EPA 601/K-15/003 I September 2015 I www.epa.gov/research
Chemical Safety
for Sustainability
STRATEGIC RESEARCH ACTION PLAN
2016-2019
Office of Research and Development
Chemical Safety for Sustainability
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EPA 601/K-15/003
Chemical Safety for Sustainability
Strategic Research Action Plan 2016 - 2019
U.S. Environmental Protection Agency
September 2015
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Table of Contents
List of Acronyms ii
Executive Summary 1
Introduction 3
Environmental Problems and Program Purpose 4
Problem Statement 5
Program Vision 5
Program Design 6
Building on the 2012-2016 Research Program 6
EPA Partner and Stakeholder Involvement 7
Integration across Research Programs 8
Statutory and Policy Context 11
Research Program Objectives 12
Research Topics 14
Topic 1: Chemical Evaluation 17
Topic 2: Life Cycle Analytics 19
Topic 3: Complex Systems Science 23
Topic 4: Solutions-Based Translation and Knowledge Delivery 26
Strategic Collaborations 32
Anticipated Research Accomplishments and Projected Impacts 33
Conclusions 35
Appendix 1: Additional Policy Context and Scientific Advice 36
Appendix 2: Examples of CSS Partnerships 39
Appendix 3: Table of Proposed Outputs 41
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List of Acronyms
ACE Air, Climate and Energy
ADME absorption, distribution, metabolism, and excretion
AOPs Adverse outcome pathways
AOPDD AOP discovery and development
AOP-KB AOP Knowledge Base
AOP-Wiki Adverse Outcome Pathway Wiki
CAA Clean Air Act
CCL Contaminant Candidate List
CEH Children's Environmental Health
CERCLA Comprehensive Environmental Response, Compensation and Liability Act
CMP3 Chemical Management Plan 3
CPCat Chemical/Product Categories Database
CPSC Consumer Product Safety Commission
CSPA Children's Safe Product Act
CSS Chemical Safety for Sustainability Research Program
CSS StRAP Chemical Safety for Sustainability Strategic Research Action Plan
CIS Chemical Transformation Simulator
CWA Clean Water Act
DoD Department of Defense
DISC Department of Toxic Substances Control, California
ECHA European Chemicals Agency
EDSP Endocrine Disrupter Screening Program
EDSP21 Endocrine Disrupter Screening Program for the 21st Century
ENMs Engineered nanomaterials
EPA Environmental Protection Agency
ERA Ecological Risk Assessment
ESA Endangered Species Act
FDA Food and Drug Administration
FFDCA Federal Food, Drug and Cosmetic Act
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
FQPA Food Quality Protection Act
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FWS (United States) Fish and Wildlife Service
FY Fiscal Year
HHRA Human Health Risk Assessment
HSRP Homeland Security Research Program
HTPK High-throughput pharmacokinetic
HTS High-throughput screening
HIT High-throughput toxicology
LCA Life-cycle assessment
MCC Methodologically challenging compounds
MCnest Markov Chain Nest Productivity Model
NAS National Academy of Sciences
NCCLCs Networks for Characterizing Chemical Life Cycle
NEHI Nanotechnology Environmental Health Implications working group
NIH National Institute of Health
NIOSH National Institute for Occupational Safety and Health
NMFS National Marine Fisheries Service
NNI National Nanotechnology Initiative
NPD National Program Director (for one of EPA's research programs)
NSF National Science Foundation
NSMDS Networks for Sustainable Molecular Design and Synthesis
OCMs Organotypic Cell Models
OCSPP Office of Chemical Safety and Pollution Prevention
OECD Organization for Economic Cooperation and Development
ORD Office of Research and Development
OSWER Office of Solid Waste and Emergency Response
OW Office of Water
PCRs Product Category Rules
PIP Pathfinder Innovation Projects
POD Points of departure
QSAR Quantitative Structure Activity Relationship
RCRA Resources Conservation and Recovery Act
SAR Structure-Activity Relationships
SDWA Safe Drinking Water Act
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SHC Sustainable and Healthy Communities
SSWR Safe and Sustainable Water Resources
STAR Science to Achieve Results
TIM Terrestrial Investigation Model
TPO Thyroperoxidase
TSCA Toxic Substances Control Act
USDA United States Department of Agriculture
VISION 20/20 Vision for 2020
VTMs Virtual tissue models
WeblCE Web-based Interspecies Correlation Estimation
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Executive Summary
Chemicals are integral to the American economy and provide key building blocks for the many
products that benefit society. Sustainable innovation and use of chemicals call for making
decisions and taking actions that improve the health of individuals and communities today without
compromising the health and welfare of future generations. Smart new strategies for designing,
producing, and using safer chemicals to minimize risks and prevent pollution is a priority for the U.S.
Environmental Protection Agency (EPA).
The challenges to meeting this mandate are formidable: Tens of thousands of chemicals are currently
in use and hundreds more are introduced into the market every year. Many of these chemicals have
not been thoroughly evaluated for potential risks to human health, wildlife and the environment,
particularly when considering the consequences of use over a chemical's life cycle (from production
to disposal). Current toxicity testing methods for evaluating risks from exposures to individual
chemicals are expensive and time consuming. Approaches for characterizing impacts across the
chemical/product life cycle are data and resource-intensive.
Characterizing real-world exposures and early indicators of adversity in a way that allows proactive
decisions to minimize impacts of existing chemicals as well as to anticipate impacts of emerging
materials requires holistic systems understanding. Potential health effects from chemicals are
associated with disruption to complex biological processes. For example, evidence is mounting that
some chemicals disrupt the endocrine system. Some of these effects relate to chronic exposures to
low levels of multiple chemicals. Prenatal and early-life exposures are of particular concern and may
lead to health impacts across the lifespan. As a result, there is a need to shift the thinking about how
potential for adverse impacts and ultimately risks are evaluated.
Today, EPA and its stakeholders are making decisions on chemical selection, design, and use at
the national, regional, and local levels. States, communities, and consumers are demanding robust
information on chemicals in products and are driving large retailers and industry to make changes.
Tools for evaluating chemical substitutions and product alternatives are evolving to meet the
demand for action. However, scientifically vetted approaches remain limited. New approaches are
required to increase the pace at which relevant information can be obtained and integrated into
decision making, and to ensure that decisions are scientifically supported and sustainable. Key
metrics that can be collected as early indicators of changes to the chemical exposure landscape are
needed to preempt or rapidly mitigate unanticipated impacts.
To address these challenges, EPA's Chemical Safety for Sustainability (CSS) Research Program
is leading development of innovative science to support safe, sustainable selection, design, and
use of chemicals and materials required to promote ecological well-being, including human and
environmental health, as well as to protect vulnerable species, lifestages, and populations. The
ultimate goal is to enable EPA to address impacts of existing chemicals, anticipate impacts of new
chemicals and materials, and evaluate complex interactions of chemical and biological systems to
support EPA decisions.
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Working in conjunction with our partners in EPA regulatory programs and regional offices, we have
identified priority needs for information and methods to make better informed, timelier decisions
about chemicals. CSS science is strategically scoped within four integrated research topics to support
EPA priorities:
1. Chemical Evaluation: Advance cutting-edge high-throughput methods in computational
toxicology and provide data for risk-based evaluation of existing chemicals and emerging
materials.
2. Life Cycle Analytics: Address critical gaps and weaknesses in accessible tools and metrics
for quantifying risks to human and ecological health across the life cycle of
manufactured chemicals, materials, and products. Advance methods to efficiently
evaluate alternatives and support more sustainable chemical design and use.
3. Complex Systems Science: Adopt a systems-based approach to examine complex
chemical-biological interactions and predict potential for adverse outcomes resulting from
exposures to chemicals.
4. Solutions-Based Translation and Knowledge Delivery: Promote Web-based tools, data,
and applications to support chemical safety evaluations and related decisions,
respond to short-term high priority science needs for CSS partners, and allow for active
and strategic engagement of the stakeholder community.
This Strategic Research Action Plan for EPA's Chemical Safety for Sustainability Research Program
maps out a research program for the near-term with an eye toward meeting longer term needs to
transform chemical evaluation. CSS scientific results and innovative tools will accelerate the pace of
data-driven chemical evaluations, enable EPA decisions that are environmentally sound and public
health protective, and support sustainable innovation of chemicals and emerging materials.
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Introduction
Chemicals are a lynchpin of innovation in
the American economy, and moving toward
sustainable innovation requires designing,
producing, and using chemicals in safer
ways. Information and methods are needed
to make better informed, timelier decisions
about chemicals, many of which have not
been thoroughly evaluated for potential
risks to human health and the environment.
EPA's Chemical Safety for Sustainability (CSS)
research program is designed to meet this
challenge and supports EPA priority of reducing
risks associated with exposure to chemicals in
commerce, the environment, products, and
food.
To help guide the program to meet its
ambitious objectives, EPA's Office of Research
and Development (ORD), EPA's science arm,
developed this ChemicalSafetyfor Sustainability
Strategic Research Action Plan, 2016-2019 (CSS
StRAP), which builds upon the original vision of
the research program outlined in the Chemical
Safety for Sustainabilitv Research Action Plan
2012-2016. The current StRAP evolved through
a series of meetings with program and regional
partners, among ORD labs and centers involved
with CSS, and through interactions with external
stakeholders.
The CSS StRAP is one of six research plans, one
for each of EPA's national research programs in
ORD. The six research programs are:
Air, Climate, and Energy (ACE)
Chemical Safety for Sustainability (CSS)
Homeland Security (HS)
Human Health Risk Assessment (HHRA)
Safe and Sustainable Water Resources
(SSWR)
Sustainable and Healthy Communities (SHC)
EPA's strategic research action plans lay the
foundation for EPA's research staff and their
partners to providefocused research effortsthat
meet EPA's legislative mandates, as well as the
goals outlined in EPA's Fiscal Year 2014 - 2018
EPA Strategic Plan. They are designed to guide
an ambitious research portfolio that at once
delivers the science and engineering solutions
EPA needs to meet such priorities, while
also cultivating a new paradigm for efficient,
innovative, and responsive environmental and
human health research.
The StRAP outlines the approach designed to
achieve EPA's objectives for advancing chemical
safety and Sustainability. It highlights how
the CSS program integrates efforts with other
research programs across ORD to provide a
seamless and efficient overall research portfolio
aligned around the central and unifying concept
of Sustainability.
No other research organization in the world
matches the diversity and breadth represented
by the collective scientific and engineering staff
of ORD, their grantees, and other partners. They
are called upon to conduct research to meet
the most pressing environmental and related
human health challenges facing the nation and
the world.
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Environmental
Problems and Program
Purpose
Sustainable innovation where chemicals are
designed, produced, and used in safer ways
to minimize risks and prevent pollution is a
priority for EPA. The challenges to meeting
this mandate are formidable; approximately
80,000 legacy chemicals are listed in EPA's Toxic
Substances Chemical Act (TSCA) inventory:
hundreds more are introduced into the market
every year. Less than 2000 of these chemicals
have health assessments available across
federal and state agencies. This translates into
only a small fraction that have been thoroughly
evaluated for potential risks to human health,
wildlife, and the environment, particularly
when considering the consequences of use
over a chemical's life cycle (from production to
disposal). Current toxicity testing methods for
evaluating risks from exposures to individual
chemicals are expensive and time consuming.
Approaches for characterizing impacts across
the chemical/product life cycle are data and
resource intensive. To address this critical need
to evaluate potential for risks associated with
thousands of chemicals in commerce, rapid
and efficient methods are required to prioritize,
screen, and evaluate chemical safety.
Characterizing real-world exposures and early
indicators of adversity (or "tipping points")
in a way that allows proactive decisions to
minimize impacts of existing chemicals as well
as to anticipate impacts of emerging materials
requires holistic systems understanding.
Potential health effects from chemicals are
associated with disruption to complex biological
processes in human and wildlife populations.
For example, evidence is mounting that some
chemicals disrupt the endocrine system.
The endocrine system regulates biological
processes throughout the body and is sensitive
to small changes in hormone concentrations.
In addition, more complex interactions and
outcomes are not addressed well with existing
models and assessment tools. Examples include
outcomes resulting from chronic low dose
exposures to multiple chemicals with similar
modes of actions, or exposures to complex
mixtures and/or chemicals with multiple modes
of action. Prenatal and early-life exposures are
of particular concern and additional complexity
is associated with the fact that these exposures
may lead to health impacts across the lifespan.
As a result, there is a need to shift thinking
about how potential for adverse impacts and
ultimately risk is evaluated.
Today, EPA and its stakeholders are making
decisions on chemical selection, design and use
at national, regional, and local levels. States,
communities, and consumers are demanding
robust information on chemicals in products
and are driving large retailers and industry to
make changes. Tools for evaluating chemical
substitutions and product alternatives are
evolving to meet the demand for action.
However, scientifically vetted approaches
remain limited.
Innovations in chemical and material design are
rapidly changing the landscape of industrial and
consumer products while novel materials, such
as engineered nanomaterials, are incorporated
to enhance their performance. New approaches
are required to increase the pace at which
relevant information can be obtained and
integrated into decision making, and to ensure
that decisions are scientifically supported and
sustainable. One goal of these approaches is
to avoid regrettable substitutions, which occur
when one chemical of concern is replaced by
another chemical that later proves to have
impacts of similar or greater magnitude. In
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addition, key metrics that can be efficiently
collected as early indicators of changes to the
chemical exposure landscape are needed to
preempt or rapidly mitigate unanticipated
impacts. Always, the assessments, predictions,
evaluations and decisions related to chemical
innovation and sustainable use must consider
the most vulnerable and sensitive species,
lifestages, and communities.
