Office of Research and Development Photo image area measures 2” H x 6.93” W and can be masked by a collage strip of one, two or three images. The photo image area is located 3.19” from left and 3.81” from top of page. Each image used in collage should be reduced or cropped to a maximum of 2” high, stroked with a 1.5 pt white frame and positioned edge -to- edge with accompanying images. 

# Chemical Safety for Sustainability: 

# EPA Research to Meet 21 st

# -Century Needs Elaine Z. Francis, Ph.D. National Program Director for Pesticides & Toxics Research

Scientific Advisory Panel May 24, 2011 

### http://www.epa.gov/ord/priorities/chemicalsafety.htmOffice of Research and Development 

# Presentation Overview • 

# Realignment of EPA’s research portfolio • 

# Chemicals issues facing EPA • 

# Description of the Chemical Safety for Sustainability 

# Research Program

– Examples of its applicability to OCSPP and others • 

# Time Line and Next Steps 1 

# Purpose of Presentation. To describe an overview of the development of EPA’s realigned chemicals research program, 

# its relationship to NAS report on Toxicity Testing in the 21 st 

# Century, and its applicability to OCSPP and other Program and Regional Office activities.Office of Research and Development 2 2Office of Research and Development



## “... To continue progress in ensuring the safety of chemicals in our 

## products, our environment and our bodies, EPA is improving how it looks at chemicals in the environment and the marketplace. We will work with all available tools, regulatory and non- regulatory, to increase our knowledge and assess the risks of these chemicals.... Because science is – and will continue to be – the backbone of our work at EPA, we are restructuring our research program to be more integrated and cross-disciplinary than ever before, a step that will 

## allow for a more efficient and effective scientific operation.”

-- EPA Administrator Lisa P. Jackson

3 

## Our Challenge: “21 st 

## century environmental problems require 21 st 

## century solutions; we cannot effectively 

## address such challenges with 20th 

## century approaches.” Dr. Paul Anastas Assistant Administrator for Research and DevelopmentOffice of Research and Development 4



# EPA Context Challenges: 1. Making more, faster, and smarter decisions, guided by science, on the problems facing us today. 2. Anticipating tomorrow's problems by identifying and applying approaches 

## that better inform and guide environmentally sustainable behavior . EPA Administrator Jackson’s priorities: Taking action on climate change Improving air quality Assuring the safety of chemicals 

### Cleaning up our communities Protecting America’s waters Environmentalism and Environmental Justice Strong State and Tribal PartnershipsOffice of Research and Development 

# Goals of the CSS

5 

## •To be a PROGRAM dealing with Chemical Safety that: • Brings a critical mass to bear • Is integrated across ORD 

## • > Lab/Center, in fact, >> Labs/Centers • Beyond the bounds of current interactions • Being co - dependent • Multiple multi authored outputs 

## • Promotes innovation and is catalytic and visible • Factors in sustainability aspects
•To be SOLUTION oriented 

## • Timely , relevant and translated
• SO THAT: • We can better protect the environment 

## • And gain Agency support for functionOffice of Research and Development



# Many Chemicals Little Data (%) 

# The Chemicals Situation

Judson, et al EHP (2009) 6Office of Research and Development 7



# Transforming Chemical 

# Safety Assessments

2005 2009 2007 2011Office of Research and Development 

# Problem Statement

Although chemicals are essential to modern life, we lack innovative, systematic, effective, and efficient approaches and tools to inform decisions that reduce negative environmental and societal impacts of 

## chemicals. 

# Vision EPA science will lead the sustainable development, use, and assessment of chemicals by developing and applying integrated chemical evaluation

strategies and decision support tools.

