OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

RE: Meeting between Dow AgroSciences (DAS) and EPA to Discuss DAS’ Work and 

Possible Enhancements to their Physiologically Based Pharmacokinetic Model

(PBPK)

List of Documents

1. Meeting Summary Page 1

2. Meeting Sign in Sheet Page 2

3. DAS PowerPoint Presentation Page 3

Meeting Summary

On Wednesday, May 23, 2012, EPA’s Office of Pesticide Programs met with DAS to discuss 

their PBPK model. DAS is considering enhancements to the model for dermal, pregnancy, and 

inhalation. The enhancements could take from as little as three months (dermal) to upwards of a 

year and a half (inhalation). DAS anticipates discussing the progress of any enhancements with 

EPA at a future data.
EPA and Registrant Meeting 

Chlorpyrifos and PBPK 

May 23,2012 

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Review of current model 

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Dow AgroSciences

May 23, 2012

Page 1
History of Source-to-Outcome Modeling for 

Chlorpyrifos

• Three phases for the work

– ACC LRI project (2006 - 2010)

– SAP preparation (2010 - 2011)

– Post SAP (2011 - 2012)

• Initial focus was research oriented

– Can models be linked?

– Do models provide plausible predictions?

– What drives human variability?

• In exposure 

• In response

Page 2
The PBPK/PBPD model

• The fundamental model has a long history of use

– Initially developed and validated with animal study and 

human volunteer data sets (Timchalk et al., 2002)

– Recently used to design and interpret results from 

Comparative Cholinesterase study conducted in adult and 

preweanling rats (Marty et al., 2012)

– LifeStage version of PBPK model used to correlate in vitro 

substrate concentrations with in vivo exposure levels 

(Bartels et al, 2012; April 2012 SAP mtg)
ACC-LRI Project 2006-2010

• Goal can you do a non cancer risk assessment with out 

uncertainty factors

• DAS/Dow/Battelle collaboration

• Based on existing metabolism data

• Focus on linking the models and comparison of predictions to 

published data

• Oral route: Two ages, 

– 3 year olds and adults

• Two publications Price et al. 2011, and Hinderliter et al. 2011 

(Awarded best modeling paper of 2011 by SOT)

Page 4
Preparation for SAP (2010 – 2011)

• Develop new Lifestage model for age-related changes of typical individual

• Incorporated human data on metabolism (Smith et al. 2011) 

– Measured human variation in key enzymes for activation and detoxification of chlorpyrifos using 

chlorpyrifos as a substrate 

– Reflecting human variation and impact of age

– Modest sample size (30 individuals)

• Develop model of human variation for ages six months to adults

• SAP report

– Comparison to published data on human variation

– Conclusions on human variation in RBC response

• Variation in response is dose dependent (more variation at high doses) 

• Minimal impact of age (infants are slightly more sensitive than adults)

• Variation is driven by interindividual variation in metabolism not physiology nor differences in levels of physical 

activity 

– Modeled inter-species and inter-individual uncertainty factors

• Values of less than 2 are predicted to be protective 

Page 5
Post SAP (2011 – Now)

• Investigation of issues raised by SAP

– Questions concerning the metabolism data

– Sensitivity analysis

– Alternative approach for assessing safety factors (separate 

modeling of uncertainty and variation)

• Initial work suggests that findings presented to SAP are unlikely to change 

after addressing the SAP comments 

• Publications

– Metabolism data published (Smith et al., 2011)

– Three additional publications are under development 

• 1) Lifestage model, 2) variation model, 3) modeling of uncertainty factors

• Model validation will be based on Kisicki human volunteer study data, pending 

EPA decision on ethical acceptance

Page 6
Future Work (needs to be priortized)

• PBPK modeling

– Extension of oral models to inhalation and dermal

– Extending existing model from 6 months back to birth

– Lactational route of exposure 

– Developing a late stage pregnancy model

• Evaluation of non-dietary exposure scenarios

– Occupational, residential, etc.

Page 7
Questions?
References

• Bartels, M. J., Poet, T. S., Price, P. S., Hinderliter, P. M., and Juberg, D. R. (2012). Use of a validated PBPK/PD model for chlorypyrifos to

correlate in vitro substrate concentrations with in vivo systemic exposures. The Toxicologist, Volume 126: March 2012. #65. 

