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Figure 3-2. Conceptual Representation of a Physiologically Based
Pharmacokinetic (PBPK) Model for a
Hypothetical Chemical Substance
Lungs
Liv er
F at
S lo w ly
perfus ed
tis s ues
R ic h ly
perfus ed
tis s ues
K idney
S k in
V
E
N
O
U
S
B
L
O
O
D
A
R
T
E
R
I
A
L
B
L
O
O
D
V
m a x
K
m
Inges tion
Inhaled c hem ic al
E x ha led c hem ic al
G I
T ra c t
F ec es
U rin e
C h e m ic a ls
contac ting sk in
Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a
hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by
ingestion, metabolized
in the liver, and excreted in the urine or by exhalation.
Source: adapted from Krishnan and Andersen 1994
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For radionuclides, the PBPK model is replaced with a set of sophisticated physiologically based
biokinetic (PBBK) models for inhalation, ingestion, and submersion. These were developed to
accomplish virtually the same end as the PBPK models above, while integrating additional parameters
(for radioactive decay,
particle and photon transport, and compound-specific factors). Goals are to
facilitate interpreting chest monitoring and bioassay data, assessing risk, and calculating radiation doses
to a variety of tissues throughout the body. The standard for these models has been set by the ICRP and
their models receive international support and acceptance. ICRP periodically considers newer science in
a type of weight of evidence approach toward improving the state of knowledge and
reducing
uncertainties associated with applying the model to any given radionuclide. ICRP publications also allow
for the use of situation- and individual-specific data to reduce the overall uncertainty in the results. Even
though there may be conflicting data for some parameters, such as absorption factors, one can use
conservative values and still reach conclusions on whether the dose is below recommended limits. One of
the strengths of the ICRP model is that it permits the use of experimentally determined material-specific
absorption parameter values rather than requiring the use of those provided for default types. If the
material of interest does not have absorption parameter values that correspond to those in the model (e.g.,
Type F, M, or S), the difference can have a profound effect on the assessment of intake
and dose from
bioassay measurements. This has been discussed in National Radiological Protection Board (NRPB)
published reports on uranium (NRPB 2002).
The ICRP (1994b, 1996a) developed a Human Respiratory Tract Model for Radiological Protection,
which contains respiratory tract deposition and clearance compartmental models for inhalation exposure
that may be applied to particulate aerosols of plutonium compounds. The ICRP (1986, 1990) has a
biokinetic model for human oral exposure that applies to plutonium. The National Council on Radiation
Protection and Measurements (NCRP) has also developed a respiratory tract model for inhaled
radionuclides (NCRP 1997). At this time, the NCRP recommends the use of the ICRP model for
calculating exposures for radiation workers and the general public. Readers interested in this topic are
referred to NCRP Report No. 125; Deposition, Retention and Dosimetry of Inhaled
Radioactive
Substances (NCRP 1997). In the appendix to the report, NCRP provides the animal testing clearance data
and equations fitting the data that supported the development of the human model for plutonium.
Models of the pharmacokinetics of plutonium have been developed for humans (ICRP 1972, 1986, 1994a;
Khokhryakov et al. 1994, 2000, 2005; Leggett 1985; Leggett et al. 2005), dogs (Mewhinney and Diel
1983; Polig et al. 2000), rats (Durbin et al. 1972), and mice (Durbin et al. 1997). Models of plutonium
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pharmacokinetics in humans that are currently being used for predicting internal exposures and radiation
doses are described below.
Human Respiratory Tract Model for Radiological Protection (ICRP 1994b)
Deposition.
The ICRP (1994b) has developed a deposition model for behavior of aerosols and vapors
in the respiratory tract. It was developed to estimate the fractions of radioactivity in breathing air that are
deposited in each anatomical region of the respiratory tract. ICRP (1994b) provides inhalation dose
coefficients that can be used to estimate radiation doses to organs and tissues throughout the body based
on a unit intake of radioactive material. The model applies to three
levels of particle solubility, a wide
range of particle sizes (approximately 0.0005–100 μm in diameter), and parameter values that can be
adjusted for various segments of the population (e.g., sex, age, and level of physical exertion). This
model also allows one to evaluate the bounds of uncertainty in deposition estimates. Uncertainties arise
from natural biological variability among individuals and the need to interpret some experimental
evidence that remains inconclusive. It is applicable to particulate aerosols
containing plutonium, but was
developed for a wide variety of radionuclides and their chemical forms.
The ICRP deposition model estimates the fraction of inhaled material initially retained in each
compartment (see Figure 3-3). The model was developed with five compartments: (1) the anterior nasal
passages (ET
1
); (2) all other extrathoracic airways (ET
2
) (posterior nasal passages, the naso- and
oropharynx, and the larynx); (3) the bronchi (BB); (4) the bronchioles (bb); and (5) the alveolar
interstitium (AI). Particles deposited in each of the regions may be removed and redistributed either
upward into the respiratory tree or to the lymphatic system and blood by different particle removal
mechanisms.
For extrathoracic deposition of particles, the model uses measured airway diameters
and experimental
data, where deposition is related to particle size and airflow parameters, and scales deposition for women
and children from adult male data. Similar to the extrathoracic region, experimental data served as the
basis for lung (bronchi, bronchioles, and alveoli) aerosol transport and deposition.
A theoretical model of
gas transport and particle deposition was used to interpret data and to predict deposition for compartments
and subpopulations other than adult males. Table 3-6 provides reference respiratory values for the
general Caucasian population during various intensities of physical exertion.