Office of Research and Development

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Chemical Safety for Sustainability: 

EPA Research to Meet 21st-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.htm
Office 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

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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 21st

Century, and its applicability to OCSPP and other Program 

and Regional Office activities.
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“... 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

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Our Challenge: “21st century environmental problems 

require 21st century solutions; we cannot effectively 

address such challenges with 20th century approaches.”

Dr. Paul Anastas

Assistant Administrator for 

Research and Development
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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 Partnerships
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Goals of the CSS

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•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 function
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Many Chemicals Little Data (%)

The Chemicals Situation

0

10

20

30

40

50

60

Acute Cancer Gentox

Dev Tox Repro Tox

1

10

100

1000

10000

IRIS TRI Pesticides

Inerts CCL 1 & 2 HPV

MPV

Judson, et al EHP (2009)6
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Transforming Chemical

Safety Assessments

2005

2009

2007

2011
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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.

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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 

stressors
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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 

Promotion

Use

•Ecological Risk 

Reduction

•Human Health Risk 

Reduction

• Land Use Optimization

•Energy Use 

Optimization

•Recyclability

•Alternate Choice 

Promotion

Disposal

Considering Sustainability Across 

Chemical Life Cycles

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CSS Collaboration 

• Initial problem formulation workshop: May 13th, 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 Innovation
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Partners Identified Agency Issues

• 13 key issues surfaced

Eleven of these 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 issues
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Timeline for CSS Program Development
Computational 

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

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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 MTS HTS uHTS

1000s/day

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Office 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 risks
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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.

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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 Attention
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CSS Conceptual Model

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Key Next Steps

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• 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 Up 
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Cell Toxicity

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

Exposure
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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 Learning
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1 300 Chemicals

ToxRefDB ToxCast

Example of CSS Potential: 

ToxCast Enabling More Chemical Assessments 

Using Less Resources

$2B

30 years

$6M

2 years

?

Traditional Toxicology Computational Toxicology Computational Toxicology
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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

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Office 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 25
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ToxPi Ranking of Chemicals

ToxScore

Reif et al, 2010

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HPTE

Methoxychlor

Pyrimethanil

Tebuthiuron

309 Chemicals sorted by ToxPi

lowest highest

Bisphenol A

Linuron

ToxPi rankings

being utilized along with other 

information for development of 

EDSP List 3
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Alternative Implementation of ToxPi
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Application of 21st 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

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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

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• 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 21st-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 Challenges
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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

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