# Endocrine Disruptor

Screening Program ( EDSP) Weight - of

- Evidence Process

Thomas M. Steeger, Ph.D. Environmental Fate and Effects Division Office of Pesticide Programs Office of Chemical Safety and Pollution Prevention U.S. Environmental Protection Agency

# Topics

 

### Focus of the SAP review (what is the question being 

### addressed)

 

### Rationale for Case Study Selection

 

### Overview of the 2011 EDSP Weight - of - Evidence 

### Guidance
 Assembling and evaluating the quality and interpreting responses of individual studies
 Formulating hypotheses and integrating data along a biological continuum

• Adverse outcome pathway (AOP)/mode of action (MOA) concepts

• Evaluating degree and nature of complementarity and redundancy in responses
 Characterization of the conclusions

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# Focus of the SAP

 

## Seek comment from the SAP on the 

## implementation of the basic interpretive process as illustrated with five case studies

 

## The purpose of this weight - of - evidence ( WoE ) analysis is not to evaluate the 2011 EDSP WoE guidance itself but rather its proposed 

## implementation

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# Focus of the SAP Review

 

### WoE analysis is focused on data interpretation as it 

### relates to these scientific questions:
 Do the data provide relevant, robust, and consistent evidence that the chemical has the potential to interact with the normal function of the E, A, or T signaling pathways?
 If the data indicate a potential of the chemical to interact with E, A, or T signaling pathways, at what level of biological organization ( e.g. , molecular, cellular, tissue/organ response, organism level) is that interaction expressed? and
 Under what conditions does the chemical perturb the endocrine system ( e.g. , in an organism with an intact HPG axis, at what dose and duration, presence of overt toxicity, etc. )?

 

### Addressing these questions is fundamental and provides 

### a critical basis for Tier 2 testing decisions

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# Case Study Selection Rationale

 

## May 2013
– Subsample of 21 chemicals from 

## List 1 that reflected a range of pesticide classes and physical - chemical properties ( e.g. , molecular weights, water solubilities, log K ow 

## , K oc 

## , volatility)

 

## Four Case Studies selected from the 21 - chemical subsample; the fifth Case Study did not receive test orders

• Reflects different pesticidal classes and modes of action

• Illustrative of the range of responses that will be 

### observed across the Tier 1 assays and OSRI

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# Case Study Selection

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# EDSP WoE Guidance

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###  

## Fundamental steps

 Assembling and evaluating the scientific quality of the individual studies



###  Formulating hypotheses and integrating data at different levels of biological organization

• 

### Evaluating extent and nature of the complementarity and redundancy in responses

 Characterizing main lines of evidence and conclusions

# Adverse Outcome Pathways (AOPs)

Structure Activity Relationships In vitro Studies In vivo Studies Population Studies/Models

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# EDSP WoE Guidance

9  

### Assembling and evaluating the scientific quality of the individual studies

 Tier 1 assays primary source of data

• May 2013 SAP
— Data reliable

– Performance criteria met or only minor deviations

– In some situations, Tier 1 in vivo responses coincident with overt toxicity
 Other Scientifically Relevant Information (OSRI)

• Journal articles, Test Guideline Data submitted in response to Part 158

– Did not conduct literature searches

– Relied on OSRI identified in response to List 1 Test Orders

– Chemical X did not receive Test Orders and limited literature search was conducted

# EDSP WoE Guidance

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###  

## Method Selection on Evaluating Endpoints in Individual Studies

• 

### May 2013 SAP1 AR: Androgen Receptor Binding Assay (OCSPP Guideline 890.1150) 2 ER: Estrogen Receptor (OCSPP Guideline 890.1250) 3 ERTA: Estrogen Receptor Transcriptional Activation (OCSPP Guideline 890.1300) 

## Decision Logic for Interpretation for a Chemical’s Potential for Endocrine Interaction

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## Decision Logic for Interpretation for a Chemical’s Potential for Endocrine Interaction

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## Decision Logic for Interpretation for a 

## Chemical’s Potential for Endocrine Interaction

13*Histology may be required by some regulatory authorities despite significant

differences in advanced and asynchronous development. 

## Decision Logic for Interpretation of the 

## Amphibian Metamorphosis Assay

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## Decision Logic for Interpretation of the



## Fish Short - Term Reproduction Assay

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# EDSP WoE Guidance

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###  

## Formulating hypotheses and integrating data at 

## different levels of biological organization

 Evaluating extent and nature of the complementarity and redundancy in responses

• 

### Provides a basis to evaluate “ biological plausibility and coherence, strength, and consistency of the body of evidence .”

– “complementarity” describes the concordance of 

### endpoints within an assay measuring multiple endpoints; and,

– “redundancy” describes the concordance of endpoints across the assaysStructure Activity

Relationships In vitro Studies In vivo Studies 

## Formulating Hypotheses and Integrating Data at Different Levels of Biological Organization

17 Population Studies/Models

Greater mechanistic understanding Greater relevance for humans and wildlife 

## Adverse Outcome Pathways (AOPs) Concept

## Application Hypothesis - Based Approach

 

### Androgen Antagonism

• Interaction of chemical with androgen receptor (measured in in vitro AR binding assay), which leads to

• Altered functional cellular response such as increased VTG production in males (measured in FSTRA), and/or a decrease in serum testosterone (measured in the male rat pubertal assay),

• Corroborated by an altered structural response at the tissue or organ level, such as increase in gonado - somatic index and decrease in mating tubercles in male fish ( measured in FSTRA), and/or decrease in androgen sensitive tissue weights (as measured in the Hershberger or male pubertal assays).

• Ultimately, androgen receptor antagonism may lead to an adverse outcome at the whole organism level, such as decreased fecundity (fish) or a delay in sexual maturation (rat).

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# Androgen Antagonism

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# WoE Analysis

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