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


-------
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

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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

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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

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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.

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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

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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

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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

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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 innovation—surface 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 disrupters—in 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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