8Office of Research and Development 9 

# Boundaries for CSS

• 

## Focuses on those chemicals (or their byproducts) that are intentionally manufactured for commercial use • Covers complete life - cycle of a chemical/product • 

## Supports research into alternative product formulations using green chemistry and green engineering principles that would lead to the design of safer chemicals/products • 

## Includes impacts on both human health and ecological species • 

## Provides information needed to identify and protect susceptible life stages and populations, and to characterize how chemical stressors may contribute to disproportionate risk • 

## Results will be used by other complementary ORD research programs • E.g., to translate information on risks of specific chemicals and mixtures into a community setting (including those with disproportionate exposures) for humans exposed to multiple 

## stressorsOffice of Research and Development 10



### Prevention Decisions (future, new chemicals) 

### Management Decisions (existing chemicals) Focusing ORD Predictive Capabilities on a Systematic Approach to Product

Development and Use With New/Enhanced Capabilities Life Cycle Analysis Green Chemistry/Green Engineering Computational Toxicology Systems Exposure/Systems Biology Susceptibility/Resiliency Next-Gen Risk Assessment Supported by Existing Core Competencies Source-to-Outcome Measurement, Modeling,

and Prediction Risk Assessment Risk Management Methods • Sustainable Feedstock • Renewable • Reduced Toxicity Raw Materials • Atom economy

• Less Toxic Solvents/Reagents • Energy Use Reduction • Water Use Reduction • Waste Reduction Process •Occupational Risk

Reduction •Safe Product Design • Effective Function • Environmental Risk Reduction Production • Risk Reduction

• Exposure/Hazard • Consumer • Ecological • Alternate Product Availability • Alternate Choice PromotionUse • Ecological Risk Reduction • Human Health Risk Reduction • Land Use Optimization • Energy Use Optimization • Recyclability • Alternate Choice Promotion Disposal 

# Considering Sustainability Across Chemical Life Cycles

10Office of Research and Development 11



# CSS Collaboration

• 

## Initial problem formulation workshop: May 13 th

## , 2010; Washington DC • Opportunity to work collaboratively during the problem formulation and build a shared vision 

## • Identify and prioritize key problem areas; and • Develop plan for working together to develop an integrated, transdisciplinary research program
• 

## Program and Regional Offices asked to nominate participants

• Office of International and Tribal Affairs • Office of Children’s Health Protection • Office of the Science Advisor • Office of the Chief Financial Officer • Office of Environmental Information • Office of Compliance and Enforcement Assurance (including OEJ) • Region 6 (ORD Lead Region) • Office of Water • Office of Solid Waste and Emergency

Response 

### • 

### Office of Chemical Safety and Pollution



### Prevention • Office of Air and Radiation • Office of Policy, Economics, and InnovationOffice of Research and Development 12



# Partners Identified Agency Issues
• 

# 13 key issues surfaced

Eleven of t 

## hese arrayed under 3 major areas • Intelligent Testing Strategies including Mixtures • Evaluation of Inherent Properties of Chemicals/Products for Sustainable Approaches 

## • Improve Relevance of Assessment Methods • Two cross cutting issues were identified • Need for translational research 

## • Need to identify and communicate basis for vulnerability • Two issues were identified but are better aligned under the Sustainable and Healthy Communities Research Program • Development of metrics for community risk 

## • Need to address EJ assessments issuesOffice of Research and Development 13



# Timeline for CSS Program DevelopmentComputational

Toxicology (all) Endocrine Disrupting Chemicals (all)

Safe Pesticides/Safe Products (all but biotech) Nanomaterials (all) Human Health Risk Assessment (NexGen) Human Health (some) Chemical Safety for Sustainability Support for Integrated Evaluation Strategies Improving Assessment and Informing Management Targeted High Priority Needs 

# Aligning EPA’s Chemicals Research Activities Existing EPA Research Areas 

### New CSS Research Areas 

### Realigned EPA Chemicals Program

14Office of Research and Development 

# CSS Research Area 1:

Developing the Scientific Knowledge, Tools and Models for Integrated Evaluation Strategies Problem • Over 80,000 chemicals in TSCA and over 4900 substances intended to be registered through REACH (as of Nov. ‘10) with relatively very few 

