The use of physiological models to assist in understanding chemical exposure and dosimetry for early life stages

Jeffrey FisherFDA/NCTR

Computational Research (PBPK/PD Modeling)

Extrapolation of data.

Adult, infant, and fetus.

Body weightTissue volumesBlood flowsBiliary and kidney excretionMetabolism

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.

Growth in PBPK modeling

Number of PBPK models published each year (Rowland et al. 2011)

My first published PBPK papers

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.

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.

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

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

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

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

Teeguarden et al. 2013

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.

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

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

-)

Schematic of Deterministic BBDR-HPT Axis Near-Term Pregnancy Model

Lumen et al. 2013

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)

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

How much of perchlorate exposure does it take to be associatedWith hypothyroxinemia and onset of sub-clinical

hypothyroidism?

Lumen et al. 2013

Probabilistic Analysis

Model predicted maternal thyroid hormone levels

for a population of pregnant women

Total T4 (nmol/L) Free T4 (pmol/L)

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)

 

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

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.

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).

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.

Contributors

• NCTR -Nysia George, Annie Lumen, library staff• US EPA-Eva McLanahan, Paul Schlosser, Santhini

Ramasamy• Contractors: Abt Associates, Teresa Leavens