Chemical Safety
for Sustainability

STRATEGIC RESEARCH ACTION PLAN

FISCAL YEARS 2023-2026

Office of Research and Development

Chemical Safety for Sustainability Research Program

Draft as of March 28, 2022


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Chemical Safety for
Sustainability (CSS)

STRATEGIC RESEARCH ACTION PLAN
Fiscal Years 2023-2026

(Draft as of March 28, 2022)

Disclaimer: This document is distributed solely for the purpose of pre-dissemination peer review
under applicable information quality guidelines. It has not been formally disseminated by the U.S.
Environmental Protection Agency. It does not represent and should not be construed to represent

any agency determination or policy.


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Table of Contents

LIST OF ACRONYMS	[N

DEFINITIONS	V

EXECUTIVE SUMMARY	1

INTRODUCTION	2

SOLUTIONS-DRIVEN RESEARCH	3

PROGRAM VISION	3

STRATEGIC DIRECTION	4

Relationship to EPA and ORD Strategic Plans	4

Changes from FY19-FY22 STRAP	4

PARTNER ENGAGEMENT	5

RESEARCH TOPICS AND RESEARCH AREAS	5

Topic 1: Chemical Evaluation	5

Research Area 1: High-Throughput Toxicology (HTT)	5

Research Area 2: Rapid Exposure and Dosimetry (RED)	6

Research Area 3: Emerging Materials and Technologies (EMT)	7

Topic 2: Complex Systems Science	7

Research Area 4: Adverse Outcome Pathways (AOP)	8

Research Area 5: Virtual and Complex Tissue Modeling (VCTM)	8

Research Area 6: Ecotoxicological Assessment and Modeling (ETAM)	9

Topic 3: Knowledge Delivery and Solutions-Driven Translation to Support Chemical Safety Decision
Making	10

Research Area 7: Chemical Characterization and Informatics (CCD	10

Research Area 8: Integration. Translation and Knowledge Delivery (ITK)	10

IMPLEMENTING THE STRATEGIC RESEARCH ACTION PLAN	11

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CROSS-CUTTING RESEARCH PRIORITIES	12

APPENDIX 1: SUMMARY OF PROPOSED OUTPUTS MAPPED TO PROGRAM. REGIONAL. STATE. AND



TRIBAL (PRST) NEEDS AND CROSS-CUTTING PRIORITIES

13

APPENDIX 2: DESCRIPTIONS OF PROGRAM. REGIONAL. STATE. AND TRIBAL (PRST) NEEDS

18

APPENDIX 3: OUTPUT DESCRIPTIONS

21

APPENDIX 4: CROSS-CUTTING RESEARCH PRIORITIES

36

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List of Acronyms

ACE

Air, Climate, and Energy

ADME

Absorption, distribution, metabolism, and excretion

CAA

Clean Air Act

CERCLA

Comprehensive Environmental Response, Compensation, and Liability Act

CIECs

Contaminants of Immediate and Emerging Concern

CSS

Chemical Safety for Sustainability

CWA

Clean Water Act

EDSP

Endocrine Disruption Screening Program

EPA

U.S. Environmental Protection Agency

ERA

Ecological risk assessment

ESA

Endangered Species Act

FFDCA

Federal Food, Drug, and Cosmetic Act

FIFRA

Federal Insecticide, Fungicide, and Rodenticide Act

FQPA

Food Quality Protection Act

HERA

Health and Environmental Risk Assessment

HSRP

Homeland Security Research Program

HTTK

High-Throughput Toxicokinetic

MCCs

Methodologically Challenging Chemicals

NAMs

New Approach Methods

NTA

Non-targeted analysis

NRP

National Research Program

OAR

Office of Air and Radiation

OLEM

Office of Land and Emergency Management

ORD

Office of Research and Development

OW

Office of Water

P3

People, Prosperity and the Planet

PFAS

Per- and Polyfluoroalkyl Substances

PRST

Program offices, Regions, States, Tribes

QSAR

Quantitative structure-activity relationship

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RA

Research Area

RACT

Research Area Coordination Team

RCRA

Resource Conservation and Recovery Act

SBIR

Small Business Innovation Research

SDR

Solutions-Driven Research

SDWA

Safe Drinking Water Act

SHC

Sustainable and Healthy Communities

SSWR

Safe and Sustainable Water Resources

STAR

Science to Achieve Results

StRAP

Strategic Research Action Plan

TSCA

Toxic Substances Control Act

UVCB

Unknown or variable composition

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Definitions

Office of Research and Development (ORD): Scientific research arm of EPA that conducts leading-
edge research to inform Agency decisions and support partner needs, including state, Tribal, and
community partners.

National Research Program (NRP): ORD's overall research effort is organized around six integrated
and transdisciplinary national programs and closely aligned with the Agency's strategic goals and
cross-Agency strategies. ORD is a matrixed organization with research direction coming from its six
NRPs, each being guided by a Strategic Research Action Plan that identifies the most pressing
environmental and public health research needs with input from many internal and external partners
and stakeholders.

Strategic Research Action Plan (StRAP): A description of the overarching direction of ORD's research
in a specified timeframe and under a specific research program. Each of ORD's NRPs is guided by a
StRAP to structure and coordinate research activities. A StRAP includes a description of identified
environmental and public health challenges, research priorities, and ORD's approach to meeting the
challenges.

Topic: Overarching research focus under a NRP that encompasses Research Areas, Outputs, and
Products.

Research Area: Science area or body of research and expertise assembled to address partner needs
in the protection of human health and the environment. It encompasses problem statements, which
are delineated through Outputs. Research Areas are nested under Topics and are composed of
Outputs, which are composed of Products.

Output: A statement of the results to be achieved in pursuing a Research Area problem statement. It
is not a tangible deliverable but encompasses Products that are deliverables. They are designed and
developed to address specific partner needs that draw on the scientific knowledge and expertise
represented in research areas. An Output can be expressed in many ways, such as an intended
intermediate outcome, a purpose, aim, goal, or target. Outputs are composed of Products and nested
within Research Areas, which are nested within Topics.

Product: A tangible scientific or technical deliverable. It addresses the research needs of ORD and
ORD's partners. Products are nested within Outputs, which are nested within Research Areas, which
are nested within Topics.

Partner: An EPA program office, EPA region, representative of a state, or a representative of a
Tribe—often referred to as PRST.

Program, Regional, State, and Tribal (PRST) needs: A description of research needs related to human
health and the environment as identified by EPA program offices, EPA regional offices, states, and/or
Tribes.

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Executive Summary

The Environmental Protection Agency's (EPA) Chemical Safety for Sustainability (CSS) National Research
Program (NRP) is focused on addressing the pressing environmental and health challenge of a lack of
sufficient information on chemicals needed to make informed, risk-based decisions. The impetus for the
program is to meet the shared health and environmental protection goals of the Agency's program and
regional offices, states, and Tribes while performing transformative research, leading to improved
science-based approaches that build broader understanding of biology, chemical toxicity, and exposure.

The current CSS Strategic Research Action Plan (i.e., StRAP 4) reflects the priority needs of Agency
partners guided by overarching strategic goals. Further, StRAP 4 is informed by the Administration's
priorities and established through extensive, systematic consultations and engagements. The CSS StRAP
4 research is engrained in the statutory authorities that authorize research to fulfill the Agency's
mission. While the organization of ongoing research remains consistent with the broad research topics
under previous StRAPs, the emphases within the areas are re-aligned to account for completed activities
and newer cross-cutting priorities such as addressing climate change and environmental justice,
potential for early lifestage susceptibility, cumulative impacts (mixtures, real-world exposures), and
contaminants of immediate and emerging concern (CIECs).

A key issue with current chemical safety assessment is that traditional approaches have been unable to
keep pace with innovations in chemical design, synthesis, and use. CSS has a history of conducting
innovative science and is a hub of global scientific expertise and leadership in many areas, such as
computational toxicology and exposure, high-throughput toxicology, and complex systems science. CSS
will continue to do the following:

•	Develop the science needed to reduce, refine, and replace vertebrate animal testing consistent
with Agency policies.

•	Accelerate the pace of chemical assessment to enable our partners to make informed and
timely decisions concerning the potential impacts of environmental chemicals on human health
and the environment.

•	Provide leadership to transform chemical testing, screening, prioritization, and risk assessment
practices.

While continuing our core research activities, we envision that the program will further incorporate
cross-cutting research priorities. To be effective over the course of the StRAP, the program will not only
develop robust scientific data and innovative tools, but also interpretative frameworks. To achieve this,
CSS commits to work collaboratively with our partners (and the broader scientific community, including
U.S. and international governmental agencies and non-governmental entities) to translate the science
such that the information and tools can be transparent and useful for decision making.

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Introduction

The Environmental Protection Agency (EPA), along with federal partners, states, and Tribes, plays a
central role in evaluating the potential impacts of chemicals on human health and the environment. EPA
strives to provide efficient, transparent, and scientifically robust approaches to evaluating chemical
safety while continually improving these approaches in response to scientific and technological
advancements. To achieve this, EPA applies advanced toxicological and exposure methods, data, tools,
models, and information access to make better-informed and more timely decisions about the safety of
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) National Research Program (NRP) is
designed to support the goal of reducing risks associated with exposure to chemicals in commerce and
the environment.

While research under CSS has realized significant accomplishments over the last several years, the long-
term vision remains ambitious. The approach to achieving this vision continues to focus on three key
components—re-aligned as appropriate to address current priorities. First, CSS will develop the science
needed to reduce, refine, and replace vertebrate animal testing consistent with Agency policies and the
goals articulated in the NAMs workplan. The second component is accelerating the pace of chemical
assessment to enable our partners to make informed and timely decisions concerning the potential
impacts of environmental chemicals on human health and the environment. The third component of
CSS's long-term vision is to provide leadership to transform chemical testing, screening, prioritization,
and risk assessment practices. Realization of the CSS vision will require not only the robust scientific
development of new data and innovative tools, but interpretive frameworks that make the information
and tools transparent and useful for decision making. To achieve this vision, CSS will work with Agency
partners as well as the broader scientific community, including U.S. and international government
agencies and non-governmental entities.

To assist the Agency in meeting its goals and objectives, the CSS Research Program developed this
Strategic Research Action Plan (StRAP) for fiscal years 2023-2026 (FY23-26). The CSS StRAP is one of six
of the following research plans for each of the NRPs in EPA's Office of Research and Development (ORD):

•	Air, Climate, and Energy (ACE)

•	Chemical Safety for Sustainability (CSS)

•	Health and Environmental Risk Assessment (HERA)

•	Homeland Security (HS)

•	Safe and Sustainable Water Resources (SSWR)

•	Sustainable and Healthy Communities (SHC)

The StRAPs outline four-year research strategies to deliver the research necessary to support EPA's
overall mission to protect human health and the environment. The StRAPs are designed to guide an
ambitious research portfolio that delivers the science and engineering solutions the Agency needs to
meet its goals now and into the future. They also inform our partners and the public of the program's
strategic direction over the next four years. The CSS StRAP FY23-26 builds upon the previous StRAP
FY19-22, and where appropriate, continues research efforts to address longer-term strategic research
objectives that can bridge between the four-year research planning cycles.

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The strategic directions and Research Areas (RAs) identified in each StRAP serve as planning guides for
ORD's research Centers to design specific research products to address the needs of EPA program and
regional offices, states, Tribes, and external partners. Partner engagement is an essential part of the
StRAP development process to identify research needs to be addressed.

Solutions-Driven Research

ORD is committed to producing research results that address real-world problems, inform
implementation of environmental regulations, and help EPA partners make timely decisions based on
sound science. This commitment includes exploring ways to improve research processes through the
application of a solutions-driven research (SDR) framework. SDR is a specific research approach that
emphasizes partner engagement and integration of tasks to develop research that is directly along the
path to a solution or decision. Solutions-driven research emphasizes the following:

•	Planned partner engagement throughout the research process, starting with problem
formulation and informing all elements of research planning, implementation, dissemination,
and evaluation.

•	A focus on solutions-oriented research Outputs identified in collaboration with partners.

•	Coordination, communication, and collaboration both among ORD researchers and between
researchers and partners to develop integrated research that multiplies value to partners.

•	Cooperation with partners to apply research results to develop solutions that are feasible,
appropriate, meaningful, and effective.

ORD is applying principles of solutions-driven research broadly across its six NRPs. ORD will also monitor
how we engage with our partners and how we design and conduct our research to ensure that it informs
solutions for our partners' most pressing environmental problems. By doing this, we are engaging in
translational science, which will continually improve and increase the value of our research for our
partners. Our emphasis on translating science is exemplified by the Outputs listed in this StRAP—they
provide solutions to problems identified by our partners.

Program Vision

The CSS NRP addresses the pressing environmental and health challenge posed by insufficient
information on chemicals necessary for informed, risk-based decision making. Its impetus is to meet the
needs of the Agency's program and regional offices, states, and Tribes while performing transformative
research, leading to improved science-based approaches that build broader understanding of biology,
chemical toxicity, and exposure. Realization of the CSS vision will require a commitment to work
collaboratively with our partners to translate the science so that the resulting information and tools can
be transparent and useful for decision making.

Managing risks from exposure to chemicals to protect human health and the environment, including the
support of scientific research, is authorized and/or mandated in several statutes. The CSS research
portfolio is largely focused on requirements authorized under the Toxic Substances Control Act (TSCA);
the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA); the Food Quality Protection Act (FQPA);
the Federal Food, Drug, and Cosmetic Act (FFDCA); the Clean Water Act (CWA); the Safe Drinking Water
Act (SDWA); the Resource Conservation and Recovery Act (RCRA); the Comprehensive Environmental

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Response, Compensation, and Liability Act (CERCLA); the Endangered Species Act (ESA); and the Clean
Air Act (CAA). Chemical assessment, regulation, and management associated with these statutes are
implemented by EPA's program offices, including the Office of Chemical Safety and Pollution Prevention
(OCSPP), the Office of Land and Emergency Management (OLEM), the Office of Water (OW), and the
Office of Air (OAR). CSS works closely with each of these offices to ensure that research is designed to
support current and future needs. Furthermore, due to the fundamental nature of CSS's work, CSS data,
tools, and models are often used to inform decisions made under other authorities, both federal and
state.

