240
P. Volarath et al.
fluorotelomer carboxylic acid (5:3 A), has the potential to accumulate and contribute
to the potential biopersistence of 6:2 FTOH [35]. This analysis identified 5:3 A as
an important biomarker for biomonitoring studies of 6:2 FTOH [35]. Furthermore,
the TK parameters estimated from the noncompartment modeling helped identify
factors to consider in future toxicological studies to determine more conclusively
whether, and to what extent, 6:2 FTOH biopersists in humans [35]. Like compartment
modeling, noncompartment modeling not only provides valuable information on the
TK profile of a substance, but also is useful in identifying data gaps necessary for
planning and designing toxicity studies for conclusively determining toxicological
potential.
12.2.2.2 Physiological TK Models
Physiological TK models incorporate known or hypothesized biological processes
into the analysis of TK of a substance (and its metabolites). Unlike classical TK models, in physiological TK models the rate constants are not defined by data, but by
physiological and anatomical components and biochemistry of a substance that influence the TK of the substance [23, 36]. These models are referred to as physiologically
based TK (PBTK) models. PBTK modeling includes mathematical representation
of important physicochemical and biological factors that influence the TK of substances [36–39]. The whole body is divided into tissue compartments identified as
anatomical structures that are involved in the TK of a substance and defined with
appropriate physiological characteristics, such as blood flow rate (ml/min or l/h),
cardiac output (l/h), alveolar ventilation rate (l/h), and partition coefficients between
total concentration in the tissue and freely diffusible concentration in the blood or
interstitial fluid. A basic structure of a PBTK model is provided in Fig. 12.2. This
model represents inhalation and oral exposure to a substance. The tissue compartments included in the PBTK model (Fig. 12.2) are lungs, fat, liver, rapidly perfused
and slowly perfused tissues and the gastrointestinal tract (GIT). The rapidly perfused
tissue compartment, as the name suggests, consists of tissues that are heavily perfused
with blood, such as heart, kidneys, brain, etc. In contrast, the slowly perfused tissue
compartment represents tissues that are less perfused with blood, such as muscle,
skin, and bone.
PBTK modeling is commonly used for prediction of tissue dosimetry and internal
exposure of substances and their metabolites. In addition, PBTK models can be used
for extrapolation of a TK response from high dose to low dose, between different
exposure routes, and across species, if appropriate physiological and TK data required
to validate a model are available [36–39]. For example, over the years several PBTK
models have been published on styrene [40–42]. A PBTK model for predicting the
kinetic behavior of inhaled styrene in humans using data from rats was developed by
Ramsey and Andersen (1984) which predicted that styrene metabolism was saturated
at inhaled concentration of 200 ppm and higher in rats, mice, and humans [40].
Another PBTK model for estimating the body burden of a key metabolite of styrene,
styrene-7,8-oxide (STO), was developed by Csanady et al. (1994) that described the
P. Volarath et al.
fluorotelomer carboxylic acid (5:3 A), has the potential to accumulate and contribute
to the potential biopersistence of 6:2 FTOH [35]. This analysis identified 5:3 A as
an important biomarker for biomonitoring studies of 6:2 FTOH [35]. Furthermore,
the TK parameters estimated from the noncompartment modeling helped identify
factors to consider in future toxicological studies to determine more conclusively
whether, and to what extent, 6:2 FTOH biopersists in humans [35]. Like compartment
modeling, noncompartment modeling not only provides valuable information on the
TK profile of a substance, but also is useful in identifying data gaps necessary for
planning and designing toxicity studies for conclusively determining toxicological
potential.
12.2.2.2 Physiological TK Models
Physiological TK models incorporate known or hypothesized biological processes
into the analysis of TK of a substance (and its metabolites). Unlike classical TK models, in physiological TK models the rate constants are not defined by data, but by
physiological and anatomical components and biochemistry of a substance that influence the TK of the substance [23, 36]. These models are referred to as physiologically
based TK (PBTK) models. PBTK modeling includes mathematical representation
of important physicochemical and biological factors that influence the TK of substances [36–39]. The whole body is divided into tissue compartments identified as
anatomical structures that are involved in the TK of a substance and defined with
appropriate physiological characteristics, such as blood flow rate (ml/min or l/h),
cardiac output (l/h), alveolar ventilation rate (l/h), and partition coefficients between
total concentration in the tissue and freely diffusible concentration in the blood or
interstitial fluid. A basic structure of a PBTK model is provided in Fig. 12.2. This
model represents inhalation and oral exposure to a substance. The tissue compartments included in the PBTK model (Fig. 12.2) are lungs, fat, liver, rapidly perfused
and slowly perfused tissues and the gastrointestinal tract (GIT). The rapidly perfused
tissue compartment, as the name suggests, consists of tissues that are heavily perfused
with blood, such as heart, kidneys, brain, etc. In contrast, the slowly perfused tissue
compartment represents tissues that are less perfused with blood, such as muscle,
skin, and bone.
PBTK modeling is commonly used for prediction of tissue dosimetry and internal
exposure of substances and their metabolites. In addition, PBTK models can be used
for extrapolation of a TK response from high dose to low dose, between different
exposure routes, and across species, if appropriate physiological and TK data required
to validate a model are available [36–39]. For example, over the years several PBTK
models have been published on styrene [40–42]. A PBTK model for predicting the
kinetic behavior of inhaled styrene in humans using data from rats was developed by
Ramsey and Andersen (1984) which predicted that styrene metabolism was saturated
at inhaled concentration of 200 ppm and higher in rats, mice, and humans [40].
Another PBTK model for estimating the body burden of a key metabolite of styrene,
styrene-7,8-oxide (STO), was developed by Csanady et al. (1994) that described the