1 

### AGENDA

U.S. ENVIRONMENTAL PROTECTION AGENCY (EPA)

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)

OPEN MEETING

December 2

- 4 , 2014

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

DOCKET NUMBER: EPA

– HQ

– OPP

– 2014

– 0 614

U.S. ENVIRONMENTAL PROTECTION AGENCY

CONFERENCE CENTER LOBBY LEVEL

ONE POTOMAC YARD (SOUTH BLDG.)

2777 S. CRYSTAL DRIVE, ARLINGTON, VA 22202

Scientific Issues Associated with Integrated Endocrine Bioactivity and Exposure

- Based

Prioritization and Screening

Please note that all times are approximate (see note at the end of the Agenda).

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

– Fred Jenkins, Ph.D.

,

Designated Federal Official, Office of Science Coordination and Policy, EPA

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

– James McManaman,

Ph.D., FIFRA Scientific Advisory Panel (SAP) Session Chair

9:10 A.M. Welcome and Opening Remarks

– David Dix, Ph.D., Director, Office of

Science Coordination and Policy (OSCP), EPA

9:20 A.M. Introduction

– Steven Knott, Director, Exposure Assessment Coordination and

Policy Division (EACPD)

, OSCP, EPA

9:40 A.M. Estrogen Pathway D ata and M odels

– Richard Judson, Ph.D., Office of

Research and Development (ORD), National Center for Computational

Toxicology (NCCT), EPA

10: 4 0 A.M. Break

10: 5 5 A.M. Curated R eview of U terotrophic L iterature and C omparison to ToxCast

E strogen R eceptor (ER) A gonist A rea Under the Curve (A UC ) D ata

– Warren Casey, Ph.D., Director, US National Toxicology Program's Interagency

Center for the Evaluation of Alternative Toxicological Methods (NI CEATM) Day 1

Tuesday, December 2 , 20142

11:25 A.M. Comparison of ToxCast D ata and List 1/Tier 1 ER A ssays and ER A gonist

B ioactivity of E ndo crine D isruptor S creening P rogram (EDSP) U niverse

C hemicals

– Patience Browne, Ph.D., EACPD , OSCP, EPA

12:00 P.M. Lunch

1:15 P.M. Androgen Pathway D ata and M odels

– Nicole Kleinstreuer, Ph.D.

, ORD,

NCCT, EPA

1 :45 P.M. A ndrogen R eceptor (AR) I nterpretation and A pplication

– Patience Browne,

Ph.D., EACPD, OSCP, EPA

2:05 P.M. Break

2:20 P.M. High Throu ghput Exposure; Toxicokinetics/ Dosimetry

– John Wambaugh,

Ph.D., ORD

, NCCT, EPA

3:00 P.M. Integrated (RTK) Bioactivity Exposure Ranking ( IBER ) , Modeling

U ncertainty

– Richard Judson, Ph.D., ORD, NCCT, EPA

3:20 P.M. IBER I nterpretation and A pplication

– Patience Browne, Ph.D., EACPD,

OSCP, EPA

3:30 P.M. Adjourn3

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

– Fred Jenkins, Ph.D.

,

Designated Federal Official, Office of Science Coordination and Policy, EPA

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

– James McManaman,

Ph.D., FIFRA Scientific Advisory Panel Session Chair

9:10 A.M. Future D irections

– Steven Knott, Director, Exposure Assessment Coordination

and Policy Division (EACPD), OSCP, EPA

9: 3 0 A.M. Public Comments

10:30 A.M Break

10:40 A.M. Public Comments (Cont’d)

12:00 P.M. Lunch

1:15 P.M. Charge to Panel

1. EPA’s proposed approach for quantifying a chemical’s potential estrogen bioactivity is based

on a computational model integrating data from 18 high throughput ToxCast

assays measuring several endpoints along the estrogen receptor (ER) signaling

pathway. The computational model outputs are expressed as area under the curve

(AUC) scores for ER agonist (R1) and antagonist (R2) bioactivity. Before routinely

using the ER computational model in the Endocrine Disruptor Screening Program

(EDSP) framework, EPA is reviewing the scientific strengths and limitations of the ER

model described in the wh ite paper to: i) prioritize chemicals for further EDSP screening

and testing based on estimated bioactivity, ii) contribute to the weight of evidence

evaluation of a chemical’s potential bioactivity, and iii) substitute for specific endpoints in

the EDSP T ier 1 battery. Please address the following charge questions relevant to

Section 2 of the white paper and estrogen bioactivity:

Charge Q uestion 1a. How clearly has EPA described the computational tools in Section 2.1

( i.e. , high throughput assays and mode ls) used to estimate ER agonist and antagonist

bioactivity?

2:15 P.M. Charge to Panel Day 2

Wednesday December 3, 20144

Charge Q uestion 1b. What are strengths and limitations of the ER AUC model’s ability to

identify reference chemicals that include a variety of structures and have a wide range of

in vitro ER bioactivities?

3:15 P.M. Break

3: 30 P.M. Charge to Panel

Charge Q uestion 1c. EPA used data from published in vivo studies that are methodologically

consistent with EDSP Tier 1 guidelines to evaluate concordance between ER AUC model scores

of in vitro bioactivity, and the in vivo uterotrophic response studies (Section 2.2.1). What are

strengths and limitations of the curation methods and quality standards used for evaluating

published in vivo studies?