• Paul M. Hinderliter, Torka S Poet, Michael J Bartels, Charles Timchalk, Paul S Price (2011), Development of a Source-to-Outcome Model for 

Dietary Exposures to Insecticide Residues: An Example Using Chlorpyrifos, Reg. Toxicol. Pharmacol., 61, 82-92. 

• Paul S. Price, Karl D. Schnelle, Cheryl B. Cleveland, Michael J. Bartels, Paul M. Hinderliter, Charles Timchalk, and Torka S. Poet (2011)). 

Application of a Source-to-Outcome Model for the Assessment of Health Impacts from Dietary Exposures to Insecticide Residues. Reg. 

Toxicol. Pharmacol, 61, 23-31. 

• Smith, J N, Timchalk, C, Bartels, M J., Poet, T S. (2011), In vitro age-dependent enzymatic metabolism of chlorpyrifos and chlorpyrifos-oxon in 

human hepatic microsomes as well as chlorpyrifos-oxon in plasma. Drug Metab. Disp, 39, 1352-1362. 

• Marty, M. S., Andrus, A. K., Bell, M. P., Passage, J. K., Perala, A. W., Brzak, K. A., Bartels, M. J., Beck,, M. J., and Juberg, D. R. (2012). 

"Cholinesterase Inhibition and Toxicokinetics in Immature and Adult Rats After Acute or Repeated Exposures to Chlorpyrifos or Chlorpyrifosoxon", Reg. Tox. Pharmacol, in press.[1]

• Timchalk C, Nolan RJ, Mendrala AL. A Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the

organophosphate insecticide chlorpyrifos in rats and humans. Toxicological Sciences: An Official Journal of the Society of Toxicology 2002; 

66:34-53 %U http://www.ncbi.nlm.nih.gov/pubmed/11861971.
Opportunities for the PBPK/PD 

Linked Model to Assist with 

Exposure Questions Raised at 

2012 SAP
Dose Reconstruction for Columbia Study

• Goal - to transparently make the best use of the data on 

exposures

• Access to raw data is very important 

– Value of assessment will be limited by the lack of 

access to exposure data 

• Privacy of participants can be protected (access to 

personal identifiers are not needed)

Page 11
Capabilities Needed

• PBPK model of maternal and fetal blood levels for late 

stage pregnancy

• Oral, dermal, and inhalation routes of exposure

• Ability to track individuals for periods of 30 or more days
Provide a Framework to Make the Best 

Assessment of Exposure Possible

• A PBPK model could serve as a framework to integrate all of the 

exposure-related data for an individual

– Cord blood, maternal blood, air monitoring, and meconium

– Timing of measurements relative to one another

– Pesticide use data in the home

– Characteristics of the home 

– Time of year

• Goal would be to use all of the data to make a prediction of the 

concentration of chlorpyrifos in fetal and maternal blood at the time the 

mother left her home 

• This value could be used in regression models for various effects
Clarify How Exposures Occurred

• Were blood levels higher in the residences then in the 

hospital?

• Was the major route of exposure inhalation, dermal, or 

oral?

• Did the route vary across individuals?

• What was the contribution of diet before and after 2001?

• What impact would variation in route have on measured 

blood levels?
Improve the Understanding of Exposures 

• Remove certain confounding factors 

– Impact of variation of time since last residential exposure

– Impact of variation in blood chemistry that could affect serum levels

– Residential mobility (did the mother move since the first trimester?)

• Provide a check on the dose estimates

– Predict the daily doses to the mother and compare the doses to 

those predicted by EPA’s residential SOPs 
Investigate Relationship of Biomonitoring data to 

Historical Exposures 

• Demonstrate if biomonitoring data can estimate historical exposures 

and if so how far back?

– Create longitudinal models of aggregate exposure

– Calibrate the models with the biomonitoring data

– Determine correlations between sampled levels and earlier exposures

• Determine if biomonitoring data can be used to predict categories of 

exposure to chlorpyrifos 

– Never exposed

– Limited potential for exposure

– Large potential for exposure