EPA 601/R-12/006 | June 2012 | www.epa.gov/research 

Chemical Safety for Sustainability 


STRATEGIC RESEARCH
 

ACTION PLAN 2012-2016
 

Office of Research and Development 

Chemical Safety for Sustainability 
EPA 601/R-12/006 

Chemical Safety for
 

Sustainability
 

Strategic Research Action Plan 2012 - 2016 

U.S. Environmental Protection Agency
 

June 2012
 
3 

 

Table of Contents 

Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
 

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9
 

Program Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9
 

Integrated, Transdisciplinary Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
 

Research to Support EPA Priorities and Regulatory Requirements . . . . . . . . . . . . . . . . . . . . .11
 

Statutory and Policy Context. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
 

High Priority Chemicals of Concern: Endocrine Disrupting Chemicals (EDCs) . . . . . . . .12
 

High Priority Chemicals of Concern: Nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
 

Research Focus Area: Computational Toxicology (Comp Tox) . . . . . . . . . . . . . . . . . . . . .13
 

Sustainable Molecular Design Approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
 

An Integrated Program Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15 

Collaborating Across Research Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
 

Developing Partnerships from the Start . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
 

CSS Design Overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
 

Research Themes and Priority Science Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23
 

Theme 1. Inherency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23 

Theme 2. Systems Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
 

Theme 3. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
 

Theme 4. Cumulative Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32 

Theme 5. Life Cycle Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34 

Theme 6. Extrapolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37
 

Theme 7. Dashboards. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39
 

Theme 8. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41
 

Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42
 

Summary Tables. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43
 

Theme 1. Inherency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43 

Theme 2. Systems Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
 

Theme 3. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49
 
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Theme 4. Cumulative Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50
 

Theme 5. Life Cycle Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52
 

Theme 6. Extrapolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .53
 

Theme 7. Dashboards. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55
 

Theme 8. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57
 

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58
 

Appendix A. Research Program Partners and Stakeholders . . . . . . . . . . . . . . . . . . . . . . . . . .60
 

Appendix B. Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62
 
5 

Executive Summary
 

Chemicals provide the key building blocks that are 

converted into end-use products or used in industrial 

processes to make products that create jobs and benefit 

society. Improving the safe production, use and disposal 

of chemicals is a major priority of research at the U.S. 

Environmental Protection Agency (EPA) to support 

decisions and actions the Agency makes to meet its 

mission to protect human health and the environment. To 

meet its mission, the Agency needs a research approach 

that advances science to meet society’s current demands 

for a safer environment but to also meet the social, 

economic and environmental health needs of future 

generations. The Agency must conduct research and 

analyses that will support the sustainable manufacture 

and use of chemicals. 

The Strategic Research 

Action Plan for EPA’s 

Chemical Safety for 

Sustainability (CSS) 

research program presents 

the purpose, design and 

themes of the Agency’s 

CSS research efforts 

to ensure safety in the 

design, manufacture and 

use of existing and future 

chemicals. 

The challenges are formidable: more than 80,000 chemicals are currently listed or registered for 

use in the U.S. under EPA authorities and at least a thousand more are introduced every year 

(EPA, 2012). Many of these chemicals have not been thoroughly evaluated for their potential 

risks to human health, wildlife and the environment, particularly throughout their life cycle 

(from the collection of raw chemical feedstocks, through their use and the final disposal of the 

products that contain them). There is also a need to focus on emerging contaminants of concern 

including endocrine disrupting chemicals (EDCs) and nanomaterials. EDCs are chemicals that 

interfere with the activity of hormones in the body and the environment. Nanomaterials are 

in a very small size range (~ 1 to 100 nanometers), which can alter the chemical’s properties 

compared with larger versions of the same chemical and in turn influence its exposure and 

toxicity. Many processes and procedures being used today to evaluate and assess the impact 

of chemicals on human health, wildlife and the environment were designed decades ago, are 

largely based on laboratory tests conducted on animals and are labor and resource intensive. 

Further, many of the current tests have not fully incorporated recent advances in chemistry, 

exposure science, biology and computer technologies. This combination of factors makes 

it difficult to meet current demands of evaluating the safety of an ever-increasing number of 

chemicals. 

As a result, a number of important aspects of chemical safety are not adequately understood, 

including: how to design and produce safer chemicals; how chemicals and their byproducts 

move through the environment; what the sources of chemical exposure are; what the critical 

biological processes and toxicity pathways are that chemicals might interact with to cause 

disease; and what the contribution of exposure to chemicals in the environment is to the overall 
6 

CHEMICAL SAFETY FOR 

SUSTAINABILITY 

PROBLEM STATEMENT: 

Although chemicals are 

essential to modern life, we 

lack innovative, systematic, 

effective and efficient 

approaches and tools to 

inform decisions that reduce 

the environmental and 

societal impact of chemicals 

while increasing economic 

value. 

VISION: EPA science 

will lead the sustainable 

development, use and 

assessment of chemicals 

by developing and applying 

integrated chemical 

evaluation strategies and 

decision-support tools. 

disease burden for susceptible populations. 

Thus, transformative approaches are needed to 

improve the information used in chemical assessments. 

New approaches developed in the CSS research 

program will enable EPA to increase the pace at which 

relevant information can be obtained and integrated 

into assessments and decision-making. The program 

will inform and advance sustainable approaches to 

chemical design, production and use across product 

life cycles. 

This Strategic Research Action Plan for EPA’s 

Chemical Safety for Sustainability Research Program 

describes the purpose, design and themes of the 

Agency’s research efforts to help ensure safety in 

the design, manufacture and use of existing and 

future chemicals. It describes how the program was 

developed with the input of EPA internal partners and 

external stakeholders from the beginning, how it is 

aligned with Agency priorities and how the research 

portfolio will harness systems-approaches to advance 

the scientific understanding of the links between 

chemical exposure, toxicity pathways and disease or 

other harmful effects to humans, wildlife and the 

environment. 

Tools produced through the CSS research program will use systems-approaches to advance 

the understanding of the links between exposures to chemicals and toxicity pathways that 

lead to the development of disease. At the same time, the research will dramatically increase 

the efficiency and speed of chemical evaluations. It will allow EPA to evaluate potential effects 

of chemical exposure on critical life stages, such as the embryo and childhood and other 

susceptibility factors, including genetics and co-existing diseases. 

Recognizing that humans and wildlife encounter numerous chemicals simultaneously, the 

CSS research program will develop methods to assess the effects of exposure to multiple 

chemicals and methods to assess cumulative chemical risk. Further, the program includes 

the development of sustainability metrics to measure how changes in parameters that affect 

hazard and exposure impact the degree to which a chemical is more or less environmentally 

sustainable throughout its life cycle. 

Working in conjunction with partners in EPA regulatory program and regional offi ces, CSS 

identified three research goals that guided the development of the overall program: 

Research Goal 1 

Developing the scientific knowledge, tools and models needed to conduct integrated, 
7 

timely and efficient chemical evaluation strategies. 

Research Goal 2 

Improving methods for assessment and informing management for chemical safety and 

 sustainability, 

Research Goal 3 

Providing targeted high-priority research solutions for immediate and focused attention. 

The first goal is intended to deliver a suite of tools (i.e., data, methods, models) that 

offers researchers and environmental decision-makers needed resources for improved 

chemical assessments. The second goal is focused on the application of the tools for 

risk assessment and chemical management to ensure the safe and sustainable design, 

production and use of chemicals, including the advancement of green chemistry. The third 

goal is intended to ensure that the high-priority human and environmental health-related 

specific research needs of the Agency, identified by its program and regional offi ces, are 

met while the long-term research solutions are advanced. 

The key research outcomes will include: 

• Improved chemical hazard assessments 

By developing a deeper understanding of the relevant physico-chemical and other 

inherent properties of chemicals that influence environmental fate, exposure and 

biological responses, CSS research will lead to improved chemical assessments. 

• Improved chemical prioritization, screening, testing and quantitative risk 

assessments 

By integrating information from multiple biological levels, including pathway-level 

information and by using advanced computational techniques (e.g., multi-scale systems 

models of virtual tissues) to develop predictive models of hazard and exposure, CSS 

research will provide decision-makers with robust risk assessment methods. 

By using consistent, justifiable and improved use of existing biomonitoring data, dose 

estimation/exposure reconstruction methods and diagnostic adverse outcome pathway 

(AOP)-based biomarkers, EPA risk assessments will be improved. 

	 Improved understanding of the relationship of chemical exposures and health 

outcomes to the fetus and children 

By understanding the molecular pathways and cellular processes underlying 

adverse pregnancy outcomes and improving methods to assess the impacts of fetal 

or neonatal chemical exposure at different stages of development and scales of 

biological organization, CSS research will increase knowledge of health effects after 

developmental exposure. 

	 Development of sustainable risk management approaches 

By identifying key links in the continuum from the production of a chemical, its release 

in the environment, its fate/transport, to the resulting exposures and adverse outcomes, 

sustainable risk management approaches can be developed that can be scaled up and 

delivered to decision-makers. 
8 

 Accessible, useful information 

By sharing research outputs and outcomes in ways that effectively communicate, 

translate and transfer the scientific information in a manner most useful to decisionmakers. 

To address the research areas and desired outcomes, the CSS program was developed 

around eight main research topics. These topics were selected because they represent the 

fundamental building blocks upon which an integrated evaluation strategy can be built to inform 

environmental and health decisions. 

The eight research topics and the questions that they address are: 

1. Inherency — How can an understanding of inherent properties of chemicals inform 

exposure and health outcomes, the design of chemical assays and tools and sustainable 

design of chemicals? 

2. Systems Models — What are the perturbations at all levels of biological organization 

(i.e., molecular, cellular, tissues, organ, whole organism), defined as “toxicity pathways,” that 

lead to adverse outcomes following exposure to an environmental chemical? 

3. Biomarkers — How can useful biomarkers of exposure and effect be optimally 

developed? 

4. Cumulative Risk — What are the ecological and human health risks of real-world 

environmental chemical exposures (i.e., exposures to mixtures of multiple chemicals over 

time)? 

5. Life Cycle Considerations — What are the impacts of an environmental chemical 

over its entire life cycle, from the collection of its raw materials all the way through its 

manufacture, use and finally its disposal? 

6. Extrapolation — Can improved extrapolation methods be developed for predicting 

toxicity in the absence of various data (e.g., extrapolating from lab animal to human, in vitro 

to in vivo)? 

7. Dashboards — What tools can be customized into useful, accessible interfaces that 

provide decision-makers with the toxicity data and information they need to support specific 

regulatory needs? 

8. Evaluation — What has been the impact of the CSS research findings and tools on EPA’s 

decision-making? 

The Strategic Research Action Plan for EPA’s Chemical Safety for Sustainability Research 

Program maps out a research program for the next 5 to 10 years. It has been designed with 

the flexibility needed to leverage scientific breakthroughs, address the emerging priorities and 

needs of decision-makers, shifting resource availability and other considerations. As such, it is a 

“living document” that will be updated as needed over that time. 
9 

Introduction 

Program Purpose 

EPA is faced with evaluating more than 1,000 additional chemicals each year prior to their commercialization and is further challenged with determining which environmental chemicals already 

in commerce may result in adverse effects to pursue risk management actions (Judson et al., 

2009). In addition, there are newer forms of chemicals, such as nanomaterials, entering the 

marketplace at an increased rate. There is also an increased need to focus on emerging health 

concerns, such as those associated with endocrine disrupting chemicals, that may require 

evaluation approaches that differ from traditional methods. 

To address these needs, the EPA and the 

National Institute of Environmental Health 

Sciences (NIEHS) requested that the National 

Research Council (NRC) develop an expert 

report. The resulting report, Toxicity Testing 

in the 21st Century: A Vision and Strategy 

(NRC, 2007), proposes a shift in chemical 

testing to one that evaluates perturbations 

in toxicity pathways, largely using in vitro 

methods. The report addressed several 

concerns about current testing methods, 

specifically, the desire to (1) reduce the 

number of animals used in testing, (2) 

reduce the overall cost and time required to 

characterize each chemical, (3) increase the 

level of mechanistic understanding of chemical 

toxicity and (4) assess toxicity for real world 

exposures. The EPA has formally adopted the 

Toxicity Testing in the 21st Century: 

A Vision and Strategy (NRC, 2007) 

“Advances in toxicogenomics, 

bioinformatics, systems biology, 

epigenetics and computational 

toxicology could transform toxicity 

testing from a system based on wholeanimal testing to one founded primarily 

on in vitro methods that evaluate 

changes in biologic processes using 

cells, cell lines, or cellular components, 

preferably of human origin.” 

recommendations of the NRC by developing 

their Strategic Plan for Evaluating the Toxicity 

of Chemicals (EPA, 2009). 

The strategic directions of the CSS research 

program are tightly aligned with the 

recommendations of the NRC (NRC, 2007) 

and EPA’s Strategic Plan (EPA, 2009) and 

also advance research in additional areas 

important to EPA, such as the exposure 

and fate of chemicals and nanomaterials, 

identifying and evaluating adverse outcome 

pathways, characterizing cumulative risk 

and providing bioinformatic tools to enable 

rapid risk assessment analyses for regulatory 

decisions. 

Looking beyond assessing potential impacts 

of environmental chemicals, the CSS research 

program recognizes the need for the design 

of safer and more sustainable (“green”) 

chemicals. The research is assisting in 

replacing existing commercial chemicals and 

materials that pose environmental and health 

risks by identifying new chemicals that exhibit 

the desired uses of existing chemicals, but can 

be manufactured with lower potential adverse 

impacts. 

The long-term vision of the CSS research 

program is that EPA science will lead 

the sustainable development, use and 

assessment of chemicals by developing 

and applying integrated chemical evaluation 

strategies and decision-support tools. 
10 

CSS OBJECTIVES 

Creating tools that inform sustainable 

chemical/material design and use 

Developing methods for much faster 

screening and prioritizing 

Providing the scientific knowledge and 

tools to effectively understand realworld risks 

Developing assessment approaches 

that are tailored to specifi c decision 

contexts 

Considering where impacts may occur 

throughout a chemical’s life cycle 

Integrated, Transdisciplinary Research 

To increase the scale of the Agency’s 

decision-support tools and improve guidance/ 

management for safer chemical design 

and use, the EPA needs an integrated, 

transdisciplinary research effort that unites 

the capabilities of a diversity of experts, 

including chemists, exposure scientists, 

biologists, engineers and economists and 

other social scientists. 

The CSS research program is focused on 

providing integrated solutions to support 

of chemical management. The data, 

methods and tools developed will guide 

the prioritization and testing process, from 

screening approaches through more complex 

testing and assessments. CSS outcomes will 

be delivered to EPA partners and decisionmakers in appropriate, accessible forms 

(NRC, 2009). 

By organizing its research to harness a 

diversity of expertise and support integrated 

evaluation strategies, the CSS research 

program will provide state-of-the-science 

tools and integration techniques to inform 

risk assessment and risk management 

activities. Such activities include those used in 

regulatory decision-making, as well as those 

utilized in developing, producing and using 

chemicals. 

To maximize relevancy of the research, the 

CSS research program will focus on the 

highest priority research needs of EPA’s 

program and regional offi ces. The program 

includes training for decision-makers and 

others so that they can fully utilize the tools 

and research produced. 

The research is conducted and/or supported 

by the EPA Office of Research and 

Development’s three national laboratories, 

four national centers and two offi ces located 

in 14 facilities around the country and in 

Washington, D.C and includes both intramural 

and extramural (primarily through EPAawarded STAR research grants and awards) 

components. 

EPA PRIORITIES 

Taking action on climate change 

Improving air quality 

Assuring the Safety of Chemicals 

Cleaning up our communities 

Protecting America’s waters 

Expanding the conversation on 

environmentalism and working for 

environmental justice 

Building strong state and tribal 

partnerships 
11 

Research to Support EPA Priorities and 

Regulatory Requirements 

Statutory and Policy Context 

The CSS research program advances EPA’s priority, Assuring the Safety of Chemicals (EPA, 

2010). The CSS research program uses novel research approaches to address the risks posed 

by chemicals in industrial and commercial use, as well as risks posed by these chemicals as 

they degrade or pass through the environment. 

