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

Paul S. Price

The Dow Chemical Company

Use of Model Predictions in the 

Risk Assessment Process
Information in this presentation 

addresses 

 Chapters in the report 

9. Model predictions of the impact of dietary dose on brain 

and RBC AChE inhibition

10. Using the source-to-outcome model to estimate 

compound- and age-specific uncertainty factors

 Charge question 

6.0 Calculating data-derived extrapolation factors

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 2
Two ways to use source-to-outcome 

models in the risk assessment process

1. Direct prediction of impacts on RBC and 

brain AChE

2. Use of models to characterize compoundspecific uncertainty factors

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

Paul Price

Model Predictions

4
These findings:

 Are the culmination of the modeling effort

– Predictions of the impact on internal dose

– Predictions of the outcomes of the key events

 Address variation in dose and response in humans

 Address specific ages: 

– Adults (30 yr), children (3 yr), and infants (6 mo) 

 Allow the exploration of the impacts of different 

portions of the source-to-outcome models on the 

predictions

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 5
Peak CPF and CPF-oxon levels in 

blood: adults (30 yr) 

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 6

1.E-11

1.E-10

1.E-09

1.E-08

1.E-07

1.E-06

1.E-05

1.E-04

1.E-08 1.E-07 1.E-06 1.E-05 1.E-04 1.E-03

Blood Concentration on day 5 (μM)

Dietary Dose on day 5 (mg/kg)

Adults

CPF-oxon

CPF
Peak CPF and CPF-oxon levels in 

blood: adults and children (3 yr)

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 7

1.E-11

1.E-10

1.E-09

1.E-08

1.E-07

1.E-06

1.E-05

1.E-04

1.E-08 1.E-07 1.E-06 1.E-05 1.E-04 1.E-03

Blood Concentration on day 5 (μM)

Dietary Dose on day 5 (mg/kg)

Adults

Children

CPF-oxon

CPF
Peak CPF and CPF-oxon levels in 

blood: adults, children, infants (3 mo)

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 8

1.E-11

1.E-10

1.E-09

1.E-08

1.E-07

1.E-06

1.E-05

1.E-04

1.E-08 1.E-07 1.E-06 1.E-05 1.E-04 1.E-03

Blood Concentration on day 5 (μM)

Dietary Dose on day 5 (mg/kg)

Adults

Children

Infants

CPF-oxon

CPF
Peak RBC AChE inhibition: 

adults (30 yr)

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 9

0.00000%

0.00000%

0.00001%

0.00010%

0.00100%

0.01000%

1.E-08 1.E-07 1.E-06 1.E-05 1.E-04 1.E-03

Percent Inhibition of RBC AChE (Day 5)

Dietary Dose on day 5 (mg/kg)

Adults

9
Peak RBC AChE inhibition: 

adults and children (3 yr)

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 10

0.00000%

0.00000%

0.00001%

0.00010%

0.00100%

0.01000%

1.E-08 1.E-07 1.E-06 1.E-05 1.E-04 1.E-03

Percent Inhibition of RBC AChE (Day 5)

Dietary Dose on day 5 (mg/kg)

Adults

Children

10
Peak RBC AChE inhibition: 

adults, children, and infants (6 mo)

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 11

0.00000%

0.00000%

0.00001%

0.00010%

0.00100%

0.01000%

1.E-08 1.E-07 1.E-06 1.E-05 1.E-04 1.E-03

Percent Inhibition of RBC AChE (Day 5)

Dietary Dose on day 5 (mg/kg)

Adults

Children

Infants

11
Peak brain AChE inhibition: 

adults, children, infants (6 mo)

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 12

0.00000%

0.00000%

0.00001%

0.00010%

0.00100%

0.01000%

1.E-08 1.E-07 1.E-06 1.E-05 1.E-04 1.E-03

Percent Inhibition of AChE (Day 5)

Dietary Dose on day 5 (mg/kg)

