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![Page 1: The use of physiological models to assist in understanding chemical exposure and dosimetry for early life stages Jeffrey Fisher FDA/NCTR.](https://reader035.fdocuments.us/reader035/viewer/2022062300/56649cfd5503460f949cdaf9/html5/thumbnails/1.jpg)
The use of physiological models to assist in understanding chemical exposure and dosimetry for early life stages
Jeffrey FisherFDA/NCTR
![Page 2: The use of physiological models to assist in understanding chemical exposure and dosimetry for early life stages Jeffrey Fisher FDA/NCTR.](https://reader035.fdocuments.us/reader035/viewer/2022062300/56649cfd5503460f949cdaf9/html5/thumbnails/2.jpg)
Computational Research (PBPK/PD Modeling)
Extrapolation of data.
Adult, infant, and fetus.
Body weightTissue volumesBlood flowsBiliary and kidney excretionMetabolism
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What is going on with early life stage PBPK models?
• Historically, environmental and food contamination safety assessments lack information about early life stages (e.g., fetus, neonate, infant).
• Best Pharmaceuticals for Children Act (BPCA) of 2002 and encouragement by FDA has resulted in a large number of pediatric PBPK models in the literature for drugs over the last 5 years.
PBPK modeling community from drugs need to get together with others using models.
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Growth in PBPK modeling
Number of PBPK models published each year (Rowland et al. 2011)
My first published PBPK papers
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Why develop mathematical PK and PD models for life stages?
• Allows for predictions of internal doses or concentrations, extrapolations across species, routes of exposure and dose. Use: Exposure and Risk Assessments
1. Models can simulate the physiological and biochemical changes over gestation and lactation.
2. Need to add chemical or drug specific information.
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Computational models for early life stages at FDA/NCTR (Example 1)
• Bisphenol A- food and environmental contaminant.
• Probably most of us are excreting very small amounts of BPA in our urine today. This is one fundamental public health concerns in my opinion.
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A large set of BPA pharmacokinetics studies conducted at NCTR with mice, rats, and monkeys including life stages.
• Relatively low experimental dose (100 µg/kg)• Use deuterated BPA to avoid contamination issue• Use modern analytical methods
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Model SchematicSerum
Liver
Fat
Gonad
Slow
Rich
Skin
Gut
Vbody
Stomach
Small IntestineUrine excretion
Oral BPA
BPA
BPAG
EHR
as B
PA
EH
R a
s B
PAG
Gut glucuronidation Hepatic glucuronidation
Urine excretion
Brain
Vbody
Urine excretion
BPAS
Oral uptake
EHR: enterohepatic recirculation
Hepatic sulfation
Gas
tric
em
pty
ing
Gut glucuronidation &
biliary excretion
Hep
atic
glu
curo
nida
tion
& b
iliar
y ex
cret
ion
Dermal exposure
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Sim
ula
ted
d6
-BP
A d
ail
y A
UC
(n
M*h
per
da
y)
0
5
10
15
20
25
30
35
Sim
ula
ted
d6
-BP
A p
eak
co
nce
ntr
ati
on
s (
nM
)
0
2
4
6
8
10
PND3 PND10 PND21 Adult PND5 PND35 PND70 Adult Newborn Adult
Rats Monkeys Humans
Theoretical: Repeated daily oral dosing with 50 µg/kg of BPA
Daily AUC –BPA inserum
Daily peak conc-BPAin serum
Sparse data
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Modeling of Infants: Simulations of BPA ingestion in food (mg/kg bw/d) 6 meals, 0.3 (mean) and 0.6 (90th) mg/kg bw/d.
BP
A o
r B
PA
gin
ser
um
(nM
)
BPAg
BPA
Infant 2 µg/L (ppb)
0.2 µg/L
0.2 /L ( )
0.02
BP
A o
r B
PA
gin
ser
um
(nM
)
BPAg
BPA
Infant
Time (days)
BP
A o
r B
PA
gin
ser
um
(nM
BPAg
BPA
BP
A o
r B
PA
gin
ser
um
(nM
BPA-G
BPA
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Teeguarden et al. 2013
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Computational efforts at FDA/NCTR for early life stages (Example 2)
Biologically Based Dose Response (BBDR) Modeling–Endocrine Disruption (hypothalamic-pituitary-thyroid axis)• Prediction of hypothyroxinemia and hypothyroidism
in pregnant mother and nursing and bottle fed infant.• Thyroid hormone model with iodine and food
contaminant perchlorate.