Managing chemical risks is covered in 

legislation and statutes mandated by 

Congress and implemented by EPA (Table 

1). Chemicals are regulated by several 

program offices under a variety of statutes 

and CSS has worked closely with each of 

these offices in developing this research 

program. As examples of chemical legislation, 

amendments to the FQPA and SDWA, both 

of 1996, contain provisions for assessing 

the potential for chemicals to interact with 

the endocrine system. Both the CWA and 

the SDWA require the Office of Water to 

prioritize possible water contaminants in the 

Contaminant Candidate List (CCL). The 

Office of Solid Waste Emergency Response 

is concerned with the end-of-use disposition 

of chemicals and is therefore interested in 

life cycle considerations of chemical use. 

Internationally, similar pressures to transform 

the chemical safety assessment paradigm are 

also present, as exemplified by the REACH 

Program and Cosmetics Directive in Europe 

and the Canadian Environmental Protection 

Act in Canada. CSS will enable the Agency 

to test and regulate numerous chemicals in 

a more efficient manner, supporting several 

statutory obligations and policies (Table 1). 

Table 1: CSS Research Supports Chemical Risk Management Decisions 

Mandated by Legislation 

Legislation 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 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 

Resources Conservation and 

Recovery Act 

RCRA http://www.epa.gov/epawaste/laws-regs/ 

index.htm 

Safe Drinking Water Act SDWA www.epa.gov/lawsregs/laws/sdwa.html 

Toxic Substances Control Act TSCA www.epa.gov/lawsregs/laws/tsca.html 
12 

High Priority Chemicals of Concern: 

Endocrine Disrupting Chemicals (EDCs) 

The CSS research program provides support 

to EPA’s Endocrine Disruptor Screening 

Program (EDSP; www.epa.gov/endo/index. 

htm). The EDSP screening program is 

mandated under Amendments to the FQPA 

and SDWA. 

CSS GOALS TO SUPPORT EDSP: 

Near-term: Rapidly prioritize 

thousands of chemicals for the current 

EDSP Tier 1 Screen (T1S) battery. 

Intermediate: Incorporate modern 

technologies directly into the EDSP 

T1S to increase the capacity to screen 

for endocrine disrupting chemicals. 

Longer term: Eventually replace the 

T1S battery with a suite of assays 

based on non-whole animal methods. 

From the EDSP21 Workplan 

(EPA, 2011b). 

By evaluating current endocrine disruption 

testing protocols, in collaboration with partners 

in EPA’s Office of Chemical Safety and 

Pollution Prevention, CSS will develop new 

approaches to advance the current EDSP that 

includes the use of high-throughput screening 

and computational models to prioritize 

chemicals in EDSP. The CSS work to support 

EDSP will be conducted with partners in 

the National Institutes of Health and the 

Food and Drug Administration through the 

“Tox21 Consortium,” a collective effort among 

governmental scientists to development and 

use new toxicological methods. 

High Priority Chemicals of Concern: 

Nanomaterials 

Public health and the environment regulatory 

agencies were called upon by the White 

House (Executive Office of the President 

Memorandum, 2011) to gather information 

about developments in nanotechnology. 

The NRC recently released a report on 

the safety of engineered nanomaterials 

that provides a strategy for addressing the 

science needs regarding the potential health 

and environmental risks of engineered 

nanomaterials (NRC, 2012). Accordingly, 

understanding the potential toxicity of 

nanomaterials is another key focus of the CSS 

research program. 

CSS NANOMATERIAL RESEARCH 

GOALS: 

Identify the nanomaterials and in 

what forms, most likely to result in 

environmental exposure. 

Identify the particular properties of a 

nanomaterial are related to toxicity 

(nanomaterials of concern). 

Identify concentrations of 

nanomaterials of concern in air, soil, 

water and biological systems. 

CSS’s nanotechnology research is focused on 

supporting and informing EPA safety decisions 

made under various environmental statutes 

the Agency is responsible for upholding. By 

achieving the goals of the CSS’s nanomaterial 

research effort, EPA decision-makers will have 

more information to determine the health risks 

for various nanomaterials. 

CSS research is coordinating with the 

National Nanotechnology Initiative (NNI, 2011) 

and collaborating with the Organization for 
13 

Economic Cooperation and Development 

(OECD, 2001), to generate protocols, data and 

risk assessment approaches to promote the 

safe development, use and disposal/recycling 

of nanomaterials. 

Research Focus Area: Computational 

Toxicology (Comp Tox) 

Computational toxicology applies 

mathematical and computer models and 

molecular biological approaches to predict 

chemical hazards and risks to human health 

and the environment (EPA, 2003a; http://www. 

epa.gov/ncct/). Computational toxicology 

tools are being developed in CSS research 

as part of the effort to move toward a 21st 

century approach to toxicity testing (NRC, 

2007) and risk assessment (NRC, 2009) by 

moving to toxicity pathway based in vitro 

assays. The CSS computational toxicology 

work will be conducted with partners in the 

National Institutes of Health and the Food 

and Drug Administration through the “Tox21 

Consortium,” a collective effort among 

governmental scientists to develop and use 

new toxicological methods. 

CSS COMP TOX EXAMPLES: 

• Dashboards to display integrated 

toxicity information for partnerspecifi c questions 

• Databases of mechanistic, whole 

animal toxicity and exposure 

data (e.g., ACToR, ExpoCast) 

• Virtual Liver and Virtual Embryo 

Sustainable Molecular Design Approaches 

As part of the CSS advancement of science 

to support regulatory decisions on chemicals, 

CSS research includes sustainable molecular 

design of less toxic (“green”) chemicals (www. 

epa.gov/greenchemistry/). 

Sustainable molecular design draws upon 

the established principles of chemistry and 

engineering to build chemicals atom by atom 

from the ground up with the end goal of 

removing the inherent risk of the chemical. 

“Green chemistry technologies” encompass 

all types of chemical processes including 

syntheses, catalyses, reaction conditions, 

separations, analyses and monitoring. It 

can, for example, explore existing synthetic 

pathways to identify opportunities to substitute 

a greener feedstock, reagent, catalyst, 

or solvent in place of more toxic ones. In 

addition, a green chemistry technology can 

replace the entire synthetic pathway. Green 

chemistry technologies can have a number 

of advantages including reduced waste, 

reduced costs (e.g., eliminating end-of-thepipe treatment), reduced energy and resource 

use and increased product safety, which can 

result in increased competitiveness of the 

manufacturers. One example of progress 

in this arena is EPA’s Presidential Green 

Chemistry Challenge Program which has 

recognized groundbreaking green chemistry 

solutions to real-world environmental 

problems. The new technologies recognized 

over the past 16 years have significantly 

reduced the hazards associated with 

designing, manufacturing and using chemicals 

and in turn, have reduced the use or 

generation of more than 199 million pounds of 

hazardous chemicals, saving 21 billion gallons 

of water and eliminating 57 million pounds of 

carbon dioxide releases to the air. 

CSS research encompasses continued 

efforts to advance the field of sustainable 

molecular design. For example, the CSS “Life 

Cycle Considerations” theme research will 

evaluate life cycle impacts that demonstrate 

sustainable molecular design approaches 

for chemicals and identify the costs of these 

solutions. As another example, the program’s 

Inherency theme research will provide a basis 

for designing chemicals with lower exposure 

and toxicity potential. CSS research builds 

on existing research of cost-effi cient resource 
14 

and energy-efficient methods for synthesizing of chemicals used by industry and consumers 

chemicals and products. CSS researchers to reduce the risks of exposure to toxic 

are collaborating with academic and industry chemicals. 

partners to fundamentally redefine the design 
15 

 

An Integrated Program Design 

The CSS research program uses a transdisciplinary approach to develop and deliver the scientific tools and knowledge necessary to inform chemical safety decisions that advance sustainability. The program integrates skills, expertise and research from a diversity of fi elds, including 

bioinformatics; computational chemistry; green chemistry and engineering; systems biology; molecular, cellular and biochemical toxicology; exposure science; process modeling; chemical and 

environmental engineering; and social sciences. 

CSS is designed to lower barriers to research 

collaboration, moving away from what has 

traditionally been a “stove-piped” approach 

to environmental science, divided along 

disciplinary divisions. Instead, the design 

of the CSS research program ensures a 

transdisciplinary approach to problem solving 

and information delivery, including training, 

cross-organization dialogue, collaboration 

and team building. The program will cultivate 

innovation, leverage efficiencies and provide 

the holistic science the Agency needs for 

chemical safety and sustainability and 

other complex, far-reaching environmental 

challenges. 

The CSS research program integrates 

elements and themes from research efforts 

previously administered across EPA’s Office 

of Research and Development (ORD) into a 

seamless, highly-coordinated, transdisciplinary 

research program. It leverages expertise and 

resources in ways that realize efficiencies 

and reinforce common themes and research 

goals across six formerly separate research 

programs: Nanotechnology, Computational 

Toxicology, Safe Pesticides/Safe Products 

(SP2), Endocrine Disruptors, Human 

Health Research and Human Health Risk 

Assessment. 

Collaborating Across Research Programs 

In order to meet the needs of the Agency 

and the nation in addressing complex 

environmental problems, research integration 

is critical to both the CSS research program 

design and the collaborations across all six 

EPA research programs. EPA’s six research 

programs collaborate to deliver results that 

meet the science needs of decision-makers 

while also establishing a broad scientific 

foundation for a sustainable future. CSS 

supports the overall effort by providing 

improved approaches to chemical testing and 

assessment and those efforts in turn support 

the research efforts of the other programs. For 

example, CSS advances in chemical safety 

and management inform research efforts in 

air toxics, drinking water, pesticides use in 

local communities and larger ecosystems 

and waste management, remediation and 

emergency response. 

There are many examples of collaboration 

across EPA’s six research programs. 

EPA’s Six Integrated Research 

Programs: 

Chemical Safety for Sustainability 

(CSS) 

Human Health Risk Assessment 

(HHRA)
 

Air, Climate and Energy (ACE)
 

Safe and Sustainable Water 

Resources (SSWR)
 

Sustainable and Healthy 

Communities (SHC) 

Homeland Security (HS) Research
 
16 

Examples include: 

• The CSS program is providing tools and 

data to EPA’s Sustainable and Healthy 

Communities (SHC) research program 

for those contaminants of highest priority 

and concern to communities, considering 

susceptibilities and exposures of the most 

vulnerable populations and life stages. 

• CSS and their partners from the Air, 

Climate and Energy (ACE) research 

program are developing green chemistry 

alternatives to existing hazardous air 

pollutants, such as halogenated solvents 

considered “hazardous air pollutants” 

under the Clean Air Act. This work 

includes developing and evaluating safer 

cleaning agents and developing chemical 

screening methods needed for volatile 

chemicals. 

• CSS is collaborating with the Human 

Health Risk Assessment (HHRA) research 

program to advance the pathway-based 

toxicity testing and risk assessment 

paradigm proposed by the National 

Academy of Science (NRC, 2009). CSS 

research complements ongoing EPA single 

chemical and cumulative risk assessment 

activities conducted by HHRA, including 

the Next Generation (NexGen; http://www. 

epa.gov/risk/nexgen/) risk assessment 

case studies. 

• In collaboration with OW partners and the 

Safe and Sustainable Water Resources 

(SSWR) research program, CSS is 

creating a web-based Office of Water for 

the 21st Century (OW21) dashboard for 

evaluating screening, testing, exposure 

and sustainability information relevant 

to prioritization of chemicals for the 

Preliminary Chemical Candidate List 

(PCCL)/CCL . 
17 

Developing Partnerships from the Start 

Collaboration with EPA internal partners 

(program and regional offices) and external 

stakeholders is vital to the success of CSS 

so that we can meet their science needs. 

Accordingly, CSS staff has engaged a broad 

range of partners and stakeholders since the 

inception of the research program in January 

of 2010, ensuring that CSS identifi ed the 

highest priority research needs. 

First, CSS researchers communicated 

internally with staff from across EPA’s Office 

of Research and Development (ORD) 

through a series of briefi ngs, workshops, 

teleconferences and meetings (called 

“listening sessions”) to identify and define 

research needs for chemical safety. Pre-briefs 

and a workshop were then held to prioritize 

key science questions with EPA research 

partners. 

Following activities to defi ne partner 

needs, workshops with ORD scientists and 

management were held to discuss and refine 

the products of the Chemical Safety and 

Sustainable research program to ensure that 

it would produce outputs and outcomes that 

meet the science needs of the Agency. A 

second workshop was subsequently held 

with partners, including the Office of Pollution 

Prevention and Toxics, the Office of Pesticide 

Programs (OPP), the Office of Water (OW) 

and the Office of Solid Waste (OSW), to 

review the draft CSS research portfolio. 

In July, 2010, CSS consulted with EPA’s 

Board of Scientific Counselors (BOSC), to 

solicit feedback to ensure that the research 

planning was on the right track. BOSC 

was established by the Agency to provide 

advice, information and recommendations 

about Office of Research and Development 

research programs. A draft of the CSS 

Research Framework (U.S. EPA, 2011a) was 

produced incorporating an inventory of existing 

chemical safety research and the input from 

partners and the BOSC. Additional input on 

the framework was gathered, through public 

webinars and other means, from external 

stakeholders, including industry groups, 

media organizations, other federal agencies 

and groups such as the American Chemistry 

Council, the Humane Society of the United 

States and the Environmental Defense 

Fund. CSS also solicited feedback on the 

CSS Research Framework document using 

IdeaScale, an internet-based, social-media 

inspired platform for generating a community 

of ideas and capturing open feedback. 

In June 2011, a joint Science Advisory Board 

(SAB) and BOSC meeting was held to review 

the CSS Framework document, as well as 

the other five Agency research programs’ 

frameworks. Using feedback from the joint 

BOSC/SAB meeting, the CSS team developed 

a Strategic Research Action Plan (this 

document). 

Understanding the importance of continual 

collaboration with EPA partners and external 

stakeholders, a CSS Program Offi ce and 

Regional Outreach Plan has been developed 

to guide the future collaboration with EPA 

partners. In addition, an external stakeholder 

engagement plan has been developed. 

CSS Design Overview 

CSS is designed to operate as an integrated 

research program organized around eight key 

research topics. 

Inherency includes research to understand 

the relationship between inherent physicochemical properties (e.g., mass, conductivity, 

reactivity, heat of combustion) of a chemical; 

fate and effects; and human and wildlife 

CSS Research Themes: 

1. Inherency 

2. Systems Models 

3. Biomarkers 

4. Cumulative Risk 

5. Life Cycle Considerations 

6. Extrapolation 

7. Dashboards 

8. Evaluation 
18 

health outcomes after chemical exposure. 

Furthermore, these properties may change as 

a chemical moves through the environment 

or a biological system such as the endocrine 

system, an organ (e.g., liver) or a whole 

organism (e.g., the embryo). Key inherency 

property models can be developed using 

information from Systems Models research 

which studies the interactions of the chemical 

with biological and environmental processes 

and the outcomes. Biomarkers are developed 

that are effective measures of chemical 

exposure and effects. 

The research methods and models developed 

for a single chemical can be repeated, 

efficiently identifying the properties of large 

numbers of other chemicals. This, in turn, 

allows for science-based generalizations that 

can be made for predicting the fate and effects 

outcomes for broader groupings of chemicals. 

In Extrapolation, scientists can use outcomes 

of Inherency and Systems Models research 

to build extrapolations that extend the known 

data for a chemical to additional biological 

systems (such as different species) and on 

environmental systems, providing important 

scientific information in support of specific 

regulatory and risk assessment decisionmaking. 

Given sufficient information on a number of 

chemicals, the Cumulative Risk of broader 

classes of chemicals can be predicted. This 

information then can be used on higher 

level activities, including the development 

of Dashboards, Life Cycle Considerations 

(including life cycle and sustainability 

analyses) and Evaluation methodologies. 

