&EPA
EPA 601/R-12/006 I June 2012 I www.epa.gov/research
United States
Environmental Protection
Agency
Chemical Safety for Sustainability
STRATEGIC RESEARCH
ACTION PLAN 2012-2016
SOEN<
Office of Research and Development
Chemical Safety for Sustainability
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EPA 601/R-12/006
Chemical Safety for
Sustainability
Strategic Research Action Plan 2012 - 2016
U.S. Environmental Protection Agency
June 2012
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Table of Contents
Executive Summary 5
Introduction 9
Program Purpose 9
Integrated, Transdisciplinary Research 10
Research to Support EPA Priorities and Regulatory Requirements 11
Statutory and Policy Context 11
High Priority Chemicals of Concern: Endocrine Disrupting Chemicals (EDCs) 12
High Priority Chemicals of Concern: Nanomaterials 12
Research Focus Area: Computational Toxicology (CompTox) 13
Sustainable Molecular Design Approaches 13
An Integrated Program Design 15
Collaborating Across Research Programs 15
Developing Partnerships from the Start 17
CSS Design Overview 17
Research Themes and Priority Science Questions 23
Theme 1. Inherency 23
Theme 2. Systems Models 25
Theme 3. Biomarkers 30
Theme 4. Cumulative Risk 32
Theme 5. Life Cycle Considerations 34
Theme 6. Extrapolation 37
Theme 7. Dashboards 39
Theme 8. Evaluation 41
Conclusion 42
Summary Tables 43
Theme 1. Inherency 43
Theme 2. Systems Models 45
Theme 3. Biomarkers . . .49
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Theme 4. Cumulative Risk 50
Theme 5. Life Cycle Considerations 52
Theme 6. Extrapolation 53
Theme 7. Dashboards 55
Theme 8. Evaluation 57
References 58
Appendix A. Research Program Partners and Stakeholders 60
Appendix B. Definitions 62
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Executive Summary
Chemicals provide the key building blocks that are
converted into end-use products or used in industrial
processes to make products that create jobs and benefit
society. Improving the safe production, use and disposal
of chemicals is a major priority of research at the U.S.
Environmental Protection Agency (EPA) to support
decisions and actions the Agency makes to meet its
mission to protect human health and the environment. To
meet its mission, the Agency needs a research approach
that advances science to meet society's current demands
for a safer environment but to also meet the social,
economic and environmental health needs of future
generations. The Agency must conduct research and
analyses that will support the sustainable manufacture
and use of chemicals.
The Strategic Research
Action Plan for EPA's
Chemical Safety for
Sustainability (CSS)
research program presents
the purpose, design and
themes of the Agency's
CSS research efforts
to ensure safety in the
design, manufacture and
use of existing and future
chemicals.
The challenges are formidable: more than 80,000 chemicals are currently listed or registered
for use in the U.S. and at least a thousand more are introduced every year. Many of these
chemicals have not been thoroughly evaluated for their potential risks to human health, wildlife
and the environment, particularly throughout their life cycle (from the collection of raw chemical
feedstocks, through their use and the final disposal of the products that contain them). There
is also a need to focus on emerging contaminants of concern including endocrine disrupting
chemicals (EDCs) and nanomaterials. EDCs are chemicals that interfere with the activity of
hormones in the body and the environment. Nanomaterials are in a very small size range (~ 1
to 100 nanometers), which can alter the chemical's properties compared with larger versions
of the same chemical and in turn influence its exposure and toxicity. Many processes and
procedures being used today to evaluate and assess the impact of chemicals on human health,
wildlife and the environment were designed decades ago, are largely based on laboratory
tests conducted on animals and are labor and resource intensive. Further, many of the current
tests have not fully incorporated recent advances in chemistry, exposure science, biology and
computer technologies. This combination of factors makes it difficult to meet current demands of
evaluating the safety of an ever-increasing number of chemicals.
As a result, a number of important aspects of chemical safety are not adequately understood,
including: how to design and produce safer chemicals; how chemicals and their byproducts
move through the environment; what the sources of chemical exposure are; what the critical
biological processes and toxicity pathways are that chemicals might interact with to cause
disease; and what the contribution of exposure to chemicals in the environment is to the overall
disease burden for susceptible populations.
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CHEMICAL SAFETY FOR
SUSTAINABILITY
PROBLEM STATEMENT:
Although chemicals are
essential to modern life, we
lack innovative, systematic,
effective and efficient
approaches and tools to
inform decisions that reduce
the environmental and
societal impact of chemicals
while increasing economic
value.
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.
Thus, transformative approaches are needed to
improve the information used in chemical assessments.
New approaches developed in the CSS research
program will enable EPA to increase the pace at which
relevant information can be obtained and integrated
into assessments and decision-making. The program
will inform and advance sustainable approaches to
chemical design, production and use across product
life cycles.
This Strategic Research Action Plan forEPA's
Chemical Safety for Sustainability Research Program
describes the purpose, design and themes of the
Agency's research efforts to help ensure safety in
the design, manufacture and use of existing and
future chemicals. It describes how the program was
developed with the input of EPA internal partners and
external stakeholders from the beginning, how it is
aligned with Agency priorities and how the research
portfolio will harness systems-approaches to advance
the scientific understanding of the links between
chemical exposure, toxicity pathways and disease
or other harmful effects to humans, wildlife and the
environment.
Tools produced through the CSS research program will use systems-approaches to advance
the understanding of the links between exposures to chemicals and toxicity pathways that
lead to the development of disease. At the same time, the research will dramatically increase
the efficiency and speed of chemical evaluations. It will allow EPA to evaluate potential effects
of chemical exposure on critical life stages, such as the embryo and childhood and other
susceptibility factors, including genetics and co-existing diseases.
Recognizing that humans and wildlife encounter numerous chemicals simultaneously, the
CSS research program will develop methods to assess the effects of exposure to multiple
chemicals and methods to assess cumulative chemical risk. Further, the program includes
the development of sustainability metrics to measure how changes in parameters that affect
hazard and exposure impact the degree to which a chemical is more or less environmentally
sustainable throughout its life cycle.
Working in conjunction with partners in EPA regulatory program and regional offices, CSS
identified three research goals that guided the development of the overall program:
Research Goal 1
Developing the scientific knowledge, tools and models needed to conduct integrated,
timely and efficient chemical evaluation strategies.
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Research Goal 2
Improving methods for assessment and informing management for chemical safety and
sustainability,
Research Goal 3
Providing targeted high-priority research solutions for immediate and focused attention.
The first goal is intended to deliver a suite of tools (i.e., data, methods, models) that
offers researchers and environmental decision-makers needed resources for improved
chemical assessments. The second goal is focused on the application of the tools for
risk assessment and chemical management to ensure the safe and sustainable design,
production and use of chemicals, including the advancement of green chemistry. The third
goal is intended to ensure that the high-priority human and environmental health-related
specific research needs of the Agency, identified by its program and regional offices, are
met while the long-term research solutions are advanced.
The key research outcomes will include:
• Improved chemical hazard assessments
By developing a deeper understanding of the relevant physico-chemical and other
inherent properties of chemicals that influence environmental fate, exposure and
biological responses, CSS research will lead to improved chemical assessments.
• Improved chemical prioritization, screening, testing and quantitative risk
assessments
By integrating information from multiple biological levels, including pathway-level
information and by using advanced computational techniques (e.g., multi-scale systems
models of virtual tissues) to develop predictive models of hazard and exposure, CSS
research will provide decision-makers with robust risk assessment methods.
By using consistent, justifiable and improved use of existing biomonitoring data, dose
estimation/exposure reconstruction methods and diagnostic adverse outcome pathway
(AOP)-based biomarkers, EPA risk assessments will be improved.
• Improved understanding of the relationship of chemical exposures and health
outcomes to the fetus and children
By understanding the molecular pathways and cellular processes underlying
adverse pregnancy outcomes and improving methods to assess the impacts of fetal
or neonatal chemical exposure at different stages of development and scales of
biological organization, CSS research will increase knowledge of health effects after
developmental exposure.
• Development of sustainable risk management approaches
By identifying key links in the continuum from the production of a chemical, its release
in the environment, its fate/transport, to the resulting exposures and adverse outcomes,
sustainable risk management approaches can be developed that can be scaled up and
delivered to decision-makers.
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• Accessible, useful information
By sharing research outputs and outcomes in ways that effectively communicate,
translate and transfer the scientific information in a manner most useful to decision-
makers.
To address the research areas and desired outcomes, the CSS program was developed
around eight main research topics. These topics were selected because they represent the
fundamental building blocks upon which an integrated evaluation strategy can be built to inform
environmental and health decisions.
The eight research topics and the questions that they address are:
1. Inherency — How can an understanding of inherent properties of chemicals inform
exposure and health outcomes, the design of chemical assays and tools and sustainable
design of chemicals?
2. Systems Models — What are the perturbations at all levels of biological organization
(i.e., molecular, cellular, tissues, organ, whole organism), defined as "toxicity pathways," that
lead to adverse outcomes following exposure to an environmental chemical?
3. Biomarkers — How can useful biomarkers of exposure and effect be optimally
developed?
4. Cumulative Risk — What are the ecological and human health risks of real-world
environmental chemical exposures (i.e., exposures to mixtures of multiple chemicals over
time)?
5. Life Cycle Considerations — What are the impacts of an environmental chemical
over its entire life cycle, from the collection of its raw materials all the way through its
manufacture, use and finally its disposal?
6. Extrapolation — Can improved extrapolation methods be developed for predicting
toxicity in the absence of various data (e.g., extrapolating from lab animal to human, in vitro
to in vivo)?
7. Dashboards — What tools can be customized into useful, accessible interfaces that
provide decision-makers with the toxicity data and information they need to support specific
regulatory needs?
8. Evaluation — What has been the impact of the CSS research findings and tools on EPA's
decision-making?
The Strategic Research Action Plan for EPA's Chemical Safety for Sustainability Research
Program maps out a research program for the next 5 to 10 years. It has been designed with
the flexibility needed to leverage scientific breakthroughs, address the emerging priorities and
needs of decision-makers, shifting resource availability and other considerations. As such, it is a
"living document" that will be updated as needed over that time.
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Introduction
Program Purpose
EPA is faced with evaluating more than 1,000 new chemicals each year prior to their commer-
cialization and is further challenged with determining which environmental chemicals already
in commerce may result in adverse effects to pursue risk management actions (Judson et al.,
2009). In addition, there are newer forms of chemicals, such as nanomaterials, entering the
marketplace at an increased rate. There is also an increased need to focus on emerging health
concerns, such as those associated with endocrine disrupting chemicals, that may require
evaluation approaches that differ from traditional methods.
To address these needs, the EPA and the
National Institute of Environmental Health
Sciences (NIEHS) requested that the National
Research Council (NRC) develop an expert
report. The resulting report, Toxicity Testing
in the 21st Century: A Vision and Strategy
(NRC, 2007), proposes a shift in chemical
testing to one that evaluates perturbations
in toxicity pathways, largely using in vitro
methods. The report addressed several
concerns about current testing methods,
specifically, the desire to (1) reduce the
number of animals used in testing, (2)
reduce the overall cost and time required to
characterize each chemical, (3) increase the
level of mechanistic understanding of chemical
toxicity and (4) assess toxicity for real world
exposures. The EPA has formally adopted the
Toxicity Testing in the 21st Century:
A Vision and Strategy (NRC, 2007)
"/Advances in toxicogenomics,
bioinformatics, systems biology,
epigenetics and computational
toxicology could transform toxicity
testing from a system based on whole-
animal testing to one founded primarily
on in vitro methods that evaluate
changes in biologic processes using
cells, cell lines, or cellular components,
preferably of human origin."
recommendations of the NRC by developing
their Strategic Plan for Evaluating the Toxicity
of Chemicals (EPA, 2009).
The strategic directions of the CSS research
program are tightly aligned with the
recommendations of the NRC (NRC, 2007)
and EPA's Strategic Plan (EPA, 2009) and
also advance research in additional areas
important to EPA, such as the exposure
and fate of chemicals and nanomaterials,
identifying and evaluating adverse outcome
pathways, characterizing cumulative risk
and providing bioinformatic tools to enable
rapid risk assessment analyses for regulatory
decisions.
Looking beyond assessing potential impacts
of environmental chemicals, the CSS research
program recognizes the need for the design
of safer and more sustainable ("green")
chemicals. The research is assisting in
replacing existing commercial chemicals and
materials that pose environmental and health
risks by identifying new chemicals that exhibit
the desired uses of existing chemicals, but can
be manufactured with lower potential adverse
impacts.
The long-term vision of the CSS research
program is that 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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CSS OBJECTIVES
Creating tools that inform sustainable
chemical/material design and use
Developing methods for much faster
screening and prioritizing
Providing the scientific knowledge and
tools to effectively understand real-
world risks
Developing assessment approaches
that are tailored to specific decision
contexts
Considering where impacts may occur
throughout a chemical's life cycle
Integrated, Transdisciplinary Research
To increase the scale of the Agency's
decision-support tools and improve guidance/
management for safer chemical design
and use, the EPA needs an integrated,
transdisciplinary research effort that unites
the capabilities of a diversity of experts,
including chemists, exposure scientists,
biologists, engineers and economists and
other social scientists.
The CSS research program is focused on
providing integrated solutions to support
of chemical management. The data,
methods and tools developed will guide
the prioritization and testing process, from
screening approaches through more complex
testing and assessments. CSS outcomes will
be delivered to EPA partners and decision-
makers in appropriate, accessible forms
(NRC, 2009).
By organizing its research to harness a
diversity of expertise and support integrated
evaluation strategies, the CSS research
program will provide state-of-the-science
tools and integration techniques to inform
risk assessment and risk management
activities. Such activities include those used in
regulatory decision-making, as well as those
utilized in developing, producing and using
chemicals.
To maximize relevancy of the research, the
CSS research program will focus on the
highest priority research needs of EPA's
program and regional offices. The program
includes training for decision-makers and
others so that they can fully utilize the tools
and research produced.
The research is conducted and/or supported
by the EPA Office of Research and
Development's three national laboratories,
four national centers and two offices located
in 14 facilities around the country and in
Washington, D.C and includes both intramural
and extramural (primarily through EPA-
awarded STAR research grants and awards)
components.
EPA PRIORITIES
Taking action on climate change
Improving air quality
Assuring the Safety of Chemicals
Cleaning up our communities
Protecting America's waters
Expanding the conversation on
environmentalism and working for
environmental justice
Building strong state and tribal
partnerships
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Research to Support EPA Priorities and
Regulatory Requirements
Statutory and Policy Context
The CSS research program advances EPA's priority, Assuring the Safety of Chemicals (EPA,
2010). The CSS research program uses novel research approaches to address the risks posed
by chemicals in industrial and commercial use, as well as risks posed by these chemicals as
they degrade or pass through the environment.
