Section 1:

Introduction

Steven Knott, Director

Exposure Assessment Coordination and Policy Division

Office of Science Coordination and Policy

Office of Chemical Safety and Pollution Prevention

Slide 1 of 18
FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 2 of 18
Presentation Roadmap

Introduction

Estrogen Receptor 

Bioactivity

Androgen Receptor 

Bioactivity

Exposure

Toxicokinetics/Dosimetry

Integrated Bioactivity 

Exposure Ranking

Future Directions

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 3 of 18
Major Points/Focus for this SAP

 Estrogen (ER) and Androgen (AR) Bioactivity

• ER model – prospective applications in IBER 

prioritization, contribution to WoE determinations, 

and substitution for Tier 1 endpoints.

• AR model – prospective application to IBER 

prioritization; further development for WoE

determinations and Tier 1 endpoint substitution in 

progress.

 Integrated Bioactivity Exposure Ranking (IBER)

• Proposed approach to prioritize chemicals based on 

ER and AR bioactivity and exposure

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 4 of 18
Endocrine Disruptor Screening Program (EDSP)

 Established in 1998

 Protection of human health and wildlife

 Includes estrogen, androgen and thyroid pathways

 Approach

• Prioritization based on exposure and high throughput bioactivity

“Data resulting from HTPS [HTS] will be combined with exposure-related information, and with any 

other effects-related information that is available, for each chemical for the purpose of setting 

priorities for T1S [screening]” (EDSTAC 1998)

• Screening for bioactivity

• Testing for dose-response and adverse effects

Prioritization

Bioactivity/ Exposure

Screening

Bioactivity

Testing 

Dose-Response/

Adversity

More chemicals Fewer chemicals

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 5 of 18
Prioritization

EDSP Chemical Universe

10,000 chemicals

(FIFRA & SDWA)

EDSP List 2

107 Chemicals

EDSP List 1

67 Chemicals

“EPA failed to sufficiently demonstrate the utility of their HTPS [HTS] 

system for the purpose of chemical sorting and priority setting of 

estrogen, androgen and thyroid active chemicals.” (SAP/SAB, 1999)

EPA subsequently focused on exposure

and regulatory considerations.

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 6 of 18
Screening – Tier 1

Tier 1 Screening Battery

Endocrine Pathway 

E + E - A + A -

HPG

Axis

HPT

Axis

In vitro

ER Binding ■ ■

ERα Transcriptional Activation* ■

AR Binding ■ ■

Steroidogenesis H295R* ■ ■ ■ ■

Aromatase Recombinant ■

In vivo

Uterotrophic* ■

Hershberger* ■ ■

Pubertal Male ■ ■ ■ ■ ■ ■

Pubertal Female ■ ■ ■ ■ ■ ■

Amphibian Metamorphosis* ■

Fish Short-term Reproduction

(male & female)* ■ ■ ■ ■ ■

*OECD harmonized guidelines

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 7 of 18
Tier 1 Battery ER-specific Endpoints

Tier 1 Screening 

Battery

Endocrine Pathway 

E + E - A + A -

HPG1

Axis

HPT1

Axis

In vitro

ER Binding ■ ■

ERα Transcriptional 

Activation* ■

In vivo

Uterotrophic* ■

Pubertal Female ■ ■ ■ ■

Fish Short-term 

Reproduction

(male & female)*

■ ■ ■ ■ ■

*OECD harmonized guidelines

Note: Full EDSP Tier 1 battery includes five in vitro and six in vivo assays that provide additional information on a chemical’s potential to interact 

with the androgen and thyroid, as well as alter steroidogenesis.

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 8 of 18
Tier 1 Battery AR-specific Endpoints

*OECD harmonized guidelines

Note: Full EDSP Tier 1 battery includes five in vitro and six in vivo assays that provide additional information on a chemical’s potential to interact 

with the androgen and thyroid, as well as alter steroidogenesis.