## evaluated for safety • EPA cannot efficiently or effectively assure the safety of all chemicals using currently available evaluation and assessment approaches Goal 

## • Develop the tools needed for efficient approaches that allow the integrated evaluation, assessment and management of thousands of chemicals over their life cycle

10s- 100s/yr 10s100s/day 10,000s100,000s/ day Gene-expression LTS HTS MTS uHTS

1000s/day 15Office of Research and Development Photos courtesy of MIT Koch Institute 

# CSS Research Area 2: Improving the Relevance of Assessment and Management Methods for Chemical Safety Problem • Our current assessment and risk management approaches cannot keep up with environmental decision - making 

## needs Goals • 

## Integrate next-generation risk 

## assessment approaches across the Agency • 

## Facilitate management decisions that can be made faster and more efficiently, 

## while reducing uncertainties about risksOffice of Research and Development 

# CSS Research Area 3:

Targeting High-Priority Research Needs for Immediate and Focused Attention Problem. EPA has near-term critical research needs that are essential to fulfilling regulatory mandates. Goal. A process to ensure that EPA’s highest- priority needs are incorporated into the CSS program. • Needs will be determined by annual (or regular) discussions between 

## the senior managers of the CSS program and those of the EPA program and regional offices, informed by input from EPA stakeholders.

17Office of Research and Development 18 

# Research Areas 1. Developing the Scientific Knowledge, Tool and Models for

Integrated Evaluation Strategies Level 1: Chemical Properties Level 2: Prioritization and Screening Level 3: Hypothesis- Driven Targeted Testing Level 4: Systems- Level Understanding of Complex



# Environmental Risk 2. Improving Methods for Assessment and Informing Management for Chemical Safety and Sustainability Level 1: Next Generation Risk Assessment Approaches Level 2: Sustainable Risk Management Approaches 

# 3. Targeted High Priority Research Needs for Immediate and

Focused AttentionOffice of Research and Development 

# CSS Conceptual Model

19Office of Research and Development 

# Key Next Steps

20 

## • Crystallizing the concepts into projects
• Working closely with Laboratories/Centers management to ensure optimum workforce engagement and that the outputs are appropriate and meaningful
• Continual discussion and feedback of the CSS Implementation Team which includes the Program and Regional Office representatives
• Identify the “Must Dos” and high priority needs
• Briefing the Office of Management and Budget
• June 29 - 30 update to a meeting of a combined EPA Science Advisory 

## Board/ORD Board of Scientific Counselors
• October 1 Start UpOffice of Research and Development 21 

### Toxicity Cell Changes Molecular Targets 

### Tissues Cellular Networks 

## Cellular Systems Tissue Dose Molecular Pathways 

# A Grand Challenge: Predicting Toxicity
   

### Biochemical HTS

Cell - Based HTS

Complex Cellular and HCS HTS

Model

Organism MTS  

## Virtual Tissues ExposureOffice of Research and Development 22



# Computational Toxicology Benefits • 

# Less expensive • 

# More chemicals screened • 

# Fewer animals • 

# Solution oriented • 

# Innovative • 

# Multi -disciplinary • 

# Collaborative • 

# Catalytic • 

# Transparent Cancer ReproTox DevTox NeuroTox PulmonaryTox ImmunoTox in vitro testing

Bioinformatics/ Machine LearningOffice of Research and Development 23 

# Example of CSS Potential: ToxCast Enabling More Chemical Assessments

Using Less Resources 

# $2B 30 years $6M

2 years 

# ?
Traditional Toxicology Computational Toxicology Computational ToxicologyOffice of Research and Development 

# ToxCast Application:

ToxPi for Endocrine Profiling and Prioritization Toxicological Prioritization Index (ToxPi): visual compilation (slices) of data from ToxCast assays, chemical properties, and pathways

Ingenuity pathways ER AR TR Other XME/ADME

KEGG pathways LogP_TPSA Predicted CaCO2 Disease classes Other NR 5 assays 4 technologies 6 assays 4 technologies 5 assays 3 technologies 36 assays 1 technology 38 assays 4 technologies 27 specific pathway components used; data from external knowledgebases Calculated using QikProp software
24Office of Research and Development



