Page 153 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

120 SECTION | I General

VetBooks.ir for an x% response (BMDLx), or a similar POD should Maximum Residue Level
be used. The BMD/BMDL approach is just one of a num-
All new pharmacologically active substances that are
ber of approaches that have been developed to refine the
ability to characterize the toxicological hazard of a veteri- intended for use in food animals must have MRLs estab-
lished prior to licensing. Termed tolerances in the United
nary drug (Edler et al., 2002).
States, they are defined as the maximum concentration of
The safe concentration is the maximal allowable con-
a residue of a pharmacologically active substance that
centration of total residues of toxicologic concern in edi-
may be permitted in food of animal origin (expressed in
ble tissue and is calculated from the ADI and considers
mg/kg or μg/kg on a fresh-weight basis). It is based on
the weight of an average person and the amount of meat,
the type and amount of residue considered to be without
milk, or eggs consumed daily by a high-consuming
any toxicological hazard for human health as expressed
individual.
by the ADI. Other relevant public risks and aspects relat-
The identification of the residue profile and its decline
ing to food technology, good practice in the use of veteri-
in the treated animal, resulting in the setting of MRLs,
nary drugs, and analytical methodologies are also
enables the exposure assessment and risk characterization
considered when establishing MRLs. In the EU those
to be determined. Additionally the theoretical maximum
drugs for which an MRL value should be established are
daily intake (TMDI) is calculated. The TMDI is an esti-
governed by Regulation (EC) No. 470/2009 (EC, 2009a),
mate of dietary intake based on multiplying the MRL by
repealing Council Regulation (EEC) No. 2377/90 (EEC,
the average food consumption for each commodity (i.e., it
1990). According to Article 6 of this regulation the scien-
is assumed that a person with a body weight of 60 kg con-
tific RA shall consider the metabolism and depletion of
sumes every day over a lifetime 500 g of mammalian or
pharmacologically active substances in relevant animal
poultry “meat” (muscle, liver, kidney, fat) or 300 g of fish
species, the type of residues and the amount thereof that
plus 1500 g of milk plus 100 g of eggs plus 20 g honey)
may be ingested by human beings over a lifetime without
and then summing the products (Table 7.6) (EMA-CVMP
an appreciable health risk expressed in terms of ADI.
and WHO, 1989). It is assumed that all the previous tis-
Alternative approaches to ADI may also be used. The RA
sues and products contain residues at a concentration
is concerned with the following: (1) the type and amount
equivalent to the MRL every day.
of residue considered not to present a safety concern for
Article 14(7) of Regulation (EC) No. 470/2009 (EC,
human health; (2) the risk of toxicological, pharmacologi-
2009a) states “where it appears necessary for the protec-
cal, or microbiological effects in human beings; and
tion of human health, the classification shall include con-
(3) residues that occur in food of plant origin or that
ditions and restrictions for the use or application of a
come from the environment. If the metabolism and deple-
pharmacologically active substance used in veterinary
tion of the substance cannot be assessed, the scientific RA
medicinal products that is subject to a MRL, or for which
may take into account monitoring data or exposure data.
no MRL has been set” (e.g., not for use in animals from
A variety of toxicological evaluations are performed
which milk or eggs are produced for human consumption)
to establish the safety of veterinary drug residues in
(see Table 7.7).
human food. The standard approach to assessing the
The Table 7.8, “prohibited substances,” includes sub-
safety of residues in foodstuffs intended for human con-
stances considered to be unsafe on the grounds of public
sumption is based on the determination of the ADI on
health (Regulation 37/2010, Table 7.2 of Annex) (EU, 2010).
which, in turn, MRLs are based. The establishment of a
TABLE 7.6 Standard Food Basket
Mammals Poultry Fish Bees
Muscle 0.300 kg Muscle 0.300 kg Muscle and skin in natural 0.300 kg Honey 0.20 kg
proportions
Fat 0.050 kg a Fat and skin in natural 0.090 kg
proportions
Liver 0.100 kg Liver 0.100 kg
Kidney 0.050 kg Kidney 0.010 kg
Milk 1.500 kg Eggs 0.100 kg
a
Fat and skin in natural proportions for pigs.