Page 170 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Toxicokinetics Chapter | 8 137

VetBooks.ir the United States) are legal limits of allowable concentra- physiological body compartments or tissues. Links
between the compartments simulate physiological pro-
tions to prevent harm in consumers from toxic compounds
cesses of partitioning, transfer, metabolism, and excretion.
in foods. The length of time following exposure required
for concentrations in animal tissues to deplete to levels If the compartments and kinetic processes are accurately
that are below these tolerances is referred to as the with- described, the concentration/time curves of chemicals in
drawal time. The length of these withdrawal times are specific organs and tissues can be estimated. This offers
closely related to the compounds’ rates of elimination, an advantage over traditional compartmental models,
and therefore their half-life, in the specific tissue of inter- because differences in physiology, anatomy, environment,
est. It is important to note that the analytical technique metabolism, and the effects of chemical-induced physio-
used to measure plasma concentrations of the toxicant is logical changes and pathology can be simulated.
unlikely to be sensitive enough to pick up the tissue Parameters can be scaled to reflect different dose ranges,
depletion rate. species, breeds, genetic polymorphism and life-stages.
The advantages of PBPK models are, however, difficult
to achieve because the necessary anatomical and physio-
PHYSIOLOGICALLY BASED
logical parameter values are often not known, and/or the
TOXICOKINETICS relevant pharmacokinetic processes are not well under-
stood. The completeness of PBPK models depends
Introduction
entirely on the completeness of knowledge of the modeled
PBTK models are mathematical simulations of physiolog- system, and complete models are therefore not attainable
ical processes that determine the rate and extent of xeno- in most situations. PBPK models tend, therefore, to be
biotic chemical absorption, distribution, metabolism, and simplified representations of reality based on assumptions
excretion. Such models can be used for predicting internal regarding the most important processes and structures that
doses at target organs and tissues due to their conformity determine the pharmacokinetic profile of the chemical in
to actual organs, tissues, and physiological processes. question.
Internal dose predictions are useful for dose response Typical PBPK models simplify the body and represent
analyses and risk assessment involving specific mechan- it as a series of well-stirred compartments representing
isms and sites of toxicity. Successes in the application of major organs and tissues of interest, a single dose and
physiologically based pharmacokinetic (PBPK) models to route of exposure, and the major route of excretion. The
predict xenobiotic concentrations at target sites have led compartments are linked by blood flow, and the move-
to its acceptance as a modeling technique in risk assess- ment of chemicals between compartments is determined
ments. It is also used in mechanistic studies of the under- by tissue/blood partitioning and blood flow rates.
lying processes that determine pharmacokinetic profiles However, when enough data is available, highly detailed,
and dose response relationships. multiple compartment models can be constructed that
In veterinary toxicology, PBPK methods can be used include complete dosing regimens or exposure scenarios,
to improve the accuracy of predictions of toxicity across detailed organ structures, and physiological processes as
species by applying data obtained in one species to pre- well as specific processes of metabolism, and simulations
dictions in another species. It can be used to predict the of metabolite pharmacokinetics. Models of varying com-
effects of changes in physiological conditions, environ- plexity focusing on specific organs and routes of absorp-
mental conditions, activity levels, and pathological tion/elimination, such as the skin and respiratory organs,
changes on xenobiotic concentrations in target tissues. have also been developed (Andersen et al., 2002;
This allows for more accurate assessment of risk in varied Frederick et al., 2002; Van der Merwe et al., 2006).
individual animals and populations. PBPK approaches can
be used to study and understand the effects of mechan- Model Construction
isms that determine the internal exposure of animals to
potential toxins, such as dermal absorption and xenobiotic The first step in the construction of a PBPK model is
metabolism. PBPK models can also be used to address determining the purpose of the model and what internal
problems associated with the exposure of food-producing tissue doses are needed to answer the specific scientific
animals to drugs and chemicals that may result in poten- questions being asked. Once that is done, a schematic dia-
tially harmful or undesirable residues in meat, milk, and gram is constructed that consists of each of the tissue
other foods of animal origin (Brocklebank et al., 1997; compartments of interest, a plasma compartment, and a
Craigmill, 2003; Buur et al., 2005). compartment or compartments that represent the rest of
PBPK models also make use of compartments, but in the physiological system. It is often necessary to include
contrast to traditional compartmental models, the com- more than one compartment to represent the remaining
partments are derived from mathematical descriptions of portions of the body to reflect the differences in high and