Strategic Direction

Relationship to EPA and ORD Strategic Plans

The FY 2023-2026 EPA Strategic Plan is designed to implement the Administrator's priorities for the next
four years. This Strategic Plan identifies four cross-cutting strategies and seven strategic goals with
related objectives, describing how the Agency will work toward its mission to protect human health and
the environment.

EPA's Strategic Plan outlines the need for chemical safety research to support EPA's responsibilities
under TSCA, FIFRA, and ESA. CSS research has a focus on supporting Goal 7 of the Agency's Strategic
Plan, to Ensure Safety of Chemicals for People and the Environment under Objective 7.1: Ensure
Chemical and Pesticide Safety and Objective 7.2: Promote Pollution Prevention. CSS research will also
support Goal 1, to Tackle the Climate Crisis and Goal 2, to Take Decisive Action to Advance
Environmental Justice and Civil Rights. CSS research will also support three Cross-Agency Strategies:
Ensure Scientific Integrity and Science-Based Decision Making (Strategy 1); Consider the Health of
Children at All Life Stages and Other Vulnerable Populations (Strategy 2); and Strengthen Tribal, State,
and Local Partnerships and Enhance Engagement (Strategy 4).

ORD will develop its own Strategic Plan to respond to and build upon the FY 2023-2026 EPA Strategic
Plan.. ORD's Strategic Plan will align with the StRAPs for ORD's six research programs, which outline
specific research activities that address objectives of the Agency's Strategic Plan.

Changes from FY19-FY22 StRAP

CSS is organized around three broad research topics that include similar areas of disciplinary expertise
and capability relevant to partner needs: Chemical Evaluation, Complex Systems Science, and
Knowledge Delivery and Solutions-Driven Translation to Support Chemical Safety Decision Making.

While the organization of ongoing research remains consistent with the previous broad research topics,
the emphases within the areas are re-aligned to account for completed activities and newer cross-
cutting priorities such as addressing climate change, environmental justice, potential for early lifestage
susceptibility, cumulative impacts (mixtures, real-world exposures), and contaminants of immediate
(e.g., Per- and Polyfluoroalkyl Substances (PFAS), Pb) and emerging concern. Climate change and
environmental justice research will be integral to the program as opposed to standalone areas.

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Partner Engagement

Development of ORD's StRAPs has been informed by ongoing and extensive engagement with EPA
program and regional offices and external (non-EPA) partners. ORD's partner engagement during
strategic research planning ensures a collaborative, transparent, and highly coordinated research
portfolio that delivers the data and information that Agency program and regional offices need, and
provides resources that help states, Tribes, local communities, and other partners. ORD relies on partner
engagement as an essential component throughout the research cycle and especially during problem
formulation to identify partner research needs and develop the research Outputs outlined in the StRAPs.

The CSS Research Program engages partners at different levels and stages throughout the research cycle
to identify and discuss their research needs. Building from engagement during StRAP FY19-22 planning
and implementation, engagement methods for the CSS StRAP FY23-26 included the following:

•	Recurring dialogues and meetings with EPA program and regional offices.

•	Listening sessions with external partners, including state, Tribal, and local partners.

•	Workshops with ORD staff and EPA program and regional offices.

•	Participation in EPA state and Tribal organization meetings (e.g., Environmental Council of the
States, Tribal Science Council).

The CSS Research Program will continue to engage with our EPA partners and state, Tribal, and local
organizations as we implement the research program outlined in the StRAP, support our research
products after they are delivered, and evaluate the usefulness and effectiveness of our research in
helping solve environmental and public health problems.

Research Topics and Research Areas

Please refer to Appendices 1-4 for additional detail on partner needs, cross-cutting priorities, and
Outputs (including the numbering scheme).

Topic 1: Chemical Evaluation

Research under Topic 1 will provide rapid methods and high-throughput data for risk-based evaluations
of new and existing chemicals and emerging materials. This Topic will emphasize development and
application of NAMs to rapidly generate exposure and hazard information for chemicals (including safer
alternatives) and emerging materials and technologies.

Research Area 1: High-Throughput Toxicology (HTT)

For most chemicals, the availability of data and information to assess the potential toxicity to humans
and other species is limited or incomplete. Existing chemical inventories and the introduction of new
chemicals have driven the need for rapid assessment approaches. The HTT Research Area (RA) is focused
on addressing the limitations of current chemical testing methods and fulfilling EPA's need to evaluate
large numbers of chemicals for potential adverse human and ecological effects. The HTT RA will design,
develop, and apply NAMs for hazard testing of chemicals (including CIECs) and chemical mixtures. The
resulting data will inform a tiered approach to toxicology testing, which may include traditional
methods for a reduced number of chemicals prioritized by HTT methods. These high-throughput

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approaches will rapidly generate chemical hazard data on specific endpoints of interest to partners (e.g.,
developmental neurotoxicology, toxicological effects from inhalation exposure, and other
priority endpoints) and should help prioritize, screen, and evaluate chemical safety for thousands of
compounds while reducing reliance on traditional toxicity tests. Work under this RA is intended to be
complementary to research conducted under the HERA program and may involve collaborative research
efforts between scientists within the HERA and CSS programs. For example, data generated by CSS may
inform HERA assessment solutions.

Work under the HTT RA addresses many priority needs of CSS partners. The Agency's NAMs workplan
outlines goals for reducing the use of animal testing while continuing to protect human health and the
environment. HTT Outputs (CSS.1.1, CSS.1.2, CSS.1.3, CSS.1.4, CSS.1.5) will work towards the goal of
providing a structured framework and building confidence in applying NAMs across a broad variety of
chemicals and decision contexts. Advancing a tiered, high-throughput toxicity testing strategy will be a
focus (CSS.1.1), including providing structured and computationally accessible data (CSS.1.2). Novel
technologies and approaches will be developed to address methodologically challenging chemicals
(CSS.1.3) as well as challenges with existing high- and medium-throughput methods (CSS.1.4). Work will
also inform data gaps in chemical safety evaluations for priority toxicological endpoints, such as
endocrine disrupting mechanisms, manifestations of toxicity in the respiratory system, developmental
neurotoxicity, and immunotoxicity (CSS.1.5). Within the HTT RA, there will be a continued focus on
advancing a tiered testing evaluation for PFAS (CSS.1.6). Cross-cutting priorities are integrated into this
RA. For example, research that includes toxicity testing of mixtures will provide information on
cumulative impacts (CSS.1.1, CSS.1.2, CSS.1.6). Also, work on priority toxicological end points such as
developmental neurotoxicity (CSS.1.5) will address vulnerable and sensitive subpopulations and the
potential for early lifestage susceptibility.

Research Area 2: Rapid Exposure and Dosimetry (RED)

The RED RA will develop methods, data, tools, models, and approaches to rapidly generate scientifically
defensible exposure and dosimetry estimates for new and existing chemicals and chemical
mixtures found in commerce and in the environment. This research will involve the development or
expansion of critical exposure-relevant data and associated computational models for priority exposure
pathways; the results from these models will be integrated into predictive consensus frameworks and
evaluated with relevant monitoring data, including data generated with emerging high-throughput
measurement approaches. In concert with the toxicity information generated in the HTT RA, new high-
throughput toxicokinetic (HTTK) data and models will be developed to enable the direct comparison of
HTT data with consensus exposure predictions. Estimates of human and ecological exposures developed
in RED represent critical inputs for high-throughput, risk-based prioritization and screening of
chemicals and chemical mixtures. The exposure and toxicokinetic data and predictions developed in this
RA will consider and provide valuable information to identify or characterize vulnerable and sensitive
subpopulations and early lifestage susceptibility; address populations experiencing disproportionate
adverse impacts, for example, from climate change disasters; inform identification of emerging
contaminants of concern; characterize cumulative risks for chemical mixtures in the environment; and
accelerate the rate of chemical evaluations. Work under this RA is intended to be complementary to
research conducted under the HERA program and may involve collaborative research efforts between
scientists within the HERA and CSS programs. For example, data generated by CSS may inform HERA
assessment solutions.

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The RED RA addresses a broad range of priority partner needs, including many of the cross-cutting
Agency priorities. Outputs will address the collection and curation of necessary exposure-relevant data
(CSS.2.1) and work on HTTK tools (CSS.2.2), both of which enable high-throughput exposure modeling
predictions for chemicals (CSS.2.3). Work to support lifecycle assessments and sustainable chemistry will
also be included (Output CSS.2.4), in addition to next-generation chemical exposure monitoring—
specifically, development, evaluation, and evidence to increase confidence in the use of non-targeted
analysis (NTA) methods for exposure assessment (Outputs CSS.2.5 and CSS.2.6). The RA will include a
focus on enabling rapid exposure evaluations for PFAS (Output CSS.2.7). Cross-cutting priorities related
to environmental justice (CSS.2.1, CSS.2.2, CSS.2.3, CSS.2.5, CSS.2.6), cumulative impacts (CSS.2.2,
CSS.2.3, CSS.2.5, CSS.2.6), vulnerable and sensitive subpopulations and the potential for early lifestage
susceptibility (CSS.2.1 and CSS.2.3), and climate change (CSS.2.5, CSS.2.6, CSS.2.7) will be addressed, as
appropriate, throughout this RA. In particular, advances in exposure models allowing for estimation of
chemical exposure developed under RED will incorporate multiple cross-cutting priorities. For example,
mining of data on co-exposures can be used to address demographic differences relevant to populations
experiencing disproportionate adverse impacts. Further, NTA methods can be effectively used to
address real-world mixtures including those associated with catastrophic events brought on by climate
change generally, as well as to disproportionately impacted communities.

Research Area 3: Emerging Materials and Technologies (EMT)

Innovations in chemical and material design are rapidly changing the landscape of industrial and
consumer products. Emerging materials and technologies often have unique physicochemical
properties, warranting specialized approaches for evaluating hazard and exposure, and necessitating an
evaluation of the environmental impacts of their use. In addition, investigation of novel products of
synthetic biology, genome editing, and metabolic engineering is needed to support risk assessment of
emerging biotechnology products. The EMT RA will develop, collate, mine, and apply information on
emerging materials and technologies to support risk-based decisions, including potential impacts of
disproportionately affected populations.

Safety assessments of emerging materials require information on human and ecological exposure from
consumer products and environmental releases. The EMT RA will address the additional data needed to
characterize potential release of and exposure to these chemicals and materials, and subsequent
environmental impacts of emerging materials on humans and ecological species (Outputs CSS.3.1,
CSS.3.2). Novel products of synthetic biology, genome editing, and metabolic engineering will also be
addressed (CSS.3.2). Research in this area will address relevant cross-cutting priorities related to
cumulative impacts (CSS.3.1, CSS.3.2) and environmental justice (CSS.3.1, CSS.3.2) potentially associated
with incidental exposures.

Topic 2: Complex Systems Science

Research conducted under Topic 2 will build the scientific foundation to predict adverse outcomes
resulting from chemical exposures in various biological contexts. This Topic will develop interpretive
frameworks and models to put complex mechanistic information into biological, chemical, and
toxicological context, moving from foundational to actionable decision making.

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Research Area 4: Adverse Outcome Pathways (AOP)

Employing data from NAMs into decision making, such as those being generated by the HTT and
RED RAs, requires understanding the role of perturbation of one or more biological pathways on
measured toxicological endpoints. The AOP framework provides a systematic and modular structure for
organizing and communicating existing knowledge concerning the linkage between molecular initiating
events (e.g., chemical protein-interaction), intermediate key events along a toxicity pathway, and apical
adverse outcomes considered relevant to risk assessment or regulatory decision making. AOPs provide
a scientifically defensible foundation for extrapolating from mechanistic data to predicted outcomes.
AOP networks can be assembled by evaluating shared nodes or key events in individual AOPs, providing
insight into the complex interactions among biological pathways. Quantitative understanding of key
event relationships can be modeled to predict thresholds of toxicological response for adverse
outcomes of regulatory concern, while also being used to address intrinsic and extrinsic factors that
influence susceptibility. Whether through individual AOPs or AOP networks, the interactions of multiple
chemicals present in both simple and complex mixtures will be assessed to facilitate analyses of more
realistic environmental exposure scenarios relevant to cumulative risk and impact assessments. This RA
will continue to develop AOPs for high-priority pathways that may also be used for assessing the effects
of real-world exposures to mixtures and the effects of climate change. The application of well-developed
and curated AOPs to address partner needs is addressed through case studies under the Integration,
Translation, and Knowledge Delivery (ITK) RA.

Investigation of AOPs in this RA is a critical component in the continued development and application of
NAMs, to achieve the goals of characterizing the risks for thousands of data-poor chemicals and
reducing the use of animal testing. Work across this RA will build confidence in the use of NAMs by
developing actionable, fit-for-purpose AOPs (Output CSS.4.1) that provide mechanistic relevance to the
hazards being assessed, conducting strategic in vitro and in vivo studies for high-priority AOPs (Output
CSS.4.2), and investigating the biological points of departure and susceptibility factors needed for
quantitative application of AOPs (Output CSS.4.3). The utility of AOPs in informing risks and associated
management actions will also be demonstrated (Output CSS.4.4). The RA will include a focus on AOPs
relevant to PFAS (Output CSS.4.5). AOPs potentially provide an opportunity to address multiple cross-
cutting issues. Customized workflows that build from the AOP framework in a systematic and modular
manner can be used effectively to address climate change (CSS.4.1, CSS.4.2, CSS.4.3, CSS.4.4),
cumulative impacts (CSS.4.1, CSS.4.2, CSS.4.3, CSS.4.4, CSS.4.5), environmental justice (CSS.4.1, CSS.4.2,
CSS.4.3), and children's health (CSS.4.1, CSS.4.2, CSS.4.3, CSS.4.5). The overall integration of fit-for-
purpose AOPs will provide options to account for high-priority AOPs relevant to populations
experiencing disproportionate adverse impacts as well as vulnerable and sensitive subpopulations,
including early lifestage susceptibility.

