### INTRODUCTION & REGULATORY CONTEXT: LINKING OF A PROBABILISTIC EXPOSURE MODEL & A PHYSIOLOGICALLY- BASED PHARMACOKINETIC/PHARMACODYNAMIC MODEL-- CHLORPYRIFOS CASE STUDY ANNA LOWIT, PH. D. SENIOR SCIENTIST USEPA, OFFICE OF PESTICIDE PROGRAMS February 15, 2011 FIFRA SAP

# Introduction
 

## Topics in this Presentation:  

## Improving risk assessment methodology & the role of probabilistic PBPK/PD modeling  

## On - going efforts to link probabilistic exposure models with PBPK/PD models  

## Regulatory context & status of chlorpyrifos human health risk assessment  

## Overview of the charge questions 2

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# Introduction
 

### 2007 & 2009 NRC Reports  

### Toxicity Testing in the 21st Century: A Vision and a Strategy:

 Emphasizes value of in vitro techniques  Human tissues & lifestage specific data  Use in PBPK models  

### Science & Decisions:  Encourages the Agency to move towards probabilistic risk assessment  Improving the scientific support of defaults, using data to replace defaults, & considering alternatives  

### Both reports discuss importance of biomonitoring data & epidemiology studies in risk assessment 3

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# Human Health Risk Assessment
 

## EPA develops many types of risk assessments for a variety of regulatory purposes  

## These risk assessments vary in their scope & purpose  

### Level of refinement depends on a variety of factors such as regulatory context & data availability

 

### Screening level to highly refined  

### Need for efficient use of resources 4

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# Ways to Refine Risk Assessment
 

## Exposure assessment:  

### Default/high end inputs Data - driven  

### Screening Models Complex models  

### Deterministic Distributional/Probabilistic 5

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# Ways to Refine Risk Assessment
 

## Hazard Assessment:  

### Incorporation of mode of action  

### Use of benchmark dose methodology over NOAELs/LOAELs  

### Data - derived defaults for inter- or intra -species extrapolation  

### PBPK models to estimate tissue dose & human equivalent concentrations

 

### More refined with lifestage specific inputs & use of distributions for parameters 6

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# Ways to Refine Risk Assessment

 

### Linked models: Probabilistic exposure assessment with distributional PBPK or PBPK/PD models  

### Efforts involving pesticides:  Collaborative effort between OPP & Office of Research and Development (NHEERL, NERL, NCCT)  Status reviewed by SAP in summer 2010  Linkage of SHEDS with permethrin PBPK model  Research effort by DowAgroSciences, Dow Chemical, & Battelle at Pacific Northwest Laboratory  Linkage of CARES with chlorpyrifos PBPK/PD model 7

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# Current SAP Review
 

## Purpose:  

### Review the approaches & concepts in the Dow research  

### Not a formal, detailed model review (code, inputs, etc.)  

## Current research & analysis is focused on  

## AChE inhibition  

## Food exposure  

## Infants, 3 year old, & adults 8

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# Regulatory Context: Chlorpyrifos
 

## Organophosphate pesticide which was first registered in 1965  

## In June 2000:  

## The technical registrants entered into an agreement with the Agency to eliminate and phase out nearly all uses that result in residential exposures  

## Some mitigation on food (apples & tomatoes)  

## Registration Eligibility Decision (RED) in 2006 9

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# Regulatory Context: Chlorpyrifos

 

### September 2007 petition from NRDC & PANNA to revoke all tolerances & cancel registrations  Settlement includes release of a preliminary human health risk assessment by June 1, 2011  

### FIFRA SAP in 2008: New science on infants, children, & pregnant women from laboratory toxicology & epidemiology studies

 Evaluated both AChE & non -cholinergic modes of action  

### EPA will not be using the PBPK/PD modeling in the June risk assessment  Report from this SAP meeting will not be available until May 2011  Key exposure pathways & lifestages is not included in the current effort 10

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# The End 13