To anticipate and predict impacts of manufacture
and use of chemicals and materials that have
not yet been developed presents a larger
context for the CSS research program. As EPA
and stakeholders seek sustainable solutions to
complex and dynamic environmental problems,
the demand for "validated" forecasts of
uncertain future states increases. At the same
time, resource constraints limit the capacity
to monitor for the continuously changing set
and combination of chemicals and materials in
commerce. The CSS research program considers
the grand challenge of how best to build and
deploy modeling capacity in concert with
efficient data collection and effective monitoring
for robust and agile policy.
Clearly, information and methods are needed to
make better-informed, timelier decisions about
chemicals. Development of innovative science
to support safe, sustainable use of chemicals
and materials is required to promote ecological
well-being, including human and environmental
health, as well as to protect vulnerable species,
lifestages, and populations. CSS is designed to
meet this challenge and supports EPA priority
of reducing risks associated with exposure
to chemicals in commerce, the environment,
products, and food. The ultimate goal is to enable
EPA to address impacts of existing chemicals,
anticipate impacts of new chemicals and
materials, and evaluate complex interactions
of chemical and biological systems to support
decisions.
Through its signature research in computational
toxicology, CSS draws from and integrates
advances in several fields, including information
technology, computational chemistry, and
molecular biology, to address EPA's data
requirements for science-based assessment
of chemicals. EPA investments in advanced
chemical evaluation and life cycle analytics
are providing decision-support tools for high-
throughput screening and efficient risk-based
decisions.
Problem Statement
Tens of thousands of chemicals are currently in
use and hundreds more are introduced into the
market every year, many in new and emerging
markets such as nanotechnology. Only a small
fraction have been thoroughly evaluated for
potential risks to human health, wildlife, and
the environment. Multiple EPA programs and
regional offices must make risk-based decisions
for addressing chemicals with inadequate or
non-existent hazard and exposure data. Current
toxicity testing methods, which are expensive
and time consuming, evaluate risks from
exposures to individual chemicals. Approaches
for characterizing impacts across the chemical/
product life cycle are data and resource
intensive.
Program Vision
The CSS research program will lead development
of innovative science to support safe, sustainable
design and use of chemicals and materials
required to promote human and environmental
health, as well as to protect vulnerable species,
lifestages, and populations. CSS research
program outputs will enable EPA to address
impacts of existing chemicals and materials
across the life cycle and to anticipate impacts of
new chemicals and emerging materials. The CSS
research program will also provide the scientific
basis for evaluating complex interactions of
chemical and biological systems to support EPA
isions.
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Program Design
Building on the 2012-2016
Research Program
Since its inception, CSS research has endeavored
to transform chemical evaluation through
groundbreaking research, translation, and tools.
A number of impactful products have begun to
change the landscape of chemical evaluations
at EPA. Some examples include:
EPA's high-throughput toxicity research
effort ToxCast uses automated chemi-
cal screening technologies to measure
changes in biological activity that may
suggest potential for hazardous effects.
Coupled with related high-throughput
exposure estimations from ExpoCast,
this multi-year effort is generating and
sharing an unprecedented volume of
exposure and toxicology data and knowl-
edge transparently through an interac-
tive iCSS Dashboard.
The Chemical / Product Categories Da-
tabase (CPCat) compiles information on
chemicals found in consumer products.
This new publicly available database
maps over 40,000 chemicals to a set of
terms categorizing use or function for
high level exposure evaluation.
The Web-based Interspecies Correla-
tion Estimation (WeblCE) application
estimates acute toxicity in aquatic and
terrestrial organisms. The Markov Chain
Nest Productivity Model (MCnest) quan-
titatively estimates the impact of pesti-
cide-use scenarios on reproductive suc-
cess of bird populations. Together these
two tools are informing ecological risk
assessments, in particular for endan-
gered species.
The Adverse Outcome Pathway Wiki
(AOP-Wiki). created through a joint ven-
ture between the European Commission
and EPA, is a web-enabled and publicly
accessible repository that stimulates and
captures new and existing crowd-sourced
AOP knowledge from the global scientific
community.
Engaging in international efforts to har-
monize green purchasing practices has
resulted in application of EPA's life cycle
assessment tools to provide clear, com-
parable information about the environ-
mental impacts of different products
evaluated internationally in the develop-
ment of product category rules.
To enhance the ability to evaluate envi-
ronmental health and safety of nanoma-
terials, fate and transport models have
been incorporated to characterize the
surface properties of silver nanopar-
ticles and how these properties affect
their fate in containment systems. These
models have also been used to develop
higher throughput methods for charac-
terizing nanoparticle transport through
soils and sediments.
These products were derivatives of the original
vision of the research program outlined in
the CSS 2012-2016 StRAP. Fiscal year 2015
(FY15) planning presented a ripe opportunity
to conduct a review of the program and look
for ways to integrate the research, strengthen
transdisciplinary collaboration, promote and
foster innovation, enhance transparency and
access to CSS products, and significantly amplify
the impact of this important research. The
most noteworthy impetus for this integration
was the demand to drive the leading edge of
science, be prepared to meet the urgent needs
of EPA in a timely and responsive fashion, and
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achieve this within a budgetary environment
that is often unpredictable. CSS rose to this
challenge by remodeling the architecture of
its research program to be robust, sustainable,
anticipatory, agile, transparent, and at all times,
responsive.
In evolvingthe CSS program, we have signifi-
cantly reformulated key program areas to focus
research and design a cohesive and impact-
ful program that meets high priority partner
needs. The CSS 2012-2016 StRAP included eight
research themes and 21 research projects. To
provide further focus and amplify the impact of
CSS research, these were integrated into four
topics and nine transdisciplinary project areas.
The first iteration of the new program was then
piloted in FY15, and with input from ORD's lab
and center leadership, project scientists, CSS
program and regional partners, as well as the
joint committee of the Science Advisory Board/
Board of Scientific Counselors (SAB/BoSC). It
was refined to improve scientific coordination
and the interactions that are foundational to
a successful transdisciplinary program. The re-
sulting CSS 2016-2019 StRAP provides the over-
all framework for CSS research that grew from
this planning process.
In the CSS 2016-2019 StRAP, the Chemical
Evaluation and Complex Systems Science topics
have been designed to support development
and integration of the science required to
revolutionize capacity for efficient and effective
chemical safety risk-based decisions. To this
end, expertise in biomarkers, pharmacokinetics,
extrapolation, and cumulative risk are
embedded throughout to advance the science
for evaluating data poor chemicals.
The Life Cycle Analytics topic is designed
to provide the science and tools needed to
evaluate safety of chemicals and materials
(including engineered nanomaterials) in the
broader context of how these are designed
and used in our society. This is where we
consider green chemical design, life cycle
impacts, and sustainable use. Here, expertise
and emerging science is directed to elucidate
relationships between inherent chemical and
material properties, function and associated
impacts in biological systems. ORD capacity
to model human and ecological exposures in
combination with key expertise in life cycle
impact analysis is being directed to efficiently
evaluate alternatives and to fill a gap in available
sustainability metrics.
In addition, all CSS research implemented based
on this StRAP will: (1) have an increased focus
on developmental health, vulnerable lifestages,
and susceptible populations; and (2) explore
higher-throughput approaches with wider cov-
erage of chemistry and biology.
Finally, with this integration, nearly half of the
programmatic resources will be devoted to
research translation and knowledge delivery,
through tools and applications that enhance and
democratize access to CSS scientific knowledge,
through partner-driven and partner-focused
tailored solutions, and finally through strategic
outreach and engagement of the stakeholder
community that relies on the products of CSS
research and helps ground truth its validity,
relevance, and applicability.
EPA Partner and Stakeholder
Involvement
The process for developing this StRAP unfolded
through a series of meetings with program
and regional partners and among labs and
centers involved with CSS. The scoping
meetings included concurrent participation and
engagement from this community and helped
map out and balance the diverse partner
priorities. Additional focus group meetings with
partners allowed more in-depth discussions and
further shaping of the plans. This document was
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profoundly strengthened by the informed and
interactive iteration among these groups over
an 18-month period. Along the way, significant
interim milestones were posted online in an
effort to transparently engage the community
of EPA partners and collaborators.
The CSS StRAP is designed to drive the longer
term science vision for the program. But within
each CSS project, specific case studies are being
developed in collaboration with program and
regional partners to reflect EPA's near-term
priorities. This case study approach ensures that
the purpose and the application of CSS science
is clearly defined upfront in collaboration with
the partners and that the product developed
is fit for the intended purpose. In addition,
as described in the Research Topics section,
the Translation and Knowledge Delivery topic
incorporates both partner-driven short term
projects and projects through which the
applicability of the emerging science will be
demonstrated and evaluated (or conceptually
"test driven") early on in each CSS project
before going too far down a research path. This
collaborative approach builds familiarity and
confidence in the products of CSS research.
Partners are not asked to adopt a final product
ortool. Rather, they are engaged and involved in
the design and development of the tools, their
early adoption for application to case studies,
and the exercise of confidence building.
Every project in CSS also has a significant
education, outreach, and engagement
component first in building and executing case
studies, and also more broadly through targeted
webinars and panel listening and discussion
sessions set up monthly with program and
regional partners. This engagement culminates
in a face-to-face meeting, held approximately
annually across CSS and with partners designed
to allow direct interaction among partners and
CSS project investigators.
Research planned for the StRAP 2016-2019
also was informed by external stakeholders and
partners. The CSS staff and researchers serve on
several task groups and are actively engaged on
projects with numerous U.S. federal agencies
and international organizations as well as with
various state and nongovernment organizations.
CSS interacts with academia through scientific
conferences, informal professional relationships
and formal grants and cooperative agreements.
These venues afford the opportunity to not
only leverage expertise and funding, but also
the ability to identify unique niche areas to
which CSS can make the greatest scientific
contributions. These external engagements are
discussed in more detail in the Collaborations
and Stakeholder Engagement and Outreach
sections later in this document.
Integration across the Research
Programs
EPA's six research programs work together to
address science challenges that are important
for more than one program. Coordination
efforts can range from formal integration
efforts across the programs at a high level, to
collaboration research among EPA scientists
working on related issues.
To accomplish formal integration of research on
significant cross-cutting issues, EPA developed
several "Research Roadmaps" that identify
ongoing relevant research and also important
science gaps that need to be filled. The
Roadmaps serve to coordinate research efforts
and to provide input that helps shape the future
research in each of the six programs. Roadmaps
have been developed for the following areas:
Nitrogen and Co-Pollutants
Children's Environmental Health
Climate Change
Environmental Justice
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The CSS research program is the lead national
program for the Children's Environmental Health
(CEH) Roadmap. Transforming EPA's capacity
for considering child-specific vulnerabilities
requires that ORD apply advanced systems
science and integrate diverse emerging data
and knowledge in exposure, toxicology, and
epidemiology to improve understanding of
the role of exposure to environmental factors
during early life on health impacts that may
occur at any point over the life course.
The CEH Research Roadmap helps to connect
the dots among the research activities being
implemented across ORD's research programs.
In addition, the vision articulated in this
Roadmap serves to focus ORD investment in
CEH research on areas where EPA can play a
significant leadership role and to ensure this
cross-cutting research is integrated and the
results are impactful. The CSS program also
informs critical research areas identified in
the ORD cross-cutting research Roadmaps, as
illustrated in Table 1.
The HHRA and CSS programs are working to-
gether to evaluate how the new data emerging
from computational toxicology can be used to
improve efficiency and reduce uncertainty in
risk assessment. CSS research is developing ap-
proaches to integrate new types of information
with existing methods and information to sup-
port science-based decisions, and to evaluate
the value added of new data. In one example,
CSS will generate data needed for HHRA to de-
velop innovative fit-for-purpose assessment
products (such as high-throughput toxicity
values). Projects in the HHRA program include
case studies to characterize the utility of several
new approaches applied to different classes of
chemicals, various endpoints, and toxicities,
and with disparate degrees of supporting evi-
Table 1. Chemical Safety for Sustainability (CSS) research program contributions to critical
needs identified by ORD Roadmaps. Multiple checkmarks indicate a larger contribution of
CSS activities and interest in the identified science gaps of the Roadmaps than a single
checkmark; a blank indicates no substantive role.
ORD Roadmap
Climate Change
Environmental Justice
Children's Health
Nitrogen & Co-Pollutants
CSS Topic Area
Chemical
Evaluation
/
v'V
/
Life Cycle
Analytics
v'V
>/
Complex
Systems
Science
^
V
SSS
V
Translation
and
Knowledge
Delivery
V
v'V
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dence for context. Characterizing the utility of
these new data and tools for improving risk as-
sessment will build stakeholder confidence and
accelerate acceptance for regulatory decision
making. Additional coordination efforts among
ORD's research programs range from formal in-
tegration efforts at a high level, to collaborative
research among EPA scientists working on re-
lated issues. For example,
CSS and Safe and Sustainable Water Re-
sources (SSWR) research program are col-
laboratingto develop more efficient ways to
assess the toxicity of harmful algal blooms.
There are additional collaborations in areas
related to contaminants, including pharma-
ceuticals, found in open or drinking water,
as well as new approaches for evaluating
their cumulative health impacts.
CSS and Sustainable and Healthy Communi-
ties (SHC) collaborate in areas such as use of
chemicals (most recently, silver nanomateri-
als) in consumer products and relevance to
predicting potential children's exposures.
