# 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
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# 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

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# 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

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# 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.

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# 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 - HPG 1 Axis HPT 1

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.

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# 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.

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## *

# 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

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# 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

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# 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 18EPA 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 T1S Battery Test+ Near-Term PHASE 1 Targeted EDSP Tier 2 Tests WOE+ WOE in vitro HTP/ in silico in vitro/in silico to target EDSP T1S Test+ Intermediate –Term PHASE 2 WOE+ WOE in vitro HTP/ in silico (full replacement of Tier 1 battery) WOE+ WOE 
### http://www.epa.gov/endo/pubs/edsp21_work_plan_summary%20_overview_final.pdf 

# EDSP21 Workplan (2011)

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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
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# EDSP Prioritization, Screening & Testing

Prioritization Bioactivity/Exposure Screening Bioactivity Testing Dose Response/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

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# 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

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