AGENDA

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)

OPEN MEETING

July 20-22, 2010

FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/

OPP Docket Telephone: (703) 305-5805

Docket Number: EPA-HQ- OPP-2010-0383

U.S. Environmental Protection Agency

Conference Center - Lobby Level

One Potomac Yard (South Bldg.)

2777 S. Crystal Drive, Arlington, VA 22202 

Scientific Issues related to SHEDS-Multimedia version 4, Peer consult on PBPK 

Modeling, and a SHEDS-PBPK Permethrin Study

Please note that all times are approximate 

(See note at the end of the Agenda)

Tuesday, July 20, 2010

9:00 A.M. Opening of Meeting and Administrative Procedures by Designated 

Federal Official – Sharlene Matten, Ph.D., Designated Federal Official, 

Office of Science Coordination and Policy, EPA

9:05 A.M. Introduction and Identification of Panel Members –

Daniel Schlenk, Ph.D., Session Chair, FIFRA Scientific Advisory Panel

9:10 A.M. Welcome and Opening Remarks – Steven Bradbury, Ph.D., Director, 

Office of Pesticide Programs, EPA

9:20 A.M. Goals and Objectives – Tina Levine, Ph.D., Director, Health Effects 

Division, Office of Pesticide Programs, EPA

9:30 A.M Introduction to and Overview of EPA/ORD/NERL’s Stochastic Human 

Exposure and Dose Simulation Model for Multimedia, 

Multiroute/Pathway Chemicals (SHEDS-Multimedia) –

Andrew Geller, Ph.D., Office of Research and Development, EPA

10:00 A.M. BREAK
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10:15 A.M. SHEDS-Multimedia Dietary Module and Permethrin Case Study

Results – Valerie Zartarian, Ph.D., Office of Research and Development, 

EPA

11:15 A\.M. SHEDS-Multimedia Residential Module and Permethrin Case Study 

Results – Valerie Zartarian, Ph.D., Office of Research and Development, 

EPA

12:15 P.M. LUNCH

1:15 P.M. SHEDS-Multimedia Model Evaluation Efforts – Valerie Zartarian, Ph.D., 

Office of Research and Development, EPA

2:00 P.M. PBPK Models of Pyrethroid Pesticides – Rogelio Tornero-Velez, Ph.D.,

Office of Research and Development, EPA

3:00 P.M. BREAK

3:15 P.M. Bayesian Calibration of PBPK Models – Jimena Davis, Ph.D., Office of 

Research and Development, EPA 

4:00 P.M. Extrapolation of Animal-Calibrated Models to Humans –

Rogelio Tornero-Velez, Ph.D., Office of Research and Development, EPA

4:45 P.M. ADJOURN
3

AGENDA

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)

OPEN MEETING

July 20-22, 2010

FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/

OPP Docket Telephone: (703) 305-5805

Docket Number: EPA-HQ- OPP-2010-0383

U.S. Environmental Protection Agency

Conference Center - Lobby Level

One Potomac Yard (South Bldg.)

2777 S. Crystal Drive, Arlington, VA 22202 

Scientific Issues related to SHEDS-Multimedia version 4, Peer consult on PBPK 

Modeling, and a SHEDS-PBPK Permethrin Study

Please note that all times are approximate 

(See note at the end of the Agenda)

Wednesday, July 21, 2010

9:00 A.M. Opening of Meeting - Administrative Procedures by Designated 

Federal Official - Sharlene Matten, Ph.D., Designated Federal Official, 

Office of Science Coordination and Policy, EPA

9:05 A.M. Introduction and Identification of Panel Members –

Daniel Schlenk, Ph.D., Session Chair, FIFRA Scientific Advisory Panel 

9:10 A.M. Follow-up from Previous Day’s Discussion – Office of Pesticide 

Programs and Office of Research and Development, EPA

9:25 A.M. Examining Uncertainty in the Linked Model – R. Woodrow Setzer, 

Ph.D., Office of Research and Development, EPA

10:15 A.M. BREAK

10:30 A.M. Permethrin SHEDS-PBPK Linked Model Case Study –

Rogelio Tornero-Velez, Ph.D., Office of Research and Development, EPA

11:15 A.M. Plans to Extend the SHEDS-PBPK Permethrin Case Study to Multiple 

Pyrethroids – Rogelio Tornero-Velez, Ph.D., Office of Research and 

Development, EPA
4

12:00 P.M. LUNCH

1:00 P.M. PUBLIC COMMENTS

2:00 P.M. Charge to the Panel – Issue 1: Usability aspects of the SHEDS 

Dietary Module (SHEDS-Dietary v.1.0) and the SHEDS Residential 

Module (SHEDS-Residential v.4.0)

A. SHEDS DIETARY

Question 1-1: What, if any, difficulties were encountered in loading or running the 

SHEDS-Dietary software?