Managing chemical risks is covered in
legislation and statutes mandated by
Congress and implemented by EPA (Table
1). Chemicals are regulated by several
program offices under a variety of statutes
and CSS has worked closely with each of
these offices in developing this research
program. As examples of chemical legislation,
amendments to the FQPA and SDWA, both
of 1996, contain provisions for assessing
the potential for chemicals to interact with
the endocrine system. Both the CWA and
the SDWA require the Office of Water to
prioritize possible water contaminants in the
Contaminant Candidate List (CCL). The
Office of Solid Waste Emergency Response
is concerned with the end-of-use disposition
of chemicals and is therefore interested in
life cycle considerations of chemical use.
Internationally, similar pressures to transform
the chemical safety assessment paradigm are
also present, as exemplified by the REACH
Program and Cosmetics Directive in Europe
and the Canadian Environmental Protection
Act in Canada. CSS will enable the Agency
to test and regulate numerous chemicals in
a more efficient manner, supporting several
statutory obligations and policies (Table 1).
Table 1: CSS Research Supports Chemical Risk Management Decisions
Mandated by Legislation
Legislation
Clean Air Act
Clean Water Act
Comprehensive Environmental
Response, Compensation and
Liability Act
Federal Food, Drug and
Cosmetic Act
Federal Insecticide and
Rodenticide Act
Food Quality Protection Act
Resources Conservation and
Recovery Act
Safe Drinking Water Act
Toxic Substances Control Act
Acronym
CAA
CWA
CERCLA
FFDCA
FIFRA
FQPA
RCRA
SDWA
TSCA
Website
www.epa.gov/lawsregs/laws/caa.html
www.epa.gov/regulations/laws/cwa.html
www.epa.gov/superfund/policy/cercla.htm
http://www.fda.gov/
regulatoryinformation/legislation/
federalfooddrugandcosmeticactfdcact/
default.htm
http://www.epa.gov/agriculture/lfra.html
http://www.epa.gov/pesticides/regulating/
laws/fqpa/backgrnd.htm
http://www.epa.gov/epawaste/laws-regs/
index.htm
www.epa.gov/lawsregs/laws/sdwa.html
www.epa.gov/lawsregs/laws/tsca.html
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High Priority Chemicals of Concern:
Endocrine Disrupting Chemicals (EDCs)
The CSS research program provides support
to EPA's Endocrine Disrupter Screening
Program (EDSP; www.epa.gov/endo/index.
htm). The EDSP screening program is
mandated under Amendments to the FQPA
and SDWA.
CSS GOALS TO SUPPORT EDSP:
Near-term: Rapidly prioritize
thousands of chemicals for the current
EDSP Tier 1 Screen (T1S) battery.
Intermediate: Incorporate modern
technologies directly into the EDSP
T1S to increase the capacity to screen
for endocrine disrupting chemicals.
Longer term: Eventually replace the
T1S battery with a suite of assays
based on non-whole animal methods.
From the EDSP21 Workplan
(EPA, 2011 b).
By evaluating current endocrine disruption
testing protocols, in collaboration with partners
in EPA's Office of Chemical Safety and
Pollution Prevention, CSS will develop new
approaches to advance the current EDSP that
includes the use of high-throughput screening
and computational models to prioritize
chemicals in EDSP. The CSS work to support
EDSP will be conducted with partners in
the National Institutes of Health and the
Food and Drug Administration through the
"Tox21 Consortium," a collective effort among
governmental scientists to development and
use new toxicological methods.
High Priority Chemicals of Concern:
Nanomaterials
Public health and the environment regulatory
agencies were called upon by the White
House (Executive Office of the President
Memorandum, 2011) to gather information
about developments in nanotechnology
The NRC recently released a report on
the safety of engineered nanomaterials
that provides a strategy for addressing the
science needs regarding the potential health
and environmental risks of engineered
nanomaterials (NRC, 2012). Accordingly,
understanding the potential toxicity of
nanomaterials is another key focus of the CSS
research program.
CSS NANOMATERIAL RESEARCH
GOALS:
Identify the nanomaterials and in
what forms, most likely to result in
environmental exposure.
Identify the particular properties of a
nanomaterial are related to toxicity
(nanomaterials of concern).
Identify concentrations of
nanomaterials of concern in air, soil,
water and biological systems.
CSS's nanotechnology research is focused on
supporting and informing EPA safety decisions
made under various environmental statutes
the Agency is responsible for upholding. By
achieving the goals of the CSS's nanomaterial
research effort, EPA decision-makers will have
more information to determine the health risks
for various nanomaterials.
CSS research is coordinating with the
National Nanotechnology Initiative (NNI, 2011)
and collaborating with the Organization for
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Economic Cooperation and Development
(OECD, 2001), to generate protocols, data and
risk assessment approaches to promote the
safe development, use and disposal/recycling
of nanomaterials.
Research Focus Area: Computational
Toxicology (Comp Tox)
Computational toxicology applies
mathematical and computer models and
molecular biological approaches to predict
chemical hazards and risks to human health
and the environment (EPA, 2003a; http://www.
epa.gov/ncct/). Computational toxicology
tools are being developed in CSS research
as part of the effort to move toward a 21st
century approach to toxicity testing (NRC,
2007) and risk assessment (NRC, 2009) by
moving to toxicity pathway based in vitro
assays. The CSS computational toxicology
work will be conducted with partners in the
National Institutes of Health and the Food
and Drug Administration through the "Tox21
Consortium," a collective effort among
governmental scientists to develop and use
new toxicological methods.
CSS COMP TOX EXAMPLES:
• Dashboards to display integrated
toxicity information for partner-
specific questions
• Databases of mechanistic, whole
animal toxicity and exposure
data (e.g., ACToR, ExpoCast)
• Virtual Liver and Virtual Embryo
Sustainable Molecular Design Approaches
As part of the CSS advancement of science
to support regulatory decisions on chemicals,
CSS research includes sustainable molecular
design of less toxic ("green") chemicals (www.
epa.gov/greenchemistry/).
Sustainable molecular design draws upon
the established principles of chemistry and
engineering to build chemicals atom by atom
from the ground up with the end goal of
removing the inherent risk of the chemical.
"Green chemistry technologies" encompass
all types of chemical processes including
syntheses, catalyses, reaction conditions,
separations, analyses and monitoring. It
can, for example, explore existing synthetic
pathways to identify opportunities to substitute
a greener feedstock, reagent, catalyst,
or solvent in place of more toxic ones. In
addition, a green chemistry technology can
replace the entire synthetic pathway. Green
chemistry technologies can have a number
of advantages including reduced waste,
reduced costs (e.g., eliminating end-of-the-
pipe treatment), reduced energy and resource
use and increased product safety, which can
result in increased competitiveness of the
manufacturers. One example of progress
in this arena is EPA's Presidential Green
Chemistry Challenge Program which has
recognized groundbreaking green chemistry
solutions to real-world environmental
problems. The new technologies recognized
over the past 16 years have significantly
reduced the hazards associated with
designing, manufacturing and using chemicals
and in turn, have reduced the use or
generation of more than 199 million pounds of
hazardous chemicals, saving 21 billion gallons
of water and eliminating 57 million pounds of
carbon dioxide releases to the air.
CSS research encompasses continued
efforts to advance the field of sustainable
molecular design. For example, the CSS "Life
Cycle Considerations" theme research will
evaluate life cycle impacts that demonstrate
sustainable molecular design approaches
for chemicals and identify the costs of these
solutions. As another example, the program's
Inherency theme research will provide a basis
for designing chemicals with lower exposure
and toxicity potential. CSS research builds
on existing research of cost-efficient resource
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and energy-efficient methods for synthesizing
chemicals and products. CSS researchers
are collaborating with academic and industry
partners to fundamentally redefine the design
of chemicals used by industry and consumers
to reduce the risks of exposure to toxic
chemicals.
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An Integrated Program Design
The CSS research program uses a transdisciplinary approach to develop and deliver the scien-
tific tools and knowledge necessary to inform chemical safety decisions that advance sustain-
ability. The program integrates skills, expertise and research from a diversity of fields, including
bioinformatics; computational chemistry; green chemistry and engineering; systems biology; mo-
lecular, cellular and biochemical toxicology; exposure science; process modeling; chemical and
environmental engineering; and social sciences.
CSS is designed to lower barriers to research
collaboration, moving away from what has
traditionally been a "stove-piped" approach
to environmental science, divided along
disciplinary divisions. Instead, the design
of the CSS research program ensures a
transdisciplinary approach to problem solving
and information delivery, including training,
cross-organization dialogue, collaboration
and team building. The program will cultivate
innovation, leverage efficiencies and provide
the holistic science the Agency needs for
chemical safety and sustainability and
other complex, far-reaching environmental
challenges.
The CSS research program integrates
elements and themes from research efforts
previously administered across EPA's Office
of Research and Development (ORD) into a
seamless, highly-coordinated, transdisciplinary
research program. It leverages expertise and
resources in ways that realize efficiencies
and reinforce common themes and research
goals across six formerly separate research
programs: Nanotechnology, Computational
Toxicology, Safe Pesticides/Safe Products
(SP2), Endocrine Disrupters, Human
Health Research and Human Health Risk
Assessment.
Collaborating Across Research Programs
In order to meet the needs of the Agency
and the nation in addressing complex
environmental problems, research integration
is critical to both the CSS research program
design and the collaborations across all six
EPA research programs. EPA's six research
programs collaborate to deliver results that
meet the science needs of decision-makers
while also establishing a broad scientific
foundation for a sustainable future. CSS
supports the overall effort by providing
improved approaches to chemical testing and
assessment and those efforts in turn support
the research efforts of the other programs. For
example, CSS advances in chemical safety
and management inform research efforts in
air toxics, drinking water, pesticides use in
local communities and larger ecosystems
and waste management, remediation and
emergency response.
There are many examples of collaboration
across EPA's six research programs.
EPA's Six Integrated Research
Programs:
Chemical Safety for Sustainability
(CSS)
Human Health Risk Assessment
(HHRA)
Air, Climate and Energy (ACE)
Safe and Sustainable Water
Resources (SSWR)
Sustainable and Healthy
Communities (SHC)
Homeland Security (HS) Research
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Examples include:
• The CSS program is providing tools and
data to EPA's Sustainable and Healthy
Communities (SHC) research program
for those contaminants of highest priority
and concern to communities, considering
susceptibilities and exposures of the most
vulnerable populations and life stages.
CSS and their partners from the Air,
Climate and Energy (ACE) research
program are developing green chemistry
alternatives to existing hazardous air
pollutants, such as halogenated solvents
considered "hazardous air pollutants"
under the Clean Air Act. This work
includes developing and evaluating safer
cleaning agents and developing chemical
screening methods needed for volatile
chemicals.
CSS is collaborating with the Human
Health Risk Assessment (HHRA) research
program to advance the pathway-based
toxicity testing and risk assessment
paradigm proposed by the National
Academy of Science (NRC, 2009). CSS
research complements ongoing EPA single
chemical and cumulative risk assessment
activities conducted by HHRA, including
the Next Generation (NexGen; http://www.
epa.gov/risk/nexgen/) risk assessment
case studies.
In collaboration with OW partners and the
Safe and Sustainable Water Resources
(SSWR) research program, CSS is
creating a web-based Office of Water for
the 21st Century (OW21) dashboard for
evaluating screening, testing, exposure
and sustainability information relevant
to prioritization of chemicals for the
Preliminary Chemical Candidate List
(PCCL)/CCL.
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Developing Partnerships from the Start
Collaboration with EPA internal partners
(program and regional offices) and external
stakeholders is vital to the success of CSS
so that we can meet their science needs.
Accordingly, CSS staff has engaged a broad
range of partners and stakeholders since the
inception of the research program in January
of 2010, ensuring that CSS identified the
highest priority research needs.
First, CSS researchers communicated
internally with staff from across EPA's Office
of Research and Development (ORD)
through a series of briefings, workshops,
teleconferences and meetings (called
"listening sessions") to identify and define
research needs for chemical safety. Pre-briefs
and a workshop were then held to prioritize
key science questions with EPA research
partners.
Following activities to define partner
needs, workshops with ORD scientists and
management were held to discuss and refine
the products of the Chemical Safety and
Sustainable research program to ensure that
it would produce outputs and outcomes that
meet the science needs of the Agency. A
second workshop was subsequently held
with partners, including the Office of Pollution
Prevention and Toxics, the Office of Pesticide
Programs (OPP), the Office of Water (OW)
and the Office of Solid Waste (OSW), to
review the draft CSS research portfolio.
In July, 2010, CSS consulted with EPA's
Board of Scientific Counselors (BOSC), to
solicit feedback to ensure that the research
planning was on the right track. BOSC
was established by the Agency to provide
advice, information and recommendations
about Office of Research and Development
research programs. A draft of the CSS
Research Framework (U.S. EPA, 2011a) was
produced incorporating an inventory of existing
chemical safety research and the input from
partners and the BOSC. Additional input on
the framework was gathered, through public
webinars and other means, from external
stakeholders, including industry groups,
media organizations, other federal agencies
and groups such as the American Chemistry
Council, the Humane Society of the United
States and the Environmental Defense
Fund. CSS also solicited feedback on the
CSS Research Framework document using
IdeaScale, an internet-based, social-media
inspired platform for generating a community
of ideas and capturing open feedback.
In June 2011, a joint Science Advisory Board
(SAB) and BOSC meeting was held to review
the CSS Framework document, as well as
the other five Agency research programs'
frameworks. Using feedback from the joint
BOSC/SAB meeting, the CSS team developed
a Strategic Research Action Plan (this
document).
Understanding the importance of continual
collaboration with EPA partners and external
stakeholders, a CSS Program Office and
Regional Outreach Plan has been developed
to guide the future collaboration with EPA
partners. In addition, an external stakeholder
engagement plan has been developed.
CSS Design Overview
CSS is designed to operate as an integrated
research program organized around eight key
research topics.
Inherency includes research to understand
the relationship between inherent physico-
chemical properties (e.g., mass, conductivity,
reactivity, heat of combustion) of a chemical;
fate and effects; and human and wildlife
CSS Research Themes:
1. Inherency
2. Systems Models
3. Biomarkers
4. Cumulative Risk
5. Life Cycle Considerations
6. Extrapolation
7. Dashboards
8. Evaluation
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health outcomes after chemical exposure.