CSS and Air Climate and Energy (ACE) are
planning to collaborate on novel higher
throughput assays for cardiopulmonary ef-
fects that are being developed in ACE but
which may have broader application in CSS.
Chemical data, including from applications
of computational chemistry, can begin to
inform evaluation and response strategies
in the Homeland Security Research Pro-
gram (HSRP), as CSS data and dashboards
are enriched with more data and informa-
tion tools, and HSRP is trained as among the
stakeholders of CSS.
The projects outlined in the Research Topics
section provide additional examples of projects
that integrate across national research pro-
grams.
Research to Support EPA Strategic Plan
Because chemical manufacture and use has
intended and unintended consequences on
the quality of the air we breathe, the water we
drink, and the communities in which we live,
work, and learn, outputs of the CSS research
program will broadly support EPA's Strategic
Goals in these areas (see box) and inform EPA
decisions to sustainably improve human health
and the environment. Very specifically, the
CSS research program is designed to directly
support EPA's Strategic Goal 4: Ensuring the
Safety of Chemicals and Preventing Pollution; as
well as the Cross-EPA Strategy: Working Toward
a Sustainable Future.
Goal 4, objective: Ensure Chemical Safety. Re-
duce the risk and increase the safety of chemi-
cals that enter our products, environment, and
bodies.
Applied Research under Goal 4: EPA chemicals
research will provide the scientific foundation
required to support safe, sustainable use of
chemicals to promote human and environmen-
tal health, as well as to protect vulnerable spe-
cies, lifestages, and populations.
FY2014 - 2018 EPA Strategic Plan:
Goals and Cross-Agency Strategies
EPA Strategic Goals
Goal 1: Addressing Climate Change and Improving
Air Quality
Goal 2: Protecting America's Waters
Goal 3: Cleaning Up Communities and Advancing
Sustainable Development
Goal 4: Ensuring the Safety of Chemicals and
Preventing Pollution
Goal 5: Protecting Human Health and the
Environment by Enforcing Laws and
Assuring Compliance
Cross-Agency Strategies
' Working Toward a Sustainable Future
Working to Make a Visible Difference in
Communities
Launching a New Era of State, Tribal, Local, and
International Partnerships
Embracing EPA as a High-Performing Organization
-------
Statutory and Policy Context
Managing chemical risks is covered in
legislation and statutes mandated by Congress
and implemented by EPA (Table 2). Chemicals
are regulated by several EPA 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 EPA's Office of Water
to prioritize possible water contaminants in
the Contaminant Candidate List. EPA's Office
of Solid Waste and 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 REACH1 program and
Cosmetics Directive in Europe and the Canadian
Environmental Protection Act. CSS will enable
EPA to test and regulate numerous chemicals
in a more efficient manner, supporting several
statutory obligations and policies.
One example of a critical EPA mandate that
provides important context for design of
the CSS 2016-2019 StRAP and selection of
relevant case studies is the Endocrine Disrupter
Screening Program (EDSP; http://www.epa.
gov/endo/). The List of the EDSP Universe
of Chemicals contains approximately 10,000
chemicals as defined under FFDCA and SDWA
1996 amendments (http://www.epa.gov/
endo/#universe). EPA recently announced
and solicited public comment on the use of
new technologies (such as high-throughput
toxicology data) to substantially speed up
screening of chemicals for their potential to
disrupt hormones in humans and wildlife, and
reduce animal use in screening (http://www.
epa.gov/endo/pubs/pivot.htm). This signaled
an imminent opportunity to demonstrate the
relevance and potential applicability of CSS
research to environmental policy in near real
time.
In addition to federal legislative mandates,
several state initiatives, summarized in
Appendix 1, are driving the needed advances
in chemical evaluation. To contextualize and
obtain additional scientific advice on how the
emerging data and science from CSS can be
Table 2. 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, Fungicide, and
Rodenticide Act
Food Quality Protection Act
Resource Conservation and Recovery Act
Safe Drinking Water Act
Toxic Substances Control Act
Acronym
CAA
CWA
CERCLA
FFDCA
FIFRA
FQPA
RCRA
SDWA
TSCA
Website
www.eDa.gov/lawsreHS/laws/caa.html
www.eDa.Hov/reHulations/laws/cwa.html
www.eDa.Hov/suDerfund/Dolicv/cercla.htm
httD://www.fda.Eov/reEulatorvinformation/leEislation/
federalfooddruEandcosmeticactfdcact/default.htm
httD://www.eDa.Hov/aEricultu re/If ra. html
httD://www.eDa.sov/Desticides/resulatins/laws/faDa/
backgrnd.htm
httD://www2.eDa.Hov/rcra
httD://water.eDa.Hov/lawsreHS/rulesreHS/sdwa/
httD://www2.eDa.Hov/laws-reHulations/summarv-toxic-
substances-control-act
^ttDV/echa.euroDa.eu/reHulations/reach
-------
translated for use in EPA decision making, EPA
commissioned a study by the National Academy
of Sciences (NAS). CSS has strategically drawn
from the NAS recommendations to address
key research gaps that are not being addressed
by partners outside EPA. The formative NAS
reports are highlighted in Appendix 1.
Research Program
Objectives
CSS conducts research to provide the
fundamental knowledge infrastructure and
complex systems understanding required
to predict potential impacts from use of
manufactured chemicals and to develop tools
for rapid chemical evaluation and sustainable
decisions. In addition, CSS research results are
translated to provide solutions and technical
support to our EPA partners and external
stakeholders. CSS research is guided by the
following four objectives:
Build Knowledge Infrastructure.
Make information publicly accessible.
Combine different types of data in new
ways to characterize impacts of chemicals
to human health and the environment.
Develop Tools for Chemical Evaluation.
Develop and apply rapid, efficient, and
effective chemical safety evaluation
methods.
Promote Complex Systems Understanding.
Investigate emergent properties in
complex chemical-biological systems by
probing how disturbances and changes in
one part affect the others and the system
as a whole.
Translate and Actively Deliver.
Demonstrate application of CSS
science and tools to anticipate, minimize,
and solve environmental health problems.
Table 3 provides descriptions for each of these
objectives as well as their near-and long-term
aims in advancing the CSS vision.
In addressing these objectives, specific science
challenges were identified which led to the
design of the CSS Research Topics described in
the next section.
Science Challenge: Thousands of chemicals have
not been evaluated and new chemicals are con-
tinually being developed and introduced into
commerce. CSS is advancing cutting-edge meth-
ods to provide data for higher throughput risk-
based evaluation of both existing chemicals and
emerging materials. The Chemical Evaluation
research topic is designed to address this chal-
lenge.
Science Challenge: Chemical substitutions and
other alternatives designed to solve one envi-
ronmental health problem may have unintend-
ed consequences. CSS is exploring new ways to
evaluate risks to human and ecological health
across the life cycle of manufactured chemicals,
materials, and products. CSS methods will effi-
ciently evaluate alternatives and support more
sustainable chemical design and use. The Life
Cycle Analytics research topic is designed to ad-
dress this challenge.
Science Challenge: The real world is inherently
more complicated than current experimental
models of toxicology can depict. CSS research
adopts a systems-based approach to examine
complex chemical-biological interactions and
predict potential for adverse outcomes result-
ing from exposures to chemicals. The Complex
Systems Science research topic is designed to ad-
dress this challenge.
Science Challenge: Decision makers need dem-
onstrated solutions to translate new informa-
tion into action. CSS promotes Web-based tools,
data, and applications to support chemical
safety evaluations and related decisions. CSS en-
gages EPA partners and stakeholders to ground
truth the transparency, access, relevance, and
applicability of our research. The Translation and
Knowledge Delivery topic is designed to address
this challenge.
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Table 3. Summary of near and longer term aims of CSS research objectives.
CSS Research Objectives
Objective
Build
Knowledge
Infrastructure
Develop Tools
for Chemical
Evaluation
Promote
Complex
Systems
Understanding
Translate
and Actively
Deliver
What We Do
Make information
publicly accessible.
Combine different
types of data in new
ways to characterize
impacts of chemicals to
human health and the
environment.
Develop and apply
rapid, efficient, and
effective chemical
safety evaluation
methods.
Investigate emergent
properties in complex
chemical-biological
systems by probing
how disturbances and
changes in one part
affect the others and
the system as a whole.
Demonstrate
application of CSS
science and tools
to anticipate,
minimize, and solve
environmental health
problems.
Near-Term Aim
Provide accessible
information to support
scientific discovery and
sustainable decisions.
Improve chemical
prioritization, screening,
and testing.
Improve understanding
of the relationship
between chemical
exposures and
ecological and human
health outcomes
including to the
developing organism.
Develop solution-
based approaches for
evaluating impacts of
high priority chemicals
in support of innovative
and sustainable
decisions.
Long-Term Aim
Generate chemical,
biological and
toxicological
information to advance
understanding of
relationships between
chemical characteristics
and potential impacts of
use.
Revolutionize chemical
assessment for potential
risks to humans and the
environment.
Predict adverse
outcomes resulting from
exposures to specific
chemicals and mixtures
over time and space.
Apply CSS tools to predict
impacts of emerging
materials, products, and
new uses.
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Research Topics
Working with program and regional partners
to define the scope of the science that will be
conducted in the CSS research project areas,
CSS used the following specific criteria:
Specific criteria:
The need is critical, and if CSS does not lead
and conduct this research, the science will
not be developed by others to address EPA
needs. To illustrate, new methods to estimate
human and ecological exposures tothousands
of chemicals more quickly and efficiently was
considered a high priority topicfor CSS. On the
other hand, additional research to elucidate
mechanisms of carcinogenicity (currently led
by NIH), was ranked a lower priority - unless
used as a specific case study in quantitative
development of Adverse Outcome Pathways.
Research activities contribute broad scientific
impact through focus on partner solutions.
Development of new methods to assess the
behavior of methodologically challenging
compounds (MCC) such as perfluorinated
compounds met an urgent EPA need, but also
provided a foundation for future research
on persistence and bioaccumulation of such
compounds and in selection of safer alterna-
tives.
The research approach is innovative and
applies emerging science and technology to
advance CSS objectives. A recent example is
integration of high-throughput bioactivity
data from ToxCast with high-throughput
exposure estimations from ExpoCast for risk-
based prioritization of endocrine disrupting
chemicals.
Research addresses CSS partners' highest
research and science priorities. For example,
the integrated bioactivity-exposure (risk-
based) prioritization described above was tai-
lored for use by the EDSP in application to es-
trogen receptor mediated pathways (http://
www.epa.gov/endo/pubs/pivot.htm).
Research activities are framed to demon-
strate value added of information, tools, and
approaches being developed to support EPA
decisions.
All data and tools are developed, evaluated,
and translated through application to case
examples of interest to partners. Case studies
with direct partner engagement or dedicated
partner advocate are prioritized.
Results are transparent and accessible. All
data and tools are accessible to EPA partners
upon delivery of product and are supported
by appropriate QA, documentation and peer
reviewed publication(s). Synergies are iden-
tified and leveraged among research topics
and project areas.
CSS resources are leveraged through integra-
tion across the program and through strategic
collaborations with other EPA programs, federal
agencies, public and private stakeholders and
the global scientific community.
In addition, to facilitate the transformation
required to meet CSS vision, address the
science challenges, and provide the strategic
thrust for Goal 4 in EPA's Strategic Plan, three
guiding principles have been applied in shaping
this StRAP.
Adopt the AOP framework
Adverse outcome pathways (AOPs) are a
conceptual framework intended to enhance
the utility of pathway-based data for use in
risk-based regulatory decision support. An
AOP portrays existing knowledge of linkage
-------
between a direct molecular initiating event and
an adverse outcome at a biological level of or-
ganization relevant to risk assessment (i.e., ac-
tionable). When developed and evaluated in a
rigorous manner, AOPs provide a scientifically-
defensible foundation for extrapolating from
mechanistic data to predicted apical outcomes.
Additionally, as individual AOPs are developed,
they can be assembled into AOP networks that
may aid the prediction of more complex inter-
actions and outcomes resulting from exposure
to complex mixtures and/or chemicals with
multiple modes of action. By considering AOPs
and AOP networks associated with important
developmental processes, as well as those as-
sociated with disease endpoints of concern,
mechanistic toxicology information and epi-
demiology insights can be brought together
for model development and analysis of critical
knowledge gaps.
Exploit complex systems modeling to advance
mechanistic understanding
A major challenge is to translate AOP frame-
works across scales of biological organization
(molecules, cells, tissues, populations) and
function, while incorporating critical windows
of exposure, dose, toxicodynamics, and toxico-
kinetics. Multiscale modeling and simulation is
a powerful approach for capturing and analyz-
ing biological information that is inaccessible
or unrealizable from traditional modeling and
experimental techniques. For example, virtual
tissue models (VTMs) afford the opportunity to
develop science without conducting studies in
children. By simulating a range of predicted ef-
fects, the earliest signs of adversity, or tipping
points, can be identified, and new testable hy-
potheses aimed at improving the accuracy of
inferences from in vitro data can be developed.
These same modeling approaches can be ap-
plied to capture the complexity of wildlife in-
teractions with the environment as well as to
postulate key environmental determinants of
population health.
Promote a life-cycle perspective
A life-cycle perspective is required to evaluate
the safety of chemicals and materials in the
context of how these are designed and used in
society. To evaluate alternatives and options,
risk (hazard and potential for human exposure
and toxicity) and environmental impact (eco-
logical risks) are characterized for chemicals
and materials within the context of the full
range of benefits and consequences. Tradeoffs
between these risks and factors, such as prod-
uct functionality, product efficacy, process safe-
ty, and resource requirements, are considered.