# ToxPi: Prioritizing Chemicals for Potential Endocrine Activity Prioritization Index = ToxPi = f( HTS assays + Chemical properties + Pathways) Bisphenol A Tebuthiuron

Ingenuity pathways ER AR TR Other XME/ADME

KEGG pathways LogP_TPSA Predicted CaCO2 Disease classes Other NR

Reif et al, Environmental Health Perspectives, 2010 25Office of Research and Development 

# ToxPi Ranking of Chemicals

ToxScore Reif et al, 2010 26 HPTE Methoxychlor Pyrimethanil
Tebuthiuron 309 Chemicals sorted by ToxPi

highest lowest Bisphenol A

Linuron

ToxPi rankings being utilized along with other information for development of EDSP List 3Office of Research and Development 27



# Alternative Implementation of ToxPiOffice of Research and Development



# Application of 21 st 

# Century Science and Computational Approaches in the Transition from Current EDSP Approach

to Potential Future EDSP Approach


# • 

# Chemical Selection Basis

– Exposure - Multiple pathways



# – Drinking Water and Pesticides Reregistration Review Priorities

– Use of Toxcast, QSAR, and exposure

– Use of Toxcast, QSAR, and exposure 

# • 

# EDSP Tier 1

– 6 in vitro and 5 short term in vivo assays



# – 6 in vitro and 5 short term in vivo assays



# – With further research - possible replacement of in vitro assays with HTPS

– With even further research - possible replacement of all current assays – more targeted approach 28Office of Research and Development 

# Potential Game Changers Computational Toxicology – Employing state of the science approaches to construct predictive signatures of toxicity
• Providing basis for more intelligent testing approaches that reduces reliance on use of animals, prioritizes chemicals for evaluation and allows chemicals to be evaluated for those endpoints that appear to be most likely to be induced while maintaining adequate safeguards of human health and the environment 

### Life Stage Susceptibility to Chemical Exposure - Recognizing that infants can be more vulnerable to toxicants and realizing that reducing exposure can save lives
• Developing and applying new scientific tools that link chemical properties to biological activities, translate the impact on biological activities to diseases of children such as birth defects, infant mortality and morbidity, and asthma; and providing knowledge to design safer alternative chemicals 

### Dashboard tools - Integrating, translating, and transferring data from multiple sources by 

### producing decision -support tools for use on laptops throughout the Agency
• Dashboard tools will be developed considering comprehensive environmental assessment and life cycle considerations, and will inform chemical -specific life cycle assessments, decision making within EPA, as well as chemicals’ design, production, and use decisions in the private sector 29Office of Research and Development 30 

## • Digitizing and making available existing information • Understanding the life cycle of chemical use and disposal, relevant to exposure and effects • Improving dose reconstruction using biomarkers of exposure • Identifying the critical biological pathways that are perturbed by environmental chemicals • Capturing the complexities of exposure and dose in high -throughput assays • Developing predictive models of hazard and exposure to prioritize further screening and testing • Improving quantitative risk assessment and reducing uncertainty by using virtual tissues • Applying 21 st

## -century toxicology advances to both human and ecological 

## assessment • Scaling up the development of sustainable risk management approaches • Providing more - effective technology transfer, translational science, and science communication 

# The Grand ChallengesOffice of Research and Development



# Summary - CSS Research Program is Being Developed:
• 

# Through realignment of parts or all of 6 current research 

# programs to form a more critical and multidisciplinary mass of resources to address chemical safety science needs • 

# To address the Administrator’s priorities for assuring chemical safety • 

# By using an integrated transdisciplinary research process • 

# By engaging Agency partners and external stakeholders throughout the process • 

# With the expectation that it will provide broad - reaching game changing results in how chemicals are tested, assessed, and managed
31Office of Research and Development 32