Comparative and Veterinary Pharmacology

of beef cattle, for example, the EMEA recommends at least twelve animals (four
groups of three animals) whereas the FDA CVM recommends at least twenty
animals (four groups of five animals or five groups of four animals). Presently, a
VICH guideline for metabolism studies is under development, a major objective of
which is to harmonise data requirements internationally.
Volume 8 of the Rules Governing Veterinary Medicinal Products in the Euro-
pean Community (European Commission 2003 ) documents the EU procedure for
establishing MRLs for veterinary medicinal products. The overall approach is
similar to that employed by the JECFA except for the exposure assessment (see
(1) and (2)).
The US FDA food safety evaluation of veterinary drug residues calculates a
tolerance (known elsewhere as a MRL; Freidlander et al. 1999 ). The tolerance is the
concentration of marker residue at the time on the residue depletion curve
corresponding to the time when total residues have decreased to the level of the
safe concentration (Fig. 2 ; see (3) for the calculation of safe concentration). The
tolerance is determined from a residue study using a radiolabelled drug, but it uses
the proposed analytical method for an unlabelled drug. The analytical procedure
typically uses the proposed method of analysis, and an in-line radiometric detection
simultaneously quantifies the total residues and the marker residue. The ratio of the
marker residue to the total residue is determined from the residue depletion curve,
using the time when the concentration of total residue equals the safe concentration.
The tolerance is calculated by multiplying the safe concentration by the ratio of the
marker residue to the total residue.

Time after treatment

Log concentration

Safe concentration

Tolerance

Total residue depletion curve

Marker residue

depletion curve

Time to safe

concentration

Fig. 2Schematic diagram of the US FDA approach for determining the tolerance of a veterinary
drug. The tolerance is the concentration of marker residue at the time on the marker residue curve
(lower curve) corresponding to the time when total residues have decreased to the level of the safe
concentration (upper curve)

Drug Residues 277