Adults

Children

Infants

12
AChE inhibition from 5 days of dietary exposure 

versus 1-day population dose response

 Impact of longitudinal 

exposures in infants

– At low doses exceeds 

inhibition from a single 

daily dose 

– At high dietary dose is 

similar to single dose

 Impacts are 3 orders of 

magnitude below doses 

that causes a 10% 

response

Population dose 

response

Population dose 

response

Dietary dose 

response 

(5th day)

Dietary dose 

response 

(5th day)

13
Using model results to directly assess 

acceptability of dietary exposures

 The model’s predictions of impact need to be 

evaluated

– Comparison to acceptable levels of change in RBC or 

brain AChE

– Consideration of the uncertainties in the model’s 

predictions

 Model report must provide information on the 

model’s ability to predict the response in the U.S. 

population and the sources of uncertainty

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 14
EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011

Paul Price

Using the Source-to-Outcome 

Model to Estimate 

Compound- and Age-Specific 

Uncertainty Factors 

15
Animal 

POD

No adverse 

effects in 

typical 

human

No adverse effect 

in sensitive 

humans (aRfD)

aPAD for children and 

women of child bearing years

UFA

UFH

FQPA factor

The relationship between POD, 

aRfD, and aPAD

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

16
Interspecies uncertainty factor (UFA)

 Strategy is to mimic the design of the animal study 

(studies) that are used to set the POD 

– AChE inhibition studies are typically based on changes in the 

mean values of groups of animals 

– Fitted to benchmark dose models

– Goal: to determine equivalent of BMDL10 for humans

 UFA is the ratio of BMDL10 in rats to BMDL10 in humans 

 Illustration is based on Marty and Andrus (2010) study 

(Attachments G and H) 

– BMDL10 was calculated to be 0.36 mg/kg

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 17
Animal data and human dose response 

in Marty and Andrus (2010)

 Population dose 

response (infants)

18

0.10

1.00

10.00

100.00

0.1 1 10

% RBC AChE Inhibition

Single Dose mg/kg 18
Animal data and human dose response 

in Marty and Andrus (2010)

 Population dose 

response (infants)

 Acute dose response 

acute dose in rats (Post 

natal day 11) 

 Data suggest that rats 

are less sensitive than 

the typical human

 But fall within the 

range of human 

response 

19

0.10

1.00

10.00

100.00

0.1 1 10

% RBC AChE Inhibition

Single Dose mg/kg 19
Using dose response predictions

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 20

0.10

1.00

10.00

100.00

0.1 1 10

% RBC AChE Inhibition

Single Dose mg/kg

Dose Response: 

Fraction of 

population with 

10% inhibition 

at different doses

Model output: 

variation in 

response at one 

dose
Range of responses in individuals 

and groups 

 Population dose 

response for RBC 

AChE inhibition 

(infants)

21

0.10

1.00

10.00

100.00

0.01 0.1 1 10

% RBC AChE Inhibition 

Single Dose mg/kg
Range of responses in individuals 

and groups 

 Population dose 

response for RBC 

AChE inhibition 

(infants)

 Range of responses at 

four doses 

22

0.10

1.00

10.00

100.00

0.01 0.1 1 10

% RBC AChE Inhibition 

Single Dose mg/kg
Range of responses in individuals 

and groups 

 Population dose 

response for RBC 

AChE inhibition 

(infants)