Furthermore, these properties may change as
a chemical moves through the environment
or a biological system such as the endocrine
system, an organ (e.g., liver) or a whole
organism (e.g., the embryo). Key inherency
property models can be developed using
information from Systems Models research
which studies the interactions of the chemical
with biological and environmental processes
and the outcomes. Biomarkers are developed
that are effective measures of chemical
exposure and effects.
The research methods and models developed
for a single chemical can be repeated,
efficiently identifying the properties of large
numbers of other chemicals. This, in turn,
allows for science-based generalizations that
can be made for predicting the fate and effects
outcomes for broader groupings of chemicals.
In Extrapolation, scientists can use outcomes
of Inherency and Systems Models research
to build extrapolations that extend the known
data for a chemical to additional biological
systems (such as different species) and on
environmental systems, providing important
scientific information in support of specific
regulatory and risk assessment decision-
making.
Given sufficient information on a number of
chemicals, the Cumulative Risk of broader
classes of chemicals can be predicted. This
information then can be used on higher
level activities, including the development
of Dashboards, Life Cycle Considerations
(including life cycle and sustainability
analyses) and Evaluation methodologies.
Figure 1 illustrates the overall conceptual
model for CSS research, beginning with
problem formulation based on identifying
the requirements and information needed to
support the regulatory actions and mandates
of an EPA regional or program office. Once
the information needed is identified, the model
identifies four levels (in blue in Figure 1)—
each of increasing complexity—of research
approaches to generate the data needed
by the end user (such as an EPA program
or regional office) to inform regulatory
assessment and management decisions.
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CSS Overview - Research Topics
Data Generation and
Interpretation Tools
Sufficient
Information
Level II:
Screening Assays
Need More Information
Targeted Testing
Need More Information
i
Level IV:
Systems Models
Sufficient
Information
Sufficient
Information
Sufficient
Information
Extrapolation
Tierl
Tier2
Tier3
Acceptable
Uncertainty
Acceptable
Uncertainty
Acceptable
Uncertainty
_- Acceptable
Uncertainty
Life Cycle
Dashboards
Cumulative
Risk
Biomarkers
Figure 1. The eight research topics/themes are mapped to a conceptual model to illustrate
the integrated nature of the CSS research program. Adapted from the Framework for an
EPA Chemical Safety for Sustainability Research Program (U.S. EPA, 2011 a). The Problem
Formulation (red box) is defined by partner decision needs and regulatory requirements.
Sustainability and Other Considerations (purple box) include sustainability, life cycle assessment
(LCA), soci-economic and alternative assessments that can inform Management Decisions (lilac
box column). Green boxes, 8 different CSS research themes. Blue rectangles, are the four (I-
IV) levels of research approaches to generate data. Gray, pink and orange column of boxes, 3
different assessment tiers.
Data generated through a particular level's
approach may apply directly to a particular
assessment or management decision.
For example, the information derived from
Level I ("Inherent Properties") alone may be
adequate for informing a decision (e.g., on
the viability of applying a green chemistry
approach to chemical management). If not,
further resources are devoted to gather more
information at that Level or the next. For
example, data generated from approaches
within Levels I and II ("Screening Assays")
may help narrow the range of testing
approaches needed for a particular chemical
or group of chemicals. Approaches developed
under Level IV ("Systems Models") are the
scientifically most complex. This may be
applied for either very complex assessment
and management problems—such as
addressing the life stage susceptibility of the
cumulative impacts of multiple chemicals
and/or exposure pathways,—or for providing
information that refines approaches within
the other three levels. The assessment
decisions also are placed in tiers, recognizing
that different types of decision outcomes (as
articulated in problem formulation) require
assessments with varying types and amounts
of information.
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The program is designed with a tiered
approach that can identify and provide
timely, needed information efficiently. The
"Management Decisions" portion of the
model acknowledges that, in addition to
environmental science data, findings and risk
assessments, decision-makers need additional
information—such as social/cultural, political
and economic considerations—to fully inform
their management strategies.
The CSS research program aims to develop
methods and tools to inform the development
of enhanced risk prevention or management
approaches for both new and existing
chemicals. To develop scientific information
that leads to improved understanding of how
to better create and manage chemicals, CSS
research incorporates four key considerations
into its research activities: (1) inherent
chemical/material properties, (2) life cycle
of chemicals, (3) chemical sustainability
and (4) increasing the scope and pace of
research to close the large gaps in our current
understanding of chemical safety.
1. Inherency. The CSS research program
incorporates the consideration of
inherent chemical properties into its
integrated testing, assessment and
management approaches.
Inherency consists of the physical,
chemical and material properties of a
chemical—for example, the structure,
composition, size and solubility that
arise from a particular chemical
formulation. For particles, such
properties also include their surface
area, surface charge and aspect ratio.
These properties may determine how
mobile, persistent, or bioavailable the
chemical is in the environment. They
also influence the ability of a chemical
to interact with biological processes
that lead to human disease or adverse
outcomes in wildlife species.
It may be possible in some cases to
apply green chemistry approaches
during chemical design to alter or
otherwise address such inherent
properties in ways that reduce
environmental impact. Often, however,
these also are the properties that give
the chemical/material the desirable
performance characteristics that make
it worthwhile to produce.
2. Life cycle. The CSS research program
addresses both new and existing
chemical issues and develops tools
that can inform the development of
sound and feasible assessment and
management approaches across the
chemical life cycle.
CSS research considers the life cycle
of a chemical (Figure 2) as it relates
to chemical safety. Impacts to people
or other parts of the environment from
chemicals can occur at any point,
from the extraction of raw materials
•Sustainable
Feedstock
• Renewable
• Reduced
Toxicity
Raw
Materials
Process
•Atom Energy
• Less Toxic
Solvents/Reagents
• Energy Use
Reduction
• Water Use
Reduction
•Waste Reduction
• Occupational Risk
Reduction
• Safe Product Design
• Effective Function
• Environmental Risk
Reduction
Production
• Risk Reduction
• Exposure/ Hazard
• Consumer
• Ecological
• Alternate Product
Availability
• Alternate Choice
Promotion
Ecological Risk
I Reduction
Human Health
Risk Reduction
Land Use
Optimization
Recyclability
Alternative
Choice
Promotion
Figure 2. Considering sustainability across a chemical's life cycle.
Disposal
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for manufacturing a chemical, to
processes that create the chemical
and incorporate it into products,
through the chemical's and product's
use to the end of life when it is
disposed of or recycled.
CSS research will address how to
assess risks from exposure throughout
a chemical's life cycle and identify the
points in the life cycle that may lead
to the greatest exposure and impact
on human and wildlife health. Each
point in a chemical's life cycle presents
an opportunity to utilize sustainable
molecular design approaches to
eliminate or reduce health impacts.
Such approaches will provide
opportunities for risk prevention early
in the life cycle. When those options
are not feasible, however, handling
measures still may be needed to help
manage downstream impacts.
3. Sustainability. The CSS research
program advances the sustainable
use and management across three
key areas: (1) what the chemical is, (2)
how it is made and (3) how it is used.
Altering any of these three aspects
changes the potential of the substance
to produce environmental impacts
throughout its life cycle and affects
sustainability metrics, such as eco-
efficiency (the ratio of value delivered
to resources consumed).
Achieving sustainability means creating
and maintaining conditions under
which humans and nature can exist in
productive harmony and that permit
fulfilling the social, economic and other
requirements of present and future
generations (Council on Environmental
Quality, 1969).
Examples of sustainability chemical
research include: investigating whether
the use of toxic materials is essential
to produce a particular chemical when
less-toxic materials are available; or,
if such alternative materials are not
available, whether there are aspects of
the current chemical-making process
that could be changed to mitigate the
impacts of toxic inputs into synthesis
and production. The use of a raw
material feedstock that requires
significant input of water and energy
and identifying an alternative feedstock
that has a smaller environmental
"footprint" in terms of carbon emissions
and resource consumption are also
important opportunities that will be
investigated through the CSS research
program.
4. Closing Assessment Knowledge
Gaps. CSS research is helping
revolutionize how chemicals are
assessed for potential toxicity to
humans and the environment.
Research outcomes will increase the
pace of chemical screening, testing
and assessment, closing large gaps in
the current understanding of chemical
safety.
Traditional chemical toxicity tests,
using laboratory tests on whole
animals, are expensive and time
consuming. As a result, only a small
fraction of the more than 80,000
chemicals currently listed for use
in the U.S. have been thoroughly
assessed for potential risk. In addition,
over a thousand new chemicals are
introduced every year.
CSS research is working to
revolutionize how chemicals are
assessed for potential toxicity to
humans and the environment. CSS
conducts innovative research that
integrates advances in molecular
biology, chemistry, high-throughput
technology and computer science to
more effectively and efficiently rank
chemicals based on hazards and
risks. Research outcomes will be rapid
exposure data, chemical screening
data and other decision-support tools
that inform potential risks to humans
-------
and the environment, closing the gap in
information needs for chemical safety.
Inherency, chemical life cycle, sustainability
and improving the pace of research in
chemical safety are the fundamental aspects
in developing approaches for making
existing and new chemicals safer and more
environmentally acceptable.
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Research Themes and Priority
Science Questions
The CSS research program consists of eight themes or topics. Brief descriptions of the theme,
research objectives, science questions and illustrative products are provided below for each of
these.
Theme 1. Inherency
Inherency is defined as the inherent physico-chemical properties that characterize a chemical.
These properties influence the potential for humans and wildlife to be exposed to a chemical
and the potential for that chemical to affect the health of humans and/or wildlife and impact the
environment.
Research Objective: Establish a system
for compiling and sharing chemical char-
acteristic data and to advance a better
understanding the relationships between
chemical characteristics and specific toxic
responses (including human disease out-
comes or population effects in wildlife or
ecological systems). Understanding these
relationships will, in turn, enhance the
ability to predict toxic responses (disease
outcomes) for specific chemicals.
Science Questions
What is the relationship between inherent
physico-chemical properties and health
outcomes and what data are needed to
define these relationships?
What approaches and information can
best advance the understanding of
physico-chemical or material properties
of chemicals and how can this knowledge
be used to predict toxicity, fate, transport,
transformation (degradation and
metabolism) and toxicologically-relevant
exposures?
How can the knowledge of inherent
properties be utilized to guide the
development of safer product design and
use throughout a chemical's life cycle?
Illustrative Outputs, Products,
and Outcomes
Example: Understanding the Relationship
between Inherent Properties of Nanomaterials
and Exposure and Toxicity
EPA researchers are working to improve
chemical hazard assessments based upon
a deeper understanding of the relevant
inherent properties of chemicals that influence
environmental fate, exposure and biological
responses. These four products (below)
highlight some of the work to understand
the inherent properties for nanomaterials,
including potential exposures to nanomaterials
in consumer products that can be utilized
directly in EPA decision-making.
Example Outputs:
(1) Nanoparticles (NPs) in the
environment: Methods for the detection
and characterization to analyze metal
and carbon-based nanoparticles in
environmental matrices.
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(2) Fate of nanoparticles in the
environment: Data on the impacts
of inherent particle properties and
environmental conditions on their fate
in environmental systems.
(3) Leaching of nanoparticles from
products: Data on the quantities and
speciation of nanoparticles leaching
from consumer products containing
nanomaterials.
(4) Nanoparticles in the environment:
Bioavailablity assessment tools for
nanoparticles.
(5) Transport and transformations
of nanoparticles in the environment:
Experimental and modeling tools
for evaluating transport and
transformations of nanoparticles in the
environment.
(6) Exposure to nanoparticles in the
environment: Data and relationships
that can be used to link ICPs of NPs
to models that predict NP transport,
transformation and exposure in the
environment.
Research Products Contributing to These
Outputs:
• A report characterizing copper
nanoparticles leaching from treated
wood. This new research on leaching
is needed by OPP and will directly
inform decision-making on treated
wood products regulated by EPA.
• The development of laboratory
and field tests, advanced analytic
techniques and quantum chemistry
calculations to evaluate the
applications, implications and
potential risks of surface-altered
nanoparticles (e.g., titanium dioxide,
carbon nanotubes, copper, zinc oxide
and silver) from consumer products
in the environment (e.g., landfills,
soil, chlorinated and brackish water,
biosolids and wetlands).
• The development and assessment
of bioavailability tools for assessing
human exposures to silver
nanoparticles.
• The development of methods,
analyses and reporting on the
detection, evaluation and assessment
of release of nanomaterials (e.g.,
carbon nanotubes) from polymers
representative of consumer products.
Outcomes of the research: Improved
chemical hazard assessments based upon
a deeper understanding of the relevant
physico-chemical properties of chemicals
that influence environmental fate, exposure
and biological responses. This research is
particularly relevant to decision-making for
emerging chemicals and materials, such
as nanomaterials, whose toxicity is less
understood.
Impacts
By establishing information about the
relationship between these inherent properties
and health outcomes, risk assessment and
other regulatory decisions can be better
informed. A number of the Inherency research
products connect with research performed
in other themes of the CSS program (e.g.,
Dashboards, Cumulative Risk and Life Cycle
Considerations) and together, their outputs
advance green chemistry and sustainable
design.
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Theme 2. Systems Models
Systems models are scaled or multiple-level models that predict or simulate exposure or effects
of complex biological or environmental systems.
Research Objective: Generate, utilize
and integrate chemical, biological and
toxicological information at all levels of
biological organization (e.g., molecule,
cell, tissue, organ, organism), such that
the potential toxicity of a chemical can be
evaluated with enhanced predictive power.
Science Questions
What are the perturbations at all levels
of biological organization, defined as
a toxicity pathway, for environmental
chemicals? (Related questions: What is
the relationship of pathway-level changes
to adverse outcomes and how do we
define adversity?)
What are the most appropriate systems
models to address the chemical-related
environmental problems of greatest
impact?
How can information be integrated into
virtual organ models?
What new tools and/or models must be
developed to ensure precise and efficient
hazard and exposure screening across the
life cycle of a chemical?
What systems models (e.g., kinetics
and dynamics) must be developed and
used to address the chemical-related
environmental problems with the greatest
impact?
The Systems Models theme is the largest
of the CSS research themes and will result
in a number of major products and outputs.
Systems Models research will investigate the
"adverse outcome pathway" (AOP), covering
the span from chemical exposure all the way
through the observation of adverse outcomes,
including interactions at all levels of biological
organization in humans and wildlife.
Illustrative Outputs, Products and
Outcomes
Example 1: Development and Use of Pathway
Perturbation Data
EPA researchers are generating adverse
outcome pathway data and studying the
relationship between pathway perturbations
and particular adverse outcomes. The
information will be compiled and methods to
utilize the data will be developed to support
Agency screening programs (e.g., EDSP) and
risk assessment.
