodology to enable identification of penicillin G procaine in edible tissues at processing. This has resulted in an increase in penicillin-residue violations in cull sows. These violations raised the concern of pork producers and veterinarians because many of the violations occurred even though the producer was following the prescribed withdrawal period. The AASV, in collaboration with the National Pork Board (NPB) and the National Pork Producers Council (NPPC), has been working diligently with FSIS and the Food and Drug Administration (FDA) to try to understand what is causing this increase in penicillin violations. Here is what we have learned.
Penicillin G procaine remains an effective treatment in cull sows. It is relatively inexpensive and can be purchased over the counter. It is most often administered intramuscularly at a dose of 33,000 IU per kg for 3 consecutive days. Given that this dosage is extra label, this administration requires a veterinary prescription and an extended withdrawal period. The Food Animal Residue Avoidance Databank (FARAD) recommends at least a 15-day withdrawal to allow the drug to clear the tissues prior to processing. Most of the recent violations we have investigated involved producers who were following the recommended withdrawal times. So why the sudden increase in violations?
The first challenge with penicillin G is that in swine, chickens, eggs, milk, sheep, quail, and pheasants, the FDA established a zero tolerance for penicillin residues in edible tissues. In beef and turkey, the threshold is 50 ppb and 10 ppb, respectively. This means that any detectable level of penicillin G in the edible tissues of swine is a violation. The FSIS samples tissues at processing for evidence of violative residues using a rapid screening test followed by confirmatory testing. This testing strategy involves sampling both muscle tissue and kidney. Both are classified as edible tissues by FSIS and thus eligible for testing.
The FSIS records these violations, and any producer having two violations within a 12-month period is listed on the FSIS Repeat Violator List, reported to the processing facility and to the FDA. It is then the responsibility of the processor to notify the producer, and FDA will likely conduct an on-farm investigation.
So why the zero tolerance in swine? Normally, FDA establishes a drug threshold level in conjunction with a specific testing methodology and based on human safety studies at a given Acceptable Daily Intake (ADI) of the drug. Unlike most veterinary drugs, when a safe intake level for penicillin is considered, allergic reactions have to be taken into account. Studies have shown that severe allergic reactions have occurred following consumption of foods containing very low levels of penicillin. Therefore, FDA considers the allergenicity concerns to be the most sensitive end point for determination of a safe ADI. Given that allergenicity is not normally a concern for most veterinary drugs, general principles and experimental protocols applicable to the allergenic potential of veterinary drugs have not been developed. As a result, FDA cannot establish an ADI for penicillin G. Also, sensitivity to penicillin varies significantly within the human population, further complicating establishment of an ADI.
Complicating the issue of a zero tolerance is the increased sensitivity of today’s test kits and methodologies which allows for detection of much lower levels of drug than when penicillin was approved many decades ago. The Limit of Detection (LoD) for the tests currently in use at FSIS is very sensitive. The FSIS has established an “action level” for penicillin G at 25 ppb.
Given the sensitivity of today’s testing methodologies, NPB funded a study at USDA’s Agriculture Research Service to investigate the withdrawal time needed to ensure a zero tolerance for penicillin G in cull sows. The investigator, Dr David Smith, used a dose of 33,000 IU per kg for 3 days with various injection strategies. His findings (not yet published) indicate that the FARAD recommendation of 15 days is adequate to prevent violative residue levels in muscle tissue. Unfortunately, the drug is depleted from the kidney much more slowly. He estimates it would require at least a 51-day withdrawal period to ensure that the kidney is free of violative residues at a 25-ppb LoD or a 47-day withdrawal period at a 50-ppb LoD.
In conversations with FDA, it appears that no one has ever pursued the establishment of a tolerance for swine. When the 50-ppb tolerance was established for beef at the request of the drug’s sponsor, the FDA followed the recommendations of an international committee comprising experts from the Food and Agriculture Organization of the United Nations and the World Health Organization. The AASV, NPB, and NPPC have asked FDA to consider establishing a threshold other than zero for swine as well. The FDA has been receptive to the idea and is currently exploring the feasibility.
We have also asked that FSIS consider declaring all sow kidneys inedible, since cull-sow kidneys are not used for human consumption in the United States. This would make the kidney ineligible for testing. The FDA, however, has expressed some reservation about doing this, since the kidney is specifically listed as a target tissue for other compounds for which they have established tolerances. This option is still under consideration.
So, in conclusion, at the time of this writing, it appears that at least a 51-day withdrawal is necessary if penicillin G is used in swine destined for processing.