The Toxicologist - Society of Toxicology

of chemical/dietary induced changes in serum thyroxine (T 4 ) concentrations in either
euthyroid or sensitive populations, such as the developing fetus. Collaborative
researchers are examining the effects of iodide deficiency on CNS development in
the rat pup at the USEPA using propylthiouracil as a positive control.
Electrophysiological, biochemical and molecular studies of the pup brain combined
with behavioral studies are used for evaluating HPT mediated developmental neurotoxicity.
A Biologically Based Dose Response (BBDR) HPT axis model for the
lactating rat and nursing pups predicts the relationship between brain concentration
of T 3 and serum concentration of T 4 as a function of iodide intake. The BBDR
HPT axis model describes two negative feedback loops: 1) TSH production controlled
by the brain concentration of T 3 , and 2) TSH stimulation of thyroid iodide
uptake and T 3 and T 4 synthesis and secretion. The model is calibrated to predict dietary
iodine deficiency-induced perturbations in serum and brain thyroid hormones.
The model successfully described published data sets in the dam and pup
for both euthyroid and iodide deficient conditions. After successful validation for
iodide deficiency, the model will be expanded to include thyroid active chemicals.
The model will allow for simulation of complex dose response and exposure conditions
and serve as a template for the future development of human gestation and
lactation BBDR HPT axis models for use in risk assessment.
703 AGE-DEPENDENT METABOLISM OF CHLOPYRIFOS
AND CHLORPYRIFOS-OXON IN HUMAN PLASMA
AND HEPATIC MICROSOMES.
T. S. Poet 1 , C. Timchalk 1 , M. J. Bartels 2 and J. N. Smith 1 . 1 Biological Monitoring
& Modeling, Battelle, Pacific Northwest Division, Richland, WA and 2 The Dow
Chemical Company, Midland, MI.
Young animals and, potentially, children may have increased sensitivity to chlorpyrifos
(CPF) exposure compared to adults at higher exposure levels, which could
be in part due to age differential metabolism of CPF and CPF-oxon (ultimate toxicant).
In humans, there have not been studies characterizing CPF or CPF-oxon metabolism
over various ages. Thus, age-dependent enzymatic metabolism of CPF and
CPF-oxon were quantified in vitro using human donor hepatic microsomes (n =
30, ages 13 d-75 y) and plasma (n = 20, ages 3 d-43 y) by measuring product formation
of 3,5,6-trichloro-2-pyridinol (TCPy) and CPF-oxon using gas chromatography/mass
spectrometry (GC/MS). Mean hepatic CPF desulfation and dearylation
Vmax values across ages were 0.35 and 0.73 nmol/min/mg microsomal
protein, respectively. The mean hepatic CPF-oxon hydrolysis Vmax value was 78
nmol/min/mg microsomal protein. All hepatic measures of metabolism were consistent
across ages on a per microsomal protein basis using a linear regression model
(p = 0.90, 0.60, and 0.17, respectively). Ratios of desulfation to dearylation also did
not show any age dependent relationships (p = 0.87). Pearson product-moment
correlation coefficients of pseudo first order rate estimates and Vmax values with
substrate marker activities provided by the vendor implicated CYP2B6, 3A4/5,
2C8, and 2D6 with CPF desulfation and CYP2C19 and 3A4/5 with CPF dearylation.
CPF-oxon metabolism in plasma showed age-dependent increases over two
factors: (1) metabolism on a per protein basis (p = 0.03) and (2) total plasma protein
levels (p = 0.005). The mean overall CPF-oxon metabolism Vmax value for
children < 6 mo of age was 1901 nmol/min/mL vs. 6829 nmol/min/mL for adults,
> 3.5 times higher. These results are useful when evaluating potential response of
different age individuals to CPF and will be integrated into a lifestage physiologically
based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF.
704 DEVELOPMENT OF A LIFESTAGE PHYSIOLOGICALLY
BASED PHARMACOKINETIC AND
PHARMACODYNAMIC (PBPK/PD) MODEL FOR
CHLORPYRIFOS IN RATS AND HUMANS.
J. N. Smith 1 , P. M. Hinderliter 1 , C. Timchalk 1 , M. J. Bartels 2 and T. S. Poet 1 .
1 Biological Monitoring & Modeling, Battelle, Pacific Northwest Division, Richland,
WA and 2 The Dow Chemical Company, Midland, MI.