Example Outputs:
(1) Connecting molecular and whole
animal effects in a knowledgebase:
Compiling information concerning
the linkages between endpoints
measured or predicted at molecular
and cellular levels and adverse
outcomes at higher levels of biological
organization traditionally considered
in risk assessments and regulatory
decision-making (e.g., organ
function in humans; survival, growth/
development and reproduction in
wildlife) and depositing this information
into a knowledge-base (called
"Effectopedia"). The initial focus will
be on depositing information about
reproductive and developmental
toxicity in fish into the Effectopedia.
(2) Predicting species effects after
chemical exposure: A web-based tool
to support prediction of which species
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are likely to be susceptible to adverse
effects of chemicals that act on specific
protein targets.
(3) Developing and applying adverse
outcome pathway knowledge and filling
data gaps, to support specific partner
needs.
(4) Environmental monitoring
approaches: Methods to incorporate
biological responses of organisms
exposed to environmental stressors
into the monitoring of contaminated
or remediated sites that are relevant
to the program offices and regions.
The biological responses used will be
based on the biological pathways that
are impacted by the exposure(s).
(5) Exposure reconstruction
approaches: Recommendations
regarding the best method for using
biological responses (based on effects
on biological pathways) of organisms
residing in polluted waters to determine
specific chemical exposures of these
organisms. Use of these biological
responses for determining what the
organisms have been exposed to
will help program ofices and regions
in conducting assessments and
investigations of polluted waters.
(6) Data sets derived from high-
throughput screening of chemicals on
program office inventories to support
the development of signatures,
or patterns of activity, for adverse
outcome endpoints of relevance to
partners. The outcomes (endpoints) of
concern include cancer, developmental
neuro- and developmental immuno-,
developmental, reproductive and
systemic toxicity.
(7) Additional screening of regulatory
chemical inventories (TSCA21,
OW21, EDSP21 and OPP21) will be
conducted to provide data sets for
prioritization of chemicals on these
lists using molecular signatures (i.e.,
patterns of response).
(8) Prioritization of regulatory chemical
inventories (TSCA21, OW21,
EDSP21 and OPP21) based on in
vitro molecular signatures (patterns
of response) for endpoints of cancer,
developmental toxicity, reproductive
toxicity.
(9) Completion of EDSP21 workplan
for 2000 chemicals: Rapid prioritization
of chemicals for further safety
evaluation based on potential for both
harm and exposure. Non-animal-based
(in vitro) tests are used to identify
the degree to which a substance can
damage living organisms (hazard)
and to determine pharmacokinetics
(how the chemicals accumulate within
the body) and computer simulations
(based on chemical structure,
inherency and mathematical models)
are used to derive potential for human
contact (exposure). The EDSP21
workplan for prioritization of 2000
chemicals will include both potential
hazard identification and chemical-
structure-derived exposure potential
simulation without pharmacokinetic
considerations.
Research Products Contributing to These
Outputs:
• AOP descriptions comparing linkages
(e.g., causal) between specific pathway
perturbations and reproductive
or developmental outcomes in
multiple species (e.g., rodents, fish,
invertebrates). These will provide
data that support the development of
tools and guidance for cross-species
extrapolation of effects and hazard.
• Case studies evaluating the utility of
transcriptomics, metabolomics and
associated bioinformatic methods for
comparing the nature and severity of
biological impairment as a function
of space and/or time to assess the
efficacy of remediation efforts within
-------
the Great Lakes Areas of Concern.
• Completion of high-throughput
screening data sets on the first
1000 Endocrine Disrupter Screening
Program 21 (EDSP21) chemicals and
ToxCast™ Phase II chemical library.
• Accelerated ToxCast™ screening
data on additional chemicals beyond
the current EDSP21 library; access
new endocrine-related assays for
EDSP21 (especially thyroid and
steroidogenesis-related); validation
studies on EDSP21 assays including
targeted in vitro data on EDSP21
chemicals; database to manage
EDSP21 data as well as data from
guideline EDSP Tier 1 and Tier
2 studies; prioritization/weight of
evidence methods/models for using
EDSP21 data by program offices.
• Prioritization and selection of
ToxCast™ Phase-l and Phase-ll
chemicals for the TSCA21, OW21
and OPP21 (EPA work plans to utilize
21st century research and methods in
these programs) case studies based
on endpoints for cancer, developmental
toxicity and reproductive toxicity.
Example 2: Sophisticated Virtual Tissue
Models (v-Liver™ and v-Embryo™)
EPA researchers continue to develop the
virtual tissue models for the liver and embryo
to eventually be used to predict exposures and
effects in the developing embryo and in the
liver.
Example Outputs:
(1) A computer model to analyze
effects of contaminants in food and
water on the liver: Linkage of gene
expression/pathways with phenotypic
outcomes in the intact rodent liver.
(2) Computer models to predict effects
on fetal development after maternal
chemical exposure: Virtual embryo
research integrates important data and
scientific knowledge into sophisticated
computer models that will simulate and
predict adverse events and outcomes
in the embryo, fetus and neonate when
the mother is exposed to different
chemicals.
(3) Delineating pathways of exposure
and mechanisms of developmental
toxicity using the virtual embryo for risk
assessment: The predictions of virtual
embryo simulations can be used to
understand and test mechanisms of
developmental toxicity across different
doses, species and life stages. This
understanding can provide guidance
for life-stage specific targeted research
to delineate pathways of exposure
and mechanisms in both the fetus and
infant.
(4) An integrated strategy for life-
stage specific risk assessment: The
outcomes of the research will lead
to improved understanding of the
molecular pathways and cellular
processes underlying adverse
pregnancy outcomes and better ways
to assess the impacts of prenatal and
postnatal exposure to chemicals at
various stages of development and
scales of biological organization.
Research Products Contributing to These
Outputs:
To support the virtual liver model -
• Quantitative dose-response models
that are predicted by biological
networks governing hepatocyte
death and proliferation underlying 20
ToxCast™ chemicals with activity on
nuclear receptor mediated pathways.
This cell agent-based model will
estimate the acute and chronic effects
of hepatic AOPs and develop a
computational framework to integrate
these effects with environmental
processes for selected chemicals
in EDSP21, TSCA21, OW21 and/or
OPP21.
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To support the virtual embryo model -
• Integration of angiogenesis information
into the virtual embryo using a
cell-agent based systems model
developed from empirical data and
biological knowledge of blood vessel
development. The angiogenesis
model will be trained with compounds
showing anti-angiogenic properties,
assessed in a forward validation for
predictive developmental toxicity
among 1,000+ ToxCast™ chemicals
in pregnant rats/rabbits and tested
for vascular disruption in zebrafish
embryos and embryonic stem cell
assays for 30+ chemicals in EDSP21,
TSCA21, OW21 and/or OPP21.
Example 3: Exposure and Effects Information
to Support Near-term Regulatory Decision-
Making
Example Outputs:
(1) Consumer product use, emissions
and other data for informing multi-tier
exposure and dose analyses.
(2) Inputs and methods needed to
model fate/transport, concentrations,
exposures and dose to a variety of
environmental chemicals.
(3) Refined Stochastic Human
Exposure and Dose Simulation
(SHEDS) and new SHEDS-Lite
models.
(4) Applications of linked source-to-
dose models to address program
office and regional priorities for
environmental chemicals.
(5) Completion of the TSCA21
workplan for 500 chemicals: Rapid
prioritization of chemicals for further
safety evaluation based on potential
for both harm and exposure. Non-
animal-based (in vitro) tests are
used to identify the degree to which
a substance can damage living
organisms (hazard) and to determine
pharmacokinetics (how the chemicals
accumulate within the body) and
computer simulations (based on
chemical structure - inherency
- and mathematical models) are
used to derive potential for human
contact (exposure). TheTSCA21
workplan for 500 chemicals will
combine high-throughput hazard data,
pharmacokinetic data and exposure
simulations to determine chemical
prioritization based upon potential risk.
(6) Completion of the EDSP21
workplan for 2000 chemicals: Rapid
prioritization of chemicals for further
safety evaluation based on potential for
both harm and exposure (similar to the
TSCA21 workplan approach above).
Research Products Contributing to These
Outputs:
• Simulation tool for modeling PCB and
SVOC emissions and transport in
buildings and formaldehyde emissions
from aqueous solutions.
• Revised version of SHEDS-Multimedia
(v4) that includes output results for
different scenarios, case-studies
and sensitivity analyses addressing
OPP needs for including dietary
and residential scenarios. This
product is responsive to a recent
recommendation of the FIFRA Science
Advisory Panel (EPA, 2010).
• The Exposure Forecaster (ExpoCast)
high-throughput exposure predictions
for prioritization of initial ToxCast™,
TSCA21 and EDSP21 chemicals
including exposure metrics and fate
and transport modeling of large
chemical libraries.
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Example 4: Systems Models for Ecological
Risk Assessment Application
Example Outputs:
(1) Integrated systems-approaches
linking exposure and outcome.
(2) Integrated systems-approaches for
predicting individual, population and
ecosystem risk from complex patterns
of chemical exposure.
(3) Understanding of inherent
properties of modifications that mediate
specific nanomaterial (NM) toxicity or
other effects.
(4) Identify mechanisms of action
for nanomaterials, AOPs and
recommendations for development
of alternative and rapid-throughput
assays.
(5) Recommendations for the
development of models linking inherent
properties and adverse outcomes (e.g.,
QSARs for NMs).
(6) Best current in vitro and in vivo
methods for tier testing of NMs
provided to Offices.
(7) AOPs identifying common and
sensitive biological receptors predictive
of adverse human and ecological
outcomes.
(8) Mechanisms of injury, mode of
action and AOP for high-throughput
and high-content screening methods
development.
(9) Credible translatable alternative
test methods, guidelines and endpoints
that predict NM in vivo toxicity with high
confidence.
Research Products Contributing to These
Outputs:
• Design and recommendations for
case studies that demonstrate
systems models approaches to evolve
from population- to community- to
ecosystem-level risk assessment and
provide information on high priority
chemicals.
• Data on toxicity of selected
nanomaterials, including exposure-
response models, uptake, distribution,
modes of action, AOPs and initiating
events for non-human species and
ecological processes.
• Guidance on the use of ecological
nanomaterial toxicity information to
identify dose metric(s) of exposure
to response, AOPs and absorption,
distribution, metabolism and excretion
(ADME) with their inherent chemical
properties for development of high
throughput and high content testing
methods and best practices and test
methods for the use of alternative
models, tiered testing and in vivo tests
to assess their toxicity.
Outcomes of the research for all four
systems models examples (above): Improved
chemical prioritization, screening, testing and
quantitative risk assessment by integrating
information from multiple biological levels,
including pathway-level information and by
using advanced computational techniques,
such as multi-scale systems models of virtual
tissues, to develop predictive models of
hazard and exposure.
Impacts
The systems model research outcome
will have a tremendous impact on EPA
toxicity testing, risk assessment and other
environmental decision-making as the Agency
moves chemical safety assessments into
the 21st century. Together, the Systems
Model outcomes moves advance the use of
the pathway-based toxicity testing and risk
assessment paradigm.
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Theme 3. Biomarkers
A biological marker, or "biomarker," is a chemical or biological characteristic that is measured or
evaluated as an indicator of a biological process and used as a marker of exposure or effect.
Research Objective: Predict health
outcomes and exposures based on
biomarkers to inform EPA risk assessment
and management decisions for human and
wildlife health.
Science Questions
How can CSS assess biomarkers that can
serve as useful indicators of toxicity for
different chemicals and endpoints such as
health or wildlife outcomes?
What are the endpoints of concern that
require development of biomarkers?
What characteristics are needed for a
biomarker to be one that is informative of
adverse outcomes to humans?
How can the program assess biomarkers
of exposure?
What models need to be developed to
better integrate biomonitoring (biomarkers
and bioindicators) data into testing
systems to help the Agency better
understand environmental and health
impacts?
Illustrative Outputs, Products and
Outcomes
Example: Development of Biomarkers of Effect
and Exposure
The Biomarkers theme is closely related to the
AOP concept of the Systems Models research
theme as it strives to characterize linkages
between external environments, internal
(biological) environments and key adverse
effects/outcomes. The Biomarkers' theme
includes research to develop and assess
biomarkers of exposure and effect. The
research will use linkages between biomarkers
and health outcomes to develop biomarker-
based predictive tools to aid in defining and
understanding the relationship between
chemical exposure and health effects.
Example Outputs:
(1) Holistic approaches to foster a
better understanding of relationship
between exposure metrics and
biomarkers, allowing for potential
to reconstruct exposures from
biomarkers.
(2) Improved methodologies for
exposure and dose estimates by
integrating biomarker data with
supporting information/data (e.g.,
exposure factors and pharmacokinetic
behaviors) into predictive models.
(3) Biomarker-based models for risk
assessment.
(4) Biomarker-based model tools to
evaluate risk management activities.
(5) Develop and maintain a state of the
art panel of biomarkers of effects for
use by risk assessors and researchers.
(6) Link biomarkers to key events in an
adverse outcome pathway and thereby
improve the diagnostic capabilities of
the biomarkers in the panel.
Research Products Contributing to These
Outputs:
For biomarkers of exposure -
• Web-based software tool to conduct
reverse dosimetry probability
calculations for estimating exposure
-------
concentrations that are likely to have
produced the observed biomarker
concentrations.
• Best practices for integrating
existing biomonitoring data into risk
assessment demonstrated with a case
study. Report will give generalizable
guidance for calculating exposure,
dose and target dose; calculating
uncertainty; predicting risk; and
identifying opportunities for mitigation
For biomarkers of effect -
• Panel of existing bioindicators
evaluated for diagnostic capability
including (1) robustness of the assay,
(2) bioindicator distribution in healthy
and affected populations and (3)
predictive capability for adverse
outcomes.
Outcomes of the research: EPA risk
assessments are improved by the (1)
consistent, justifiable and improved use of
existing biomonitoring data (e.g., NHANES);
(2) availability of dose estimation/exposure
reconstruction methods; and (3) availability
of diagnostic AOP-based biomarkers with
annotations to evaluate published data.
Impacts
The impact of the resulting Biomarkers'
research is that the program's partners will
possess the tools (e.g., diagnostic biomarkers
for AOPs) and methods needed to improve
estimates of exposure, dose and outcome
and utilize available biomarker data. In
addition, some of the work directly supports
the development of biomarkers for emerging
contaminants of concern.
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Theme 4. Cumulative Risk
Cumulative risk is the combined risks from aggregate exposures to multiple agents ofstressors.
