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for five of the subjects were obtained 1 year following exposure and data for the other two
subjects were
obtained 7 or 21 years after exposure. Whole-body retention half-times ranged from 84 to 175 years
(mean: 118 years). Retention of plutonium in blood exhibited multi-phasic kinetics, with the fastest
phase (52% of clearance) having a half-time of approximately 20 minutes, and the slowest phase (0.4% of
clearance) having a half-time of approximately 80 days. The corresponding time to half of the initial
blood burden was approximately 1 hour. Fecal excretion was the dominant pathway for excretion during
the first 30 days
following exposure, after which urinary excretion exceeded fecal excretion (Leggett
1985). Urinary and fecal excretion rates (fraction of blood burden excreted/day) were approximately
0.08 and 0.07 during the period 19–24 days postexposure; corresponding half-times are approximately 8–
9 days (Leggett 1985).
Urinary excretion of plutonium has also been monitored in healthy volunteers following intravenous
injection of
237
Pu (as the citrate) with a short half-life (45.66 days) compared to 24,100 years for
239
Pu.
Mean 24-hour urinary excretion of
237
Pu ranged from 0.8 to 1.4% following intravenous injection of
Pu(IV) citrate into 10 healthy subjects (4 males, 6 females); retention was generally greater in women
than men (Talbot et al. 1997). Results of a similar study of two healthy male volunteers indicated 2.0–
2.4% urinary excretion during 21 days postinjection (Talbot et al. 1993).
Excretion of plutonium following intravenous injection of plutonium has been
studied in nonhuman
primates, dogs, and rodents (e.g., Bair et al. 1973; Bruenger et al. 1991a; Durbin et al. 1972, 1997;
Guilmette et al. 1978; Polig 1989; Polig et al. 2000; USNRC 1992).
3.4.5
Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models
Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and
disposition of chemical substances to quantitatively describe the relationships among critical biological
processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry
models. PBPK models are increasingly used in risk assessments, primarily to predict the
concentration of
potentially toxic moieties of a chemical that will be delivered to any given target tissue following various
combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based
pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to
quantitatively describe the relationship between target tissue dose and toxic end points.
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PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to
delineate and characterize the relationships between: (1) the external/exposure
concentration and target
tissue dose of the toxic moiety; and (2) the target tissue dose and observed responses (Andersen and
Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can
be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from
route to route, between species, and between subpopulations within a species.
The biological basis of
PBPK models results in more meaningful extrapolations than those generated with the more conventional
use of uncertainty factors.
The PBPK model for a chemical substance is developed in four interconnected steps: (1) model
representation; (2) model parameterization; (3) model simulation; and (4) model validation (Krishnan and
Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of
toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen
1994; Leung 1993). PBPK models for a particular substance require estimates of the
chemical substance-
specific physicochemical parameters, and species-specific physiological and biological parameters. The
numerical estimates of these model parameters are incorporated within a set of differential and algebraic
equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations
provides the predictions of tissue dose. Computers then provide process simulations based on these
solutions.
The structure and mathematical expressions used in PBPK models significantly simplify the true
complexities of biological systems. If the uptake and disposition of the chemical substance(s) are
adequately described, however, this simplification is desirable because data are often unavailable for
many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The
adequacy of the
model is, therefore, of great importance, and model validation is essential to the use of
PBPK models in risk assessment.
PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the
maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994).
PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in
humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste
sites) based on the results of studies where doses were higher or were administered in different species.
Figure 3-2 shows a conceptualized representation of a PBPK model. Figures 3-3–3-8
show models for
radionuclides in general or specifically for plutonium.