Research Area 5: Virtual and Complex Tissue Modeling (VCTM)

To bridge the gap from molecular changes to endpoints used in conventional hazard identification or
risk assessment, models of biological systems are needed that can be experimentally probed and
computationally simulated. Virtual tissue models connect in vitro molecular and pathway perturbations
with in vivo tissue- and organ-level observations. The VCTM RA will focus on developing organotypic
culture models, engineered microphysiological systems, and in silico agent-based and computational
models to test hypotheses regarding organ-specific toxicity of priority chemicals for major routes of
exposure (e.g., inhalation, oral), including pathways and endpoints relevant to human toxicity across

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early lifestages or for disease states to inform risk-based assessments of new and existing chemicals. To
support tiered toxicity-testing approaches, the VCTM RA will focus on computational and experimental
models at the cellular, organ, or tissue level in an effort to help predict potential in vivo health effects.

Development, characterization, and application of organotypic and complex tissue models to bridge
between in vitro and organismal assays will be addressed (Output CSS.5.1), as well as the development
and application of in silico agent-based and computational models to evaluate the effects of chemicals
on biological pathways (Output CSS.5.2). VCTM can provide a means to account for variability that may
be associated with differing degrees of vulnerability and sensitivity. To advance the understanding of the
impact of these differences, research to identify or characterize vulnerable and sensitive subpopulations
and early lifestage susceptibility, address populations experiencing disproportionate adverse impacts
(for example, from climate change disasters) as well as cumulative impacts, are now integrated into
VCTM (CSS.5.1 and CSS.5.2).

Research Area 6: Ecotoxicological Assessment and Modeling (ETAM)

A tiered risk assessment approach is typically used to evaluate and regulate the potential impacts of
pesticides and other chemicals on ecological resources. Chemicals are first screened using rapid
assessment tools that require minimal data, followed by more detailed and complex assessments for
selected chemicals and scenarios. For chemicals and ecological species with limited data, assessments
must rely on modeled estimates of exposure and effects. The ETAM RA will advance efficient and
integrated modeling approaches to improve risk assessments of chemicals with limited data, as well as
more complex, refined approaches that can address data-rich applications. The integrated models span
the sequence of events typical of ecological toxicity, including environmental release, fate and transport,
exposure, internal dosimetry, metabolism, and toxicological responses relevant to organismal- and
population-level effects in species of interest to Agency decisions. Further, the effects of climate change
will be a key consideration in developing the Outputs in this RA.

The ETAM RA addresses a wide range of partner priorities related to ecotoxicology. The EPA is under
legislative mandates to evaluate the potential health and ecological effects of new and existing
pesticides. Work to inform pesticide risk assessments is included in this RA (Output CSS.6.1). Further,
assessing the safety of pesticides specifically to pollinators is an Agency priority (Output CSS.6.2). More
generally, to inform ecological risk assessments and decisions, data are needed on the adverse effects of
chemical stressors to ecologically relevant aquatic and terrestrial species (Output CSS.6.3), and
approaches are needed for using surrogate species in these assessments Output (CSS.6.4). A focus on
improving ecological methods and models related to PFAS will be included in this RA (Output CSS.6.5).
Research under ETAM offers a valuable opportunity to address cross-cutting issues like climate change
(CSS.6.1, CSS.6.2, CSS.6.3, CSS.6.4) and cumulative impacts (CSS.6.5) in an integrated way. For example,
research in this area will develop and demonstrate ecological models to characterize environmental
contaminants for risk assessment at national, regional, and local scales. This range of scales can be used
to understand environmental conditions affecting populations experiencing disproportionate adverse
impacts, for example, from climate change.

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Topic 3: Knowledge Delivery and Solutions-Driven Translation to
Support Chemical Safety Decision Making

Regulatory decisions in chemical safety are complex and involve the interpretation of multiple data
streams across a wide variety of disciplines. Research under this Topic will focus on continuing to
improve the underlying chemical and biological knowledge, efficient management and integration of
knowledge and information, and developing mature software tools relevant to chemical safety
evaluations in a scientifically robust, transparent manner. This work will aid the translation of these
approaches by evaluating, establishing, and demonstrating their effectiveness to EPA partners. The
intended impact is for risk assessors and decision-makers to have confidence that the new approaches,
data, and tools developed in CSS are scientifically sound and improve environmental decision making.

Research Area 7: Chemical Characterization and Informatics (CCI)

Chemistry and the use of structural information to predict properties and activities of chemicals are a
fundamental part of chemical safety decision making. The CCI RA will focus on providing the high-quality
chemical structures and advancing the computational models and analog approaches used to predict
those properties. The chemical structures and associated identifiers will be extensively curated and
quality checked to ensure the information is accurate. Research will include quantitative structure-
activity relationship (QSAR) models for physicochemical properties and chemical transformation as well
as systematic approaches to read across and cross-species extrapolation. This research will improve the
understanding of chemical fate and activity in organisms (human and ecological receptors) and the
environment through the use of cheminformatics and bioinformatics, which will provide important input
relevant to understanding priorities in climate change, populations experiencing disproportionate
adverse impacts, and real-world exposure to chemical mixtures. Work under this RA is intended to be
complementary to research conducted under the HERA program and may involve collaborative research
efforts between scientists within the HERA and CSS programs. For example, data generated by CSS may
inform HERA assessment solutions.

The CCI RA will address many foundational partner needs. The generation and curation of data relevant
to chemical substances, structures, and properties (Output CSS.7.1) are required for a broad array of
Agency decisions and are needed to develop and refine structure activity relationship models in support
of risk assessment (Output CSS.7.3). In addition, the Agency utilizes chemical categories and analog
approaches to fill data gaps in TSCA (Output CSS.7.4) and performs cross-species extrapolation in
ecological risk assessments (ERAs) generally and specifically for the Endangered Species Act (ESA)
(Output CSS.7.2). The CCI RA will also include a focus on investigation of PFAS (Output CSS.7.5). The
cross-cutting priority of cumulative impacts (CSS.7.1, CSS.7.5) will be addressed in this RA through the
analysis of chemical mixtures occurring in real-world scenarios.

Research Area 8: Integration, Translation and Knowledge Delivery (ITK)

High-throughput NAMs, coupled with continually expanding amounts of traditional hazard and exposure
data, enable more informed chemical safety decisions, assuming data are accessible and can be
integrated. The ITK RA will integrate and translate chemical information to better inform partners'
specific needs. The RA serves to bring together work from across the CSS portfolio, and to translate CSS
research for use in chemical safety decision making, ranging from prioritization to risk determinations.
Efforts in this RA will build confidence in the use of CSS data by building and supporting systems to

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ensure that key data, tools, and models are appropriately managed, tracked, and satisfy quality
standards. As the keystone for data dissemination and translation in the CSS research program, this RA
will also support efforts to ensure cross-disciplinary tools and knowledge are available and accessible in
forms convenient for partners, both through tool availability and through directed translation and
communication efforts. Work under this RA is intended to be complementary to research conducted
under the HERA program and may involve collaborative research efforts between scientists within the
HERA and CSS programs. For example, data generated by CSS may inform HERA assessment solutions.

By integrating and translating chemical information from across the CSS portfolio, the ITK RA will inform
and address priority needs of Agency partners for a range of chemical safety decisions. The availability
and accessibility of well-documented data to support decision making is needed to support the efficient
implementation of mandates under chemical safety legislation (e.g., TSCA, FIFRA). In the ITK RA, data
availability and accessibility will be addressed through both integration of data systems (Output CSS.8.1)
and subsequent knowledge delivery (Output CSS.8.2). In addition, the need to synthesize information
across multiple scientific domains for the implementation of legislative mandates will be addressed
through cross-disciplinary integration, decision support workflows, and applied case studies (Output
CSS.8.3). ITK will include a specific focus on strengthening the science to support new chemicals
evaluation (Output CSS.8.4) and improved translation of research through training, outreach, and
engagement (Output CSS.8.5). With an increased emphasis on improved integration and translation of
information from across all RAs, ITK will support all Agency cross-cutting priorities.

Implementing the Strategic Research Action Plan

In collaboration with EPA program, regional, state, and Tribal partners, ORD scientists and engineers
design specific research products responsive to the Outputs outlined in the StRAPs. During the
implementation of the previous FY19-22 StRAPs, ORD piloted a successful process in which Research
Area Coordination Teams (RACTs), made up of ORD scientists and engineers, EPA program and regional
staff, and state members, collaborated to determine the individual research products responding to
each Output. ORD is continuing this process for the FY23-26 StRAPs.

Each Output in the StRAPs is reviewed by a RACT, which develops goals and objectives for the Output
and establishes criteria for the work needed to accomplish it. ORD researchers propose research
products, which the RACT reviews and refines to ensure products will meet the goals and objectives of
the Output and reflect the timing and specific needs of EPA program and regional, state, and Tribal
partners. RACT members serve as liaisons to their programs or organizations, which ensures that ORD's
partners are able to provide input into the proposed research products. Products developed to address
the Outputs may take the form of assessments, reports, tools, methods, journal articles, or other
deliverables.

Throughout implementation of the StRAPs, ORD's researchers develop and deliver products. Research to
deliver StRAP products is implemented by staff scientists and engineers at research laboratories and
facilities in twelve locations across the country, which collectively comprise ORD's four Centers and four
Offices. EPA staff are joined in this endeavor by a network of collaborators and partners within and
external to EPA. In addition to the extensive intramural research program outlined in the StRAPs, ORD's
research portfolio includes extramural research programs that complement or add special focus areas to
the overarching program.

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Cross-Cutting Research Priorities

For priorities that cut across their programs, ORD's six NRPs will work together to integrate efforts,
provide a research portfolio aligned around the Agency's goals, and assist all of EPA's program and
regional offices, as well as states and Tribes. Where appropriate, the NRPs will combine efforts to
conduct research that advances the science and informs public and ecosystem health decisions and
community efforts on the following cross-cutting priorities (Appendix 4):

•	Environmental Justice

•	Climate Change

•	Cumulative Impacts

•	Community Resiliency

•	Children's Environmental Health

•	Contaminants of Immediate and Emerging Concern

EPA program and regional offices and external (non-EPA) partners and stakeholders will also be engaged
for these integrated efforts. Long-term, innovative, and multi-disciplinary research is needed to make
progress on these complex issues to support a sustainable pathway towards equitable distribution of
social, economic, health, and environmental benefits.

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Appendix 1: Summary of Proposed Outputs Mapped to
Program, Regional, State, and Tribal (PRST) Needs and Cross-
Cutting Priorities

The following table lists the proposed CSS Research Program Outputs organized by topic and mapped to
PRST needs and Cross-Cutting Priorities. It should be noted that the Outputs might change as new
scientific findings emerge and are also contingent on budget appropriations. See Appendix 2 for more
detailed descriptions of the PRST needs, Appendix 3 for detailed descriptions of the Outputs, and
Appendix 4 for detailed descriptions of Cross-Cutting Priorities.

Research Area

Output

PRST Need(s) and Cross-
Cutting Priorities

Topic 1: Chemical Evaluation

CSS.l High-
Throughput
Toxicology (HTT)

CSS.l.1 Advance a tiered, high-throughput
toxicity testing strategy

•	Tiered toxicity testing
strategies

•	Building confidence in
new approach methods
(NAMs)

•	Cumulative impacts and
mixtures

CSS.l.2 Provide structured and
computationally accessible data to support
tiered toxicity testing

CSS.l.3 Develop and apply novel technologies
for improving chemical hazard identification
for methodologically challenging chemicals

•	Tiered toxicity testing
strategies

•	Challenging chemicals and
methods

CSS.1.4 Develop and apply novel technologies
for improving chemical hazard
identification to address limitations of
existing methods

CSS.l.5 Inform data gaps in chemical safety
evaluations for high-priority toxicological
endpoints

•	Tiered toxicity testing
strategies

•	Priority toxicological endpoints

•	Vulnerable and sensitive
subpopulations

•	Children's environmental
health

•	Building confidence in NAMs

CSS.l.6 Advance a tiered testing evaluation for
Per- and Polyfluoroalkyl Substances (PFAS)

•	Contaminants of
immediate and emerging
concern (CIECs)

•	Cumulative impacts and
mixtures

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Research Area

Output

PRST Need(s) and Cross-
Cutting Priorities

Topic 1: Chemical Evaluation

CSS.2 Rapid
Exposure and
Dosimetry (RED)

CSS.2.1 Collect and curate exposure-
relevant data

•	Exposure factor data

•	Vulnerable and sensitive
subpopulations

•	Children's environmental
health

•	Environmental justice

CSS.2.2 High-throughput toxicokinetic (HTTK)
tools to support in vitro to in
vivo extrapolation

•	Toxicokinetics

•	Environmental justice

•	Cumulative impacts and
mixtures

CSS.2.3 Refine exposure models that enable
high-throughput exposure predictions for
chemicals

•	Chemical exposure models

•	Building confidence in NAMs

•	Cumulative impacts and
mixtures

•	Vulnerable and sensitive
subpopulations

•	Children's environmental
health

•	Environmental justice

CSS.2.4 Inform life cycle risk assessments for
new and existing chemicals

•	Chemical exposure models

•	Cumulative impacts and
mixtures

CSS.2.5 Develop and evaluate next-generation
monitoring methods for exposure assessment