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Dose- Response for the HPT axis
Traditional dose response
PBPK and PD model
Administered dose
Internal dose/MOA
HPT axis homeostatic
controls
Adverseoutcome
?Dose-Response
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Thyroid Axis Perturbations
• Iodide Deficiency– Substrate and
iodide stores depletion
• Exposure to Thyroid Active Chemicals– Perchlorate (ClO4
-)
– Thiocyanate (SCN-)– Nitrate (NO3
-)
Mode of ActionInhibition to NIS-mediated uptake of iodide
*NIS – Sodium Iodide Symporter
Uptake Organification, Biosynthesis and Distribution
Elim
ination
(ClO4-, SCN-, NO3
-)
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Schematic of Deterministic BBDR-HPT Axis Near-Term Pregnancy Model
Lumen et al. 2013
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Estimates of Iodide Status in the U.S. Population
• FDA Total Diet Study (Murray et al. 2008)– Women of reproductive age: 145 to 197 µg/day of iodide.
• Biomonitoring (Caldwell et al. 2011)– Median urinary concentration of iodide in pregnant women: 125 µg/L. – Of which 57% of the pregnant women’s urinary iodide concentrations <150 µg/L.
Estimates of Perchlorate Exposure in the U.S. Population • FDA Total Diet Study (Murray et al. 2008)
– Women of reproductive age: 0.08 – 0.11 µg/kg/day of perchlorate• Biomonitoring (Huber et al. 2011)
– Mean perchlorate dose in the U.S.: 0.101 µg/kg/day, including a potential drinking water component.
– Pregnant women mean food intake dose: 0.093 µg/kg/day of perchlorate
For the total population of the United States, the perchlorate contributions was estimated to be
80% from food and remaining 20% from drinking water (Huber et al. 2011)
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Application of BBDR-HPT Axis Near-Term Pregnancy ModelEvaluation of the effects of iodide nutrition and perchlorate exposure on
maternal thyroid hormone levels
Lumen et al. 2013*HPT, Hypothalamus Pituitary Thyroid
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How much of perchlorate exposure does it take to be associatedWith hypothyroxinemia and onset of sub-clinical
hypothyroidism?
Lumen et al. 2013
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Probabilistic Analysis
Model predicted maternal thyroid hormone levels
for a population of pregnant women
Total T4 (nmol/L) Free T4 (pmol/L)
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Estimates of Perchlorate Exposure in the U.S. Population
• FDA Total Diet Study (Murray et al. 2008) – lower and upper bound average of perchlorate intakes for all age groups spans
from 0.08 – 0.39 µg/kg/day (2005-2006)– For women 25-30 years and 40-45 years the range was 0.08 – 0.11 µg/kg/day
(2005-2006).
• NHANES (2001-2002) and UCMR (2001-2003) (Huber et al. 2011) – Mean food perchlorate intake in the U.S. is 0.081 µg/kg/day and 0.101
µg/kg/day including drinking water.– Pregnant women had a mean perchlorate food intake of 0.093 µg/kg/day
In the United States, the perchlorate contribution from food is 80% and from drinking water 20% (Huber et al. 2011)
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Exposure Scenarios
Maternal fT4 (pmol/L)
Geometric Mean
95% Confidence Interval (CI)
Lower Upper
Iodine intake (75 to 250 µg/day) without perchlorate exposure
10.5 10.3 10.7
Iodine intake with perchlorate exposure from food intake (0.08 – 0.39 µg/kg/day) (Huber et al. 2011 and Murray et al. 2008)
10.4 10.2 10.6
95th percentile food intake of perchlorate (0.278 µg/kg/day) and iodine intake (Huber et al. 2011)
10.4 10.2 10.6
Perchlorate intake of 3.4 µg/kg/day associated with non-overlapping CI compared to without perchlorate exposure and iodine intake
10.1 9.9 10.2
Preliminary Analysis with Perchlorate Exposure
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Lactating mom and nursing infant and bottle fed infant
• Currently we are working on thyroid hormone models and iodine model to predict perchlorate induced changes in serum thyroid hormones as a function of iodine intake and perchlorate exposure.
• Predict serum thyroid hormones in newborn to 90
days of age.
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Infant HPT axis
• Revved up, high through-put.• Many comparisons to thyroid hormones or
iodine stores in young compared to adults. Young very sensitive compared to adults.
• Relative to functioning of the HPT axis, the young appear more resistant to insult than adults (not for radioactive iodines).
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Regulatory science for early life stages and perchlorate
• Publication of models in peer reviewed literature.
• Peer review of model code by EPA. Does the model have merit for an intended purpose?
• If the model has merit does it provide important information for regulatory science?
• What are the major uncertainties, gaps in data or gaps in knowledge.
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Contributors
• NCTR -Nysia George, Annie Lumen, library staff• US EPA-Eva McLanahan, Paul Schlosser, Santhini
Ramasamy• Contractors: Abt Associates, Teresa Leavens