Page 139 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

106 SECTION | I General

VetBooks.ir TABLE 7.1 Safety and Residue Tests in Respect of Testing of Veterinary Medicinal Products

3A. Safety Tests
3B. Residue Tests
Precise identification of the product and of its active substance(s); Introduction; metabolism and residue kinetics (pharmacokinetics
pharmacology (pharmacodynamics, pharmacokinetics); toxicology (absorption, distribution, metabolism, excretion); depletion of
(single-dose toxicity, repeat-dose toxicity); tolerance in the target residues); residue analytical method
species, reproductive toxicity including developmental toxicity
(study of the effects on reproduction, study of developmental
toxicity), genotoxicity, carcinogenicity, exceptions; other
requirements (special studies, microbiological properties of
residues (potential effects on the human gut flora; potential effects
on the microorganisms used for industrial food processing)),
observations in humans; development of resistance; user safety;
environmental risk assessment (environmental risk assessment of
veterinary medicinal products not containing or consisting of
genetically modified organisms; environmental risk assessment for
veterinary medicinal products containing or consisting of
genetically modified organisms)

Independent national procedures can also be used for studies required in the preapproval process for veterinary
extensions of authorized veterinary medicinal products as drugs, since the primary concern has focused on chronic
far as no a priori harmonization has been achieved for the effects (i.e., carcinogenesis). The acute studies evaluate ani-
initial marketing authorization. mals for problems such as allergies. Acute effects of food-
The safety evaluation for a veterinary medicinal product borne drug residues on human health have also been
and its residues is based on a package listed in Part 3 of the described. These acute effects are defined as those that occur
Commission Directive 2009/9/EC (EC, 2009a) (Table 7.1). or develop rapidly after a single administration of chemical
substances in a period of 24 h or fewer. Approach of a
short-term high residue exposure must be presented because
HUMAN HEALTH RISKS FROM DRUG it could give rise to acute health effects in relation to short
RESIDUES IN FOODS periods of intake, to anticipate that it is probable an ARfD
(acute reference dose) will also recommended in addition to
Edible or target tissues containing veterinary drug resi-
the ADI. Some examples of acute toxicity effects are hyper-
dues can pose a risk to human health, including direct
sensitivity and pharmacological and teratogenic effects.
toxic effects, allergic reactions, and increased bacterial
resistance to common antibiotics.
The toxicity of drugs is an inherent part of all uses of Hypersensitivity
medication, and there are differences from one animal or
Meat and other dietary products from treated food animals
human to another, especially in allergic reactions. Residues
may contain residues of many antimicrobials or hapte-
of drugs or their metabolites in food products from treated
nized macromolecules. For small molecules to become
animals are major considerations in the safety of drugs
immunologic, they must be able to form covalent bonds
approved for use in food animals. In Europe, EMA or mem-
with macromolecules (i.e., proteins, polysaccharides, and
ber states approve of drug dosages, routes of administration,
polynucleotides). Allergic reactions can be caused by
durations of treatment and withdrawal times, and MRLs are
beta-lactam drugs (penicillins, cephalosporins), aminogly-
designed to ensure the safety of foods derived from treated
cosides, sulfonamides and in a few cases nitrofurans, and
animals. EU regulations have effectively prevented aller-
tetracyclines. Adverse human reactions are manifested as
genic, toxic, and potential carcinogenic drug residues from
severe swelling of the skin, serum sickness and shock;
entering the food supply. Any adverse reaction is likely to
less serious reactions such as skin rashes, asthma, and
occur due to acute rather than long-term chronic effects.
fever have been described. Drug sensitization can be
acquired by antimicrobial drugs, their metabolites, or deg-
radation products. However, cases of proven allergy to
Acute Toxicity Effects
such substances in food are extremely rare, based on clin-
For toxicology testing, the sponsor should perform acute and ical and laboratory experience of an immunological reac-
chronic dosing studies. For example, the acute impact of tion, whereas there are less well-substantiated reports
antibiotics is not directly examined in the toxicological blaming antibiotics in up to 50% of cases of chronic