# Presentation: 793543

## Overview of EPA’s Regulatory Program on Endocrine Disruptors

## US Approach to Endocrine Disruptors

- Two Part Approach
- Research:
- Understand the basic science and mechanisms of action, and
- Develop measurement methods and risk assessment models
- Screening, Testing and Risk Management:
- Identify potential endocrine disruptors
- Determine adverse effects and dose-response
- Assess risk
- Manage risk under current laws

## ED Regulatory Program Activities

**Next 4 years:**
**Development of priority setting mechanism**
**Development and validation of screens and tests**
**Development of procedures and policies for the EDSP**
**Develop standard evaluation procedures and risk assessment guidelines**
**Require screening and testing**

## US Timeline

- Priority Setting

- Tier I Validation

- Tier II Validation

- Screening 1st
-  Chemicals

## ED Regulatory Program Activities

**Long term:**
**Review test data**
**Conduct hazard/risk assessments**
**Take appropriate risk management **

## U.S. Endocrine Disruptor Screening Program

**Required by the Food Quality Protection Act of 1996**
- - **Screen pesticides for estrogenic effects that may affect human health **
**Develop a screening and testing program by August 1998 **
**Implement the screening and testing program by August 1999**
**Report to Congress by August 2000**

## U.S. Endocrine Disruptor Screening Program

**EPA must use appropriate validated test systems or other scientifically relevant information **
**EPA can require screening and testing of:**
**-   Certain drinking water contaminants**
** ****Other endocrine effects**
** ****Certain other substances that have an effect cumulative to that of a pesticide chemical**

##  EDSTAC RECOMMENDATIONS

- EDSTAC  made 71 recommendations. The overarching ones are:
**EPA should use a High Throughput Pre-Screen to help prioritize chemicals**
**EPA should develop a data base to help prioritize chemicals**
**Use 3 *****in vitro *****and 5 *****in vivo *****assays in the  tier 1 screen to cover all known modes of E,A,T action **
**Use 5 tests in tier 2 to cover mammals, birds, fish, invertebrates and amphibians**
**EPA should validate the screens and tests prior to regulatory implementation**

## SCOPE OF EPA’S ENDOCRINE DISRUPTOR SCREENING PROGRAM

**Based on current science, the scope of the screening program includes:**
**Estrogen, Androgen and Thyroid hormones**
**Human health and ecological effects**
**Broad range of chemicals and mixtures**

## THE UNIVERSE OF CHEMICALS

**Chemicals Under EPA’s Purview**
**950 pesticide active ingredients**
**2500 “inerts” in 20,500 products**
**75,500 industrial chemicals on the TSCA inventory**
** ****environmental contaminants (?)**
**Chemicals Under Other’s Purview **
**cosmetics**
**food additives**
**nutritional supplements**

## Framework

**Initial Sorting **
**Priority Setting**
**Screening (Tier 1)**
- Identifies substances for further testing
**Testing (Tier 2)**
- Identifies adverse effects and establishes dose-response relationship for hazard assessment

## Screening, Testing and Assessment Strategy

**Current efforts focused on:**
**Pesticide active ingredients (~950)**
**Chemicals which are both “inert” formulation ingredients and HPV commercial (~600) chemicals**
**Chemicals positive on QSAR**
**Meets statutory mandate for screening pesticides**
**Reasonable number of chemical candidates**

## + QSAR

## Implementation Strategy: Commercial Chemicals

**Goal:**** ****Set priorities for**** ****chemicals according to potential exposure and potential endocrine effects**
**How:**
**Develop Priority Setting Database **
**Group chemicals based on common effects and exposure information**
**Compare chemicals within groups and establish priorities within groups**
**Pick highest priority chemicals in each group**

## EDPSD v.2 Exposure Data Screen

**EDPSD v.2 Exposure Data Screen**

## EDPSD v.2 Effects Data Screen

**EDPSD v.2 Effects Data Screen**

## PROBLEM: LACK OF EFFECTS INFORMATION FOR PRIORITY SETTING

**PROPOSED SOLUTION # 1**
**Use High Throughput Screening Technology (HTPS)**
**EPA to run ER, AR assays (Tier 1) assays before priority setting on 15,000 chemicals**
**Use data to help set priorities for remainder of Tier 1 screen **
**PROPOSED SOLUTION # 2**
**Develop and validate QSAR models based on receptor binding data**

## USING MODELS  FOR PRIORITY SETTING

**Explore the use of QSAR models rather than HTPS for priority setting for 1****st**** group of screening candidates**
**Building a QSAR model involves two steps:**
**Generation of descriptors to encode chemical information**
**Correlation of descriptors with biological activity**
**QSAR will be validated and peer reviewed**

