238
P. Volarath et al.
involve developing a model to apply certain TK conditions (i.e., TK modeling) and
computing the results of the applied conditions on the mathematical model (i.e.,
simulation). TK modeling and simulation is based on mass balance and kinetics
of reactions involved in absorption, distribution, metabolism, and elimination of a
substance (or its metabolites). TK modeling and simulation are used to estimate
parameters that define the disposition of a substance (and its metabolites) referred to
as markers of internal exposure. Based on the underlying concepts of mathematical
modeling, TK modeling and simulation can be classified into two types of models:
classical and physiological [23].
12.2.2.1 Classical TK Models
Classical TK models assume that the body is a system of one or more compartments,
though the compartments may not exactly correspond with anatomical structures.
Classical TK models are of two types:
Compartment TK models: Compartment TK models, also known as data-based
models, consist of a central compartment and may have multiple peripheral compartments. A one-compartment TK model (Fig. 12.1a) assumes that the changes in
concentration over time reflect proportional changes in the tissue (or blood) over the
same amount of time and that the elimination follows a first-order process. In contrast, a two-compartment TK model (Fig. 12.1b) assumes that upon administration
into the central compartment, the substance distributes between two compartments;
however, it does not achieve instantaneous distribution or equilibration between the
two compartments [24].
Compartment TK modeling has been commonly used for examining the TK of
many food ingredients for years. For example, several research articles [25–29] were
published in the 1970s and 1980s that examined the TK of styrene, whose polymers
are approved for food contact uses. Some studies have reported increased incidences
in lung tumors following chronic inhalation [30] or oral [31] exposure to styrene
in rodents. Although the human relevance of the reported carcinogenic findings
in rodents has been a subject of debate [32], analysis of TK data across different
exposure routes generated by compartment modeling [25–29] provides important
information on TK profiles of styrene after oral versus non-oral (e.g., inhalation)
exposure. More recently, due to advancements in the field of TK modeling and
simulation that provide opportunities of incorporating physiological parameters or
biological response for predicting effects (described further under “Physiological
TK models”), investigators have been slowly moving away from compartment modeling. However, compartment modeling is still often used for hazard identification,
examination of TK profiles of substances (and their metabolites), and identification
of data gaps necessary for planning and designing future studies needed for further
evaluating the toxicological potential of a substance.
Noncompartment TK models: Noncompartment TK models assume that the estimation of TK parameters does not depend on the number of compartments. Noncompartment TK modeling is used to estimate markers of internal exposure, such as
P. Volarath et al.
involve developing a model to apply certain TK conditions (i.e., TK modeling) and
computing the results of the applied conditions on the mathematical model (i.e.,
simulation). TK modeling and simulation is based on mass balance and kinetics
of reactions involved in absorption, distribution, metabolism, and elimination of a
substance (or its metabolites). TK modeling and simulation are used to estimate
parameters that define the disposition of a substance (and its metabolites) referred to
as markers of internal exposure. Based on the underlying concepts of mathematical
modeling, TK modeling and simulation can be classified into two types of models:
classical and physiological [23].
12.2.2.1 Classical TK Models
Classical TK models assume that the body is a system of one or more compartments,
though the compartments may not exactly correspond with anatomical structures.
Classical TK models are of two types:
Compartment TK models: Compartment TK models, also known as data-based
models, consist of a central compartment and may have multiple peripheral compartments. A one-compartment TK model (Fig. 12.1a) assumes that the changes in
concentration over time reflect proportional changes in the tissue (or blood) over the
same amount of time and that the elimination follows a first-order process. In contrast, a two-compartment TK model (Fig. 12.1b) assumes that upon administration
into the central compartment, the substance distributes between two compartments;
however, it does not achieve instantaneous distribution or equilibration between the
two compartments [24].
Compartment TK modeling has been commonly used for examining the TK of
many food ingredients for years. For example, several research articles [25–29] were
published in the 1970s and 1980s that examined the TK of styrene, whose polymers
are approved for food contact uses. Some studies have reported increased incidences
in lung tumors following chronic inhalation [30] or oral [31] exposure to styrene
in rodents. Although the human relevance of the reported carcinogenic findings
in rodents has been a subject of debate [32], analysis of TK data across different
exposure routes generated by compartment modeling [25–29] provides important
information on TK profiles of styrene after oral versus non-oral (e.g., inhalation)
exposure. More recently, due to advancements in the field of TK modeling and
simulation that provide opportunities of incorporating physiological parameters or
biological response for predicting effects (described further under “Physiological
TK models”), investigators have been slowly moving away from compartment modeling. However, compartment modeling is still often used for hazard identification,
examination of TK profiles of substances (and their metabolites), and identification
of data gaps necessary for planning and designing future studies needed for further
evaluating the toxicological potential of a substance.
Noncompartment TK models: Noncompartment TK models assume that the estimation of TK parameters does not depend on the number of compartments. Noncompartment TK modeling is used to estimate markers of internal exposure, such as