Research Objective: Assess the potential
human health and environmental outcomes
that result from multiple and continuous
exposures to chemicals and provide
this information about specific chemical
mixtures, including chemical mixtures
found in consumer products, to support
priority regulatory decisions.
Science Questions
What are the ecological and human health
risks of combined real-world exposures to
environmental chemicals?
What are the chemical targets at the
molecular, cellular, tissue, organ and whole
animal levels? and, Can these targets be
used to assess cumulative effects?
How can recent scientific advances help
describe the impacts of exposures to
chemical mixtures?
How can recent scientific advances help
describe human variability (e.g., across life
stages, population groups) ?
What kinds of tools, including
computational, systems-based tools, are
required to fully describe the overall impact
of aggregate exposures on organisms?
What enhancements will be required to
describe the impact of factors that affect
an organism's response to chemical
exposure, such as life stage, gender and
aggregate exposures?
What new methods/models are needed to
account for exposure from all sources and
pathways?
Illustrative Outputs, Products and
Outcomes
Example 1: Effects and Exposure Predictive
Tools for Real-World Mixtures
Real world chemical exposures are rarely
limited to a single chemical, but involve
often complex mixtures of different agents or
stressors. This set of products helps identify,
predict, assess and prioritize how chemical
mixtures interact with humans and wildlife in
real-world settings.
Example Outputs:
(1) Predictive tools for identifying
and prioritizing real-world mixtures
ofstressors (e.g., environmental,
residential, SES, diet) based on:
sources (including commercial and
consumer products); surrogate
exposure and hazard indices; and
toxicity of chemical mixtures.
(2) Methods to predict the effect of
chemical mixtures based on outcome
pathways.
(3) Methods to select chemical
mixtures for testing based on likelihood
of toxicity.
Research Products Contributing to These
Products:
• Linked SHEDS and PBPK modeling
system to support Food Quality
Protection Act (FQPA) cumulative risk
assessments.
• Computational method to utilize
chemicals' similarities in kinetics and
dynamic (response) determinants to
optimize clustering and interactions of
-------
clusters of chemicals within complex
mixtures.
Example 2: Chemical Mixture Data, Methods
and Models to Support Near-Term Regulatory
Decision-Making
Example Outputs:
(1) Evaluation of selected compounds
in municipal solid waste landfills.
(2) Final data on the fate and transport
of emerging chemicals of interest
following land application of biosolids.
(3) Data on the fate and transport
of emerging chemicals of interest
following land application of biosolids
for mixtures identified in CSS
cumulative risk research.
(4) Evaluation of selected compounds
in municipal solid waste compost.
(5) Data, science and methods
to support Agency decisions on
perfluorochemicals (PFCs).
(6) Data, methods and science to
inform PCB exposure and mitigate risk
to children to support EPA regional
decisions.
Research Products Contributing to These
Products:
• Methods and approaches for
evaluating the fate and transport of
mixtures of emerging contaminants
and selected modes of action in
wastewater treatment in support of
Toxic Substance Chemical Act (TSCA)
rule making.
Preliminary data on the fate and
transport of emerging chemicals of
interest following land application
of biosolids to support of TSCA rule
making.
Data gap analysis on presence, fate
and transport of selected compounds
in the municipal solid waste stream.
Evaluation of PFC mixture effects by in
vitro and in vivo models.
Market trend monitoring for PFCA
precursors in consumer articles.
Data and model results for PCBs
in schools to provide information
needed to develop improved and cost-
effective mitigation and remediation
approaches.
Outcomes of the research for both of these
Cumulative Risk examples: A set of predictive
models from the cellular level to the population
level that can be integrated into a source-to-
outcome modeling platform that incorporates
real world exposure scenarios.
Impact
The impact of the Cumulative Risk research
are new data and predictive tools to inform
risk management decisions for EPA's
priority regulatory, risk assessment and risk
management decisions for chemical mixtures.
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Theme 5. Life Cycle Considerations
Life cycle is defined as the "cradle-to-grave" (also referred to as "cradle-to-cradle") activities
fora product, process, or activity, including the stages of resource acquisition, material
manufacture, production, transportation/distribution, use, recycling/reuse and final disposal.
Research Objective: Utilize data to inform
the design of more sustainable, green
chemicals by reducing their environmental
and human health impacts while
recognizing the need for chemicals in a
sustainable economy.
Science Questions
How can life-cycle assessments and
other innovative tools be integrated with
more traditional methods to produce
assessments that inform decision-making
and identify safer and more sustainable
approaches?
How can life cycle assessment approaches
and methods be applied to decision
analysis to reduce uncertainties associated
with the analysis of alternatives at multiple
decision-making scales or levels?
What are the critical components of a
sustainability-driven paradigm for risk
management of chemical and product
systems that incorporate life cycle factors
relevant to environmental, economic and
societal issues?
How can effective and reliable screening-
level approaches for life-cycle assessment
be developed that can be efficiently and
strategically applied to the large number of
chemicals?
Illustrative Outputs, Products and
Outcomes
Example:
Transforming EPA's risk management
strategy into a holistic approach requires
the application of a life cycle perspective to
incorporate sustainability into decision-making.
The Life Cycle Considerations' research
outcomes will inform green chemistry design.
Building on other CSS projects, research
in this effort will: develop a data network to
meet the emerging assessment needs of
EPA program and regional offices to address
sustainability; identify research opportunities
with respect to the life cycle stages of a
chemical; and serve as a platform for research
conducted in a holistic, multi-stakeholder
manner (e.g., initiating collaborations among
EPA, industrial partners and stakeholders) to
generate improved sustainability.
Example Outputs:
(1) A database of information about
the life cycle of a chemical that will
aid in incorporating sustainability in
environmental decision-making.
(2) A framework to help include
sustainability in decision-making within
the EPA using experiences from case
studies with program offices and
regions.
(3) Reaction systems, membrane
materials and separation processes
will be developed using the principles
of green chemistry to address
sustainability in chemical processes.
(4) Solutions will be provided and
demonstrated for the sustainable
design, production and use of
chemicals using the principles of green
engineering to reduce the utilization of
-------
energy intensive chemical processes.
(5) Innovative approaches to
manufacturing of chemicals will be
developed using sustainable molecular
design, life cycle material safety and
chemical process indicators.
(6) The development and
demonstration of life cycle methods for
sustainable design practices for the
manufacture, use and evaluation of
commercial products.
Research Products Contributing to These
Outputs:
• Preliminary sustainability database
design based on a model case of life
cycle inventory (LCI) generated for a
nano-silver consumer product.
• Extramural research to advance the
science and application of life-cycle
thinking and assessment for chemicals.
This research will be conducted in
two academic institutions under EPA's
Science to Achieve Results (STAR)
Program.
• Demonstration of the successful
synthesis and characterization of a
cellulose membrane with controllable
cross-linking for application in
sustainable water treatment.
• Documentation (including through
the patent development) describing
greener production of nanomaterials to
promote sustainable nanotechnologies
and mitigate regulatory needs.
• Assess biobutanol as fuel substitute
for bioethanol to potentially lessen
greenhouse gas emissions: 1)
Membrane for the green separation of
ethanol from water using combinations
of zeolitic and polymeric materials; and
2) Joint patent application with CRADA
partner for butanol recovery from
dilute solutions during manufacturing
via membrane-based separation
processes in response to the need of
OTAQ (OAR).
• Demonstration of how the
GREENSCOPE (Gauging Reaction
Effectiveness for the Environmental
Sustainability of Chemistries with a
multi-Objective Process Evaluator)
sustainability indicator model
can evaluate human health and
environmental risks, for an example
such as manufacturing of biodiesel.
• Demonstration of how the
GREENSCOPE sustainability indicator
model can implement green chemistry
principles through an in-house
developed green chemical reaction,
which can be applied by OSCPP in
educational and evaluation activities
and projects.
• International guidance document
on product category rules for
environmental product claims. This
international guidance document will
provide direct support to the missions
of the Office of Resource Conservation
and Recovery (in OSWER) for
their Sustainable Products-related
efforts and to the Office of Pollution
Prevention and Toxics (in OCSPP)
for their Environmental Preferable
Purchasing Program established
for needs expressed within the
cross-agency 'Sustainable Products
Network'. This work will support a key
element of the 'International Product
Life-Cycle Partnership' draft proposal
for U.S. Commitment for Rio+20 being
prepared by the Office of International
and Tribal Affairs.
Outcomes of the research: The identification
of key linkages in the continuum between
the production of a chemical, its release, fate/
transport of a chemical in the environment, the
resulting exposures and adverse outcomes
for humans and/or the environment in order
that sustainable risk management approaches
can be scaled up and delivered to decision-
makers.
-------
Impact
Chemical decision-making is better informed
because of the information about a chemical's
toxicity across the entire life cycle. Safer,
more sustainable chemicals are available and
sustainable molecular design approaches are
defined.
-------
Theme 6. Extrapolation
Extrapolation is the technique of estimating a variable outside a known range through
calculations based on equations and models built from data based on values and variables from
within a known range.
Research Objective: Maximize the use of
available data by developing approaches
that extrapolate between (1) test organisms
and human or ecological receptors, (2)
test and real-world exposure durations,
(3) laboratory to field conditions, (4)
individuals to populations and (5) in vitro
to in vivo health outcomes.
Extrapolation methods are needed that
improve the reliability and precision of
environmental effect estimates. CSS
research will address that, characterizing
the uncertainty in current risk management
decision-making that result from extrapolating
measured data and develop new approaches
for extrapolation. Research conducted
under this topic will maximize the use of
available data by developing approaches
that extrapolate between test organisms and
human or ecological receptors, test and real-
world exposure durations and from laboratory
to field conditions.
This research will provide methods that
may be used across CSS topic areas for
consistency of data interpretation and
application.
Science Questions
What enhancements will be required to
describe the impact of factors that affect
an organism's response to chemical
exposure, such as life stage, gender and
aggregate exposures?
How can recent scientific advances help
describe human variability, life stages and
population groups?
With the emphasis on developing in vitro
assays for toxicity testing, how can we
extrapolate from in vitro assay response to
in vivo response?
Illustrative Outputs, Products and
Outcomes
Example 1: Extrapolation Tools
Example Outputs:
(1) Chemical Class-Based Expert
Systems: Automated rule-based
decision trees are being developed
to predict which chemicals have the
potential to disrupt endocrine systems.
This is done by testing key chemicals
within a chemical class to represent
others, determining what is similar
about the chemical structures and
properties that explain their biological
activity and writing rules that help
categorize similar but untested
chemicals.
(2) Refined tools that exist for
estimating species sensitivity to
pesticides and other contaminants:
Expansion to add algal toxicity data.
(3) Refined tools that exist for
estimating species sensitivity to
pesticides and other contaminants:
Expansion to add mode of action
information.
(4) Refined tools that exist for
estimating species sensitivity to
pesticides and other contaminants:
Guidance to standardize methods.
(5) Population models that incorporate
sub-groups of fish or aquatic
-------
invertebrates separated by life stage,
age or time.
(6) Methods and models for translating
toxicity test endpoints into quantitative
estimates of changes in demographic
rates, such as fecundity and juvenile
survival rates, for use in population-
level risk assessment.
Research Products Contributing to These
Outputs:
• Framework for extrapolating in vitro
to in vivo effects from in silico models
based on empirical data that predict
unbound chemical concentrations in
vitro from inherent chemical properties.
• Provide definitive interspecies mode of
action-based extrapolation models for
predicting ecotoxicity to OCSPP.
• Guidance for using population
modeling endpoints in risk
assessments for any aquatic animal
species for which there are traditional
toxicity data. Guidance includes an
MS Excel model for deriving default
population demographic parameters
(survival rates for different life stages
and fecundity rates) when traditional
toxicity data are not available.
• Avian toxicity translator model for
extrapolation from individual to
population level effects (basic version,
MCnest) including a users manual and
a technical support manual.
Example 2: Extrapolation Methods to Support
Environmental Decision-Making for EDCs
Example Outputs:
Methods and models to apply in vitro and in
silico derived data to individuals.
Research Products Contributing to These
Outputs:
• Integrated method linking endocrine
active substance exposure in the
environment with biological effects
observed in in vitro and in vivo assays.
• Guidance document on the use of
in vitro data for predicting biological
effects after exposure to endocrine
active substances in non-target
species.
Outcomes of the research for both of these
examples: An improved understanding of the
utility of adverse outcome pathway models
that provide increase confidence in the
extrapolation of exposure and effects across
different levels of biological organization,
doses, genders, life stages, species and
populations.
Impact
This research will provide methods that may
be used by program offices in risk assessment
and other decision-making and across CSS
research themes to improve consistency of
data interpretation and application.
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Theme 7. Dashboards
A dashboard is an interactive web site that provides access to the tools and data required to
carry out a specific analysis or decision-related task.
Research Objective: Produce dashboards
that provide partners with accessible,
useful graphical depictions of all available
chemical data (e.g., information and
studies) related to the user's specific
queries to help answer the chemical-
related question.
Science Questions
What kind of tools, including
computational, systems-based
tools, are required to fully describe
the overall impact of exposure on
organisms?
How can tools be customized to supply
the data and information needed by
partners to address specific regulatory
and environmental questions?
How can inherency, exposure, hazard
and risk management options be
integrated to supply a greater degree
of certainty in decisions, reduced risk
and enhanced sustainability?
Illustrative Outputs, Products and
Outcomes
Example: Prototype Dashboard Development
CSS-produced dashboards will provide
decision-makers with web-based tools that
produce a summary of information derived
from chemical exposure and hazard data,
decision-rules and predictive models.
Dashboards will seamlessly integrate
information from diverse sources to help
partners arrive at more holistic and novel risk
assessment and risk management decisions.
Dashboard research will produce customized
web-based tools based on the queries of
partners using the web-based tool.
Example Outputs:
(1) Initial prototype dashboards
delivered to program offices: Prototype
versions of web-based dashboards for
evaluating screening, testing, exposure
and sustainability information relevant
to EDSP21 (potential endocrine
disruption), OPP21 (pesticidal
actives, inerts and antimicrobials),
TSCA21 (prioritizing and assessing
new and existing chemicals), OW21
(prioritization of chemicals for the
PCCL/CCL and other purposes), and
HHRA21 (Provisional Peer Reviewed
Toxicity Value [PPRTV] and NexGen
risk assessments).
(2) Regular updates (6-month cycles)
of all EPA program office web-based
dashboards, taking into account
user feedback and new scientific
developments.
Research Products Contributing to These
Outputs:
• Prototype version 1.0 of web-based
dashboards followed by updates every
six months including: OPP21 (Office
of Pesticide Programs for the 21st
Century) dashboard for evaluating
screening, testing, exposure and
sustainability information relevant
to pesticidal actives, inerts and
antimicrobials.