•	Next-generation chemical
exposure monitoring

•	Cumulative impacts and
mixtures

•	Environmental justice

•	Climate change

CSS.2.6 Build confidence in the use of NTA for
exposure assessment through applications

CSS.2.7 Develop methods, data, approaches,
and frameworks to enable rapid exposure
evaluations for Per-and Polyfluoroalkyl
Substances (PFAS)

•	CIECs

•	Cumulative impacts and
mixtures

CSS.3 Emerging
Materials and
Technologies
(EMT)

CSS.3.1 Evaluate environmental impacts of
emerging materials on human and
ecological species

•	Emerging materials
and technology

•	Cumulative impacts and
mixtures

•	Environmental justice

CSS.3.2 Support for risk assessments of novel
products of synthetic biology, genome editing
and metabolic engineering

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Research Area

Output

PRST Need(s) and Cross-
Cutting Priorities

Topic 2: Complex Systems Science

CSS.4 Adverse
Outcome Pathways
(AOP)

CSS.4.1 Develop actionable, fit for
purpose high-priority AOPs to grow the AOP
Knowledgebase

•	Building confidence in NAMs

•	Climate change

•	Cumulative impacts and
mixtures

•	Environmental justice

•	Vulnerable and sensitive
subpopulations

•	Children's environmental
health

CSS.4.2 Develop and conduct strategic in
vitro and in vivo studies that support
development of high-priority AOPs

CSS.4.3 Conduct studies to elucidate and
define biological points of departure and
susceptibility factors that need to be
considered for quantitative application of
AOPs

CSS.4.4 Demonstrate the utility of AOPs along
with data derived from various sources to
inform risks and associated management
actions

•	Building confidence in NAMs

•	CIECs

•	Cumulative impacts and
mixtures

•	Climate change

CSS.4.5 Develop AOPs relevant to human
health and ecological impacts of Per- and
Polyfluoroalkyl Substances (PFAS) and
evaluate applicability across species, chemical
groupings, and mixtures

•	Building confidence in NAMs

•	CIECs

•	Cumulative impacts and
mixtures

•	Vulnerable and sensitive
subpopulations

•	Children's environmental
health

CSS.5 Virtual and
Complex Tissue
Modeling (VCTM)

CSS.5.1 Develop, characterize, and apply
organotypic and complex tissue models that
bridge between in vitro and organismal assays
for decision-relevant endpoints

•	Vulnerable and sensitive
subpopulations

•	Children's environmental
health

•	Tiered toxicity testing
strategies

•	Building confidence in NAMs

•	Cumulative impacts and
mixtures

•	Environmental justice

CSS.5.2 Develop and apply in silico agent-
based and computational models to evaluate
the effects of chemicals on biological
pathways

CSS. 6

Ecotoxicological
Assessment and
Modeling (ETAM)

CSS.6.1 Develop and demonstrate ecological
models to characterize risk of environmental
contaminants for risk assessment at national,
regional, and local scales

•	Pesticide risk assessment

•	CIECs

•	Threatened and endangered
species models

•	Climate change

CSS.6.2 Develop methods and data to assess
the impacts of pesticides on pollinators

•	Pollinators

•	Climate change

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Research Area

Output

PRST Need(s) and Cross-
Cutting Priorities

Topic 2: Complex Systems Science

CSS. 6

Ecotoxicological
Assessment and
Modeling (ETAM)

CSS.6.3 Identify, assemble, and curate toxicity
data for ecologically relevant species for risk
assessment (ECOTOX)

•	Chemical impacts on aquatic
and terrestrial species

•	Climate change

CSS.6.4 Advance approaches for using
surrogate species in ecological risk
assessment

•	Cross-species extrapolation of
toxicity

•	Climate change

CSS.6.5 Improve ecological methods and
models for predicting exposure,
accumulation, and effects of Per- and
Polyfluoroalkyl Substances (PFAS)

•	CIECs

•	Challenging chemicals and
methods

•	Cumulative impacts and
mixtures

Topic 3: Knowledge Delivery and Solutions-Driven Translation to Support Chemical Safety

Decision Making

CSS.7 Chemical
Characterization
and Informatics
(CCI)

CSS.7.1 Generate and curate data relevant to
chemical substances, structures, samples, and
properties

•	Chemical curation and
informatics

•	Cumulative impacts and
mixtures

CSS.7.2 Develop data, tools, and models to
support cross-species extrapolation for
human health and ecological assessments

• Cross-species extrapolation of
toxicity

CSS.7.3 Develop new and improve existing
structure activity relationship models to
support risk assessment

• Chemical curation and
informatics

CSS.7.4 Advancing chemical categorization
approaches for aiding the interpretation and
prediction of bioassay and toxicity outcomes

CSS.7.5 Advancing use of structural,
mechanistic, and toxicokinetic data to support
categorization and classification of Per- and
Polyfluoroalkyl Substances (PFAS)

•	CIECs

•	Cumulative impacts and
mixtures

CSS.8 Integration,
Translation and
Knowledge
Delivery (ITK)

CSS.8.1 Integrating data systems to enable
knowledge delivery

• Data availability and
accessibility

CSS.8.2 Knowledge delivery and
interoperability in support of chemical safety
decisions

•	Data availability and
accessibility

•	Building confidence in NAMs

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Research Area

Output

PRST Need(s) and Cross-
Cutting Priorities

Topic 3: Knowledge Delivery and Solutions-Driven Translation to Support Chemical Safety

Decision Making

CSS.8 Integration,
Translation and
Knowledge
Delivery (ITK)

CSS.8.3 Cross-disciplinary integration and
applied case studies to support chemical
safety decision making

•	Decision support and
translation

•	Building confidence in NAMs

•	Environmental justice

•	Climate change

CSS.8.4 Innovative science to support new
chemicals evaluation

•	Tiered toxicity testing
strategies

•	Building confidence in NAMs

•	Data availability and
accessibility

•	Decision support and
translation

CSS.8.5 Translation of research for chemical
safety decision making through
demonstration, training, outreach,
and partner engagement

•	Decision support and
translation

•	Building confidence in NAMs

•	Environmental justice

•	Climate change

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Appendix 2: Descriptions of Program, Regional, State, and Tribal
(PRST) Needs

The following describe, in more detail, the PRST needs summarized in the body of the Chemical Safety

for Sustainability Research Program StRAP for each Research Area and as listed in Appendix 1.

•	Building confidence in new approach methods (NAMs): Achieving the goals of characterizing the
risks for thousands of data-poor chemicals and reducing the use of animal testing—while continuing
to protect human health and the environment—requires the development and implementation of
new methods and approaches that demonstrate equivalent or better scientific quality and relevance
than existing approaches (TSCA Section 4(h)). As outlined in the EPA NAMs workplan, achieving
these goals involves the continued development and application of NAMs. NAMs can be used for
evaluating the toxicity of chemicals as well as characterizing exposure and toxicokinetics. To build
confidence in these new methods, integrated and synthesized knowledge is needed to establish the
scientific rationale that support their use in evaluating the potential human health or ecological risks
that are of management or regulatory concern—for example, within the Endocrine Disruption
Screening Program (EDSP). This work should inform incorporation of NAMs into human and
ecological risk assessment.

•	Tiered toxicity testing strategies: Tiered testing strategies are used to evaluate chemical safety in an
efficient, risk-based context. These strategies typically use higher throughput (HT) approaches to
prioritize chemicals for subsequent testing and to screen chemicals for potential hazards. The tiered
strategies include a range of test methods including HT assays, novel technologies, and relevant
traditional methods, where appropriate. While progress has been made on development of high-
throughput testing methods, there is a continuing need to demonstrate, evaluate, and apply them.
In addition, continued refinement and development of downstream data management and
processing are needed to provide actionable data to support tiered decision making for both human
health and ecological risks.

•	Priority toxicological endpoints: In Agency risk assessments, there exist a number of priority
endpoints that characterize the potential hazard of a chemical. The understanding of chemical
perturbation of estrogen, androgen, and thyroid signaling, steroid biosynthesis (e.g., as part of the
EDSP), manifestations of lung toxicity, developmental neurotoxicity (DNT), and
immunotoxicity endpoints are all of interest. There is a need for evaluating alternative approaches
for all priority endpoints, including valid in vitro methods and modeling approaches.

•	Vulnerable and sensitive subpopulations: Chemical assessments under TSCA must include
consideration of risks to vulnerable and sensitive subpopulations and lifestages. Since TSCA
promotes less reliance on traditional animal testing, NAMs (that reflect the best available
knowledge of human developmental biology and exposure) are needed to address these sub-
populations and lifestages, including potential adverse developmental outcomes.

•	Toxicokinetics: Acceptance and use of in vitro data for hazard characterization is limited, in part, by
uncertainties associated with extrapolation of dosimetry and metabolism. Most in vitro systems lack
the biotransformation capabilities of intact in vivo systems, raising the possibility of over-estimating
the hazard of compounds that may be rapidly metabolized in vivo or under-estimating the hazard of
compounds that may be transformed to more active metabolites. Additionally, there is a need to
understand the possible lifestage differences in metabolism, which may impact assessment of risk.

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Challenging chemicals and methods: There is a need to develop novel technologies to
address methodologically challenging chemicals (MCCs) as well as to address challenges with
existing methods (e.g., the need to develop new toxicological assays when existing assays do not
meet a need) to inform chemical risk assessments. MCCs are chemicals whose physicochemical,
behavioral, and toxicological properties are not well understood, and which typically fall outside of
the domain of applicability of existing assays, models, and analytical methods. Challenges with
existing in vitro methods arise, for example, when characterizing the inhalation toxicity of volatile,
semi-volatile, and aerosolized chemicals.

Exposure factor data: Models to estimate exposure to chemicals in consumer or occupational use
products require a variety of inputs, including information on chemical ingredients and product
composition, product use patterns (e.g., duration and frequency of product use), and human
behavioral data, including how behaviors may vary by lifestage or between consumers and
occupational users. For life cycle risk assessments, there is a need for automated standardized
emission and waste inventories. For many chemicals and product types, there remain critical gaps in
this information.

Chemical exposure models: Chemical exposure evaluations require approaches to estimate
exposure for a variety of high-priority pathways, including scenario-specific models particular to
consumer products and materials in the indoor environment, as well as occupational, ambient, and
ecological pathways. Chemical exposure models are also needed to inform life cycle risk
assessments for new and existing chemicals. Consideration must also be given in chemical exposure
evaluations to lifestage differences which may impact assessments. When appropriate, ORD models
should be harmonized with program office models.

Next-generation chemical exposure monitoring: Chemical assessments under TSCA, emergency
response scenarios, and other chemical assessments consider exposure and conditions-of-use
information which may be reflected in monitoring data. Traditional monitoring, while considered
the gold-standard of exposure data, is resource- and time-intensive. Therefore, methods and tools
(e.g., NTA methods) are necessary to bring next-generation high-throughput monitoring data into
agency decision making.

Emerging materials and technology: Safety assessments of emerging materials (e.g., novel products
of synthetic biology, nanopesticides, nano/micro plastics, engineered nanomaterials, and incidental
nanomaterials) require information on human and ecological exposure from consumer products and
environmental releases. Additional data are needed to characterize potential release of and
exposure to these chemicals and materials.

Pesticide risk assessment: FIFRA mandates that EPA evaluate the potential health and ecological
risks of new and existing pesticides. Though a substantial amount of data is required in submissions
to evaluate pesticides, additional testing may be needed to further evaluate toxicological pathways
of concern. In others, further analysis and interpretation of the data are required to inform decision-
relevant endpoints.

Pollinators: Assessing the safety of pesticides to pollinators is an Agency priority, as detailed in the
Pollinator Protection Strategic Plan. Additional methods and data to support evaluation of effects
in honeybees and other non-Apis bees are needed; in particular, methods to identify effects to other
species of bees when honeybees are not a suitable surrogate. Honeybee colony simulation
models continue to be a critical tool informing pesticide safety assessments. Further, examination of
the relative sensitivity of the honeybee to non-Apis bees and other insect pollinators (e.g.,
butterflies) is needed.

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Chemical impacts on aquatic and terrestrial species: The ECOTOX Knowledgebase, containing data
on adverse effects of single chemical stressors to ecologically relevant aquatic and terrestrial
species, is a critical tool used in ecological risk assessments and decisions. There exists a need for
the Knowledgebase content to reflect the current state of knowledge, and for enhanced analysis
capabilities and improved data acquisition and retrieval methods.

Cross-species extrapolation of toxicity: Chemical safety assessments are often conducted with
limited or no toxicological data for the animal or plant species of interest. Further, it is frequently
impractical to generate new data for those species. Therefore, the sensitivity of each species must
be estimated based on scientifically based methods of cross-species extrapolation. The problem is
compounded for ecological assessments by the large number of species in the wild and is
particularly problematic for species listed under the Endangered Species Act.

Threatened and endangered species models: The Endangered Species Act outlines requirements to
consider potential impacts from the cumulative exposure to multiple environmental chemicals,
including pesticides. There is a need to further develop methods used to complete national level
endangered species risk assessments for hundreds of pesticides and thousands of threatened and
endangered species.

Chemical curation and informatics: Curated chemical structures and scientifically defensible
physicochemical properties, metabolism and transformation products are required for Agency
chemical safety decisions. However, such data may not be available for chemicals of interest. There
is a need to advance methods for describing and storing chemical structures, increasing the
availability of physicochemical properties (through measurement or modeling), and applying read-
across and chemical categorization techniques to support decision making.

Data availability and accessibility: Chemical safety decisions and management can be hindered by
the lack of ready access to the ever-expanding array of data, tools, and models. Data used to
support decision making must be well documented and meet relevant quality criteria standards.
Though many chemical safety resources are available, obtaining access to and integrating multiple
data sources can be time-consuming and complex. Readily available and accessible resources can
support the efficient implementation of mandates under chemical safety legislation (e.g., TSCA,
FIFRA).

