Chemical Safety

for Sustainability

STRATEGIC RESEARCH ACTION PLAN

2016–2019

EPA 601/K-15/003 | November 2015 | www.epa.gov/research

Office of Research and Development

Chemical Safety for Sustainability 
Chemical Safety for Sustainability

Strategic Research Action Plan 2016–2019

U.S. Environmental Protection Agency

November 2015

EPA 601/K-15/003
Table of Contents

List of Acronyms ii

Executive Summary 1

Introduction 3

Environmental Problems and Program Purpose 4

 Problem Statement 5

Program Vision 5

Program Design 6

Building on the 2012–2016 Research Program 6

EPA Partner and Stakeholder Involvement 7

Integration across Research Programs 8

Research Supports EPA Strategic Plan 10

Statutory and Policy Context 11

Research Program Objectives 12

Research Topics 14

Topic 1: Chemical Evaluation 17

 Topic 2: Life Cycle Analytics 19

 Topic 3: Complex Systems Science 23

 Topic 4: Solutions-Based Translation and Knowledge Delivery 26

Strategic Collaborations 32

Anticipated Research Accomplishments and Projected Impacts 33

Conclusions 36

Appendix 1: Additional Policy Context and Scientific Advice 37

Appendix 2: Examples of CSS Partnerships 40

Appendix 3: Table of Proposed Outputs 42

i
List of Acronyms 

ACE Air, Climate and Energy

ADME Absorption, Distribution, Metabolism, and Excretion

AOPs Adverse Outcome Pathways 

AOPDD Adverse Outcome Pathway Discovery and Development 

AOP-KB Adverse Outcome Pathway Knowledge Base 

AOP-Wiki Adverse Outcome Pathway Wiki 

CAA Clean Air Act 

CCL Contaminant Candidate List 

CEH Children’s Environmental Health 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CMP3 Chemical Management Plan 3 

CPCat Chemical/Product Categories Database

CPSC Consumer Product Safety Commission 

CSPA Children’s Safe Product Act 

CSS Chemical Safety for Sustainability Research Program

CSS StRAP Chemical Safety for Sustainability Strategic Research Action Plan 

CTS Chemical Transformation Simulator 

CWA Clean Water Act 

DoD Department of Defense

DTSC Department of Toxic Substances Control, California 

ECHA European Chemicals Agency

EDSP Endocrine Disruptor Screening Program 

EDSP21 Endocrine Disruptor Screening Program for the 21st Century

ENMs Engineered Nanomaterials

EPA Environmental Protection Agency 

ERA Ecological Risk Assessment

ESA Endangered Species Act 

FDA Food and Drug Administration 

FFDCA Federal Food, Drug, and Cosmetic Act 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FQPA Food Quality Protection Act 

ii
FWS Fish and Wildlife Service 

FY Fiscal Year

HHRA Human Health Risk Assessment

HSRP Homeland Security Research Program

HTPK High-Throughput Pharmacokinetic

HTS High-Throughput Screening 

HTT High-Throughput Toxicology

LCA Life Cycle Assessment

MCC Methodologically Challenging Compounds 

MCnest Markov Chain Nest Productivity Model

NAS National Academy of Sciences

NCCLCs Networks for Characterizing Chemical Life Cycle 

NEHI Nanotechnology Environmental Health Implications working group 

NIH National Institute of Health

NIOSH National Institute for Occupational Safety and Health

NMFS National Marine Fisheries Service

NNI National Nanotechnology Initiative 

NPD National Program Director (for one of EPA’s research programs)

NSF National Science Foundation

NSMDS Networks for Sustainable Molecular Design and Synthesis

OCMs Organotypic Cell Models 

OCSPP Office of Chemical Safety and Pollution Prevention

OECD Organization for Economic Cooperation and Development

ORD Office of Research and Development 

OSWER Office of Solid Waste and Emergency Response 

OW Office of Water 

PCRs Product Category Rules 

PIP Pathfinder Innovation Projects 

POD Points of Departure

QSAR Quantitative Structure Activity Relationship

RCRA Resources Conservation and Recovery Act 

SAP Scientific Advisory Panel

SAR Structure-Activity Relationships 

iii
SDWA Safe Drinking Water Act 

SHC Sustainable and Healthy Communities

SSWR Safe and Sustainable Water Resources

STAR Science to Achieve Results 

TIM Terrestrial Investigation Model

TPO Thyroperoxidase 

TSCA Toxic Substances Control Act 

USDA United States Department of Agriculture

VISION 20/20 Vision for 2020

VTMs Virtual Tissue Models 

Web-ICE Web-based Interspecies Correlation Estimation

iv
Executive Summary

Chemicals are integral to the American economy and provide key building blocks for the many 

products that benefit society. Sustainable innovation and use of chemicals call for making 

decisions and taking actions that improve the health of individuals and communities today without 

compromising the health and welfare of future generations. Smart new strategies for designing, 

producing, and using safer chemicals to minimize risks and prevent pollution are a priority for the 

U.S. Environmental Protection Agency (EPA). 

The challenges to meeting this mandate are formidable: Tens of thousands of chemicals are currently 

in use and hundreds more are introduced into the market every year. Many of these chemicals have 

not been thoroughly evaluated for potential risks to human health, wildlife, and the environment, 

particularly when considering the consequences of use over a chemical’s life cycle (from production 

to disposal). Current toxicity testing methods for evaluating risks from exposures to individual 

chemicals are expensive and time consuming. Approaches for characterizing impacts across the 

chemical/product life cycle are data and resource intensive. 

Characterizing real-world exposures and early indicators of adversity in a way that enables proactive 

decisions to minimize impacts of existing chemicals and to anticipate impacts of emerging materials 

requires holistic systems understanding. Potential health effects from chemicals are associated with 

disruption to complex biological processes. For example, evidence is mounting that some chemicals 

disrupt the endocrine system. Some of these effects relate to chronic exposures to low levels of 

multiple chemicals. Prenatal and early life exposures are of particular concern and may lead to 

health impacts across the lifespan. As a result, a shift in thinking is needed about how potential for 

adverse impacts and ultimately risks are evaluated. 

Today, EPA and its stakeholders are making decisions on chemical selection, design, and use at 

the national, regional, and local levels. States, communities, and consumers are demanding robust 

information on chemicals in products and are driving large retailers and industry to make changes. 

Tools for evaluating chemical substitutions and product alternatives are evolving to meet the 

demand for action. Scientifically vetted approaches, however, remain limited. New approaches 

are required to increase the pace at which relevant information can be obtained and integrated 

into decision making and to ensure that decisions are scientifically supported and sustainable. Key 

metrics that can be collected as early indicators of changes to the chemical exposure landscape are 

needed to preempt or rapidly mitigate unanticipated impacts. 

To address these challenges, EPA’s Chemical Safety for Sustainability (CSS) Research Program is 

leading the development of innovative science to support safe and sustainable selection, design, 

and use of chemicals and materials required to promote ecological well-being, including human 

and environmental health as well as to protect vulnerable species, lifestages, and populations. The 

ultimate goal is to enable EPA to address impacts of existing chemicals, anticipate impacts of new 

chemicals and materials, and evaluate complex interactions of chemical and biological systems to 

support EPA’s decisions.

1
Working in conjunction with our partners in EPA regulatory programs and regional offices, CSS has 

identified priority needs for information and methods to make better informed, timelier decisions 

about chemicals. CSS science is strategically scoped within four integrated research topics to support 

EPA priorities:

1. Chemical Evaluation: Advance cutting-edge high-throughput methods in computational 

toxicology and provide data for risk-based evaluation of existing chemicals and emerging 

materials.

2. Life-Cycle Analytics: Address critical gaps and weaknesses in accessible tools and metrics 

for quantifying risks to human and ecological health across the life cycle of manufactured

chemicals, materials, and products. Advance methods to evaluate alternatives efficiently

and support more sustainable chemical design and use.

3. Complex Systems Science: Adopt a systems-based approach to examine complex 

chemical-biological interactions and predict potential for adverse outcomes resulting from 

exposures to chemicals.

4. Solutions-Based Translation and Knowledge Delivery: Promote Web-based tools, data, 

and applications to support chemical safety evaluations and related decisions, 

respond to short-term high-priority science needs for CSS partners, and allow for active 

and strategic engagement of the stakeholder community. 

This Strategic Research Action Plan for EPA’s Chemical Safety for Sustainability Research Program

maps out a research program for the near term with an eye toward meeting longer-term needs to 

transform chemical evaluation. CSS scientific results and innovative tools will accelerate the pace 

of data-driven chemical evaluations, enable EPA decisions that are environmentally sound and

public health protective, and support sustainable innovation of chemicals and emerging materials. 

2
Introduction

Chemicals are a lynchpin of innovation in 

the American economy, and moving toward 

sustainable innovation requires designing, 

producing, and using chemicals in safer 

ways. Information and methods are needed 

to make better informed, timelier decisions 

about chemicals, many of which have not 

been thoroughly evaluated for potential risks 

to human health and the environment. EPA’s 

Chemical Safety for Sustainability (CSS) research 

program is designed to meet this challenge 

and supports EPA’s priority of reducing risks 

associated with exposure to chemicals in 

commerce, the environment, products, and 

food. 

To help guide the program to meet its 

ambitious objectives, EPA’s Office of Research 

and Development (ORD), EPA’s science arm, 

developed this Chemical Safety for Sustainability 

Strategic Research Action Plan, 2016–2019 (CSS 

StRAP), which builds on the original vision of 

the research program outlined in the Chemical 

Safety for Sustainability Research Action 

Plan 2012–2016.1

 The current StRAP evolved 

through a series of meetings with program and 

regional partners, among ORD labs and centers 

involved with CSS, and through interactions 

with external stakeholders. 

The CSS StRAP is one of six research plans, one 

for each of EPA’s national research programs in 

ORD. The six research programs are:

• Air, Climate, and Energy (ACE)

• Chemical Safety for Sustainability (CSS)

• Homeland Security Research Program (HSRP)

• Human Health Risk Assessment (HHRA)

• Safe and Sustainable Water Resources 

(SSWR)

• Sustainable and Healthy Communities (SHC)

EPA’s strategic research action plans lay the 

foundation for EPA’s research staff and their 

partners to provide focused research efforts 

that meet EPA’s legislative mandates as well 

as the goals outlined in EPA’s Fiscal Year 2014 

–2018 EPA Strategic Plan. They are designed 

to guide an ambitious research portfolio that 

delivers the science and engineering solutions 

EPA needs to meet such priorities, while 

also cultivating a new paradigm for efficient, 

innovative, and responsive environmental and 

human health research. 

The StRAP outlines the approach designed to 

achieve EPA’s objectives for advancing chemical 

safety and sustainability. It highlights how 

the CSS program integrates efforts with other 

research programs across ORD to provide a 

seamless and efficient overall research portfolio 

aligned around the central and unifying concept 

of sustainability.

No other research organization in the world 

matches the diversity and breadth represented 

by the collective scientific and engineering staff 

of ORD, their grantees, and other partners. They 

are called upon to conduct research to meet 

the most pressing environmental and related 

human health challenges facing the Nation and 

the world.

3

1

http://www2.epa.gov/research/chemical-safety-sustainability-research-action-plan-2012-2016
Environmental 

Problems and Program 

Purpose

Sustainable innovation through which chemicals 

are designed, produced, and used in safer 

ways to minimize risks and prevent pollution 

is a priority for EPA. The challenges to meeting 

this mandate are formidable; approximately 

80,000 legacy chemicals are listed in EPA’s Toxic 

Substances Chemical Act (TSCA) inventory;2

hundreds more are introduced into the market 

every year. Fewer than 2000 of these chemicals 

have health assessments available across federal 

and state agencies. This number translates to 

only a small fraction that have been thoroughly 

evaluated for potential risks to human health, 

wildlife, and the environment, particularly 

when considering the consequences of use 

over a chemical’s life cycle (from production to 

disposal). Current toxicity testing methods for 

evaluating risks from exposures to individual 

chemicals are expensive and time consuming. 

Approaches for characterizing impacts across 

the chemical/product life cycle are data and 

resource intensive. To address the critical need 

for evaluating potential for risks associated with 

thousands of chemicals in commerce, rapid and 

efficient methods are required to prioritize, 

screen, and evaluate chemical safety.

Characterizing real-world exposures and early 

indicators of adversity (or “tipping points”) 

in a way that enables proactive decisions to 

minimize impacts of existing chemicals, as well 

as to anticipate impacts of emerging materials 

requires holistic systems understanding. 

Potential health effects from chemicals are 

associated with disruption to complex biological 

processes in human and wildlife populations. 

For example, evidence is mounting that some 

chemicals disrupt the endocrine system. 

The endocrine system regulates biological 

processes throughout the body and is sensitive 

to small changes in hormone concentrations. 

In addition, more complex interactions and 

outcomes are not addressed well with existing 

models and assessment tools. Examples include 

outcomes resulting from chronic low dose 

exposures to multiple chemicals with similar 

modes of actions, or exposures to complex 

mixtures or chemicals with multiple modes of 

action. Prenatal and early life exposures are of 

particular concern, and additional complexity 

is associated with the potential for these 

exposures to lead to health impacts across the 

lifespan. As a result, a shift in thinking is needed 

regarding how potential for adverse impacts 

and ultimately risk are evaluated. 

Today, EPA and its stakeholders are making 

decisions on chemical selection, design, and 

use at national, regional, and local levels. 

States, communities, and consumers are 

demanding robust information on chemicals 

in products and are driving large retailers and 

industry to make changes. Tools for evaluating 

chemical substitutions and product alternatives 

are evolving to meet the demand for action. 

Scientifically vetted approaches, however, 

remain limited.