Figure 1 illustrates the overall conceptual 

model for CSS research, beginning with 

problem formulation based on identifying 

the requirements and information needed to 

support the regulatory actions and mandates 

of an EPA regional or program office. Once 

the information needed is identified, the model 

identifies four levels (in blue in Figure 1)— 

each of increasing complexity—of research 

approaches to generate the data needed 

by the end user (such as an EPA program 

or regional office) to inform regulatory 

assessment and management decisions. 
19 

 

 

 

CSS Overview – Research Topics
 

Problem Formula on 

Data Genera on and 

Interpreta on Tools 

Need More Informa on 

Need More Informa on 

Level I: 

Inherent Proper es 

Level III: 

Targeted Tes ng 

Level II: 

Screening Assays 

Level IV: 

Systems Models 

Sufficient 

Information 

Tier 3 

Assessment 

Decisions 

Tier 2 

Tier 1 

Management 

Decisions Sustainability and other Considera ons 

Acceptable 

Uncertainty 

Dashboards 

Evalua on 

Systems 

Models 

Inherency 

Life Cycle 

Extrapola on 

Need More Informa on 

Sufficient 

Information 

Sufficient 

Information 

Sufficient 

Information 

Acceptable 

Uncertainty 

Acceptable 

Uncertainty 

Acceptable 

Uncertainty 

Cumula ve 

Risk 

Biomarkers 

Figure 1. The eight research topics/themes are mapped to a conceptual model to illustrate 

the integrated nature of the CSS research program. Adapted from the Framework for an 

EPA Chemical Safety for Sustainability Research Program (U.S. EPA, 2011a). The Problem 

Formulation (red box) is defined by partner decision needs and regulatory requirements. 

Sustainability and Other Considerations (purple box) include sustainability, life cycle assessment 

(LCA), soci-economic and alternative assessments that can inform Management Decisions (lilac 

box column). Green boxes, 8 different CSS research themes. Blue rectangles, are the four (IIV) levels of research approaches to generate data. Gray, pink and orange column of boxes, 3 

different assessment tiers. 

Data generated through a particular level’s 

approach may apply directly to a particular 

assessment or management decision. 

For example, the information derived from 

Level I (“Inherent Properties”) alone may be 

adequate for informing a decision (e.g., on 

the viability of applying a green chemistry 

approach to chemical management). If not, 

further resources are devoted to gather more 

information at that Level or the next. For 

example, data generated from approaches 

within Levels I and II (“Screening Assays”) 

may help narrow the range of testing 

approaches needed for a particular chemical 

or group of chemicals. Approaches developed 

under Level IV (“Systems Models”) are the 

scientifically most complex. This may be 

applied for either very complex assessment 

and management problems—such as 

addressing the life stage susceptibility of the 

cumulative impacts of multiple chemicals 

and/or exposure pathways,—or for providing 

information that refines approaches within 

the other three levels. The assessment 

decisions also are placed in tiers, recognizing 

that different types of decision outcomes (as 

articulated in problem formulation) require 

assessments with varying types and amounts 

of information. 
The program is designed with a tiered 

approach that can identify and provide 

timely, needed information effi ciently. The 

“Management Decisions” portion of the 

model acknowledges that, in addition to 

environmental science data, findings and risk 

assessments, decision-makers need additional 

information—such as social/cultural, political 

and economic considerations—to fully inform 

their management strategies. 

The CSS research program aims to develop 

methods and tools to inform the development 

of enhanced risk prevention or management 

approaches for both new and existing 

chemicals. To develop scientifi c information 

that leads to improved understanding of how 

to better create and manage chemicals, CSS 

research incorporates four key considerations 

into its research activities: (1) inherent 

chemical/material properties, (2) life cycle 

of chemicals, (3) chemical sustainability 

and (4) increasing the scope and pace of 

research to close the large gaps in our current 

understanding of chemical safety. 

1. Inherency. The CSS research program 

incorporates the consideration of 

inherent chemical properties into its 

integrated testing, assessment and 

management approaches. 

Inherency consists of the physical, 

chemical and material properties of a 

chemical—for example, the structure, 

composition, size and solubility that 

arise from a particular chemical 

formulation. For particles, such 

properties also include their surface 

area, surface charge and aspect ratio. 

These properties may determine how 

mobile, persistent, or bioavailable the 

chemical is in the environment. They 

also influence the ability of a chemical 

to interact with biological processes 

that lead to human disease or adverse 

outcomes in wildlife species. 

It may be possible in some cases to 

apply green chemistry approaches 

during chemical design to alter or 

otherwise address such inherent 

properties in ways that reduce 

environmental impact. Often, however, 

these also are the properties that give 

the chemical/material the desirable 

performance characteristics that make 

it worthwhile to produce. 

2. Life cycle. The CSS research program 

addresses both new and existing 

chemical issues and develops tools 

that can inform the development of 

sound and feasible assessment and 

management approaches across the 

chemical life cycle. 

CSS research considers the life cycle 

of a chemical (Figure 2) as it relates 

to chemical safety. Impacts to people 

or other parts of the environment from 

chemicals can occur at any point, 

from the extraction of raw materials 

20 

Figure 2. Considering sustainability across a chemical’s life cycle. 
21 

for manufacturing a chemical, to 

processes that create the chemical 

and incorporate it into products, 

through the chemical’s and product’s 

use to the end of life when it is 

disposed of or recycled. 

CSS research will address how to 

assess risks from exposure throughout 

a chemical’s life cycle and identify the 

points in the life cycle that may lead 

to the greatest exposure and impact 

on human and wildlife health. Each 

point in a chemical’s life cycle presents 

an opportunity to utilize sustainable 

molecular design approaches to 

eliminate or reduce health impacts. 

Such approaches will provide 

opportunities for risk prevention early 

in the life cycle. When those options 

are not feasible, however, handling 

measures still may be needed to help 

manage downstream impacts. 

3. Sustainability. The CSS research 

program advances the sustainable 

use and management across three 

key areas: (1) what the chemical is, (2) 

how it is made and (3) how it is used. 

Altering any of these three aspects 

changes the potential of the substance 

to produce environmental impacts 

throughout its life cycle and affects 

sustainability metrics, such as ecoefficiency (the ratio of value delivered 

to resources consumed). 

Achieving sustainability means creating 

and maintaining conditions under 

which humans and nature can exist in 

productive harmony and that permit 

fulfilling the social, economic and other 

requirements of present and future 

generations (Council on Environmental 

Quality, 1969). 

Examples of sustainability chemical 

research include: investigating whether 

the use of toxic materials is essential 

to produce a particular chemical when 

less-toxic materials are available; or, 

if such alternative materials are not 

available, whether there are aspects of 

the current chemical-making process 

that could be changed to mitigate the 

impacts of toxic inputs into synthesis 

and production. The use of a raw 

material feedstock that requires 

significant input of water and energy 

and identifying an alternative feedstock 

that has a smaller environmental 

“footprint” in terms of carbon emissions 

and resource consumption are also 

important opportunities that will be 

investigated through the CSS research 

program. 

4. Closing Assessment Knowledge 

Gaps. CSS research is helping 

revolutionize how chemicals are 

assessed for potential toxicity to 

humans and the environment. 

Research outcomes will increase the 

pace of chemical screening, testing 

and assessment, closing large gaps in 

the current understanding of chemical 

safety. 

Traditional chemical toxicity tests, using 

laboratory tests on whole animals, are 

expensive and time consuming. As a 

result, only a small fraction of the more 

than 80,000 chemicals currently listed 

or registered for use in the U.S. under 

EPA authorities have been thoroughly 

assessed for potential risk (EPA, 2012). 

Further, over a thousand additional 

chemicals subject to EPA oversight are 

introduced every year. 

CSS research is working to 

revolutionize how chemicals are 

assessed for potential toxicity to 

humans and the environment. CSS 

conducts innovative research that 

integrates advances in molecular 

biology, chemistry, high-throughput 

technology and computer science to 

more effectively and effi ciently rank 

chemicals based on hazards and 

risks. Research outcomes will be rapid 

exposure data, chemical screening 

data and other decision-support tools 
22 

that inform potential risks to humans 

and the environment, closing the gap in 

information needs for chemical safety. 

Inherency, chemical life cycle, sustainability 

and improving the pace of research in 

chemical safety are the fundamental aspects 

in developing approaches for making 

existing and new chemicals safer and more 

environmentally acceptable. 
23 

Research Themes and Priority

Science Questions 

The CSS research program consists of eight themes or topics. Brief descriptions of the theme, 

research objectives, science questions and illustrative products are provided below for each of 

these. 

Theme 1. Inherency 

Inherency is defined as the inherent physico-chemical properties that characterize a chemical. 

These properties influence the potential for humans and wildlife to be exposed to a chemical 

and the potential for that chemical to affect the health of humans and/or wildlife and impact the 

environment. 

Research Objective: Establish a system 

for compiling and sharing chemical characteristic data and to advance a better 

understanding the relationships between 

chemical characteristics and specifi c toxic 

responses (including human disease outcomes or population effects in wildlife or 

ecological systems). Understanding these 

relationships will, in turn, enhance the 

ability to predict toxic responses (disease 

outcomes) for specific chemicals. 

Science Questions 

What is the relationship between inherent 

physico-chemical properties and health 

outcomes and what data are needed to 

define these relationships? 

What approaches and information can 

best advance the understanding of 

physico-chemical or material properties 

of chemicals and how can this knowledge 

be used to predict toxicity, fate, transport, 

transformation (degradation and 

metabolism) and toxicologically-relevant 

exposures? 

How can the knowledge of inherent 

properties be utilized to guide the 

development of safer product design and 

use throughout a chemical’s life cycle? 

Illustrative Outputs, Products, 

and Outcomes 

Example: Understanding the Relationship 

between Inherent Properties of Nanomaterials 

and Exposure and Toxicity 

EPA researchers are working to improve 

chemical hazard assessments based upon 

a deeper understanding of the relevant 

inherent properties of chemicals that influence 

environmental fate, exposure and biological 

responses. These four products (below) 

highlight some of the work to understand 

the inherent properties for nanomaterials, 

including potential exposures to nanomaterials 

in consumer products that can be utilized 

directly in EPA decision-making. 

Example Outputs: 

(1) Nanoparticles (NPs) in the 

environment: Methods for the detection 

and characterization to analyze metal 

and carbon-based nanoparticles in 

environmental matrices. 
24 

(2) Fate of nanoparticles in the 

environment: Data on the impacts 

of inherent particle properties and 

environmental conditions on their fate 

in environmental systems. 

(3) Leaching of nanoparticles from 

products: Data on the quantities and 

speciation of nanoparticles leaching 

from consumer products containing 

nanomaterials. 

(4) Nanoparticles in the environment: 

Bioavailablity assessment tools for 

nanoparticles. 

(5) Transport and transformations 

of nanoparticles in the environment: 

Experimental and modeling tools 

for evaluating transport and 

transformations of nanoparticles in the 

environment. 

(6) Exposure to nanoparticles in the 

environment: Data and relationships 

that can be used to link ICPs of NPs 

to models that predict NP transport, 

transformation and exposure in the 

environment. 

Research Products Contributing to These 

Outputs: 

 A report characterizing copper 

nanoparticles leaching from treated 

wood. This new research on leaching 

is needed by OPP and will directly 

inform decision-making on treated 

wood products regulated by EPA. 

 The development of laboratory 

and field tests, advanced analytic 

techniques and quantum chemistry 

calculations to evaluate the 

applications, implications and 

potential risks of surface-altered 

nanoparticles (e.g., titanium dioxide, 

carbon nanotubes, copper, zinc oxide 

and silver) from consumer products 

in the environment (e.g., landfills, 

soil, chlorinated and brackish water, 

biosolids and wetlands). 

 The development and assessment 

of bioavailability tools for assessing 

human exposures to silver 

nanoparticles. 

 The development of methods, 

analyses and reporting on the 

detection, evaluation and assessment 

of release of nanomaterials (e.g., 

carbon nanotubes) from polymers 

representative of consumer products. 

Outcomes of the research: Improved 

chemical hazard assessments based upon 

a deeper understanding of the relevant 

physico-chemical properties of chemicals 

that influence environmental fate, exposure 

and biological responses. This research is 

particularly relevant to decision-making for 

emerging chemicals and materials, such 

as nanomaterials, whose toxicity is less 

understood. 

Impacts 

By establishing information about the 

relationship between these inherent properties 

and health outcomes, risk assessment and 

other regulatory decisions can be better 

informed. A number of the Inherency research 

products connect with research performed 

in other themes of the CSS program (e.g., 

Dashboards, Cumulative Risk and Life Cycle 

Considerations) and together, their outputs 

advance green chemistry and sustainable 

design. 
25 

Theme 2. Systems Models 

Systems models are scaled or multiple-level models that predict or simulate exposure or effects 

of complex biological or environmental systems. 

Research Objective: Generate, utilize 

and integrate chemical, biological and 

toxicological information at all levels of 

biological organization (e.g., molecule, 

cell, tissue, organ, organism), such that 

the potential toxicity of a chemical can be 

evaluated with enhanced predictive power. 

Science Questions 

What are the perturbations at all levels 

of biological organization, defi ned as 

a toxicity pathway, for environmental 

chemicals? (Related questions: What is 

the relationship of pathway-level changes 

to adverse outcomes and how do we 

defi ne adversity?) 

What are the most appropriate systems 

models to address the chemical-related 

environmental problems of greatest 

impact? 

How can information be integrated into 

virtual organ models? 

What new tools and/or models must be 

developed to ensure precise and efficient 

hazard and exposure screening across the 

life cycle of a chemical? 

What systems models (e.g., kinetics 

and dynamics) must be developed and 

used to address the chemical-related 

environmental problems with the greatest 

impact? 

The Systems Models theme is the largest 

of the CSS research themes and will result 

through the observation of adverse outcomes, 

including interactions at all levels of biological 

organization in humans and wildlife. 

Illustrative Outputs, Products and 

Outcomes 

Example 1: Development and Use of Pathway 

Perturbation Data 

EPA researchers are generating adverse 

outcome pathway data and studying the 

relationship between pathway perturbations 

and particular adverse outcomes. The 

information will be compiled and methods to 

utilize the data will be developed to support 

Agency screening programs (e.g., EDSP) and 

r isk assessment. 

Example Outputs: 

(1) Connecting molecular and whole 

animal effects in a knowledgebase: 

Compiling information concerning 

the linkages between endpoints 

measured or predicted at molecular 

and cellular levels and adverse 

outcomes at higher levels of biological 

organization traditionally considered 

in risk assessments and regulatory 

decision-making (e.g., organ 

function in humans; survival, growth/ 

development and reproduction in 

wildlife) and depositing this information 

into a knowledge-base (called 

“Effectopedia”). The initial focus will 

be on depositing information about 

reproductive and developmental 

toxicity in fish into the Effectopedia. 

in a number of major products and outputs. (2) Predicting species effects after Systems Models research will investigate the chemical exposure: A web-based tool “adverse outcome pathway” (AOP), covering to support prediction of which species the span from chemical exposure all the way 
26 

are likely to be susceptible to adverse 

effects of chemicals that act on specific 

protein targets. 

(3) Developing and applying adverse 

outcome pathway knowledge and filling 

data gaps, to support specifi c partner 

needs. 

(4) Environmental monitoring 

approaches: Methods to incorporate 

biological responses of organisms 

exposed to environmental stressors 

into the monitoring of contaminated 

or remediated sites that are relevant 

to the program offices and regions. 

The biological responses used will be 

based on the biological pathways that 

are impacted by the exposure(s). 

(5) Exposure reconstruction 

approaches: Recommendations 

regarding the best method for using 

biological responses (based on effects 

on biological pathways) of organisms 

residing in polluted waters to determine 

specific chemical exposures of these 

organisms. Use of these biological 

responses for determining what the 

organisms have been exposed to 

will help program ofices and regions 

in conducting assessments and 

investigations of polluted waters. 

(6) Data sets derived from highthroughput screening of chemicals on 

program office inventories to support 

the development of signatures, 

or patterns of activity, for adverse 

outcome endpoints of relevance to 

partners. The outcomes (endpoints) of 

concern include cancer, developmental 

neuro- and developmental immuno-, 

developmental, reproductive and 

systemic toxicity. 