• Prototype version 1.0 of web-based
dashboards followed by updates
every six months including: EDSP21
(Endocrine Disrupter Screening
Program for the 21st Century)
-------
dashboard for evaluating screening,
testing, exposure and sustainability
information relevant to potential
endocrine disruption.
Prototype version 1.0 of web-based
dashboards followed by updates every
six months including: TSCA21 (Toxic
Substances Control Act for the 21st
Century) dashboard for evaluating
screening, testing, exposure and
sustainability information relevant to
prioritizing and assessing new and
existing chemicals.
Prototype version 1.0 of web-based
dashboards followed by updates every
six months including: OW21 (Office of
Water for the 21st Century) dashboard
for evaluating screening, testing,
exposure and sustainability information
relevant to prioritization of chemicals
for the Preliminary Chemical Candidate
List (PCCL)/CCL and other purposes.
Prototype version 1.0 of web-based
dashboards followed by updates every
six months including: HHRA21 (Human
Health Risk Assessment in the 21st
Century) dashboard for evaluating
screening, testing, exposure and
sustainability information relevant to
PPRTV and NexGen risk assessments.
Outcomes of the research: Communicate,
translate and transfer all available scientific
information about chemicals in ways most
useful to decision-makers.
Impact
The impact of the Dashboards research is an
improved ability (including improved efficiency)
for CSS partners (EDSP21, TSCA21, OPP,
OW, etc.) to make scientifically-based
decisions. Providing regulatory decision-
makers with user-friendly tools to access all
available data about chemicals is critical to the
success of EPA's CSS research.
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Theme 8. Evaluation
This last CSS research theme evaluates the results and impact of the CSS research program.
This effort will develop the tools needed to evaluate the reliability and uncertainty of data,
methods and models developed under the other CSS themes for their collective ability to
improve risk assessment and management.
Research Objective: Provide decision
analyses, support tools and feedback
mechanisms that inform and enable the
optimal delivery and use of CSS data,
methods and models and to evaluate the
impact of the CSS research program on
EPA decision-making capabilities.
Science Questions
How have CSS research findings and
tools impacted and supported EPA's
decision-making ?
What are the measures needed to
evaluate the predictive value of the
tools (e.g., Dashboards, enhanced
ToxCast™; produced from the CSS
research program?
Do the partners find that the tools and
other data from the CSS research
program will improve environmental
decision-making, including risk
assessment?
How can the critical pieces of
information required for different
assessment tiers be systematically
identified, evaluated, integrated,
reviewed and used in assessments
and subsequent management
decisions?
Illustrative Outputs, Products and
Outcomes
Example: Assessing CSS Partner Needs,
Product Utility and Program Success
Example Outputs:
(1) Understanding of partner needs
and how to measure product utility;
information obtained through pro forma
surveys and interviews.
(2) Overall program performance and
success assessment of CSS research
based on understanding of how the
partners will benefit from CSS research
products.
Research Products Contributing to These
Outputs:
• Initial and follow-up pro forma surveys
of program office, regional and external
partners.
• A program office and regional partners
outreach and engagement plan.
Outcomes of the research: The overall impact
of the CSS research is assessed. CSS
tools and information are delivered to the
partners along with training in order that the
partners have an ability to efficiently apply
the information. The CSS tools, new assays
and scientific knowledge have increased our
confidence in utilizing 21st century pathway-
based approaches for priority setting, toxicity
testing and risk assessment.
Impact
The impact of the Evaluation work is that CSS
products are developed in response to partner
needs and are then delivered efficiently to
partners for use in Agency decisions. Further,
the overall impact of the CSS research outputs
(information, tools, etc.) on EPA decision-
making will be understood.
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Conclusion
EPA's Chemical Safety and Sustainable research program presents a comprehensive set
of efforts for transforming toxicity testing and performing chemical risk assessment using
toxicity pathway-based approaches. The combined products of the program will transform the
paradigm of chemical safety assessment to using 21st-century tools and approaches through a
number of key activities.
CSS research addresses chemical testing
needs, such as the significant numbers of
existing and new chemicals that need to be
tested for toxicity risks, by rapidly increasing
the knowledge base about the key drivers of
potential toxicity of chemicals. The heart of
the transformation in toxicity testing requires
intensive pathway-based research and assay
design in order to assess human and wildlife
health within part of a larger system (the
ecosystem), as EPA moves to a sustainable
molecular design approach to chemical safety.
To improve EPA assessments, reliable,
pathway-based biomarkers of effect will
be developed and needed extrapolation
methods will be developed. Risk assessment
of multiple chemicals and exposures to
chemicals plus nonchemical stressors,
requires new methods and approaches
that CSS will provide and cumulative risk
assessment will require methods to use
human exposure data. The program
anticipates that the Agency will be better
positioned to perform its mission of protecting
human health and the environment as
scientific information becomes digitized and
readily available, methods and models to
capture the complexities of chemical exposure
and hazard in toxicity testing are developed
and approaches focused on development of
more sustainable alternatives are provided
to decision-makers. Producing user-friendly
tools, such as dashboards, will specifically
address various partner needs in an efficient
manner. Finally, the impact of the CSS
research tools, data and new approaches are
evaluated through training and feedback.
The Strategic Research Action Plan forEPA's
Chemical Safety for Sustainability Research
Program maps out a research program for the
next five to ten years. Partner needs have
been the driver of CSS product development.
Communication with partners began at
the inception of the program development
and will continue throughout. In fact, the
entire program has moved EPA to adopt a
new approach to engage its partners in the
research and development process. This
plan, however, is a living document and will
be updated as science evolves and decision-
makers' needs change.
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Summary Tables
EPA's Chemical Safety and Sustainable research program presents a comprehensive set
of efforts for transforming toxicity testing and performing chemical risk assessment using
toxicity pathway-based approaches. The combined products of the program will transform the
paradigm of chemical safety assessment to using 21st-century tools and approaches through
a number of key activities. The tables (below) are organized by research theme and within
theme are organized by research project tasks. Each task number refers to a particular project
task that has one or more expected outputs. Outputs were defined by partners and represent
synthesized and/or translated research products that are in the format needed by the end user.
These summary tables reflect the CSS research outputs as of February 2012.
Theme 1. Inherency
Science Questions: What is the relationship between inherent physico-chemical properties and health
outcomes and what data are needed to define these relationships?
What approaches and information can best advance the understanding of physico-chemical or
material properties of chemicals and how can this knowledge be used to predict toxicity, fate, transport,
transformation (degradation and metabolism) and toxicologically-relevant exposures?
How can the knowledge of inherent properties be utilized to guide the development of safer product
design and use throughout a chemical's life cycle?
Outcome: Improved chemical hazard assessments based upon a deeper understanding of the relevant
physico-chemical and other inherent properties of chemicals that influence environmental fate, exposure
and biological responses.
Task
No.
1.1.1
1.1.2
1.1.3
Outputs
(1) A resource of inherent chemical properties (ICP), molecular
descriptors and selected biological activities for chemicals of
interest to OCSPP.
(2) Provide tools and methods for chemical space analysis
and domain of applicability for models to be incorporated into
Dashboards.
(1) DSSTox chemical structure files, covering EPA's high-
throughput testing programs (ToxCast™, Tox21), eco-toxicological
databases (ECOTOX) and FDA's food additive database (PAFA),
to support predictive modeling and to be incorporated into
structure-searching tools and CSS Dashboards (see Theme 7
below).
(2) Efficient structure-entry process and
DSSTox central structure inventory and
properties and data in CSS Dashboard.
workflow to update
link new structures to ICP
(1) Physico-Chemical Properties Calculator, linked to existing EPA
models (e.g., EPI Suite, enhanced SPARC) provides molecular
properties for building improved environmental fate & transport
models.
43
Output
Year
FY16
FY14
FY16
FY16
Relevance to
other
CSS Themes
2,3,4,5,7
2,5, 7
2,5,7
2,5,7
-------
Task
No.
1.1.3
1.2.1
1.2.2
1.3.1
1.3.2
Outputs
(2) Integration of Physico-Chemical Properties Calculator with
outputs of Tasks 1.1.1 and 1.1.2 to supply ICP for chemicals of
Agency interest and to provide key properties for environmental
fate & transport models accessed through the CSS Dashboard.
(3) Predict types of chemicals more likely to require metabolic
activation to produce animal toxicity, incorporated within an
automated workflow and linked to other ICP and toxicity related
chemical features for use in CSS Dashboard.
(1) Nanoparticles in the environment: Methods for the detection
and characterization to analyze metal and carbon-based
nanoparticles in environmental matrices.
(2) Fate of nanoparticles in the environment: Data on the impacts
of inherent particle properties and environmental conditions on
their fate in environmental systems.
(3) Leaching of nanoparticles from products: Data on the quantities
and speciation of nanoparticles leaching from consumer products
containing nanomaterials.
(1) Nanoparticles in the environment: Bioavailablity Assessment
Tools for nanoparticles.
(2) Transport of nanoparticles in the environment: High throughput
protocols for estimating the transport of nanoparticles in
environmental systems (e.g., waste water treatment plants).
(3) Transport and transformations of nanoparticles in the
environment: Experimental and modeling tools for evaluating
transport and transformations of nanoparticles in the environment.
(4) Exposure to nanoparticles in the environment: Data and
relationships that can be used to link ICPs of nanoparticles to
models that predict NP transport, transformation and exposure in
the environment.
(5) Data on emissions produced from the use of diesel fuel
containing ceria additive.
(1) Pesticide MOA profiling tool to OPP.
(2) Database of MOAs and assignment methodology to OCSPP.
(3) Improved MOA-based QSAR ecotoxicity models to OCSPP.
(1) A molecular-based ligand-biological target resource that can be
used to inform toxicity and in silico-;n vitro-in vivo correlations and
extrapolations.
(2) A web-accessible (within EPA only [intranet]) in silico/knowledge
based ADME (absorption-distribution-metabolism-elimination)
resource in support of physiologically-based pharmacokinetic
(PBPK) dosimetry models and exposure-dose extrapolation.
Output
Year
FY16
FY16
FY16
FY16
FY16
FY16
FY16
FY16
FY16
FY16
FY15
FY15
FY15
FY15
FY15
Relevance to
other
CSS Themes
2,5,7
2,5,7
2
2
2
2
2
2
2
2
5,7
5,7
5,7
2,4, 5,7
2,4, 5,7
-------
Theme 2. Systems Models
Science Questions: What are the perturbations at all levels of biological organization, defined as a
toxicity pathway, for environmental chemicals?
What are the most appropriate systems models to address the chemical-related environmental
problems of greatest impact?
How can information be integrated into virtual organ models?
What new tools and/or models must be developed to ensure precise and efficient hazard and exposure
screening across the life cycle of a chemical?
What systems models (e.g., kinetics and dynamics) must be developed and used to address the
chemical-related environmental problems with the greatest impact?
Outcome: Improve chemical prioritization, screening, testing and quantitative risk assessment by
integrating information from multiple biological levels, including pathway-level information and by using
advanced computational techniques, such as multi-scale systems models of virtual tissues, to develop
predictive models of hazard and exposure.
Task
No.
Outputs
Output
Year
Relevance to
other
CSS Themes
2.1.1
(1) Connecting molecular and whole animal effects in a
knowledgebase: Compiling information concerning the linkages
between endpoints measured or predicted at molecular and
cellular levels and adverse outcomes at higher levels of biological
organization traditionally considered in risk assessments and
regulatory decision-making (e.g., organ function in humans;
survival, growth/development and reproduction in wildlife)
and depositing this information into a knowledge-base (called
Effectopedia). The initial focus will be on depositing information
about reproductive and developmental toxicity in fish into the
Effectopedia.
FY16
7,4
(2) Predicting species effects after chemical exposure: A web-
based tool to support prediction of which species are likely to be
susceptible to adverse effects of chemicals that act on specific
protein targets.
FY16
(3) Developing and applying adverse outcome pathway knowledge
and filling data gaps, to support specific partner needs.
FY16
2.1.2
(1) Environmental monitoring approaches: Methods to incorporate
biological responses of organisms exposed to environmental
stressors into the monitoring of contaminated or remediated sites
that are relevant to the program offices and regions. The biological
responses used will be based on the biological pathways that are
impacted by the exposure(s).
FY16
3,6
-------
Task
No.
Outputs
Output
Year
Relevance to
other
CSS Themes
2.1.2
(2) Best practices for surface water samples: Determining the best
method to collect, store and transport surface waters collected
in the environment to use in laboratory experiments that look at
responses of living cells (not live animals) to exposure to these
waters. These experiments will be used to test environmental
samples for specific types of biological responses that are known
to result in unfavorable effects that are of concern to the program
offices and regions.
FY16
(3) Exposure Reconstruction Approaches: Recommendations
regarding the best method for using biological responses (based
on effects on biological pathways) of organisms residing in
polluted waters to determine specific chemical exposures of these
organisms. Use of these biological responses for determining
what the organisms have been exposed to will help program
offices and regions in conducting assessments and investigations
of polluted waters.
FY16
2.2.1
A computer model to analyze effects of contaminants in food and
water on the liver: Linkage of gene expression/pathways with
phenotypic outcomes in the intact rodent liver.
FY16
2.2.2
(1) Computer models to predict effects on fetal development after
maternal chemical exposure: Virtual embryo research integrates
important data and scientific knowledge into sophisticated
computer models that will simulate and predict adverse events and
outcomes in the embryo, fetus and neonate when the mother is
exposed to different chemicals.
FY16
3,6, 7
(2) Delineating pathways of exposure and mechanisms
of developmental toxicity using the virtual embryo for risk
assessment: The predictions of virtual embryo simulations can be
used to understand and test mechanisms of developmental toxicity
across different doses, species and life stages. This understanding
can provide guidance for life-stage specific targeted research to
delineate pathways of exposure and mechanisms in both the fetus
and infant.
FY16
3,6,7
(3) An integrated strategy for life-stage specific risk assessment:
The outcomes of the research will lead to improved understanding
of the molecular pathways and cellular processes underlying
adverse pregnancy outcomes and better ways to assess the
impacts of prenatal and postnatal exposure to chemicals at various
stages of development and scales of biological organization.
FY16
7,8
2.2.3
(1) Develop computer programs to predict the effects of chemicals
on hormone activity in the body.
FY16
3,6,7
(2) Develop methods to use information about chemicals from cell
and tissue studies to inform the effects of chemicals on hormone
activity in the body.
FY16
3,6,7
2.3.1
(1) Consumer product use, emissions and other data for informing
multi-tier exposure and dose analyses.
FY15
1,4
-------
Task
No.
