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WILLIAM JORDANDEPUTY DIRECTOR, OFFICE OF PESTICIDE PROGRAMS
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
US EPA Regulation of Endocrine Disrupting Chemicals
2015 Regulatory Conference ECPA-ECCA
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Overview
US and international developments on endocrine disruptors policy: do opportunities for cooperation exist?Pesticide Regulation in the USUS EPA’s Current Endocrine Disruptor Screening Program
(EDSP)Future Directions for the EDSP Concluding Thoughts
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Pesticide Regulation in the US
What is a Pesticide?4
In the US, a pesticide is defined as any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest. Examples: insecticides rodenticides
fungicides plant growth regulators
herbicides antimicrobialsmicrobials biochemicals
Federal Food DrugAnd Cosmetic Act
(FFDCA)
*MRLs (Tolerance) Established
*Maximum Residue LevelReasonable Certainty of No
Harm(Risk only)
Products Registered Periodic Reevaluation
No Unreasonable Adverse Effects(Risk/Benefit)
Federal Insecticide FungicideAnd Rodenticide Act
(FIFRA)
U. S. Pesticide Laws
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Human Health Risk Assessment for Pesticides (1)
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EPA follows the National Academy of Sciences (NAS) four-step risk assessment paradigm*:
*From the National Research Council’s Risk Assessment in theFederal Government: Managing the Process, 1983.
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Human Health Risk Assessment for Pesticides (2)
“Hazard” is a type of adverse effect; Hazard identification – what are the possible toxic effects
“Dose–response” refers the relationship between a dose of a pesticide and the occurrence of an adverse effect; at what dose(s) are the possible effects seen?
“Exposure” is the level of contact of a pesticidal substance
“Risk” refers to the likelihood of an adverse effect; risk takes account of hazard, dose-response, and exposure
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Data Requirements to Support Pesticide Registration & MRLs
Typically EPA requires over 100 studies for a new pesticide:Human Hazard Studies: multiple endpoints (all organ systems
and functions); durations (acute – chronic); lifestages (fetus – adult); routes (oral, dermal, inhalation)
Ecological Toxicity Studies: multiple species (birds, fish, insects, invertebrates, plants)
Human Exposure Studies: occupational (handlers, workers); bystanders; residential activities
Environmental Exposure Studies: hydrolysis, photodegradation, solubility, leaching, volatility, aerobic and anaerobic metabolism
Risks to Humans Assessed for Multiple Pathways and Routes of Exposure
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Oral exposure Food supply Drinking water Incidental ingestion
Dermal exposure Applying pesticide Harvesting crops Spray drift Turf contact
Inhalation exposure Applying pesticide Bystander
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US EPA’s Current Endocrine Disruptor Screening Program
1996 Legislative Mandates
Slide 11 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 pesticide chemicals 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 1457Testing of chemical substances that may be found in sources of
drinking water, if substantial human populations may be exposed.
EDSP Chronology12
1996 FFDCA and SDWA 1998 EDSTAC recommendations 1999 EPA established the EDSP 2008 Validated eleven Tier 1 screening assays 2009 Initial test orders for Tier 1 assays 2011 EDSP21 Work plan 2012 EDSP Comprehensive Mgmt Plan 1999-2014 Scientific Advisory Panel Reviews
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Public Engagement for EDSP
EDSP established and implemented with robust public engagement: The Endocrine Disruptor Screening and Testing Advisory
Committee (EDSTAC) of 1996-1998 Endocrine Disruptor Methods Validation Advisory Committee
(2004) Public comments on policy papers and management plans Public reports to Congress and Pesticide Program Dialogue
Committee EPA’s FIFRA Scientific Advisory Panel EPA website: http://www.epa.gov/scipoly/oscpendo/index.htm
1998 Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC)
Slide 14 of X
EDSTAC Key Recommendations:Expand Protection to Include Human Health
and WildlifeInclude Estrogen, Androgen and Thyroid
PathwaysPrioritization based on exposure and high
throughput screening [HTS] for bioactivityDevelop a Two-Tiered Screening and Testing
Program: bioactivity and adversity
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EDSTAC Tiered Testing Approach
