Residues surveillance studies

The safe concentration of drug-related residue must be known in order to determine the withdrawal period for a veterinary product. Often the toxicity data is incomplete and an estimate must be made to progress with requisite residue studies. One approach is to conduct a total residue study with sufficiently widely-spaced sacrifice intervals to assess the rate of depletion of total residue over the projected range of probable safe concentrations. A zero-withdrawal sacrifice interval should be included. The target tissue and marker residue are identified and surveillance/confirmatory assays developed. If a major portion of residue is non-extractable (bound) and the marker is undetectable at times when total residue is still significant, a residue bioavailability study may be necessary. To complete the data package, final residue and comparative metabolism studies are conducted. Studies on the metabolism of flunixin in cattle will illustrate this approach. 

Following development of the assays for the marker residue (flunixin), liver tissue from feeder cattle dosed intravenously daily for three days with C-flunixin NHG (second total residue depletion study) was assayed by the surveillance method. Based on this assay, mean values of flunixin in the liver at 12 and 24 hours post final dose were 531 and 36 ng/g tissue, respectively. Liver samples collected at 72 and 120 hours contained flunixin concentrations below the limit of quantitation of the assay. The flunixin concentrations at.12 and 24 hours represented less than one-third of the total u residues, and although no fluni n was detected at 72 and 120 hours, there were still detectable residues at these sacrifice intervals. 

The mean concentration of flunixin in the liver was 389 ng/g after 12 hours, 53 ng/g after 24 hours, and 13 ng/g after 48 hours of withdrawal from treatment. At 48 hours, only two of the five animals treated had residues above the limit of quantitation (8 ng/g). No flunixin was detected in the 72-hour withdrawal liver samples. Confirmation analyses by GC-MS indicated that detected residues were flunixin. As shown in Figure 2, the flunixin concentrations detected in the livers of treated cattle at 12 and 24 hours post final dose in both the total and final residue depletion studies are similar. However, in both studies, the concentrations of detected flunixin are low with respect to total radiolabeled residue. These results suggest that a significant portion of the total residue may be bound and/or the existing surveillance and confirmatory assays do not adequately extract flunixin residues from the tissue of treated animals. The need for further work on the bound residues and the existing assays will depend on the final safe concentration assigned to the drug. 

Overall, in 234 ready-to-eat foods tested 37 times each as part of the FDA Total Diet Studies from 1982 to 1991, endrin was found only 26 times at an average concentration of 0.0027 pg/g (2.7 ppb) in 9 different foods broccoli, cantaloupe, collards, cucumbers, onion rings, dill pickles, pumpkin pie, summer squash, and winter squash (KAN-DO Office and Pesticides Team 1995). Concentrations ranged from 0.0011 pg/g (1.1 ppb) (broccoli) to 0.0041 pg/g (4.1 ppb) (summer squash). In a summary of 1985-91 FDA pesticide residue findings, endrin was not reported in more than 10,000 surveillance samples of domestic and imported foods that may be eaten by infants or children, or in more than 4,000 analyses of Total Diet Study foods eaten by infants and children (Yess et al. 1993). 

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