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 9 of 18

*
Evolution of the EDSP

 Based on current pace it could take decades to screen all 

10,000 chemicals for potential to interact with the endocrine 

system

 To address thousands of chemicals for potential to interact 

with the endocrine system, we must implement a more 

strategic approach to prioritize chemicals for targeted 

screening

 Recent advances in computational toxicology herald an 

important “evolutionary turning point” and an accelerated 

pace of screening and testing

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 10 of 18
Utility of Computational Toxicology 

 Rapidly screen chemicals and use predictive models 

to evaluate thousands of chemicals for potential risk 

to human health and environment

 Increase capacity to prioritize, screen and predict 

chemical toxicity and exposure

 Overcome throughput limitations of traditional 

chemical toxicity testing, augmenting current data 

sources

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 11 of 18
Utility of Computational Toxicology 

 Eventual replacement of some existing tests 

with non-animal alternatives

 Provide open access to data

 Identify key events along adverse outcome 

pathway

Partner across EPA, with other federal agencies, 

state agencies, industry and non-governmental 

organizations to validate and apply tools

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 12 of 18
EPA Research provides basis for improving the suite of assays and models to 

advance chemical prioritization and screening

The universe of chemicals passes through each 

version of the HTP/in silico pipeline to evaluate 

chemicals in refined tests, for new pathways, 

to evaluate, improve, and validate methods.

Building Confidence: “Learn by Doing”

Phase 1: Incorporates HTP/in silico prioritization methods

Phase 2: Run subset of current T1S assays indicated by HTP and in silico predictions 

Phase 3: Full replacement of EDSP T1S Battery

Chemicals 

Of Regulatory 

Interest

in vitro HTP/ in silico

Current EDSP 

Near-Term Test+ T1S Battery

PHASE 1

Targeted

EDSP Tier 

2 Tests

WOE+

WOEin vitro HTP/ in silico in vitro/in silico to target 

EDSP T1S

Intermediate –Term Test+

PHASE 2

WOE+

WOEin vitro HTP/ in silico 

(full replacement of Tier 1 battery) WOE+

WOEhttp://www.epa.gov/endo/pubs/edsp21_work_plan_summary%20_overview_final.pdf

EDSP21 Workplan (2011)

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 13 of 18

Longer-Term 

PHASE 3
Evolution of the EDSP

In FY 2012, EPA began a multi-year transition for the EDSP to validate and 

incorporate computational toxicology methods and high-throughput screens:

 Must demonstrate that these methods are scientifically sound

 Can effectively detect endocrine bioactivity via receptor-mediated 

interactions

 Can effectively detect endocrine bioactivity via broader endocrine pathway 

effects

Series of FIFRA SAP reviews focused on “Fit-for-Purpose” applications

 Scientific Issues Associated with Prioritizing the Universe of EDSP Chemicals 

Using Computational Toxicology Tools – January 2013

 Scientific Issues Associated with New High Throughput Methods to Estimate 

Chemical Exposure – July 2014

 Integrated Endocrine Bioactivity and Exposure-Based Prioritization and 

Screening for the Endocrine Disruptor Screening Program- December 2014

 FUTURE: Use of Computational Toxicology for predicting endocrine 

bioactivity in an Adverse Outcome Pathway framework

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 14 of 18
EDSP Prioritization, Screening & Testing

Prioritization

Bioactivity/Exposure

Screening

Bioactivity

Testing

DoseResponse/Adversity

Relies on:

• QSARs

• ToxCast/ExpoCast

• Monitoring data

• OSRI

Relies on:

• QSARs

• ToxCast

• EDSP Tier 1 data

• OSRI

Relies on:

• EDSP Tier 2 data

• OSRI

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 15 of 18
Current FIFRA SAP Review

Additional HTS bioactivity tools for the estrogen and androgen pathways

• use in chemical prioritization

• potential to substitute for specific endpoints in lower throughput 

EDSP Tier 1 screening assays

Approach that utilizes both bioactivity and exposure to prioritize chemicals for 

further consideration (Integrated Bioactivity-Exposure Ranking or IBER)

Figure 1.3

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 16 of 18
Fit for Purpose

 ToxCast

• ER – Prioritization, Tier 1 Substitution, WoE

• AR – Prioritization (future Tier 1 

Substitution, WoE)

 ExpoCast

• High throughput exposure

• July 2014 FIFRA SAP

 HTTK/RTK

• Bridges in vitro, concentration-based 

ToxCast data to in vivo, dose-based 

Exposures

• July 2014 FIFRA SAP

 IBER Approach to Prioritization

ToxCast

ExpoCast

IBER 

Prioritization

Tier 1 

Substitution

/WoE

HTTK/RTK

Tools and approach not intended to provide a precise assessment similar to traditional low throughput 

risk assessments (e.g., quantitative risk assessments using data from EDSP Tier 2 studies).

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 17 of 18
For More Info

 Endocrine Disruptor Screening Program

• www.epa.gov/endo

 FIFRA Scientific Advisory Panel

• www.epa.gov/scipoly/sap

• http://www.regulations.gov/#!documentDetail;D=

EPA-HQ-OPP-2014-0614-0003

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2-5, 2014 Slide 18 of 18