The intent is to promote a knowledge-driven
approach that integrates multiple and diverse
data streams for decision making based on spe-
cific context and priorities. However, regardless
of this context, sustainable decisions require
consequences of use over a chemical's life cycle
(from production to disposal) be evaluated.
These criteria and guiding principles helped to
quickly focus the scope of the program on re-
search topics and project areas that promise to
have transformative impact within and outside
the CSS research program, and that inherently
lend themselves to an integrated and collabora-
tive research construct. CSS FY16-19 research is
organized by four Research Topics and imple-
mented by transdisciplinary teams of scientists
working within and across these topics.
CSS research is often conducted in collaboration
with program and regional partners through
specific case studies that provide the
opportunity to evaluate real-world applicability
of its research. In addition, the leading edge of
CSS science is driven through transformative
research conducted in academia through
EPA's Science to Achieve Results (STAR) grants
program. Within each topic, collaborations
developed with the academic researchers
further enable CSS to benefit from and integrate
the emerging science, methods, and tools.
It also provides an opportunity for academic
-------
researchers to learn about and contribute to
research relevant to the science challenges
that underpin CSS topics. In addition, several
research efforts in CSS germinated through
awards in the Pathfinder Innovation Projects
(PIP) program, which provides ORD scientists
the opportunity to stretch beyond their
existing research and experiment with creative
ideas that have the potential to transform
environmental protection and sustainability.
In CSS, these projects are shepherded through
their nascent stages, and when ready and
applicable, the research or results are applied to
or integrated programmatically into CSS. Some
of these synergies are provided as examples in
describing the CSS topics below.
Three research topics provide core systems
science and tools:
1. Chemical Evaluation
Advance cutting-edge methods and provide
data for risk-based evaluation of existing
chemicals and emerging materials.
2. Life Cycle Analytics
Address critical gaps and weaknesses in
accessible tools and metrics for quantifying
risks to human and ecological health across
the life cycle of manufactured chemicals,
materials, and products. Advance methods to
efficiently evaluate alternatives and support
more sustainable chemical design and use.
3. Complex Systems Science
Adopt a systems-based approach to examine
complex chemical - biological interactions
and predict potential for adverse outcomes
resulting from exposures to chemicals.
A fourth research topic focuses on translation
and active delivery of CSS research products,
demonstration and application of CSS scientific
tools, and knowledge delivery to EPA Partners:
4. Solutions-based Translation and
Knowledge Delivery
(1) Promote Web-based tools, data, and
applications focused on tailored solutions
to support chemical safety evaluations and
related decisions; (2) Respond to short-term
high priority science needs for CSS partners;
and (3) Allow for active and strategic
engagement of the stakeholder community.
CSS project areas associated with each of
these four topics are described below. The
CSS program structure in Figure 1 depicts the
dynamic and interdependent relationship
between the topics and project areas, and
among the research and translational topics.
Integrated research will also be required
across these topics and projects to effectively
address scientific gaps and provide tools to
enable EPA decisions. EPA priorities for specific
classes of chemicals, human and ecological
health endpoints, and vulnerable species
and lifestages will be used to focus case
studies, design specific research activities,
and further focus this integration. The priority
areas for FY16-19 include: (1) Emerging and
methodologically challenging compounds;
(2) Endocrine disruption (including thyroid);
and (3) Children's environmental health.
Importantly, signature CSS research in
computational toxicology will exploit new and
emerging scientific tools in molecular biology,
computational chemistry, and informatics to
transform chemical safety evaluation. Table 4
summarizes the scientific challenges addressed
by the project areas, the interim outputs they
provide that feed into the larger programmatic
outputs, as well as the measures of success for
these projects.
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Figure 1. CSS Research Topics and Projects.
Topic 1: Chemical Evaluation
The Chemical Evaluation topic will provide cost-
efficient methods and high-throughput data for
rapid risk-based evaluation of existing chemicals
and emerging materials. One research project
area focuses on hazard profiling and a second
on exposure forecasting.
Research Project Area: High-Throughput
Toxicology
Research in the High-Throughput Toxicology
(HTT) project area is driven by limitations of
current chemical testing methods and EPA
needs to evaluate large sets of chemicals
for potential adverse human and ecological
health effects. Rapid and efficient methods
are required by EPA to prioritize, screen, and
evaluate chemical safety for thousands of
compounds. The ToxCast research program was
initiated to generate data and predictive models
on a large number of chemicals of interest to
EPA using high-throughput screening methods
and computational toxicology approaches to
rank and prioritize chemicals. The focus of this
project area will be to provide the foundation
and contextually relevant tools for extending
utility of the HTT strategy to benefit regulatory
decisions ranging from chemical prioritization
to applications for more in-depth risk decision
paradigms.
To provide contextual or fit-for-purpose valida-
tion of the HTT testing strategy, guidance and
-------
performance criteria for assay validation will be
developed covering appropriate biological do-
mains, technical description and assessments,
interpretation of results, and linkages to high-
er level biological complexity. To broaden the
screening approach and fill gaps in coverage of
toxicity pathways, there will be collaboration
with the Adverse Outcome Pathway project to
identify and develop assays for key molecular
initiating events for incorporation into the test-
ing program. Data will be generated for key as-
says and used to generate predictive models
covering critical toxicity endpoints. Resources
will be devoted to evaluating cutting-edge
methods to incorporate and account for xeno-
biotic metabolism in to the high-throughput
testing strategy using a case study approach.
Methods will also be evaluated for generating
high-throughput screening data on challeng-
ing classes of chemicals such as volatiles. The
project will build toward a broader and more ef-
ficient high-throughput testing strategy, includ-
ing the use of global assays capable of extensive
biological activity recognition. Such assays may
serve to prioritize chemicals for more detailed
in vitro or short term in vivo testing, possibly
directing the type of testing required.
Examples of research activities in this project
area include support to interpret ToxCast
data and development of new assays to cover
priority endpoints:
The ToxCast program has used a series of
high-throughput assays on a large number
of chemicals to rapidly generate toxicity
data. Using this data for regulatory purpos-
es requires the ability to interpret technical
quality of the data, as well as understand
the relationship of these high-throughput
assays to biological outcomes. A guideline
document will be produced by this proj-
ect, providing standardized descriptors and
methods for interpreting data based upon
level of biological complexity. This guideline
document will enable evaluation and inter-
pretation of high-throughput ToxCast data in
several decision contexts.
Thyroperoxidase (TPO) catalyzes a critical
step in the synthesis of thyroid hormones and
inhibition of TPO by environmental chemicals
leads to severe and irreversible impacts on
brain development. In this project, a novel
high-throughput screening assay for TPO
inhibition is being developed, validated with
21 well-characterized chemicals, and used
to screen the ToxCast Phase I and II chemical
libraries (1074 chemicals).
Research in the High-Throughput Toxicology
project area will provide rapid and efficient tox-
icity testing paradigms and data on chemicals
and endpoints of interest to the EPA as well as
the tools to understand the significance of the
results.
Research Project Area: Rapid Exposure and
Dosimetry
As data from high-throughput screening
methods become available, this new toxicity
information must be translated to assess
potential risks to human and ecological health
from environmental exposures. In concert with
the toxicity information, estimates of human
and ecological exposures are required as critical
input to risk-based prioritization and screening
of chemicals. The ExpoCast effort was initiated
to ensure that the required exposure science
and computational tools
are developed and ready
to address global needs for
rapid characterization of
exposure potential arising
from the manufacture
and use of thousands of
chemicals and to support
use of emerging toxicity
data for risk-based chemical
RESEARCH HIGHLIGHT
ExpoCast includes
science and
computational tools for
rapid characterization
of exposure potential
arising from the
manufacture and use of
thousands of chemicals.
-------
evaluation. The focus of the Rapid Exposure
and Dosimetry project area will be to develop
the data, tools, and evaluation approaches
required to generate rapid and scientifically
defensible exposure and estimates for the full
universe of existing and proposed commercial
chemicals.
Tools applied in this project area will include
innovative data mining approaches, advanced
computational models, and higher throughput
analytical methods. The scope of this project
will include development, evaluation, and ul-
timately application of high-throughput com-
putational exposure prediction methods to
support regulatory, industry, community, and
individual decisions that protect human health
and the environment. Research in this project
area will also generate and analyze in vitro data
on key determinants of human pharmacokinet-
ics and develop population-based models for
using these data to compare human exposures
and hazards. Consideration will be given to
identifying chemical classes and aspects of hu-
man variability not currently well-characterized
by rapid methods including: biological variabil-
ity (e.g., genetic polymorphisms); behavioral
variability (e.g., consumer use) that lead to dif-
ferences for key demographics; and life stage
variability (e.g., children).
Research in the Rapid Exposure and Dosim-
etry project area will provide high-throughput
pharmacokinetic and exposure data and mod-
els for risk-based prioritization to address case
examples of interest to EPA program office
partners. The chemical exposures and poten-
tially hazardous doses predicted by this project
will ultimately be applied in the Demonstration
and Evaluation project for application of new
data streams and rapid assessment approaches
to support EPA chemical safety assessments.
Results will advance computational exposure
science required to transform chemical evalu-
ation.
New Methods in 21st Century Exposure Science
To complement intramural research under the
Chemical Evaluation Topic, CSS has funded
five universities through the EPA STAR grants
program to conduct innovative research to
advance methods for characterizing real-world
human exposure to chemicals associated with
consumer products in indoor environments.
One of the cross cutting activities among these
grantees was their interest in applications
of non-targeted analyses, based on high-
resolution mass spectrometry platforms, to
screen for xenobiotic chemicals in a variety of
environmental and biological media.
RESEARCH HIGHLIGHT
EPA STAR grants are advancing
methods for characterizing
real-world, indoor exposures to
chemicals in consumer products.
Topic 2: Life Cycle Analytics
Research in the Life Cycle Analytics Topic is
exploring and advancing new ways to evaluate
risks to human and ecological health across
the life cycle of manufactured chemicals,
materials and products. Under four integrated
CSS research projects, methods are being
developed and demonstrated to efficiently
evaluate alternatives and support more
sustainable chemical design and use.
Research Project Area: Sustainable Chemistry
Strategies are required to apply information
on inherent chemical properties to predict
potential for transformation and activity of
compounds in biological and environmental
systems. The intersection of recent advances in
high-throughput screening (HTS), mechanistic
-------
toxicology, computational chemistry and
cheminformatics provide the foundation to
identify influential chemical determinants of
adverse biological impacts of chemicals and
materials. The Sustainable Chemistry project
area will take advantage of these advances to
improve understanding
of chemical features as-
sociated with potential
for environmental and
human health impacts.
RESEARCH
HIGHLIGHT
Improved
understanding
of chemical
features in
biological and
environmental
systems informs
design and
evaluation of
safer chemical
alternative*
In this project area,
knowledge of inherent
chemical properties and
features will be explored
to distill principles for
chemical classes that
capture the full range of
chemistries represented
in commerce. For the set of compounds rep-
resented in the ToxCast library, knowledge of
chemical features will be applied to inform in-
terpretation of high-throughput toxicity (HIT)
data and models. At the same time the HIT
data and models will be used to elucidate key
features associated with potential for hazard.
For select sets of high interest chemicals, mech-
anistic-based case studies will be conducted to
link upstream chemistry with downstream bi-
ology incorporating considerations of transfor-
mations in real-world biological and environ-
mental systems. This core research will further
establish common chemistry principles linking
inherent chemical structural features and prop-
erties to potential for toxicity, environmental
persistence, and transformations in environ-
mental and biological systems.
Examples of research activities in this project
area include development and application of
computational chemistry / cheminformatics
tools to better inform safety and exposure as-
sessments of organic chemicals. Software tools
such as the Chemical Transformation Simula-
tor (CTS) are being developed and evaluated
through case studies focused on screening car-
bamate and organophosphorus pesticides as
well as high interest flame retardants for toxic-
ity, persistence, bioaccumulation and transfor-
mation potential.
The Sustainable Chemistry project area will
provide a chemical knowledge resource that
consolidates basic chemical data, along with
cheminformatics and computational chemistry
tools for shared use, and will empower more
effective, integrated evaluation of chemicals.
Improved understanding of chemical features
associated with fate and activity in biological
and environmental systems will inform design
and evaluation of safer chemical alternatives
and support sustainable decisions.
Research Project Area: Emerging Materials
Innovations in chemical and material design
are rapidly changing the landscape of indus-
trial and consumer products as novel ma-
terials, such as engineered nanomaterials
(ENMs), are incorporated to enhance their
performance. Scientifically supported ap-
proaches are required to efficiently screen for
and evaluate potential impacts of ENMs to hu-
man health and the environment. The Emerg-
ing Materials project area will conduct applied
research to develop, collate, mine, and apply
information on ENMs to support risk-based
decisions on sustainable manufacture and use.
RESEARCH HIGHLIGHT
Through case examples of
engineered nanomaterials (indue
silver nanoparticles and carbo
nanotubes), researchers identify
information required to charade
potential for exposure and haza
arms?; the life cycle of the prorli
-------
In this project area, a life-cycle perspective is
applied and available information synthesized
to consider potential for impacts associated
with manufacture, use, and disposal of prod-
ucts containing ENM. Through a set of case ex-
amples focused on priority and data-rich mate-
rial classes (including silver nanoparticles and
carbon nanotubes), extant information will be
mined to identify key information required to
characterize material form, potential for expo-
sure, and hazard across the product life cycle
for data-poor materials. To address these key
gaps, a library of core nanomaterials, including
systematically aged materials, will be consid-
ered. Interactions between ENMs and biologi-
cal or other complex media will be explored.
