A marker residue compound and a target tissue are selected on the basis of the
findings of metabolism studies. A marker residue compound is selected that pro-
vides an assurance that when residues of the marker are compliant with MRL, all
residues of toxicological concern are compatible with the ADI. As the marker
residue may not be the only residue of toxicological or microbiological concern,
its persistence in tissue must be sufficient to assure that all residues of toxicological
concern have depleted prior to depletion of the marker residue. National govern-
ments and industry use the marker residue for MRL enforcement purposes.
The target tissue is the edible tissue selected for monitoring the total residue in
the target animal species. The target tissue is usually, but not necessarily, the tissue
with the slowest residue depletion rate. Not all jurisdictions select a single target
tissue for monitoring residues: some jurisdictions regard any edible tissue for which
an MRL has been established as a target tissue.
Comparative metabolism studies are conducted to ensure that the laboratory
animals used in toxicity studies for deriving the ADI are exposed to the same array
of substances as human consumers of edible tissues from treated animals (Ellis
2004 ). Auto-exposure of metabolites is taken as evidence that the safety of meta-
bolites has been adequately assessed in the toxicological studies. In vivo compara-
tive metabolism studies involve qualitative metabolite analysis of samples of blood,
blood fractions, excreta, liver, bile, kidney and fat collected from the laboratory
animal test species and the target food-animal species. Qualitative metabolite
information may also be obtained from in vitro metabolism studies and structure–
activity relationships.
The procedure for establishing MRLs for veterinary drugs is not consistent
amongst the jurisdictions, or between the jurisdictions and the JECFA. The
JECFA recommends MRLs that are no higher than necessary, that reflect the
residues expected when the veterinary drug is used in accordance with good
practice, and can be enforced by regulatory programmes using available analytical
methodology. The JECFA procedure for establishing MRLs for veterinary drugs is
shown in Fig. 1. It is an iterative process based on the data provided, and it is
facilitated by the model food basket (WHO 2006 ). A statistical tool for establishing
MRLs was agreed at the 66th meeting (WHO 2006 ), and it is now used routinely
with all data sets that are suitable for statistical analysis. An important feature of the
statistical tool is that it takes account of both the ADI and the kinetic behaviour of
the residues in muscle, fat, liver and kidney. The MRLs allocated therefore main-
tain the tissue distributional relationships observed in pharmacokinetic studies. The
statistical tool initially performs a linear regression analysis on the kinetic data
describing the terminal depletion of the marker residue in edible tissues following
the last administration of the drug. The results of the regression analysis are then
used to estimate the upper limits of the 95% confidence interval for the upper one-
sided tolerance limit on the 95% of the test animal population. Finally, the MRL is
a point on the curve describing the upper one-sided 95% confidence limit over
the 95%, at or beyond which the predicted median intake (EDI) is equal to, or less
than, the ADI. The minimum number of food-producing animals recommended for
metabolism studies varies with the animal species and the jurisdiction. In the case
Drug Residues 275