(7) Additional screening of regulatory 

chemical inventories (TSCA21, 

OW21, EDSP21 and OPP21) will be 

conducted to provide data sets for 

prioritization of chemicals on these 

lists using molecular signatures (i.e., 

patterns of response). 

(8) Prioritization of regulatory chemical 

inventories (TSCA21, OW21, 

EDSP21 and OPP21) based on in 

vitro molecular signatures (patterns 

of response) for endpoints of cancer, 

developmental toxicity, reproductive 

toxicity. 

(9) Completion of EDSP21 workplan 

for 2000 chemicals: Rapid prioritization 

of chemicals for further safety 

evaluation based on potential for both 

harm and exposure. Non-animal-based 

(in vitro) tests are used to identify 

the degree to which a substance can 

damage living organisms (hazard) 

and to determine pharmacokinetics 

(how the chemicals accumulate within 

the body) and computer simulations 

(based on chemical structure, 

inherency and mathematical models) 

are used to derive potential for human 

contact (exposure). The EDSP21 

workplan for prioritization of 2000 

chemicals will include both potential 

hazard identification and chemicalstructure-derived exposure potential 

simulation without pharmacokinetic 

considerations. 

Research Products Contributing to These 

Outputs: 

 AOP descriptions comparing linkages 

(e.g., causal) between specifi c pathway 

perturbations and reproductive 

or developmental outcomes in 

multiple species (e.g., rodents, fish, 

invertebrates). These will provide 

data that support the development of 

tools and guidance for cross-species 

extrapolation of effects and hazard. 

 Case studies evaluating the utility of 

transcriptomics, metabolomics and 

associated bioinformatic methods for 

comparing the nature and severity of 

biological impairment as a function 

of space and/or time to assess the 

efficacy of remediation efforts within 
27 

the Great Lakes Areas of Concern. 

 Completion of high-throughput 

screening data sets on the first 

1000 Endocrine Disruptor Screening 

Program 21 (EDSP21) chemicals and 

ToxCastTM Phase II chemical library. 

 Accelerated ToxCastTM screening 

data on additional chemicals beyond 

the current EDSP21 library; access 

new endocrine-related assays for 

EDSP21 (especially thyroid and 

steroidogenesis-related); validation 

studies on EDSP21 assays including 

targeted in vitro data on EDSP21 

chemicals; database to manage 

EDSP21 data as well as data from 

guideline EDSP Tier 1 and Tier 

2 studies; prioritization/weight of 

evidence methods/models for using 

EDSP21 data by program offices. 

 Prioritization and selection of 

ToxCastTM Phase-I and Phase-II 

chemicals for the TSCA21, OW21 

and OPP21 (EPA work plans to utilize 

21st century research and methods in 

these programs) case studies based 

on endpoints for cancer, developmental 

toxicity and reproductive toxicity. 

Example 2: Sophisticated Virtual Tissue 

Models (v-LiverTM and v-EmbryoTM) 

EPA researchers continue to develop the 

virtual tissue models for the liver and embryo 

to eventually be used to predict exposures and 

effects in the developing embryo and in the 

liver. 

Example Outputs: 

(1) A computer model to analyze 

effects of contaminants in food and 

water on the liver: Linkage of gene 

expression/pathways with phenotypic 

outcomes in the intact rodent liver. 

(2) Computer models to predict effects 

on fetal development after maternal 

chemical exposure: Virtual embryo 

research integrates important data and 

scientific knowledge into sophisticated 

computer models that will simulate and 

predict adverse events and outcomes 

in the embryo, fetus and neonate when 

the mother is exposed to different 

chemicals. 

(3) Delineating pathways of exposure 

and mechanisms of developmental 

toxicity using the virtual embryo for risk 

assessment: The predictions of virtual 

embryo simulations can be used to 

understand and test mechanisms of 

developmental toxicity across different 

doses, species and life stages. This 

understanding can provide guidance 

for life-stage specific targeted research 

to delineate pathways of exposure 

and mechanisms in both the fetus and 

infant. 

(4) An integrated strategy for lifestage specific risk assessment: The 

outcomes of the research will lead 

to improved understanding of the 

molecular pathways and cellular 

processes underlying adverse 

pregnancy outcomes and better ways 

to assess the impacts of prenatal and 

postnatal exposure to chemicals at 

various stages of development and 

scales of biological organization. 

Research Products Contributing to These 

Outputs: 

To support the virtual liver model – 

 Quantitative dose-response models 

that are predicted by biological 

networks governing hepatocyte 

death and proliferation underlying 20 

ToxCastTM chemicals with activity on 

nuclear receptor mediated pathways. 

This cell agent-based model will 

estimate the acute and chronic effects 

of hepatic AOPs and develop a 

computational framework to integrate 

these effects with environmental 

processes for selected chemicals 

in EDSP21, TSCA21, OW21 and/or 

OPP21. 
28 

To support the virtual embryo model – 

 Integration of angiogenesis information 

into the virtual embryo using a 

cell-agent based systems model 

developed from empirical data and 

biological knowledge of blood vessel 

development. The angiogenesis 

model will be trained with compounds 

showing anti-angiogenic properties, 

assessed in a forward validation for 

predictive developmental toxicity 

among 1,000+ ToxCastTM chemicals 

in pregnant rats/rabbits and tested 

for vascular disruption in zebrafish 

embryos and embryonic stem cell 

assays for 30+ chemicals in EDSP21, 

TSCA21, OW21 and/or OPP21. 

Example 3: Exposure and Effects Information 

to Support Near-term Regulatory DecisionMaking 

Example Outputs: 

(1) Consumer product use, emissions 

and other data for informing multi-tier 

exposure and dose analyses. 

(2) Inputs and methods needed to 

model fate/transport, concentrations, 

exposures and dose to a variety of 

environmental chemicals. 

(3) Refined Stochastic Human 

Exposure and Dose Simulation 

(SHEDS) and new SHEDS-Lite 

models. 

(4) Applications of linked source-todose models to address program 

office and regional priorities for 

environmental chemicals. 

(5) Completion of the TSCA21 

workplan for 500 chemicals: Rapid 

prioritization of chemicals for further 

safety evaluation based on potential 

for both harm and exposure. Nonanimal-based (in vitro) tests are 

used to identify the degree to which 

a substance can damage living 

organisms (hazard) and to determine 

pharmacokinetics (how the chemicals 

accumulate within the body) and 

computer simulations (based on 

chemical structure -- inherency 

-- and mathematical models) are 

used to derive potential for human 

contact (exposure). The TSCA21 

workplan for 500 chemicals will 

combine high-throughput hazard data, 

pharmacokinetic data and exposure 

simulations to determine chemical 

prioritization based upon potential risk. 

(6) Completion of the EDSP21 

workplan for 2000 chemicals: Rapid 

prioritization of chemicals for further 

safety evaluation based on potential for 

both harm and exposure (similar to the 

TSCA21 workplan approach above). 

Research Products Contributing to These 

Outputs: 

 Simulation tool for modeling PCB and 

SVOC emissions and transport in 

buildings and formaldehyde emissions 

from aqueous solutions. 

 Revised version of SHEDS-Multimedia 

(v4) that includes output results for 

different scenarios, case-studies 

and sensitivity analyses addressing 

OPP needs for including dietary 

and residential scenarios. This 

product is responsive to a recent 

recommendation of the FIFRA Science 

Advisory Panel (EPA, 2010). 

 The Exposure Forecaster (ExpoCast) 

high-throughput exposure predictions 

for prioritization of initial ToxCastTM, 

TSCA21 and EDSP21 chemicals 

including exposure metrics and fate 

and transport modeling of large 

chemical libraries. 
29 

Example 4: Systems Models for Ecological 

Risk Assessment Application 

Example Outputs: 

(1) Integrated systems-approaches 

linking exposure and outcome. 

(2) Integrated systems-approaches for 

predicting individual, population and 

ecosystem risk from complex patterns 

of chemical exposure. 

(3) Understanding of inherent 

properties of modifications that mediate 

specific nanomaterial (NM) toxicity or 

other effects. 

(4) Identify mechanisms of action 

for nanomaterials, AOPs and 

recommendations for development 

of alternative and rapid-throughput 

assays. 

(5) Recommendations for the 

development of models linking inherent 

properties and adverse outcomes (e.g., 

QSARs for NMs). 

(6) Best current in vitro and in vivo 

methods for tier testing of NMs 

provided to Offices. 

(7) AOPs identifying common and 

sensitive biological receptors predictive 

of adverse human and ecological 

outcomes. 

(8) Mechanisms of injury, mode of 

action and AOP for high-throughput 

and high-content screening methods 

development. 

(9) Credible translatable alternative 

test methods, guidelines and endpoints 

that predict NM in vivo toxicity with high 

confidence. 

Research Products Contributing to These 

Outputs: 

 Design and recommendations for 

case studies that demonstrate 

systems models approaches to evolve 

from population- to community- to 

ecosystem-level risk assessment and 

provide information on high priority 

chemicals. 

 Data on toxicity of selected 

nanomaterials, including exposureresponse models, uptake, distribution, 

modes of action, AOPs and initiating 

events for non-human species and 

ecological processes. 

 Guidance on the use of ecological 

nanomaterial toxicity information to 

identify dose metric(s) of exposure 

to response, AOPs and absorption, 

distribution, metabolism and excretion 

(ADME) with their inherent chemical 

properties for development of high 

throughput and high content testing 

methods and best practices and test 

methods for the use of alternative 

models, tiered testing and in vivo tests 

to assess their toxicity. 

Outcomes of the research for all four 

systems models examples (above): Improved 

chemical prioritization, screening, testing and 

quantitative risk assessment by integrating 

information from multiple biological levels, 

including pathway-level information and by 

using advanced computational techniques, 

such as multi-scale systems models of virtual 

tissues, to develop predictive models of 

hazard and exposure. 

Impacts 

The systems model research outcome 

will have a tremendous impact on EPA 

toxicity testing, risk assessment and other 

environmental decision-making as the Agency 

moves chemical safety assessments into 

the 21st century. Together, the Systems 

Model outcomes moves advance the use of 

the pathway-based toxicity testing and risk 

assessment paradigm. 
30 

Theme 3. Biomarkers 

A biological marker, or “biomarker,” is a chemical or biological characteristic that is measured or 

evaluated as an indicator of a biological process and used as a marker of exposure or effect. 

Research Objective: Predict health 

outcomes and exposures based on 

biomarkers to inform EPA risk assessment 

and management decisions for human and 

wildlife health. 

Science Questions 

How can CSS assess biomarkers that can 

serve as useful indicators of toxicity for 

different chemicals and endpoints such as 

health or wildlife outcomes? 

What are the endpoints of concern that 

require development of biomarkers? 

What characteristics are needed for a 

biomarker to be one that is informative of 

adverse outcomes to humans? 

How can the program assess biomarkers 

of exposure? 

What models need to be developed to 

better integrate biomonitoring (biomarkers 

and bioindicators) data into testing 

systems to help the Agency better 

understand environmental and health 

impacts? 

Illustrative Outputs, Products and 

Outcomes 

Example: Development of Biomarkers of Effect 

and Exposure 

The Biomarkers theme is closely related to the 

AOP concept of the Systems Models research 

theme as it strives to characterize linkages 

between external environments, internal 

(biological) environments and key adverse 

effects/outcomes. The Biomarkers’ theme 

includes research to develop and assess 

biomarkers of exposure and effect. The 

research will use linkages between biomarkers 

and health outcomes to develop biomarkerbased predictive tools to aid in defi ning and 

understanding the relationship between 

chemical exposure and health effects. 

Example Outputs: 

(1) Holistic approaches to foster a 

better understanding of relationship 

between exposure metrics and 

biomarkers, allowing for potential 

to reconstruct exposures from 

biomarkers. 

(2) Improved methodologies for 

exposure and dose estimates by 

integrating biomarker data with 

supporting information/data (e.g., 

exposure factors and pharmacokinetic 

behaviors) into predictive models. 

(3) Biomarker-based models for risk 

assessment. 

(4) Biomarker-based model tools to 

evaluate risk management activities. 

(5) Develop and maintain a state of the 

art panel of biomarkers of effects for 

use by risk assessors and researchers. 

(6) Link biomarkers to key events in an 

adverse outcome pathway and thereby 

improve the diagnostic capabilities of 

the biomarkers in the panel. 

Research Products Contributing to These 

Outputs: 

For biomarkers of exposure -

 Web-based software tool to conduct 

reverse dosimetry probability 

calculations for estimating exposure 
31 

concentrations that are likely to have 

produced the observed biomarker 

concentrations. 

 Best practices for integrating 

existing biomonitoring data into risk 

assessment demonstrated with a case 

study. Report will give generalizable 

guidance for calculating exposure, 

dose and target dose; calculating 

uncertainty; predicting risk; and 

identifying opportunities for mitigation 

For biomarkers of effect -

 Panel of existing bioindicators 

evaluated for diagnostic capability 

including (1) robustness of the assay, 

(2) bioindicator distribution in healthy 

and affected populations and (3) 

predictive capability for adverse 

outcomes. 

Outcomes of the research: EPA risk 

assessments are improved by the (1) 

consistent, justifiable and improved use of 

existing biomonitoring data (e.g., NHANES); 

(2) availability of dose estimation/exposure 

reconstruction methods; and (3) availability 

of diagnostic AOP-based biomarkers with 

annotations to evaluate published data. 

Impacts 

The impact of the resulting Biomarkers’ 

research is that the program’s partners will 

possess the tools (e.g., diagnostic biomarkers 

for AOPs) and methods needed to improve 

estimates of exposure, dose and outcome 

and utilize available biomarker data. In 

addition, some of the work directly supports 

the development of biomarkers for emerging 

contaminants of concern. 
32 

Theme 4. Cumulative Risk 

Cumulative risk is the combined risks from aggregate exposures to multiple agents or stressors. 

Research Objective: Assess the potential Illustrative Outputs, Products and 

human health and environmental outcomes Outcomes 

that result from multiple and continuous 

exposures to chemicals and provide 

this information about specifi c chemical 

mixtures, including chemical mixtures 

found in consumer products, to support 

priority regulatory decisions. 

Science Questions 

What are the ecological and human health 

risks of combined real-world exposures to 

environmental chemicals? 

What are the chemical targets at the 

molecular, cellular, tissue, organ and whole 

animal levels? and, Can these targets be 

used to assess cumulative effects? 

How can recent scientific advances help 

describe the impacts of exposures to 

chemical mixtures? 

How can recent scientific advances help 

describe human variability (e.g., across life 

stages, population groups)? 

What kinds of tools, including 

computational, systems-based tools, are 

required to fully describe the overall impact 

of aggregate exposures on organisms? 

What enhancements will be required to 

describe the impact of factors that affect 

an organism’s response to chemical 

exposure, such as life stage, gender and 

aggregate exposures? 

What new methods/models are needed to 

account for exposure from all sources and 

pathways? 

Example 1: Effects and Exposure Predictive 

Tools for Real-World Mixtures 

Real world chemical exposures are rarely 

limited to a single chemical, but involve 

often complex mixtures of different agents or 

stressors. This set of products helps identify, 

predict, assess and prioritize how chemical 

mixtures interact with humans and wildlife in 

real-world settings. 

Example Outputs: 

(1) Predictive tools for identifying 

and prioritizing real-world mixtures 

of stressors (e.g., environmental, 

residential, SES, diet) based on: 

sources (including commercial and 

consumer products); surrogate 

exposure and hazard indices; and 

toxicity of chemical mixtures. 

(2) Methods to predict the effect of 

chemical mixtures based on outcome 

pathways. 

(3) Methods to select chemical 

mixtures for testing based on likelihood 

of toxicity. 

Research Products Contributing to These 

Outputs: 

 Linked SHEDS and PBPK modeling 

system to support Food Quality 

Protection Act (FQPA) cumulative risk 

assessments. 

 Computational method to utilize 

chemicals’ similarities in kinetics and 

dynamic (response) determinants to 

optimize clustering and interactions of 
33 

clusters of chemicals within complex 

mixtures. 