Innovations in chemical and material design are 

rapidly changing the landscape of industrial and 

consumer products while novel materials, such 

as engineered nanomaterials, are incorporated 

to enhance their performance. New approaches 

are required to increase the pace at which 

relevant information can be obtained and 

integrated into decision making and to ensure 

that decisions are scientifically supported and 

sustainable. One goal of these approaches is 

to avoid regrettable substitutions, which occur 

when one chemical of concern is replaced by 

another chemical that later proves to have 

impacts of similar or greater magnitude. In 

4

2

http://www2.epa.gov/tsca-inventory
addition, key metrics that can be efficiently 

collected as early indicators of changes to the 

chemical exposure landscape are needed to 

preempt or rapidly mitigate unanticipated 

impacts. Always, the assessments, predictions, 

evaluations, and decisions related to chemical 

innovation and sustainable use must consider 

the most vulnerable and sensitive species, 

lifestages, and communities. 

To anticipate and predict impacts of manufacture 

and use of chemicals and materials that have 

not yet been developed presents a larger 

context for the CSS research program. As EPA 

and stakeholders seek sustainable solutions to 

complex and dynamic environmental problems, 

the demand for “validated” forecasts of 

uncertain future states increases. At the same 

time, resource constraints limit the capacity 

to monitor for the continuously changing set 

and combination of chemicals and materials in 

commerce. The CSS research program considers 

the grand challenge of how best to build and 

deploy modeling capacity in concert with 

efficient data collection and effective monitoring 

for robust and agile policy.

Clearly, information and methods are needed to 

make better-informed, timelier decisions about 

chemicals. Development of innovative science 

to support safe, sustainable use of chemicals 

and materials is required to promote ecological 

well-being, including human and environmental 

health, as well as to protect vulnerable species, 

lifestages, and populations. CSS is designed 

to meet this challenge and supports EPA’s 

priority of reducing risks associated with 

exposure to chemicals in commerce, the 

environment, products, and food. The ultimate 

goal is to enable EPA to address impacts of 

existing chemicals, anticipate impacts of new 

chemicals and materials, and evaluate complex 

interactions of chemical and biological systems 

to support decisions.

Through its signature research in computational 

toxicology, CSS draws from and integrates 

advances in several fields, including information 

technology, computational chemistry, and 

molecular biology, to address EPA’s data 

requirements for science-based assessment 

of chemicals. EPA investments in advanced 

chemical evaluation and life-cycle analytics 

are providing decision-support tools for highthroughput screening and efficient risk-based 

decisions.

Problem Statement

Tens of thousands of chemicals are currently 

in use and hundreds more are introduced 

every year, many in new and emerging 

markets such as nanotechnology. Only a small 

fraction have been thoroughly evaluated for 

potential risks to human health, wildlife, and 

the environment. Multiple EPA programs and 

regional offices must make risk-based decisions 

for addressing chemicals with inadequate 

or non-existent hazard and exposure data. 

Current toxicity testing methods, which are 

expensive and time consuming, evaluate 

risks from exposures to individual chemicals. 

Approaches for characterizing impacts across 

the chemical/product life cycle are data and 

resource intensive. 

Program Vision

The CSS research program will lead 

development of innovative science to support 

safe, sustainable design and use of chemicals 

and materials required to promote human and 

environmental health, as well as to protect 

vulnerable species, lifestages, and populations. 

CSS research program outputs will enable EPA 

to address impacts of existing chemicals and 

materials across the life cycle and to anticipate 

impacts of new chemicals and emerging 

materials. The CSS research program will also 

provide the scientific basis for evaluating 

complex interactions of chemical and biological 

systems to support EPA decisions.

5
Program Design

Building on the 2012–2016 

Research Program

Since its inception, CSS research has endeavored 

to transform chemical evaluation through 

groundbreaking research, translation, and 

tools. Several impactful products have begun to 

change the landscape of chemical evaluations 

at EPA. Some examples include: 

•

•

•

•

•

•

These products were derivatives of the original 

vision of the research program outlined in 

the CSS 2012–2016 StRAP. Fiscal Year 2015 

(FY15) planning presented a ripe opportunity 

to conduct a review of the program and seek 

ways to integrate the research, strengthen 

transdisciplinary collaboration, promote and 

foster innovation, enhance transparency and 

access to CSS products, and significantly amplify 

the impact of this important research. The 

most noteworthy impetus for this integration 

was the demand to drive the leading edge of 

science, be prepared to meet the urgent needs 

of EPA in a timely and responsive fashion, and

6

EPA’s high-throughput toxicity research

effort, ToxCast,3 uses automated chemical 

screening technologies to measure changes 

in biological activity that suggest potential 

for hazardous effects. Coupled with related 

high-throughput exposure estimations from 

ExpoCast,4 this multi year effort is generating and sharing an unprecedented volume of 

exposure and toxicology data and knowledge 

transparently through an interactive iCSS 

(Interactive Chemical Safety for Sustainability) 

Dashboard.5

The Chemical/Product Categories Database 

(CPCat)6 compiles information on chemicals 

found in consumer products. This new publicly available database maps over 40,000 

chemicals to a set of terms categorizing 

use or function for high-level exposure 

evaluation. 

To enhance the ability to evaluate environmental health and safety of nanomaterials, 

fate and transport models have been incorporated to characterize the surface properties 

of silver nanoparticles and understand how 

these properties affect their fate in containment systems. These models have also been 

used to develop higher-throughput methods for characterizing nanoparticle transport 

through soils and sediments.

Engaging in international efforts to harmonize 

green purchasing practices has resulted in application of EPA’s life-cycle assessment tools 

to provide clear, comparable information 

about the environmental impacts of different 

products evaluated internationally in the development of product category rules.

The Adverse Outcome Pathway Wiki (AOPWiki)9

, created through a joint venture between the European Commission and EPA, is 

a Web-enabled and publicly accessible repository that stimulates and captures new and existing crowd-sourced AOP knowledge from the 

global scientific community.

The Web-based Interspecies Correlation

Estimation (Web-ICE)7 application estimates 

acute toxicity in aquatic and terrestrial 

organisms. The Markov Chain Nest Productivity Model (MCnest)8

 quantitatively estimates 

the impact of pesticide-use scenarios on 

reproductive success of bird populations. 

Together, these two tools are informing ecological risk assessments, in particular for endangered species.

3

http://www2.epa.gov/chemical-research/toxicity-forecasting

4

http://www2.epa.gov/chemical-research/rapid-chemical-exposure-and-dose-research

5

http://actor.epa.gov/dashboard/

6

http://actor.epa.gov/cpcat

7

http://www3.epa.gov/ceampubl/fchain/webice/

8

http://www2.epa.gov/chemical-research/markov-chain-nest-productivity-model

9

https://aopkb.org/aopwiki
achieve these aims within a budgetary 

environment that is often unpredictable. 

CSS rose to this challenge by remodeling 

the architecture of its research program to 

be robust, sustainable, anticipatory, agile, 

transparent, and at all times, responsive.

In evolving the CSS program, key program areas 

have been significantly reformulated to focus 

research and design a cohesive and impactful program that meets high-priority partner 

needs. The CSS 2012–2016 StRAP included 8 

research themes and 21 research projects. To 

provide further focus and amplify the impact 

of CSS research, the themes and projects were 

integrated into four topics and nine transdisciplinary project areas. The first iteration of the 

new program was piloted in FY15. With input 

from ORD’s lab and center leadership, project 

scientists, CSS program and regional partners, 

as well as the joint committee of the Science 

Advisory Board/Board of Scientific Counselors (SAB/BoSC), the program was refined to 

improve scientific coordination and the interactions that are foundational to a successful 

transdisciplinary program. The resulting CSS 

2016–2019 StRAP provides the overall framework for CSS research that grew from this planning process.

In the CSS 2016–2019 StRAP, the Chemical 

Evaluation and Complex Systems Science topics 

have been designed to support development 

and integration of the science required to 

revolutionize capacity for efficient and effective 

chemical safety risk-based decisions. To this 

end, expertise in biomarkers, pharmacokinetics, 

extrapolation, and cumulative risk are 

embedded throughout to advance the science 

for evaluating data-poor chemicals. 

The Life - Cycle Analytics topic is designed 

to provide the science and tools needed to 

evaluate safety of chemicals and materials 

(including engineered nanomaterials) in the 

broader context of how these are designed 

and used in our society. This topic includes 

consideration of green chemical design, lifecycle impacts, and sustainable use. Here, 

expertise and emerging science are directed 

to elucidate relationships among inherent 

chemical and material properties, function, 

and associated impacts in biological systems. 

ORD capacity to model human and ecological 

exposures combined with key expertise in lifecycle impact analysis are being directed to 

evaluate alternatives efficiently and to fill a gap 

in available sustainability metrics. 

In addition, all CSS research implemented based 

on this StRAP will (1) have an increased focus 

on developmental health, vulnerable lifestages, 

and susceptible populations; and (2) explore 

higher-throughput approaches with wider coverage of chemistry and biology. 

Finally, with this integration, nearly half the 

programmatic resources will be devoted to 

research translation and knowledge delivery 

–through tools and applications that enhance 

and democratize access to CSS scientific 

knowledge, partner-driven and partner-focused 

tailored solutions, and strategic outreach and 

engagement of the stakeholder community 

that rely on the products of CSS research and 

help ground truth its validity, relevance, and 

applicability.

EPA Partner and Stakeholder 

Involvement

The process for developing this StRAP unfolded 

through a series of meetings with program 

and regional partners and among labs and 

centers involved with CSS. The scoping 

meetings included concurrent participation and 

engagement from this community and helped 

map out and balance the diverse partner 

priorities. Additional focus group meetings with 

partners enabled more in-depth discussions and 

7
further shaping of the plans. This document was 

profoundly strengthened by the informed and 

interactive iteration among these groups over 

an 18-month period. Along the way, significant 

interim milestones were posted online in an 

effort to engage the community of EPA partners 

and collaborators transparently.

The CSS StRAP is designed to drive the longerterm science vision for the program. Within each 

CSS project, however, specific case studies are 

being developed in collaboration with program 

and regional partners to reflect EPA’s near-term 

priorities. This case study approach ensures 

that the purpose and application of CSS science 

is clearly defined upfront in collaboration with 

the partners and that the product developed is 

fit for the intended purpose (‘fit for purpose’). 

In addition, as described in the Research 

Topics section, the Translation and Knowledge 

Delivery topic incorporates both partner-driven 

short-term projects and projects through which 

the applicability of the emerging science will be 

demonstrated and evaluated (or conceptually 

“test driven”) early in each CSS project before 

proceeding too far down a research path. This 

collaborative approach builds familiarity and 

confidence in the products of CSS research. 

Partners are not asked to adopt a final product 

or tool. Rather, they are engaged and involved in 

the design and development of the tools, their 

early adoption for application to case studies, 

and the exercise of confidence building. 

Every project in CSS also has a significant education, outreach, and engagement component 

first in building and executing case studies, and 

also more broadly through targeted webinars 

and panel listening and discussion sessions set 

up monthly with program and regional partners. This engagement culminates in a faceto-face meeting, held approximately annually 

across CSS and with partners, designed to enable direct interaction among partners and CSS 

project investigators. 

Research planned for the StRAP 2016–2019 

also was informed by external stakeholders and 

partners. The CSS staff and researchers serve 

on several task groups and are actively engaged 

on projects with numerous U.S. federal agencies and international organizations as well as 

with various state and nongovernmental organizations. CSS interacts with academia through 

scientific conferences, informal professional relationships, and formal grants and cooperative 

agreements. These venues afford not only the 

opportunity to leverage expertise and funding, 

but also the ability to identify unique niche areas to which CSS can make the greatest scientific contributions. These external engagements 

are discussed in more detail in the Collaborations and Stakeholder Engagement and Outreach sections later in this document.

Integration across the Research 

Programs

EPA’s six research programs work together to 

address science challenges that are important 

for more than one program. Coordination 

efforts can range from formal integration 

efforts across the programs at a high level, to 

collaboration research among EPA scientists 

working on related issues. 

To accomplish formal integration of research on 

significant cross-cutting issues, EPA developed 

several “Research Roadmaps” that identify 

ongoing relevant research and important 

science gaps that need to be filled. The 

Roadmaps serve to coordinate research efforts 

and to provide input that helps shape the future 

research in each of the six programs. Roadmaps 

have been developed for the following areas:

• Nitrogen and Co-Pollutants

• Children’s Environmental Health

• Climate Change

• Environmental Justice

8
9

The CSS research program is the lead national 

program for the Children’s Environmental Health 

(CEH) Roadmap.10 Transforming EPA’s capacity 

for considering child-specific vulnerabilities 

requires that ORD apply advanced systems 

science and integrate diverse emerging data 

and knowledge in exposure, toxicology, and 

epidemiology to improve understanding of how 

exposure to environmental factors during early 

life influence health outcomes over the life 

course. 

The CEH Research Roadmap helps connect 

the dots among the research activities being 

implemented across ORD’s research programs. 

In addition, the vision articulated in the 

Roadmap serves to focus ORD’s investment in 

CEH research on areas in which EPA can play 

a significant leadership role and to ensure this 

cross cutting research is integrated and the 

results are impactful. The CSS program also 

informs critical research areas identified in 

the ORD cross cutting research Roadmaps, as 

illustrated in Table 1.

The HHRA and CSS programs are working together to evaluate how new data emerging 

from computational toxicology can be used to 

improve efficiency and reduce uncertainty in 

risk assessment. CSS research is developing approaches to integrate new types of information 

with existing methods and information to support science-based decisions, and to evaluate 

the value added of new data. In one example, 

CSS will generate data needed for HHRA to develop innovative fit-for-purpose assessment 

products (such as high-throughput toxicity 

values). Projects in the HHRA program include 

case studies to characterize the utility of several 

new approaches applied to different classes of 

chemicals, various endpoints, and toxicities, 

and with disparate degrees of supporting eviTable 1. CSS Research Program Contributions to Critical Needs Identified by ORD Roadmaps

Multiple checkmarks indicate a larger contribution of CSS activities and interest in the identified 

science gaps of the Roadmaps than a single checkmark; a blank indicates no substantive role.