And, the complexity of relating nanomaterial
features directly to risk will be addressed by
considering critical intermediate properties of
ENMs that are predictive of potential impacts,
and identifying associated functional assays.
Results of the Emerging Materials project area
will provide the methods and tools to enable
EPA to efficiently evaluate emission, transfor-
mation, potential exposure, and impacts of
ENMs across the material/product life cycle.
The long term impact will be to accelerate the
pace at which the safety of existing nanomate-
rials is assessed and to inform the sustainable
design and development of emerging materials
and products.
Research Project Area: Life Cycle and Human
Exposure Modeling
Evaluation of alternatives for sustainable deci-
sions requires understanding the broad range of
impacts to human health and the environment
associated with a chemical or product through-
out the life cycle. Efficient tools are required to
consider, among the broad range of impacts,
the potential for exposures to human and eco-
logical species across the chemical life cycle
where limited data are available. This project
area will take the novel approach of integrating
chemical exposure and life cycle knowledge to
model and assess human health and ecological
impacts of alternatives. Approaches will be de-
veloped to efficiently evaluate environmental
and human health impacts and metrics iden-
tified to quantify tradeoffs between risks and
other sustainability factors.
RESEARCH HIGHLIGHT
By integrating chemical
exposure and life cycle
approaches, researchers will
model and assess the human
health and ecological impacts
of substituting alternative
chemicals or processes.
By bringing together two of ORD's leading disci-
plines in exposure science and life cycle assess-
ments, this project is transforming how scien-
tists in the broader community are attacking
these same challenges. Research in this area
will be focused on operationalizing sustainabil-
ity analysis for chemical safety evaluation by
leveraging and extending methods in life-cycle
assessment (LCA) and exposure modeling to in-
corporate metrics of human and ecological risk.
An approach will be developed that harmoniz-
es the product-centric nature of LCA with the
chemical-centric focus of comparative risk anal-
ysis by considering chemical function. The two
primary objectives of the CSS Life Cycle Assess-
ment and Human Exposure Modeling project
are to: (1) develop a framework and database
structure that brings together chemical expo-
sure and life cycle modeling; and, (2) develop
a tool for evaluating chemical/product impacts
in a life cycle assessment framework to support
decision making through improved risk and sus-
tainability analysis.
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Through application to a select set of case ex-
amples of interest to EPA program partners (in-
cluding building materials/semi-volatile organic
compounds), this project area will provide ef-
ficient tools and metrics to evaluate chemical
impacts across the life cycle and to support al-
ternatives assessment and sustainable chemi-
cal use.
Research Project Area: Ecological Modeling
EPA's process for registering and regulating
chemical compounds includes a tiered eco-
logical risk assessment (ERA). Within the ERA
process, chemicals are first screened using
rapid assessment tools that require minimal
data and provide conservative estimates of
ecological risk. Chemicals determined to pres-
ent an appreciable risk are subject to higher-
level assessments that provide quantitative es-
timates of ecologically-relevant risk and identify
risk mitigation options. For the vast majority of
chemicals and species, little or no data exist
and refined assessments must rely on modeled
estimates of exposure and effects. The Eco-
logical Modeling project area will advance ef-
ficient methods to improve risk assessments
with limited data availability, as well as more
complex approaches that can target data-rich
applications.
Research in this project area will integrate
existing and novel models into an ecosystem-
based framework that combines the fate and
transport of chemicals in the environment with
RESEARCH HIGHLIGHT
To predict effects of pesticides on
endangered aquatic species and wildlife
populations, researchers are developing,
integrating and evaluating ecological models
into an efficient decision framework.
improved toxicity interpretation for ecological
endpoints based on surrogate species. For
assessments which rely on minimal data (e.g.,
endangered species), this project will develop
and evaluate approaches to maximize the
use of available information and demonstrate
their usefulness in increasing ERA efficiencies,
identifying and reducing critical uncertainties,
and identifying critical information that would
improve decisions. This will be accomplished
through proof-of-concept studies that apply
advanced molecular, modeling, and landscape
analysis methodologies to verify model
predictions. For higher tier assessments,
including those that characterize spatially
varying chemical impacts and impacts to
threatened and endangered species, this
project will advance the science that will allow
EPA to describe chemical impacts in ecologically
relevant terms that align with sustainable
ecosystem services endpoints.
Research in this project area will focus on
developing and evaluating ecological models
for endangered aquatic species and wildlife
populations exposed to pesticides. A population
modeling framework for predicting chemical
effects to avian species will integrate three
models currently used extensively to assess
ERA: (1) TIM (Terrestrials Investigation Model);
2) MCnest (Markov Chain Nest Productivity
Model); and (3) HexSim (Spatially explicit
individual based model).
The Ecological Modeling project area will
provide demonstrated efficient ERA tools
that reduce uncertainty for high-priority and
methodologically challenging chemicals. The
resulting decision framework for using models
of various complexities, data requirements, and
levels of ecological realism for differing ERA
requirements or fit-for-purpose will enhance
EPA capacity to protect sensitive ecosystems
and species.
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Within the Life Cycle Analytics Topic, CSS has
funded complementary extramural research
to advance the scientific understanding of po-
tential for chemical impacts across the life cycle
and to foster innovation of safer alternatives,
including the following:
EPA/NSF Networks for Sustainable
Molecular Design and Synthesis
Investigating the sustainable molecular
design of chemical alternatives to determine
traits of chemicals that indicate they are
functional for their intended purpose and
have the least impact on human health and
the environment.
EPA/NSF Networks for Characterizing
Chemical Life Cycle
Investigating ways to characterize
and predict environmental and health
implications of chemicals by following
chemicals through their life cycle from
design, manufacture, use and disposal.
EPA/NSF Centers for the Environmental
Implications of Nanotechnology
Elucidating the relationship between
nanomaterials and potential for
environmental exposures, biological effects,
and ecological consequences. In addition,
these grants have germinated a community-
based effort to develop higher throughput
approaches to predict toxicological effects
associated with those exposures.
Systems-Based Research for Evaluating
Ecological Impacts of Manufactured
Chemicals
EPA STAR grants provide integrated,
transdisciplinary research to advance scientific
understanding of the impacts of manufactured
chemicals on ecosystem health. The studies
require use of systems-based research to
develop innovative metrics and modeling
approaches that support evaluation of
ecological resilience and inform sustainable
risk-based decisions. An important dimension is
to translate emerging and advanced methods,
data, and computational tools to address
complexity of these systems and distill drivers
of adverse outcomes to ecological organisms
and populations.
Topic 3: Complex Systems Science
Research conducted in the Complex Systems
Science topic is focused on building the scien-
tific foundation to predict adverse outcomes
resulting from exposures to specific chemicals
and mixtures over time and space. The Adverse
Outcome and Virtual Tissues project areas are
highly complementary. These projects are also
very integrated with the projects in the Chemi-
cal Evaluation topic.
Research Project Area: Adverse Outcome
Pathway (AOP) Discovery and Development
To use new data being generated in the CSS
Chemical Evaluation Topic for EPA decisions,
there is a need to evaluate the human health
and/or ecological relevance of effects observed
in in vitro or in vivo models. Both qualitative
and quantitative linkages between measures
of biological perturbation provided by new
and emerging methods and metrics of adverse
outcome relevant to EPA risk-based decisions
are required.
The AOP framework provides a systematic and
modular structure for organizing and commu-
nicating existing knowledge concerning the
linkage between molecular initiating events,
intermediate key events along a toxicity path-
way, and apical adverse outcomes traditionally
considered relevant to risk assessment and/
or regulatory decision making (i.e., actionable
outcomes). When developed and evaluated in
a rigorous manner, AOPs provide a scientifically
defensible foundation for extrapolating from
mechanistic data to predicted apical outcomes.
Additionally, as individual AOPs are developed,
they can be assembled into AOP networks by
evaluating shared nodes or key events in indi-
vidual pathways. These networks may aid the
prediction of more complex interactions and
outcomes resulting from exposure to com-
plex mixtures and/or chemicals with multiple
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modes of action. AOP networks also afford the
opportunity to integrate and evaluate the po-
tential for impacts associated with nonchemical
stressors, in addition to chemical stressors. By
considering AOPs and AOP networks associated
with important developmental processes, as
well as those associated with disease endpoints
of concern, there is the potential to bring to-
gether mechanistic toxicology information and
epidemiology insights for model development
and analysis of critical knowledge gaps.
RESEARCH HIGHLIGHT
The AOP Discovery and Development
team is developing innovative
approaches for applying pathway-based
bioactivity data, in the context of adverse
outcome pathways, to predict biological
hazard(s) associated with exposure to
complex chemical mixtures.
The AOP Discovery and Development (AOPDD)
project area focuses on research that advances
predictive applications of the AOP framework
and supports the use of alternative data, i.e.,
other than direct measures of apical toxicity
outcomes, as a credible basis for risk-based de-
cision making concerning potential impacts of
chemicals on ecological and human health.
For example, to support the application of the
high-throughput toxicology and the adverse
outcome pathway framework as a basis for de-
cision making, bioactivity measures and haz-
ard predictions must be complemented with
understanding of chemical-specific proper-
ties that dictate external exposure and tissue-
specific dose. The AOPDD project team has
conducted case studies focused on acetylcho-
linesterase inhibitors and thyroid peroxidase
inhibitors to demonstrate the use of a novel
strategy and workflow for incorporating these
considerations.
The AOPDD project team is also developing
innovative approaches for applying pathway-
based bioactivity data, in the context of adverse
outcome pathways, to predict integrated bio-
logical hazards which may be associated with
exposure to complex mixtures of chemicals
present in the environment. Approaches have
been demonstrated through case studies either
using high-throughput in vitro bioassays for the
direct testing of surface water extracts, or by
mapping chemical concentrations detected in
surface waters to sources of chemical-specific
bioactivity data.
The research will provide a critical scientific
foundation for 21st century approaches to tox-
icity testing which seek to make increased use
of lower cost, higher throughput and/or higher
content, in vitro, in silico, and/or short-term in
vivo testing for single chemical hazard assess-
ment. It also provides the scientific framework
to assess the human/ecological relevance of
pathway-based effects across different model
systems and address the challenges posed by
exposure to multiple stressors in the environ-
ment.
Research Project Area: Virtual Tissue Models
Innovation in methods to predict consequences
of decisions requires application of ever-ad-
vancing and emerging science. A major chal-
lenge is to translate AOP frameworks across
scales of biological organization (molecules,
cells, tissues, populations) and function, while
incorporating critical windows of exposure,
dose, pharmacodynamics, and pharmacokinet-
ics. Complex models of prototype biological
systems are needed that can be probed (experi-
mental) and simulated (computational) analyti-
cally to integrate knowledge and identify gaps
in knowledge. Multiscale modeling and simula-
tion is a powerful approach for capturing and
analyzing biological information that is inacces-
sible or unrealizable from traditional modeling
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and experimental techniques. For example,
virtual tissue models (VTMs) afford the oppor-
tunity to develop science without conducting
studies in children. By simulating a range of pre-
dicted effects, the earliest signs of adversity, or
tipping points, can be identified, along with new
testable hypotheses aimed at improving the ac-
curacy of inferences from in vitro data. In the
Virtual Tissue Model project area, knowledge-
based models of tissues and organ functions
that integrate dynamics of cellular function into
biological networks governing system behavior
are developed and applied to assess informa-
tive case examples of developmental toxicity.
RESEARCH HIGHLIGHT
EPA STAR research centers are
developing organotypic cell models
for high-priority biological systems
such as the brain, liver, heart and
kidney to accelerate research on
the interactions of chemicals with
key biological processes.
VTMs are uniquely positioned to capture the
connectivity between different scales of bio-
logical organization and predict key events in
an Adverse Outcome Pathway (AOP). The VTM
approach is transformative for ORD as a new
way to integrate in vitro and in vivo data into in
silico models that can be used to unravel bio-
logical complexity and predict performance of
a complex biological system with respect to:
(a) homeostasis and systems failure (e.g., adap-
tive versus adverse responses); (b) integrat-
ing kinetics-dynamics (e.g., modeling different
exposure scenarios); (c) exploring combina-
tions of adverse circumstances that converge
onto sensitive pathways and processes (e.g.,
mixed modes-of-action, cumulative or aggre-
gate exposure, cross-species comparison); and
(d) addressing lifestage considerations (e.g.,
Children's Environmental Health Roadmap).
The VTM project area will focus on prenatal
developmental toxicity and early postnatal de-
velopmental toxicity; however, the concepts
and principles for multiscale modeling will be
extensible across lifestages and ecological pop-
ulations.
Research in the VTM project area will provide
improved quantitative understanding of the
molecular pathways and cellular processes
underlying AOPs in building an integrated pre-
dictive system. Focused examples considered
in the Virtual Tissues Modeling project area
will provide improved understanding of the
relationship between chemical exposures and
ecological and human health outcomes, includ-
ing impact on the thyroid system and on the
developing organism. Ultimately, the vision for
2020 is a platform of experimental and compu-
tational models that capture system dynamics
for predictive toxicology.