## NCTR Stepwise Approach for ER Binding 

**Step 1 Simple filters**
** ****Molecular weight: 94-1000 **
**HC with at least one ring**
** ****Step 2 Qualitative Activity Prediction**
**3-D Pharmacophore ****Atomic distance and bond angles like E2 or DES**
**Classification models **
**Step 3 CoMFA**
**3D correlation of steric-electrostatic interactions between ligand and receptor**

## COmmon REactivity PAttern (COREPA)

**3-D Approach**
**High computational intensity**
**Computations performed once**
**Provides conformational flexibility**
**Uses descriptors based on published data**
**Screens large sets of structurally-diverse chemicals based on stereo-electronic properties of each chemical**

## Proposed Implementation Strategy:Registered Active Ingredients

**Conduct Pilot Program with 25-50 “potentially high EAT hazard concern” substances **
**Pilot will be used to develop criteria for evaluating existing information and sorting pesticides and chemicals into Categories 2, 3 and 4.**
**Contractor will conduct literature search and assessment using developed criteria**
**Obtain screening or testing data by periodic issuance of testing orders for additional substances**

## TIER 1 SCREENING Interaction with endocrine system

**Screens should be**
**inexpensive, quick, simple**
**standardized and validated**
**more sensitive than specific**
**able to detect multiple endpoints**
**readily interpretable**
**Use information to **
**make initial judgments**
**direct and focus tier 2 tests   **

## Modes of Action

**Hormone synthesis and clearance**
**Hormone storage and release**
**Hormone transport**
**Receptor binding**
**Altered post-receptor activation**

## PROPOSED SCREENING BATTERY (Tier 1)

**PROPOSED SCREENING BATTERY (Tier 1)**

***In vitro *****Screens**
**ER Binding / Reporter Gene Assay**
**AR Binding / Reporter Gene Assay**
**Steroidogenesis Assay with minced testis**
**In vivo Screens**
**Rodent 3-day Uterotrophic Assay (sc)**
**Rodent 20-day Pubertal Female Assay with Thyroid**
**Rodent 5-7 day Hershberger Assay**
**Frog Metamorphosis Assay**
**Fish Reproduction Screening Assay**

## ALTERNATE SCREENING ASSAYS 

**Rodent 20-day Pubertal Male  Assay with Thyroid **
**Placental aromatase**
**Rodent in utero through Lactation Assay**

## TIER 2 TESTING Confirm and characterize endocrine effects 

**Tests should **
**if found, determine if effects are a primary or secondary disturbance of  endocrine function**
**establish exposure/concentrations/timing and effects relationships  **
**be sensitive and specific**
**assess relevant endpoints**
**include life cycle of live-bearing and egg-laying species**
**include a dose range for full characterization of  effects **
**be conducted in accordance with GLP**
**be validated   **

## PROPOSED  TIER 2 TESTING  BATTERY

**PROPOSED  TIER 2 ****TESTING  BATTERY**

**Multigeneration reproduction and development studies**
**Rodents**
**Birds**
**Frogs**
**Fish **
**Shrimp**

## Development of Policies and Procedures

- EPA proposed policy in Dec 1998
- Re-propose statement of EPA policy 2002
- Final statement of policy 2003

## Development of Policies and Procedures

- Statement of Policy may address:
- Authorities EPA will use to require testing
- Data compensation issues
- Data development and submission requirements
- Program mechanics
- Other legal and policy issues

## EPA REGULATORY IMPLEMENTATION

- Use Order (FIFRA, FQPA, SDWA) and /or Test Rule authority (TSCA) to require industry to develop screening and testing data
- EPA conducts hazard/risk assessment

## Endocrine Disruptors Will Be Regulated Under Existing Laws 

- Insecticide, Fungicide, Rodenticide Act
- Food Drug and Cosmetics Act
- Toxic Substances Control Act
- Clean Water Act
- Safe Drinking Water Act
- Clean Air Act

## RESEARCH

**RESEARCH**

**Risk Assessment Guidelines**

**TEST **
**DATA**

**Standardization**
**Validation**

**Standard Evaluation**
**Procedures**

** ****EVALUATE STUDIES**
** ****ASSESS HAZARD**

**EXPOSURE**

-  **ASSESS RISK**

**Assay **
**Development**

## US Timeline

- Priority Setting

- Tier I Validation

- Tier II Validation

- Screening 1st
-  Chemicals