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 interaction
Prioritization

• 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

Multigeneration 

reproduction 

studies 

Slide 8 of X

Step 1: Prioritization of EDSP Universe of Chemicals: SAP January 29-31st, 2013

Step 2: Tier 1 assay and battery: SAP May 21-23rd, 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 battery
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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.

• Principles 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
Steroid Synthesis

Pubertal female X X X X X

In vivo

In vitro

ER Transcriptional X

Activation

X

X

HPT

X

X

HPG

Aromatase (Recombinant) X

Uterotrophic X

Hershberger X X

Pubertal male X X X

Steroidogenesis (H295R) X X

AR Binding X X

ER Binding X X

E E- A A- T E

Amphibian Metamorphosis

Fish Reproductive Screen X X X X X X

Steroid Synthesis

Pubertal female X X X X X

In vivo

In vitro

ER Transcriptional X

Activation

X

X

HPT

X

X

HPG

Aromatase (Recombinant) X

Uterotrophic X

Hershberger X X

Pubertal male X X X

Steroidogenesis (H295R) X X

AR Binding X X

ER Binding X X

E E- A A- T E

Amphibian Metamorphosis

Fish Reproductive Screen X X X X X X

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