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Modeling Human Variation in 

Response at Specific Ages

Paul Hinderliter, PhD, DABT

Battelle Pacific Northwest Division

paul.hinderliter@pnl.gov

EPA Scientific Advisory Panel, Washington, DC February 

15-18, 2011
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Information in this presentation 

addresses:

• Chapters in the report

4. Creation of Variation PBPK/PD model

• Charge Questions

1. Physiologically Based Pharmacokinetic/Pharmacodynamic 

(PBPK/PD) Modeling

3. Model Calibration and Evaluation with Direct Dosing Human 

Studies

5. Sensitivity Analyses, Variability, and Uncertainty

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011
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Variation modeling steps

• Perform a local sensitivity analysis to identify 

parameters in the LifeStage model that drive 

variation in response

• Develop distributions of interindividual variation in 

values for the identified sensitive parameters

• Define how correlations between input values are 

addressed

• Compare prediction of variability to data from human 

volunteer studies.

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 3
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Model Sensitivity Analysis

• The sensitivity coefficient of a parameter is defined by the 

change in peak RBC or brain AChE inhibition divided by 

the change in the parameter value. 

• In local sensitivity analysis a small change (1%) was 

made in the parameter value and the impact on peak 

RBC and brain AChE inhibition was calculated. 

• A sensitivity coefficient of 1 indicates that the 1% change 

in parameter produces a 1% change in either the peak 

RBC or brain AChE inhibition. 

• Values greater than 1 indicate a greater than 1% change 

in one of the two target effects. 

• Values close to zero indicate that neither brain nor RBC 

AChE levels were affected by changes in the parameter. 

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011
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Model Sensitivity Analysis

Parameter Normalized Sensitivity 

Coefficient

AChE Basis

Tissue Volume 

Rapidly perfused tissues 0.09 Brain

Slowly perfused tissues 0.20 Brain

Liver 0.74 Brain

Blood 1.77 RBC

Fat 0.19 Brain

Tissue Specific Blood Flows

Rapidly perfused tissues <0.01 RBC

Slowly perfused tissues <0.01 RBC

Liver 0.30 RBC

Fat <0.01 RBC

Liver 0.47 RBC

• Note: All of the physiological parameters above are calculated for each 

individual using the LifeStage model.

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011
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Model Sensitivity Analysis

Parameter Normalized Sensitivity 

Coefficient

AChE Basis

Liver Metabolism Cytochrome CYP that converts CPF into: 

Oxon (activation) 0.98 RBC

TCPy (detoxification) 0.92 RBC

Brain Metabolism -Cytochrome CYP that converts CPF into:

Oxon (activation) 0.32 Brain

TCPy (detoxification) 0.10 Brain

PON1 

Blood 0.26 RBC

Liver 0.47 RBC

• Very few of the model parameters impacted the estimates of peak 

RBC or brain AChE inhibition. 

• Only 8 parameters had sensitivity coefficients greater than 0.1. It is 

recognized that some parameters that vary widely across a 

population with coefficients smaller than 0.1 might also contribute 

to variation in response. 

• However, using a cutoff criterion of 0.1 should capture the major 

drivers of variation in response. 
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Variability Model Variability Model

Data from:

Lafortuna, 2005, Butte, 2000; 

or Valentin, 2002

LifeStage simulation of fat volumes

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011
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• Adapted from work rates from (Jonsson et al. 2001)

• Decrease in relative perfusion of major organs

• Liver

• Richly perfused (Red Marrow, GI Organs, Pancreas, Thyroid, Spleen, Kidney)

• Increased perfusion

• Skin and Muscle – Movement and cooling

• Fat – energy stores

Model 

Compartment

Change in Perfusion 

Change in work level

Perfusion (L/hr) 

at Rest (0W)

Perfusion (L/hr) 

at Work (50W)

Fat 0.00017 4.8 6.3

Liver -0.0019 25.7 22.7

Brain 0 38.2 38.2

Slowly 

perfused 0.075 15.9 239.7

Richly 

perfused -0.0019 46.5 44.7

Total Cardiac 

Output 131 352

Impact of work on

Organ-Specific Perfusion Rates
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Z-score Tutorial

• A method of describing variation in terms of 

a distribution’s mean and standard deviation. 

• Z-scores of -2, -1, 0, 1, 2 are values that fall 

at two standard deviations below the mean, 

one standard deviation below the mean, the 

mean value, one standard deviation above 

the mean and two standard deviations above 

the mean. 

• The table at the right gives the Z-scores that 

correspond to various percentiles for normal 

distributions.

• Plotting the values of a distribution against their Z-score produces a straight 

line if the data are normally distributed. 

• Plotting the logs of data against Z-scores produces a straight line when the 

data are log-normally distributed. 

Percentiles Z-score

1 -2.3

5 -1.6

10 -1.3

25 -0.7

50 0

75 0.7

90 1.3

95 1.6

99 2.3
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• Distribution of in vitro enzyme liver activities for CYP (CPF to Oxon and 

TCPy) and PON1 (Oxon to TCPy). 

• Data points represent measured in vitro values scaled to the standard 

adult (30 samples). 