EDSTAC recommended a two-tiered approachTier 1 battery (in vitro and in vivo assays)
To identify substances that have the potential to interact with the estrogen, androgen, or thyroid hormone systems
Tier 2 testing (multigenerational tests) To identify, and establish a dose-response relationship for any adverse effects that might result from the interactions identified through the Tier 1 assays
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EDSP Prioritization, Screening & Testing
Prioritization Exposure
ScreeningBioactivity
TestingDose-Response/
Adversity
Relies on:
• Monitoring data
• OSRI
Relies on:
• EDSP Tier 1 data
• OSRI
Relies on:
• EDSP Tier 2 data
• OSRI
UNEP Advisory Group Meeting December 12, 2014 Slide 16 of 24
Tier 1 Screening Assays: Bioactivity
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Tier 2 Test Methods: Adversity
Rat: Two-generation rat reproduction test (OECD TG 416) • Rat: Extended F1-Generation (OECD TG 443)
Fish: Medaka Multi-generation Toxicity Test (MMT) and Medaka Reproduction Test (MRT) methods
Frog: characterize perturbations of normal development and growth – Xenopus Laevis
Bird: determine long-term effects of maternal transfer and in ovo exposure – Japanese Quail
M F
EDSP Tier 1 Data Review: Current Pace192009-
2010EDSP Issued Initial Tier 1 Test Orders on 67 chemicals
2012-2013Tier 1 Data Submitted to the Agency on 52 chemicals
2014-2015Agency Completes 52 Tier 1 Data Reviews and WOE Determinations
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Future Direction for U.S. Endocrine Disruptor Screening Program
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EDSP Universe of Chemicals
Chemical List Number of Compounds
Conventional Active Ingredients 838
Antimicrobial Active Ingredients 324
Biological Pesticide Active Ingredients
287
Non Food Use Inert Ingredients 2,211
Food Use Inert Ingredients 1,536
Fragrances used as Inert Ingredients
1,529
Safe Drinking Water Act Chemicals
3,616
TOTAL 10,341
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EDSP Chemical Universe10,000
chemicals(FIFRA & SDWA)
EDSP List 2107 Chemicals
EDSP List 167 Chemicals
Based on current pace it could take decades to screen all 10,000 chemicals in EDSP Universe
Use compuational toxicology to rapidly screen chemicals for potential bioactivity and exposure
Implement a strategic approach to prioritize chemicals for targeted screening
Evolution of EDSP
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Use of HTS / Computational Toxicology Methodologies: Objectives
1. Prioritize chemicals for further EDSP screening and testing based on estimated bioactivity
2. Contribute to the weight of evidence evaluation of a chemical’s potential bioactivity
3. Substitute for specific endpoints in the EDSP Tier 1 battery
UNEP Advisory Group Meeting December 12, 2014 Slide 23 of 24
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ToxCast High Throughput Screening (HTS)
Detect agonist and antagonist activities18 Estrogen receptor assays 9 Androgen receptor assays3 Thyroid receptor assayshttp://www.epa.gov/ncct/toxcast/
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Example: Estrogen AgonismID Assay Name Source Gene Species Type
A1 NVS bovine ER Novascreen ESR1 Bos taurusReceptor Binding
A2 NVS human ER Novascreen ESR1Homo sapiens
Receptor Binding
A3 NVS mouse ERa Novascreen Esr1Mus musculus
Receptor Binding
A4 OT ERa-ERa (8 h) Odyssey Thera ESR1Homo sapiens Dimerization
A5OT ERa-ERa (24 h) Odyssey Thera ESR1
Homo sapiens Dimerization
A6 OT ERa-ERb (8 h) Odyssey TheraESR1, ESR2
Homo sapiens Dimerization
A7OT ERa-ERb (24 h) Odyssey Thera
ESR1, ESR2
Homo sapiens Dimerization
A8 OT ERb-ERb (8 h) Odyssey Thera ESR2Homo sapiens Dimerization
A9OT ERb-ERb (24 h) Odyssey Thera ESR2
Homo sapiens Dimerization
A10
OT GFP ERa-ERE (2 h) Odyssey Thera
ESR1, ERE
Homo sapiens DNA Binding
A11
OT GFP ERa-ERE (8 h) Odyssey Thera
ESR1, ERE
Homo sapiens DNA Binding
A12 ATG ERa (TRANS) Attagene ESR1
Homo sapiens
RNA Reporter Gene
A13 ATG ERE (CIS) Attagene ESR1
Homo sapiens
RNA Reporter Gene
A14
Tox21 ERa BLA Agonist ratio NCGC ESR1
Homo sapiens
Reporter Gene
A15
Tox21 ERa LUC BG1 Agonist NCGC ESR1
Homo sapiens
Reporter Gene
A16 ACEA T47D (80 h) ACEA ESR1
Homo sapiens Proliferation
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Proposed Methodological Approach
Use computational tools to model ER bioactivity
16 ToxCast assays relevant to agonist pathway Model AUC for R1 (agonist) and R2
(antagonist) activities
UNEP Advisory Group Meeting December 12, 2014 Slide 26 of 24
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Scientific Confidence Needed To Use any New Assay
Are reference chemicals that include a range of structures and potencies accurately detected?