Example 2: Chemical Mixture Data, Methods 

and Models to Support Near-Term Regulatory 

Decision-Making 

Example Outputs: 

(1) Evaluation of selected compounds 

in municipal solid waste landfills. 

(2) Final data on the fate and transport 

of emerging chemicals of interest 

following land application of biosolids. 

(3) Data on the fate and transport 

of emerging chemicals of interest 

following land application of biosolids 

for mixtures identified in CSS 

cumulative risk research. 

(4) Evaluation of selected compounds 

in municipal solid waste compost. 

(5) Data, science and methods 

to support Agency decisions on 

perfl uorochemicals (PFCs). 

(6) Data, methods and science to 

inform PCB exposure and mitigate risk 

to children to support EPA regional 

decisions. 

Research Products Contributing to These 

Outputs: 

 Methods and approaches for 

evaluating the fate and transport of 

mixtures of emerging contaminants 

and selected modes of action in 

wastewater treatment in support of 

Toxic Substance Chemical Act (TSCA) 

rule making. 

 Preliminary data on the fate and 

transport of emerging chemicals of 

interest following land application 

of biosolids to support of TSCA rule 

making. 

 Data gap analysis on presence, fate 

and transport of selected compounds 

in the municipal solid waste stream. 

 Evaluation of PFC mixture effects by in 

vitro and in vivo models. 

 Market trend monitoring for PFCA 

precursors in consumer articles. 

 Data and model results for PCBs 

in schools to provide information 

needed to develop improved and costeffective mitigation and remediation 

approaches. 

Outcomes of the research for both of these 

Cumulative Risk examples: A set of predictive 

models from the cellular level to the population 

level that can be integrated into a source-tooutcome modeling platform that incorporates 

real world exposure scenarios. 

Impact 

The impact of the Cumulative Risk research 

are new data and predictive tools to inform 

risk management decisions for EPA’s 

priority regulatory, risk assessment and risk 

management decisions for chemical mixtures. 
34 

 

Theme 5. Life Cycle Considerations 

Life cycle is defined as the “cradle-to-grave” (also referred to as “cradle-to-cradle”) activities 

for a product, process, or activity, including the stages of resource acquisition, material 

manufacture, production, transportation/distribution, use, recycling/reuse and final disposal. 

Research Objective: Utilize data to inform 

the design of more sustainable, green 

chemicals by reducing their environmental 

and human health impacts while 

recognizing the need for chemicals in a 

sustainable economy. 

Science Questions 

How can life-cycle assessments and 

other innovative tools be integrated with 

more traditional methods to produce 

assessments that inform decision-making 

and identify safer and more sustainable 

approaches? 

How can life cycle assessment approaches 

and methods be applied to decision 

analysis to reduce uncertainties associated 

with the analysis of alternatives at multiple 

decision-making scales or levels? 

What are the critical components of a 

sustainability-driven paradigm for risk 

management of chemical and product 

systems that incorporate life cycle factors 

relevant to environmental, economic and 

societal issues? 

How can effective and reliable screeninglevel approaches for life-cycle assessment 

be developed that can be effi ciently and 

strategically applied to the large number of 

chemicals? 

Illustrative Outputs, Products and 

Outcomes 

strategy into a holistic approach requires 

the application of a life cycle perspective to 

incorporate sustainability into decision-making. 

The Life Cycle Considerations’ research 

outcomes will inform green chemistry design. 

Building on other CSS projects, research 

in this effort will: develop a data network to 

meet the emerging assessment needs of 

EPA program and regional offices to address 

sustainability; identify research opportunities 

with respect to the life cycle stages of a 

chemical; and serve as a platform for research 

conducted in a holistic, multi-stakeholder 

manner (e.g., initiating collaborations among 

EPA, industrial partners and stakeholders) to 

generate improved sustainability. 

Example Outputs: 

(1) A database of information about 

the life cycle of a chemical that will 

aid in incorporating sustainability in 

environmental decision-making. 

(2) A framework to help include 

sustainability in decision-making within 

the EPA using experiences from case 

studies with program offi ces and 

regions. 

(3) Reaction systems, membrane 

materials and separation processes 

will be developed using the principles 

of green chemistry to address 

sustainability in chemical processes. 

(4) Solutions will be provided and 

demonstrated for the sustainable 

Example: design, production and use of 

chemicals using the principles of green

Transforming EPA’s risk management engineering to reduce the utilization of 
35 

energy intensive chemical processes. 

(5) Innovative approaches to 

manufacturing of chemicals will be 

developed using sustainable molecular 

design, life cycle material safety and 

chemical process indicators. 

(6) The development and 

demonstration of life cycle methods for 

sustainable design practices for the 

manufacture, use and evaluation of 

commercial products. 

Research Products Contributing to These 

Outputs: 

 Preliminary sustainability database 

design based on a model case of life 

cycle inventory (LCI) generated for a 

nano-silver consumer product. 

 Extramural research to advance the 

science and application of life-cycle 

thinking and assessment for chemicals. 

This research will be conducted in 

two academic institutions under EPA’s 

Science to Achieve Results (STAR) 

Program. 

 Demonstration of the successful 

synthesis and characterization of a 

cellulose membrane with controllable 

cross-linking for application in 

sustainable water treatment. 

 Documentation (including through 

the patent development) describing 

greener production of nanomaterials to 

promote sustainable nanotechnologies 

and mitigate regulatory needs. 

 Assess biobutanol as fuel substitute 

for bioethanol to potentially lessen 

greenhouse gas emissions: 1) 

Membrane for the green separation of 

ethanol from water using combinations 

of zeolitic and polymeric materials; and 

2) Joint patent application with CRADA 

partner for butanol recovery from 

dilute solutions during manufacturing 

via membrane-based separation 

processes in response to the need of 

OTAQ (OAR). 

 Demonstration of how the 

GREENSCOPE (Gauging Reaction 

Effectiveness for the Environmental 

Sustainability of Chemistries with a 

multi-Objective Process Evaluator) 

sustainability indicator model 

can evaluate human health and 

environmental risks, for an example 

such as manufacturing of biodiesel. 

 Demonstration of how the 

GREENSCOPE sustainability indicator 

model can implement green chemistry 

principles through an in-house 

developed green chemical reaction, 

which can be applied by OSCPP in 

educational and evaluation activities 

and projects. 

 International guidance document 

on product category rules for 

environmental product claims. This 

international guidance document will 

provide direct support to the missions 

of the Office of Resource Conservation 

and Recovery (in OSWER) for 

their Sustainable Products-related 

efforts and to the Office of Pollution 

Prevention and Toxics (in OCSPP) 

for their Environmental Preferable 

Purchasing Program established 

for needs expressed within the 

cross-agency ‘Sustainable Products 

Network’. This work will support a key 

element of the ‘International Product 

Life-Cycle Partnership’ draft proposal 

for U.S. Commitment for Rio+20 being 

prepared by the Office of International 

and Tribal Affairs. 

Outcomes of the research: The identification 

of key linkages in the continuum between 

the production of a chemical, its release, fate/ 

transport of a chemical in the environment, the 

resulting exposures and adverse outcomes 

for humans and/or the environment in order 

that sustainable risk management approaches 

can be scaled up and delivered to decisionmakers. 
36 

Impact 

Chemical decision-making is better informed 

because of the information about a chemical’s 

toxicity across the entire life cycle. Safer, 

more sustainable chemicals are available and 

sustainable molecular design approaches are 

defined. 
37 

Theme 6. Extrapolation 

Extrapolation is the technique of estimating a variable outside a known range through 

calculations based on equations and models built from data based on values and variables from 

within a known range. 

Research Objective: Maximize the use of 

available data by developing approaches 

that extrapolate between (1) test organisms 

and human or ecological receptors, (2) 

test and real-world exposure durations, 

(3) laboratory to field conditions, (4) 

individuals to populations and (5) in vitro 

to in vivo health outcomes. 

Extrapolation methods are needed that 

improve the reliability and precision of 

environmental effect estimates. CSS 

research will address that, characterizing 

the uncertainty in current risk management 

decision-making that result from extrapolating 

measured data and develop new approaches 

for extrapolation. Research conducted 

under this topic will maximize the use of 

available data by developing approaches 

that extrapolate between test organisms and 

human or ecological receptors, test and realworld exposure durations and from laboratory 

to fi eld conditions. 

This research will provide methods that 

may be used across CSS topic areas for 

consistency of data interpretation and 

application. 

Science Questions 

What enhancements will be required to 

describe the impact of factors that affect 

an organism’s response to chemical 

exposure, such as life stage, gender and 

aggregate exposures? 

How can recent scientific advances help 

describe human variability, life stages and 

population groups? 

assays for toxicity testing, how can we 

extrapolate from in vitro assay response to 

in vivo response? 

Illustrative Outputs, Products and 

Outcomes 

Example 1: Extrapolation Tools 

Example Outputs: 

(1) Chemical Class-Based Expert 

Systems: Automated rule-based 

decision trees are being developed 

to predict which chemicals have the 

potential to disrupt endocrine systems. 

This is done by testing key chemicals 

within a chemical class to represent 

others, determining what is similar 

about the chemical structures and 

properties that explain their biological 

activity and writing rules that help 

categorize similar but untested 

chemicals. 

(2) Refined tools that exist for 

estimating species sensitivity to 

pesticides and other contaminants: 

Expansion to add algal toxicity data. 

(3) Refined tools that exist for 

estimating species sensitivity to 

pesticides and other contaminants: 

Expansion to add mode of action 

information. 

(4) Refined tools that exist for 

estimating species sensitivity to 

pesticides and other contaminants: 

Guidance to standardize methods. 

With the emphasis on developing in vitro (5) Population models that incorporate

sub-groups of fish or aquatic 
38 

invertebrates separated by life stage, 

age or time. 

(6) Methods and models for translating 

toxicity test endpoints into quantitative 

estimates of changes in demographic 

rates, such as fecundity and juvenile 

survival rates, for use in populationlevel risk assessment. 

Research Products Contributing to These 

Outputs: 

 Framework for extrapolating in vitro 

to in vivo effects from in silico models 

based on empirical data that predict 

unbound chemical concentrations in 

vitro from inherent chemical properties. 

 Provide definitive interspecies mode of 

action-based extrapolation models for 

predicting ecotoxicity to OCSPP. 

 Guidance for using population 

modeling endpoints in risk 

assessments for any aquatic animal 

species for which there are traditional 

toxicity data. Guidance includes an 

MS Excel model for deriving default 

population demographic parameters 

(survival rates for different life stages 

and fecundity rates) when traditional 

toxicity data are not available. 

 Avian toxicity translator model for 

extrapolation from individual to 

population level effects (basic version, 

MCnest) including a users manual and 

a technical support manual. 

Example 2: Extrapolation Methods to Support 

Environmental Decision-Making for EDCs 

Example Output: 

Methods and models to apply in vitro and in 

silico derived data to individuals. 

Research Products Contributing to This 

Output: 

 Integrated method linking endocrine 

active substance exposure in the 

environment with biological effects 

observed in in vitro and in vivo assays. 

 Guidance document on the use of 

in vitro data for predicting biological 

effects after exposure to endocrine 

active substances in non-target 

species. 

Outcomes of the research for both of these 

examples: An improved understanding of the 

utility of adverse outcome pathway models 

that provide increase confidence in the 

extrapolation of exposure and effects across 

different levels of biological organization, 

doses, genders, life stages, species and 

populations. 

Impact 

This research will provide methods that may 

be used by program offices in risk assessment 

and other decision-making and across CSS 

research themes to improve consistency of 

data interpretation and application. 
39 

Theme 7. Dashboards 

A dashboard is an interactive web site that provides access to the tools and data required to 

carry out a specific analysis or decision-related task. 

Research Objective: Produce dashboards 

that provide partners with accessible, 

useful graphical depictions of all available 

chemical data (e.g., information and 

studies) related to the user’s specific 

queries to help answer the chemicalrelated question. 

Science Questions 

What kind of tools, including 

computational, systems-based 

tools, are required to fully describe 

the overall impact of exposure on 

organisms? 

How can tools be customized to supply 

the data and information needed by 

partners to address specifi c regulatory 

and environmental questions? 

How can inherency, exposure, hazard 

and risk management options be 

integrated to supply a greater degree 

of certainty in decisions, reduced risk 

and enhanced sustainability? 

Illustrative Outputs, Products and 

Outcomes 

Example: Prototype Dashboard Development 

CSS-produced dashboards will provide 

decision-makers with web-based tools that 

produce a summary of information derived 

from chemical exposure and hazard data, 

decision-rules and predictive models. 

Dashboards will seamlessly integrate 

information from diverse sources to help 

partners arrive at more holistic and novel risk 

assessment and risk management decisions. 

Dashboard research will produce customized 

web-based tools based on the queries of 

partners using the web-based tool. 

Example Outputs: 

(1) Initial prototype dashboards 

delivered to program offi ces: Prototype 

versions of web-based dashboards for 

evaluating screening, testing, exposure 

and sustainability information relevant 

to EDSP21 (potential endocrine 

disruption), OPP21 (pesticidal 

actives, inerts and antimicrobials), 

TSCA21 (prioritizing and assessing 

new and existing chemicals), OW21 

(prioritization of chemicals for the 

PCCL/CCL and other purposes), and 

HHRA21 (Provisional Peer Reviewed 

Toxicity Value [PPRTV] and NexGen 

risk assessments). 

(2) Regular updates (6-month cycles) 

of all EPA program offi ce web-based 

dashboards, taking into account 

user feedback and new scientific 

developments. 

Research Products Contributing to These 

Outputs: 

 Prototype version 1.0 of web-based 

dashboards followed by updates every 

six months including: OPP21 (Office 

of Pesticide Programs for the 21st 

Century) dashboard for evaluating 

screening, testing, exposure and 

sustainability information relevant 

to pesticidal actives, inerts and 

antimicrobials. 

 Prototype version 1.0 of web-based 

dashboards followed by updates 

every six months including: EDSP21 

(Endocrine Disruptor Screening 

Program for the 21st Century) 
40 

dashboard for evaluating screening, 

testing, exposure and sustainability 

information relevant to potential 

endocrine disruption. 

 Prototype version 1.0 of web-based 

dashboards followed by updates every 

six months including: TSCA21 (Toxic 

Substances Control Act for the 21st 

Century) dashboard for evaluating 

screening, testing, exposure and 

sustainability information relevant to 

prioritizing and assessing new and 

existing chemicals. 

 Prototype version 1.0 of web-based 

dashboards followed by updates every 

six months including: OW21 (Offi ce of 

Water for the 21st Century) dashboard 

for evaluating screening, testing, 

exposure and sustainability information 

relevant to prioritization of chemicals 

for the Preliminary Chemical Candidate 

List (PCCL)/CCL and other purposes. 

 Prototype version 1.0 of web-based 

dashboards followed by updates every 

six months including: HHRA21 (Human 

Health Risk Assessment in the 21st 

Century) dashboard for evaluating 

screening, testing, exposure and 

sustainability information relevant to 

PPRTV and NexGen risk assessments. 

Outcomes of the research: Communicate, 

translate and transfer all available scientific 

information about chemicals in ways most 

useful to decision-makers. 

Impact 

The impact of the Dashboards research is an 

improved ability (including improved efficiency) 

for CSS partners (EDSP21, TSCA21, OPP, 

OW, etc.) to make scientifically-based 

decisions. Providing regulatory decisionmakers with user-friendly tools to access all 

available data about chemicals is critical to the 

success of EPA’s CSS research. 
41 

Theme 8. Evaluation 

This last CSS research theme evaluates the results and impact of the CSS research program. 

This effort will develop the tools needed to evaluate the reliability and uncertainty of data, 

methods and models developed under the other CSS themes for their collective ability to 

improve risk assessment and management. 

Research Objective: Provide decision 

analyses, support tools and feedback 

mechanisms that inform and enable the 

optimal delivery and use of CSS data, 

methods and models and to evaluate the 

impact of the CSS research program on 

EPA decision-making capabilities. 

Science Questions 

How have CSS research fi ndings and 

tools impacted and supported EPA’s 

decision-making? 

