Page 166 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

VetBooks.ir Chapter 8

Toxicokinetics in Veterinary Toxicology

Deon van der Merwe, Ronette Gehring and Jennifer L. Buur

INTRODUCTION human food chain. Kinetic parameters, such as duration
of internal exposure and tissue concentrations, are
The epithelial barriers that form the body’s interface with
therefore useful metrics for assessing risk.
the environment, and the cellular barriers that separate
Mathematical models are used to characterize these para-
internal organs and tissues, have to be permeable to a
meters by describing changes in toxicant concentrations
wide variety of chemicals to allow nutrient absorption
over time. Models are most often used as predictive tools
and waste product elimination. The permeability of these
following exposure to toxicants, but they can also be used
physiological barriers, however, also allows toxicants to as an aid to understanding the underlying physiological
penetrate. Exposure to toxicants through ingestion, inhala-
mechanisms of chemical absorption, transport and elimina-
tion, and dermal contact may therefore result in harmful
tion. Various types of toxicokinetic models have been
absorption. The degree of adverse effects following expo-
developed and the appropriateness of a specific model type
sure to a toxicant is dependent on the rate and extent of
depends on the available data and the model’s purpose
absorption into the body, distribution to susceptible
(Riviere, 2011). One of the key challenges to the successful
organs and tissues, and specific interactions with biologi-
use of models is identifying the appropriate conditions for
cal targets. Living organisms are adapted to toxicant
its application. Two fundamentally different types of toxico-
exposure through the development of transport and elimi-
kinetic models are recognized: traditional (also called “clas-
nation mechanisms that prevent the build-up of harmful
sic”) toxicokinetic models, and physiologically based
chemical concentrations in organs and tissues.
toxicokinetic (PBTK) models. Traditional toxicokinetic
Toxicokinetics refers to the movement and fate, also
models are mathematical descriptions of concentration/time
referred to as the disposition, of toxicants. The term is
profiles that are constructed without assuming that the com-
most commonly used when describing the time course of
partments and functions used in the models are directly rep-
absorption, distribution, and elimination (including bio-
resentative of physical structures or physiological processes.
transformation and excretion) of toxicants in an organism.
The selection of compartments and functions are therefore
Toxicokinetics is closely related to pharmacokinetics, and
solely dependent on their ability to describe experimentally
may even be viewed as the same discipline, with the only
observed concentration/time profiles. PBTK models, on the
difference being the class of compound (toxicant or
other hand, are mathematical simulations of kinetic pro-
pharmaceutical) that is involved. Compared to typical
cesses in organs and tissues. The mathematical constructs
pharmaceutical exposure, exposure to toxicants is often
therefore represent actual organs, tissues, and physiological
uncontrolled and variable, and very large doses may be
processes.
involved. Toxicants are also more likely to cause lesions
and abnormal physiological function that may alter the
toxicant disposition, compared to exposures to pharma- UNDERLYING PHYSIOLOGY
ceutical drugs below toxic levels. When very large doses
Absorption
are involved, kinetic processes that can become saturated
are more likely to reach their maximum rates, resulting in Most hazardous substances must gain access to the systemic
altered disposition. circulation to exert their toxic effects through interaction
Predicting tissue concentrations over time is essen- with one or more internal organs. Notable exceptions are
tial for the prediction of adverse effects (Andersen those compounds that cause a local reaction at the site
et al., 2006). It is also needed to prevent unwanted of exposure. Absorption is the process whereby toxic sub-
xenobiotic residues in animal tissues from entering the stances gain entrance to the body from the external
Veterinary Toxicology. DOI: http://dx.doi.org/10.1016/B978-0-12-811410-0.00008-8
Copyright © 2018 Elsevier Inc. All rights reserved. 133