ORD Roadmap

CSS Topic Area

Chemical 

Evaluation

Life-Cycle 

Analytics

Complex 

Systems 

Science

Translation 

and 

Knowledge 

Delivery

Climate Change  

Environmental Justice   

Children’s Health    

Nitrogen & Co-Pollutants  

10http://www2.epa.gov/research/research-roadmaps
10

dence for context. Characterizing the utility of 

these new data and tools for improving risk assessment will build stakeholder confidence and 

accelerate acceptance for regulatory decision 

making. Additional coordination efforts among 

ORD’s research programs range from formal integration efforts at a high level to collaborative 

research among EPA scientists working on related issues. For example,

•

•

•

•

Projects outlined in the Research Topics section 

include additional examples of activities that integrate across national research programs.

CSS Research Supports EPA 

Strategic Plan

Chemical manufacture and use has intended 

and unintended consequences on the quality of 

the air we breathe, the water we drink, and the 

communities in which we live, work, and learn. 

Outputs of the CSS research program therefore 

will broadly support EPA’s Strategic Goals in 

these areas (see box) and inform EPA decisions 

on improving human health and the environment sustainably. Very specifically, the CSS research program is designed directly to support 

EPA’s Strategic Goal 4: Ensuring the Safety of 

Chemicals and Preventing Pollution; and the 

Cross-Agency Strategy: Working Toward a Sustainable Future.

Goal 4 Objective: Ensure Chemical Safety. Reduce the risk and increase the safety of chemicals that enter our products, environment, and 

bodies. 

Applied Research under Goal 4: EPA chemicals 

research will provide the scientific foundation 

required to support safe, sustainable use of 

chemicals to promote human and environmental health, as well as to protect vulnerable species, lifestages, and populations.

CSS and Safe and Sustainable Water Resources (SSWR) are collaborating to develop more efficient ways to assess the toxicity 

of harmful algal blooms. Additional collaborations are in areas related to contaminants, including pharmaceuticals, found 

in open or drinking water, as well as new 

approaches for evaluating their cumulative 

health impacts.

CSS and Sustainable and Healthy Communities (SHC) collaborate in areas such as use of 

chemicals (most recently, silver nanomaterials) in consumer products and relevance to 

predicting potential children’s exposures.

CSS and Air Climate and Energy (ACE) plan 

to collaborate on novel higher-throughput 

assays for cardiopulmonary effects being 

developed in ACE that may have broader 

application in CSS.

Chemical data, including from applications 

of computational chemistry, can begin to 

inform evaluation and response strategies 

in the Homeland Security Research Program (HSRP), as CSS data and dashboards 

are enriched with more data and information tools and as HSRP is trained among the 

stakeholders of CSS. 

EPA Strategic Plan (FY2014–2018)

Goals and Cross-Agency Strategies

EPA Strategic Goals

Goal 1: Addressing Climate Change and 

 Improving Air Quality

Goal 2: Protecting America’s Waters

Goal 3: Cleaning Up Communities and 

 Advancing Sustainable Development

Goal 4: Ensuring the Safety of Chemicals

 and Preventing Pollution

Goal 5: Protecting Human Health and the 

 Environment by Enforcing Laws and 

 Assuring Compliance

Cross-Agency Strategies

	 • 	Working Toward a Sustainable Future

	 • 	Making a Visible Difference in 	 	

 Communities

	 • 	Launching a New Era of State, Tribal,

	 	 Local, and International Partnerships

	 • 	Embracing EPA as a High-Performing

 Organization
Statutory and Policy Context

Managing chemical risks is covered in legislation and statutes mandated by Congress and 

implemented by EPA (Table 2). Chemicals are 

regulated by several EPA program offices under 

a variety of statutes and CSS has worked closely 

with each of these offices in developing this research program. As examples of chemical legislation, amendments to the FQPA and SDWA, 

both of 1996, contain provisions for assessing 

the potential for chemicals to interact with 

the endocrine system. Both the CWA and the 

SDWA require EPA’s Office of Water to prioritize 

possible water contaminants in the Contaminant Candidate List. EPA’s Office of Solid Waste 

and Emergency Response is concerned with 

the end-of-use disposition of chemicals and is 

therefore interested in life-cycle considerations 

of chemical use. Internationally, similar pressures to transform the chemical safety assessment paradigm are also present, as exemplified 

by the REACH11 program and Cosmetics Directive in Europe and the Canadian Environmental 

Protection Act. CSS will enable EPA to test and 

regulate numerous chemicals more efficiently, 

supporting several statutory obligations and 

policies.

One example of a critical EPA mandate that 

provides important context for design of the CSS 

2016–2019 StRAP and selection of relevant case 

studies is the Endocrine Disruptor Screening 

Program (EDSP).12 The List of the EDSP Universe 

of Chemicals contains approximately 10,000 

chemicals as defined under FFDCA and SDWA 

1996 amendments. EPA recently announced 

and solicited public comment on the use of 

new technologies (such as high-throughput 

toxicology data) to accelerate substantially 

the screening of chemicals for their potential 

to disrupt hormones in humans and wildlife 

and to reduce animal use in screening. 

This announcement signaled an imminent 

opportunity to demonstrate the relevance 

and potential applicability of CSS research to 

environmental policy in near real time.

In addition to federal legislative mandates, 

several state initiatives, summarized in 

Appendix 1, are driving the needed advances 

in chemical evaluation. To contextualize and 

11

11http://echa.europa.eu/regulations/reach

12http://go.usa.gov/ccfxm

Table 2. CSS Research Supports Chemical Risk Management Decisions Mandated by Legislation

Legislation Acronym Website

Clean Air Act CAA www.epa.gov/lawsregs/laws/caa.html

Clean Water Act CWA www.epa.gov/regulations/laws/cwa.html

Comprehensive Environmental Response, 

Compensation, and Liability Act

CERCLA www.epa.gov/superfund/policy/cercla.htm

Federal Food, Drug, and Cosmetic Act FFDCA http://www.fda.gov/regulatoryinformation/legislation/

federalfooddrugandcosmeticactfdcact/default.htm

Federal Insecticide, Fungicide, and 

Rodenticide Act

FIFRA http://www.epa.gov/agriculture/lfra.html

Food Quality Protection Act FQPA http://www.epa.gov/pesticides/regulating/laws/fqpa/

backgrnd.htm

Resource Conservation and Recovery Act RCRA http://www2.epa.gov/rcra

Safe Drinking Water Act SDWA http://water.epa.gov/lawsregs/rulesregs/sdwa/

Toxic Substances Control Act TSCA http://www2.epa.gov/laws-regulations/summary-toxicsubstances-control-act
obtain additional scientific advice on how the 

emerging data and science from CSS can be 

translated for use in EPA decision making, EPA 

commissioned a study by the National Academy 

of Sciences (NAS). CSS has strategically drawn 

from NAS recommendations to address key 

research gaps that are not being addressed 

by partners outside EPA. The formative NAS 

reports are highlighted in Appendix 1.

Research Program 

Objectives 

CSS conducts research to provide the fundamental knowledge infrastructure and complex 

systems understanding required to predict 

potential impacts from use of manufactured 

chemicals and to develop tools for rapid chemical evaluation and sustainable decisions. In 

addition, CSS research results are translated 

to provide solutions and technical support to 

our EPA partners and external stakeholders.

CSS research is guided by the following four 

objectives:

Objective 1: Build Knowledge Infrastructure

Make information publicly accessible. 

Combine different types of data in new ways 

to characterize impacts of chemicals to human 

health and the environment. 

Objective 2: Develop Tools for Chemical 

Evaluation 

Develop and apply rapid, efficient, and 

effective chemical safety evaluation methods.

Objective 3: Promote Complex 

Systems Understanding 

Investigate emergent properties in complex 

chemical-biological systems by probing how 

disturbances and changes in one part affect 

the others and the system as a whole.

Objective 4: Translate and Actively Deliver 

Demonstrate application of CSS science 

and tools to anticipate, minimize, and solve 

environmental health problems. 

Table 3 provides descriptions of each of these 

objectives and their near- and long-term aims 

in advancing the CSS vision.

In addressing these objectives, specific science 

challenges were identified that led to the design 

of the CSS Research Topics described in the next 

section.

Science Challenge: Thousands of chemicals have 

not been evaluated, and new chemicals are continually being developed and introduced into 

commerce. CSS is advancing cutting-edge methods to provide data for higher-throughput riskbased evaluation of both existing chemicals and 

emerging materials. The Chemical Evaluation 

research topic is designed to address this challenge.

Science Challenge: Chemical substitutions and 

other alternatives designed to solve one environmental health problem may have unintended consequences. CSS is exploring new ways to 

evaluate risks to human and ecological health 

across the life cycle of manufactured chemicals, 

materials, and products. CSS methods will efficiently evaluate alternatives and support more 

sustainable chemical design and use. The LifeCycle Analytics research topic is designed to

address this challenge.

Science Challenge: The real world is inherently 

more complicated than current experimental 

models of toxicology can depict. CSS research 

adopts a systems-based approach to examine 

complex chemical-biological interactions and 

predict potential for adverse outcomes resulting from exposures to chemicals. The Complex 

Systems Science research topic is designed to address this challenge.

Science Challenge: Decision makers need demonstrated solutions to translate new information into action. CSS promotes Web-based tools, 

data, and applications to support chemical 

safety evaluations and related decisions. CSS engages EPA partners and stakeholders to ground 

truth the transparency, access, relevance, and 

applicability of our research. The Translation and 

Knowledge Delivery topic is designed to address

this challenge.

12
13

CSS Research Objectives

Objective What We Do Near-Term Aim Long-Term Aim

Build 

Knowledge 

Infrastructure

Make information 

publicly accessible. 

Combine different 

types of data in new 

ways to characterize 

impacts of chemicals to 

human health and the 

environment.

Provide accessible 

information to support 

scientific discovery and 

sustainable decisions.

Generate chemical, 

biological, and 

toxicological 

information to advance 

understanding of 

relationships between 

chemical characteristics 

and potential impacts of 

use.

Develop Tools 

for Chemical 

Evaluation

Develop and apply 

rapid, efficient, and 

effective chemical 

safety evaluation 

methods.

Improve chemical 

prioritization, screening, 

and testing.

Revolutionize chemical 

assessment for potential 

risks to humans and the 

environment.

Promote 

Complex 

Systems 

Understanding

Investigate emergent 

properties in complex 

chemical-biological 

systems by probing 

how disturbances and 

changes in one part 

affect the others and 

the system as a whole.

Improve understanding 

of the relationship 

between chemical 

exposures and 

ecological and human 

health outcomes, 

including to the 

developing organism.

Predict adverse 

outcomes resulting from 

exposures to specific 

chemicals and mixtures 

over time and space.

Translate 

and Actively 

Deliver

Demonstrate 

application of CSS 

science and tools 

to anticipate, 

minimize, and solve 

environmental health 

problems.

Develop solutionbased approaches for 

evaluating impacts of 

high-priority chemicals 

in support of innovative 

and sustainable 

decisions.

Apply CSS tools to predict 

impacts of emerging 

materials, products, and 

new uses.

Table 3. Summary of Near- and Longer-Term Aims of CSS Research Objectives
14

Research Topics

Working with program and regional partners 

to define the scope of the science that will be 

conducted in the CSS research project areas, 

CSS used the following specific criteria:

•

•

•

•

•

•

•

•

In addition, to facilitate the transformation 

required to meet CSS vision, address the 

science challenges, and provide the strategic 

thrust for Goal 4 in EPA’s Strategic Plan, three 

guiding principles have been applied in shaping 

this StRAP.

Adopt the AOP framework 

Adverse outcome pathways (AOPs) are a conceptual framework intended to enhance 

the utility of pathway-based data for use in 

risk-based regulatory decision support. An 

AOP portrays existing knowledge of the link

between a direct molecular initiating event 

and an adverse outcome at a biological level of 

organization relevant to risk assessment (i.e., 

actionable). When rigorously developed and 

evaluated, AOPs provide a scientifically defenThe need is critical, and if CSS does not lead 

and conduct this research, the science will 

not be developed by others to address EPA 

needs. To illustrate, new methods to estimate 

human and ecological exposures to thousands 

of chemicals more quickly and efficiently was 

considered a high-priority topic for CSS. On the 

other hand, additional research to elucidate 

mechanisms of carcinogenicity (currently led 

by NIH), was ranked a lower priority – unless 

used as a specific case study in quantitative 

development of adverse outcome pathways. 

Results are transparent and accessible. All 

data and tools are accessible to EPA partners 

upon delivery of product and are supported 

by appropriate quality assurance, documentation, and peer-reviewed publication(s). 

Synergies are identified and leveraged among 

research topics and project areas. 

All data and tools are developed, evaluated, 

and translated through application to case 

examples of interest to partners. Case studies 

with direct partner engagement or dedicated 

partner advocates are prioritized. 

Research activities are framed to demonstrate value added of information, tools, and 

approaches being developed to support EPA 

decisions. 

Research activities contribute broad scientific 

impact through focus on partner solutions. 

Development of new methods to assess the 

behavior of methodologically challenging 

compounds (MCC) such as perfluorinated 

compounds met an urgent EPA need, but also 

provided a foundation for future research 

on persistence and bioaccumulation of such 

compounds and in selection of safer alternatives.

CSS resources are leveraged through integration across the program and through strategic 

collaborations with other EPA programs, federal agencies, public and private stakeholders, and the global scientific community.

The research approach is innovative and 

applies emerging science and technology to 

advance CSS objectives. A recent example is 

integration of high-throughput bioactivity 

data from ToxCast with high-throughput 

exposure estimations from ExpoCast for riskbased prioritization of endocrine disrupting 

chemicals.

Research addresses CSS partners’ highest 

research and science priorities. For example, 

the integrated bioactivity-exposure (riskbased) prioritization described above was 

tailored for use by the EDSP in application 

to estrogen receptor mediated pathways. 
15

sible foundation for extrapolating from mechanistic data to predicted apical outcomes. Additionally, as individual AOPs are developed, they 

can be assembled into AOP networks that may 

aid the prediction of more complex interactions 

and outcomes resulting from exposure to complex mixtures or chemicals with multiple modes 

of action. By considering AOPs and AOP networks associated with important developmental processes, as well as those associated with 

disease endpoints of concern, mechanistic toxicology information and epidemiology insights 

can be assembled for model development and 

analysis of critical knowledge gaps.