Through the EPA STAR grants program, CSS has
also funded complementary extramural re-
search under the complex system science topic
to advance scientific understanding and devel-
opment of methods to enhance capacity for
predictive toxicology, including the following:
Development and Use of Adverse Outcome
Pathways that Predict Adverse Developmental
Neurotoxicity
Four grants are awarded to develop adverse
outcome pathways that map how chemicals
interact with biological processes and how
these interactions may lead to developmen-
tal neurotoxicity. The studies are focused on
improving EPA's ability to predict the potential
health effects of chemical exposures.
Organotypic Culture Models for Predictive
Toxicology Center
Center grants are awarded to develop
Organotypic Cell Models for high-priority bio-
logical systems such as the brain, liver, kidney,
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testis, breast tissue, heart and neurovascular,
and evaluate them as testing platforms for
research into the interactions of chemicals
with key biological processes. This research
will provide new biological insight as to how
tissues and organs function during chemi-
cal exposures. The data will then be used to
develop advanced computational models of
how organs and tissues respond to chemicals,
and use them ultimately to validate predic-
tive models of human disease or response.
Susceptibility and Variability in Human
Response to Chemical Exposure
The long-term objective of this grant is to
uncover the mechanistic linkages between
the genome (e.g., variation in DNA sequence
among individuals), metabolism (e.g., forma-
tion of organ-specific toxic intermediates), and
adverse molecular events (e.g., transcriptional
changes associated with toxicity) for high in-
terest chemicals.
Topic 4: Solutions-Based
Translation and Knowledge Delivery
Research Project Area: Demonstration and
Evaluation for Risk-Based Decisions
Work conducted in CSS is generating numer-
ous new approaches and data streams that
are intended to benefit environmental deci-
sion making by reducing time, cost and/or the
uncertainty of decisions. The purpose of this
research is to further aid translation of these
approaches by evaluating, establishing, and
demonstrating their effectiveness to EPA part-
ners and stakeholders. This project will: (1) de-
velop qualitative and quantitative approaches
to integrate these new types of information
with existing methods and information to sup-
port science-based decisions, and (2) evaluate
the value added of new data streams, particu-
larly HTP data (experimental and computation-
al), in terms of efficiency, as well as their ability
to reduce uncertainty in the risk assessment
process. This research will produce an objective
framework to systematically evaluate the inte-
gration of these new testing and computational
methods, and provide measures of confidence
and uncertainty to determine "fit-for-purpose"
for different EPA actions. The impacts will be
that risk assessors will have confidence that
the new approaches, data, and tools developed
in CSS are scientifically sound and provide val-
ue added to environmental decision making.
Other research ongo-
ing in CSS will ben-
efit from the lessons
learned from this proj-
ect, as this information
will help establish fu-
ture research priorities
within CSS.
RESEARCH
HIGHLIGHT
EPA's Office of
Chemical Safety and
Pollution Prevention
is collaborating
with ORD, using
high-throughput
toxicity and exposure
data, to develop
approaches for
screening and
prioritizing endocrine
disrupting chemicals
for more advanced
testing.
For example, the
EDSP21 program led
by EPA's Office Chemi-
cal Safety and Polllution
Prevention (OCSPP)
is collaborating with
ORD to use its high-
throughput toxicity
and exposure data to develop integrated ap-
proaches for screening and prioritizing endo-
crine disrupting chemicals for further testing.
These proposed approaches are being evalu-
ated by their Science Advisory Panels (SAP) for
adoption into the program. The expectation is
that over time, as approaches are developed
and "validated" for these applications, their use
may be expanded to address the broader uni-
verse of chemicals, including chemicals covered
by TSCA.
A second example comes out of strategic in-
tegration between the CSS and HHRA national
research programs. There are over 80,000
legacy or current chemicals listed in the TSCA
inventory; less than 2000 of these have health
assessments available across federal and state
-------
agencies. Multiple EPA programs and regional
offices are tasked with making decisions, in a
risk management context, for chemicals with
inadequate or non-existent hazard databases.
In this example project, CSS would generate
data needed for HHRAto develop innovative fit-
for-purpose assessment products (such as high-
throughput toxicity values or rapid tox).
Research Project Area: Partner-Driven
Research
Research conducted in this area will be
motivated by CSS partners' high-priority, short-
term needs that are not otherwise anticipated
or addressed in the StRAP. The project will be
defined by the NPD in collaboration with the
partner(s) and in consultation with ORD lab/
center leadership. Projects within this theme
will have deliverables tailored to the needs of
the partners, but the research from this project
will be otherwise amplifiable and relevant to
other efforts in CSS. While the lifespan of a
typical project is not expected to exceed 18
months, the effort may give rise to a longer-
term research project in CSS through future
planning cycles.
For example, the EDSP21 collaboration with OC-
SPP first began as a partner-driven effort with
a narrow focus on the estrogen pathway and a
limited number of high-throughput assays. The
success of that collaboration, peer reviewed by
an SAP and in a variety of peer reviewed jour-
nals, led to its development into a full CSS proj-
ect (described above).
Additionally, in several cases CSS research is
developed through engagement of and col-
laboration with regional partners. This provides
an opportunity to provide near-term support
to address regional needs and also to evaluate
the relevance and applicability of some CSS re-
search in "real-world" contexts. For example,
in the Adverse Outcome Pathway Discovery
and Development project area, collaborations
developed with Region 5 and other federal
partners under the Great Lakes Restoration Ini-
tiative and the Great Lakes National Program
Office have resulted in a biological effects sur-
veillance program. CSS is providing critical sup-
port to the development of this program which
is necessary to evaluate the impacts of chemi-
cals of emerging concern on Great Lakes fish
and wildlife. This project presents a significant
opportunity for EPA Office of Water to pursue
the applicability of effect-based biomonitoring
for evaluating the pollutant burden. Research
in this area is being conducted collaboratively
with scientists in SSWR conducting similar re-
search in other regional offices.
RESEARCH HIGHLIGHT
Collaborations with EPA Region 5 and
other federal partners have resulted in a
biological effects surveillance program
to evaluate the impacts of chemicals of
emerging concern on Great Lakes fish
and wildlife.
Research Project Area: Stakeholder
Engagement and Outreach
This effort will encompass strategic outreach
and engagement of CSS's broad stakeholder
community who will serve as a "sounding
board" and help ground truth the transparency,
access, relevance, and applicability of CSS re-
search. Stakeholders will be engaged through
public workshops, tailored webinars and train-
ing events, national scientific meetings, stra-
tegic collaborations, funded challenges, and
other outreach activities. This effort has been
shaped by two large stakeholder engagement
workshops held in 2014 and led by the NPD
team, in collaboration with project scientific
leads and partners.
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Table 4. CSS Research Topics: Project Areas, Challenges Addressed, Intermediate Outputs,
and Measures of Success
Project Areas | Challenges Addressed | Intermediate Outputs
Measures of Success
Topic 1: Chemical Evaluation
High-
Throughput
Toxicology
Expand coverage in
HTP toxicity screening
schemes for high priority
biological areas such as
endocrine disruption and
adverse outcomes such as
developmental toxicity.
Incorporate xenobiotic
metabolism into HTP test
methods.
Guidance for evaluating
technical performance
and biological domain of
high-throughput assays.
New medium- and
high-throughput assays
and development of
models (signatures) to
cover important areas
of biological space, high
priority adverse outcome
pathways and chemical-
biological interactions.
Approaches for
incorporation of
xenobiotic metabolism
and challenging chemical
classes into high-
throughput test methods.
HTT assays covering
key events in AOPs for
estrogenic, androgenic,
thyroid, steriodogenesis,
and developmental
endpoints are fit-for-
purpose validated
(e.g. for a regulatory
application, or by a
convening body such as
OECD).
Increased use of HTT
data by program and
regional partners as well
as other stakeholders for
risk-based decisions (e.g.
number of downloads of
data via Dashboards).
High priority chemicals
are screened using HTT
assays for estrogenic,
androgenic, thyroid,
steriodogenesis,
and developmental
endpoints, and the data
made publicly available.
Rapid
Exposure and
Dosimetry
Rapidly characterize
potential for real-world
exposure to chemicals,
including those associated
with consumer product
use.
Develop critical HTP
data required to forecast
exposure and dose for
thousands of chemicals of
interest to EPA.
High-throughput
pharmacokinetic (HTPK)
data and models for risk-
based prioritization.
High-throughput exposure
data and models for risk-
based prioritization.
Tools are provided via
the iCSS Dashboards
to rapidly generate
quantitative human
exposure and internal
dose predictions for large
numbers of chemicals.
Curated monitoring,
chemical, and consumer
product usage data are
provided to the exposure
assessment community.
Evaluated exposure
predictions for priority
chemical lists, including
estimates of variability
and/or uncertainty, are
provided to EPA decision
makers.
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Project Areas | Challenges Addressed | Intermediate Outputs Measures of Success
Topic 2: Life Cycle Analytics
Sustainable
Chemistry
Chemical feature sets
and models for use with
selected AOPs.
Strategies to evaluate
potential for environmental
and human health impacts
of new and alternative
chemicals to support
safer chemical design and
chemical screening.
Elucidate chemical
properties and structural
features associated
with potential for
environmental and human
health impacts.
Integrate novel data
streams and predictive
models for toxicity,
environmental persistence
and transformations
in environmental and
biological systems to
inform design and
evaluation of safer
chemical alternatives.
Biologically-informed
publicly available SAR/
QSAR models developed
to identify adverse
outcomes that will make
use of new HTS data
to improve predictive
capacity.
A Web-based Chemical
Transformation
Simulator will automate
calculation and
collection of molecular
descriptors for parent
chemical and predicted
products resulting
from transformation
in environmental and
biological systems for use
by decision makers.
Emerging
Materials
Develop robust approaches
to rapidly and efficiently
screen environmental
nanomaterial (ENM) for
safety in humans and the
environment.
Identify critical
intermediate properties of
ENMs that are predictive of
potential risks associated
with real-world exposures.
Protocols and methods
for evaluating engineered
nanomaterials in
complex biological or
environmental systems.
Tools to efficiently screen
for potential toxicity
and exposure based on
features of ENMs.
Curated information
from ORD ENM research
including data on physical
chemical characterization
parameters and results of
release, fate, transport,
transformation, and
effects studies provided
to the assessment
community.
Set of functional assays
based on intermediate
properties for efficient
evaluation of ENMs are
developed and applied to
a subset of ENMs.
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Project Areas Challenges Addressed Intermediate Outputs
Measures of Success
Topic 2: Life Cycle Analytics
Life Cycle
and Human
Exposure
Modeling
Integrate chemical
exposure and life cycle
knowledge to model and
assesses human health
impacts of alternatives.
Develop approaches
to rapidly evaluate
environmental and human
health impacts.
Life Cycle Harmonization
Tool that will allow
greater interoperability of
Life Cycle and Exposure
databases and tools.
Case study evaluation of
a chemical/product Life
Cycle/Human Exposure
Modeling framework.
LC-HEMToolfor
evaluating chemical/
product impacts in a
life cycle assessment
framework.
Improved models for
considering impacts
associated with
human exposure are
incorporated into LCAs.
Modeling and assessment
of alternatives is
conducted for chemicals/
products with less
extensive data.
New approaches for
more rapid and higher
throughput assessments
are adopted and used
inside/outside EPA.
Ecological
Modeling
Rapidly evaluate ecological
impacts associated with
use of manufactured
chemicals with limited
data.
Capture spatial and
temporal dynamics to
target critical experimental
measurements required
to understand chemical
impacts on populations
of vulnerable ecological
species.
Demonstration
of ecological risk
assessment (ERA) tools
that reduce uncertainty
for high-priority and
methodologically
challenging chemicals,
comparing ecologically
relevant risk assessments
to those based on limited
data.
Decision framework
for using models of
various complexities,
data requirements,
and levels of real-world
ecological conditions
forfit-for-purpose
application to differing
ERA requirements.
ERA tools are provided
to address high-priority
and methodologically
challenging chemicals
being evaluated by EPA
program and regional
partners.
Tools to incorporate risks
to terrestrial and aquatic
endangered species
are applied to inform
pesticide risk assessments
conducted by EPA and
other federal partners.
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Project Areas | Challenges Addressed | Intermediate Outputs
Measures of Success
Topic 3: Complex Systems Science
Adverse
Outcome
Pathway (AOP)
Discovery and
Development
Apply AOP framework
in concert with new
data streams to predict
potential impacts of
chemicals on ecological
and human health to
support risk-based decision
making.
An Adverse Outcome
Pathway knowledgebase
that enhances the utility
of pathway-based data
for risk-based decision
making.
Case studies
demonstrating relevant
application of adverse
outcome pathway
knowledge to risk-based
decision making.
Outline and make
publicly available putative
AOPs that qualitatively
link ToxCast assays to
potential human and/or
ecological hazards.
Submit new formal AOP
descriptions for review
and evaluation by OECD
AOP working group.
Use AOP networks to
predict the effect of
a multiple-stressor or
mixed MOA exposure in a
demonstrative case study.
Virtual Tissue
Models (VTMs)
Capture system
dynamics in a platform
of experimental and
computational models
for predictive toxicology
to support hypothesis
development and
targeted study to improve
understanding of chemical
impacts on biological
organisms.
Assemble pathway data
and biological knowledge
into dynamic systems
models for assessing
developmental toxicity.
Integrated predictive
system to assemble
pathway data, information
and knowledge of
embryological systems
into dynamical VTMs
for assessing prenatal
developmental toxicity.
Integrated predictive
system to assemble
pathway data, information
and knowledge into
dynamical VTMs for
assessing neuro-
developmental toxicity
linked to thyroid
disruption.