Step 1: Does CompTox accurately identify chemicals with demonstrated in vitro bioactivities?
Step 2: Does CompTox accurately identify chemicals with demonstrated in vivo bioactivities?
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Step 1: In Vitro Estrogen-Active Chemicals
40 reference chemicals selected for recognized in vitro ER activity and include:• Range of structures• Range of potencies
• Strong: AC50 < 0.0001 μM
• Moderate: AC50 < 0.1 μM• Weak: AC50 < 1 μM• Very Weak: all other
actives• Peer Reviewed• OECD• ICCVAM
http://ntp.niehs.nih.gov/pubhealth/evalatm/iccvam/test-method-evaluations/endocrine-disruptors/in-vitro-assay-review/brd/index.html
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Step 1: ToxCast results vs. reference chemical results
Reference Chemicals
ToxCast POS NEG
POS 36 0
NEG 2 10
Overall concordance ~90% (36/40)
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Step 2: In vivo Estrogen-Active Chemicals
Comparison of ToxCast results for chemicals with recognized in vivo ER activityLeverage existing in vivo data
Systematic literature search of publically available (e.g. PubMed) Uterotrophic studies
Review published studies for QC and consistency with EPA (890.1600) guideline 6 minimum criteria to establish methodological
consistency Two independent reviewers evaluate studies based on
criteria All 6 criteria must be met to consider a study “guideline-
like”
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Step 2: ToxCast results vs. Uterotrophic results
Uterotrophic
ToxCast POS NEG
POS 43 8
NEG 6 32
Overall concordance ~84% (75/89)
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Integrated Bioactivity-Exposure Ranking: Objective
Prioritize chemicals for further EDSP screening and testing based on rank of ER bioactivity and estimated exposure
UNEP Advisory Group Meeting December 12, 2014 Slide 32 of 24
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Proposed Method
BioactivityToxCast
ExposureExpoCast
HTTKIntegrated BioactivityExposure Ranking(IBER)
Prioritization
Screening
Some or AllEDSP Tier 1
Assays
Some or AllEDSP Tier 1
Assays
TestingSome or AllEDSP Tier 2
Assays
UNEP Advisory Group Meeting December 12, 2014 Slide 33 of 24
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Integrated Bioactivity-Exposure Ranking
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FIFRA Scientific Advisory Panel Peer Reviewshttp://www.epa.gov/scipoly/sap/index.htm
Prioritizing the Universe of Endocrine Disruptor Screening Program (EDSP) Chemicals Using Computational Toxicology Tools (January 2013) http://www.regulations.gov (Search under EPA docket number: EPA-HQ-OPP-2012-0818)
Endocrine Disruptor Screening Program (EDSP) Tier 1 Screening Assays and Battery Performance (May 2013) http://www.regulations.gov (Search under EPA docket number:EPA-HQ-OPP-2013-0075)
Endocrine Disruptor Screening Program (EDSP) Tier 2 Ecotoxicity Tests (June 2013) http://www.regulations.gov (Search under EPA docket number:EPA-HQ-OPP-2013-0182)
Weight-of-Evidence: Evaluating Results of EDSP Tier 1 Screening (July 2013) http://www.regulations.gov (Search under EPA docket number: EPA-HQ-OPP-2013-0230)
New High Throughput Methods To Estimate Chemical Exposure (July 2014) http://www.regulations.gov (Search under EPA docket number: EPA-HQ-OPP-2014-0331)
Endocrine Activity and Exposure-based Prioritization and Screening (December 2014) http://www.regulations.gov (Search under EPA docket ID: EPA-HQ-OPP-2014-0614)
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EDSP Prioritization, Screening & Testing
PrioritizationBioactivity/Exposure
ScreeningBioactivity
TestingDose-Response/
Adversity
Relies on:
• QSARs• ToxCast/
ExpoCast• Monitoring
data• OSRI
Relies on:
• QSARs• ToxCast• EDSP Tier 1
data• OSRI
Relies on:
• EDSP Tier 2 data
• OSRI
UNEP Advisory Group Meeting December 12, 2014 Slide 36 of 24
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Concluding Thoughts
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US Views on EC Roadmap for EDs
The United States expressed concerns that the options provided in the EC’s Roadmap for defining criteria for identifying endocrine disruptors, specifically as it relates to plant protection products, does not appear to take into account risk from exposure in its approach, and may impose unnecessary and burdensome restrictions, that do not benefit public health or environmental protection.
Further, implementation of an EU policy that removes the requirement for conducting a full risk assessment, [as required by the WTO], is likely to have severe implications for EU imports of U.S. agricultural goods and plant protection products which serve an important public health objective by controlling pests and diseases.
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YES!
Are There Opportunities for EU-US Collaboration for ED Chemicals?