Exploit complex systems modeling to advance 

mechanistic understanding 

A major challenge is translating  AOP frameworks across scales of biological organization 

(molecules, cells, tissues, populations) and 

function, while incorporating critical windows 

of exposure, dose, toxicodynamics, and toxicokinetics. Multiscale modeling and simulation is 

a powerful approach for capturing and analyzing biological information that is inaccessible 

or unrealizable from traditional modeling and 

experimental techniques. For example, virtual 

tissue models (VTMs) afford the opportunity to 

develop science without conducting studies on 

children. By simulating a range of predicted effects, the earliest signs of adversity, or tipping 

points, can be identified, and new testable hypotheses aimed at improving the accuracy of 

inferences from in vitro data can be developed. 

These same modeling approaches can be applied to capture the complexity of wildlife interactions with the environment and to postulate 

key environmental determinants of population 

health.

Promote a life-cycle perspective 

A life-cycle perspective is required to evaluate 

the safety of chemicals and materials in the 

context of how these are designed and used in 

society. To evaluate alternatives and options, 

risk (hazard and potential for human exposure 

and toxicity) and environmental impact (ecological risks) are characterized for chemicals 

and materials within the context of the full 

range of benefits and consequences. Tradeoffs 

between these risks and factors, such as product functionality, product efficacy, process safety, and resource requirements, are considered. 

The intent is to promote a knowledge-driven 

approach that integrates multiple and diverse 

data streams for decision making based on specific context and priorities. Regardless of this 

context, however, sustainable decisions require 

that consequences of use over a chemical’s life 

cycle (from production to disposal) be evaluated.

These criteria and guiding principles helped 

quickly focus the scope of the program on research topics and project areas that promise to 

have transformative impact within and outside 

the CSS research program, and that inherently 

lend themselves to an integrated and collaborative research construct. CSS FY16–19 research 

is organized by four Research Topics and implemented by transdisciplinary teams of scientists 

working within and across these topics. 

CSS research often is conducted in collaboration with program and regional partners 

through specific case studies that provide the 

opportunity to evaluate real-world applicability of its research. In addition, the leading edge 

of CSS science is driven through transformative research conducted in academia through 

EPA’s Science to Achieve Results (STAR) grants 

program. Within each topic, collaborations developed with the academic researchers further 

enable CSS to benefit from and integrate the 

emerging science, methods, and tools. It also 

provides an opportunity for academic researchers to learn about and contribute to research 

relevant to the science challenges that underpin CSS topics. In addition, several research
16

efforts in CSS germinated through awards in the 

Pathfinder Innovation Projects (PIP) program, 

which provides ORD scientists the opportunity 

to stretch beyond their existing research and experiment with creative ideas that can transform 

environmental protection and sustainability. In 

CSS, these projects are shepherded through 

their nascent stages, and when ready and applicable, the research or results are applied to 

or integrated programmatically into CSS. Some 

of these synergies are provided as examples in 

describing the CSS topics below.

Three research topics provide core systems 

science and tools:

1. Chemical Evaluation

2. Life Cycle Analytics

3. Complex Systems Science 

A fourth research topic focuses on translation 

and active delivery of CSS research products, 

demonstration and application of CSS scientific 

tools, and knowledge delivery to EPA Partners:

4. Solutions-based Translation and 

Knowledge Delivery

CSS project areas associated with each of 

these four topics are described below. The 

CSS program structure in Figure 1 depicts the 

dynamic and interdependent relationship 

between the topics and project areas, and 

among the research and translational topics.

Integrated research also will be required across 

these topics and projects to address scientific 

gaps effectively and provide tools to enable 

EPA decisions. EPA priorities for specific classes 

of chemicals, human and ecological health 

endpoints, and vulnerable species and lifestages 

will be used to focus case studies, design 

specific research activities, and further focus 

this integration. The priority areas for FY16 –19 

include (1) Emerging and methodologically 

challenging compounds, (2) Endocrine 

disruption (including thyroid), and (3) Children’s 

environmental health. Importantly, signature 

CSS research in computational toxicology will 

exploit new and emerging scientific tools in 

molecular biology, computational chemistry, 

and informatics to transform chemical safety 

evaluation. Table 4 summarizes the scientific 

challenges addressed by the project areas, 

interim outputs they provide that feed into the 

larger programmatic outputs, and measures of 

success for these projects.

Advance cutting-edge methods and provide 

data for risk-based evaluation of existing 

chemicals and emerging materials.

Address critical gaps and weaknesses in accessible tools and metrics for quantifying 

risks to human and ecological health across 

the life cycle of manufactured chemicals, materials, and products. Advance methods to 

efficiently evaluate alternatives and support 

more sustainable chemical design and use. 

(1) Promote Web-based tools, data, and applications focused on tailored solutions to 

support chemical safety evaluations and related decisions; (2) Respond to short-term 

high-priority science needs for CSS partners; 

and (3) Allow for active and strategic engagement of the stakeholder community.

Adopt a systems-based approach to examine 

complex chemical - biological interactions 

and predict potential for adverse outcomes 

resulting from exposures to chemicals.
Topic 1: Chemical Evaluation

The Chemical Evaluation topic will provide costefficient methods and high-throughput data for 

rapid risk-based evaluation of existing chemicals 

and emerging materials. One research project 

area focuses on hazard profiling and a second 

on exposure forecasting. 

Research Project Area: High-Throughput 

Toxicology

Research in the High-Throughput Toxicology 

(HTT) project area is driven by limitations of 

current chemical testing methods and EPA’s 

need to evaluate large sets of chemicals 

for potential adverse human and ecological 

health effects. EPA requires rapid and efficient 

methods to prioritize, screen, and evaluate 

chemical safety for thousands of compounds. 

The ToxCast research program was initiated 

to generate data and predictive models on a 

large number of chemicals of interest to EPA 

using high-throughput screening methods 

and computational toxicology approaches to 

rank and prioritize chemicals. The focus of this 

project area will be to provide the foundation 

and contextually relevant tools for extending 

utility of the HTT strategy to benefit regulatory 

decisions ranging from chemical prioritization 

to applications for more in-depth risk decision 

paradigms. 

To provide contextual or fit-for-purpose validation of the HTT testing strategy, guidance and 

17

Figure 1. CSS Research Topics and Projects.
performance criteria for assay validation will 

be developed covering appropriate biological domains, technical description and assessments, interpretation of results, and linkages to 

higher-level biological complexity. To broaden 

the screening approach and fill gaps in coverage of toxicity pathways will be expanded in 

collaboration with the AOP project to identify 

and develop assays for key molecular initiating events for incorporation into the testing 

program. Data will be generated for key assays 

and used to generate predictive models covering critical toxicity endpoints. Resources will be 

devoted to evaluating cutting-edge methods to 

incorporate into the high-throughput testing 

strategy using a case study approach and account for xenobiotic metabolism. Methods also 

will be evaluated for generating high-throughput screening data on challenging classes of 

chemicals such as volatiles. The project will 

build toward a broader and more efficient highthroughput testing strategy, including the use 

of global assays capable of extensive biological 

activity recognition. Such assays may serve to 

prioritize chemicals for more detailed in vitro or 

short-term in vivo testing, possibly directing the 

type of testing required. 

Examples of research activities in this project 

area include support to interpret ToxCast 

data and development of new assays to cover 

priority endpoints: 

•

•

Research in the HTT project area will provide 

rapid and efficient toxicity testing paradigms 

and data on chemicals and endpoints of interest to EPA as well as the tools to understand the 

significance of the results.

Research Project Area: Rapid Exposure and 

Dosimetry

As data from high-throughput screening 

methods become available, this new toxicity 

information must be translated to assess 

potential risks to human and ecological health 

from environmental exposures. In concert 

with the toxicity information, estimates of 

human and ecological exposures are required 

as critical input to risk-based prioritization and 

screening of chemicals. The ExpoCast effort was 

initiated to ensure that the required exposure 

science and computational tools are developed 

and ready to address global needs for rapid 

characterization of exposure potential arising 

from the manufacture and use of thousands 

of chemicals and to support use of emerging 

toxicity data for risk-based chemical evaluation. 

The focus of the Rapid Exposure and Dosimetry 

project area will be to develop the data, 

tools, and evaluation approaches required to 

generate rapid and scientifically defensible 

exposure estimates for the full universe of 

existing and proposed commercial chemicals.

18

document will enable evaluation and interpretation of high-throughput ToxCast data in 

several decision contexts.

The ToxCast program has used a series of 

high-throughput assays on a large number 

of chemicals to generate toxicity data rapidly. Using these data for regulatory purposes requires the ability to interpret the 

technical quality of the data and understand 

the relationship of these high-throughput 

assays to biological outcomes. A guideline 

document will be produced by this project, providing standardized descriptors and 

methods for interpreting data based on 

level of biological complexity. This guideline

Thyroperoxidase (TPO) catalyzes a critical 

step in the synthesis of thyroid hormones. 

Inhibition of TPO by environmental chemicals 

leads to severe and irreversible impacts on 

brain development. In this project, a novel 

high-throughput screening assay for TPO 

inhibition is being developed, validated with 

21 well-characterized chemicals, and used 

to screen the ToxCast Phase I and II chemical 

libraries (1074 chemicals). 
Tools to be applied in this project area include 

innovative data mining approaches, advanced 

computational models, and higher-throughput 

analytical methods. The scope of this project includes development, evaluation, and ultimately 

application of high-throughput computational 

exposure prediction methods to support regulatory, industry, community, and individual 

decisions that protect human health and the 

environment. Research in this project area will 

generate and analyze in vitro data on key determinants of human pharmacokinetics and 

develop population-based models for using 

these data to compare human exposures and 

hazards. Consideration will be given to identifying chemical classes and aspects of human variability not currently well characterized by rapid 

methods, including biological variability (e.g., 

genetic polymorphisms); behavioral variability 

(e.g., consumer use) that lead to differences 

for key demographics; and lifestage variability 

(e.g., children).

Research in the Rapid Exposure and Dosimetry project area will provide high-throughput 

pharmacokinetic and exposure data and models for risk-based prioritization to address case 

examples of interest to EPA program office partners.  The chemical exposures and potentially 

hazardous doses this project predicts ultimately 

will be used in the Demonstration and Evaluation project for application of new data streams 

and rapid assessment approaches to support 

EPA chemical safety assessments.Results will 

advance computational exposure science required to transform chemical evaluation.

New Methods in 21st Century Exposure Science

To complement intramural research under the 

Chemical Evaluation Topic, CSS has funded 

five universities through the EPA STAR grants 

program to conduct innovative research to 

advance methods for characterizing real-world 

human exposure to chemicals associated with 

consumer products in indoor environments. 

One cross cutting element among these 

grantees was their interest in applying non 

targeted analyses, based on high-resolution 

mass spectrometry platforms, to screen 

for xenobiotic chemicals in a variety of 

environmental and biological media.

Topic 2: Life-Cycle Analytics

Research in the Life-Cycle Analytics Topic is 

exploring and advancing new ways to evaluate 

risks to human and ecological health across 

the life cycle of manufactured chemicals, 

materials, and products. Under four integrated 

CSS research projects, methods are being 

developed and demonstrated to evaluate 

alternatives efficiently and support more 

sustainable chemical design and use. 

Research Project Area: Sustainable Chemistry

Strategies are required to apply information 

on inherent chemical properties to predict 

potential for transformation and activity of 

compounds in biological and environmental 

systems. The intersection of recent advances in 

high-throughput screening (HTS), mechanistic

19

RESEARCH HIGHLIGHT

EPA STAR grants are advancing 

methods for characterizing 

real-world, indoor exposures to 

chemicals in consumer products.

RESEARCH HIGHLIGHT

ExpoCast includes science and 

computational tools for rapid 

characterization of exposure potential 

arising from the manufacture and use of 

thousands of chemicals. 
toxicology, computational chemistry, and 

cheminformatics provides the foundation to 

identify influential chemical determinants of 

adverse biological impacts of chemicals and 

materials. The Sustainable Chemistry project 

area will take advantage of these advances to

in commerce. For the set of compounds represented in the ToxCast library, knowledge of 

chemical features will be applied to inform interpretation of high-throughput toxicity (HTT) 

data and models. At the same time, the HTT 

data and models will be used to elucidate key 

features associated with potential for hazard. For select sets of high-interest chemicals, 

mechanistic-based case studies will be conducted to link upstream chemistry with downstream biology, incorporating considerations 

of transformations in real-world biological and 

environmental systems. This core research will 

further establish common chemistry principles 

linking inherent chemical structural features 

and properties to potential for toxicity, environmental persistence, and transformations in environmental and biological systems.

Examples of research activities in this project 

area include development and application of 

computational chemistry/cheminformatics 

tools so that safety and exposure assessments 

of organic chemicals can be better informed. 

Software tools such as the Chemical Transformation Simulator (CTS) are being developed 

and evaluated through case studies focused 

on screening carbamate, organophosphorus 

pesticides, and high-interest flame retardants 

for toxicity, persistence, bioaccumulation, and 

transformation potential. 

The Sustainable Chemistry project area will 

provide a chemical knowledge resource that 

consolidates basic chemical data, along with 

cheminformatics and computational chemistry 

tools for shared use, and will empower more 

effective, integrated evaluation of chemicals. 

Improved understanding of chemical features 

associated with fate and activity in biological 

and environmental systems will inform design 

and evaluation of safer chemical alternatives 

and support sustainable decisions.

Research Project Area: Emerging Materials

Innovations in chemical and material design 

are rapidly changing the landscape of industrial and consumer products as novel materials, 

such as engineered nanomaterials (ENMs), are 

incorporated to enhance their performance. 

Scientifically supported approaches are required to efficiently screen for and evaluate 

potential impacts of ENMs on human health 

and the environment. The Emerging Materials project area will conduct applied research to develop, collate, mine, and apply 

information on ENMs to support risk-based 

decisions on sustainable manufacture and use. 

20

RESEARCH 

HIGHLIGHT

Improved 

understanding of 

chemical features 

in biological and 

environmental 

systems informs 

design and 

evaluation of 

safer chemical 

alternatives.

