Estimating provisional acceptable residues for extralabel drug use in livestock

In 1996, the United States Congress passed legislation (Animal Medicinal Drug Use Clarification Act, AMDUCA), which allows some veterinary or human drugs to be used off label in food-producing animals. In order to implement this Act and protect the U.S. consumer, tolerances or safe concentrations are required before a withdrawal time can be estimated for extralabel drug use. Use of foreign MRLs to satisfy these data needs may not be applicable because of differences in safety standards between the U.S. and other countries. This paper presents strategies that can be used to derive equivalent safe concentrations, referred to as provisional acceptable residues (PARs), that may then be used to estimate drug withdrawal times. Health-based methods are proposed for calculating a PAR for a tissue. Procedure A partitions 50% of the acceptable daily intake (ADI) to edible tissues and reserves the remainder for milk. Procedure B equally partitions the ADI into all edible tissues. Procedure C partitions 50% of the ADI to milk and equally partitions the remaining 50% ADI into edible tissues. Simulations were performed for florfenicol, tetracycline, dexamethasone, azaperone, ivermectin, eprinomectin, and doramectin. In general, these simulations resulted in derivation of conservative PARs, which did not result in daily intakes of residues greater than the health-based ADI. These simulations demonstrated that provided the safe concentrations or equivalent PARs are based on rigorous toxicology safety data (e.g., NOELs, ADIs), the safety of food animal products will not be compromised. It is proposed that these PARs can be used for estimating withdrawal times after extralabel drug use or inadvertent exposure to an environmental contaminant where no approved withdrawal time exists. Finally, implementing similar transparent methods could have a positive impact on international harmonization and trade.