Young animals and, potentially, children may have increased sensitivity to chlorpyrifos
(CPF) exposure compared to adults at higher exposure levels. Thus, an agedependent,
lifestage PBPK/PD model was developed to computationally predict
disposition of CPF and its metabolites chlorpyrifos-oxon (CPF-oxon) and 3,5,6trichloro-2-pyridinol
(TCPy) as well as corresponding cholinesterase (ChE) inhibition
in rats and humans. In this model, age-dependent body weight was calculated
from a generalized Gompertz function, and compartments (liver, brain, fat, blood,
diaphragm, rapid, and slow) were scaled based on body weight from polynomial
functions on a fractional body weight basis. Blood flows among compartments
were calculated as a constant flow per compartment volume. Carboxylesterase activity,
hepatic microsomal protein, and CPF-oxon metabolism in plasma have all
demonstrated age-dependency and were scaled as such. PK of TCPy was handled as
a one compartment model. Consistent with literature results, simulations of rats
152 SOT 2011 ANNUAL MEETING
dosed with a single dose of 10 mg/kg CPF orally at 5, 12, and 45 days of age
demonstrate increased peak CPF concentrations in blood (0.72, 0.49, and 0.40
μM) and greater maximal inhibition of plasma ChE activity (97, 93, and 77%), red
blood cell ChE activity (82, 67, and 34%), and brain ChE activity (80, 56, and
25%), respectively. In humans, PBPK/PD model simulations predict similar agedependent
outcomes. For humans 6 mo, 3 y, and 30 y of age, peak CPF concentration
in blood were (0.20, 0.18, and 0.17 μM), maximal inhibition of plasma ChE
activity were (98, 91, and 85%), and red blood cell ChE activity were (19, 11, and
9%), respectively, after receiving a single oral dose of 0.5 mg/kg CPF. This model
provides a computational framework for age comparative simulations that can be
utilized to evaluate age-related responses resulting from CPF exposure.
705 EFFECT OF PARAMETER VARIABILITY AND
UNCERTAINTY IN A LIFESTAGE PBPK MODEL FOR
CHLORPYRIFOS.
P. M. Hinderliter 1 , J. N. Smith 1 , M. J. Bartels 2 , P. S. Price 2 and T. S. Poet 1 .
1 Biological Monitoring & Modeling, Battelle, Pacific Northwest Division, Richland,
WA and 2 The Dow Chemical Company, Midland, MI.
Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models
are important tools in risk assessment, allowing for the evaluation of predicted effects
of chemical exposures on humans that occur as the result of real world exposures.
Human populations are unique in their differences and more specifically are
sexually dimorphic and exhibit a wide range in heights and weights and body composition.
A lifestage model has been constructed to include growth from birth to
adulthood and inter-individual variability in organ sizes and metabolic parameters.
The model incorporates measured body weights (from NHANES or other published
datasets) and calculates the necessary model body compartments (i.e., liver,
brain, fat, blood, rapid, and slow) which are scaled based on body weight from
polynomial functions on a fractional body weight basis. Variability in enzymatic parameters
is included, based on measured chlorpyrifos bioactivation and detoxification
in humans of different ages. To validate the model, human exposure data were
simulated and matched from two controlled human oral studies. Variability was determined
by calculating confidence intervals around in vitro-derived metabolic rate
constants for age-dependent plasma PON1 activity. The activities measured in vitro
were bootstrapped into the PBPK/PD model to account for variability and uncertainty
in these parameters. As an example, RBC AChE was examined as a function
of metabolic and physiological parameters using daily oral exposures from diet
(CARES). The results indicate that there are no trends between RBC AChE inhibition
with BMI, cardiac output, liver PON1, blood PON1, liver P450, or brain
P450 in adults. Simulation of higher doses does show a trend between PON1 activities
and AChE inhibition. This suggests that human variability will not substantially
impact predictions of inhibition at real-world low exposures. At higher doses
reduced levels of PON1 may be associated with increased inhibition.
706 DEVELOPMENT OF HUMAN GESTATION AND
LACTATION PBPK MODELS FOR
PERFLUOROOCTANOATE (PFOA) AND
PERFLUOROOCTANESULFONATE (PFOS).
A. E. Loccisano 1 , M. E. Andersen 1 , J. Butenhoff 2 and H. J. Clewell 1 . 1 The
Hamner Institutes for Health Sciences, Research Triangle Park, NC and 2 3M
Corporation, St. Paul, MN.
Conflicting results have been reported for associations between maternal
serum/plasma concentrations of perfluorooctanoate (PFOA) and perfluorooctanesulfonate
(PFOS) and human birth outcomes. Physiological changes during pregnancy
such as plasma volume expansion can affect pharmacokinetics and can also
be associated with birth outcomes. We have developed PBPK models for PFOA
and PFOS for the gestation and lactation life stages in humans to understand more
fully how the physiological changes associated with development affect tissue distributions
of these compounds in the mother, fetus, and neonate. These models were
derived from PBPK models for PFOA and PFOS that we previously developed for
adult humans and for rats during gestation and lactation. The same model structure
and parameters used in the adult human model could be used to simulate plasma
concentrations in pregnant and lactating women, indicating that pharmacokinetics
is not appreciably affected. Transfer of both chemicals to the human fetus was described
by simple diffusion, while transfer of chemical from plasma to milk was assumed
to be flow-limited. The models simulated PFOA and PFOS concentrations
in maternal and fetal plasma and milk and were compared to available epidemiologic
data and also used to estimate maternal exposure in the populations studied.
Another application was to estimate maternal and fetal PFOA plasma concentrations
in communities with contaminated drinking water. The model development
identified several research needs, including the identification of transporters involved
in renal resorption to explain the multi-year half-lives of these compounds
in humans, factors affecting the clearance of PFOA and PFOS during gestation,
and data to estimate clearance of PFOA and PFOS in the human neonate.