Page 157 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

124 SECTION | I General

VetBooks.ir develop international food standards and guidelines under residue to calculate the TMDI. JECFA’s previous
approach (which is still used in the EU), stated that expo-
the Joint FAO/WHO Food Standards Program. The main
sure was estimated on the basis of the MRL (throughout
purposes of this program are protecting the health of con-
sumers and ensuring fair trade practices in the food trade TMDI calculation) and proposed MRLs were checked for
industry. The advice to CAC on residues of veterinary compliance with the ADI. The new procedure uses the
drugs is provided by the Codex Committee on Residues same formula as used previously for the calculation of the
of Veterinary Drugs in Food (CCRVDF). FAO and WHO TMDI, including factors such as the ratio of marker to
have complementary functions in selecting experts to total residue concentrations. The only exception is that
serve on the committee. For residues of veterinary drugs, median residue level replaces the MRL as the point esti-
the WHO panel of the Joint Expert Committee is respon- mate of the residue concentration (i.e., median residue
sible for the toxicological evaluations of the substances levels take place of MRLs as a starting point from which
under consideration in order to establish ADIs (or provi- to calculate chronic exposure); therefore it is the median
sional ADIs) when possible. The FAO panel develops residue levels that are compared to the ADI rather than
specifications for the identity and purity of substances, MRLs (WHO, 2006). The new concept is to use median
assesses residue levels of veterinary drugs in food, and residue levels in animal-derived food for the calculation of
checks the quality of the monitoring data. It also proposes the new estimate of exposure termed the “estimated daily
limits (MRLs or provisional MRLs) for residues of veteri- intake” (EDI) from a daily model food basket (i.e., the cal-
nary drugs in products of animal origin, based on the culation of the EDI is based on the same standard
WHO ADIs and on information about the distribution of figures of food basket and correction for ratios of marker
the residues in tissues of the target animal. In setting the to total residue concentrations as used for the calculation
MRLs, the TMDI is estimated using the exaggerated of the TMDI; the only exception in this procedure was the
consumption package for products of animal origin. use of median residues instead of the MRLs as the point
Veterinary drug residues include parent drugs as well as estimate of the residue concentration in animal-derived
their metabolites. Metabolites are taken into account if food). The EDI does not cover the scenario of a short-term/
they are toxicologically relevant, i.e., present in a consid- high-concentration exposure but rather is an estimate of the
erable quantity or having a toxicological or pharmacologi- long-term average intake, based on long-term average con-
cal potential. The MRL is expressed in terms of parent sumption behavior, and long-term average residue level.
drug levels or in terms of levels of a marker metabolite, if Using this new approach, the MRL is calculated at the
the percentage of the marker metabolite formed from the upper tolerance limit (confidence limit) in a residue study at
parent drug is known. the time point when the median residues in the food basket
are below the EDI. The TMDI represents the worst case
assumption of maximum permitted residue levels (i.e., at
Changes in Calculation of MRLs
the MRL) in each food commodity consumed. This change
In the new JECFA approach, median residue concentra- of the model was initiated because the TMDI approach was
tion levels are used to derive an estimated daily intake thought to grossly overestimate the true chronic level of
rather than the MRL to better reflect estimates of chronic exposure to the population. It was recognized that, if good
(lifetime) exposure (WHO, 2006). The most significant veterinary practice is observed, there is a relatively low sta-
change introduced by the new approach is that the calcula- tistical probability that residues in edible tissues approach
tion of the MRL is independent of the ADI. The point at the MRL.
and beyond which the predicted median intake (estimated With the current EU-MRL approach, chronic expo-
daily intake, EDI) equals the ADI is deemed an sure is calculated on the basis of the MRL and TMDI.
acceptable POD for the derivation of MRLs. The MRL Summarizing, the EU throughout the EMEA should
and the median concentration are derived from the same carefully consider the new MRL JECFA proposals
time point of the depletion data of the marker residue. The because some impact is expected in the existing MRL
MRL itself is a point on the curve describing the upper assessments.
one-sided 95% confidence limit over the 95th percentile, To the same extent, the modified chronic model pro-
and the median is the corresponding point on the regres- posed by JECFA is consistent with the approach already
sion line for the same time point. The MRL represents the used by JMPR in the assessment of chronic exposure to
upper tolerance limit for the marker residue concentration pesticide residues. In this procedure, the TMDI concept
in the edible tissue at the time point when the EDI reached was reviewed in 1997 and it was proposed to use results
the level of the ADI. The JECFA concluded that the of STMR levels instead of the MRL to estimate a chronic
TMDI is no longer used as the most suitable estimate of intake (WHO, 1997). The JMPR and JECFA residue eval-
chronic intake. However, where a median residue cannot uation processes contribute to a better harmonization of
be derived, the MRL may be substituted for the median Codex Alimentarius residue assessment procedures for