• Lines represent the fitted lognormal distribution used in the Variation 

model. 

• Note that the distribution is allowed to extend beyond the limits of the 

measured data.

In vitro enzyme liver activities
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• Total Vmax of human enzymatic PON1 metabolism of CPF-oxon to TCPy

in the plasma over various ages. 

• Symbols represent in vivo rates extrapolated from the in vitro data. 

• Error bars show the 95% CI of Vmax values used in the model.

Total human PON1 metabolism

0.01 0.1 1 10 100

1

10

100

1000

10000

QR

RR

QQ

Age (yr)

Vmax (mmol/hr)

0.01 0.1 1 10 100

1

10

100

1000

10000

QR

RR

QQ

Age (yr)

Vmax (mmol/hr)
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-3 -2 -1 0 1 2 3

10-2

10-1

100

101

102

103

104

105

106

107

Liver PON

Blood PON

Liver CPF to TCP

Liver CPF to oxon

Brain CPF to TCP

Brain CPF to oxon

Z-Score

Vmax (

μmol/hrl)

-3 -2 -1 0 1 2 3

10-2

10-1

100

101

102

103

104

105

106

107

Liver PON

Blood PON

Liver CPF to TCP

Liver CPF to oxon

Brain CPF to TCP

Brain CPF to oxon

Z-Score

Vmax (

μmol/hrl)

The range of the variation in 

metabolism can be inferred 

by comparing the ranges of 

the curves for the various 

enzymes.

Variation in vivo metabolic rates

Children

Adults

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011
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0.01

0.1

1

10

Blood TCP (nmol/ml)

0.5 mg/kg 1 mg/kg 2 mg/kg

• AChE inhibition and TCPy in blood in volunteers (Kisicki et al., 1999) 

following a single oral dose of CPF. 

• Triangles and error bars reflect actual data. 

• Black line is mean predictions and gray area presents the 5th and 95 

percentiles of predicted range of response for individuals.

AChE inhibition and TCPy in blood 

in volunteers

0 24 48 72 96 120

Hours

0 24 48 72 96 120

Hours

0 24 48 72 96 120

50

60

70

80

90

100

110

Hours

RBC AChE (% basal)

0.5 mg/kg 1 mg/kg 2 mg/kg

0 24 48 72 96 120

Hours

0 24 48 72 96 120

Hours

0 24 48 72 96 120

Hours
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Physical Activity (PA)

PA+ P+ CYP + Liver and Plasma PON1

PA + Physiology (P)

Liver PON1

Liver and Plasma PON1

PA+ P+ CYP Enzymes

Relative variation in RBC AChE Inhibition 

from a single dose of 0.5 mg/kg (adult)

* Ratio of RBC AChE inhibition to the median individual
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Comparison of RBC AChE inhibition from a 

single dose of 0.5 mg/kg across age

Physical Activity (PA)

PA+ P+ CYP + Liver and Plasma PON1

PA + Physiology (P)

Liver PON1

Liver and Plasma PON1

PA+ P+ CYP Enzymes

Adults (30 years)

Children (3 years)

Infants (6 months)
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Comparison of RBC AChE inhibition from a 

single dose of 0.1-1.0 mg/kg (adult)

Physical Activity (PA)

PA+ P+ CYP + Liver and Plasma PON1

PA + Physiology (P)

Liver PON1

Liver and Plasma PON1

PA+ P+ CYP Enzymes

0.5 mg/kg

1.0 mg/kg

0.1 mg/kg
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Comparison of RBC and Brain AChE inhibition 

from a single dose of 0.5 mg/kg (adult)

Physical Activity (PA)

PA+ P+ CYP + Liver and Plasma PON1

PA + Physiology (P)

Liver PON1

Liver and Plasma PON1

PA+ P+ CYP Enzymes

RBC

Brain

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011
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Summary of Age and Dose 

Dependencies

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011
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Peak blood concentrations of CPF and CPF-oxon following a single oral dose

Dose response relationships

Chlorpyrifos

Chlorpyrifos Oxon
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• Peak blood RBC AChE inhibition following single oral doses.

• The lines represent the typical 30 year-old and 6 month-old from the 

LifeStage model.

Dose response of RBC AChE

0.01 0.1 1 10

0.01

0.1

1

10

100

1000

Dose (mg/kg)

0.01 0.1 1 10

0.001

0.01

0.1

1

10

100

30 yr old

6 mo old

Dose (mg/kg)

% Basal % Control
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• Peak blood RBC AChE inhibition following single oral doses.

• The lines represent the typical 30 year-old and 6 month-old from the 

LifeStage model.

Dose response of Brain AChE

% Basal % Control

0.01 0.1 1 10

0.1

1

10

100

1000

Dose (mg/kg)

 

 

0.01 0.1 1 10

0.001

0.01

0.1

1

10

100

Dose (mg/kg)
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Summary

• Identified most sensitive model parameters and 

added estimate of interindividual variation in the 

LifeStage model

• Simulations of human volunteer studies compare 

favorably

• The range of various dose metrics can be calculated 

as a function of dose

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011