August 15, 2016


 Withdrawal times may improve with disease consideration

Posted July 27, 2016 

Recommended waiting periods between administering drugs to livestock and sending them to slaughter should account for effects of disease on metabolism, a scientific article indicates. 

The article “Human food safety implications of variation in food animal drug metabolism” was published June 15 in Scientific Reports, an online, open-access journal from the publishers of Nature.

The authors wrote that recommended withdrawal times prior to slaughter, under guidance from the Food and Drug Administration, are developed through tests on healthy animals to learn how much time is needed to reduce residues to an acceptable concentration. In practice, the substances are administered to diseased animals, which may have altered metabolisms, increasing the risk of illegal residue concentrations even when animals are held in line with established withdrawal times. 

Withdrawal times are based on ratios between the amounts of pharmaceuticals administered and the amounts of certain marker residues detected in tissues, and the ratios between parent drugs and metabolites are assumed to be constant. The authors claim that those ratios are “fundamentally flawed.”

Differences in the rates or extent of metabolism by disease—and even factors such as foods eaten or breeds treated—make marker residues poor indicators of tissue exposure to unsafe drug concentrations, the article states.

The authors used “physiologically based pharmacokinetic” computational models to estimate withdrawal times of ceftiofur, enrofloxacin, flunixin, and sulfamethazine, chosen because they have been among drugs most often connected with residue violations. Those models address administration in cattle and swine.

The authors wrote that differences between recommended withdrawal times and the times needed to reach acceptable residue concentrations varied by drugs administered and disease severity, among other factors. For example, one simulated enrofloxacin treatment required an extra day of holding time when swine were diseased, and the time needed to hold swine after a simulated sulfamethazine treatment expanded by 12 days when they were ill.

“Overall, our results strongly suggest that the current FDA guideline on the withdrawal time determination may need to be revised,” it states.

The results also challenge toxicological interpretations of residues for metabolized drugs, the article states. The methods used to determine the risk to humans of eating meat from animals with drug residues rely on flawed assumptions of fixed ratios, and marker residues could suggest illegal residues exist despite safe drug concentrations. 

But the article also indicates developing individual models for each drug may be impractical because of time and monetary costs.

FDA officials did not respond to a request for comment in time for publication.