What are the measures needed to 

evaluate the predictive value of the 

tools (e.g., Dashboards, enhanced 

ToxCastTM) produced from the CSS 

research program? 

Do the partners find that the tools and 

other data from the CSS research 

program will improve environmental 

decision-making, including risk 

assessment? 

How can the critical pieces of 

information required for different 

assessment tiers be systematically 

identified, evaluated, integrated, 

reviewed and used in assessments 

and subsequent management 

decisions? 

Illustrative Outputs, Products and 

Outcomes 

Example: Assessing CSS Partner Needs, 

Product Utility and Program Success 

Example Outputs: 

(1) Understanding of partner needs 

and how to measure product utility; 

information obtained through pro forma 

surveys and interviews. 

(2) Overall program performance and 

success assessment of CSS research 

based on understanding of how the 

partners will benefit from CSS research 

products. 

Research Products Contributing to These 

Outputs: 

 Initial and follow-up pro forma surveys 

of program office, regional and external 

partners. 

 A program office and regional partners 

outreach and engagement plan. 

Outcomes of the research: The overall impact 

of the CSS research is assessed. CSS 

tools and information are delivered to the 

partners along with training in order that the 

partners have an ability to effi ciently apply 

the information. The CSS tools, new assays 

and scientific knowledge have increased our 

confidence in utilizing 21st century pathwaybased approaches for priority setting, toxicity 

testing and risk assessment. 

Impact 

The impact of the Evaluation work is that CSS 

products are developed in response to partner 

needs and are then delivered effi ciently to 

partners for use in Agency decisions. Further, 

the overall impact of the CSS research outputs 

(information, tools, etc.) on EPA decisionmaking will be understood. 
42 

 

Conclusion 

EPA’s Chemical Safety and Sustainable research program presents a comprehensive set 

of efforts for transforming toxicity testing and performing chemical risk assessment using 

toxicity pathway-based approaches. The combined products of the program will transform the 

paradigm of chemical safety assessment to using 21st-century tools and approaches through a 

number of key activities. 

CSS research addresses chemical testing 

needs, such as the significant numbers of 

existing and new chemicals that need to be 

tested for toxicity risks, by rapidly increasing 

the knowledge base about the key drivers of 

potential toxicity of chemicals. The heart of 

the transformation in toxicity testing requires 

intensive pathway-based research and assay 

design in order to assess human and wildlife 

health within part of a larger system (the 

ecosystem), as EPA moves to a sustainable 

molecular design approach to chemical safety. 

To improve EPA assessments, reliable, 

pathway-based biomarkers of effect will 

be developed and needed extrapolation 

methods will be developed. Risk assessment 

of multiple chemicals and exposures to 

chemicals plus nonchemical stressors, 

requires new methods and approaches 

that CSS will provide and cumulative risk 

assessment will require methods to use 

human exposure data. The program 

anticipates that the Agency will be better 

positioned to perform its mission of protecting 

human health and the environment as 

scientific information becomes digitized and 

readily available, methods and models to 

capture the complexities of chemical exposure 

and hazard in toxicity testing are developed 

and approaches focused on development of 

more sustainable alternatives are provided 

to decision-makers. Producing user-friendly 

tools, such as dashboards, will specifically 

address various partner needs in an efficient 

manner. Finally, the impact of the CSS 

research tools, data and new approaches are 

evaluated through training and feedback. 

The Strategic Research Action Plan for EPA’s 

Chemical Safety for Sustainability Research 

Program maps out a research program for the 

next five to ten years. Partner needs have 

been the driver of CSS product development. 

Communication with partners began at 

the inception of the program development 

and will continue throughout. In fact, the 

entire program has moved EPA to adopt a 

new approach to engage its partners in the 

research and development process. This 

plan, however, is a living document and will 

be updated as science evolves and decisionmakers’ needs change. 
43 

Summary Tables 

EPA’s Chemical Safety and Sustainable research program presents a comprehensive set 

of efforts for transforming toxicity testing and performing chemical risk assessment using 

toxicity pathway-based approaches. The combined products of the program will transform the 

paradigm of chemical safety assessment to using 21st-century tools and approaches through 

a number of key activities. The tables (below) are organized by research theme and within 

theme are organized by research project tasks. Each task number refers to a particular project 

task that has one or more expected outputs. Outputs were defined by partners and represent 

synthesized and/or translated research products that are in the format needed by the end user. 

These summary tables reflect the CSS research outputs as of February 2012. 

Theme 1. Inherency
 

Science Questions: What is the relationship between inherent physico-chemical properties and health 

outcomes and what data are needed to define these relationships? 

What approaches and information can best advance the understanding of physico-chemical or 

material properties of chemicals and how can this knowledge be used to predict toxicity, fate, transport, 

transformation (degradation and metabolism) and toxicologically-relevant exposures? 

How can the knowledge of inherent properties be utilized to guide the development of safer product 

design and use throughout a chemical’s life cycle? 

Outcome: Improved chemical hazard assessments based upon a deeper understanding of the relevant 

physico-chemical and other inherent properties of chemicals that influence environmental fate, exposure 

and biological responses. 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

1.1.1 (1) A resource of inherent chemical properties (ICP), molecular 

descriptors and selected biological activities for chemicals of 

interest to OCSPP. 

(2) Provide tools and methods for chemical space analysis 

and domain of applicability for models to be incorporated into 

Dashboards. 

FY16 2, 3, 4, 5, 7 

1.1.2 (1) DSSTox chemical structure files, covering EPA’s highthroughput testing programs (ToxCastTM, Tox21), eco-toxicological 

databases (ECOTOX) and FDA’s food additive database (PAFA), 

to support predictive modeling and to be incorporated into 

structure-searching tools and CSS Dashboards (see Theme 7 

below). 

FY14 2, 5, 7 

(2) Efficient structure-entry process and workflow to update 

DSSTox central structure inventory and link new structures to ICP 

properties and data in CSS Dashboard. 

FY16 2, 5, 7 

1.1.3 (1) Physico-Chemical Properties Calculator, linked to existing EPA 

models (e.g., EPI Suite, enhanced SPARC) provides molecular 

properties for building improved environmental fate & transport 

models. 

FY16 2, 5, 7 
44 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

1.1.3 (2) Integration of Physico-Chemical Properties Calculator with 

outputs of Tasks 1.1.1 and 1.1.2 to supply ICP for chemicals of 

Agency interest and to provide key properties for environmental 

fate & transport models accessed through the CSS Dashboard. 

FY16 2, 5, 7 

(3) Predict types of chemicals more likely to require metabolic 

activation to produce animal toxicity, incorporated within an 

automated workflow and linked to other ICP and toxicity related 

chemical features for use in CSS Dashboard. 

FY16 2, 5, 7 

1.2.1 (1) Nanoparticles in the environment: Methods for the detection 

and characterization to analyze metal and carbon-based 

nanoparticles in environmental matrices. 

FY16 2 

(2) Fate of nanoparticles in the environment: Data on the impacts 

of inherent particle properties and environmental conditions on 

their fate in environmental systems. 

FY16 2 

(3) Leaching of nanoparticles from products: Data on the quantities 

and speciation of nanoparticles leaching from consumer products 

containing nanomaterials. 

FY16 2 

1.2.2 (1) Nanoparticles in the environment: Bioavailablity Assessment 

Tools for nanoparticles. 

FY16 2 

(2) Transport of nanoparticles in the environment: High throughput 

protocols for estimating the transport of nanoparticles in 

environmental systems (e.g., waste water treatment plants). 

FY16 2 

(3) Transport and transformations of nanoparticles in the 

environment: Experimental and modeling tools for evaluating 

transport and transformations of nanoparticles in the environment. 

FY16 2 

(4) Exposure to nanoparticles in the environment: Data and 

relationships that can be used to link ICPs of nanoparticles to 

models that predict NP transport, transformation and exposure in 

the environment. 

FY16 2 

(5) Data on emissions produced from the use of diesel fuel 

containing ceria additive. 

FY16 2 

1.3.1 (1) Pesticide MOA profiling tool to OPP. FY15 5, 7 

(2) Database of MOAs and assignment methodology to OCSPP. FY15 5, 7 

(3) Improved MOA-based QSAR ecotoxicity models to OCSPP. FY15 5, 7 

1.3.2 (1) A molecular-based ligand-biological target resource that can be 

used to inform toxicity and in silico-in vitro-in vivo correlations and 

extrapolations. 

FY15 2, 4, 5, 7 

(2) A web-accessible (within EPA only [intranet]) in silico/knowledge 

based ADME (absorption-distribution-metabolism-elimination) 

resource in support of physiologically-based pharmacokinetic 

(PBPK) dosimetry models and exposure-dose extrapolation. 

FY15 2, 4, 5, 7 
45 

Theme 2. Systems Models 

Science Questions: What are the perturbations at all levels of biological organization, defined as a 

toxicity pathway, for environmental chemicals? 

What are the most appropriate systems models to address the chemical-related environmental 

problems of greatest impact? 

How can information be integrated into virtual organ models? 

What new tools and/or models must be developed to ensure precise and efficient hazard and exposure 

screening across the life cycle of a chemical? 

What systems models (e.g., kinetics and dynamics) must be developed and used to address the 

chemical-related environmental problems with the greatest impact? 

Outcome: Improve chemical prioritization, screening, testing and quantitative risk assessment by 

integrating information from multiple biological levels, including pathway-level information and by using 

advanced computational techniques, such as multi-scale systems models of virtual tissues, to develop 

predictive models of hazard and exposure. 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

2.1.1 (1) Connecting molecular and whole animal effects in a 

knowledgebase: Compiling information concerning the linkages 

between endpoints measured or predicted at molecular and 

cellular levels and adverse outcomes at higher levels of biological 

organization traditionally considered in risk assessments and 

regulatory decision-making (e.g., organ function in humans; 

survival, growth/development and reproduction in wildlife) 

and depositing this information into a knowledge-base (called 

Effectopedia). The initial focus will be on depositing information 

about reproductive and developmental toxicity in fish into the 

Effectopedia. 

FY16 7, 4 

(2) Predicting species effects after chemical exposure: A webbased tool to support prediction of which species are likely to be 

susceptible to adverse effects of chemicals that act on specific 

protein targets. 

FY16 6 

(3) Developing and applying adverse outcome pathway knowledge 

and filling data gaps, to support specific partner needs. 

FY16 7 

2.1.2 (1) Environmental monitoring approaches: Methods to incorporate 

biological responses of organisms exposed to environmental 

stressors into the monitoring of contaminated or remediated sites 

that are relevant to the program offices and regions. The biological 

responses used will be based on the biological pathways that are 

impacted by the exposure(s). 

FY16 3, 6 
46 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

2.1.2 (2) Best practices for surface water samples: Determining the best 

method to collect, store and transport surface waters collected 

in the environment to use in laboratory experiments that look at 

responses of living cells (not live animals) to exposure to these 

waters. These experiments will be used to test environmental 

samples for specific types of biological responses that are known 

to result in unfavorable effects that are of concern to the program 

offices and regions. 

FY16 

(3) Exposure Reconstruction Approaches: Recommendations 

regarding the best method for using biological responses (based 

on effects on biological pathways) of organisms residing in 

polluted waters to determine specific chemical exposures of these 

organisms. Use of these biological responses for determining 

what the organisms have been exposed to will help program 

offices and regions in conducting assessments and investigations 

of polluted waters. 

FY16 3 

2.2.1 A computer model to analyze effects of contaminants in food and 

water on the liver: Linkage of gene expression/pathways with 

phenotypic outcomes in the intact rodent liver. 

FY16 

2.2.2 (1) Computer models to predict effects on fetal development after 

maternal chemical exposure: Virtual embryo research integrates 

important data and scientific knowledge into sophisticated 

computer models that will simulate and predict adverse events and 

outcomes in the embryo, fetus and neonate when the mother is 

exposed to different chemicals. 

FY16 3, 6, 7 

(2) Delineating pathways of exposure and mechanisms 

of developmental toxicity using the virtual embryo for risk 

assessment: The predictions of virtual embryo simulations can be 

used to understand and test mechanisms of developmental toxicity 

across different doses, species and life stages. This understanding 

can provide guidance for life-stage specific targeted research to 

delineate pathways of exposure and mechanisms in both the fetus 

and infant. 

FY16 3, 6, 7 

(3) An integrated strategy for life-stage specific risk assessment: 

The outcomes of the research will lead to improved understanding 

of the molecular pathways and cellular processes underlying 

adverse pregnancy outcomes and better ways to assess the 

impacts of prenatal and postnatal exposure to chemicals at various 

stages of development and scales of biological organization. 

FY16 7, 8 

2.2.3 (1) Develop computer programs to predict the effects of chemicals 

on hormone activity in the body. 

FY16 3, 6, 7 

(2) Develop methods to use information about chemicals from cell 

and tissue studies to inform the effects of chemicals on hormone 

activity in the body. 

FY16 3, 6, 7 

2.3.1 (1) Consumer product use, emissions and other data for informing 

multi-tier exposure and dose analyses. 

FY15 1, 4 
47 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

(2) Physiological data and algorithms supporting the development 

of PBPK and other dose models. 

FY15 1, 4 

(3) Inputs and methods needed to model fate/transport, 

concentrations, exposures and dose to a variety of environmental 

chemicals. 

FY15 1, 4 

2.3.2 (1) Enhanced environmental models (e.g., IEMS, EFAST, PRZM/ 

EXAMS, ChemSTEER, WPEM, IAQX) that include the capacity for 

spatial and/or temporal resolution (inputs/algorithms). 

FY16 1, 3, 4, 6 

(2) Refined SHEDS & new SHEDS-Lite models FY16 1, 3, 4, 6 

(3) PK & PBPK models and toolboxes for environmental chemicals FY16 1, 3, 4, 6 

(4) Applications of linked source-to-dose models to address 

program office and regional priorities for environmental chemicals 

FY16 1, 3, 4, 6 

2.4.1 (1) Integrated systems-approaches linking exposure and outcome FY16 6 

(2) Integrated systems-approaches for predicting individual, 

population and ecosystem risk from complex patterns of chemical 

exposure. 

FY16 6 

2.5.1 (1) Data sets derived from high-throughput screening of chemicals 

on program office inventories to support the development of 

signatures, or patterns of activity, for adverse outcome endpoints 

of relevance to partners. The outcomes (endpoints) of concern 

include cancer, developmental neuro- and developmental 

immuno-, developmental, reproductive and systemic toxicity. 

FY16 

(2) Additional screening of regulatory chemical inventories 

(TSCA21, OW21, EDSP21 and OPP21) will be conducted to 

provide data sets for prioritization of chemicals on these lists using 

molecular signatures (i.e., patterns of response) 

FY16 

2.5.2 (1) Prioritization of regulatory chemical inventories (TSCA21, 

OW21, EDSP21 and OPP21) based on in vitro molecular 

signatures (patterns of response) for endpoints of cancer, 

developmental toxicity, reproductive toxicity. 

FY13 

(2) Prioritization of regulatory chemical inventories (TSCA21, 

OW21, EDSP21 and OPP21) based on in vitro molecular 

signatures (patterns of response) endpoints for systemic toxicity, 

developmental neurotoxicity and immunotoxicity. 

FY16 
48 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

2.5.3 (1) Completion of TSCA21 workplan for 500 chemicals: Rapid 

prioritization of chemicals for further safety evaluation based 

on potential for both harm and exposure. Non-animal-based (in 

vitro) tests are used to identify the degree to which a substance 

can damage living organisms (hazard) and to determine 

pharmacokinetics (how the chemicals accumulate within the 

body) and computer simulations (based on chemical structure 

-- inherency -- and mathematical models) are used to derive 

potential for human contact (exposure). The TSCA21 workplan 

for 500 chemicals will combine high-throughput hazard data, 

pharmacokinetic data and exposure simulations to determine 

chemical prioritization based upon potential risk. 