 Range of responses at 

four doses 

 Range of responses in 

in groups of 8 humans

23

0.10

1.00

10.00

100.00

0.01 0.1 1 10

% RBC AChE Inhibition 

Single Dose mg/kg
Derivation of human equivalent to 

the animal BMDL10

 BMDL10 estimated by 

interpolating between 

the 95% UCL of 

response at 0.5 and 0.2 

mg/kg for groups

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

0 0.5 1 1.5

%RBC AChE Inhibition 

Single Dose mg/kg

24
Derivation of human equivalent to 

the animal BMDL10

 BMDL10 estimated by 

interpolating between 

the 95% UCL of 

response at 0.5 and 0.2 

mg/kg for groups

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

0 0.5 1 1.5

%RBC AChE Inhibition 

Single Dose mg/kg 25
Derivation of human equivalent to 

the animal BMDL10

 BMDL10 estimated by 

interpolating between 

the 95% UCL of 

response at 0.5 and 0.2 

mg/kg for groups

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

0 0.5 1 1.5

%RBC AChE Inhibition 

Single Dose mg/kg 26
Derivation of human equivalent to 

the animal BMDL10

 BMDL10 estimated by 

interpolating between 

the 95% UCL of 

response at 0.5 and 0.2 

mg/kg for groups

 BMDL10 is 0.33 mg/kg

 BMDL10 in rats is 0.36 

mg/kg (Marty and 

Andrus, 2010)

 UFA = 0.36/0.33 = 1.1

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

0 0.5 1 1.5

%RBC AChE Inhibition 

Single Dose mg/kg 27
Interindividual uncertainty factor 

(UFH)

 Goal: determine the impact of human variation on the human 

equivalent of the POD 

 Requires the establishment of a “sensitive human POD”

– Defined in terms of a level of AChE inhibition and a fraction of the 

population that is protected 

– These are policy decisions that are beyond the scope of this presentation

 The following is an illustration of how the model could be used 

to determine values of UFH based on a “sensitive human POD”:

– Peak RBC AChE inhibition will be less than 10%

– 95 or 99% of the population addressed 

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 28
Derivation of “sensitive human POD” 

 The values of the sensitive 

human POD are determined 

by interpolation of responses 

for 95 and 99th percent of the 

population (single individuals) 

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

0 0.5 1 1.5

%RBC AChE Inhibition 

Single Dose mg/kg

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 29
 The values of the sensitive 

human POD are determined 

by interpolation of responses 

for 95 and 99th percent of the 

population (single individuals) 

 Response for doses at 0.5 and 

0.2 mg/kg are used for 

interpolations

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

0 0.5 1 1.5

%RBC AChE Inhibition 

Single Dose mg/kg

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

Derivation of “sensitive human POD” 

30
 The values of the sensitive 

human POD are determined 

by interpolation of responses 

for 95 and 99th percent of the 

population (single individuals) 

 Responses at doses of 0.5 and 

0.2 mg/kg are used for 

interpolations

 Values of acceptable dose are 

similar for the 95 and 99th

percentiles

– 0.24 and 0.22 mg/kg

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

0 0.5 1 1.5

%RBC AChE Inhibition 

Single Dose mg/kg

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

Derivation of “sensitive human POD” 

31
Derivation of UFH values for infants

 UFH is defined as the correction necessary to 

convert the BMDL10 equivalent in humans to the 

sensitive human POD

 The values for the sensitive human POD based on 

protecting 95th and 99th percent of the population 

are:

– UFH (for 95% of pop.) = 0.33/0.24 = 1.4 

– UFH (for 99% of pop.) = 0.33/0.22 = 1.5 

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 32
Age-related differences

 A comparison of the adult animal data to the model 

predictions for response in adults results in similar 

values UFA and UFH (<2).

 Conclusion: age-related differences in sensitivity to 

CPF are modest in both rats and humans

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 33
Summary

 The source-to-outcome model predicts that the 

differences between rats and humans are modest

– Predicted values of UFA are small (<2)

 The source-to-outcome model predicts that at doses 

below 0.3 mg/kg variation in response is modest:

– Predicted values of UFH are small (<2)

– Predicted values necessary to protect >99% of the 

population will be small

 Age-related differences are small 

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 34
Conclusions

 The source-to-outcome models provide insights 

that can be used to inform risk assessments

 The data can be used 

– To predict the potential for human health effects

– To predict compound and age-specific uncertainty 

factors

EPA Scientific Advisory Panel, Washington, DC, February 15-18, 2011 35