OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

RE: Teleconference between Dow AgroSciences (DAS) and EPA to Update EPA on 

the Current Status of the Physiologically Based Pharmacokinetic Model (PBPK)

List of Documents

1. Meeting Summary Page 1

2. Meeting Attendees Page 1

3. DAS Talking Points for the Meeting Page 2

1. Meeting Summary

On Wednesday, August 7, 2013, EPA’s Office of Pesticide Programs met with Dow 

AgroSciences (DAS) via teleconference to get an update on DAS’ PBPK model activities. DAS 

indicated that a third party review for validating the model was currently underway. They expect 

to have a complete version of model to submit to the Agency by the end of September 2013. 

They have already submitted the oral and dermal components of the model to EPA. Only the 

inhalation portion is outstanding.

2. Meeting Attendees

DAS attendees

Mike Bartells, Dow

Daland Juberg, Dow

Paul Price, Dow

Torka Poet, Battelle

EPA attendees

Anna Lowit, HED

Jeff Dawson, HED

Wade Britton, HED

Chester Rodriguez, HED

Mike Metzger, HED

Tom Myers, PRD

Joel Wolf, PRD
Chlorpyrifos PBPK Model ProjectsDow AgroSciences

August 7, 2013 Update

Michael Bartels, Ph.D.- Dow Chemical

Paul Price, Ph.D.- Dow Chemical

Torka Poet, Ph.D.- Battelle PNL
• PBPK model for Chlorpyrifos (CPF)

– used to predict biomarkers of exposure: 

• CPF, CPF-oxon and trichloropyridinol (TCP)

– and cholinesterase inhibition effects in:

• plasma, RBC, brain

– has been expanded to support: 

• human life-stages

• CPF-oxon exposures

• multiple exposure routes

PBPK Model Applications
• 1984/2002 Models-

– showed correlation between CPF/TCP levels and ChE inhibition 

in rats and humans

• 2009-

– utilized model to design Comparative Cholinesterase assay

– published gestational model, providing tool to back-calculate 

CPF exposures from Columbia Univ epidemiology study data

• 2011-

– proposed improved, chemical-specific safety factors for 

chlorpyrifos to EPA Science Advisory Panel

• 2013-

– showed lack of ChE effects in RBC and brain following simulated 

exposures to Oxon in drinking water

– will issue finalized chemical-specific safety factors for CPF

– will derive Biomonitoring Equivalents value for CPF exposures

PBPK Model Applications
PBPK Model ProjectsTimeline

Model Exposure(s) Lifestages Report/Paper 

PK Oral, Dermal Adult (human) Nolan- TAP: 73, 8-15)

PBPK/PD Oral Adult (rat/human) Timchalk- Tox Sci: 66, 34-53)

Gestation Oral Human (maternal/fetus) Lowe- Tox Sci 108: 258-272)

Life-Stage Oral Human (1 month-adult) Submitted (Reg Tox Pharm)

Variation Oral Human (1 month-adult) Manuscript in Preparation

Oxon Oral Human (1 month-adult) DAS Report- MRID 49047701

Dermal Oral, Dermal Human (1 month-adult)* DAS Report- MRID 49074901

Inhalation Oral, Dermal, Inhalation Human (1 month-adult)* In Progress- September, 2013

External Validation of Oral / Dermal / Inhalation PBPK model In Progress- September, 2013

* portal-of-entry tissue metabolism for dermal & inhalation routes will based on average adult values
Chlorpyrifos Chloropyrifos Oxon

Exposure

Route Data Variation Data Variation Data Variation Data Variation

Oral Yes ** Done Yes *** Not applicable No In progress Yes *** Not applicable

Dermal Yes ** Possible

Inhalation **** No Possible Yes Not applicable No Possible Yes Not applicable

* All Lifestages can be modeled (6 months - adult)

** Model fit to data from Nolan (Tox. Appl. Pharm., 73: 8-15, 1984)

*** Model fit to data from Timchalk et al. (Tox. Sci., 66: 34-53, 2002) and Marty et al. (Reg. Tox. Pharm, 63: 209-224, 2012)

**** In progress, as of 8/7/13. Model will be fit to 2010 and 2013 Inhalation study data of DAS for CPF and Oxon

Human * Rat * Human * Rat *

Not applicable Not applicable Not applicable

PBPK Model ProjectsCombined-Route model capabilities

Applications of PBPK model, with data sources used for validation
• August – September Timeline details

– Variation model completed- draft manuscript in preparation

– Chemical-specific safety Factors report draft by September 16

• for oral CPF exposures, but will be extended to Oxon

– Inhalation model in development- status update by August 27

• will include CPF and Oxon

– Model 3rd party validation in progress

• Any EPA input on scope of validation ?

PBPK Model Applications- Miscellaneous