Question 1-2: Please comment on the organization, clarity, completeness, and 

usefulness of the SHEDS Dietary Technical Manual and the User Guide. Please provide 

any suggestions for improvement.

Question 1-3: Please comment on the organization and usability of the SHEDS-Dietary 

GUI (Graphic User Interface), and whether additional changes would be helpful the 

Dietary SHEDS.

B. SHEDS RESIDENTIAL

Question 1-4: What, if any, difficulties were encountered in loading or running the 

software for SHEDS-Residential software?

Question 1-5: Please comment on the organization, clarity, completeness, and 

usefulness of the SHEDS Residential Technical Manual and the User Guide? Please 

provide any suggestions for improvement.

Question 1-6: Please comment on the organization and usability of the SHEDS 

Residential GUI, and whether additional changes would be helpful for the Residential 

SHEDS.

3:15 P.M. BREAK

3:30 P.M. Charge to the Panel – Issue 2: Documentation, completeness, and 

clarity of technical aspects of SHEDS Dietary v. 1.0 and SHEDS 

Residential v. 4.0

Question 2-1:

BACKGROUND: In August 2007, the FIFRA SAP reviewed the model and

documentation for the SHEDS Residential module (then termed “SHEDS-Multimedia

version 3”), plans for the dietary module, and plans for extending the model to 
5

aggregate the dietary and residential modules. The 2007 SAP report, EPA responses to 

the 2007 SAP comments, and specific changes from version 3 to version 4 of the 

Residential module have been provided to this SAP in the materials and background 

documents.

Please comment on whether the exposure algorithms and model components as 

described in the Technical Manuals are science based and technically correct for a) the 

Dietary module and b) the Residential module.

Question 2.2:

BACKGROUND: The 2007 FIFRA SAP, which reviewed the SHEDS Residential model 

and code, was provided with the SAS code and asked to comment on whether the code 

was consistent with the descriptions provided in the SHEDS Technical Manual, and 

whether the code was clear and was adequately described and annotated such that the 

algorithms could be followed and understood. At that time, the Panel was not provided 

with a code and there was no graphical user interface for the SHEDS dietary module. 

The 2007 SAP review of the dietary aspect of SHEDS was limited to reviewing several 

conceptual issues associated with dietary exposure and covered both data issues and 

algorithms. In the intervening three years, the Agency has updated SHEDS residential 

model to include applicator exposures (the 2007 version was limited to post application 

exposures only) and has made a number of additional changes as per the 2007 Panel 

review comments. Additional changes were made based on considerations that arose 

during review of the model and the desire to simplify the code and reduce the number of 

user-specified inputs. The specific changes that were made are listed and detailed in 

Section 1.6 of the Residential Technical Manual entitled “Changes from SHEDSResidential version 3 to version 4”. The current status of the SHEDS-Dietary module 

remains behind the residential module. Nevertheless, a number of advances have been 

made, including: (i) development of a GUI through which users can more easily develop 

and produce dietary exposure estimates, (ii) ability to read residue input files from 

another aggregate model (*.rdf), (iii) option to use the NHANES\WWEIA food 

consumption data (FCID recipes will be incorporated following public release), (iv) the 

ability to conduct Eating Occasions Analyses, (v) the ability to select among different 

Food Residue Options, (vi) simultaneous use of multi-chemical residue inputs for 

cumulative exposure assessment (i.e., pre-simulation adjustments using RPFs not 

required), and (vii) options for generating longitudinal (multi-day) consumption patterns. 

The Agency also prepared a draft User Guide and a Technical Manual for the SHEDSDietary module, and we anticipate future work on both of these documents and SHEDSdietary advances.

A. SHEDS RESIDENTIAL

Version 4 of SHEDS-Residential provides a number of additional capabilities compared 

to the SHEDS-Multimedia v.3 model reviewed in August, 2007. A summary the main 

changes from SHEDS-Residential version 3 to version 4 is provided in Section 1.6 of 

the Residential Technical Manual to which the Panel may wish to refer. The changes 
6

include: the ability to perform multichemical runs; the ability to reproduce (pseudo-) 

random number seeds; the capability of evaluating applicator (handler) exposures (and 

not just post application exposures); a new longitudinal diary assembly method based 

on the D&A statistic which supplements the 8-diary method from version 3; and a new 

option for evaluating uncertainty using bootstrap methods and the implementation of 

Sobol’s method for sensitivity analysis, among numerous others. 