RESEARCH HIGHLIGHT

Through case examples of engineered 

nanomaterials (including silver 

nanoparticles and carbon nanotubes), 

researchers identify key information 

required to characterize potential for 

exposure and hazard across the life 

cycle of the product. 

improve understanding 

of chemical features associated with potential 

for environmental and 

human health impacts.

In this project area, 

knowledge of inherent 

chemical properties and 

features will be explored 

to distill principles for 

chemical classes that 

capture the full range of 

chemistries represented
In this project area, a life-cycle perspective is 

applied and available information synthesized 

to consider potential for impacts associated 

with manufacture, use, and disposal of products containing ENM. Through a set of case examples focused on priority and data-rich material classes (including silver nanoparticles and 

carbon nanotubes), extant information will be 

mined to identify key information required to 

characterize material form, potential for exposure, and hazard across the product life cycle 

for data-poor materials. To address these key 

gaps, a library of core nanomaterials, including 

systematically aged materials, will be considered. Interactions between ENMs and biological 

or other complex media will be explored. Additionally, the complexity of relating nanomaterial features directly to risk will be addressed by 

considering critical intermediate properties of 

ENMs that are predictive of potential impacts 

and identifying associated functional assays.

Results of the Emerging Materials project area 

will provide the methods and tools to enable 

EPA to evaluate emission, transformation, potential exposure, and impacts of ENMs efficiently across the material/product life cycle. 

The long-term impact will be to accelerate the 

pace at which the safety of existing nanomaterials is assessed and to inform the sustainable 

design and development of emerging materials 

and products.

Research Project Area: Life-Cycle and Human 

Exposure Modeling

Evaluation of alternatives for sustainable decisions requires understanding the broad range of 

impacts on human health and the environment 

associated with a chemical or product throughout the life cycle. Efficient tools are required to 

consider, among the broad range of impacts, 

the potential for exposures to human and ecological species across the chemical life cycle 

when limited data are available. This project 

area will take the novel approach of integrating 

chemical exposure and life-cycle knowledge to 

model and assess human health and ecological 

impacts of alternatives. Approaches will be developed to evaluate environmental and human 

health impacts and identified metrics efficiently 

to quantify tradeoffs between risks and other 

sustainability factors.

By bringing together two of ORD’s leading 

disciplines in exposure science and life-cycle 

assessments, this project is transforming 

how scientists in the broader community are 

tackling these same challenges. Research in this 

area will be focused on making sustainability 

analysis for chemical safety evaluation operational by leveraging and extending methods in 

life-cycle assessment (LCA) and exposure modeling to incorporate metrics of human and ecological risk. An approach will be developed that 

harmonizes the product-centric nature of LCA 

with the chemical-centric focus of comparative 

risk analysis by considering chemical function. 

The two primary objectives of the CSS Life-Cycle Assessment and Human Exposure Modeling project are to develop (1) a framework and 

database structure that brings together chemical exposure and life-cycle modeling, and (2) a 

tool for evaluating chemical/product impacts in 

a life-cycle assessment framework to support 

decision making through improved risk and sustainability analysis.

21

RESEARCH HIGHLIGHT

By integrating chemical exposure 

and life-cycle approaches, 

researchers will model and 

assess the human health and 

ecological impacts of substituting 

alternative chemicals or 

processes.
Through application to a select set of case examples of interest to EPA program partners (including building materials/semivolatile organic 

compounds), this project area will provide efficient tools and metrics to evaluate chemical 

impacts across the life cycle and to support alternatives assessment and sustainable chemical use.

Research Project Area: Ecological Modeling

EPA’s process for registering and regulating 

chemical compounds includes a tiered ecological risk assessment (ERA). Within the ERA 

process, chemicals are first screened using 

rapid assessment tools that require minimal 

data and provide conservative estimates of 

ecological risk. Chemicals determined to present an appreciable risk are subject to higherlevel assessments that provide quantitative estimates of ecologically relevant risk and identify 

risk mitigation options. For the vast majority 

of chemicals and species, little or no data exist 

and refined assessments must rely on modeled 

estimates of exposure and effects. The Ecological Modeling project area will advance efficient methods to improve risk assessments 

with limited data availability and more complex approaches that can target data - rich 

applications.

Research in this project area will integrate 

existing and novel models into an ecosystembased framework that combines the fate and 

transport of chemicals in the environment with 

improved toxicity interpretation for ecological 

endpoints based on surrogate species. For 

assessments that rely on minimal data (e.g., 

endangered species), this project will develop 

and evaluate approaches to maximize the 

use of available information and demonstrate 

their usefulness in increasing ERA efficiencies, 

identifying and reducing critical uncertainties, 

and identifying critical information that will 

improve decisions. This will be accomplished 

through proof-of-concept studies that apply 

advanced molecular, modeling, and landscape 

analysis methodologies to verify model 

predictions. For higher-tier assessments, 

including those that characterize spatially 

varying chemical impacts and impacts on 

threatened and endangered species, this 

project will advance the science that will enable 

EPA to describe chemical impacts in ecologically 

relevant terms that align with sustainable 

ecosystem services endpoints. 

Research in this project area will focus 

on developing and evaluating ecological 

models for endangered aquatic species and 

wildlife populations exposed to pesticides. A 

population-modeling framework for predicting 

chemical effects to avian species will integrate 

three models currently used extensively to 

assess ERA: (1) TIM (Terrestrials Investigation 

Model); 2) MCnest (Markov Chain Nest 

Productivity Model); and (3) HexSim (spatially 

explicit individual-based model).

The Ecological Modeling project area will 

provide demonstrated efficient ERA tools 

that reduce uncertainty for high-priority and 

methodologically challenging chemicals. The 

resulting decision framework for using models 

of various complexities, data requirements, and 

levels of ecological realism for differing ERA 

requirements or fit for purpose will enhance 

EPA’s capacity to protect sensitive ecosystems 

and species.

22

RESEARCH HIGHLIGHT

To predict effects of pesticides on 

endangered aquatic species and 

wildlife populations, researchers are 

developing, integrating, and evaluating 

ecological models into an efficient 

decision framework.
Within the Life-Cycle Analytics Topic, CSS has 

funded complementary extramural research 

to advance the scientific understanding of potential for chemical impacts across the life cycle 

and to foster innovation of safer alternatives, 

including the following:

•

•

•

•

Topic 3: Complex Systems Science

Research conducted in the Complex Systems 

Science topic is focused on building the scientific foundation to predict adverse outcomes 

resulting from exposures to specific chemicals 

and mixtures over time and space. The Adverse 

Outcome and Virtual Tissues project areas are 

highly complementary. These projects are also 

highly integrated with the projects in the Chemical Evaluation topic.

Research Project Area: Adverse Outcome 

Pathway (AOP) Discovery and Development

To use new data being generated in the CSS 

Chemical Evaluation Topic for EPA decisions, 

evaluation of the human health and ecological 

relevance of effects observed in in vitro or in 

vivo models is needed. Both qualitative and 

quantitative linkages are required between 

measures of biological perturbation provided 

by new and emerging methods and metrics of 

adverse outcome relevant to EPA risk-based 

decisions. 

The AOP framework provides a systematic and 

modular structure for organizing and communicating existing knowledge concerning the 

linkage between molecular initiating events, 

intermediate key events along a toxicity pathway, and apical adverse outcomes traditionally considered relevant to risk assessment or 

regulatory decision making (i.e., actionable outcomes). When developed and evaluated rigorously, AOPs provide a scientifically defensible 

foundation for extrapolating from mechanistic 

data to predicted apical outcomes. Additionally, as individual AOPs are developed, they can 

be assembled into AOP networks by evaluating 

shared nodes or key events in individual pathways. These networks may aid the prediction 

of more complex interactions and outcomes resulting from exposure to complex mixtures or 

chemicals with multiple modes of action. AOP 

23

EPA/NSF Networks for Sustainable 

Molecular Design and Synthesis.

Investigating the sustainable molecular 

design of chemical alternatives to determine 

traits of chemicals that indicate they are 

functional for their intended purpose and 

have the least impact on human health and 

the environment.

Systems-Based Research for Evaluating 

Ecological Impacts of Manufactured 

Chemicals.

EPA STAR grants provide integrated, 

transdisciplinary research to advance scientific 

understanding of the impacts of manufactured 

chemicals on ecosystem health. The studies 

require use of systems-based research to 

develop innovative metrics and modeling 

approaches that support evaluation of 

ecological resilience and inform sustainable 

risk-based decisions. An important dimension is 

to translate emerging and advanced methods, 

data, and computational tools to address 

complexity of these systems and distill drivers 

of adverse outcomes to ecological organisms 

and populations. 

EPA/NSF Centers for the Environmental 

Implications of Nanotechnology.

Elucidating the relationship between 

nanomaterials and potential for 

environmental exposures, biological effects, 

and ecological consequences. In addition, 

these grants have germinated a communitybased effort to develop higher throughput 

approaches to predict toxicological effects 

associated with those exposures.

EPA/NSF Networks for Characterizing 

Chemical Life Cycle.

Investigating ways to characterize 

and predict  environmental and  health 

implications of chemicals by following 

chemicals through their life cycle from 

design, manufacture, use, and disposal.
networks also afford the opportunity to integrate and evaluate the potential for impacts 

associated with nonchemical stressors, in addition to chemical stressors. By considering AOPs 

and AOP networks associated with important 

developmental processes, as well as those associated with disease endpoints of concern, 

there is the potential to bring together mechanistic toxicology information and epidemiology 

insights for model development and analysis of 

critical knowledge gaps.

The AOP Discovery and Development (AOPDD) 

project area focuses on research that advances 

predictive applications of the AOP framework 

and supports the use of alternative data, that 

is, other than direct measures of apical toxicity 

outcomes, as a credible basis for risk-based decision making concerning potential impacts of 

chemicals on ecological and human health. 

For example, to support the application of the 

HTT and the AOP framework as a basis for decision making, bioactivity measures and hazard predictions must be complemented with 

understanding of chemical-specific properties that dictate external exposure and tissuespecific dose. The AOPDD project team has 

conducted case studies focused on acetylcholinesterase inhibitors and thyroid peroxidase 

inhibitors to demonstrate the use of a novel 

strategy and workflow for incorporating these 

considerations. 

The AOPDD project team is also developing 

innovative approaches for applying pathwaybased bioactivity data, in the context of AOPs, 

to predict integrated biological hazards that 

may be associated with exposure to complex 

mixtures of chemicals present in the environment. Approaches have been demonstrated 

through case studies either using high-throughput in vitro bioassays for the direct testing of 

surface water extracts, or by mapping chemical 

concentrations detected in surface waters to 

sources of chemical-specific bioactivity data.

This research will provide a critical scientific 

foundation for 21st century approaches to toxicity testing, which seek to make increased use 

of lower-cost, higher-throughput or higher-content in vitro, in silico, or short-term in vivo testing for single-chemical hazard assessment. It 

also provides the scientific framework to assess 

the human/ecological relevance of pathwaybased effects across different model systems 

and address the challenges exposure to multiple stressors poses in the environment.

Research Project Area: Virtual Tissue Models

Innovation in methods to predict consequences 

of decisions requires application of ever-advancing and emerging science. A major challenge is translating AOP frameworks across 

scales of biological organization (molecules, 

cells, tissues, populations) and function, while 

incorporating critical windows of exposure, 

dose, pharmacodynamics, and pharmacokinetics. Complex models of prototype biological systems are needed that can be probed 

(experimental) and simulated (computational) 

analytically to integrate knowledge and identify 

gaps in knowledge. Multiscale modeling and 

simulation is a powerful approach for capturing and analyzing biological information that 

is inaccessible or unrealizable from traditional 

modeling and experimental techniques. For 

24

RESEARCH HIGHLIGHT

The AOP Discovery and Development team 

is developing innovative approaches for 

applying pathway-based bioactivity data, in 

the context of adverse outcome pathways, 

to predict biological hazard(s) associated 

with exposure to complex chemical 

mixtures.
example, virtual tissue models (VTMs) afford 

the opportunity to develop science without 

conducting studies in children. By simulating a 

range of predicted effects, the earliest signs of 

adversity — or tipping points — can be identified, along with new testable hypotheses aimed 

at improving the accuracy of inferences from in 

vitro data. In the VTM project area, knowledgebased models of tissues and organ functions 

that integrate dynamics of cellular function into 

biological networks governing system behavior 

are developed and applied to assess informative case examples of developmental toxicity.

VTMs are uniquely positioned to capture the 

connectivity between different scales of biological organization and predict key events in an 

AOP. The VTM approach is transformative for

ORD as a new way to integrate in vitro and in vivo data into in silico models that can be used to unravel biological 

complexity and predict performance of a 

complex biological system with respect to

(1) homeostasis and systems failure (e.g., adaptive versus adverse responses); (2) integrating kinetics-dynamics (e.g., modeling different 

exposure scenarios); (3) exploring combinations of adverse circumstances that converge 

onto sensitive pathways and processes (e.g., 

mixed modes of action, cumulative or aggregate exposure, cross-species comparison); and 

(4) addressing lifestage considerations (e.g., 

Children’s Environmental Health Roadmap). 

The VTM project area will focus on prenatal 

developmental toxicity and early postnatal developmental toxicity; however, the concepts 

and principles for multiscale modeling will be 

extensible across lifestages and ecological populations. 

Research in the VTM project area will provide 

improved quantitative understanding of the 

molecular pathways and cellular processes underlying AOPs in building an integrated predictive system. Focused examples considered in 

the VTM project area will provide improved understanding of the relationship between chemical exposures and ecological and human health 

outcomes, including impact on the thyroid system and on the developing organism. Ultimately, the vision for 2020 is a platform of experimental and computational models that capture 

system dynamics for predictive toxicology. 

Through the EPA STAR grants program, CSS has 

funded complementary extramural research 

under the Complex System Science topic to 

advance scientific understanding and development of methods to enhance capacity for predictive toxicology, including the following:

•

•

25

RESEARCH HIGHLIGHT

EPA STAR research centers are 

developing organotypic cell models 

for high-priority biological systems 

such as the brain, liver, heart, and 

kidney to accelerate research on the 

interactions of chemicals with key 

biological processes.

