2

http://www.epa.gov/heasd/products/sheds_multimedia/sheds_mm.html (note: please scroll 

down about half the page past the SHEDS v. 3 section at the top to the part entitled “Download 

Drafts of SHEDS-Multimedia (Residential Module) version 4 and Dietary Module version 1.0”

in order to view the material for this Panel Meeting )

As indicated earlier, the upcoming July 2010 SAP will focus on work conducted by ORD and OPP 

scientists since the SHEDS 2007 review on these models, and will consist of:

 (i) A formal review of SHEDS-Multimedia version 4 which consists of 2 modules: 

SHEDS-Dietary v.1 and SHEDS-Residential v. 4. SHEDS-Dietary v.1 is a probabilistic, 

population-based dietary exposure assessment model that can simulate individual 

exposures to chemicals in food and drinking water over different time periods (e.g., 

daily, yearly). SHEDS-Residential v. 4 is a probabilistic, population-based residential 

exposure assessment model that can simulate cumulative (multiple chemicals) or 

aggregate (single chemical) residential exposures over time via multiple routes of 

exposure for different types of chemicals and scenarios. 

 (ii) A peer consult on refinements to ORD’s PBPK models and how SHEDS outputs are 

introduced into and used by PBPK models; and

 (iii) Demonstration of the application of linked SHEDS-PBPK models with a permethrin 

case study is part of the Agency’s ongoing process to enhance probabilistic risk 

assessments and OPP’s ongoing efforts to address statutory requirements under the

Food Quality Protection Act (FQPA) of 1996. The overall goal of this SAP is to review 

various methods and models that will inform the Agency’s anticipated cumulative risk 

assessment (CRA) for pyrethroids in addition to future cumulative risk assessments on 

other pesticide groups. The SAP session will review individual and linked state-of-thescience exposure and dose assessment tools in the context of an example case study

(permethrin), including proposed methodologies using linked SHEDS and PBPK models. 

Additional details regarding this upcoming July SAP review were provided to the panel in the 

June 16 transmittal memo and are not repeated here.

To assist the July 20-22, 2010 FIFRA SAP in their review of the SHEDS-model, the PBPK and the 

SHEDS-PBPK linkage, and the permethrin case study, each FIFRA SAP member was earlier 

provided with relevant material on two CD-ROMs. The present transmittal package contains the 

following additional material which pertains to the SHEDS- PBPK linkage issues, the permethrin 

case study, and model comparisons:
3

List of SHEDS SAP Deliverables: Package #2

CD-ROM Deliverable Title/Description/Comments

CD-ROM

3

OF

3

Charge Questions for 

Issues 3 through 5

Provided in Attachment 1 of this transmittal letter in which all charge 

questions for the Panel are included. 

Background paper for 

PBPK aspects

Physiologically-Based Pharmacokinetic Models of Pyrethroids: Bayesian 

Calibration and Their Use in Interpreting Probabilistic Exposure Data. 

[PBPK_Calibration_Uncertainty_and_Linkage.pdf]

SHEDS permethrin 

case study input 

spreadsheets (.xls)

See: 

SAP_SHEDSv4_permethrin_inputs_All Scenarios_06-22-

2010_FINAL.xls

ACS/ISEA ModelModel Comparison 

(pdf)

See:

ISEA 2008 ModelComparison SAP slides_FINAL.pdf

SHEDS Arsenic 

Evaluation Paper (EHP)

Xue, J. et al. Probabilistic Modeling of Dietary Arsenic Exposure and 

Dose and Evaluation with 2003-2004 NHANES Data. 2010. 

Environmental Health Perspectives 118(3): 345-350. 

Available at: Environmental Health Perspectives 118: 345-350

The charge questions, in their entirety and covering all five issues, are presented in Attachment 

1 to this memorandum. A complete list of material provided to the Panel (both in the previous 

July 16 letter and this July 24 letter) is presented as a summary in Attachment 2. 
4

ATTACHMENT 1: 

SAP Charge Questions for FIFRA SAP July 20-22, 2010
5

SAP Charge Questions for FIFRA SAP July 20-22, 2010

Review of EPA’s Stochastic Human Exposure and Dose Simulation (SHEDSMultimedia) Model -- Dietary and Residential Modules; PBPK Modeling; and 

SHEDS-PBPK Permethrin Case Study

______________________________________________________________________________

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

helpful for the Residential SHEDS.
6

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. 

QUESTION 2-1: 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(a) and 2-2(b): 

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 userspecified 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) 
7

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 

QUESTION 2-2(a): 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 

QUESTION 2-2(b): 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? 
8

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-tohuman 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?

Issue 4: Model Evaluation

Question 4:

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:
9

(i) 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))

(ii) 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) 

(iii) 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). 

(iv) 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)1these 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? 

 

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:

 

1

The 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

 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)2;

 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.