Please comment on whether the annotated code for the SHEDS residential model (i) is 

sufficiently clear such that the algorithms can be followed and understood; and (ii) 

whether the algorithms defined in the Residential Technical Manual are consistent with 

those present in the code. In what ways might the code, its annotations, or the 

description in the Technical Manual be improved? Please consider in particular the new 

components of the code (i.e., added or modified since the 2007 SAP) as detailed and 

described in Section 1.6 of the Residential Technical Manual.

B. SHEDS DIETARY

Version 1 of SHEDS-Dietary represents the first version which provides the user with a 

graphical “point and click” interface and other enhancements and capabilities such as 

the ability to read residue input files from other aggregate models (*.rdf), the option to 

use the NHANES\WWEIA food consumption data, and Eating Occasions Analyses 

options. These are detailed in the Dietary User Guide and Dietary Technical Manual. 

While the underlying SAS code has not at this time been fully annotated and/or is not as 

“reader-friendly” as the residential code, does the Panel have any comments or 

suggestions on the structure or form of the code or ways in which the code may be 

improved? Can the Panel identify any apparent discrepancies between the calculations 

described in the Dietary Technical Manual and the algorithms operating in and 

described by the SAS code?

5:30 P.M. Adjourn
7

AGENDA

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)

OPEN MEETING

July 20-22, 2010

FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/

OPP Docket Telephone: (703) 305-5805

Docket Number: EPA-HQ- OPP-2010-0383

U.S. Environmental Protection Agency

Conference Center - Lobby Level

One Potomac Yard (South Bldg.)

2777 S. Crystal Drive, Arlington, VA 22202 

Scientific Issues related to SHEDS-Multimedia version 4, Peer consult on PBPK 

Modeling, and a SHEDS-PBPK Permethrin Study

Please note that all times are approximate 

(See note at the end of the Agenda)

Thursday, July 22, 2010

9:00 A.M. Opening of Meeting - Administrative Procedures by Designated 

Federal Official – Sharlene Matten, Ph.D., Designated Federal Official, 

Office of Science Coordination and Policy, EPA

9:05 A.M. Introduction and Identification of Panel Members –

Daniel Schlenk, Ph.D., Session Chair, FIFRA Scientific Advisory Panel

9:10 A.M. Follow-up from Previous Day’s Discussion – Office of Pesticide 

Programs and Office of Research and Development, EPA

9:30 A.M. Charge to the Panel – Issue 3: Strengths and Limitations of PBPK 

Approaches

BACKGROUND: The FIFRA Scientific Advisory Panel (SAP) convened in August 16 -

17, 2007, to address science issues on approaches to model pyrethroids. To guide 

discussions, four charge questions were developed concerning: (1) application of a 

common model structure; (2) the parallelogram approach for extrapolation; (3) dose 

metric considerations; and, (4) pyrethroid stereochemistry. Recognizing that the 2007 

SAP has commented on these approaches, the Agency seeks comment from the 

current SAP on issues concerning PBPK model calibration and the coupling of SHEDS 

and PBPK.
8

Question 3-1: Please comment on the strengths and limitations of the pharmacokinetic 

modeling approach for pyrethroids with added attention to the PBPK structures for 

interpreting aggregate exposure data from SHEDS. 

Question 3-2: Please comment on the Bayesian approach outlined here for calibrating 

the PBPK model against rodent PK data, including the use of computational and in vitro 

methods to develop priors for chemical-specific parameters.

Question 3-3: Please comment on the approach used to characterize the animal-to 

human extrapolation, including the uncertainty of the extrapolation.

Question 3-4: Please comment on the plausibility and limitations of model-predicted 

dose-metrics, such as area under the curve (AUC), peak tissue values, time above a 

toxicological threshold, or AUC above a toxicological threshold, in analyzing animal 

dose-response data and in extrapolation to humans.

Question 3-5: The presentation described methods for addressing uncertainty in model 

parameters and extrapolation from animals to humans. What other important sources of 

uncertainty need to be addressed for either the SHEDS exposure model or the PBPK 

model?

10:30 A.M. BREAK

10:45 A.M. Charge to the Panel – Issue 3: Strengths and Limitations of PBPK 

Approaches, continued

12:00 P.M. LUNCH

1:00 P.M. Charge to the Panel – Issue 4: Model Evaluation

BACKGROUND: Model evaluation is an important component of model development 

that helps ensure that the quality of the model meets the regulatory needs of OPP and 

other end-users. In performing its model evaluation, the Agency compared SHEDS 

model output – specifically exposure and urinary concentration estimates – with both 

output from other exposure assessment models and data from observational studies. 

