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



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

 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 

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 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
SHEDS-Residential 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 SHEDS-Dietary module, and we
anticipate future work on both of these documents and SHEDS-dietary
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 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

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.

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: 

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));

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);

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

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)  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: 

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);

quantification of dietary vs. residential contribution, including
relative contribution of residential exposure pathways (dermal,
inhalation, hand-to-mouth, object-to mouth);

D[iversity] & A[utocorrelation] longitudinal diary assembly approach
(Glen et al., 2007, reviewed for residential module by 2007 SAP);

identifying significant contributors at upper percentiles of dietary
exposure; and

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
SHEDS-PBPK 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.

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

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

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