Page 159 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

126 SECTION | I General

VetBooks.ir different types of consumption data to estimate chronic withdrawal and discard time. Total residue and metabo-
The GECDE uses median residues combined with two
lism studies provide information to establish the appropri-
ate marker residue (i.e., the parent drug or any of its
dietary exposure. Firstly, the highest exposure at the
97.5th percentile of consumption is selected from all the metabolites or a combination of any of these with a
foods relevant to exposure. This value is derived from known relationship to the concentration of the total resi-
chronic consumers of the food, and secondly, the mean due in each of the various edible tissues at the expected
dietary exposure is derived from the total population. In withdrawal time). A marker residue may be the parent
addition to the general population and children, dietary compound, a major metabolite, the sum of the parent
exposure of infants can also be estimated (FAO/WHO, compound and/or a metabolite or metabolites, or a deriva-
2014). tive formed during analysis by chemical reaction of the
As indicated in the modification draft of the Council parent drug and/or metabolites. When the marker residue
Regulation (EEC) No. 2377/90 (EEC, 1990), the in the target tissue has depleted to the MRL, the total resi-
European Community contributes in the context of the due will have depleted to the safe concentration in all edi-
Codex Alimentarius to the development of international ble tissues and to determine the target tissue (represents
standards on MRLs, while ensuring that the high level the edible carcass from which residue depletes most
of human health protection adopted in the European slowly and is the edible tissue selected to monitor for the
Community is not reduced. The European Community marker residue in the target animal). It is considered
should therefore take over, without a further RA, those suitable for monitoring compliance with the MRL of each
codex MRLs it has supported in the relevant CAC meet- edible tissue from a treated animal. The target tissue is
ing. Consistency between international standards and frequently liver or kidney for the purpose of domestic
community legislation on residue limits in food will monitoring and muscle or fat for monitoring meat or car-
thereby be further enhanced. casses in international trade. For the FDA, and following
With the modification of the Council Regulation the guidance above when the tolerance is based on a toxi-
(EEC) No. 2377/90 (EEC, 1990) a provisional MRL may cological endpoint, the concentration of the marker resi-
be established for a pharmacologically active substance in due (i.e., the compound used to monitor the depletion of
cases where scientific data are incomplete, provided that total residue in a food animal tissue) in the target tissue
there are no grounds for supposing that residues of the (i.e., the edible tissue from which the residue depletes
specific substance at the proposed level present a hazard most slowly) at the time the total radiolabeled residues in
for human health. the target tissue have depleted to less than the target tissue
in safe concentration, is the target tissue tolerance (word
similar to MRLs).
United States of America: Food and Drug When the ADI is based on a microbiological endpoint
(FDA, 2013), a similar approach is used; however, only
Administration Tolerance Setting
residues of microbiological concern are considered. In the
The FDA does not separately regulate drugs for food- FDA approach when the concentration of the marker resi-
producing animals from the feed additives for animal due in the target tissue is less than the target tissue toler-
nutrition. The toxicological assessment of a veterinary ances, total residues in all the edible tissues are less than
drug or a feed additive establishes the basis for identify- their respective safe concentrations (i.e., the entire food
ing the most appropriates in vitro an in vivo study upon animal carcass is safe). Safe concentrations of residues in
which a NOEL and, subsequently, an ADI, can be estab- the animal tissues are related to the ADI and food con-
lished. Based on the quantity and quality of the data and sumption factors. The FDA uses the same food consump-
the scientific interpretation of those data, a safety factor is tion factors as those used in the JECFA; however, they
applied to the NOEL to establish the ADI. The second are applied differently (Ellis, 2004). The FDA assumes
major component described in that guidance (FDA, that if a person consumes 300 g of muscle tissue, he/she
2003a) in regards to safety evaluation is exposure to will not consume an allocation of liver or kidney tissue
humans from consumption of residues of toxicological but may consume a full allocation of milk and eggs. The
concern in tissues (and milk and eggs, as appropriate). food allocation is 300 g for muscle, 100 g for liver, 50 g
That process begins with metabolism and radiolabeled for kidney and fat, 1500 g for milk, and 100 g for eggs.
residue studies in the target animals. The three principal Therefore, for a safe concentration in muscle for a 60 kg
components of this endeavor include comparative metabo- consumer, the ADI (in mg/kg) is multiplied by 60 kg and
lism in the toxicological species, total radiolabeled resi- that value is divided by 0.3 kg. For liver, the denominator
due and metabolism studies in the food-producing will be 0.1 kg and for kidney and fat the denominator will
animals, and residue depletion studies to establish the pre- be 0.05 kg. The daily intake of meat products is deter-
slaughter withdrawal period and, when needed, the milk mined to be one third of the total solid diet of 1500 g