FY16 1, 4, 7 

(2) Completion of EDS21P workplan for 2000 chemicals: Rapid 

prioritization of chemicals for further safety evaluation based 

on potential for both harm and exposure. Non-animal-based (in 

vitro) tests are used to identify the degree to which a substance 

can damage living organisms (hazard) and to determine 

pharmacokinetics (how the chemicals accumulate within the body) 

and computer simulations (based on chemical structure, inherency 

and mathematical models) are used to derive potential for human 

contact (exposure. The EDSP21 workplan for prioritization of 

2000 chemicals will include both potential hazard identifi cation and 

chemical-structure-derived exposure potential simulation without 

pharmacokinetic considerations. 

FY16 1, 4, 7 

2.6.1 (1) Nanomaterials life cycle based effects. FY16 1, 4, 5, 6 

(2) Credible translatable alternative test methods, guidelines and 

endpoints that predict NM in vivo toxicity with high confidence. 

FY16 1, 3, 8 

(3) Mechanisms of injury, mode of action and AOP for HTP and 

HCS methods development. 

FY16 1, 3, 8 

(4) Nano-QSARs and inform green nano chemistry/applications. FY16 1, 5 

(5) Best current in vitro and in vivo methods for tier testing of NMs 

provided to Offices. 

FY16 1, 3, 8 

6) AOPs identifying common and sensitive biological receptors 

predictive of adverse human and ecological outcomes. 

FY16 1, 3, 5, 6, 8 

2.6.2 (1) Approaches for standardized testing of nanomaterials. FY12 1 

(2) Quantify acute toxicity of selected nanomaterials. FY13 1 

(3) Understanding of inherent properties of modifi cations that 

mediate specific nanomaterial toxicity or other effects. 

FY15 1 

(4) Identify mechanisms of action for nanomaterials, AOPs and 

recommendations for development of alternative and rapid 

throughput assays. 

FY15 1 

(5) Recommendations for the development of models linking 

inherent properties and adverse outcomes (e.g., QSARs for 

nanomaterials). 

FY16 1 
49 

Theme 3. Biomarkers 

Science Questions: How can CSS assess biomarkers that can serve as useful indicators of toxicity for 

different chemicals and endpoints such as health or wildlife outcomes? 

What are the endpoints of concern that require development of biomarkers? 

What characteristics are needed for a biomarker to be one that is informative of adverse outcomes to 

humans? 

How can the program assess biomarkers of exposure? 

What models need to be developed to better integrate biomonitoring (biomarkers and bioindicators) 

data into testing systems to help the Agency better understand environmental and health impacts? 

Outcome: EPA risk assessments are improved by the (1) consistent, justifiable and improved use of 

existing biomonitoring data (e.g., NHANES); (2) availability of dose estimation/exposure reconstruction 

methods; and (3) availability of diagnostic AOP-based biomarkers with annotations to evaluate 

published data. 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

3.1.1 (1) Holistic approaches to foster a better understanding of 

relationship between exposure metrics and biomarkers, allowing 

for potential to reconstruct exposures from biomarkers. 

FY16 2 

(2) Improved methodologies for exposure and dose estimates by 

integrating biomarker data with supporting information/data (e.g., 

exposure factors and pharmacokinetic behaviors) into predictive 

models.

 FY16 2 

3.1.2 (1) Develop and maintain a state of the art panel of biomarkers of 

effects for use by risk assessors and researchers. 

FY16 2, 7 

(2) Link biomarkers to key events in an adverse outcome pathway 

and thereby improve the diagnostic capabilities of the biomarkers 

in the panel. 

FY16 2, 7 

3.2.1 (1) Biomarker-based models for risk assessment. FY16 

(2) Biomarker-based model tools to evaluate risk management 

activities. 

FY16 
50 

 

Theme 4. Cumulative Risk 

Science Questions: What are the ecological and human health risks of combined real-world exposures 

to environmental chemicals? 

What are the chemical targets at the molecular, cellular, tissue, organ and whole animal levels? and can 

these targets be used to assess cumulative effects? 

How can recent scientific advances help describe the impacts of exposures to chemical mixtures? 

How can recent scientific advances help describe human variability (e.g., across life stages, population 

groups)? 

What kinds of tools, including computational, systems-based tools, are required to fully describe the 

overall impact of aggregate exposures on organisms? 

What enhancements will be required to describe the impact of factors that affect an organism’s 

response to chemical exposure, such as life stage, gender and aggregate exposures? 

What new methods/models are needed to account for exposure from all sources and pathways? 

Outcome: A set of predictive models from the cellular level to the population level that can be 

integrated into a source-to-outcome modeling platform that incorporates real world exposure scenarios. 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

4.1.1 (1) Predictive tools for identifying and prioritizing real-world 

mixtures of stressors (environmental, residential, SES, diet, etc.) 

based on: Sources (including commercial and consumer products); 

Surrogate exposure and hazard indices; and Toxicity of chemical 

mixtures. 

FY15 2, 3 

(2) Examination and optimization of prototypical AHHS and CCS 

survey study designs to document real-world mixtures spatially 

and temporally. 

FY15 2, 3 

4.1.2 1) Methods to predict the effect of chemical mixtures based on 

outcome pathways. 

FY15 2 

(2) Methods to select chemical mixtures for testing based on 

likelihood of toxicity. 

FY16 2 

4.1.3 (1) Evaluation of selected compounds in municipal solid waste 

landfills. 

FY16 

(2) A reduced list of "indicator chemicals" for routine monitoring 

of emerging contaminants in wastewater and receiving waters in 

support of regulatory policy for limits of discharge. 

FY16 2 

(3) Final data on the fate and transport of emerging chemicals of 

interest following land application of biosolids. 

FY16 
51 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

(4) Weight of evidence approach using "indicator chemicals" 

and selected MOA based bioassays to assess the effi cacy of 

risk management of emerging contaminants in wastewater and 

receiving waters. 

FY16 2 

(5) Evaluation of selected compounds in municipal solid waste 

compost. 

FY16 

(6) Data on the fate and transport of emerging chemicals of 

interest following land application of biosolids for mixtures 

identified in CSS cumulative risk research. 

FY16 

4.2.1 Science from the InterAgency Agricultural Health Study (AHS) for 

use by EPA 

FY16 

4.2.2 (1) Data, science and methods to support Agency decisions on 

perfl uorochemicals (PFCs). 

FY17 

(2) Data, methods and science to inform PCB exposure and 

mitigate risk to children to support EPA regional decisions. 

FY13 

(3) Data, science and tools to support OPPT's rulemaking for 

formaldehyde. 

FY17 

(4) Data, methods and models for understanding exposure and 

effects from indoor source emissions for Spray Polyurethane Foam 

(SPF)-based products. 

FY16 

(5) Data, case studies and guidance to support EPA next 

generation assessments for the Integrated Risk Information 

System (IRIS), PPRTV and Integrated Science Assessment (ISA) 

programs. 

FY15 

(6) Social science research on the consumer behavior patterns 

and trends and how these influence consumer product use and 

resulting chemical exposure. 

FY17 
52 

Theme 5. Life Cycle Considerations 

Science Questions: How can life-cycle assessments and other innovative tools be integrated with 

more traditional methods to produce assessments that inform decision making and identify safer and 

more sustainable approaches? 

How can life cycle assessment approaches and methods be applied to decision analysis to reduce 

uncertainties associated with the analysis of alternatives at multiple decision-making scales or levels? 

What are the critical components of a sustainability-driven paradigm for risk management of chemical 

and product systems that incorporate life cycle factors relevant to environmental, economic and societal 

issues? 

How can effective and reliable screening-level approaches for life-cycle assessment be developed that 

can be efficiently and strategically applied to the large number of chemicals? 

Outcome: The identification of key linkages in the continuum between the production of a chemical, 

its release, fate/transport of a chemical in the environment, the resulting exposures and adverse 

outcomes for humans and/or the environment so that sustainable risk management approaches can be 

scaled up and delivered to decision-makers. 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

5.1.1 A database of information about the life cycle of a chemical that 

will aid in incorporating sustainability in environmental decisionmaking.

 FY16 7, 8 

5.1.2 A framework to help include sustainability in decision-making within 

the EPA using experiences from case studies with program offices 

and regions. 

FY16 1, 7, 8 

5.2.1 Reaction systems, membrane materials and separation processes 

will be developed using the principles of green chemistry to 

address sustainability in chemical processes. 

FY16 1, 2, 4, 7 

5.2.2 Solutions will be provided and demonstrated for the sustainable 

design, production and use of chemicals using the principles of 

green engineering to reduce the utilization of energy intensive 

chemical processes. 

FY14 4, 7 

5.2.3 Innovative approaches to manufacturing of chemicals will be 

developed using sustainable molecular design, life cycle material 

safety and chemical process indicators. 

FY16 1, 2, 4, 7 

5.2.4 The development and demonstration of life cycle methods for 

sustainable design practices for the manufacture, use and 

evaluation of commercial products. 

FY16 7 
53 

Theme 6. Extrapolation 

Science Questions: What enhancements will be required to describe the impact of factors that affect 

an organism’s response to chemical exposure, such as life stage, gender and aggregate exposures? 

How can recent scientific advances help describe human variability, life stages and population groups? 

With the emphasis on developing in vitro assays for toxicity testing, how can we extrapolate from in vitro 

assay response to in vivo response? 

Outcome: An improved understanding of the utility of adverse outcome pathway models that provide 

increase confidence in the extrapolation of exposure and effects across different levels of biological 

organization, doses, genders, life stages, species and populations. 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

6.1.1 Chemical class-based expert systems: Automated rule-based 

decision trees are being developed to predict which chemicals 

have the potential to disrupt endocrine systems. This is done 

by testing key chemicals within a chemical class to represent 

others, determining what is similar about the chemical structures 

and properties that explain their biological activity and writing 

rules that help categorize similar but untested chemicals. The 

program offices use these tools to decide which, of the hundreds 

of chemicals on Agency chemical lists, should be evaluated first 

because they are most likely to disrupt one of these endocrinemediated pathways.

 FY16 1, 2, 7 

6.1.2 Methods and models to apply in vitro and in silico derived data to 

individuals. 

FY15 2 

6.1.3 Predicting chemical impacts using computational models and 

small-scale experiments: Validated methods and models for 

interpretation and extrapolation of data generated by in vitro 

and small-scale in vivo systems designed to test interactions of 

chemicals with biological pathways or targets.

 FY16 1, 2, 4, 5 

6.2.1 (1) Refined tools that exist for estimating species sensitivity to 

pesticides and other contaminants: Expansion to add algal toxicity 

data. 

(2) Refined tools that exist for estimating species sensitivity to 

pesticides and other contaminants: Expansion to add mode of 

action information. 

(3) Refined tools that exist for estimating species sensitivity to 

pesticides and other contaminants: Guidance to standardize 

methods. 

FY14 2 

6.2.2 Population models that incorporate sub-groups of fish or aquatic 

invertebrates separated by life stage, age or time. 

FY15 2 
54 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

6.2.3 Methods and models for translating toxicity test endpoints into 

quantitative estimates of changes in demographic rates, such as 

fecundity and juvenile survival rates, for use in population-level risk 

assessment. 

FY16 2 
55 

Theme 7. Dashboards 

Science Questions: What kind of tools, including computational, systems-based tools, are required to 

fully describe the overall impact of exposure on organisms? 

How can tools be customized to supply the data and information needed by partners to address specific 

regulatory and environmental questions? 

How can inherency, exposure, hazard and risk management options be integrated to supply a greater 

degree of certainty in decisions, reduced risk and enhanced sustainability? 

Outcome: Communicate, translate and transfer all available scientific information about chemicals in 

ways most useful to decision-makers. 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

7.1.1 Process developed used to gather scientific information that EPA 

risk assessors need to make environmental decisions. This will 

help us build useful decision support tools for partners. 

FY14 

7.1.2 We will support existing ORD databases and tools used by 

decision-makers: Maintenance, data input and upgrade of support 

tools. 

FY16 

7.1.3 Prototype dashboard (decision support tools) for OPP to support 

ecological risk assessment is delivered. This dashboard will 

expand and update current OPP decision support tools. 

FY15 

7.1.4 (1) Initial prototype dashboards delivered to program offices: 

Prototype versions of web-based dashboards for evaluating 

screening, testing, exposure and sustainability information relevant 

to EDSP21 (potential endocrine disruption), OPP21 (pesticidal 

actives, inerts and antimicrobials), TSCA21 (prioritizing and 

assessing new and existing chemicals), OW21 (prioritization 

of chemicals for the PCCL/CCL and other purposes), HHRA21 

(PPRTV and NexGen risk assessments). 

(2) Initial prototype dashboards delivered to program offices: 

Regular updates (6-month cycles) of all EPA program offi ce webbased dashboards, taking into account user feedback and new 

scientifi c developments.

 FY16 

7.2.1 (1) Dashboards for environmental decision-making: Identification 

of databases decision-makers use the most. 

(2) Dashboards for environmental decision-making: Different 

databases will be combined to provide this information in 

dashboards using web-services (i.e., computer programs web sites 

use to send information to web-browsers). 

FY16 1, 2, 3, 4, 5, 

6, 8 

7.2.2 Dashboards for environmental decision-making: Computer 

programs developed that translate and combine information 

from different databases using ontologies (i.e., dictionaries that 

computer programs use to organize and link databases). 

FY16 1, 2, 3, 4, 5, 

6, 8 
56 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

7.2.3 Dashboards for environmental decision-making: Software 

developed to build dashboards for web browsers and to get 

information from databases using web-services. Free tools will be 

used that we can easily reuse and maintain. 

FY16 1, 2, 3, 4, 5, 

6, 8 

7.2.4 (1) Dashboards for environmental decision-making: Identify 

computer models decision-makers use to forecast how chemicals 

spread in the environment and affect living things. 

(2) Dashboards for environmental decision-making: Develop 

software that makes it easy to use these computer models from 

web-based dashboards. 

FY16 1, 2, 3, 4, 5, 

6, 8 
57 

Theme 8. Evaluation 

Science Questions: How have CSS research findings and tools impacted and supported EPA’s 

decision making? 

What are the measures needed to evaluate the predictive value of the tools (e.g., Dashboards, 

enhanced ToxCastTM) produced from the CSS research program? 

Do the partners find that the tools and other data from the CSS research program will improve 

environmental decision making, including risk assessment? 

How can the critical pieces of information required for different assessment tiers be systematically 

identified, evaluated, integrated, reviewed and used in assessments and subsequent management 

decisions? 

Outcome: The overall impact of the CSS research is assessed. CSS tools and information are 

delivered to the partners along with training in order that the partners have an ability to effi ciently apply 

the information. The CSS tools, new assays and scientific knowledge have increased our confidence 

in utilizing 21st century pathway-based approaches for priority setting, toxicity testing and risk 

assessment. 

Task 

No. 

Outputs Output

Year 

Relevance to 

other 

CSS Themes 

8.1.1 (1) Understanding of partner needs and how to measure product 

utility; information obtained through pro forma surveys and 

interviews. 

FY12 7 

(2) Overall program performance and success assessment of CSS 

research based on understanding of how the partners will benefit 

from CSS research products. 

FY16 

8.1.2 Overall program performance and success assessment of CSS 

research based on understanding of how the partners will benefit 

from CSS research products. 

FY16 

8.2.1 (1) CSS product utility improved through regular communication 

with partners and employment of partner-informed utility metrics. 

FY16 5, 7 

(2) Identification of best practices for future projects and potential 

future impacts of CSS Program products. 

FY16 7 

8.2.2 Identification of best practices for future projects and potential 

future impacts of CSS Program products. 

FY16 7 

8.2.3 Identification of best practices for future projects and potential 

future impacts of CSS Program products. 

FY16 7 
58 

References 

Council on Environmental Quality, 1969. 

National Environmental Policy Act. Available 

at: http://ceq.hss.doe.gov/nepa/regs/nepa/ 

nepaeqia.htm 

Executive Office of the President, 9 June 

2011. Policy principles for the U.S. decisionmaking concerning regulation and oversight 

of applications of nanotechnology and 

nanomaterials. Memorandum for the Heads 

of Executive Departments and Agencies. 

Available at: www.whitehouse.gov/ 

General Accounting Office (GAO), 2009. 

Biomonitoring: EPA Needs to Coordinate Its 

Research Strategy and Clarify Its Authority to 

Obtain Biomonitoring Data (Report 09 353). 