2.3.2
2.4.1
2.5.1
2.5.2
Outputs
(2) Physiological data and algorithms supporting the development
of PBPK and other dose models.
(3) Inputs and methods needed to model fate/transport,
concentrations, exposures and dose to a variety of environmental
chemicals.
(1) Enhanced environmental models (e.g., IEMS, EFAST, PRZIW
EXAMS, ChemSTEER, WPEM, IAQX) that include the capacity for
spatial and/or temporal resolution (inputs/algorithms).
(2) Refined SHEDS & new SHEDS-Lite models
(3) PK & PBPK models and toolboxes for environmental chemicals
(4) Applications of linked source-to-dose models to address
program office and regional priorities for environmental chemicals
(1) Integrated systems-approaches linking exposure and outcome
(2) Integrated systems-approaches for predicting individual,
population and ecosystem risk from complex patterns of chemical
exposure.
(1) Data sets derived from high-throughput screening of chemicals
on program office inventories to support the development of
signatures, or patterns of activity, for adverse outcome endpoints
of relevance to partners. The outcomes (endpoints) of concern
include cancer, developmental neuro- and developmental
immuno-, developmental, reproductive and systemic toxicity.
(2) Additional screening of regulatory chemical inventories
(TSCA21 , OW21 , EDSP21 and OPP21) will be conducted to
provide data sets for prioritization of chemicals on these lists using
molecular signatures (i.e., patterns of response)
(1) Prioritization of regulatory chemical inventories (TSCA21,
OW21, EDSP21 and OPP21) based on in vitro molecular
signatures (patterns of response) for endpoints of cancer,
developmental toxicity, reproductive toxicity.
(2) Prioritization of regulatory chemical inventories (TSCA21,
OW21, EDSP21 and OPP21) based on in vitro molecular
signatures (patterns of response) endpoints for systemic toxicity,
developmental neurotoxicity and immunotoxicity.
Output
Year
FY15
FY15
FY16
FY16
FY16
FY16
FY16
FY16
FY16
FY16
FY13
FY16
Relevance to
other
CSS Themes
1,4
1,4
1,3,4,6
1,3,4,6
1,3,4,6
1,3,4,6
6
6
-------
Task
No.
2.5.3
2.6.1
2.6.2
Outputs
(1) Completion of TSCA21 workplan for 500 chemicals: Rapid
prioritization of chemicals for further safety evaluation based
on potential for both harm and exposure. Non-animal-based (in
vitro) tests are used to identify the degree to which a substance
can damage living organisms (hazard) and to determine
pharmacokinetics (how the chemicals accumulate within the
body) and computer simulations (based on chemical structure
- inherency - and mathematical models) are used to derive
potential for human contact (exposure). The TSCA21 workplan
for 500 chemicals will combine high-throughput hazard data,
pharmacokinetic data and exposure simulations to determine
chemical prioritization based upon potential risk.
(2) Completion of EDS21P workplan for 2000 chemicals: Rapid
prioritization of chemicals for further safety evaluation based
on potential for both harm and exposure. Non-animal-based (in
vitro) tests are used to identify the degree to which a substance
can damage living organisms (hazard) and to determine
pharmacokinetics (how the chemicals accumulate within the body)
and computer simulations (based on chemical structure, inherency
and mathematical models) are used to derive potential for human
contact (exposure. The EDSP21 workplan for prioritization of
2000 chemicals will include both potential hazard identification and
chemical-structure-derived exposure potential simulation without
pharmacokinetic considerations.
(1) Nanomaterials life cycle based effects.
(2) Credible translatable alternative test methods, guidelines and
endpoints that predict NM in vivo toxicity with high confidence.
(3) Mechanisms of injury, mode of action and AOP for HTP and
HCS methods development.
(4) Nano-QSARs and inform green nano chemistry/applications.
(5) Best current in vitro and in vivo methods for tier testing of NMs
provided to Offices.
6) AOPs identifying common and sensitive biological receptors
predictive of adverse human and ecological outcomes.
(1) Approaches for standardized testing of nanomaterials.
(2) Quantify acute toxicity of selected nanomaterials.
(3) Understanding of inherent properties of modifications that
mediate specific nanomaterial toxicity or other effects.
(4) Identify mechanisms of action for nanomaterials, AOPs and
recommendations for development of alternative and rapid
throughput assays.
(5) Recommendations for the development of models linking
inherent properties and adverse outcomes (e.g., QSARs for
nanomaterials).
Output
Year
FY16
FY16
FY16
FY16
FY16
FY16
FY16
FY16
FY12
FY13
FY15
FY15
FY16
Relevance to
other
CSS Themes
1,4,7
1,4,7
1,4,5,6
1,3,8
1,3,8
1,5
1,3,8
1,3,5,6,8
1
1
1
1
1
-------
Theme 3. Biomarkers
Science Questions: How can CSS assess biomarkers that can serve as useful indicators of toxicity for
different chemicals and endpoints such as health or wildlife outcomes?
What are the endpoints of concern that require development of biomarkers?
What characteristics are needed for a biomarker to be one that is informative of adverse outcomes to
humans?
How can the program assess biomarkers of exposure?
What models need to be developed to better integrate biomonitoring (biomarkers and bioindicators)
data into testing systems to help the Agency better understand environmental and health impacts?
Outcome: EPA risk assessments are improved by the (1) consistent, justifiable and improved use of
existing biomonitoring data (e.g., NHANES); (2) availability of dose estimation/exposure reconstruction
methods; and (3) availability of diagnostic AOP-based biomarkers with annotations to evaluate
published data.
Task
No.
3.1.1
3.1.2
3.2.1
Outputs
(1) Holistic approaches to foster a better understanding of
relationship between exposure metrics and biomarkers, allowing
for potential to reconstruct exposures from biomarkers.
(2) Improved methodologies for exposure and dose estimates by
integrating biomarker data with supporting information/data (e.g.,
exposure factors and pharmacokinetic behaviors) into predictive
models.
(1) Develop and maintain a state of the art panel of biomarkers of
effects for use by risk assessors and researchers.
(2) Link biomarkers to key events in an adverse outcome pathway
and thereby improve the diagnostic capabilities of the biomarkers
in the panel.
(1) Biomarker-based models for risk assessment.
(2) Biomarker-based model tools to evaluate risk management
activities.
Output
Year
FY16
FY16
FY16
FY16
FY16
FY16
Relevance to
other
CSS Themes
2
2
2,7
2,7
-------
Theme 4. Cumulative Risk
Science Questions: What are the ecological and human health risks of combined real-world exposures
to environmental chemicals?
What are the chemical targets at the molecular, cellular, tissue, organ and whole animal levels? and can
these targets be used to assess cumulative effects?
How can recent scientific advances help describe the impacts of exposures to chemical mixtures?
How can recent scientific advances help describe human variability (e.g., across life stages, population
groups)?
What kinds of tools, including computational, systems-based tools, are required to fully describe the
overall impact of aggregate exposures on organisms?
What enhancements will be required to describe the impact of factors that affect an organism's
response to chemical exposure, such as life stage, gender and aggregate exposures?
What new methods/models are needed to account for exposure from all sources and pathways?
Outcome: A set of predictive models from the cellular level to the population level that can be
integrated into a source-to-outcome modeling platform that incorporates real world exposure scenarios.
Task
No.
4.1.1
4.1.2
4.1.3
Outputs
(1) Predictive tools for identifying and prioritizing real-world
mixtures of stressors (environmental, residential, SES, diet, etc.)
based on: Sources (including commercial and consumer products);
Surrogate exposure and hazard indices; and Toxicity of chemical
mixtures.
(2) Examination and optimization of prototypical AHHS and CCS
survey study designs to document real-world mixtures spatially
and temporally.
1) Methods to predict the effect of chemical mixtures based on
outcome pathways.
(2) Methods to select chemical mixtures for testing based on
likelihood of toxicity.
(1) Evaluation of selected compounds in municipal solid waste
landfills.
(2) A reduced list of "indicator chemicals" for routine monitoring
of emerging contaminants in wastewater and receiving waters in
support of regulatory policy for limits of discharge.
(3) Final data on the fate and transport of emerging chemicals of
interest following land application of biosolids.
Output
Year
FY15
FY15
FY15
FY16
FY16
FY16
FY16
Relevance to
other
CSS Themes
2,3
2,3
2
2
2
-------
Task
No.
4.2.1
4.2.2
Outputs
(4) Weight of evidence approach using "indicator chemicals"
and selected MOA based bioassays to assess the efficacy of
risk management of emerging contaminants in wastewater and
receiving waters.
(5) Evaluation of selected compounds in municipal solid waste
compost.
(6) Data on the fate and transport of emerging chemicals of
interest following land application of biosolids for mixtures
identified in CSS cumulative risk research.
Science from the InterAgency Agricultural Health Study (AHS) for
use by EPA
(1) Data, science and methods to support Agency decisions on
perfluorochemicals (PFCs).
(2) Data, methods and science to inform PCB exposure and
mitigate risk to children to support EPA regional decisions.
(3) Data, science and tools to support OPPT's rulemaking for
formaldehyde.
(4) Data, methods and models for understanding exposure and
effects from indoor source emissions for Spray Polyurethane Foam
(SPF)-based products.
(5) Data, case studies and guidance to support EPA next
generation assessments for the Integrated Risk Information
System (IRIS), PPRTV and Integrated Science Assessment (ISA)
programs.
(6) Social science research on the consumer behavior patterns
and trends and how these influence consumer product use and
resulting chemical exposure.
Output
Year
FY16
FY16
FY16
FY16
FY17
FY13
FY17
FY16
FY15
FY17
Relevance to
other
CSS Themes
2
-------
Theme 5. Life Cycle Considerations
Science Questions: How can life-cycle assessments and other innovative tools be integrated with
more traditional methods to produce assessments that inform decision making and identify safer and
more sustainable approaches?
How can life cycle assessment approaches and methods be applied to decision analysis to reduce
uncertainties associated with the analysis of alternatives at multiple decision-making scales or levels?
What are the critical components of a sustainability-driven paradigm for risk management of chemical
and product systems that incorporate life cycle factors relevant to environmental, economic and societal
issues?
How can effective and reliable screening-level approaches for life-cycle assessment be developed that
can be efficiently and strategically applied to the large number of chemicals?
Outcome: The identification of key linkages in the continuum between the production of a chemical,
its release, fate/transport of a chemical in the environment, the resulting exposures and adverse
outcomes for humans and/or the environment so that sustainable risk management approaches can be
scaled up and delivered to decision-makers.
Task
No.
5.1.1
5.1.2
5.2.1
5.2.2
5.2.3
5.2.4
Outputs
A database of information about the life cycle of a chemical that
will aid in incorporating sustainability in environmental decision-
making.
A framework to help include sustainability in decision-making within
the EPA using experiences from case studies with program offices
and regions.
Reaction systems, membrane materials and separation processes
will be developed using the principles of green chemistry to
address sustainability in chemical processes.
Solutions will be provided and demonstrated for the sustainable
design, production and use of chemicals using the principles of
green engineering to reduce the utilization of energy intensive
chemical processes.
Innovative approaches to manufacturing of chemicals will be
developed using sustainable molecular design, life cycle material
safety and chemical process indicators.
The development and demonstration of life cycle methods for
sustainable design practices for the manufacture, use and
evaluation of commercial products.
Output
Year
FY16
FY16
FY16
FY14
FY16
FY16
Relevance to
other
CSS Themes
7,8
1,7,8
1,2,4,7
4,7
1,2,4,7
7
-------
Theme 6. Extrapolation
Science Questions: What enhancements will be required to describe the impact of factors that affect
an organism's response to chemical exposure, such as life stage, gender and aggregate exposures?
How can recent scientific advances help describe human variability, life stages and population groups?
With the emphasis on developing in vitro assays fortoxicity testing, how can we extrapolate from in vitro
assay response to in vivo response?
Outcome: An improved understanding of the utility of adverse outcome pathway models that provide
increase confidence in the extrapolation of exposure and effects across different levels of biological
organization, doses, genders, life stages, species and populations.
Task
No.
6.1.1
6.1.2
6.1.3
6.2.1
6.2.2
Outputs
Chemical class-based expert systems: Automated rule-based
decision trees are being developed to predict which chemicals
have the potential to disrupt endocrine systems. This is done
by testing key chemicals within a chemical class to represent
others, determining what is similar about the chemical structures
and properties that explain their biological activity and writing
rules that help categorize similar but untested chemicals. The
program offices use these tools to decide which, of the hundreds
of chemicals on Agency chemical lists, should be evaluated first
because they are most likely to disrupt one of these endocrine-
mediated pathways.
Methods and models to apply in vitro and in silico derived data to
individuals.
Predicting chemical impacts using computational models and
small-scale experiments: Validated methods and models for
interpretation and extrapolation of data generated by in vitro
and small-scale in vivo systems designed to test interactions of
chemicals with biological pathways or targets.
(1) Refined tools that exist for estimating species sensitivity to
pesticides and other contaminants: Expansion to add algal toxicity
data.
(2) Refined tools that exist for estimating species sensitivity to
pesticides and other contaminants: Expansion to add mode of
action information.
(3) Refined tools that exist for estimating species sensitivity to
pesticides and other contaminants: Guidance to standardize
methods.
Population models that incorporate sub-groups offish or aquatic
invertebrates separated by life stage, age or time.
Output
Year
FY16
FY15
FY16
FY14
FY15
Relevance to
other
CSS Themes
1,2,7
2
1,2,4,5
2
2
-------
Task
No.
6.2.3
Outputs
Methods and models for translating toxicity test endpoints into
quantitative estimates of changes in demographic rates, such as
fecundity and juvenile survival rates, for use in population-level risk
assessment.
Output
Year
FY16
Relevance to
other
CSS Themes
2
-------
Theme 7. Dashboards
Science Questions: What kind of tools, including computational, systems-based tools, are required to
fully describe the overall impact of exposure on organisms?
How can tools be customized to supply the data and information needed by partners to address specific
regulatory and environmental questions?
How can inherency, exposure, hazard and risk management options be integrated to supply a greater
degree of certainty in decisions, reduced risk and enhanced sustainability?
Outcome: Communicate, translate and transfer all available scientific information about chemicals in
ways most useful to decision-makers.
Task
No.
7.1.1
7.1.2
7.1.3
7.1.4
7.2.1
7.2.2
Outputs
Process developed used to gather scientific information that EPA
risk assessors need to make environmental decisions. This will
help us build useful decision support tools for partners.
We will support existing ORD databases and tools used by
decision-makers: Maintenance, data input and upgrade of support
tools.