Development and Use of AOPs that Predict 

Adverse Developmental Neurotoxicity 

Four grants are awarded to develop AOPs 

that map how chemicals interact with biological processes and how these interactions 

may lead to developmental neurotoxicity. The 

studies are focused on improving EPA’s ability to predict the potential health effects of 

chemical exposures. 

Organotypic Culture Models for Predictive 

Toxicology Center

Center grants are awarded to develop 

Organotypic Cell Models for high-priority biological systems, such as the brain, 

liver, kidney, testes, breast tissue, heart, 

and neurovascular, and evaluate them 

as testing platforms for research into the
•

Topic 4: Solutions-Based 

Translation and Knowledge Delivery

Research Project Area: Demonstration and 

Evaluation for Risk-Based Decisions

Work conducted in CSS is generating numerous 

new approaches and data streams that are intended to benefit environmental decision making by reducing time, cost, and the uncertainty 

of decisions. The purpose of this research is to 

further aid translation of these approaches by 

evaluating, establishing, and demonstrating 

their effectiveness to EPA partners and stakeholders. This project will (1) develop qualitative 

and quantitative approaches to integrate these 

new types of information with existing methods and information to support science-based 

decisions, and (2) evaluate the value added of 

new data streams, particularly HTT data (experimental and computational), in terms of efficiency, and their ability to reduce uncertainty 

in the risk assessment process. This research 

will produce an objective framework to evaluate systematically the integration of these new 

testing and computational methods, and provide measures of confidence and uncertainty 

to determine fit for purpose for different EPA 

actions. The impact will be that risk assessors 

will have confidence that the new approaches, 

data, and tools developed in CSS are scientifically sound and provide value to environmental decision making. Other research ongoing 

in CSS will benefit from the lessons learned 

from this project, as this information will help 

establish future research priorities within CSS.

For example,  the EDSP21 program led 

by EPA’s Office of Chemical Safety and Pollution 

Prevention (OCSPP) is collaborating with ORD to 

use its HTT and exposure data to develop integrated approaches for screening and prioritizing endocrine disrupting chemicals for further 

testing. These proposed approaches are being 

evaluated by their Scientific Advisory Panels 

(SAP) for adoption into the program. The expectation is that over time, as approaches are 

developed and “validated” for these applications, their use may be expanded to address the 

broader universe of chemicals, including chemicals covered by TSCA.

A second example derives from strategic integration between the CSS and HHRA national 

research programs. More than 80,000 legacy 

or current chemicals are listed in the TSCA inventory; fewer than 2000 of these have health 

assessments available across federal and state 

agencies. Multiple EPA programs and regional 

offices are tasked with making decisions, in a 

risk management context, for chemicals with 

inadequate or nonexistent hazard databases. 

26

RESEARCH HIGHLIGHT

EPA’s Office of Chemical Safety and Pollution 

Prevention is collaborating with ORD, using 

high-throughput toxicity and exposure data, 

to develop approaches for screening and 

prioritizing endocrine disrupting chemicals for 

more advanced testing.

Susceptibility and Variability in Human 

Response to Chemical Exposure

The long-term objective of this grant is to 

uncover the mechanistic linkages between 

the genome (e.g., variation in DNA sequence 

among individuals), metabolism (e.g., formation of organ-specific toxic intermediates), and 

adverse molecular events (e.g., transcriptional 

changes associated with toxicity) for highinterest chemicals.

interactions of chemicals with key biological processes. This research will provide new 

biological insight as to how tissues and organs function during chemical exposures. 

The data then will be used to develop advanced computational models of how organs and tissues respond to chemicals, 

and use them ultimately to validate predictive models of human disease or response.
27

In this example project, CSS would generate 

data needed for HHRA to develop innovative 

fit-for-purpose assessment products (such 

as high-throughput toxicity values or "rapid 

tox").

Research Project Area: Partner-Driven 

Research 

Research conducted in this area will be 

motivated by CSS partners’ high-priority, shortterm needs that are not otherwise anticipated 

or addressed in the StRAP. The project will 

be defined by the National Program Director 

(NPD) in collaboration with the partner(s) 

and in consultation with ORD lab and center 

leadership. Projects within this theme will 

have deliverables tailored to the needs of the 

partners, but the research from this project 

will be otherwise amplifiable and relevant to 

other efforts in CSS. Although the lifespan of 

a typical project is not expected to exceed 18 

months, the effort may give rise to a longerterm research project in CSS through future 

planning cycles.

For example, the EDSP21 collaboration with OCSPP first began as a partner-driven effort with 

a narrow focus on the estrogen pathway and a 

limited number of high-throughput assays. The 

success of that collaboration, peer reviewed by 

an SAP and in a variety of peer-reviewed journals, led to its development into a full CSS project (described above).

Additionally, in several cases, CSS research is 

developed through engagement of and collaboration with regional partners. This provides an 

opportunity to provide near-term support to 

address regional needs and to evaluate the relevance and applicability of some CSS research 

in “real-world” contexts. For example, in the 

AOPDD project area, collaborations developed 

with Region 5 and other federal partners under the Great Lakes Restoration Initiative and 

the Great Lakes National Program Office have 

resulted in a biological effects surveillance program. CSS is providing critical support to the development of this program, which is necessary 

to evaluate the impacts of chemicals of emerging concern on Great Lakes fish and wildlife. 

This project presents a significant opportunity 

for EPA’s Office of Water to pursue the applicability of effect-based biomonitoring for evaluating pollutant burdens. Research in this area is 

being conducted collaboratively with scientists 

in SSWR doing similar research in other regional 

offices.

Research Project Area: Stakeholder 

Engagement and Outreach

This effort will encompass strategic outreach 

and engagement of CSS’s broad stakeholder 

community who will serve as a ”sounding 

board” and help ground truth the transparency, 

access, relevance, and applicability of CSS research. Stakeholders will be engaged through 

public workshops, tailored webinars and training events, national scientific meetings, strategic collaborations, funded challenges, and 

other outreach activities. This effort has been 

shaped by two large stakeholder engagement 

workshops held in 2014 and led by the NPD 

team, in collaboration with project scientific 

leads and partners.

RESEARCH HIGHLIGHT

Collaborations with EPA Region 5 and other 

federal partners have resulted in a biological 

effects surveillance program to evaluate the 

impacts of chemicals of emerging concern on 

Great Lakes fish and wildlife.
28

Project Areas Challenges Addressed Intermediate Outputs Measures of Success

Topic 1: Chemical Evaluation

HighThroughput 

Toxicology

Expand coverage in 

HTT toxicity screening 

schemes for high-priority 

biological areas such as 

endocrine disruption and 

adverse outcomes such as 

developmental toxicity.

Incorporate xenobiotic 

metabolism into HTT test 

methods.

Guidance for evaluating 

technical performance 

and biological domain of 

high-throughput assays.

New medium- and 

high-throughput assays 

and development of 

models (signatures) to 

cover important areas 

of biological space, 

high-priority AOPs, and 

chemical-biological 

interactions.

Approaches for 

incorporation of 

xenobiotic metabolism 

and challenging chemical 

classes into highthroughput test methods.

HTT assays covering 

key events in AOPs for 

estrogenic, androgenic, 

thyroid, steroidogenesis, 

and developmental 

endpoints are fit-forpurpose validated 

(e.g., for a regulatory 

application, or by a 

convening body such as 

OECD).

Increased use of HTT 

data by program and 

regional partners as well 

as other stakeholders for 

risk-based decisions (e.g., 

number of downloads 

of data via iCSS 

Dashboards).

High-priority chemicals 

are screened using HTT 

assays for estrogenic, 

androgenic, thyroid, 

steroidogenesis, 

and developmental 

endpoints, and the data 

made publicly available.

Rapid 

Exposure and 

Dosimetry

Rapidly characterize 

potential for real-world 

exposure to chemicals, 

including those associated 

with consumer product 

use.

Develop critical HTT 

data required to forecast 

exposure and dose for 

thousands of chemicals of 

interest to EPA.

High-throughput 

pharmacokinetic (HTPK) 

data and models for riskbased prioritization.

High-throughput exposure 

data and models for riskbased prioritization.

Tools are provided via 

the iCSS Dashboards to 

generate quantitative 

human exposure and 

internal dose predictions 

for large numbers of 

chemicals rapidly.

Curated monitoring, 

chemical, and consumerproduct usage data are 

provided to the exposure 

assessment community.

Evaluated exposure 

predictions for priority 

chemical lists, including 

estimates of variability 

and uncertainty, are 

provided to EPA decision 

makers.

Table 4. CSS Research Topics: Project Areas, Challenges Addressed, Intermediate Outputs, and 

Measures of Success
29

Project Areas Challenges Addressed Intermediate Outputs Measures of Success

Topic 2: Life-Cycle Analytics

Sustainable 

Chemistry

Chemical feature sets 

and models for use with 

selected AOPs.

Strategies to evaluate 

potential for environmental 

and human health impacts 

of new and alternative 

chemicals to support 

safer chemical design and 

chemical screening.

Elucidate chemical 

properties and structural 

features associated 

with potential for 

environmental and human 

health impacts.

Integrate novel data 

streams and predictive 

models for toxicity, 

environmental 

persistence, and 

transformations in 

environmental and 

biological systems to 

inform design and 

evaluation of safer 

chemical alternatives.

Biologically informed 

publicly available SAR/

QSAR models developed 

to identify adverse 

outcomes that will make 

use of new HTS data 

to improve predictive 

capacity.

A Web-based Chemical 

Transformation 

Simulator will automate 

calculation and 

collection of molecular 

descriptors for parent 

chemical and predicted 

products resulting 

from transformation 

in environmental and 

biological systems for use 

by decision makers.

Emerging 

Materials

Develop robust approaches 

to screen environmental 

nanomaterials (ENMs) 

rapidly and efficiently for 

safety in humans and the 

environment.

Identify critical 

intermediate properties of 

ENMs that are predictive of 

potential risks associated 

with real-world exposures.

Protocols and methods 

for evaluating ENMs in 

complex biological or 

environmental systems.

Tools to efficiently screen 

for potential toxicity 

and exposure based on 

features of ENMs.

Curated information 

from ORD ENM research 

including data on physical 

chemical characterization 

parameters and results of 

release, fate, transport, 

transformation, and 

effects studies provided 

to the assessment 

community.

Set of functional assays 

based on intermediate 

properties for efficient 

evaluation of ENMs are 

developed and applied to 

a subset of ENMs.

Table 4. (continued) CSS Research Topics: Project Areas, Challenges Addressed, Intermediate 

Outputs, and Measures of Success
30

Project Areas Challenges Addressed Intermediate Outputs Measures of Success

Topic 2: Life-Cycle Analytics

Life-Cycle 

and Human 

Exposure 

Modeling

Integrate chemical 

exposure and life-cycle 

knowledge to model and 

assess human health 

impacts of alternatives.

Develop approaches to 

evaluate environmental 

and human health impacts 

rapidly.

Life-Cycle Harmonization 

Tool that will allow 

greater interoperability 

of life-cycle and exposure 

databases and tools.

Case study evaluation of 

a chemical/product LifeCycle/Human Exposure 

Modeling (LC-HEM) 

framework.

LC-HEM Tool for 

evaluating chemical/

product impacts in a 

life-cycle assessment 

framework.

Improved models for 

considering impacts 

associated with 

human exposure are 

incorporated into LCAs.

Modeling and assessment 

of alternatives is 

conducted for chemicals/

products with less 

extensive data.

New approaches for 

more rapid and higherthroughput assessments 

are adopted and used 

inside and outside EPA.

Ecological 

Modeling

Rapidly evaluate ecological 

impacts associated with 

use of manufactured 

chemicals with limited 

data.

Capture spatial and 

temporal dynamics to 

target critical experimental 

measurements required 

to understand chemical 

impacts on populations 

of vulnerable ecological 

species.

Demonstration 

of ecological risk 

assessment (ERA) tools 

that reduce uncertainty 

for high-priority and 

methodologically 

challenging chemicals, 

comparing ecologically 

relevant risk assessments 

to those based on limited 

data.

Decision framework 

for using models of 

various complexities, 

data requirements, 

and levels of real-world 

ecological conditions 

for fit-for-purpose 

application to differing 

ERA requirements.

ERA tools are provided 

to address high-priority 

and methodologically 

challenging chemicals 

being evaluated by EPA 

program and regional 

partners.

Tools to incorporate risks 

to terrestrial and aquatic 

endangered species 

are applied to inform 

pesticide risk assessments 

conducted by EPA and 

other federal partners.

Table 4. (continued) CSS Research Topics: Project Areas, Challenges Addressed, Intermediate 

Outputs, and Measures of Success
Project Areas Challenges Addressed Intermediate Outputs Measures of Success

Topic 3: Complex Systems Science

Adverse 

Outcome 

Pathway 

Discovery and 

Development

Apply AOP framework 

in concert with new 

data streams to predict 

potential impacts of 

chemicals on ecological 

and human health to 

support risk-based decision 

making.

An AOP knowledgebase 

that enhances the utility 

of pathway-based data 

for risk-based decision 

making.

Case studies 

demonstrating relevant 

application of AOP 

knowledge to risk-based 

decision making.

Outline and make 

publicly available putative 

AOPs that qualitatively 

link ToxCast assays to 

potential human or 

ecological hazards.

Submit new formal AOP 

descriptions for review 

and evaluation by OECD 

AOP working group.

Use AOP networks to 

predict the effect of 

a multiple-stressor 

or mixed mode-ofaction exposure in a 

demonstrative case study.

Virtual Tissue 

Models

Capture system 

dynamics in a platform 

of experimental and 

computational models 

for predictive toxicology 

to support hypothesis 

development and 

targeted study to improve 

understanding of chemical 

impacts on biological 

organisms.

Assemble pathway data 

and biological knowledge 

into dynamic systems 

models for assessing 

developmental toxicity.

Integrated predictive 

system to assemble 

pathway data, 

information, and 

knowledge of 

embryological systems 

into dynamical VTMs 

for assessing prenatal 

developmental toxicity.

