1. Endocrine Disruptor Screening and Testing: An Industry Update
Sue Marty, Ph.D., D.A.B.T.
The Dow Chemical Company
ICCA Representative
UNEP Endocrine Disruptor Advisory Group
24-25 September 2015
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2. DOW CONFIDENTIAL - Do not share without permission
Agenda
EDSP Screening and Testing Program
Screening of 52 List 1 Chemicals
WoE Results
Tier 2 Testing Requirements
EPA’s EDSP21 program to Prioritize List 2
Based on Bioactivity and Exposure
Conclusions/Future Directions
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3. Background on Priority List I: Chemicals for EDSP Screening
EDSP List 1
52 chemicals on first priority list were screened in Tier 1
Primarily pesticides plus 2 inerts
Compounds placed on List 1 due to exposure potential, not due to potential endocrine activity
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4. EDSP Tier I Screening Assays
In Vitro Assays
1. Estrogen Receptor (ER) Binding
2. Androgen Receptor (AR) Binding
3. ER Transcriptional Activation
4. Steroidogenesis
5. Aromatase
Mammalian In Vivo Assays
6. Uterotrophic (estrogen-associated)
7. Hershberger (androgen-associated)
8. Pubertal Female
9. Pubertal Male
Non-Mammalian In Vivo Assays
10. Amphibian Metamorphosis
11. Fish Short-Term Reproduction
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5. OECD Conceptual Framework for ED Assessment
5 Levels
Toolbox – lists assays providing different types of information on hazard; it is not to be used as a tiered testing strategy; Info on use, volume, fate, levels, duration and route of exposure also are important, but not considered; can enter/leave matrix at any level depending on info needs. Generally, one assay is insufficient to determine if a compound is an EDC. Levels 1-3 provide information on potential endocrine MoA/mechanistic information needed to identify an endocrine active substance. Levels 4-5 provide information on adverse effect of potential EDCs

6. Weight of Evidence and Tier 1 Implications
Test orders issued in
OSRI
TIER 1 DATA
WoE:
Is the compound positive across the screening battery? NO
YES
No Further Testing
PROCEED TO TIER 2
(2013)
Tier 1 only examines:
-Potential to interact
with endocrine system
-Whether Tier 2 testing
is needed
Assays must be evaluated as a battery, not in isolation such that limitations of one assay are complemented by the strengths of another
(2015)
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7. List 1 WoEs: EPA’s Perspective
EPA WoE Results:
Negative compounds will be low priority for further work
Potential endocrine activity was generally supported by both Tier 1 assays and OSRI (few surprises)
No addl testing required if endocrine activity:
Occurs in the presence of overt toxicity
Occurs at greater dose levels than current PoD
WoEs are available publicly on the EPA website:
<
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8. Results of Priority List 1 WoE Evaluation
Industry spent $50M for EDSP Tier 1 screening of List 1 compounds
52 Chemicals were evaluated
20 Chemicals: No evidence of potential interaction with endocrine pathways
14 Chemicals: Showed potential interaction with endocrine pathways, but EPA has enough information to conclude that they do not pose risks
18 Chemicals: Tier 2 testing recommendations
4 Chemicals: Comparative Thyroid Assay (mammalian)
13 Chemicals: MEOGRTS (wildlife estrogen/androgen)
5 Chemicals: LAGDA (thyroid interactions in wildlife)
“…better understand the potential of these chemicals to cause adverse effects through interaction with the endocrine system”
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9. EDSP21: Transitioning the Screening Program
Tier 1 screening of 52 chemicals has taken almost 6 years and cost ~$1M per chemical
Not many surprises; results primarily agreed with OSRI data
None of the list 1 compounds were estrogenic
Possibly screened out during ag chemical testing
With 10,000 chemicals for endocrine screening, a more efficient approach is needed
EPA released a scientific policy document (June 2015)
Allows a "pivot point" to use HTP data for prioritization and as "alternative" screens
Prioritizes compounds based on bioactivity and exposure
Prioritize List 2 and future lists with EDSP21 data
Industry also supports this approach
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10. ToxCast Assays to Evaluate ER Pathway
Evaluate ER agonism and antagonism
False bioactivity due to Interference, Noise, Cytotoxicity and can include technology-specific factors
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11. IBER –Integrated Bioactivity Exposure Ranking
Bioactivity = AUC from ToxCast assays; HTTK = determination of exposure needed to achieve bioactive concentration; ExpoCast = HTP estimates of actual human exposures -----IBER score (similar to MoE)
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12. Conclusions/Future Directions
New approach will prioritize compounds that show bioactivity at concentrations that approach exposures
Industry supports focusing on compounds with lower Margins of Exposure
Approach works well for ER and AR
Future directions for EPA EDSP21 program
Modeling thyroid and steroidogenesis pathways
Metabolically-competent assays
Continued improvement in IVIVE
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