Page 127 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

94 SECTION | I General

VetBooks.ir residue of a new animal drug in or on food, when con- repeat-dose testing, two 90-day oral toxicity studies are
usually conducted (one in a rodent species and one in a
sumed, presents a reasonable certainty of no harm to
nonrodent mammalian species) to inform the conduct of a
humans (FDA/CVM, 2016a). The overall human food
safety evaluation includes hazard identification, hazard chronic oral toxicity study (usually 1 year) in the most
characterization, exposure assessment, and exposure miti- appropriate species determined from the 90-day studies.
gation. The assessment is conducted from the perspectives Reproduction toxicity testing (usually two generations) is
of toxicology, residue chemistry, and microbial food performed to detect any effect of the compound on mam-
safety (for antimicrobial drugs). Pivotal toxicology studies malian reproduction, including effects on male and female
should be conducted in compliance with the GLP regula- fertility, conception, implantation, ability to maintain
tions set forth in 21 CFR Part 58, or should address the pregnancy to term, parturition, lactation, survival, growth
requirements for studies not conducted under these and development of offspring, and subsequent re-
regulations. productive function of the offspring at adulthood.
Developmental toxicity testing is conducted to detect any
adverse effects on the pregnant female and development
Toxicological Studies of the embryo and fetus subsequent to exposure to the
The purpose of toxicological studies is to define the bio- drug; adverse effects may include embryo or fetal death,
logical effect(s) of the new animal drug and to establish altered fetal growth, and structural changes to the fetus. A
the threshold dose for the effect(s). Factors considered in battery of genotoxicity tests is typically used to identify
determining the approach to toxicological testing needed substances that damage the genetic information within
for a new animal drug and its residues include its physico- cells. Substances considered to be genotoxic based on a
chemical properties, proposed use, mechanism of action, weight of the evidence evaluation for the battery of geno-
probable amounts and patterns of human exposure under toxicity studies and information are regarded as potential
the proposed conditions of use, possible biological effects carcinogens. Examples of additional tests that may be
of the residues as deduced through structure-activity com- recommended to address safety concerns such as those
parisons, and observed effects when new animal drugs are based on structure, class, and mode of action of the drug
tested in toxicological and biological model systems. In include testing for effects on the human intestinal flora
addition to the information regarding the test new animal (for antimicrobials), immunotoxicity testing to investigate
drug, separate information on the toxicology of metabo- the potential for the drug to elicit an immunological or
lites and/or excipients may also be considered necessary allergic reaction in sensitive individuals, neurotoxicity
to assess human food safety. Oral administration is gener- testing if neurotoxic potential is identified in repeat-dose
ally the route of choice for in vivo tests, and both rodent tests, and carcinogenicity testing, based on results of gen-
and nonrodent toxicological testing species are included otoxicity testing, structure activity relationship informa-
in the testing approach in order to maximize the chance tion, and results of repeat-dose and mechanistic studies.
of identifying and characterizing a potential adverse effect FDA may also require special tests in order to understand
in humans. the mode of action of the drug and aid in the interpreta-
The recommended general testing approach is outlined tion or assessment of the relevance of the data obtained in
in the FDA GFI #149 (VICH GL33): Studies to Evaluate the basic and/or additional tests.
the Safety of Residues of Veterinary Drugs in Human
Food: General Approach to Testing (FDA/CVM, 2009b).
Acceptable Daily Intake, Acute Reference
This GFI references additional human food safety toxicol-
ogy guidance documents and VICH guidelines. Basic tox- Dose and Safety Factors
icity tests recommended for all new animal drugs used in The safety of residues in food is usually addressed through
food-producing animals include repeat-dose subchronic calculation of an acceptable daily intake (ADI), defined as
and chronic, reproduction, developmental, and genotoxi- the daily intake which, during up to an entire life of a
city testing. Repeat-dose subchronic and chronic toxicity human, appears to be without adverse effects or harm to
testing is performed to define toxic effects based on the health of a consumer. The toxicological ADI is based
repeated and/or cumulative exposures to the compound on the new animal drug’s toxicological or pharmacological
and its metabolites, to determine the incidence and sever- properties as determined through the recommended toxi-
ity of effects in relation to dose and/or duration of expo- cology studies and other applicable scientific information,
sure, to determine the doses associated with toxic and and reflects uncertainties within the information. It is
biological responses, and to determine a no-observed- usually expressed in micrograms of the total residues of
effect level (NOEL) or no-observed-adverse-effect-level the drug per kilogram body weight per day (μg/kg body
(NOAEL). The spacing of the doses should provide an wt/day) or the milligrams of the total residues of the drug
assessment of the dose response relationship. For the per kilogram body weight per day (mg/kg body wt/day).