Integrated predictive 

system to assemble 

pathway data, 

information, and 

knowledge into dynamical 

VTMs for assessing 

neurodevelopmental 

toxicity linked to thyroid 

disruption.

Publicly disseminate 

novel predictive models 

for developmental 

toxicity that can be linked 

with chemical evaluation 

(e.g., ToxCast).

Provide computational 

framework to make the 

knowledge from these 

models accessible and 

transparent.

Demonstrated case study 

in which results are 

translated such that the 

systems understanding 

and dynamic model 

predictions can be used 

to inform decisions.

31

Table 4. (continued) CSS Research Topics: Project Areas, Challenges Addressed, Intermediate 

Outputs, and Measures of Success
Project Areas Challenges Addressed Intermediate Outputs Measures of Success

Topic 4: Solutions-Based Translation and Knowledge Delivery

Demonstration 

and Evaluation

Integrate new information 

with existing methods and 

infrastructure to develop 

qualitative and quantitative 

approaches that support 

specific EPA science-based 

decisions.

Systematically evaluate 

new information and 

approaches to determine 

when these can be applied 

fit for purpose for EPA 

decisions.

Develop measures of 

confidence and uncertainty 

to support use of new 

approaches fit for purpose 

by EPA decision makers.

Develop and evaluate a 

process to produce rapid 

points of departure for 

use in evaluating and 

managing data-poor 

chemicals.

Develop a framework(s) 

to evaluate novel groups 

of assays, methods, 

and models for hazard 

identification, screening, 

and prioritization.

Guidance on clear 

frameworks and 

best practices for 

incorporation of novel 

data streams and tools 

into EPA decision making 

processes is issued by the 

NAS.

Guidance for how 

to incorporate and 

implement more global 

datasets and models 

(e.g., ToxCast data, QSAR 

and ADME models) into 

decisions is applied to 

case studies for EPA 

program and regional 

partners and other 

stakeholders.

Strategic 

Collaborations

CSS proposes an ambitious and significant 

paradigm shift in how existing and emerging 

chemicals and products can be evaluated 

for safety. The focus is on building predictive 

capacity and agile responses. The objective is 

to move from a knowledge-poor management 

posture to one that is proactive and sustainable, 

and fosters innovation. To achieve this paradigm 

shift, CSS relies heavily on strategic partnerships 

with dozens of organizations ranging from

industry, academia, trade associations, other 

federal agencies, state government, and nongovernmental organizations. Strategic partnerships are formalized through numerous types 

of agreements, including Cooperative Research 

and Development Agreements, Materials 

Transfer Agreements, and Memoranda of Understanding. Examples of partnerships for advancing potential applications of CSS research 

are described in Appendix 2.

32

Table 4. (continued) CSS Research Topics: Project Areas, Challenges Addressed, Intermediate 

Outputs, and Measures of Success
Anticipated Research 

Accomplishments and 

Projected Impacts 

The programmatic outputs of the CSS FY 2016–

2019 StRAP, described in Appendix 3, were defined in close collaboration with EPA program 

and regional partners and were designed to 

meet their needs. To ensure collaborative, integrated, and transdisciplinary research throughout the course of a CSS project and across the 

CSS program, successful delivery of each output 

is predicated on synthesis of results from multiple projects. Note that programmatic outputs 

will be evaluated and finalized each year based 

on current information about resources, stateof-the-science, and partner priorities.

Proposed Integrated FY16–19 CSS 

Program Outputs

FY16: Evaluation framework for highthroughput toxicity testing schemes to inform 

specific EPA chemical evaluation objectives

A framework for evaluating the technical 

performance of HTT assays, explaining the 

biological context, and understanding the 

relationship to adverse outcomes of regulatory 

concern will be developed to address a range of 

EPA decisions. The collaborative development 

of this framework will help EPA lead the global 

conversation around innovations in evaluation/

validation schemes for in vitro methods, for 

analysis of high-throughput/high-content data, 

and for in vitro to in vivo extrapolations. 

FY16: Demonstrated knowledge tools for 

development of adverse outcome pathways 

to enable incorporation of pathway level 

information in EPA decision making

Web-based infrastructure that facilitates organization of toxicological knowledge into AOP 

frameworks will be piloted through application 

to develop selected AOPs. AOP development 

includes assembly and evaluation of the weight 

of evidence supporting mode-of-action-based 

prediction/extrapolation for various EPA assessments. Tools and information will be disseminated to program offices and regional partners. 

In addition to helping disentangle complex 

biological pathways, this output is expected 

to enable more health-protective decisions by 

identifying earlier markers of adversity along a 

perturbed biological pathway.

FY17: Enhanced capacity for using inherent 

chemical properties to predict potential 

environmental fate, biological dose, and 

adverse outcomes to support EPA evaluation 

of a wide range of compounds 

Provide Web-based infrastructure including a 

dashboard to support elucidation of structurebased chemical feature sets linked to biological activity and chemical properties as well as 

analytical tools to predict potential for chemical transformation in environmental systems. 

For selected sets of chemicals and high-priority 

AOPs, identify critical properties and intermediate properties of chemicals and materials that 

are predictive of potential risks. This output is 

expected to have broad application to datapoor chemicals and emerging materials, significantly enhancing EPA’s ability to anticipate the 

human health and environmental impacts of 

manufactured chemicals/materials.

FY17: Evaluated, accessible exposure tools to 

provide EPA capacity for advanced exposure 

analysis to support program-specific chemical 

evaluations and sustainable decisions 

Develop rapid measurement methods and

computational approaches to characterize efficiently the potential for real-world human 

and ecological exposure to large sets of datapoor chemicals developed and demonstrated 

through case examples based on EPA exposure 

assessment needs. These tools are expected 

33
to enable EPA to make exposure-informed and 

risk-based determinations in a variety of decision scenarios.

FY17: Translation of diverse data streams 

including high-throughput toxicity data to 

inform EPA chemical evaluation and riskbased assessments 

Demonstrate novel approaches for combining 

data and models produced and developed 

under other CSS and related projects through 

application in a variety of decision contexts 

to inform specific EPA chemical evaluation 

objectives. Value of information for chemicals 

with few traditional toxicity data will be 

evaluated, and uncertainty in risk estimates 

will be characterized. This output will provide 

examples that enable EPA to integrate data from 

any variety of legacy and novel data sources 

using innovations in computational science and 

“big data” approaches to make more informed 

decisions.

FY18: Next generation high-throughput 

toxicity testing chemical evaluation scheme 

that includes assays to broaden utility and 

application 

Provide increased coverage of toxicity pathways in terms of new assays and models for key 

AOPs. Expand the types of chemicals that can 

be screened, and identify methods for incorporating xenobiotic metabolism into in vitro assay 

systems. This output will bring innovations in 

computational and molecular science to enable 

EPA to realize further the recommendations of 

the NAS report, Toxicity Testing in the 21st Century.

FY18: Tools for evaluating impacts of 

chemicals /materials / products early in 

development and across their life cycles that

can be used to identify critical data needs 

and support sustainable decisions 

Provide Web-based infrastructure to support 

integration of data related to chemical/material and product characteristics, exposure, and 

adverse impacts across the chemical/material 

life cycle. For selected case examples, pilot application of efficient tools and metrics to evaluate chemical impacts across the life cycle to 

support alternatives assessment and sustainable innovation. These tools will help inform 

the design of future laboratory and observational studies to enhance their relevance and 

applicability to EPA decisions. In addition, they 

will provide opportunities to test and evaluate 

hypotheses generated in observational studies.

FY19: Tools that shift the framework for 

evaluating toxicity from direct observation of 

apical outcomes to characterizing resilience 

and identifying tipping points that predictably 

lead to adverse outcomes

Exploit new data streams to advance systems 

understanding of early indicators of adversity 

associated with chemical exposures and begin 

to build predictive models that enable effective 

EPA actions to protect human health and the 

environment including the health of children 

and other vulnerable lifestages, species, and 

groups.

34
Anticipated Accomplishments

Building on the impact of the CSS 2012–2016 

research, CSS research will provide the data and 

methods to infuse 21st century science into EPA 

decisions. By shifting the thinking and increasing 

predictive capacity, CSS will lighten the burden 

of chemical assessment and promote proactive 

action and sustainable innovation. Anticipated 

impact of the CSS research program in the next 

5–10 years is as follows.

•

•

•

35

Accelerate the pace of data-driven chemical 

evaluations.

Develop, collate, and organize information on 

human and ecological exposure and impacts 

to provide accessible data to predict and estimate risks from exposures to chemicals efficiently in a manner fit for the specific decision 

context and regulatory need. 

Enable decisions that are sustainable and 

public health protective.

Provide methods for advanced analysis to assess safety of high-priority chemicals and inform EPA actions to anticipate, manage, and 

mitigate exposures to contaminants of greatest concern throughout their life cycle.

Shift the paradigm of toxicity characterization 

from apical endpoints to tipping points.

Advance systems understanding of early indicators of adversity associated with chemical 

exposures to build predictive models that enable effective EPA actions to protect human 

health and the environment, including the 

health of children and other vulnerable lifestages, species, and groups.

Apply CSS tools to support sustainable innovation of chemicals and emerging materials.

Translate and incorporate emerging and highthroughput exposure and toxicology data 

streams to evaluate impacts of EPA decisions, 

select safer chemical alternatives or substitutes, and inform the sustainable design 

and development of emerging materials and 

products. 

•
36

Conclusions

Chemicals are integral to the American economy and provide key building blocks for the 

many products that benefit society. Sustainable 

development can yield unprecedented benefits 

to society today without compromising the 

health and welfare of future generations. Smart 

new strategies are needed to make decisions 

that protect public health and promote sustainable chemical design and use. 

Chemicals fuel innovation: Surface coatings 

make buildings more resistant to wear; detergents allow energy-efficient laundering; preservatives keep cosmetics and foods fresh. Depending on their use, however, chemicals may 

have harmful impacts on human health and the 

environment. For instance, evidence is mounting that some chemicals found in everyday 

products may disrupt the endocrine system and 

affect the development of children and sensitive ecological species. Novel information and 

methods are needed to make informed, timely 

decisions about thousands of chemicals in commerce.

As one of its highest priority goals described in 

the FY14–18 Strategic Plan, EPA aims to reduce 

the risks and increase the safety of chemicals 

that enter our products, environment, and bodies. The Agency proposes to assess and reduce 

risks posed by chemicals and promote the use 

of safer chemicals in commerce. CSS research 

will provide the data and methods to infuse 21st 

century science into EPA decisions. Importantly, CSS proposes a significant paradigm shift in 

how existing and emerging chemicals and products can be evaluated for safety. By shifting the 

thinking and increasing predictive capacity, CSS 

will lighten the burden of chemical assessment 

and promote proactive action and sustainable 

innovation. 
Appendix 1: Additional 

Policy Context and 

Scientific Advice 

In addition to federal legislative mandates, 

several state initiatives are driving the needed 

advances in chemical evaluation.

The California State Drinking Water and Toxic 

Enforcement Act of 1986 (also known as 

Proposition 65) requires the State to publish a 

list of chemicals13 known to cause cancer, birth 

defects, or other reproductive harm. Since its 

inaugural publication in 1987, this list has grown 

to include nearly 800 chemicals. Proposition 

65 requires businesses to notify Californians 

about significant amounts of these chemicals 

in their homes, workplace, drinking water, or 

environment. The public disclosure is designed 

to enable informed decisions by the consumer.

More recently, the California Safer Consumer 

Products Program also strives to reduce toxic 

chemicals in consumer products. It identifies 

specific products with potentially harmful 

chemicals and requires manufacturers to 

evaluate further whether these chemicals are 

necessary or safer alternatives exist. The Priority 

Product Work Plan14 will identify consumer 

'Priority Products' that contain 'Candidate 

Chemicals'—those with characteristics that 

could harm people or the environment—for 

public disclosure. It is the first set of productchemical combinations to be considered by 

the DTSC under the Safer Consumer Products 

Regulations.

The State of Washington’s Reducing Toxic 

Threats15 initiative states that preventing exposures to toxics is the smartest, cheapest, 

and healthiest way to protect people and the 

environment. The Children’s Safe Product Act 

(CSPA - Chapter 70.240 RCW) establishes the 

Children’s Safe Product Reporting Rule.16 It requires manufacturers of children’s products to 

report any sale of products containing a Chemical of High Concern to Children. The CSPA limits 

the amount of lead, cadmium, and phthalates 

allowed in children’s products, and these limits 

were substantially preempted by federal law. 

The Washington State Department of Ecology 

also works with the Consumer Product Safety 

Commission to ensure compliance with these 

requirements.

Finally, over the past few years, EPA has 

commissioned the National Academies of 

Science to provide guidance on the state-ofthe-science and approaches for using emerging 

science to promote effective, health-protective 

decisions and actions. CSS has strategically 

drawn from the NAS recommendations to 

address key research gaps that are not being 

addressed by partners outside EPA. The 

formative National Academy of Sciences 

Reports (NAS) are as follows.

Toxicity Testing in the 21st Century:

A Vision and a Strategy (2007)

Traditional methods used to test chemicals for 

potential toxicity are expensive and time consuming. To help address this issue, EPA asked 

the National Research Council (NRC) of the NAS 

to conduct a comprehensive review of current 

toxicity testing approaches and propose a longrange vision and strategy for toxicity testing 

that incorporates emerging methods and technologies. The report’s overall objective was to 

foster a transformative paradigm shift in toxicology based largely on the increased use of in 

37

13http://oehha.ca.gov/prop65/prop65_list/Newlist.html

14https://www.dtsc.ca.gov/SCP/PriorityProductWorkPlan.cfm

15http://www.ecy.wa.gov/toxics/index.htm

16https://fortress.wa.gov/ecy/publications/summarypages/173334.html
vitro systems and computational modeling. The

NRC report indicated implementation of the vision would require a substantial commitment 

of resources; involvement of multiple organizations in government, academia, industry, and 

the public; and time (10–20 years) to achieve. 

EPA’s CSS research program has already made 

significant strides toward realizing the vision in 

the report. 