Decision support and translation: In the implementation of legislative mandates, there often exists
a need to synthesize information across multiple scientific domains (e.g., bringing together chemical
exposure and toxicity data to investigate the potential impacts on human health and the
environment). Decision support tools and prioritization workflows may be needed to support
chemical safety decisions. Further, case study applications showing the use of data, models, and
tools in decision making are needed to build confidence needed for regulatory acceptance. Outreach
and engagement that include demonstration and training are recognized needs for appropriate
application of the data and tools in decision making.

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Appendix 3: Output Descriptions

The following describe, in more detail, the Chemical Safety for Sustainability Research Program Outputs
listed in Appendix 1. Outputs are planned under each Topic and respective Research Area (RA).

Topic 1: Chemical Evaluation

RA CSS.l: High-Throughput Toxicology (HTT)

Output CSS.l.1: Advance a tiered, high-throughput toxicity testing strategy

There is a continuing need to demonstrate and apply emerging technologies to provide actionable
information to support tiered decision making and address key information needs of assessments. This
Output is intended to produce hazard information using a tiered testing approach in support of
defensible, non-traditional, fit-for-purpose risk assessment applications. Tiered testing strategies
typically use higher throughput (HT) approaches and high-content methods (e.g., transcriptomics,
phenotypic profiling, and other methods) to screen chemicals for potential hazards followed by targeted
assays to confirm activation or inhibition of a particular cellular pathway or molecular target. Data from
HT assays along with other traditional and novel methods will be used to build confidence in the use of
NAMs for decision making. Both human and ecological receptors may be covered under this Output.
Examples of activities that could be covered include methods/assay development (as needed);
generating data from developed assays (e.g., high-throughput transcriptomics (HTTr)), high-throughput
phenotypic profiling (HTPP; cell painting), ecotoxicogenomics; case studies that link HT/high-content
approaches; confirmation by targeted assays; in vivo studies to inform rapid chemical assessments; non-
HT studies (e.g., 90 day studies) to build confidence in NAMs results; likely tissue or organ effects using
organotypic culture models (e.g., as provided under the VCTM RA); and data generation for real-world
mixtures identified in RED that may have relevance to disproportionately impacted populations, or are a
result of catastrophic climate change events. This Output involves coordination and collaborative
research efforts between scientists within the HERA and CSS research programs.

Output CSS.l.2: Provide structured and computationally accessible data to support tiered
toxicity testing

To support the advancement of NAMs, there is a need for well-documented, curated hazard information
from varied available sources including in vitro, human, and animal studies. Work may include expansion
of existing databases (e.g., ToxValDB, ToxRefDB, InvitroDB) through extraction and curation of data from
the published literature, or pipelining of data generated from high-throughput (HT) assays (e.g., HTTr,
HTPP). Efforts under this Output will include the development of computational or modeling tools,
including new approaches to data interpretation in the context of risk assessment (e.g., data mining and
machine learning techniques to automate data collection, curation, and pipelining) may all be employed,
to make data interpretable in the context of risk assessment applications.

Output CSS.l.3: Develop and apply novel technologies for improving chemical hazard
identification for methodologically challenging chemicals

MCCs are chemicals whose physicochemical, behavioral, and toxicological properties are not well
understood, and which typically fall outside of the range of current assays, models, or analytical
methods. There is a need to develop and apply approaches for measuring or modeling the toxicity and

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exposure of these MCCs, including mixtures, to inform assessments and decision making. It is the intent
to develop and apply novel technologies to address this need.

Output CSS.1.4: Develop and apply novel technologies for improving chemical hazard
identification to address limitations of existing methods

To support the advancement of NAMs with the goal of reducing the use of animals for testing, there is a
need for development of new medium- to high-throughput methodologies and approaches to improve
chemical hazard identification when existing methods are not sufficient to provide the necessary
information. Work included under this Output may include improvements to medium- to high-
throughput assays (e.g., xenobiotic metabolism, repeated dose), development of novel technologies to
assess chemical hazard of mixtures from formulations/complex mixtures, and repeated dosing to inform
cumulative impacts research and address challenges related to assessment of inhalation toxicology.

Output CSS.1.5: Inform data gaps in chemical safety evaluations for high-priority
toxicological endpoints

In agency risk assessments, information and analysis are needed on priority endpoints for chemical
assessments. This Output is intended to address the continued need to develop datasets, models,
assays, and frameworks for understanding chemical perturbation of estrogen, androgen, and thyroid
signaling, and steroid biosynthesis (e.g., as part of EDSP). In addition, research to reduce uncertainty for
developmental neurotoxicity and other toxicological endpoints (e.g., immunotoxicity) deemed high
priority by program partners will be addressed in the Output. Research under this Output may include
both fit-for-purpose analyses of existing HT assay data as well as generation of new data, analyses,
and/or methods.

Output CSS.1.6: Advance a tiered testing evaluation of bioactivity for Per- and Polyfluoroalkyl
Substances (PFAS)

Per- and polyfluoroalkyl substances (PFAS) chemicals are frequently being detected in a variety of
environmental media. As a class, PFAS chemicals are structurally diverse and typically lack adequate
exposure and hazard information needed to support decisions. This Output is intended to generate
additional data to continue refining PFAS categories, identify potential effects of individual PFAS,
develop points of departure and toxicity values for data-poor PFAS, and address effects of
environmentally relevant PFAS mixtures. The Output will be guided by the objectives of the EPA's PFAS
Strategic Roadmap, to meet the goals of program offices (e.g., the National PFAS Testing Strategy). The
research could inform chemical grouping and mixtures strategies. A library of PFAS chemicals that could
be used to leverage research will continue to be maintained.

RA CSS.2: Rapid Exposure and Dosimetry (RED)

Output CSS.2.1: Collect and curate exposure-relevant data

A wide variety of exposure relevant data are necessary to support chemical safety decision making for
priority chemicals and mixtures. Relevant data streams include those that describe chemical source,
release, and fate and transport, as well as those that characterize human and ecological receptor
populations. These data streams are often highly heterogeneous, and must be curated and harmonized
to be fit-for-purpose for use as input for chemical exposure models both within and outside of ORD. This
Output will cover both the curation of reported exposure-relevant data and new laboratory experiments

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to collect measured data, harmonization of meta-data, and subsequent expansion of established
databases (e.g., CPDat, ChemExpoDB, MMDB, FuSE). Data types of interest may include chemical use
data (including information about chemical functional role); chemical source data (e.g., reported or
measured concentrations in consumer products or articles); human behavior patterns (including
consumer product habits and practices); human (general population, consumer, occupational),
ecological, and environmental chemical monitoring data; chemical production, release, or emission
data; and built-environment characteristics. The scope of this Output includes the curation of existing
data and generation of new, relevant experimental data. Where available, data specific to populations
and settings of interest will be targeted, including data related to occupational settings, data specific to
early lifestage exposures, and data informing investigation of exposures in populations experiencing
disproportionate adverse impacts to inform environmental justice concerns. Methods used in this
Output may include implementation of emerging tools in data mining, text mining, and machine learning
to ensure that exposure factor information is optimally representative of current conditions and trends
(e.g., in chemical use or manufacture, product formulation, or human/consumer behavior). The data
delivered under this Output will be used to support partner decisions related to prioritization of large
chemical inventories, individual chemical assessments, or as input for chemical exposure models.

Output CSS.2.2: High-throughput toxicokinetic (HTTK) tools to support in vitro to in vivo
extrapolation

Toxicokinetics (TK) provide critical information for interpreting both toxicological data (in vitro and in
vivo) and exposure information (for example, biomonitoring). However traditional TK methods require
intensive, chemical-specific in vivo data generation and TK data is unavailable for most chemicals. HTTK
tools fill the TK data gaps by using generic, physiologically based TK (PBTK) or empirically based
compartmental models that can be parametrized with TK data rapidly measured in vitro or predicted in
silico. This Output covers further developments of high-throughput toxicokinetic (HTTK) models and
tools; measurement and prediction of TK parameters; and evaluation of the performance of HTTK
approaches. Development of TK models includes models that reflect exposure routes of interest;
lifestages of interest; non-human species of interest; challenging chemistries; and absorption,
distribution, metabolism, and excretion (ADME) processes of interest. Measurement and prediction of
TK parameters include new and existing in vitro TK measurement techniques; new in vitro culture
models for absorption, metabolism, and excretion; in silico approaches to rapidly predict TK parameter
values; disposition of chemicals within in vitro test systems, and approaches to estimate population TK
variability, particularly for potentially sensitive or highly exposed sub-populations and lifestages. The
addition of new measurement techniques, in vitro methods, or in silico models will focus on TK
parameters that contribute to the highest uncertainty in existing HTTK models for environmental
chemicals (e.g., restrictive vs. nonrestrictive clearance; active transport, slowly cleared compounds).
Evaluation of HTTK performance includes ongoing collection, curation, and experimental generation of
in vivo measured TK data, as well as statistical and computational methods for quantitative comparison
of these TK data with HTTK predictions. This Output involves coordination and collaborative research
efforts between scientists within the HERA and CSS research programs.

Output CSS.2.3: Refine exposure models that enable high-throughput exposure predictions
for chemicals

Risk-based analysis of chemicals requires estimates of both toxicity and exposure. Exposure estimates
(for example, measured biomonitoring concentrations or exposure predictions for humans or ecological

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species) are unavailable for most of the tens or hundreds of thousands of chemicals thought to be
present in commerce and the environment. Exposures are complex, involving multiple sources,
pathways, and routes, and largely determined by behaviors and location (i.e., time-activity patterns).
New and improved exposure models are needed that can address this complexity while still being able
to address thousands of chemicals. In general, research covered in this Output will align with and
complement existing models in use by program partners. This Output includes refinement and
development of high-throughput exposure models that address key chemical sources (e.g., consumer
products and articles, biosolids), exposure pathways (e.g., consumer, occupational, and ambient
pathways), and human and ecological receptor populations. Methods will also be developed for
quantification of both uncertainty and variability in exposure predictions, and to continue refinement of
consensus statistical modeling frameworks that integrate the predictions of various exposure models
with other exposure-relevant data. Of particular interest is the development of new models for
exposure-relevant human behaviors that incorporate demographic or geographic specificity and
harmonization of existing ORD and program partner models. The various models developed under this
Output may allow for the prediction of exposures across lifestages (including early lifestages), the
consideration of other susceptible or highly exposed populations (e.g., workers), the prediction of
chemical co-exposures to inform cumulative impacts research, and investigation of exposures in
populations experiencing disproportionate adverse impacts to inform environmental justice concerns.

Output CSS.2.4: Inform life cycle risk assessments for new and existing chemicals

Conceptual models are used to understand and quantify chemical releases from various well-defined
industrial activities associated with the conditions of use for the substance. These industrial activities
can occur throughout the chemical life cycle and involve any aspect of synthesis, product manufacturing,
facility transfer, and end-of-use management (recycling, recovery, reuse, or disposal). The various
activities may be regulated by separate EPA statutes (e.g., TSCA, municipal solid waste management
under RCRA). Often there are data gaps associated with the various activities throughout the chemical
life cycle and generic activity models are used to address those gaps, including for the estimation of
workplace and ambient releases. These data and generic activity models may be necessary for
evaluating exposure to both new and existing chemicals. Work under this Output is intended to develop
new and improved models and tools for estimating common scenario needs, provide data and methods
for estimating new chemical applications, develop end-of-use models for chemical disposal and life cycle
releases, and provide support for occupational exposure modeling. Work will complement existing
generic scenarios and models in use by program partners. Generic scenario and end-of-use research will
support life cycle chemical risk evaluations and should be able to support alternatives assessments.

Output CSS.2.5: Develop and evaluate next-generation monitoring methods for exposure
assessment

Next-generation monitoring methods are necessary to inform the diversity and magnitude of chemical
exposures in a wide variety of scenarios. In particular, new monitoring methods are needed to rapidly
characterize chemicals of immediate and emerging concern (CIECs), real-world mixtures, substances of
unknown or variable composition (UVCBs), and methodologically challenging analytes. NTA methods,
which utilize high-resolution mass spectrometry, allow the identification of previously unknown or
understudied chemicals, and the characterization of complex chemical mixtures, in consumer products
and virtually all environmental and biological media. NTA methods further allow rapid quantitation and
risk-based prioritization of newly identified analytes. Work under this Output will focus on the

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development of analytical and computational tools that will enable defensible and transparent
implementation of NTA methods to support rapid chemical evaluations. This includes the development
of proof-of-concept software and web applications to support ORD researchers and partners. This also
includes the development of standardized performance metrics, benchmarks, and guidance for the
global NTA research community. Guidance on NTA method performance evaluation will be developed in
close coordination with the international Benchmarking and Publications for Non-Targeted Analysis
(BP4NTA) workgroup. Performance metrics and benchmarks will be established considering data from
EPA's Non-Targeted Analysis Collaborative Trial (ENTACT).

Output CSS.2.6: Build confidence in the use of NTA for exposure assessment through
applications

Building confidence in the use of NAMs for exposure assessment is necessary before such methods can
be adopted for use in chemical safety decision making. Applications of NAMs, including in regulatory-
relevant contexts, can build confidence in their ability to provide sound data to inform exposure
assessment. The application of NTA methods will be covered in this Output, including but not limited to:
measurement of chemicals in various media using NTA, including biosolids or identification of CIECs; the
use of NTA methods to inform climate change research, specifically, identification of chemicals in
environmental media after catastrophic events such as wildfires or flooding; and advancing the
understanding of the exposome to inform cumulative impacts research.