Publicly disseminate
novel predictive models
for developmental
toxicity that can be linked
with chemical evaluation
(e.g., ToxCast).
Provide computational
framework to make the
knowledge from these
models accessible and
transparent.
Demonstrated case study
in which results are
translated such that the
systems understanding
and dynamic model
predictions can be used
to inform decisions.
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Project Areas | Challenges Addressed | Intermediate Outputs Measures of Success
Topic 4: Solutions-Based Translation and Knowledge Delivery
Demonstration
and Evaluation
Integrate new information
with existing methods and
infrastructure to develop
qualitative and quantitative
approaches that support
specific EPA science-based
decisions.
Systematically evaluate
new information and
approaches to determine
when these can be applied
"fit-for-purpose" for EPA
decisions.
Develop measures of
confidence and uncertainty
to support use of new
approaches "fit-for-
purpose" by EPA decision
makers.
Develop and evaluate a
process to produce rapid
points of departure (POD)
for use in evaluating and
managing data-poor
chemicals.
Develop a framework(s)
to evaluate novel groups
of assays, methods, and
models for hazard ID
and/or screening and
prioritization.
Guidance on clear
frameworks and
best practices for
incorporation of novel
data streams and tools
into EPA decision making
processes is issued by the
MAS.
Guidance for how
to incorporate and
implement more global
datasets and models
(e.g. ToxCast data, QSAR
and ADME models, etc.)
into decisions is applied
to case studies for EPA
program and regional
partners and other
stakeholders.
Strategic
Collaborations
CSS proposes an ambitious and significant
paradigm shift in how existing and emerging
chemicals and products can be evaluated
for safety. The focus is on building predictive
capacity and agile responses. The objective is
to move from a knowledge-poor management
posture to one that is proactive, sustainable, and
fostering of innovation. To achieve this paradigm
shift, CSS relies heavily on strategic partnerships
with dozens of organizations ranging from
industry, academia, trade associations, other
federal agencies, state government and non-
governmental organizations. Strategic partner-
ships are formalized through numerous types
of agreements, including Cooperative Research
and Development Agreements, Materials
Transfer Agreements and Memoranda of Un-
derstanding. Examples of partnerships for ad-
vancing potential applications of CSS research
are described in Appendix 2.
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Anticipated Research
Accomplishments and
Projected Impacts
The programmatic outputs of CSS FY 2016-2019
StRAP, described in Appendix 3, have been de-
fined in close collaboration with EPA program
and regional partners and were designed to
meet their needs. To ensure collaborative, inte-
grated, and transdisciplinary research through-
out the course of a CSS project and across the
CSS program, successful delivery of each out-
put is predicated upon synthesis of results from
multiple projects. Note that programmatic out-
puts will be evaluated and finalized each year
based on current information about resources,
state-of-the-science, and partner priorities.
Proposed Integrated FY16-19 CSS
Program Outputs
FY16: Evaluation framework for high-
throughput toxicity (HTT) testing schemes
to inform specific EPA chemical evaluation
objectives
A framework for evaluating the technical
performance of HTT assays, explaining the
biological context, and understanding the
relationship to adverse outcomes of regulatory
concern will be developed to address a range of
EPA decisions. The collaborative development
of this framework will help EPA lead the global
conversation around innovations in evaluation/
validation schemes for in vitro methods, for
analysis of HT/HC data, and for in vitro to in vivo
extrapolations.
FY16: Demonstrated knowledge tools for
development of Adverse Outcome Pathways
(AOPs) to enable incorporation of pathway
level information in EPA decision making
Web-based infrastructure that facilitates
organization of toxicological knowledge into
adverse outcome pathway (AOP) frameworks
will be piloted through application to develop
selected AOPs. AOP development includes as-
sembly and evaluation of the weight of evi-
dence supporting mode-of-action based predic-
tion/extrapolation for various EPA assessments.
Tools and information will be disseminated to
program offices and regional partners. In ad-
dition to helping disentangle complex biologi-
cal pathways, this output is expected to enable
more health-protective decisions by identifying
earlier markers of adversity along a perturbed
biological pathway.
FY 17: Enhanced capacity for using inherent
chemical properties to predict potential
environmental fate, biological dose, and
adverse outcomes to support EPA evaluation
of a wide range of compounds
Provide Web-based infrastructure including a
dashboard to support elucidation of structure-
based chemical feature sets linked to biologi-
cal activity and chemical properties as well as
analytical tools to predict potential for chemi-
cal transformation in environmental systems.
For selected sets of chemicals and high priority
AOPs, identify critical properties and intermedi-
ate properties of chemicals and materials that
are predictive of potential risks. This output is
expected to have broad application to data-
poor chemicals and emerging materials, signifi-
cantly enhancing EPA's ability to anticipate the
human health and environmental impacts of
manufactured chemicals/materials.
FY17: Evaluated, accessible exposure tools to
provide EPA capacity for advanced exposure
analysis to support program-specific chemical
evaluations and sustainable decisions
Rapid measurement methods and compu-
tational approaches to efficiently characterize
potential for real-world human and ecological
exposure to large sets of data-poor chemicals
developed and demonstrated through case
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examples based on EPA exposure assessment
needs. These tools are expected to enable EPA
to make exposure informed and risk-based de-
terminations in a variety of decision scenarios.
FY17: Translation of diverse data streams
including high-throughput toxicity (HTT) data
to inform EPA chemical evaluation and risk-
based assessments
Demonstrate novel approaches for combining
data and models produced and developed
under other CSS and related projects through
application in a variety of decision context
to inform specific EPA chemical evaluation
objectives. Value of information for chemicals
with little traditional toxicity data will be
evaluated and uncertainty in risk estimates
will be characterized. This output will provide
examples that enable EPA to integrate data from
any variety of legacy and novel data sources
using innovations in computational science and
"big data" approaches to make more informed
decisions.
FY18: Next generation high-throughput
toxicity testing (HTT) chemical evaluation
scheme that includes assays to broaden utility
and application
Provide increased coverage of toxicity path-
ways in terms of new assays and models for key
AOPs. Expand the types of chemicals that can
be screened, and identify methods for incorpo-
rating xenobiotic metabolism into in vitro assay
systems. This output will bring innovations in
computational and molecular science to allow
EPA to further realize the recommendations of
the NRC report, Toxicity Testing in the 21st Cen-
tury.
FY18: Tools for evaluating impacts of
chemicals/materials/products early in
development and across their life cycles that
can be used to identify critical data needs
and support sustainable decisions
Provide Web-based infrastructure to support
integration of data related to chemical/mate-
rial and product characteristics, exposure, and
adverse impacts across the chemical/material
life cycle. For selected case examples, pilot ap-
plication of efficient tools and metrics to evalu-
ate chemical impacts across the life cycle to
support alternatives assessment and sustain-
able innovation. These tools will help inform
the design of future laboratory and observa-
tional studies to enhance their relevance and
applicability to EPA decisions. In addition, they
will provide opportunities to test and evaluate
hypotheses generated in observational studies.
FY19: Tools that shift the framework for
evaluating toxicity from direct observation of
apical outcomes to characterizing resilience
and identifying tipping points that predictably
lead to adverse outcomes.
Exploit new data streams to advance systems
understanding of early indicators of adversity
associated with chemical exposures and begin
to build predictive models that enable effective
EPA actions to protect human health and the
environment including the health of children
and other vulnerable lifestages, species, and
groups.
Anticipated Accomplishments
Building on the impact of the CSS 2012-2016
research, CSS research will provide the data and
methods to infuse 21st century science into EPA
decisions. By shifting the thinking and increasing
predictive capacity, CSS will lighten the burden
of chemical assessment and promote proactive
action and sustainable innovation. Anticipated
impact of the CSS research program in the next
5-10 years is as follows:
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Accelerate the pace of data-driven chemical
evaluations
Develop, collate, and organize information on
human and ecological exposure and impacts
to provide accessible data to predict and es-
timate risks from exposures to chemicals effi-
ciently in a manner fit for the specific decision
context and regulatory need.
Enable decisions that are sustainable and
public health protective
Provide methods for advanced analysis to as-
sess safety of high-priority chemicals and in-
form EPA actions to anticipate, manage, and
mitigate exposures to contaminants of great-
est concern throughout their life cycle.
Shift the paradigm of toxicity characterization
from apical endpoints to tipping points
Advance systems understanding of early indi-
cators of adversity associated with chemical
exposures to build predictive models that en-
able effective EPA actions to protect human
health and the environment, including the
health of children and other vulnerable life-
stages, species, and groups.
Apply CSS tools to support sustainable inno-
vation of chemicals and emerging materials
Translate and incorporate emerging and high-
throughput exposure and toxicology data
streams to evaluate impacts of EPA decisions,
select safer chemical alternatives or sub-
stitutes, and inform the sustainable design
and development of emerging materials and
products.
Conclusions
Chemicals are integral to the American econ-
omy and provide key building blocks for the
many products that benefit society. Sustainable
development can yield unprecedented benefits
to society today without compromising the
health and welfare of future generations. Smart
new strategies are needed to make decisions
that protect public health and promote sustain-
able chemical design and use.
Chemicals fuel innovationsurface coatings
that make buildings more resistant to wear;
detergents that allow energy-efficient laun-
dering; preservatives that keep cosmetics and
foods fresh. However, depending on their use,
chemicals may have harmful impacts on human
health and the environment. For instance, evi-
dence is mounting that some chemicals found
in everyday products may disrupt the endo-
crine system and affect the development of
children and sensitive ecological species. Novel
information and methods are needed to make
informed, timely decisions about thousands of
chemicals in commerce.
As one of its highest priority goals described in
the FY14-18 Strategic Plan, EPA aims to reduce
the risks and increase the safety of chemicals
that enter our products, environment, and
bodies. It proposes to assess and reduce risks
posed by chemicals and promote the use of
safer chemicals in commerce. CSS research will
provide the data and methods to infuse 21st
century science into EPA decisions. Important-
ly, CSS proposes a significant paradigm shift in
how existing and emerging chemicals and prod-
ucts can be evaluated for safety. By shifting the
thinking and increasing predictive capacity, CSS
will lighten the burden of chemical assessment
and promote proactive action and sustainable
innovation.
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Appendix 1: Additional
Policy Context and
Scientific Advice
In addition to federal legislative mandates,
several state initiatives are driving the needed
advances in chemical evaluation.
The California State Drinking Water and Toxic
Enforcement Act of 1986 (also known as
Proposition 65) requires the State to publish a
list of chemicals known to cause cancer, birth
defects, or other reproductive harm. Since its
inaugural publication in 1987, this list has grown
to include nearly 800 chemicals. Proposition
65 requires businesses to notify Californians
about significant amounts of these chemicals
in their homes, workplace, drinking water, or
environment. The public disclosure is designed
to allow informed decisions by the consumer.
More recently, the California Safer Consumer
Products Program also strives to reduce toxic
chemicals in consumer products. It identifies
specific products with potentially harmful
chemicals and requires manufacturers to further
evaluate whetherthese chemicals are necessary
or safer alternatives exist. The Priority Product
Work Plan will identify consumer "Priority
Products" that contain "Candidate Chemicals"
- those with traits that could harm people or
the environment - for public disclosure. It is
the first set of product-chemical combinations
to be considered by the DTSC under the Safer
Consumer Products Regulations.
The State of Washington's ReducingToxicThreats
initiative states that preventing exposures to
toxics is the smartest, cheapest, and healthiest
way to protect people and the environment.
The Children's Safe Product Act (CSPA - Chapter
70.240 RCW) establishes the Children's
Safe Product Reporting Rule. It requires
manufacturers of children's products to report
any sale of products containing a Chemical of
High Concern to Children. The CSPA limits the
amount of lead, cadmium, and phthalates
allowed in children's products and these limits
were substantially preempted by federal law.
The Washington State Department of Ecology
also works with the Consumer Product Safety
Commission to ensure compliance with these
requirements.
Finally, over the last few years EPA has
commissioned the National Academies of
Science to provide guidance on the state-of-
the-science and approaches for using emerging
science to promote effective, health-protective
decisions and actions. CSS has strategically
drawn from the NAS recommendations to
address key research gaps that are not being
addressed by partners outside EPA. The
formative National Academy of Sciences
Reports are as follows.
Toxicity Testing in the 21st Century:
A Vision and a Strategy (2007)
Traditional methods used to test chemicals
for potential toxicity are expensive and time-
consuming. To help address this issue, EPA
asked the National Research Council (NRC)
of the National Academy of Sciences (NAS) to
conduct a comprehensive review of current
toxicity testing approaches and propose a long-
range vision and strategy for toxicity testing
that incorporates emerging methods and
technologies. The report's overall objective
was to foster a transformative paradigm shift in
toxicology based largely on the increased use of
in vitro systems and computational modeling.
The NRC report indicated implementation of
the vision would take a substantial commitment
of resources, the involvement of multiple
organizations in government, academia,
industry, and the public, and would take time
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(10-20 years) to achieve. EPA's CSS research
program has already made significant strides
towards realizing the vision in the report.
Science and Decisions: Advancing Risk
Assessment (2009)
Science and Decisions provides practical scien-
tific and technical recommendations to address
the many challenges facing risk assessments
today, including the lack of adequate (exposure
and hazard) data leading to uncertainties in as-
sessments, and lengthy delays necessitated by
complex assessments. These recommendations
are placed within a broader framework for risk-
based decision making to allow for more tai-
lored assessments that are fit for purpose. CSS
has begun to use this approach to evaluate and
demonstrate how the data it generates can be
used to augment and accelerate EPA's risk as-
sessment practices.