4 :30 P.M. Charge to Panel

Charge Q uestion 1d. Based on all the data presented in Section 2 on ER AUC model

performance including characterization of reference chemicals, and concordance with in vivo

uterotrophic results, what are strengths and limitations of using the ER AUC

Page 2 of 3 model to dist inguish and prioritize chemicals based on potential estrogen

bioactivity?

5:30 P.M. Adjourn

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

– Fred Jenkins, Ph.D.

Designated Federal Official, Office of Science Coordination and Policy, EPA

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

– James McManaman,

Ph.D., FIFRA SAP Advisory Panel Session Chair

9:10 A.M. Charge to Panel (Cont’d)

Charge Q uestion 1e . Based on all the data presented in Section 2 on ER AUC model

performance including characterization of reference chemicals, concordance with in vivo

uterotrophic results, and comparison with Tier 1 assay endpoints, what are strengths and

limitations of the ER AUC model to contribute to the weight of evidence determination of a

chemical’s potential estrogen bioactivity?

9: 55 A.M. Charge to Panel Day 3

Thursday December 4 , 20145

Charge Q uestion 1 f. Based on all the data presented in Section 2 on ER AUC model

performance including characterization of reference chemicals, concordance with in vivo

uterotrophic results, and comparison with Tier 1 assay endpoints, what are strengths and

limitations of us i ng the ER AUC model to substitute for EDSP Tier 1 ER binding, ER

transactivation, or Uterotrophic assays for the purpose of characterizing a chemical’s potential

estrogen bioactivity?

10: 45 A.M. Break

1 1 : 00 A.M. Charge to Panel

2

. EPA’s proposed approach for quantifying a chemical’s potential androgen bioactivity is

based on a computational model integrating data from nine high throughput ToxCast

assays measuring several endpoints along the androgen receptor (AR) signaling

pathway. The computational model outputs are expressed as area under the curve

(AUC) scores f

or AR agonist (R1) and antagonist (R2) bioactivity. Before routinely

using the AR computational models in the EDSP framework, EPA is reviewing the

scientific strengths and limitations of the AR AUC model described in this white paper

to: i) prioritize chem icals for further EDSP screening and testing based on estimated

bioactivity, and ii) contribute to the weight of evidence evaluation of a chemical’s

potential bioactivity. Please address the following charge questions relevant to Section

3 of the white pap er and androgen bioactivity:

Charge Q uestion 2a . How clearly has EPA described the computational tools in Section 3.1

( i.e. , high throughput assays and models) used to estimate AR agonist and antagonist bioactivity?

11:30 A.M. Charge to Panel

Charge Q uestion 2b . What are strengths and limitations of the AR AUC model’s ability to

identify reference chemicals that include a variety of structures and have a wide range of

in vitro AR bioactivities?

12:00 P.M. Lunch

1:15 P.M. Charge to Panel (Cont’d)

Charge Q uestion 2c . EPA plans to use data from published in vivo studies that are

methodologically consistent with EDSP Tier 1 guidelines to evaluate concordance between AR

Page 3 of 3 AUC model scores of in vitro bioactivity, and the in vivo androgenic an d

antiandrogenic responses (Section 3.2.1). What are strengths and limitations of the

planned curation methods and quality standards for evaluating published in vivo

studies?

2: 1 5 P.M. Charge to Panel6

Charge Q uestion 2d . Based on the data presented in Section 3 on AR AUC model’s

performance, what are strengths and limitations of using the AR AUC model to distinguish and

prioritize chemicals based on potential androgen bioactivity?

3:15 P.M. Break

3:30 P.M. Charge to Panel

3 . For Endocrine Disruptor Screening Program (EDSP) chemicals with ToxCast estrogen

receptor (ER) and androgen receptor (AR) bioactivity scores (Section 2 and 3), and ExpoCast

high throughput toxicokinetics and exposure estimates (Sections 4 and 5), the IBER approach

was used to ra nk chemicals based on the ratio between the bioactivity dose range, and the

expected exposure range (Section 6). The IBER approach extends point estimates of

bioactivity, toxicokinetics, and exposure for a chemical, to distribution ranges based on

uncertai nty and population variability. Chemical rankings are based on the ratio of the lower

range of the bioactive dose, to the upper range of the exposure estimate. Please address the

following charge questions relevant to Section 6 of the white paper and the I BER approach:

Charge Q uestion 3a . How clearly has EPA described the computational tools in Section 6 to

develop IBER values, including modeling uncertainty and population variability?

3: 45 P.M. Charge to Panel

Charge Q uestion 3b. What are strengths and limitations of using the IBER approach to

prioritize chemicals for further EDSP screening based on the ratio between the ER bioactivity

dose range, and the expected exposure range?

4:30 P.M. Charge to Panel

Charge Q uestion 3c

. What are strengths and limitations of using the IBER approach to

prioritize chemicals for further EDSP screening based on the ratio between the AR bioactivity

dose range, and the expected exposure range?

5: 15 P.M. Adjourn

Note: 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. Fred Jenkins, via telephone:

(202) 564

- 33 27; fax: (202) 564

- 8382; or email: jenkins.fred@epa.gov.