Output CSS.2.7: Develop methods, data, approaches, and frameworks to enable rapid
exposure evaluations for Per- and Polyfluoroalkyl Substances (PFAS)

Concern over exposure to and potential health effects of per- and polyfluoroalkyl substances (PFAS) has
increased significantly as more is learned about their widespread environmental presence, persistence
and bioaccumulative potential. The limited measurement, monitoring, toxicokinetic and toxicologic data
currently available is inadequate to inform risk evaluations across this diverse group of chemicals. This
Output is intended to address key data gaps that include but are not limited to measurement and
characterization of PFAS emissions; biotransformation, degradation, and/or fate in a broad range of
environmental media and source substances; collection and/or generation of PFAS biomonitoring data;
and continued consideration of in vitro toxicokinetics, including metabolism, transport/uptake, protein
binding and disposition to refine current in vitro-in vivo extrapolation approaches to predict internal
dosimetry. Continued analytical evaluation of PFAS quality and stability in biological matrices and
screening stocks used across CSS research areas is planned. The resulting data will be employed in a
wide range of modeling efforts that will advance and refine modeling of direct and indirect PFAS
exposure, provide a PFAS-specific exposure modeling workflow, and inform other efforts describing
PFAS biotransformation/fate, exposure reconstruction, and dosimetry. The data will also be made
available for subsequent in silico model development. The research will leverage the development of
these methods, data, and approaches to refine and expand current PFAS toxicokinetic and exposure
NAMs and models. The Output will be guided by the objectives of EPA's PFAS Strategic Roadmap, to
meet the goals of program offices (e.g., the National PFAS Testing Strategy).

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RA CSS.3: Emerging Materials and Technologies (EMT)

Output CSS.3.1: Evaluate environmental impacts of emerging materials on humans and
ecological species

Safety assessments of emerging materials require evaluation of the environmental impacts of emerging
materials on humans and ecological species. Emerging materials of relevance and interest to Agency
partners may include nanopesticides, nano/micro plastics, engineered nanomaterials, and incidental
nanomaterials, depending on partner interest. Specifically, support to program offices for
implementation of an evaluation framework for nanomaterials under FIFRA is an ongoing need.

Research relevant to the impact of emerging materials on disproportionately impacted communities to
inform environmental justice concerns, and on work to inform cumulative impacts research, is of
particular interest.

Output CSS.3.2: Support for risk assessments of novel products of synthetic biology, genome
editing and metabolic engineering

Over the last decade, there has been explosive growth in development of novel products of
biotechnology through genome editing, synthetic biology, and metabolic engineering. Consequently, the
scale, scope, and complexity of biotechnology products that EPA is mandated to make prompt
regulatory decisions on has increased greatly. When these products have unique properties and
uncertain risks, they pose additional regulatory challenges. This is true for many novel biotechnology
products such as engineered microbes (regulated under TSCA, as amended by the Frank R. Lautenberg
Chemical Safety for the 21st Century Act) and biopesticides (regulated under FIFRA). Safety questions
remain regarding potential impacts to human health and the environment from these products. The
goal of this research is to improve the certainty and timeliness of biotechnology risk assessments made
by OPPT and OPP. More broadly, this will increase opportunities to realize the potential benefits of
novel biotechnology while avoiding unintended consequences. Research from this Output will address
needs prioritized by OPPT and OPP for new data and models to inform risk assessments of engineered
microbes and biopesticides that are intended for open release into the environment. Focus areas will
include but are not limited to long-term stability and reliability of synthetic biology microbial
biocontainment strategies and potential for horizontal transfer of genetic material out of and into
related microorganisms; ecological impacts of synthetic biology genetic constructs in microbial genomes
for bacteria or fungi used as biofertilizers, bioremediation agents, and biosensors; and impacts of
various formulants on biopesticidal substances.

Topic 2: Complex Systems Science

RA CSS.4: Adverse Outcome Pathways (AOP)

Output CSS.4.1: Develop actionable, fit for purpose high-priority AOPs to grow the AOP
Knowledgebase

To increase efficiency and reduce costs and animal use associated with chemical safety assessment,

EPA's program offices and regions are interested in incorporating data from NAMs, including in vitro
assays or in silico models, into their decision making. However, biological effects (molecular initiating
events) measured or predicted using NAMs are typically not the apical adverse outcomes that have been
traditionally used in regulatory decisions. Thus, linking pathway-based biological effects (e.g., binding to

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a receptor, activation of transcription factors, inhibition of an enzyme activity, metabolomic changes,
alteration of gene expression/epigenetics) to probable apical hazards will help facilitate the use of
NAMs. The AOP framework provides a systematic approach to organizing and synthesizing existing
knowledge that supports extrapolation from pathway-based biological effects to apical hazards. To be
effective, a broad knowledgebase of AOPs linking measurable biological effects to adverse outcomes of
significance to risk assessment is needed. Work under this Output would develop fit-for-purpose AOPs
deemed high-priority by partners, AOPs relevant to Agency-wide priorities (e.g., contaminants of
immediate and emerging concern), and AOPs that capture the relatively non-specific interactions of
environmental chemicals with biological systems. The Output includes work needed to undergo
comprehensive technical review with the goal of endorsement from the OECD. This work may include
experimentation to fill data critical gaps along with literature reviews, and technical review submissions.

Output CSS.4.2: Conduct strategic in vitro and in vivo studies that support development of
high-priority AOPs

This Output is intended to provide partners with products that foster development of a common,
integrating framework with which to link chemical hazard and exposure information from NAMs and
better understand linkages between molecular initiating events and apical endpoints, particularly non-
transient/relatively fixed human and ecological impacts at the whole organism level. AOPs provide a
scientifically defensible foundation for extrapolating from NAMs data to predicted apical outcomes,
potentially increasing confidence in the use of NAMs data in risk assessment and regulatory decision
making. Successful AOP development for pathways deemed high priority by partners requires sufficient
fundamental knowledge about biological pathways that is in part derived from experimental studies.
This includes identification of relevant biological effects measurable by NAMs and generation of
strategic confirmatory in vivo experimental testing refinements or human-based organotypic models
and microphysiological systems to demonstrate effects at the tissue, organ, and organism-levels and are
linked with apical endpoints of regulatory concern. Complementary efforts using both NAMs and
traditionally derived data would help provide the scientific knowledge to support their use in evaluating
the potential human health or ecological consequences that are of management or regulatory concern.

Output CSS.4.3: Conduct studies to elucidate and define biological points of departure and
susceptibility factors that need to be considered for quantitative application of AOPs

The organizational scaffold of an AOP defines requisite key events (KEs) bridging early molecular effects
with adverse outcomes of regulatory interest. By assigning quantitative relationships for these KEs, one
can establish points of departure that may be measured in short-term assays for chemical screening,
create computational models for predictive assessments, and provide critical characterization of the link
between internal dose associated with the KEs and external exposure that will facilitate the required
dose-response analyses. Quantitative relationships are dependent on extrinsic and intrinsic modifying
factors that may shift dose-response relationships for defined AOPs following exposure to an
environmental toxicant. These factors may include prior exposures (e.g., early lifestage exposure to
environmental chemicals, which alters developmental programming), pre-existing conditions, age, and
genetic/epigenetic-based susceptibilities. By capturing this type of information in AOPs, key
susceptibilities can be defined and quantified (e.g., environmental justice concerns), informing
cumulative impacts research and risk determination.

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Output CSS.4.4: Demonstrate the utility of AOPs along with data derived from various sources
to inform risks and associated management actions

Environmental authorities increasingly detect CIECs in environmental media. However, the toxicological
data required to inform decision making can be lacking, particularly for complex mixtures of
contaminants. This makes it difficult for managers to assess which CIECs pose risks, the types of effects
to expect, and how to prioritize, monitor, and manage relevant risks. AOPs and AOP networks are
intended to address these needs, in particular related to real-world mixtures, and can be used to
identify and address data gaps that currently lead to uncertainty in chemical safety evaluations. This
Output is intended to demonstrate how pathway-based data from existing sources (e.g., Adverse
Outcome Pathway Database (AOP-DB), ECOTOX knowledgebase, ToxCast database) or from effects-
based monitoring and surveillance approaches can be used, along with AOPs, to inform risks and
associated management actions.

Output CSS.4.5: Develop AOPs relevant to human health and ecological impacts of Per- and
Polyfluoroalkyl Substances (PFAS) and evaluate applicability across species, chemical
groupings, and mixtures

Given the large number of PFAS of concern, knowledge gaps cannot be adequately addressed solely
through collection of data from whole animal tests. Consequently, there is a need to develop predictive
approaches to support assessment of PFAS. These predictive approaches feature databases (e.g.,
ECOTOX, electronic medical records) and tools like computational models, pathway-based in vitro
assays, and short-term in vivo tests with molecular/biochemical endpoints. While these tools can
produce biological response data more efficiently than conventional whole-animal tests, linking
mechanistic information to the apical endpoints facilitates application of the data to risk assessment.
Application of the AOP framework to challenges associated with assessing human health and ecological
effects of PFAS addresses several practical needs, including (a) developing predictive assessment
approaches; (b) organization/integration of complex biological datasets to identify critical knowledge
and evidence gaps; (c) enhancement of the use of observational and mechanistic data for effects
prediction to support decision making; (d) focus testing on endpoints, species, lifestages, and taxa of
most concern for given chemicals; and (d) support assessment of effects of PFAS mixtures. The Output
will be guided by the objectives of the EPA's PFAS Strategic Roadmap, to meet the goals of program
offices (e.g., the National PFAS Testing Strategy).

RA CSS.5: Virtual and Complex Tissue Modeling (VCTM)

Output CSS.5.1: Develop, characterize, and apply organotypic and complex tissue models that
bridge between in vitro and organismal assays for decision-relevant endpoints

Tiered testing strategies are used to evaluate chemical safety in an efficient, risk-based context. These
strategies typically use higher throughput approaches to screen chemicals for potential hazards and
prioritize chemicals for subsequent testing. There is a need to develop, demonstrate, and apply
organotypic and complex tissue models that can reduce uncertainty and ensure use of the best available
science in high-throughput testing strategies, with a focus across all lifestages relevant to priority target
tissues. Specifically, the integration and evaluation of phenotypic responses from human-based
organotypic and complex tissue model systems will help bridge the gap between the molecular pathway
endpoints measured in high-throughput in vitro assays with the tissue and organ apical effects observed
with in vivo toxicity studies. In addition to organotypic and complex tissue modeling, work may use

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microphysiological systems for hazard characterization or further AOP development. Results from this
Output may be used to better understand the effects of chemicals on early lifestages, the impacts of
exposure to cumulative stressors, and concerns of disproportionately impacted communities.

Output CSS.5.2: Develop and apply in silico agent-based and computational models to
evaluate the effects of chemicals on biological pathways

Chemical assessments typically rely on apical endpoints at the tissue, organ, or organism-level to derive
quantitative points of departure or classify and label hazards. In addition, under chemical safety
legislation (e.g., TSCA, FIFRA, FFDCA), EPA considers risks to vulnerable subpopulations and early
lifestages, with a goal of reduced reliance on traditional animal testing. Thus, NAMs are needed to
address adverse outcomes that reflect the best available knowledge of human biology at different scales
corresponding to the various key events in AOPs that may serve as the basis of response analyses. To
meet this research need, computational (in silico) models are an essential part of the NAMs portfolio.
This Output is intended to build and test computer models of development and homeostasis for critical
routes and target tissues (e.g., inhalation, pregnancy, development, kidney). These sophisticated
computer models will recapitulate normal tissue biology as well as simulate the response of a virtual
biological system to chemical perturbation and other stressors. Outputs of the simulation provide a
unique and essential prospective mechanistic prediction of tissue, organ, or lifestage-specific
toxicological effects in vivo that could supplement or supplant animal studies. Multiscale models under
this Output will enable mechanistic inference into tissue, organ, lifestage, or disease specific
toxicological and toxicokinetic responses along the adaptive to adverse continuum.

RA CSS.6: Ecotoxicological Assessment and Modeling (ETAM)

Output CSS.6.1: Develop and demonstrate ecological models to characterize risk of
environmental contaminants for risk assessment at national, regional, and local scales

Ecological Risk Assessment (ERA) must consider the context (environment, species, additional stressors)
within which exposure and effects occur. However, toxicity test results are usually generated in
controlled laboratory-conducted experiments that must be translated to an ecological context to
understand how they inform risk. For every federal action, including chemical registration and
developing water quality standards, the ESA requires the assessment of the action for thousands of
species. Other regulatory statutes such as FIFRA and TSCA require the protection of diverse ecological
communities from chemical exposure. In both scenarios, risk is based on toxicity tests that are typically
conducted in controlled laboratory settings for model species and require several extrapolations prior to
application in ERA including 1) inter-species, 2) lab-to-field, and 3) individual to population. Approaches
to these extrapolations must be compatible with exposure models and flexible to be incorporated with
spatial data layers (e.g., crop coverage) for integrative ERAs. Toxicity translators are mathematical
models that use ecological theory to make such extrapolations from available toxicity data to inform
ERA under realistic exposure scenarios. Development, application, and demonstration of the models
developed under this Output can be used to refine evaluations where screening estimates indicate a
potential risk. Approaches will be flexible to allow for consideration of species-specific factors that may
influence risk, as well as probabilistic approaches that can quantify the likelihood of effects. Products
under this Output will continue or develop bodies of research on pesticides, federally listed species,
climate change, and adverse outcome pathway development.

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Output CSS.6.2: Develop methods and data to assess the impacts of pesticides on pollinators

Pollinator assessments are a key aspect of Agency ERAs, and honeybees continue to be used as a
surrogate for other species of bees. Methods are needed to identify exposure to other species of bees in
areas where honeybees are not a suitable surrogate. Furthermore, an examination is needed to
determine the relative sensitivity/toxicity of honeybees to non-Apis bees, as well as other insect
pollinators (e.g., butterflies). Work under this Output may include the development of a tiered approach
to toxicity testing of honeybees and other pollinators as well as investigation to understand potential
linkages between declines in pollinators and the impacts to plants covered by the Endangered Species
Act.

