# FIFRA Scientific Advisory Panel 

# July 30

- August 2, 2013 Overview of the Endocrine Disruptor Screening Program Mary Manibusan, Director

# Data Review Process

• From Data Generation to Data Review and Weight of Evidence

• Prioritization of the initial list of Chemicals

• Screening for “Potential” to interact with the endocrine system



## • Weight of Scientific Evidence: Tier 1 and Other Scientifically Relevant Information

• Programmatic Focus: Building a Solid Foundation for Sound Scientific Decisions

# Mission

To protect public health and wildlife by screening and testing chemicals and taking appropriate actions for those chemicals that are found to have



### endocrine effects.

# Legislative Mandate

Slide 4 of X 1996 Federal Food, Drug and Cosmetic Act, section 408(p) Requires the U. S. EPA to develop a screening program using appropriate validated test systems and other scientifically relevant methods to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate. 1996 Safe Drinking Water Act Amendments, section 1457 Testing of chemical substances that may be found in sources of drinking water, if substantial human populations may be exposed.

## Endocrine Disruptor Screening and Testing

EDSTAC Key Recommendations:

• Expand Protection to Include Human Health and Wildlife

• Include Estrogen, Androgen and Thyroid Pathways

• Develop a Two

- Tiered Screening and Testing Program: Conceptual Framework: Tier 1 Screening for Potential to Interact Potential to interact with the estrogen, androgen or thyroid hormone systems

Tier 2 Testing to determine Interaction with the endocrine system If endocrine

- mediated adverse effects then quantify dose

- response relationship

Slide 5 of X If weight of evidence is (+) for interactionPrioritization • Federal Food Drug and Cosmetic Act, 1996

• Prioritization based on having ≥ 3 Exposure Pathways

• Not based on likelihood/probability of endocrine potential

Screening • In vitro and In vivo assays for Estrogen, Androgen and

Thyroid pathways

• Capturing both mammalian and aquatic species

Weight of Evidence • Adverse outcome pathway concept

• All available and relevant data 

# EDSP List 1 Road map

# EDSP List 1 Chemicals

• April 15, 2009: Agency issued the initial list of chemicals for Tier 1 screening

– 58 active ingredients and 9 inert ingredients



### – Some options to respond to test orders:

• 15 Chemicals voluntarily left the pesticide market

• Registrants submitted available published data in response to test orders (23% accepted by the agency)



## • 2011

- 2013: Tier 1 data have been submitted to the agency and data evaluation records (DER) developed

– Documentation of study quality and conclusions regarding the results of a study

# From Prioritization to Screening and Testing: 2013 EDSP Roadmap January SAP Step1:  Prioritization of Chemicals for Tier 1 Screening using effects based chemical categorization and exposure data.

May and July SAP Step 2: Tier 1 assay data review Step 3: weight of evidence determinations with other scientifically relevant data

June SAP Step 4: Tier 2 Assays Data review Multi

generation reproduction studies

Slide 8 of X Step 1: Prioritization of EDSP Universe of Chemicals: SAP January 29

- 31 st , 2013 Step 2: Tier 1 assay and battery: SAP May 21

- 23 rd , 2013 Step 3: Weight of Evidence Review: SAP July 30

- August 2, 2013 Step 4: Validation of Tier 2 test methods: SAP June 25

- 28, 2013

# Validated Tier 1 Battery

• Battery includes 11 assays, in vitro and in vivo

• FIFRA SAP in 2008 concluded that the battery of assays was a good start and include necessary redundancy and complementarity

• FIFRA SAP report in May 2013

– 21 subsample of chemicals with broad coverage of biological and chemical space

– Reviewed individual assay performance and 

### performance of the batterySlide 10 of X 

# Tier 1 Screening Battery

In vitro Estrogen Receptor (ER) Binding Estrogen Receptor Transcriptional Activation Assay (ERTA) Androgen Receptor (AR) Binding Steroidogenesis Aromatase 

## In vivo Uterotrophic (rat) Hershberger (rat) Pubertal Female (rat) Pubertal Male (rat) Amphibian Metamorphosis Assay (frog) Fish Short
- Term Reproduction Assay (fish)

# Data Evaluation Review Process

1. Primary Review for each assay

– by Technical Contractor 2. Secondary Review for each assay

– by OPP Scientists 3. Tier 1 Assessment Review Committee for 

## groups of assays

– by Agency Experts 4. Weight of Evidence Evaluation of the totality of the data

– Lead Scientists and internal 

## expert committee review

## • Not a prescriptive process

• An integrative and interpretive process routinely used by EPA to evaluate health and ecological information.



