# Section 6.3 : 

# Interpretation and Application: IBER

Patience Browne 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

Androgen Receptor Bioactivity Introduction Estrogen Receptor Bioactivity Exposure 

### Toxicokinetics/Dosimetry

Integrated Bioactivity Exposure Ranking

Future Directions FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2 -5, 2014 Slide 2 of 20

# Major Points of the Section  Computational tools discussed in previous sections have been peer- reviewed by SAP and for publication 

#  Models with continue to be refined as more data become available  Approach for including high throughput and 

# computational methods in EDSP framework  Identifying chemicals with lower exposurebioactivity ratios, allows EPA to efficiently use 

# resources  Multicentury project becomes multiyear
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# Introduction  Over the past several years, EPA has initiated a step 

# wise scientific review of computational tools and defined specific applications in EDSP • January 2013 SAP meeting “Prioritizing the Universe of 

# Endocrine Disruptor Screening Program (EDSP) Chemicals Using Computational Toxicology Tools”:

– The approach presented is appropriate for prioritizing the EDSP chemical inventory to identify chemicals based on ER interactions. 

# • July 2014 SAP “New High Throughput Methods to Estimate Chemical Exposure”:

– SEEM framework represents quality science adequate for testing 

# or validating predictions using conservative ‘worst-case’ scenarios.

– HTE be used simultaneously with HTP bioactivity for screening FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2 -5, 2014 Slide 4 of 20

# Objectives: IBER  Before using the IBER approach in the EDSP 

# framework, EPA is reviewing the scientific strengths and limitations of the approach 1. Prioritize chemicals for further EDSP screening 

# and testing based on rank of ER bioactivity and estimated exposure 2. Prioritize chemicals for further EDSP screening 

# and testing based on rank of AR bioactivity and estimated exposure

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# Bioactivity ToxCast 

# Exposure ExpoCast 

# HTTK Integrated Bioactivity Exposure Ranking (IBER) 

# Prioritization Screening Some or All EDSP Tier 1 Assays 

# Testing Some or All EDSP Tier 2 Assays 

# Proposed Methodological Approach

Figure 6.2 FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2 -5, 2014 Slide 6 of 20

# Bioactivity ToxCast 

# Exposure ExpoCast 

# HTTK Integrated Bioactivity Exposure Ranking (IBER) 

# Prioritization Screening Some or All EDSP Tier 1 Assays 

# Testing Some or All EDSP Tier 2 Assays 

## CompTox CompTox 

## CompTox 

# Proposed Methodological Approach

Figure 6.2 FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2 -5, 2014 Slide 7 of 20

# Estrogen Agonist Bioactivity Figure 2.16

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# Androgen Antagonist Bioactivity

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# Proposed Method

Bioactivity ToxCast Exposure ExpoCast HTTK Integrated Bioactivity Exposure Ranking (IBER) 

## Prioritization 

# Screening Some or All EDSP Tier 1 Assays 

# Testing Some or All EDSP Tier 2 Assays FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2 -5, 2014 Slide 10 of 20

# Integrated Bioactivity Exposure Ranking

Figure 1.3 FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2 -5, 2014 Slide 11 of 20

# Integrated ER Bioactivity Exposure Ranking

EC = 4.96 X 10 - 3 ER = 0 

### Dimethyl phthalate Pyridaben

ER = 4.09X10- 5 EC= 8.15x10-6 

### 2- Phenylphenol

ER = 0.12

EC = 6.96X10 -4 ER = 2.26 

### Vinclozolin

ER = 39.7

EC = 4.95 X 10 -6 

### Cyproconazole

EC = 1.7 X 10 -8 

## Figure 1.3 FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2 -5, 2014 Slide 12 of 20

IBER > 1 X 10 6 IBER > 1 X 10 6 IBER > 1 X 10 6 IBER = 2.1 X 10 3 IBER = 4.8

# IBER for ER

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# IBER for AR

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# Chemical Space EDSP Universe

L1 

## L2 TK 

## 1855 185 1444 ~10,000 49 56

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# Integrated Bioactivity Exposure Ranking

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# Integrated Bioactivity Exposure Ranking

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# Integrated Bioactivity Exposure Ranking

# Advantages of IBER  Models will continue to be revised and improved as more data are available • Provides predictions for thousands of chemicals 

#  Allows resources to be focused on chemicals more likely to have endocrine effects • List 1 chemicals have limited estrogen and/or 

# androgen receptor- mediated bioactivity • Prioritizes chemicals based on bioactivity and exposure

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# Revisiting Objectives: IBER  Before using the IBER approach in the EDSP framework, EPA is reviewing the scientific strengths and limitations of the approach 1. Prioritize chemicals for further EDSP screening and testing based on rank of ER bioactivity and 

# estimated exposure 2. Prioritize chemicals for further EDSP screening and testing based on rank of AR bioactivity and estimated exposure

– List 1: 4 ER & 4 AR chemicals < 10 6



# – List 2: 0 ER & 2 AR chemicals < 10 6



# – Universe: 58 ER & 55 AR chemicals < 10 6

FIFRA SAP: Integrated Bioactivity Exposure Ranking Dec 2 -5, 2014 Slide 20 of 20