Output CSS.6.3: Identify, assemble, and curate toxicity data for ecologically relevant species
for risk assessment (ECOTOX)

The ECOTOXicology Knowledgebase (ECOTOX) is the world's largest compilation of ecotoxicity data,
available publicly through a web-based database of curated single-chemical toxicity data for ecologically
relevant species, including aquatic life, terrestrial plants, and wildlife. Curated data may include that
which informs the impacts of changing temperatures due to climate change. There is a continual need to
identify, assemble, and describe available evidence on the adverse effects of chemical stressors for use
in risk assessments and regulatory decisions comprehensively and systematically. Relevant work
includes continued literature searches and review, data extraction from relevant studies, regular
updates to the Knowledgebase after inclusion of curated data, and a framework to support study
evaluation. This Output provides data for chemical effects on aquatic and terrestrial organisms to
program partners (e.g., Office of Water, Office of Pesticide Programs, Office of Pollution Prevention and
Toxics, Office of Land and Emergency Management, Regional Offices) for risk evaluation and
criteria/benchmark development. The ECOTOX data curation pipeline uses systematic methods that
meet the need for reproducibility and data transparency.

Output CSS.6.4: Advance approaches for using surrogate species in ecological risk assessment

ERAs of chemicals largely rely on the use of toxicity test data collected from standardized model
organisms and traditional whole organism biological responses. These data are used to represent
potential chemical effects in the risk characterization of a vast diversity of plant, invertebrate and
vertebrate species. Surrogacy of toxicological responses, metabolism and bioaccumulation in species
and biological responses of measured results in common test species are commonly applied to infer
results in species not tested. Limited empirical toxicity data is available across species and generating
such data is impractical both in terms of cost and animal use. While development of predictive
toxicology tools for chemical assessment has been ongoing for some time, application and integration of
current scientific advances such as (but not limited to) advanced multi-omic and bioinformatic
approaches, within the context of AOPs, to understand taxa-specific responses to chemical exposures
may provide a mechanistic basis for improved interspecies extrapolations and refine toxicity predictions.
Additionally, recent Agency policy mandates require a significant reduction in whole organism
vertebrate testing—leading to a need for not only the use of predictive toxicology tools to augment
effects characterizations, but to potentially replace traditional testing methods. Work under this Output
is expected to address the goal of development of new methods, extrapolation tools and models, or the
refinement and evolution of existing methodologies to improve the predictivity and reliance on
surrogate species in ERAs.

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Output CSS.6.5: Improve ecological methods and models for predicting exposure,
accumulation, and effects of Per- and Polyfluoroalkyl Substances (PFAS)

Ecological methods and models for exposure, accumulation, and effects are an integral part of EPA's
tiered approach to ERA for chemicals of concern, particularly per- and polyfluoroalkyl substances (PFAS).
Initially, chemicals are evaluated using rapid assessment tools that require minimal data and provide
conservative estimates of risk. Research is required to support the development of models for
bioaccumulation across aquatic food webs and species consumed by humans and wildlife. In addition,
work with NAMs that enables the rapid collection and analysis of mechanistic data, such as novel
biological and genomic endpoints, is required to support the development and testing of AOPs and
other frameworks that will help inform the chemical categories used to group assess the diverse
universe of PFAS and should be consistent with the potential population-level effects of PFAS. New
models and approaches appropriate for PFAS are needed to complement or replace those currently
used to predict exposure and effects that require extrapolations extending orders of magnitude beyond
existing data and yield predictions with an unacceptably high level of uncertainty. The research will be
guided by the objectives of EPA's PFAS Strategic Roadmap, to meet the goals of program offices (e.g.,
the National PFAS Testing Strategy). The purpose of this Output is to continue to identify and curate
existing exposure and effects information from the scientific literature, generate field and laboratory
data to fill in gaps, and develop new models and approaches for predicting the ecological accumulation
and effects of PFAS.

Topic 3: Knowledge Delivery and Solutions-Driven Translation to
Support Chemical Safety Decision Making

RA CSS.7: Chemical Characterization and Informatics (CCI)

Output CSS.7.1: Generate and curate data relevant to chemical substances, structures,
samples, and properties

Chemistry serves as the primary integrator of data for supporting research across the CSS program. A
well-curated database of chemical substance information—including chemical structures and associated
properties, as well as linkages to the chemical sample library, available as part of the ToxCast screening
program—is necessary. The generation (through experimental measurement, or by extraction from
previously published sources) and curation of data on chemical identifiers, structures, physicochemical
properties, and transformation data (products, rates, and associated measurement conditions) into
established databases (e.g., DSSTox, ChemProp) will be included under this Output. Generation of data
may also include modeling to predict potential metabolites and environmental transformation products
(e.g., those generated by the Chemical Transformation Simulator (CTS) and other predictive tools).
Curation may include registration of new chemicals in ORD databases; establishing linkages of chemical
identifiers (including structures) to associated data; and registration, mapping, and updates of priority
chemical lists (e.g., the TSCA inventory). Related cheminformatics research such as incorporating new
standards for chemical identifiers (e.g., updates to InChl versions), or developing appropriate
information management solutions for chemicals that currently cannot be effectively represented using
existing structure-based approaches (e.g., mixtures) or UVCBs (i.e., substances of unknown or variable
composition, complex reaction products and biological materials) will also be carried out.

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Output CSS.7.2: Develop data, tools, and models to support cross-species extrapolation for
human health and ecological assessments

Human and environmental risk assessments for chemicals use a limited number of model organisms to
generate toxicity data, which are subsequently extrapolated to species of concern. For ecological
assessments this can involve extrapolation of effects from a few surrogate species to many thousands.
While it would be ideal to conduct an adequate level of in vivo toxicity tests to explicitly address
questions regarding species differences in chemical sensitivity, it is not feasible (particularly for
threatened/endangered species). Further, testing resources are limited, there is an international interest
to reduce animal use, and there exists an ever-increasing demand to evaluate more chemicals in a
timely and sometimes expedited manner. Bioinformatics is a valuable tool that can be used to
understand conservation of biological pathways through sequence, structural, and functional
comparisons across species. Advancing computational and bioinformatics approaches that rapidly
maximize the use of existing data through tools such as the Sequence Alignment to Predict Across
Species Susceptibility (SeqAPASS) tool, are necessary for cross-species chemical safety evaluations.
Additionally, it is important to characterize data quality, define the domain of applicability, and identify
strengths and limitations for these tools, including through the use of laboratory studies when
necessary.

Output CSS.7.3: Develop new and improve existing structure activity relationship models to
support risk assessment

Quantitative structure-activity relationship (QSAR) models provide an automated method for the
estimation of all types of chemical safety relevant endpoints for data-poor chemicals. To provide robust
QSAR models to inform chemical evaluation, it is important to adopt a set of modeling best practices
(e.g., the OECD QSAR framework), as well as clearly define domain of applicability approaches. In
addition, there is a need to investigate cheminformatics approaches to model management and
versioningto enable real-time model predictions and data provenance. The Output may include
development of automated workflows to transform raw experimental data to modeling data sets and
then to QSAR models. The endpoints should be consistent with Agency priorities, and may include the
prediction of toxicities, in vitro bioactivities (HTT), toxicokinetics (RED), and environmental fate and
physicochemical properties to support exposure modeling (RED, ETAM). Where feasible, the predictive
performance of models should be compared with current models being used by the program offices to
ensure fit for purpose application. Finally, this Output may include research into the interplay between
dataset attributes (e.g., size, noisiness, curation level, source disparities) and model quality (predictive
performance) to better estimate the uncertainty of the predictions and to provide guidance in improving
QSAR modeling strategies in the future.

Output CSS.7.4: Advancing chemical categorization approaches for aiding the interpretation
and prediction of bioassay and toxicity outcomes

Data on the toxicity and properties of environmental chemicals or their transformation products is often
limited or unavailable. In addition, QSAR models are available for a limited number of endpoints of
concern, and predictions for some chemicals may fall outside of the model's prediction applicability
domain. Thus, for many chemicals and endpoints, there are insufficient or unsuitable data available to
support a global QSAR model approach. Approaches that focus within more localized areas of chemistry,
or within structure-bounded chemical categories, have the potential to expand the reach of SAR

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approaches and yield useful predictive insights. Multiple approaches, including but not limited to read-
across (e.g., GenRA), thresholds of toxicological concern (TTC), chemotype enrichment (e.g., ToxPrints),
and custom fingerprint representations, may be utilized in this Output to assess chemical, metabolic,
and biological similarity, and quantify uncertainties in predictions. These approaches operate within
localized regions of chemical space that become synonymous with the operational definition of
"chemical categories". Flexible means of creating structure-based categories suited to Agency programs
and applications, and the structure-based articulation of historical categories used within the Agency,
will allow for structure/substructure/similarity-based search and analysis tools to be more readily and
systematically applied to Agency programs. This Output involves coordination and collaborative research
efforts between scientists within the HERA and CSS research programs.

Output CSS.7.5: Advancing use of structural, mechanistic, and toxicokinetic data to support
categorization and classification of Per- and Polyfluoroalkyl Substances (PFAS)

Per- and polyfluoroalkyl substances (PFAS) are frequently being detected in a variety of environmental
media. PFAS chemicals are structurally diverse and typically lack adequate information needed to inform
conventional risk evaluations on individual substances. To address this challenge, the Agency is pursuing
a categorization approach that is informed by structure, mechanistic, and toxicokinetic information. The
research will be guided by the objectives of EPA's PFAS Strategic Roadmap, to meet the goals of
program offices (e.g., the National PFAS Testing Strategy). This Output is intended to be developed in
coordination with and be responsive to the needs of multiple Program Office (e.g., OCSPP, OLEM, OW)
and other partners, and may include continued development and refinement of PFAS categories for
multiple decision contexts, development of QSAR models for physicochemical properties of PFAS,
modeling of biodegradation of PFAS and mapping to parent substances, and related data generation,
integration, modeling, and analysis.

RA CSS.8: Integration, Translation and Knowledge Delivery (ITK)

Output CSS.8.1: Integrating data systems to enable knowledge delivery

Measurement and modeling efforts across the CSS portfolio continue to generate a wealth of data. For
data to be used in support of regulatory decision making, it needs to be stored and managed in a
manner that is appropriately versioned and meets relevant quality standards. In addition, experimental
and computational data across the CSS portfolio should be available for integration with other data
streams and knowledge delivery tools. Findability, Accessibility, Interoperability, and Reuse (FAIR)
principles of scientific data management should be adopted as appropriate and relevant. The research in
this Output will continue to develop new and refine existing transactional data management systems
and software for all of the overarching topical focus areas in CSS (e.g., toxicology, exposure, dosimetry,
chemistry, ecotoxicology, hazard, etc.). The data management systems and software that will enable
tracking data provenance and origin, versioning of data, facilitating data curation, and data quality
review, will be developed, maintained, and supported under this Output (e.g., DataHub, ChemReg,
ChemTrak, Factotum, ToxDCT, DAT, HTTr pipeline software package, HTPP software, ToxCast pipeline
software (tcpl)). The Output will also integrate data management systems (e.g., through development of
internal application programming interfaces (APIs) for system integration, support for programmatic
registration of chemicals in ORD databases and associated lists from other systems such as exposure and
hazard databases, or automated retrieval of experimental and predicted physicochemical and fate and
transport properties). The data management systems developed under this Output will be inherently

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coupled to products encompassing data generation, analysis, and curation across the CSS portfolio and
will be a precursor for the knowledge delivery tools.

Output CSS.8.2: Knowledge delivery and interoperability in support of chemical safety
decisions

The accessibility of data generated within the CSS portfolio for Agency and external partners ensures
that the work of the CSS program is readily available to support chemical safety decisions. In addition,
the broader scientific community utilizes CSS data for a variety of research activities. Key work of this
Output should focus on enhancing the accessibility of CSS data, models, and tools for partners and the
scientific community, while adopting FAIR principles as appropriate and relevant. The development
(including modification of existing tools to accommodate new data streams or functionalities and
integration of existing tools), maintenance, and support of key user interfaces (Uls) for data delivery
(e.g., CompTox Chemicals Dashboard, ECOTOX, SeqAPASS, CTS, Web-ICE, AOP Knowledgebase) under
this Output will address this need. In addition to Uls, development of internal or external application
programming interfaces (APIs) for the purposes of interoperability and knowledge delivery to partners
and the scientific community is also important. Cohesive strategies for knowledge sharing within the
Agency, and with other governmental agencies or external partners, should be coupled with these
knowledge delivery and visualization tools. The development of Uls and APIs (specifically, those
designed to deliver information to partners and the scientific community) under this Output should be
driven by stated partner needs and is intended to support the breadth of the CSS portfolio, relevant
support for decision making (e.g., TSCA chemical evaluations), and other agency risk assessments.

Output CSS.8.3: Cross-disciplinary integration and applied case studies to support chemical
safety decision making

The greatest impact of the work of the CSS program can be realized when data and models that span
scientific domains are brought together for a specific application, decision context, or to investigate a
hypothesis (e.g., an analysis which brings together exposure and toxicity data or models). In addition,
demonstrating the utility to partners of CSS work products through applied case studies can maximize
the value of investments in CSS research. This Output will include integrated work efforts in the form of
decision support tools or workflows (e.g., RapidTox, Minnesota Toxic Free Kids chemical prioritization
workflow, or the Public Information Curation and Synthesis (PICS) approach for TSCA and biosolids);
demonstration of the application and utility of models, tools, and other mature CSS research products
from all Research Areas through applied case studies incorporating the unique decision contexts of
relevant partners; case studies under the Accelerating the Pace of Chemical Risk Assessment (APCRA)
collaboration; and operationalizing models to demonstrate their utility for specific hazard and/or risk
predictions to inform ongoing or future partner needs. The usefulness of such tools, workflows, and case
studies is maximized when they are developed with a solutions-driven approach, collaborating with
partners throughout the development process.

