Page 128 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Regulatory Considerations in Veterinary Toxicology Chapter | 6 95

VetBooks.ir animal drug and its principal metabolites are considered, for interspecies variability and the default 10-fold for
When establishing the ADI, the toxicity of the new
human interindividual variability) is usually applied when
a POD from a chronic toxicology study is used for the
and the ADI is based on the most relevant toxicological
end-point. The derivation of the ADI is determined by ADI determination. However, information on a chemical-
dividing an appropriate point of departure (POD) by an specific adjustment factor, when available, may justify a
appropriate safety factor. The POD is typically identified nondefault (either reduced or increased) safety factor.
as a NOEL/NOAEL (or benchmark dose lower confi-
dence limit (BMDL)) from an appropriate toxicology Residue Chemistry Studies
study in the most sensitive species. ADIs for animal drugs
The purpose of residue chemistry studies is to assess the
established by FDA are codified under 21 CFR Part 556,
quantity and nature of residues in tissues derived from
and are used to derive the enforceable tolerances for
animals treated with new animal drugs. The CVM has
marker residues in edible tissues.
published guidance documents (FDA GFI # 3, 205, 207,
For antimicrobial drugs used in food-producing ani-
and 208) which inform sponsors on the conduct of total
mals, a microbiological ADI may be determined if resi-
residues and metabolism studies, comparative metabolism
dues of antimicrobial drugs reaching the human colon
studies, residue depletion studies, and analytical method
remain microbiologically active and affect intestinal bac-
validation (FDA/CVM, 2011b, 2015c,d, 2016a). Total res-
teria. FDA GFI #159 (VICH GL36(R)) describes the
idue and metabolism studies are designed to develop
recommended approach (FDA/CVM, 2013).
information on the amount, persistence, and chemical
In certain cases, there may be the potential for a new
nature of the total residues, as well as the metabolic fate
animal drug to cause acute toxicity to the human con-
of the new animal drug in the treated target animals. The
sumer following consumption of a single meal or con-
total residue and metabolism data are used to determine
sumption of food over a single day. Some toxicological
the marker residue, the target tissue, and the marker resi-
tests may suggest the need for a safe intake value in addi-
due to total residue ratio. The marker residue is the resi-
tion to the ADI to account for the possibility of acute tox-
due for which the concentration is in a known
icity. In these cases, the ADI is not the appropriate safe
relationship to the concentration of total residue in an edi-
intake value for quantifying the dose above which expo-
ble tissue, and the target tissue refers to the edible tissue
sure from a single meal or over a single day can produce
selected to monitor for residues in the target animal.
acute adverse effects; instead, determining an acute refer-
Using information from the calculated ADI, safe con-
ence dose (ARfD) is the more appropriate approach which
centrations, and target tissue and marker residue, a toler-
is described in FDA Draft GFI #232 (FDA/CVM, 2015b).
ance is determined for the new animal drug. Tolerance is
An ARfD is an estimate of the amount of residues,
the maximum concentration of a marker residue, or other
expressed on a body weight basis, which can be ingested
residue indicated for monitoring, that can legally remain in
in a period of 24 h or less without adverse effects or harm
a specific edible tissue of a treated animal. The tolerance is
to the health of the human consumer. The ARfD, usually
determined by examining depletion data consisting of the
reported as an amount of the drug substance on a per per-
total residue concentrations and marker residue concentra-
son (mg/person) or body weight basis (mg/kg body wt), is
tions by a proposed analytical method. Tolerances for new
determined by dividing an appropriate POD by an appro-
animal drugs approved for use in food-producing animals
priate safety factor.
are listed in the USC of Federal Regulations (21 CFR Part
The safety factors used in these calculations, whether
556). The CVM may assign the tolerance by harmonizing
for acute or chronic effects, reflect the uncertainties asso-
with previously established international safety limits
ciated with the extrapolation of data and information from
(maximum residue limits, or MRLs). Tolerances and
toxicology studies to humans, including extrapolation of
MRLs both describe the limits of residues, but are not
long-term, chronic effects from laboratory studies with
derived in the same manner and are used for different pur-
shorter-term exposures, extrapolation of animal data to
poses. Tolerances are used to establish withdrawal periods
humans, and interindividual variability in the sensitivity
or milk discard times for new animal drugs. The with-
to the toxicity of the new animal drug among humans.
drawal period or milk discard time is the interval between
The safety factor generally consists of multiples of 10,
the time of the last administration of a new animal drug
with each factor representing a specific uncertainty inher-
and the time when the animal can be safely slaughtered for
ent in the available data. The overall safety factor is
food or the milk can be safely consumed.
dependent upon the interplay of many factors, including
the type of study from which the NOEL/NOAEL or
BMDL was derived, the species of animals used in the Regulating Carcinogenic Compounds
study, and the endpoint(s) observed in the study. For Carcinogenic risk assessment is one of the most important
example, a safety factor of 100 (the default 10-fold factor aspects in the safe assessment of animal drug residues.