## • P rinciples and criteria for weighing and integrating different lines of evidence are not 

## different for evaluating Tier 1 screening data. “Weight of Evidence: Evaluating Results 

### of EDSP Tier 1 Screening to Identify the Need for Tier 2 Testing ” September 14, 2011.

# What is the Question?

What is the process?

• Assemble the relevant data

• Evaluate data for quality and relevance

• Integrate the different lines of evidence to support conclusions concerning whether a chemical has the potential to interact with the 

## endocrine system. Question: Does the chemical have the “potential” to interact with the endocrine system (E, A, or T)?

# Mode of Action Framework
Adapted Bradford Hill Criteria:

• Sequence of key events

• Coherence

• Strength and limitations

• Consistency



## • Biological Plausibility
*Note: No one study or endpoint is generally expected to 

### support a regulatory decision

# Totality of Available Scientific

Information Tier 1 OSRI

# Tier 1 Screening Assays

Slide 16 of X

# Other Scientifically Relevant Information

• Sources may include results from EPA or OECD equivalent test guideline studies

– 40CFR Part 158, subparts F and G (870 Guideline Series and 850 Guideline Series)

– Subject to GLP regulations (40CFR Part 160 and 792)



### • Information from published or publically available peer reviewed studies

– Conducted in accord with standard scientific methods that include hypothesis development, testing, observations, experimentation and verification.



### • Information is systematically reviewed and evaluated 

### for quality and relevance

# Weight of Evidence Characterization

• Available results from Tier 1 together with OSRI will span multiple levels of biological organization from MIE to adverse effects.



### • Detailed analyses of individual studies and integrative analysis of the multiple lines of evidence

• Identify uncertainties and existing “data gaps”



### • Telling the story : Characterization should be clear and transparent with a descriptive rationale of whether there is sufficient demonstration of potential to 

### interact with the endocrine system and what, if any, additional testing is warranted.

# SAP Tier 1 Data Review (2013)

5 WoE Case Studies
21 Chemicals for Tier 1 SAP Review
52 Chemicals for Tier 1 Screening

# Weight of Evidence 5 Case Studies

• Case studies are anonymous (A, S, N, J and X) to focus the review on general scientific methods of interpretation that would be broadly applicable and not chemical specific and not necessarily limited to List 1



### • Represent the more unique and challenging examples

• Data provided in the case studies are intended to be a representative “slice” of the data and not comprehensive in nature



### • Inclusive of different classes of compounds, with different ranges of available toxicity data from other sources (OSRI)

• Mode(s) of toxic action and chemical properties 

### considered: corrosivity

, solubility, inhibition of acetylcholinesterase , inhibition of mitochondrial phosphorylation, etc.

# Overall Charge to Panel
Anchoring the Science:

• Has the agency presented clear, scientifically sound and robust weight of evidence 

## assessments that considered the totality of available data?

• Recognizing the unique Tier 1 battery of assays are built to screen for E, A and T pathways, has the agency optimized the consideration of other scientifically relevant information when 

## completing the WoE ?

# Sagamore Hill, Oyster Bay, NY

“Far better it is to dare mighty things, to win glorious triumphs, even though checkered by failure, than to take rank with those poor spirits who neither enjoy much nor suffer much, because they live in the gray twilight that knows neither victory nor defeat.”

― Theodore Roosevelt , Strenuous Life

# Acknowledgements

• OCSPP Team

– Dr. Greg Akerman, OPP

– Case Study Chemical A

– Dr. John Liccione, OPP

– Case Study Chemical S

– Catherine Aubee, OPP

- Case Study Chemical N

– Amy Blankinship, OPP

– Case Study Chemical J

– Dr. Patience Browne, OSCP

– Case Study Chemical X

– Dr. Tom Steeger , OPP

– Dr. Vicki Dellarco, OPP (retired)

– Dr. Scott Lynn, OSCP

– Dr. Don Bergfelt, OSCP

– Dr. Les Touart, OSCP

– Dr. Beth Doyle, OW

– Dr. Jennifer Seed, OPPT

– Jim Kariya, OSCP (retired)

• ORD Team
–

– Dr(s). Ralph Cooper, Tammy Stoker, Susan Laws, Vickie Wilson, Gary Ankley, ORD

• Management Team

– Dr. Steven Bradbury, OPP Director

– Dr. David Dix, OSCP Director

– William Jordan, OPP Deputy Office Director

– Steven Knott, OSCP, Deputy Office Director

– Jack Housenger, OPP HED Director

– Don Brady, OPP EFED Director

– Jess Rowland, OPP HED Deputy Director

– Laura Bailey, OSCP SAP Executive Secretary

– Joe Bailey, OSCP SAP Designated Federal Official