Available at: http://www.gao.gov/new.items/ 

d09353.pdf 

Judson, R., Richard, A., Dix, D., Houck, K., 

Martin, M., Kavlock, R., Dellarco, V., Henry, T., 

Holderman, T., Sayre, P., Tan, S., Carpenter, 

T., and Smith, E., 2009. The Toxicity Data 

Landscape for Environmental Chemicals. 

Environmental Health Perspectives 17(5): 685-

695. 

National Nanotechnology Initiative (NNI), 

2011. NNI Environmental Health and Safety 

Research Strategy. Available at: http://www. 

nano.gov/node/681 

National Research Council (NRC), 2006. 

Human Biomonitoring for Environmental 

Chemicals. Washington, DC: The National 

Adademies Press. Available at: http://www. 

nap.edu/catalog/11700.html 

National Research Council (NRC), 2007. 

Toxicity Testing in the 21st Century: A Vision 

and a Strategy. Washington, DC: The National 

Adademies Press. Available at: http://www. 

nap.edu/openbook.php?record_id=11970 

National Research Council (NRC), 2009. 

Science and Decisions: Advancing Risk 

Assessment. Washington, DC: The National 

Academies Press.
 

National Research Council (NRC), 2012. 

A Research Strategy for Environmental, 

Health and Safety Aspects of Engineered 

Nanomaterials. Washington, DC: The National 

Academies Press. Available at: http://www.
 

nap.edu/catalog.php?record_id=13347
 

Organisation for Economic Co-operation and 

Development (OECD), 2001. Environmental 

Strategy for the First Decade of the 21st 

Century. Adopted by OECD Environment 

Ministers. 16 May 2001. Available at: http://
 

www.oecd.org/dataoecd/33/40/1863539.pdf
 

U.S. EPA, 2003a. A Framework for a 

Computational Toxicology Research Program 

in ORD. EPA/600/R-03/065. US Environmental 

Protection Agency, Office of Research and 

Development, Washington, DC. Available at: 

http://www.epa.gov/ncct/download_files/basic_ 

information/comptoxframework06_02_04.pdf 

U.S. EPA, 2003b. Framework for Cumulative 

Risk Assessment. EPA/630/P-02/001F. Risk 

Assessment Forum. U.S. Environmental 

Protection Agency. Washington, DC. Available 

at: oaspub.epa.gov/eims/eimscomm.getfile?p_ 

download_id=36939 

U.S . EPA, 2009. The U.S. Environmental 

Protection Agency’s Strategic Plan for 

Evaluating the Toxicity of Chemicals, 

EPA/100/K-09/00. US Environmental 

Protection Agency, Office of Research and 

Development, Washington, DC. Available at: 

http://www.epa.gov/spc/toxicitytesting/docs/ 

toxtest_strategy_032309.pdf 

U.S. EPA, 2010. A Set of Scientifi c Issues 

Being Considered by the Environmental 

Protection Agency Regarding: SHEDSMultimedia version 4, Peer Consult on PBPK 
59 

 

Modeling and a SHEDS-PBPK Permethrin 

Study. FIFRA Scientifi c Advisory Panel 

Meeting, July 20-22, 2010, Arlington, Virginia, 

SAP Minutes No. 2010-06. Available at: http:// 

www.epa.gov/scipoly/sap/meetings/2010/ 

july/072010minutes.pdf 

U.S. EPA, 2011a. Framework for an 

EPA Chemical Safety for Sustainability 

Research Program. US Environmental 

Protection Agency, Office of Research and 

Development, Washington, DC. Available 

at: http://www.epa.gov/ord/priorities/docs/ 

CSSFrameworkMarch2011WorkingDocument. 

pdf 

U.S. EPA, 2011b. Endocrine Disruptor 

Screening Program for the 21st Century: 

(EDSP21 Work Plan) The Incorporation of in 

silico Models and in vitro High Throughput 

Assays in the Endocrine Disruptor Screening 

Program (EDSP) for Prioritization and 

Screening Summary Overview A Part of the 

EDSP Comprehensive Management Plan. 

Office of Chemical Safety and Pollution 

Prevention, US Environmental Protection 

Agency, Washington, DC. Available at: http:// 

www.epa.gov/endo/pubs/edsp21_work_plan_ 

summary%20_overview_final.pdf. 

U.S. EPA 2012. Basic information about 

the Toxic Substance Control Act Inventory. 

Office of Pollution, Prevention and Toxics 

(OPPT) in the Office of Chemical Safety and 

Pollution Prevention (OCSPP), Washington, 

DC. Available at: http://www.epa.gov/oppt/ 

existingchemicals/pubs/tscainventory/basic. 

html#background. (accessed July 27, 2012). 

Websites: 

EPA’s Computational Toxicology Research: 

http://www.epa.gov/ncct/ 

EDSP: EPA’s Endocrine Disruptor Screening 

Program; http://www.epa.gov/endo/index.htm 

EPA’s Green Chemistry: www.epa.gov/ 

greenchemistry/ 

NEPA: National Environmental Policy Act; 

http://ceq.hss.doe.gov/nepa/regs/nepa/ 

nepaeqia.htm 

NexGen: Advancing the Next Generation of 

Risk Assessment; http://www.epa.gov/risk/ 

nexgen/ 

NNI: National Nanotechnology Initiative; www. 

nano.gov 

REACH: The European Community Regulation 

for the Registration, Evaluation, Authorisation 

and Restriction of Chemical substances; 

http://ec.europa.eu/environment/chemicals/ 

reach/reach_intro.htm 

TSCA: www.epa.gov/lawsregs/laws/tsca.html 
60 

Appendix A. Research Program Partners 

and Stakeholders 

EPA Program and Regional Partners in the 

CSS Program: 

 Innovation Team (ORD) 

 National Center for Environmental 

Assessment (ORD) 

 National Center for Environmental 

Economics (OPEI) 

 Office of Air and Radiation (OAR) 

 Office of Chemical Safety and Pollution 

Prevention (OCSPP) 

 Office of Children’s Health Protection 

(OCHP) 

 Office of Environmental Information (OEI) 

 Office of the Science Advisor (OSA) 

 Office of Solid Waste Emergency 

Response (OSWER) 

 Office of Water (OW) 

 Regions 2, 5, 6, 8 and 9 

External Stakeholders: 

 Idealscale invites to +1000 Organizations 

 Webinars to Stakeholders 

 Participants included: 

o ACC 

o CropLife 

o EDF 

o HSUS 

o NRDC 

U.S. Federal and State Government 

Agencies and Committees: 

 ATSDR/CDC 

 California Air Resources Board (ARB) 

 CPSC 

 Extramural Nano Consortium 

 National Toxicology Program, NIEHS 

 NCI 

 NIEHS/NTP 

 NIHCGC 

 NIH, NCI, National Nano-Characterization 

Center 

 NIST 

 NNI 

 Oak Ridge National Laboratory Center for 

Nanophase Materials Sciences (CNMS 

 State of Illinois 

 US Army Corps of Engineers 

 USDA 

 U.S. FDA 

 USFWS 

 USGS 

International and Foreign Agencies and 

Organizations: 

 CAAT-Europe 

 Department of Environment, Food and 

Rural Affairs (DEFRA), UK 

 Environment Canada 

 European Chemical Agency (ECA) 

 European Commission Joint Research 

Centre 

 Finnish Centre for Alternative Methods 

(FICAM) 

 Institute for Health and Consumer 

Protection (JRC) 

 International Standardization Organization 

(ISO) 

 Korea National Institute of Environmental 

Research (NIER) 

 National Institute for Environmental 

Sciences (Japan) 

 Netherlands Organisation for Applied 

Scientifi c Research (TNO) 

 OECD 

Nongovernmental Organizations and 

Corporations: 

 4 Rivers 

 Agilent Technologies 

 American Center for Life Cycle 

Assessment 

 Astellas Pharma Inc. 

 NIOSH  BASF
 
61 

 

 Biomathematics Consulting 

 ChemScreen 

 Cytek 

 DOW Chemical Co. 

 DuPont 

 Dupont Haskell Labs 

 Emery Oleochemical 

 GlaxoSmithKline 

 Global Electric Electronics Processing 

(GEEP) Inc. 

 Hoffman-LaRoche Inc 

 ILSI/HESI 

 Interface, Inc. 

 L’OREAL 

 Membrane Technology and Research 

(MTR) 

 Merck 

 NanoRelease program of ILSI 

 Osmose 

 Pfi zer Inc. 

 Polyone Corporation 

 Product Carbon Footprint World Forum 

 Sanofi Aventis 

 Shimadzu 

 Stemina Biomarker and Discovery 

 Syngenta Crop Protection, Inc. 

 ThalesNano 

 The Hamner Institutes 

 Toxicology Excellence for Risk Assessment 

(TERA) 

 USEtox (www.usetox.org) 

 Warner-Babcock 

 World Resources Institute 

 World Wildlife Fund 

Universities (some funded via EPA’s NCER 

STAR program): 

Arizona State University 

Baylor University 

Clemson University 

Colorado School of Mines 

Duke University 

Duke University Center for the 

Environmental Implications of Nano 

Technology (CEINT) 

Fraunhofer Institute of Toxicology and 

Experimental Medicine (ITEM) 

Indiana University 

Johns Hopkins University 

Kunming University of Science and 

Technology (China) 

Michigan State University 

Mississippi State University 

MIT 

Northern Arizona University 

Oregon Health and Sciences University 

Oregon State University 

Purdue University 

Rice University 

Texas A&M University 

UC Berkeley University of Pannonia 

(Hungary) 

UCLA 

University of Aarhus (Denmark) 

University of Arizona 

University of Bern (Switzerland) 

University of Cincinnati 

University of Georgia 

University of Houston 

University of Maryland 

University of Michigan 

University of North Carolina-Chapel Hill 

University of St. Thomas 

University of Texas-Austin 

University of Toronto at Scarborough 

Virginia Commonwealth University 

Virginia Tech 

Yale University 
62 

 

 

Appendix B. Definitions
 

Aggregate Exposure: Aggregate exposure 

and risk assessment involve the analysis of 

exposure to a single chemical by multiple 

pathways and routes of exposure (from 2001 

EPA/OPP Document). 

Adverse Outcome Pathway (AOP): The 

linkage of adverse effects to perturbations in 

specific toxicity pathways. 

Biomarker or biological marker: A chemical 

or biological characteristic that is measured 

or evaluated as an indicator of a biological 

process and used as a marker of exposure or 

effect. 

Chemicals: Intentionally produced or 

manufactured chemicals, particle and 

material, as well as a product into which 

they are incorporated. It may refer to single 

chemicals, particles, or materials, or mixtures 

of chemicals, particles and/or materials, 

products, as well as forms of chemicals that 

are transformed as they move through the 

environment. 

Computational Toxicology: The application 

of mathematical and computer models and 

molecular biological approaches to predict 

chemical hazards and risks to human health 

and the environment. 

Cumulative Risk: The combined risks from 

aggregate exposures to multiple agents or 

stressors (EPA, 2003b). 

Cumulative Risk Assessment: An analysis, 

characterization and possible quantification 

of the combined risks to health or the 

environment from multiple agents or stressors 

(EPA, 2003b). 

Dashboard: An interactive web site that 

provides access to tools and data that are 

required to carry out a specific analysis or 

decision-related task. 

Endocrine Disrupting Chemical (EDC): 

An exogenous agent that interferes with the 

activity (via effects at the level of synthesis, 

secretion, transport, binding, action, or 

elimination) of hormones in the body which are 

responsible for the regulation of development 

and the maintenance of homeostasis of 

numerous organs and physiological systems 

(e.g., reproduction and behavior). 

Extrapolation: Estimate of the value of a 

variable outside a known range calculated 

using a model or an equation based on values 

within a known range. 

High-Throughpu t System (HTS): in vitro 

biochemical or cellular assays that can be run 

quickly and efficiently (i.e., high-throughput) 

on a large number of compounds to determine 

their activity on biological targets. 

Inherency: The physical, chemical and 

biological properties of a chemical, chemical 

formulation, or product that influence 

exposure, effects and sustainability. 

Inherent Chemical Properties (ICP): 

Inherent physical and chemical properties. 

Life Cycle: The “cradle to grave” (also 

referred to as “cradle to cradle”) activities 

for a product, process, or activity including 

the stages of resource acquisition, material 

manufacture, production, transportation/ 

distribution, use, recycling/reuse and final 

disposal. 

Life Cycle Assessment (LCA): A holistic way 

to consider multiple environmental and human 

health issues associated with a product or a 

process from resource acquisition through 

manufacture, transportation, distribution and 

use, to waste management and disposal. 

Applied to chemical design and manufacturing, 

the results of an LCA along with understanding 

potential social and economic implications of 

a product or process system provide the basis 

for moving toward sustainability. 
63 

 

Life Cycle Inventory (LCI): A database 

of individual life cycle accounting of the 

energy and material flows into and out of 

the environment that are associated with 

producing a material, component, or assembly. 

Nanomaterial: A nanoscale material or 

material that contains nanoscale structures 

internally or on their surfaces. These can 

include engineered nano-objects, such as 

nanoparticles, nanotubes and nanoplates and 

naturally occurring nanoparticles, such as 

volcanic ash, sea spray and smoke (from the 

National Nanotechnology Initiative; www.nano. 

gov). 

Nanoscale: The dimensional range of 

approximately 1 to 100 nanometers (nm) (1 

nm is equivalent to one billionth or 10-9 of a 

meter; from the National Nanotechnology 

Initiative; www.nano.gov). 

Nanotechnology: Nanotechnology is 

the understanding and control of matter 

at the nanoscale, at dimensions between 

approximately 1 and 100 nanometers, where 

unique phenomena enable novel applications 

(from the National Nanotechnology Initiative; 

www.nano.gov). 

Outcome: The expected results, impacts, or 

consequence that a Partner or Stakeholder will 

be able to accomplish due to ORD research. 

Output: Synthesized and/or translated from 

Products into the format needed by the End 

User. Outputs should be defined, to the extent 

possible, by Partners/Stakeholders during 

Problem Formulation. 

Physico-chemical properties: Measurable 

characteristics of chemical substances 

relating to physical (e.g., boiling point, mass, 

conductivity) and chemical properties (e.g., 

reactivity, heat of combustion, water solubility), 

also encompassing computable properties 

based on molecular structures. 

Product: A deliverable that results from 

a specific Research Project or Research 

Task. This may include (not an exhaustive 

list) journal articles, reports, databases, 

test results, methods, models, publications, 

technical support, workshops, best practices, 

patents, etc. These may require translation or 

synthesis for inclusion as an Output. 

Rare earth elements (REE): Comprised of 

scandium, yttrium and 15 lanthanide elements, 

of which, cerium, lanthanum and neodymium 

are the most abundant. They are found in 

several minerals; almost all production comes 

from less than 10 minerals, primarily monazite 

and bastnasite. 

Stochastic Human Exposure and Dose 

Simulation (SHEDS): A flexible and broadly 

applicable probabilistic model to estimate 

exposure and dose. 

Sustainability: To create and maintain 

conditions, under which humans and 

nature can exist in productive harmony, that 

permit fulfilling the social, economic and 

other requirements of present and future 

generations (Council on Environmental 

Quality, 1969). 

Sustainable molecular design: Using 

established principles of chemistry and 

engineering to build chemicals with the end 

goal of removing the inherent health and 

environmental risks of the chemical. 

Systems Model: Multiple level or scale 

models that predict or simulate exposure or 

effects of complex biological or environmental 

systems. 

ToxCastTM: A cost-effective approach, for 

rapidly prioritizing in vivo toxicity testing of 

large numbers of chemicals developed by the 

EPA’s Office of Research and Development, 

that integrates data from state-of-the-art 

high-throughput system bioassays to build 

computational models to forecast the potential 

human toxicity of chemicals. 

Toxicity Pathways: Cellular and molecular 

processes and functions that can be perturbed 

by chemical exposure leading to abnormal 

biological function. 

Workbench: A complex dashboard that allows 

customization of the set of tools and the 

workflow for using them. 
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