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 (Resi dential 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 mo dels, 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 (multip le 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 s t atutory 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 c umulative r isk

a ssessment (CRA) for pyrethroids in addition to futur e cumulative risk assessments on other pesticide groups . The SAP session will review individual and linked state

- of

- the

science exposure and dose assessment tools in the context of an example case study (permethrin), including proposed methodologies using linked SHEDS and PBPK models.

Additional d etails 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 pertain s to the SHEDS

- P BPK linkage issues , the permethrin case study, and model comparisons :3 L ist 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 D ata

. [ 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 Model

Model Comparison (pdf) See: ISEA 2008 ModelComparison SA P 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 ch arge questions, in their entiret y and covering all five issues, are presented in Attachment 1 to this memorandum. A complet e 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

- 2 2 , 20105



## SAP Charge Questions for FIFRA SAP July 20

- 2 2 , 2010

Review of EPA’s Stochastic Human Exposure and Dose Simulation (SHEDS

Multimedia ) 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 runni ng 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 comm ent 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 runni ng 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.

Questi on 1

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

Residential GUI (Graphic User Interface), and whether additional changes would be helpful for the Residential SHEDS.6

Issue 2: Documentation, completeness, and clarity of technical as pects 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 m odule, 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 S AP 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 Resi dential 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 interfac e 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 entitle d “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 ca n 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 rele ase), (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 R PFs 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 an d 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 evaluatin g 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 algorit hms 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 impro ved? 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 \ WWEI A 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 re sidential 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 Ma nual 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) pyret hroid 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 s trengths 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 cal ibrating 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 extrapolatio n, 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 abov e 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 impo rtant 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 qual ity 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 assessmen t 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 re asons 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) compariso n of SHEDS

- Dietary cross

- sectional output to DEEM

- FCID TM ; the DEEM

- FCID TM model is commonly used by OPP in its regulatory decisions and was reviewed by the SAP in 2000 (see SHEDS

- Dietary Technical Manual (S ection .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 SHED

PBPK linked model with the measured arsenic concentrations in urine from the 2003

- 2004 NHANES bi omonitoring 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) followi ng 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 ver ification 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 interpre t 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_mult imedia/sheds_mm.html10  linking dietary consumption diaries and resi dential 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 p athways (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 NHA NES (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 asse ssing SHEDS

PBPK 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 l inkage 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

- 2 2 , 201012



## July 20

- 22, 2010 FIFRA SAP Background Material

CD

- ROM Deliverable Title/Description/Comments

CD

- ROM

1

OF

3 Installation I nstructions:

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: SHEDS

Residential v.4 (pdf) The S tochastic H uman E xposure and D ose Si mulation 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 SHEDS

Dietary v.1 (

. pdf) The S tochastic H uman E xposure and D ose Si mulation Mode l 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 S tochastic H uman E xposure and D ose Si mulation 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

– SHE DS Dietary v.1 (pdf) 2 files; main and appendices The S tochastic H uman E xposure and D ose Si mulation 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

a nd 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

- RESIDENT IAL 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 ht tp://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 includ ed.

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 Perspecti ves 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 webs ite are equivalent.