Exposure Science in the 21st Century: A Vision
and a Strategy (2012)
Recognizing that exposure science is a key com-
ponent for providing the best public health and
ecosystem protection, EPA asked the NRC to de-
velop a long-range vision for exposure science
in the 21st century, and a strategy for imple-
menting this vision over the next twenty years.
This report, along with three other NAS reports,
Toxicity Testing in the 21st Century, Science and
Decisions: Advancing Risk Assessment, and
Sustainability and the US EPA, chart future di-
rections for using innovative technology and
scientific advances to better understand how
chemicals impact human health and the envi-
ronment. EPA's CSS research is already aligning
with the research recommendations described
in the report.
A Research Strategy for Environmental,
Health, and Safety Aspects of Engineered
Nanomaterials (2012)
In this report, the committee presents a stra-
tegic approach for developing the science and
research infrastructure needed to address un-
certainties regarding the potential EHS risks of
ENMs. The committee identified three require-
ments for the strategy: (1) focus on human and
environmental health, (2) provide flexibility to
anticipate and adjust to emerging challenges,
and (3) provide decision makers with timely,
relevant, and accessible information. The com-
mittee's conceptual framework is characterized
by a life-cycle perspective, a focus on linking key
properties of ENMs in complex media to hazard
and exposure, and a focus on anticipating sig-
nificant risks from emerging ENMs.
Design and Evaluation of Safer Chemical
Substitutions (2014)
EPA asked NRC to recommend a framework
to inform government and industry decisions
made about the use of chemical alternatives.
A chemical alternatives assessment identifies,
compares, and selects safer alternatives to
chemicals of concern. The goal was to facilitate
an informed consideration of the advantages
and disadvantages of chemical alternatives.
Alternatives for chemicals such as Bisphenol-A
(used in plastic products) and perfluorinated
chemicals (used in stain- and grease-resistant
products) are currently being used in consumer
products. The report, A Framework Guide for
the Selection of Chemical Alternatives, consid-
ered potential impacts early in chemical design;
considers both human health and ecologi-
cal risks; integrates multiple and diverse data
streams; considers tradeoffs between risks and
factors such as product functionality; and iden-
tifies scientific information and tools required.
This framework includes several important
unique elements or advancements, such as:
an increased emphasis on comparative expo-
sure assessment; and a two-tiered approach to
evaluating chemical alternatives that includes
health and ecotoxicity, followed by a consider-
ation of broader impacts.
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Assessing Risks to Endangered and Threatened
Species from Pesticides (2013)
The U.S. Fish and Wildlife Service (FWS) and
the National Marine Fisheries Service (NMFS)
are responsible for protecting species that are
listed as endangered or threatened under the
Endangered Species Act (ESA) and for protect-
ing habitats that are critical for their survival.
EPA is responsible for registering or reregister-
ing pesticides under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) and
must ensure that pesticide use does not cause
any unreasonable adverse effects on the envi-
ronment, which is interpreted to include listed
species and their critical habitats. In the report,
the NRC reviewed the state-of-the-science and
identified research gaps required to support
Ecological Risk Assessments for endangered
and threatened species.
Review of the Environmental Protection
Agency's State-of-the-Science Evaluation of
Nonmonotonic Dose-Response Relationships
as they Apply to Endocrine Disrupters (2014)
NAS was asked to review EPA's state-of-the-
science paper. The purpose of the state-of-the-
science paper was to help EPA policy makers
determine if NMDRs capture adverse effects
that are not detected using current chemi-
cal testing strategies and if there are adverse
effects that current EPA testing misses. While
EPA is interested in all aspects of NMDR, the
state-of-the-science paper focused on en-
docrine disruptersin particular, estrogen,
androgen and thyroid active chemicals. The
NAS review included an expert public com-
ment period.
Incorporating 21st Century Science in Risk-
Based Evaluations (In progress)
One of the CSS research program's goals is to
develop approaches for integrating advances
in toxicity testing and exposure science to ac-
celerate the pace and enhance the predictive
capacity of risk-based evaluations. In August
2014, EPA requested guidance from the Na-
tional Academy of Sciences (NAS) on how to
foster this integration and take advantage of
the broader spectrum of 21st century science
emerging from diverse research fields includ-
ing biotechnology and computational sciences.
This resulting NRC study will provide EPA rec-
ommendations on integrating new scientific ap-
proaches into risk-based evaluations, how best
to integrate and use emerging results in evalu-
ating chemical risk, and identify how traditional
risk assessment can incorporate new science.
Unraveling Low Dose: Case Studies of
Systematic Review of Evidence (In progress)
As a follow-up study to the NAS review of the
draft Non-Monotonic Dose Response State-
of-the-Science Paper, the National Research
Council (NRC) will convene an expert committee
to develop a systematic review approach for
determining whether EPA's current hazard
assessment approach is sufficient to consider
evidence of low-dose adverse effects that act
via an endocrine-mediated toxicity pathway.
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Appendix 2: Examples
of CSS Partnerships
National Nanotechnology Initiative
(Formed in 2000)
The National Nanotechnology Initiative (NNI) is
a U.S. government research and development
(R&D) initiative involving the nanotechnology-
related activities of 20 departments and inde-
pendent agencies (including EPA, National Sci-
ence Foundation, National Institutes of Health,
Department of Defense, National Institute of
Occupational Safety and Health, Food and Drug
Administration, and United States Department
of Agriculture). Under its Nanotechnology En-
vironmental Health Implications working group
(NEHI), EPA participates in coordinated research
to address research to assess the potential hu-
man and environmental risks of nanomaterials.
The NNI and NEHI advance collaboration and
coordination of activities both among U.S.-
based agencies and internationally with various
regulatory and coordinating bodies primarily in
Europe and Asia.
Consumer Products Safety Commission
EPA and the U.S. Consumer Product Safety
Commission (CPSC) are collaborating to de-
velop protocols to assess the potential release
of nanomaterials from consumer products; de-
velop credible rules for consumer product test-
ing to evaluate exposure; and to determine po-
tential public health impacts of nanomaterials
used in consumer products.
Toxicity Testing in the 21st Century
(Tox21, established in 2008)
Tox21 pools funding, expertise, chemical re-
search, data and screening tools from multiple
federal agencies including EPA, the National
Toxicology Program/National Institute of Envi-
ronmental Health Science, National Center for
Advancing Translational Sciences and the Food
and Drug Administration. EPA's contribution
to Tox21 is primarily through ToxCast, which
to date, has screened nearly 2000 chemicals
across approximately 700 assay endpoints.
Tox21 has screened nearly 8200 chemicals
across approximately 50 endpoints. The part-
nership has worked extremely effectively to en-
hance the ability to predict the safety of chemi-
cals. Significant improvements have also been
made in data access, reliability, and usability for
the community of stakeholders inside and out-
side EPA.
European Chemicals Agency
(Established in 2010)
EPA's Office of Chemical Safety and Pollution
Prevention (OCSPP) and the Office of Research
and Development (ORD) are partnering with the
European Chemicals Agency (ECHA) to enhance
technical cooperation and to share knowledge,
experience and best practices about chemical
management practices. ECHA and EPA meet at
least quarterly through conference calls and in-
person meetings. The partnership is ongoing
and has resulted in scientific data exchanges;
sharing of regulatory chemical management
plans; joint participation in scientific and regu-
latory workshops; and trainings across both
organizations to demonstrate various online
chemical databases and tools.
Organization of Economic Cooperation and
Development
(Established in 2012)
EPA, in collaboration with the international
scientific community, the European Joint Re-
search Center, the US Army Corp of Engineers,
and the Organization of Economic Cooperation
and Development are developing tools to facili-
tate the use of AOPs to help evaluate chemicals
for potential risks. The strategic partnership
has resulted in the development of the AOP
Knowledge Base (AOP-KB) and the AOP Wiki.
The AOP-KB is the foundational Web-based
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platform designed to bring together knowledge
about how chemicals can prompt adverse out-
comes. The AOP Wiki, a module of the AOP-KB,
is an interactive virtual encyclopedia for AOP
development that is being populated with input
from international scientific experts.
California Department of Toxic Substances
Control
(Established in 2012)
California's Department of Toxic Substances
Control (DTSC) and EPA's Office of Chemi-
cal Safety and Pollution Prevention, Region 9,
and the Office of Research and Development
are collaborating on efforts to advance Green
Chemistry practices and activities. The CSS re-
search program's role in the collaboration is to
expand the applications of developed CSS tools
to inform product and chemical alternative
analyses. Specifically, CSS has shared database
architecture and chemical information to help
California develop publically available chemical
information databases.
Health Canada
(Established in 2013)
Health Canada and EPA are collaborating to ex-
plore approaches for using new data streams
to assess chemicals for potential risks to hu-
man health. Health Canada is currently under a
regulatory mandate to develop Chemical Man-
agement Plan 3 (CMP3). The chemicals in CMP3
include chemicals lacking traditional toxicity
data. Health Canada is working with EPA CSS to
determine how to use high-throughput screen-
ing data and other types of non-traditional
chemical data to help fill the data gaps for the
chemicals in CMP3.
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Appendix 3: Table of Proposed Outputs,
Chemical Safety for Sustainability Research
Program, FY16-FY19
The following table lists the expected outputs from the Chemical Safety for Sustainability research
program, organized by topic. Note that outputs may change as new scientific findings emerge.
Outputs are also contingent on budget appropriations.
Project Area
Outputs
Topic 1: Chemical Evaluation
High-Throughput
Toxicology
FY16 - Evaluation framework for high-throughput toxicity testing schemes
to inform specific Agency chemical evaluation objectives
FY18 - Next generation high-throughput toxicity testing chemical
evaluation scheme that includes assays to broaden utility and application
Rapid Exposure and
Dosimetry
FY17 - Evaluated, accessible exposure tools to provide Agency capacity
for advanced exposure analysis to support program-specific chemical
evaluations and sustainable decisions
FY18 - Next generation high-throughput toxicity testing chemical
evaluation scheme that includes assays to broaden utility and application
FY19 - Tools that shift the framework for evaluating toxicity from
direct observation of apical outcomes to characterizing resilience and
identifying tipping points that predictably lead to adverse outcomes
Topic 2: Life Cycle Analytics
Sustainable
Chemistry
FY17 - Enhanced capacity for using inherent chemical properties to
predict potential environmental fate, biological dose, and adverse
outcomes to support Agency evaluation of a wide range of compounds
FY18 - Tools for evaluating impacts of chemicals/materials/products early
in development and across their life cycles that can be used to identify
critical data needs and support sustainable decisions
Emerging Materials
FY17 - Enhanced capacity for using inherent chemical properties to
predict potential environmental fate, biological dose, and adverse
outcomes to support Agency evaluation of a wide range of compounds
FY18 - Tools for evaluating impacts of chemicals/materials/products early
in development and across their life cycles that can be used to identify
critical data needs and support sustainable decisions
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Project Area
Outputs
Topic 2: Life Cycle Analytics
Life Cycle and
Human Exposure
Modeling
FY17 - Evaluated, accessible exposure tools to provide Agency capacity
for advanced exposure analysis to support program-specific chemical
evaluations and sustainable decisions
FY18 - Tools for evaluating impacts of chemicals/materials/products early
in development and across their life cycles that can be used to identify
critical data needs and support sustainable decisions
Ecological Modeling
FY17 - Evaluated, accessible exposure tools to provide Agency capacity
for advanced exposure analysis to support program-specific chemical
evaluations and sustainable decisions
FY17 - Enhanced capacity for using inherent chemical properties to
predict potential environmental fate, biological dose, and adverse
outcomes to support Agency evaluation of a wide range of compounds
FY18 - Tools for evaluating impacts of chemicals/materials/products early
in development and across their life cycles that can be used to identify
critical data needs and support sustainable decisions
Topic 3: Complex Systems Science
AOP Discovery and
Development
FY16 - Demonstrated knowledge tools for development of adverse
outcome pathways to enable incorporation of pathway level information
in Agency decisions
FY17 - Translation of CSS data streams including high-throughput toxicity
data to inform Agency chemical evaluation and risk-based assessments
FY19 - Tools that shift the framework for evaluating toxicity from
direct observation of apical outcomes to characterizing resilience and
identifying tipping points that predictably lead to adverse outcomes
Virtual Tissues
FY16 - Demonstrated knowledge tools for development of adverse
outcome pathways to enable incorporation of pathway level information
in Agency decisions
FY17 - Translation of CSS data streams including high-throughput toxicity
data to inform Agency chemical evaluation and risk-based assessments
FY19 - Tools that shift the framework for evaluating toxicity from
direct observation of apical outcomes to characterizing resilience and
identifying tipping points that predictably lead to adverse outcomes
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Project Area
Outputs
Topic 4: Solutions-Based Translation and Knowledge Delivery
Demonstration and
Evaluation
Partner-Driven
Research
Strategic Outreach
FY16 - Evaluation framework for high-throughput toxicity testing (HIT)
schemes to inform specific Agency chemical evaluation objectives
FY17 - Translation of CSS data streams including high-throughput toxicity
data to inform Agency chemical evaluation and risk-based assessments
Products based on short term partner needs for high priority technical
support and targeted research.
Products will include public workshops, tailored meetings and webinars,
training and strategic collaborations, among others.
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United States
Environmental Protection
Agency
PRESORTED STANDARD
POSTAGES FEES PAID
EPA
PERMIT NO. G-35
Office of Research and Development (8101R)
Washington, DC 20460
Official Business
Penalty for Private Use
$300
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