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

FIFRA SAP February 15, 2011
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

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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

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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

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Ways to Refine Risk Assessment

 Exposure assessment:

 Default/high end inputs Data-driven

 Screening Models Complex models

 Deterministic Distributional/Probabilistic

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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

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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

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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

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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

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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

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13 The End