Science and Decisions: Advancing Risk 

Assessment (2009)

Science and Decisions provides practical scientific and technical recommendations to address the many challenges of risk assessments 

today, including the lack of adequate (exposure 

and hazard) data leading to uncertainties in 

assessments and lengthy delays necessitated by 

complex assessments. These recommendations 

are placed within a broader framework for riskbased decision making to allow for more tailored assessments that are fit for purpose. CSS 

has begun to use this approach to evaluate and 

demonstrate how the data it generates can be 

used to augment and accelerate EPA’s risk assessment practices.

Exposure Science in the 21st Century: A Vision 

and a Strategy (2012)

Recognizing that exposure science is a key component for providing the best public health and 

ecosystem protection, EPA asked the NRC to 

develop a long-range vision for exposure science in the 21st century, and a strategy for implementing this vision over the next 20 years. 

This report, along with three other NAS reports, 

Toxicity Testing in the 21st Century, Science and 

Decisions: Advancing Risk Assessment, and 

Sustainability and the U.S. EPA, chart future 

directions for using innovative technology and 

scientific advances to understand better how 

chemicals affect human health and the environment. EPA’s CSS research is already aligning 

with the research recommendations described 

in the report. 

A Research Strategy for Environmental, 

Health, and Safety Aspects of Engineered 

Nanomaterials (2012)

In this report, the committee presents a strategic approach for developing the science and 

research infrastructure needed to address uncertainties regarding the potential environmental, health, and safety (EHS) risks of engineered nanomaterials (ENMs). The committee 

identified three requirements for the strategy: 

(1) focus on human and environmental health, 

(2) provide flexibility to anticipate and adjust to 

emerging challenges, and (3) provide decision 

makers with timely, relevant, and accessible information. The committee’s conceptual framework is characterized by a life-cycle perspective, focus on linking key properties of ENMs 

in complex media to hazard and exposure, and 

emphasis on anticipating significant risks from 

emerging ENMs.

Design and Evaluation of Safer Chemical 

Substitutions (2014)

EPA asked NRC to recommend a framework 

to inform government and industry decisions about the use of chemical alternatives. 

A chemical alternatives assessment identifies, 

compares, and selects safer alternatives to 

chemicals of concern. The goal was to facilitate 

an informed consideration of the advantages 

and disadvantages of chemical alternatives. 

Alternatives for chemicals such as bisphenol-A 

(used in plastic products) and perfluorinated 

chemicals (used in stain- and grease-resistant 

products) are currently being used in consumer 

products. The report, A Framework Guide for 

the Selection of Chemical Alternatives,17 considered potential impacts early in chemical design, considers both human health and ecological risks, integrates multiple and diverse data 

streams, considers tradeoffs between risks and 

factors such as product functionality, and identifies scientific information and tools required. 

38

17http://www.nap.edu/catalog/18872/a-framework-to-guide-selection-of-chemical-alternatives
This framework includes several important 

unique elements or advancements, such as an 

increased emphasis on comparative exposure

assessment, and a two-tiered approach to 

evaluating chemical alternatives that includes 

health and ecotoxicity, followed by a consideration of broader impacts.

Assessing Risks to Endangered and 

Threatened Species from Pesticides (2013)

The U.S. Fish and Wildlife Service (FWS) and the 

National Marine Fisheries Service (NMFS) are 

responsible for protecting species listed as endangered or threatened under the Endangered 

Species Act (ESA) and for protecting habitats 

that are critical for their survival. EPA is responsible for registering or reregistering pesticides 

under the Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) and must ensure that 

pesticide use causes no unreasonable adverse 

effects on the environment, which is interpreted to include listed species and their critical 

habitats. In the report, the NRC reviewed the 

state-of-the-science and identified research 

gaps required to support ecological risk assessments for endangered and threatened species. 

Review of the Environmental Protection 

Agency’s State-of-the-Science Evaluation of 

Nonmonotonic Dose-Response Relationships 

as They Apply to Endocrine Disruptors (2014)

NAS was asked to review EPA’s state-of-thescience paper. The purpose of the state-of-thescience paper was to help EPA policy makers 

determine if nonmonotonic dose-response relationships (NMDRs) capture adverse effects that 

are not detected using current chemical testing 

strategies and if current EPA testing misses adverse effects. Although EPA is interested in all 

aspects of NMDR, the state-of-the-science paper focused on endocrine disruptors—in particular, estrogen, androgen, and thyroid active 

chemicals. The NAS review included an expert 

public comment period. 

Incorporating 21st Century Science in RiskBased Evaluations (In progress)

One of the CSS research program’s goals is to 

develop approaches for integrating advances 

in toxicity testing and exposure science to accelerate the pace and enhance the predictive 

capacity of risk-based evaluations. In August 

2014, EPA requested guidance from the National Academy of Sciences (NAS) on how to 

foster this integration and take advantage of 

the broader spectrum of 21st century science 

emerging from diverse research fields, including biotechnology and computational sciences. 

This resulting NRC study will provide EPA with 

recommendations on integrating new scientific 

approaches into risk-based evaluations, integrating and using emerging results in evaluating 

chemical risk, and identifying how traditional 

risk assessment can incorporate new science.

Unraveling Low Dose: Case Studies of 

Systematic Review of Evidence (In progress)

As a follow-up study to the NAS review of the 

draft paper Non-Monotonic Dose Response 

State-of-the-Science, the NRC will convene 

an expert committee to develop a systematic 

review approach for determining whether 

EPA’s current hazard assessment approach is 

sufficient to consider evidence of low dose 

adverse effects that act via an endocrinemediated toxicity pathway. 

39
Appendix 2: Examples 

of CSS Partnerships

National Nanotechnology Initiative

(Formed in 2000)

The National Nanotechnology Initiative (NNI) is 

a U.S. government research and development 

(R&D) initiative involving the nanotechnologyrelated activities of 20 departments and independent agencies (including EPA, National Science Foundation, National Institutes of Health, 

Department of Defense, National Institute 

of Occupational Safety and Health, Food and 

Drug Administration, and U.S. Department of 

Agriculture). Under its working group, Nanotechnology Environmental Health Implications 

(NEHI), EPA participates in coordinated research 

to address research for assessing the potential 

human and environmental risks of nanomaterials. The NNI and NEHI advance collaboration 

and coordination of activities among U.S.-based 

agencies and internationally with various regulatory and coordinating bodies primarily in 

Europe and Asia. 

Consumer Products Safety Commission

EPA and the U.S. Consumer Product Safety 

Commission (CPSC) are collaborating to develop protocols to assess the potential release 

of nanomaterials from consumer products, 

develop credible rules for consumer product 

testing to evaluate exposure, and determine 

potential public health impacts of nanomaterials used in consumer products. 

Toxicity Testing in the 21st Century 

(Tox21, established in 2008)

Tox2118 pools funding, expertise, chemical research, data, and screening tools from multiple federal agencies, including EPA, National 

Toxicology Program/National Institute of Environmental Health Science, National Center 

for Advancing Translational Sciences, and Food 

and Drug Administration. EPA’s contribution to 

Tox21 is primarily through ToxCast, which to 

date has screened nearly 2000 chemicals across 

approximately 700 assay endpoints. Tox21 

has screened nearly 8200 chemicals across 

approximately 50 endpoints. The partnership 

has worked extremely effectively to enhance 

the ability to predict the safety of chemicals. 

Significant improvements have been made in 

data access, reliability, and usability for the 

community of stakeholders inside and outside 

EPA.

European Chemicals Agency 

(Established in 2010)

EPA’s Office of Chemical Safety and Pollution 

Prevention and the Office of Research and Development are partnering with the European 

Chemicals Agency (ECHA) to enhance technical cooperation and to share knowledge, experience, and best practices about chemical 

management practices. ECHA and EPA meet at 

least quarterly through conference calls and inperson meetings. The ongoing partnership has 

resulted in scientific data exchanges, sharing of 

regulatory chemical management plans, joint 

participation in scientific and regulatory workshops, and trainings across both organizations 

to demonstrate various online chemical databases and tools. 

Organization of Economic Cooperation and 

Development 

(Established in 2012)

EPA, in collaboration with the international 

scientific community, European Joint Research 

Center, U.S. Army Corp of Engineers, and Organization of Economic Cooperation and Development, are developing tools to facilitate the use 

of AOPs to help evaluate chemicals for potential 

risks. The strategic partnership has resulted in 

the development of the AOP Knowledge Base 

40

18http://www.ncats.nih.gov/tox21
(AOP-KB) and the AOP-Wiki. The AOP-KB is the 

foundational Web-based platform designed 

to assemble knowledge about how chemicals 

can prompt adverse outcomes. The AOP-Wiki, 

a module of the AOP-KB, is an interactive virtual encyclopedia for AOP development that is 

being populated with input from international 

scientific experts. 

California Department of Toxic Substances 

Control 

(Established in 2012)

California’s Department of Toxic Substances 

Control (DTSC) and EPA’s Office of Chemical 

Safety and Pollution Prevention, Region 9, and 

Office of Research and Development are collaborating on efforts to advance green chemistry 

practices and activities. The CSS research program’s role in the collaboration is to expand the 

applications of developed CSS tools to inform 

product and chemical alternative analyses. Specifically, CSS has shared database architecture 

and chemical information to help California develop publically available chemical information 

databases. 

Health Canada 

(Established in 2013)

Health Canada and EPA are collaborating to explore approaches for using new data streams to 

assess chemicals for potential risks to human 

health. Health Canada is currently under a regulatory mandate to develop Chemical Management Plan 3 (CMP3). The chemicals in CMP3 include chemicals lacking traditional toxicity data. 

Health Canada is working with EPA CSS to determine how to use high-throughput screening 

data and other types of nontraditional chemical 

data to help fill the data gaps for the chemicals 

in CMP3.

41
Appendix 3: Table of Proposed Outputs, 

Chemical Safety for Sustainability Research 

Program, FY16–FY19

The following table lists the expected outputs from the Chemical Safety for Sustainability research 

program, organized by topic. Note that outputs may change as new scientific findings emerge. 

Outputs are also contingent on budget appropriations.

Project Area Outputs

Topic 1: Chemical Evaluation

High-Throughput 

Toxicology

FY16 - Evaluation framework for high-throughput toxicity testing schemes 

to inform specific Agency chemical evaluation objectives 

FY18 - Next generation high-throughput toxicity testing chemical 

evaluation scheme that includes assays to broaden utility and application

Rapid Exposure and 

Dosimetry

FY17 - Evaluated, accessible exposure tools to provide Agency capacity 

for advanced exposure analysis to support program-specific chemical 

evaluations and sustainable decisions 

FY18 - Next generation high-throughput toxicity testing chemical 

evaluation scheme that includes assays to broaden utility and application

FY19 - Tools that shift the framework for evaluating toxicity from 

direct observation of apical outcomes to characterizing resilience and 

identifying tipping points that predictably lead to adverse outcomes

Topic 2: Life-Cycle Analytics

Sustainable 

Chemistry

FY17 - Enhanced capacity for using inherent chemical properties to 

predict potential environmental fate, biological dose, and adverse 

outcomes to support Agency evaluation of a wide range of compounds 

 

FY18 - Tools for evaluating impacts of chemicals/materials/products early 

in development and across their life cycles that can be used to identify 

critical data needs and support sustainable decisions 

Emerging Materials FY17 - Enhanced capacity for using inherent chemical properties to 

predict potential environmental fate, biological dose, and adverse 

outcomes to support Agency evaluation of a wide range of compounds 

 

FY18 - Tools for evaluating impacts of chemicals/materials/products early 

in development and across their life cycles that can be used to identify 

critical data needs and support sustainable decisions 

42
Project Area Outputs

Topic 2: Life-Cycle Analytics

Life-Cycle and 

Human Exposure 

Modeling

FY17 - Evaluated, accessible exposure tools to provide Agency capacity 

for advanced exposure analysis to support program-specific chemical 

evaluations and sustainable decisions 

FY18 - Tools for evaluating impacts of chemicals/materials/products early 

in development and across their life cycles that can be used to identify 

critical data needs and support sustainable decisions 

Ecological Modeling FY17 - Evaluated, accessible exposure tools to provide Agency capacity 

for advanced exposure analysis to support program-specific chemical 

evaluations and sustainable decisions 

FY17 - Enhanced capacity for using inherent chemical properties to 

predict potential environmental fate, biological dose, and adverse 

outcomes to support Agency evaluation of a wide range of compounds 

 

FY18 - Tools for evaluating impacts of chemicals/materials/products early 

in development and across their life cycles that can be used to identify 

critical data needs and support sustainable decisions 

Topic 3: Complex Systems Science

Adverse Outcome 

Pathway Discovery 

and Development

FY16 - Demonstrated knowledge tools for development of AOPs to enable 

incorporation of pathway level information in Agency decisions

FY17 - Translation of CSS data streams including high-throughput toxicity 

data to inform Agency chemical evaluation and risk-based assessments 

FY19 - Tools that shift the framework for evaluating toxicity from 

direct observation of apical outcomes to characterizing resilience and 

identifying tipping points that predictably lead to adverse outcomes

Virtual Tissues FY16 - Demonstrated knowledge tools for development of AOPs to enable 

incorporation of pathway level information in Agency decisions

FY17 - Translation of CSS data streams including high-throughput toxicity 

data to inform Agency chemical evaluation and risk-based assessments 

FY19 - Tools that shift the framework for evaluating toxicity from 

direct observation of apical outcomes to characterizing resilience and 

identifying tipping points that predictably lead to adverse outcomes

43
Project Area Outputs

Topic 4: Solutions-Based Translation and Knowledge Delivery

Demonstration and 

Evaluation 

FY16 - Evaluation framework for high-throughput toxicity testing (HTT) 

schemes to inform specific Agency chemical evaluation objectives 

FY17 - Translation of CSS data streams including high-throughput toxicity 

data to inform Agency chemical evaluation and risk-based assessments 

Partner-Driven 

Research

Products based on short-term partner needs for high priority technical 

support and targeted research.

Strategic Outreach Products will include public workshops, tailored meetings and webinars, 

training and strategic collaborations, among others.

44
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