Output CSS.8.4: Innovative science to support new chemicals evaluation

The review of new chemical substances prior to their introduction into U.S. commerce is required under
the TSCA legislation (Section 5). There is a need to refine and update the approaches, methods and tools
used to evaluate the chemistry, environmental release/fate, hazard (human health and ecological), and
exposure (environmental and human [occupational, general population, and consumers]) of new
chemicals and efficiently integrate this information to evaluate the human and environmental risks in a

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timely and transparent manner. This Output will contribute to modernizing the information used in
decisions related to new chemical submissions. Specific research efforts may include representations
and linkages of UVCB substances; updating and refining chemical category and analog approaches;
developing and maintaining a library of new chemicals for testing; structure-based predictions of
chemical properties, hazard, environmental fate/transport, or amenability for NAMs; in vitro toxicity
testing and modeling of these data; application of modeling approaches to in vitro to in vivo
extrapolation of dose; further development and/or demonstration of rapid exposure estimation tools
for occupational, general population, and consumer scenarios; automated literature mining of available
information; and integration of all of this information in a risk-informed workflow. Research will include
consideration of priority areas such as susceptible populations, environmental justice, and others, as
appropriate. This Output will be informed by research carried out under other research areas in the CSS
portfolio such as HTT, RED, AOP, ETAM, and CCI, as well as the HERA program.

Output CSS.8.5: Translation of research for chemical safety decision making through
demonstration, training, outreach, and partner engagement

Focused outreach (to Partners and the broader scientific community) to increase awareness and utility
of CSS data, models, and tools will support the goal of seeing the greatest impact of the investment in
CSS work. Demonstrating and facilitating the use of mature CSS research products from all Research
Areas through communications, training, and other forms of education will encompass the work of this
Output. This Output involves coordination and collaborative outreach efforts between scientists within
the HERA and CSS research programs.

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Appendix 4: Cross-Cutting Research Priorities

Working together on Agency priorities that cut across the six National Research Programs (NRPs), ORD
will integrate efforts, provide a research portfolio aligned around the Agency's goals, and assist all of
EPA's program and regional offices as well as states and Tribes. Where appropriate, the NRPs will
combine efforts on the following cross-cutting priorities to conduct research that advances the science
and informs public and ecosystem health decisions and community efforts. Although research efforts
have been highlighted for each of these cross-cutting priorities, this does not mean that the research
efforts only support that priority; the efforts may cut across priorities.

NRPs: Air, Climate, and Energy (ACE); Chemical Safety for Sustainability (CSS); Health and Environmental
Risk Assessment (HERA); Homeland Security (HS); Sustainable and Healthy Communities (SHC); and Safe
and Sustainable Water Resources (SSWR). The Strategic Research Action Plans for the NRPs are available
on ORD's website at epa.gov/research/strategic-research-action-plans-2023-2026.

Environmental Justice

ORD's NRPs will integrate research efforts to identify, characterize, and
solve environmental problems where they are most acute, in and with
communities that are most at risk and least resilient. Research will
strengthen the scientific foundation for actions at the Agency, state,
tribal, local, and community levels to address environmental and health
inequalities in vulnerable populations and communities with
environmental justice and equity concerns. Coordinating research
efforts will lead to a better understanding of how health disparities can arise from unequal
environmental conditions, including impacts from climate change and exposures to pollution, and
inequitable social and economic conditions. By working across NRPs, and through partner engagement,
information, tools, and other resources will be developed that help support decision-making and
empower overburdened and under-served communities to take action for revitalization.

Integrated Efforts Across National Research Programs

ACE

Understand inequities in air pollution exposures and impacts, and impacts of climate change,
accounting for social, cultural, and economic determinants that can lead to disproportionate exposures
and impacts. Develop science to support effective interventions to reduce air pollution exposures and
impacts, and adaptation and resilience measures to address climate impacts, including excessive heat
(urban heat islands), flooding, and wildfires.

CSS

Investigate factors relevant to exposures for populations experiencing disproportionate adverse
impacts from chemical exposures.

HERA

Expand the identification and consideration of information on susceptibility and differential risk in
assessments, advance the evaluation of chemical mixtures and improve cumulative risk assessment
practices to better characterize and assess health disparities.

HS

Assess and address community needs and vulnerabilities to ensure equitable incident management
during disaster response and recovery by analyzing the community-specific cumulative impacts and the
social implications of environmental cleanup; and by identifying potential interventions.

SHC

Identify risks and impacts to vulnerable communities and groups and improve the ability of
communities to address cumulative impacts from contamination, climate (e.g., natural disasters and
extreme events), and other stressors on health and the environment.

SSWR

Help provide clean and adequate drinking water and tools for stormwater management and urban
heat island mitigation.

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Climate Change

Understanding and addressing climate change impacts to human health
and the environment is a critical component of ORD's research. To be
effective, climate change research must be scientifically broad and
systems-based. Where appropriate, the NRPs will integrate efforts to
avoid duplicative efforts, fill critical gaps, and provide results that reflect
the multiplicity of impacts and needs associated with climate change.
Each NRP recognizes the critical need for continued communication
with ORD partners to ensure that we are taking advantage of opportunities for collaboration,
integration, and understanding.

integrated Efforts Across National Research Programs

ACE

Better understand and characterize air pollution and climate change and their individual and
interrelated impacts on ecosystems and public health and identify and evaluate approaches to reduce
the impacts of climate change through mitigation of climate forcing emissions, adaptation strategies,
and building resilience in communities and ecosystems. Model energy, emissions, and environmental
impacts of transformations in the nation's energy, transportation, and building sectors, and identify
approaches to increase equitable benefits of those transformations.

CSS

Explore the use of newer analysis methods for identifying chemical contamination in environmental
media after large catastrophic environmental events, such as wildland fires.

HERA

Continue development of assessments of air pollutants to inform climate policy efforts and leverage
expertise, approaches, tools, and technologies in support of further climate change impact
assessments.

HS

Enhance capabilities and develop new information and tools to maximize relevance and support for
response and recovery from natural disasters related to climate change.

SHC

Integrated systems-approach research applicable to challenges that communities, including those with
contaminated sites, face in preparing for and recovering from the impacts of natural disasters and
climate change, ensuring that approaches are beneficial and equitable for the communities at risk.

SSWR

Improve resiliency of water resources and infrastructure to mitigate impacts related to climate change,
including coastal acidification and hypoxia, harmful algal blooms, wildland fires, drought and water
availability, stormwater flooding and combined sewer overflows, and urban heat islands.

Addressing the cumulative impacts of exposure to multiple chemical
and non-chemical stressors is necessary for EPA to fulfill its mission to
protect human health and the environment with the best available
science. Cumulative Impacts refers to the total burden—positive,
neutral, or negative—from chemical and non-chemical stressors and
their interactions that affect the health, well-being, and quality of life of
an individual, community, or population at a given point in time or over
a period of time. It is the combination of these effects and any resulting environmental degradation or
health effects that are the focus of ORD's cumulative impacts research. The NRPs will integrate efforts to
improve understanding of cumulative impacts and develop and apply the necessary models, methods,
and tools to conduct real-world assessments of cumulative impacts that result in both adverse and
beneficial health and environmental effects. With this information, internal and external partners can

Cumulative Impacts

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make informed, scientifically credible decisions to protect and promote individual, community, and
environmental health.

Integrated Efforts Across National Research Programs

ACE

Develop measurement methods and approaches to characterize ambient air quality and deposition,
and human and ecosystem exposures to chemical (including criteria pollutants and air toxics) and non-
chemical (including built environment, social, and climate-related) stressors, and health impacts from
exposure to the combination of chemical and non-chemical stressors

CSS

Development and application of new approach methodologies to rapidly generate exposure and
hazard information for chemicals, chemical mixtures, and emerging materials and technologies
(including safer alternatives).

HERA

Research to advance the evaluation of chemical mixtures and improve cumulative risk assessment
practices to better characterize and assess health disparities in communities with environmental
justice and equity concerns.

HS

Through a focus on resilience equity, ensure that information and tools include the multitude of
stressors impacting a community when used to support incident response. Research will recognize that
resilience to an incident is directly impacted by the cumulative impacts of the incident and other
stressors affecting a community.

SHC

Address the risks and impacts to improve the ability of communities to address cumulative impacts
from contamination, climate, and other chemical and nonchemical stressors on health and the
environment.

SSWR

Support human health ambient water quality criteria for chemical mixtures through research using
bioassays and risk management, and assessment for exposure to groups of regulated and unregulated
disinfection byproducts (DBPs) and opportunistic pathogens.

Community Resiliency

It is critical that communities have the knowledge and resources needed
to prepare for and recover from adverse situations, such as natural
disasters, contamination incidents, and failing infrastructure. Through
combined research efforts, the NRPs will provide information and
resources that support and empower communities to make science-
based decisions to withstand, respond to, and recover from adverse
situations.

Integrated Efforts Across National Research Programs

ACE

Improve evaluations of climate change adaptation and mitigation measures and community resiliency
to extreme events in a changing climate, such as wildfire, floods, heat waves, and drought—especially
for vulnerable and disadvantaged communities experiencing environmental injustice.

CSS

Efforts relevant to chemical safety evaluations will be leveraged with other NRP activities.

HERA

Continue to expand the portfolio of assessment products to improve understanding of potential
human health and environmental impacts of contamination incidents.

HS

Generate resources and tools for environmental cleanup, risk communication, outreach, building
relationships, and community engagement to improve equitable community resilience for
environmental contamination incidents and other disasters.

SHC

Increase resilience by reducing potential risks, promoting health, and revitalizing communities.

SSWR

Support coastal resilience by advancing monitoring, mapping, and remote sensing and by the economic
valuation of coastal resources. Improve the performance, integrity, and resilience of water treatment
and distribution systems through research on water infrastructure and water quality models.

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Children's Environmental Health

From EPA's 2021 Policy on Children's Health, "children's environmental
health refers to the effect of environmental exposure during early life:
from conception, infancy, early childhood and through adolescence
until 21 years of age." Environmental exposures that impact health can
occur before conception, and during pregnancy, infancy, childhood, and
adolescence; and include long-term effects on health, development,
and risk of disease across lifestages. Much of ORD's research is relevant
to communities, including susceptible and vulnerable populations. Where appropriate, the NRPs will
combine efforts to conduct research that will inform public health decisions, advance our scientific
understanding of early-life susceptibility to environmental stressors, and inform community efforts that
create sustainable and healthy environments protective of all lifestages.

Integrated Efforts Across National Research Programs

ACE

Explore air pollution and climate health impacts within different lifestages and populations, including
overburdened groups. Assess vulnerabilities to air pollution for those with chronic illnesses and
sequelae from respiratory viruses. Research social determinants of health, and air pollution impacts
resulting from different exposure time-activity patterns.

CSS

Research will build the scientific foundation to predict adverse outcomes resulting from chemical
exposures in various biological contexts, including early life-stage susceptibility.

HERA

Continue to evaluate health effects, over the course of a lifetime, from environmental exposure to
stressors during early life (i.e., from conception to early adulthood) to inform decision-making and
advance research on methods to properly characterize risks to children.

HS

Improve and develop decision-support tools and cleanup capabilities to make children less vulnerable
during response to, and recovery from, contamination incidents.

SHC

Address the risks and impacts to vulnerable communities and lifestages, including
underserved/overburdened communities, and improve the ability of communities to address
cumulative impacts from contamination, such as site clean-ups of per- and polyfluoroalkyl substances
(PFAS) and lead; climate, such as natural disasters and extreme events; and other stressors on health
and the environment.

SSWR

Evaluate health effects and toxicity related to algal toxins and expanded research that will explore
exposure risks for lead, DBPs, and—through quantitative microbial risk assessment models—for high
priority opportunistic pathogens in drinking water (e.g., Mycobacterium, Pseudomonas, Naegleria
fowleri).

Contaminants of Immediate and Emerging Concern

Contaminants of immediate and emerging concern (CIECs) include
chemical substances that may cause ecological or human health impacts
and are either new or existing contaminants of increased priority. The
NRPs will work with EPA partners in the program and regional offices,
along with input from Agency leadership, to identify the highest priority
contaminants (broadly defined to include chemical, biological, and other

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categories as appropriate), including those of immediate concern, such as PFAS and lead, that warrant
further research attention.

Integrated Efforts Across National Research Programs

ACE

Develop and evaluate measurement methods and approaches to characterize sources of air pollutants
and climate forcing pollutants, such as measurement of emissions of criteria pollutant precursors and
air toxics, including emerging concerns, such PFAS and EtO.

CSS

Continue to develop new approach methods for CIECs with a focus on applying these, as appropriate,
for prioritization, screening, and risk assessment for decision making.

HERA

Continue and expand the portfolio of assessment products, as well as advance risk assessment models
and tools, to better characterize potential human health and environmental impacts of new and
existing contaminants.

HS

Predict the movement of chemical, biological, and radiological contaminants in the environment
resulting from environmental contamination events and develop tools and methods for effective
characterization, decontamination, and waste management.

SHC

Advance site clean-ups of PFAS and lead to protect vulnerable groups, especially children.

SSWR

Research on PFAS, including innovative drinking water and wastewater treatments, support for future
drinking water regulations, the development of aquatic life criteria, management in water resources,
and evaluation of land-applied biosolids; contaminants of emerging concern (CECs), lead, opportunistic
pathogens, and DBPs in drinking water; cyanobacterial metabolites other than microcystin (e.g.,
anatoxin, saxitoxin, and nodularin); microplastics in sediments and surface water; and CECs (non-PFAS)
in wastewater treatment systems and biosolids.

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