These comparisons permit the SHEDS development team and model end-users to 

compare and contrast outputs among different models, to compare estimates with 

measured real-world data, to explore and investigate reasons for any differences, and to 

evaluate and better understand the reasons behind these differences. As part of the 

model evaluation procedure for SHEDS, the Agency has attempted to evaluate the 

SHEDS model in a number of ways. These include:

a) comparison of SHEDS-Dietary cross-sectional output to DEEM-FCIDTM; the

DEEM-FCIDTM model is commonly used by OPP in its regulatory decisions and

was reviewed by the SAP in 2000 (see SHEDS-Dietary Technical Manual

(Section.2.8.1) and EPA 2010 Response to Comment (p.10));
9

b) comparison of (a) SHEDS-Dietary arsenic and permethrin estimates against

duplicate diet data and (b) the predicted urinary concentrations from the 

SHEDPBPK linked model with the measured arsenic concentrations in urine from 

the 2003-2004 NHANES biomonitoring program (see SHEDS-Dietary Technical

Manual and link to Xue et al. 2010 article provided in background materials);

c) comparison of SHEDS Residential outputs with outputs from other models or

calculation methods (ORD’s Draft Protocol, OPP’s Residential Standard

Operating Procedures (1997), Calendex, CARES, and ConsExpo) which was 

originally organized as a day long symposium at the annual meeting of ISEA in

2008 held in Pasadena, CA (see slides in background materials); and

d) following the model quality assurance procedures as detailed in Chapter 8 of the

SHEDS-Residential Technical Manual and EPA’s SHEDS-Multimedia Quality

Assurance Project Plan (QAPP)1 these included EPA-contractor cross-checking 

of the code and hand-calculation verification on a subset of data for a simulated

individual to ensure the SHEDS-Residential algorithms were implemented and

performing as intended.

Question 4: Please comment on the process used to evaluate SHEDS. Are the above 

listed ways in which SHEDS was evaluated appropriate? In what ways could they be 

improved? Are there other methods through which the model should or can be 

evaluated? Are there other data (e.g., biomonitoring data, duplicate diet data) that the 

Panel is aware of through which the SHEDS model can be compared?

3:00 P.M. BREAK

3:15 P.M. Charge to the Panel – Issue 5: SHEDS-PBPK Permethrin Case Study

Question 5-1: EPA has used a pyrethroid insecticide, permethrin, as a case study to 

link the SHEDS exposure model with PBPK modeling in order to be able to better 

interpret and understand exposure data in terms of dose and target-organ dose and 

assist in refining exposure estimates and associated risk. 

Please comment on the approaches and offer alternatives and suggestions for: 

a) linking dietary consumption diaries and residential activity information (e.g. key 

factors used for matching food consumption and activity pattern diaries such as 

caloric consumption);

 

1The QAPP (and additional material related to SHEDS) is available on the ORD SHEDS website at

http://www.epa.gov/heasd/products/sheds_multimedia/sheds_mm.html
10

b) quantification of dietary vs. residential contribution, including relative contribution 

of residential exposure pathways (dermal, inhalation, hand-to-mouth, object-to 

mouth);

c) D[iversity] & A[utocorrelation] longitudinal diary assembly approach (Glen et al., 

2007, reviewed for residential module by 2007 SAP);

d) identifying significant contributors at upper percentiles of dietary exposure; and

e) techniques and utility of bootstrapping approaches for quantifying uncertainty and 

its interpretation.

Question 5-2: Please comment on whether the model evaluation approach comparing 

the linked SHEDS-PBPK dose predictions and NHANES (National Health and Nutrition 

Exams Survey) biomonitoring data is reasonable. Are there other model evaluation 

methods that the Panel would like to see the Agency perform?

Question 5-3: Please comment on the approaches presented to extend the SHEDSPBPK Permethrin Case Study to include exposure to cypermethrin and cyfluthrin. 

Furthermore, please advise on other methodologies (e.g., cross-sectional vs. 

longitudinal), exposure scenarios, chemicals, and datasets which may be useful to 

consider in assessing SHEDSPBPK simulations of pyrethroids.

5:30 P.M. ADJOURN

Please be advised that agenda times are approximate; when the discussion for 

one topic is completed, discussions for the next topic will begin. For further information, 

please contact the Designated Federal Official for this meeting, Dr. Sharlene Matten, via 

telephone: (202)-564-0130; fax: (202) 564-8382; or email: matten.sharlene@epa.gov.