 

2 Note that this cannot be done as part of either the SHEDS-Dietary or SHEDS-Residential graphical user interface 

and is not a standard component or feature of SHEDS at this time. For purposes of this permethrin case study, this 

linkage of dietary consumption diaries and residential activity information was performed by ORD outside and 

independent of SHEDS using SAS code specifically designed for this purpose. 
11

ATTACHMENT 2:

Material Provided to Panel for FIFRA SAP July 20-22, 2010
12

July 20-22, 2010 FIFRA SAP Background Material 

CD-ROM Deliverable Title/Description/Comments

CD-ROM

1

OF

3

Installation Instructions: 

SHEDS-Residential v.4 

& SHEDS-Dietary v. 1 

(.pdf)

INSTALLATION INSTRUCTIONS FOR SHEDS-MULTIMEDIA VERSION 4 

(both SHEDS-Dietary and SHEDS-Residential modules)

June 10, 2010

[See SHEDS_Installation.pdf]

SAS code and GUIs: 

SHEDS-Residential v.4 

& SHEDS-Dietary v.1 

(.exe) 

SHEDS_Multimedia_Setup_4.00.exe (for SHEDS-Residential) a

[See SHEDS_Residentialv4_Setup_4.00.exe]

SHEDS_Dietary_Setup_1.0.exe (for SHEDS-Dietary)

[See SHEDS_Dietary_Setup_1.0.exe]

User Guide: SHEDSResidential v.4 (pdf) 

The Stochastic Human Exposure and Dose Simulation Model

for Multimedia, Multipathway Chemicals (SHEDS-Multimedia): Residential 

Module

SHEDS-Residential version 4

Draft User Guide

June 16, 2010

[See SHEDS_Residential_UsersGuide_6_16_2010.pdf]

User Guide for SHEDSDietary v.1 (.pdf)

The Stochastic Human Exposure and Dose Simulation Model

for Multimedia, Multipathway Chemicals (SHEDS-Multimedia): Dietary Module 

SHEDS-Dietary version 1

Draft User Guide

June 16, 2010

[See SHEDS_Dietary_UsersGuide_6-16-2010.pdf]

CD-ROM

2

OF

3

Technical Manual –

SHEDS Residential v.4 

(.pdf)

The Stochastic Human Exposure and Dose Simulation Model

for Multimedia, Multipathway Chemicals (SHEDS-Multimedia):

Residential Module 

SHEDS-Residential version 4

Draft Technical Manual

June 16, 2010

[See SHEDS_Residentialv4_Techmanual_06-16-2010.Final.pdf]
13

CD-ROM Deliverable Title/Description/Comments

Technical Manual –

SHEDS Dietary v.1 (pdf)

2 files; main and 

appendices

The Stochastic Human Exposure and Dose Simulation Model

for Multimedia, Multipathway Chemicals

(SHEDS-Multimedia): Dietary Module

SHEDS-Dietary version 1

Draft Technical Manual

June 16, 2010

[See SHEDS_Dietary_Techmanual_06-16-2010.FINAL.pdf

and

SHEDS_Dietary_TechManual_APPENDICES_06-16-

2010_FINAL.pdf]

Response to 2007 SAP 

comments (dietary and 

residential) (pdf) 

AUGUST 2007 FIFRA SCIENTIFIC ADVISORY PANEL RECOMMENDATIONS FOR 

SHEDS-DIETARY AND SHEDS-RESIDENTIAL MODULES

(SUMMARIZED)

AND EPA RESPONSES

Meeting Minutes from 

2007 SAP on v.3 (pdf)

Available as PDF in SAP Package as well as on 2007 SAP website at 

http://www.epa.gov/scipoly/sap/meetings/2007/august/sap_minutes_aug_14_15_2007.pdf

Charge Questions for 

Issues 1 and 2 

(Contained in this letter)

Reproduced in Attachment 1 of this transmittal letter in which all charge 

questions for the Panel are included. 

ORD SHEDS website 

with background on v.3

Available at 

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

CD-ROM

3

OF

3

Charge Questions for 

Issues 3 through 5

Provided in Attachment 1 of this transmittal letter in which all charge 

questions for the Panel are included. 

Background paper for 

PBPK aspects

Physiologically-Based Pharmacokinetic Models of Pyrethroids: Bayesian 

Calibration and Their Use in Interpreting Probabilistic Exposure Data

[PBPK_Calibration_Uncertainty_and_Linkage[2].pdf]

SHEDS permethrin case 

study input 

spreadsheets (.xls)

See: 

SAP_SHEDSv4_permethrin_inputs_All Scenarios_06-22-

2010_FINAL.xls

ACS/ISEA Model-Model 

Comparison (pdf)

See: 

ISEA 2008 ModelComparison SAP slides_FINAL.pdf

SHEDS Arsenic 

Evaluation Paper (EHP)

Xue, J. et al. Probabilistic Modeling of Dietary Arsenic Exposure and 

Dose and Evaluation with 2003-2004 NHANES Data. 2010. 

Environmental Health Perspectives 118(3): 345-350. 

Available at: Environmental Health Perspectives 118: 345-350

a

This file has been renamed SHEDS_Residentialv4_Setup_4.00.exe on the SHEDS website 

(http://www.epa.gov/heasd/products/sheds_multimedia/sheds_mm.html) at which this download is available. In addition, several 

other minor name changes in downloadable files on this website have been made in order to improve clarity. The documents 

provided to the Panel and the documents available on this EPA ORD website are equivalent.