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 compound specific uncertainty factors

EPA Scientific Advisory Panel, Washington, DC, February 15 - 18, 2011 3EPA 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 - 03Blood Concentrationon 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 - 03Blood 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 - 03Blood 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 - 03PercentInhibition ofRBCAChE (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 - 03PercentInhibition ofRBCAChE (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 - 03PercentInhibition ofRBCAChE (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 - 03Percent 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 (5 th day)

Dietary dose

response (5 th 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 14EPA 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

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### 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 (UF A 

# )  

# 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 BMDL 10 

# for humans  

# UFA 

# is the ratio of BMDL 10 

# in rats to BMDL 10 

# in humans  

# Illustration is based on Marty and Andrus (2010) study (Attachments G and H)

– BMDL 10 

# 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 BMDL 10  

# BMDL 10 

# 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 BMDL 10  

# BMDL 10 

# 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 BMDL 10  

# BMDL 10 

# 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 BMDL 10  

# BMDL 10 

# estimated by interpolating between the 95% UCL of response at 0.5 and 0.2 mg/kg for groups  

# BMDL 10 

# is 0.33 mg/kg  

# BMDL 10 

# 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 (UF H

# )  

# 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 99 th 

# 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 99 th 

# 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 99 th 

# 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 99 th 

# 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 UF H 

# values for infants  

# UFH 

# is defined as the correction necessary to convert the BMDL 10 

# equivalent in humans to the sensitive human POD  

# The values for the sensitive human POD based on protecting 95 th 

# and 99 th 

# 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 UF H 

# 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