Prototype dashboard (decision support tools) for OPP to support
ecological risk assessment is delivered. This dashboard will
expand and update current OPP decision support tools.
(1) Initial prototype dashboards delivered to program offices:
Prototype versions of web-based dashboards for evaluating
screening, testing, exposure and sustainability information relevant
to EDSP21 (potential endocrine disruption), OPP21 (pesticidal
actives, inerts and antimicrobials), TSCA21 (prioritizing and
assessing new and existing chemicals), OW21 (prioritization
of chemicals for the PCCL/CCL and other purposes), HHRA21
(PPRTV and NexGen risk assessments).
(2) Initial prototype dashboards delivered to program offices:
Regular updates (6-month cycles) of all EPA program office web-
based dashboards, taking into account user feedback and new
scientific developments.
(1) Dashboards for environmental decision-making: Identification
of databases decision-makers use the most.
(2) Dashboards for environmental decision-making: Different
databases will be combined to provide this information in
dashboards using web-services (i.e., computer programs web sites
use to send information to web-browsers).
Dashboards for environmental decision-making: Computer
programs developed that translate and combine information
from different databases using ontologies (i.e., dictionaries that
computer programs use to organize and link databases).
Output
Year
FY14
FY16
FY15
FY16
FY16
FY16
Relevance to
other
CSS Themes
1,2,3,4,5,
6,8
1,2,3,4,5,
6,8
-------
Task
No.
7.2.3
7.2.4
Outputs
Dashboards for environmental decision-making: Software
developed to build dashboards for web browsers and to get
information from databases using web-services. Free tools will be
used that we can easily reuse and maintain.
(1) Dashboards for environmental decision-making: Identify
computer models decision-makers use to forecast how chemicals
spread in the environment and affect living things.
(2) Dashboards for environmental decision-making: Develop
software that makes it easy to use these computer models from
web-based dashboards.
Output
Year
FY16
FY16
Relevance to
other
CSS Themes
1,2,3,4,5,
6,8
1,2,3,4,5,
6,8
-------
Theme 8. Evaluation
Science Questions: How have CSS research findings and tools impacted and supported EPA's
decision making?
What are the measures needed to evaluate the predictive value of the tools (e.g., Dashboards,
enhanced ToxCast™) produced from the CSS research program?
Do the partners find that the tools and other data from the CSS research program will improve
environmental decision making, including risk assessment?
How can the critical pieces of information required for different assessment tiers be systematically
identified, evaluated, integrated, reviewed and used in assessments and subsequent management
decisions?
Outcome: The overall impact of the CSS research is assessed. CSS tools and information are
delivered to the partners along with training in order that the partners have an ability to efficiently apply
the information. The CSS tools, new assays and scientific knowledge have increased our confidence
in utilizing 21st century pathway-based approaches for priority setting, toxicity testing and risk
assessment.
Task
No.
8.1.1
8.1.2
8.2.1
8.2.2
8.2.3
Outputs
(1) Understanding of partner needs and how to measure product
utility; information obtained through pro forma surveys and
interviews.
(2) Overall program performance and success assessment of CSS
research based on understanding of how the partners will benefit
from CSS research products.
Overall program performance and success assessment of CSS
research based on understanding of how the partners will benefit
from CSS research products.
(1) CSS product utility improved through regular communication
with partners and employment of partner-informed utility metrics.
(2) Identification of best practices for future projects and potential
future impacts of CSS Program products.
Identification of best practices for future projects and potential
future impacts of CSS Program products.
Identification of best practices for future projects and potential
future impacts of CSS Program products.
Output
Year
FY12
FY16
FY16
FY16
FY16
FY16
FY16
Relevance to
other
CSS Themes
7
5,7
7
7
7
-------
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U.S. EPA, 2010. A Set of Scientific Issues
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-------
Modeling and a SHEDS-PBPK Permethrin
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Screening Program for the 21st Century:
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silico Models and in vitro High Throughput
Assays in the Endocrine Disrupter Screening
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Screening Summary Overview A Part of the
EDSP Comprehensive Management Plan.
Office of Chemical Safety and Pollution
Prevention, US Environmental Protection
Agency, Washington, DC. Available at: http://
www.epa.gov/endo/pubs/edsp21_work_plan_
summary%20_overview_final.pdf
Websites:
EPA's Computational Toxicology Research:
http://www.epa.gov/ncct/
EDSP: EPA's Endocrine Disrupter Screening
Program; http://www.epa.gov/endo/index.htm
EPA's Green Chemistry: www.epa.gov/
greenchemistry/
NEPA: National Environmental Policy Act;
http://ceq.hss.doe.gov/nepa/regs/nepa/
nepaeqia.htm
NexGen: Advancing the Next Generation of
Risk Assessment; http://www.epa.gov/risk/
nexgen/
NNI: National Nanotechnology Initiative; www.
nano.gov
REACH: The European Community Regulation
for the Registration, Evaluation, Authorisation
and Restriction of Chemical substances;
http://ec.europa.eu/environment/chemicals/
reach/reach_i ntro. htm
TSCA Chemical Substance Inventory: http://
www.epa.gov/oppt/existingchemicals/pubs/
tscainventory/basic.html#background
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Appendix A. Research Program Partners
and Stakeholders
EPA Program and Regional Partners in the
CSS Program:
• Innovation Team (ORD)
• National Center for Environmental
Assessment (ORD)
• National Center for Environmental
Economics (OPEI)
• Office of Air and Radiation (OAR)
• Office of Chemical Safety and Pollution
Prevention (OCSPP)
• Office of Children's Health Protection
(OCHP)
• Office of Environmental Information (OEI)
• Office of the Science Advisor (OSA)
• Office of Solid Waste Emergency
Response (OSWER)
• Office of Water (OW)
• Regions 2, 5, 6, 8 and 9
External Stakeholders:
• Idealscale invites to +1000 Organizations
• Webinars to Stakeholders
• Participants included:
o ACC
o CropLife
o EOF
o HSUS
o NRDC
U.S. Federal and State Government
Agencies and Committees:
• ATSDR/CDC
• California Air Resources Board (ARE)
• CPSC
• Extramural Nano Consortium
• National Toxicology Program, NIEHS
• NCI
• NIEHS/NTP
• NIHCGC
• NIH, NCI, National Nano-Characterization
Center
• NIOSH
NIST
NNI
Oak Ridge National Laboratory Center for
Nanophase Materials Sciences (CNMS
State of Illinois
US Army Corps of Engineers
USDA
U.S. FDA
USFWS
USGS
International and Foreign Agencies and
Organizations:
• CAAT-Europe
• Department of Environment, Food and
Rural Affairs (DEFRA), UK
• Environment Canada
• European Chemical Agency (EGA)
• European Commission Joint Research
Centre
• Finnish Centre for Alternative Methods
(FICAM)
• Institute for Health and Consumer
Protection (JRC)
• International Standardization Organization
(ISO)
• Korea National Institute of Environmental
Research (NIER)
• National Institute for Environmental
Sciences (Japan)
• Netherlands Organisation for Applied
Scientific Research (TNO)
• OECD
Nongovernmental Organizations and
Corporations:
• 4 Rivers
• Agilent Technologies
• American Center for Life Cycle
Assessment
• Astellas Pharma Inc.
• BASF
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Biomathematics Consulting
ChemScreen
Cytek
DOW Chemical Co.
DuPont
Dupont Haskell Labs
Emery Oleochemical
GlaxoSmith Kline
Global Electric Electronics Processing
(GEEP) Inc.
Hoffman-LaRoche Inc
ILSI/HESI
Interface, Inc.
L'OREAL
Membrane Technology and Research
(MTR)
Merck
NanoRelease program of ILSI
Osmose
Pfizer Inc.
Polyone Corporation
Product Carbon Footprint World Forum
Sanofi Aventis
Shimadzu
Stemina Biomarker and Discovery
Syngenta Crop Protection, Inc.
ThalesNano
The Hamner Institutes
Toxicology Excellence for Risk Assessment
(TERA)
USEtox (www.usetox.org)
Warner-Babcock
World Resources Institute
World Wildlife Fund
Fraunhofer Institute of Toxicology and
Experimental Medicine (ITEM)
Indiana University
Johns Hopkins University
Kunming University of Science and
Technology (China)
Michigan State University
Mississippi State University
MIT
Northern Arizona University
Oregon Health and Sciences University
Oregon State University
Purdue University
Rice University
Texas A&M University
UC Berkeley University of Pannonia
(Hungary)
UCLA
University of Aarhus (Denmark)
University of Arizona
University of Bern (Switzerland)
University of Cincinnati
University of Georgia
University of Houston
University of Maryland
University of Michigan
University of North Carolina-Chapel Hill
University of St. Thomas
University of Texas-Austin
University of Toronto at Scarborough
Virginia Commonwealth University
Virginia Tech
Yale University
Universities (some funded via EPA's NCER
STAR program):
• Arizona State University
• Baylor University
• Clemson University
• Colorado School of Mines
• Duke University
• Duke University Center for the
Environmental Implications of Nano
Technology (CEI NT)
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Appendix B. Definitions
Aggregate Exposure: Aggregate exposure
and risk assessment involve the analysis of
exposure to a single chemical by multiple
pathways and routes of exposure (from 2001
EPA/OPP Document).
Adverse Outcome Pathway (AOP): The
linkage of adverse effects to perturbations in
specific toxicity pathways.
Biomarker or biological marker: A chemical
or biological characteristic that is measured
or evaluated as an indicator of a biological
process and used as a marker of exposure or
effect.
Chemicals: Intentionally produced or
manufactured chemicals, particle and
material, as well as a product into which
they are incorporated. It may refer to single
chemicals, particles, or materials, or mixtures
of chemicals, particles and/or materials,
products, as well as forms of chemicals that
are transformed as they move through the
environment.
Computational Toxicology: The application
of mathematical and computer models and
molecular biological approaches to predict
chemical hazards and risks to human health
and the environment.
Cumulative Risk: The combined risks from
aggregate exposures to multiple agents or
stressors (EPA, 2003b).
Cumulative Risk Assessment: An analysis,
characterization and possible quantification
of the combined risks to health or the
environment from multiple agents or stressors
(EPA, 2003b).
Dashboard: An interactive web site that
provides access to tools and data that are
required to carry out a specific analysis or
decision-related task.
Endocrine Disrupting Chemical (EDC):
An exogenous agent that interferes with the
activity (via effects at the level of synthesis,
secretion, transport, binding, action, or
elimination) of hormones in the body which are
responsible for the regulation of development
and the maintenance of homeostasis of
numerous organs and physiological systems
(e.g., reproduction and behavior).
Extrapolation: Estimate of the value of a
variable outside a known range calculated
using a model or an equation based on values
within a known range.
High-Throughput System (HTS): in vitro
biochemical or cellular assays that can be run
quickly and efficiently (i.e., high-throughput)
on a large number of compounds to determine
their activity on biological targets.
Inherency: The physical, chemical and
biological properties of a chemical, chemical
formulation, or product that influence
exposure, effects and sustainability.
Inherent Chemical Properties (ICP):
Inherent physical and chemical properties.
Life Cycle: The "cradle to grave" (also
referred to as "cradle to cradle") activities
for a product, process, or activity including
the stages of resource acquisition, material
manufacture, production, transportation/
distribution, use, recycling/reuse and final
disposal.
Life Cycle Assessment (LCA): A holistic way
to consider multiple environmental and human
health issues associated with a product or a
process from resource acquisition through
manufacture, transportation, distribution and
use, to waste management and disposal.
Applied to chemical design and manufacturing,
the results of an LCA along with understanding
potential social and economic implications of
a product or process system provide the basis
for moving toward sustainability.
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Life Cycle Inventory (LCI): A database
of individual life cycle accounting of the
energy and material flows into and out of
the environment that are associated with
producing a material, component, or assembly.
Nanomaterial: A nanoscale material or
material that contains nanoscale structures
internally or on their surfaces. These can
include engineered nano-objects, such as
nanoparticles, nanotubes and nanoplates and
naturally occurring nanoparticles, such as
volcanic ash, sea spray and smoke (from the
National Nanotechnology Initiative; www.nano.
gov).
Nanoscale: The dimensional range of
approximately 1 to 100 nanometers (nm) (1
nm is equivalent to one billionth or 10~9 of a
meter; from the National Nanotechnology
Initiative; www.nano.gov).
Nanotechnology: Nanotechnology is
the understanding and control of matter
at the nanoscale, at dimensions between
approximately 1 and 100 nanometers, where
unique phenomena enable novel applications
(from the National Nanotechnology Initiative;
www.nano.gov).
Outcome: The expected results, impacts, or
consequence that a Partner or Stakeholder will
be able to accomplish due to ORD research.
Output: Synthesized and/or translated from
Products into the format needed by the End
User. Outputs should be defined, to the extent
possible, by Partners/Stakeholders during
Problem Formulation.
Physico-chemical properties: Measurable
characteristics of chemical substances
relating to physical (e.g., boiling point, mass,
conductivity) and chemical properties (e.g.,
reactivity, heat of combustion, water solubility),
also encompassing computable properties
based on molecular structures.
Product: A deliverable that results from
a specific Research Project or Research
Task. This may include (not an exhaustive
list) journal articles, reports, databases,
test results, methods, models, publications,
technical support, workshops, best practices,
patents, etc. These may require translation or
synthesis for inclusion as an Output.
Rare earth elements (REE): Comprised of
scandium, yttrium and 15 lanthanide elements,
of which, cerium, lanthanum and neodymium
are the most abundant. They are found in
several minerals; almost all production comes
from less than 10 minerals, primarily monazite
and bastnasite.
Stochastic Human Exposure and Dose
Simulation (SHEDS): A flexible and broadly
applicable probabilistic model to estimate
exposure and dose.
Sustainability: To create and maintain
conditions, under which humans and
nature can exist in productive harmony, that
permit fulfilling the social, economic and
other requirements of present and future
generations (Council on Environmental
Quality, 1969).
Sustainable molecular design: Using
established principles of chemistry and
engineering to build chemicals with the end
goal of removing the inherent health and
environmental risks of the chemical.
Systems Model: Multiple level or scale
models that predict or simulate exposure or
effects of complex biological or environmental
systems.
ToxCast™: A cost-effective approach, for
rapidly prioritizing in vivo toxicity testing of
large numbers of chemicals developed by the
EPA's Office of Research and Development,
that integrates data from state-of-the-art
high-throughput system bioassays to build
computational models to forecast the potential
human toxicity of chemicals.
Toxicity Pathways: Cellular and molecular
processes and functions that can be perturbed
by chemical exposure leading to abnormal
biological function.
Workbench: A complex dashboard that allows
customization of the set of tools and the
workflow for using them.
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