Children's
           Environmental Health
                     RESEARCH ROADMAP
Office of Research and Development

Research Roadmap: Children's Environmental Health
United States
Environmental Protection
Agency

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                                   EPA601/R-15/001
Children's Environmental Health (CEH)
          Research Roadmap
         U.S. ENVIRONMENTAL PROTECTION AGENCY
         OFFICE OF RESEARCH AND DEVELOPMENT

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Table  of  Contents
Authors and Contributors	ill

Executive Summary	1

Introduction	4

     Background	4

       Current Drivers for CEH Research	9

     Purpose	14

Research Scope	17

     Expanded Problem Statement	17

     CEH Research Areas	19

       Research Area 1:  Knowledge infrastructure to address the problem that information and
       data are distributed and difficult to access	19

       Research Area 2:  Systems understanding of the relationship between environmental
       exposures and health outcomes across development	20

       Research Area 3:  Methods and models to evaluate early lifestage-specific risks and to
       support decisions protective of all lifestages	21

       Research Area 4:  Translational research and tools to support community actions and
       decisions	22

     Research Alignment  and Coordination	23

Cross-Cutting ORD Research	25

     Current ORD Research	25

       Research Area 1:  Knowledge Infrastructure to address the problem that information and
       data are distributed and difficult to access	25

       Research Area 2:  Systems understanding of the relationship between environmental
       exposures and health outcomes across development	27

       Research Area 3:  Methods and models to evaluate early lifestage-specific risks and to
       support decisions protective of all lifestages	31

       Research Area 4:  Translational research and tools to support community actions and
       decisions	33

       Summary of ORD  CEH Research Partnerships	38

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Research Gaps and Priority Research Needs	40

       Research Area 1: Knowledge infrastructure to address the problem that information
       and data are distributed and difficult to access	41

       Research Area 2: Systems understanding of the relationship between environmental
       exposures and health outcomes across development	42

       Research Area 3: Methods and models to evaluate early lifestage-specific risks and to
       support decisions protective of all lifestages	43

       Research Area 4: Translational research and tools to support community actions and
       decisions	44

     Informing 2016-2019 ORD Research Planning	45

       Conceptual Framework	45
       Conceptual Approach	46

Summary	55

References	56

Appendices

Appendix A. ORD's Current Research Activities	60

       Research Area 1: Knowledge infrastructure to provide early lifestage-specific data and
       information	60

       Research Area 2: Systems understanding of the relationship between environmental
       exposures and health outcomes across development	61

       Research Area 3: Methods and models to evaluate early lifestage-specific risks and to
       support decisions protective of all susceptible and vulnerable early lifestages	62

       Research Area 4: Translational research and tools fit for purpose to support community
       actions and decisions	62

Appendix B. Literature Search of ORD CEH Activities	87

Appendix C. CEH Tools and Databases	102

Appendix D. Environmental Stressors and Childhood Disorders	104

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Authors and  Contributors

U.S. EPA ORD CEH Roadmap Working Group Members

Elaine Cohen Hubal, Ph.D., Working Group Chair

Tina Bahadori, Sc.D.
Richard Callan, M.P.H.
Sally Darney, Ph.D.
Jan Dye, DVM, Ph.D.
Stephen Edwards, Ph.D.
Michael Firestone, Ph.D.
Stiven Foster, M.S.
Janet Gamble, Ph.D.
Andrew Geller, Ph.D.
Maureen Gwinn, Ph.D., DABT
Erin Mines, Ph.D.
Ronald Mines, Ph.D.
Sid Hunter, Ph.D.
Annie Jarabek, Ph.D.
John Kenneke, Ph.D.
Thomas Knudsen, Ph.D.
Danelle  Lobdell, Ph.D.
Michael McDonald, Ph.D.
Jacqueline Moya, B.S.
James Quackenboss, Ph.D.
Kathleen Raffaele, Ph.D.
NishaSipes, Ph.D.
Emily Snyder, Ph.D.
Nicolle Tulve, Ph.D.
Tim Watkins, M.S.
Alan Vette, Ph.D.
John Wambaugh,  Ph.D.

Support

Susan Goldhaber,  M.P.H.
SBG Consulting, Inc., Raleigh, NC

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Executive  Summary
EPA's Office of Research and Development's (ORD) National Research Programs (Air, Climate, and
Energy; Safe and Sustainable Water Resources; Sustainable and Healthy Communities; Chemical
Safety for Sustainability; Human Health Risk Assessment; and Homeland Security are aligned on
the core principle of sustainability and are designed to provide the solutions the Agency and the
nation need to meet today's complex environmental and human health challenges. Inevitably,
important scientific issues will arise that cut across these six programs. Rather than create addi-
tional research programs for every cross-cutting issue, ORD is developing Research Roadmaps to
clearly identify the science questions and associated research efforts that are ongoing in the six
programs. These Roadmaps identify scientific gaps that inform the National Research  Programs
in the development of their Strategic Research Action Plans. As new high-priority, cross-cutting
issues emerge, ORD expects to use this approach to integrate existing research efforts and to
identify needed work. Specific research products/deliverables are  not included in the Roadmap, as
these may change as a result of ORD's planning and budgeting each year. However, ORD will use
the EPA website to provide details regarding research products associated with implementation of
this Roadmap. This Roadmap is devoted specifically to the issue of children's environmental health
(CEH).

Sustainable decisions and actions are those that improve the well-being of individuals and com-
munities today without compromising the health and welfare of future generations. The current
EPA Administrator has committed  "to engaging closely with states, tribes, local partners, federal
agencies and business and industry leaders in the most pragmatic, collaborative and flexible way
possible to achieve environmental benefits for our children and future generations." (U.S. EPA,
2014h). To meet this commitment, the Agency and stakeholders require information and tools to
incorporate consideration of early lifestage sensitivity, susceptibility, and vulnerability to support
sustainable decisions and actions.

Today, there is increasing public awareness and concern around the prevalence of children's
health outcomes in the United States, and a desire to understand the potential role of environ-
mental factors on those outcomes. Recent high visibility research publications have identified as-
sociations between environmental factors and  risk of diseases, including asthma, autism spectrum
disorder, and childhood obesity. To date, research in this area has  been limited and the complexity
of exposures,  disease etiology, and health outcomes make it difficult to evaluate and interpret
associations between  exposures and environmental factors.  However, as a result of high-profile
reports of links between CEH and environmental factors, including air pollution and chemicals in
consumer products, the public is looking to the Agency to address or mitigate these environmen-
tal factors. While evidence is building of important links between CEH and environmental factors,
the science in many cases is still far from actionable. More efficient and effective approaches are
needed to develop an understanding of the biological basis of complex environmental disease to
support intervention and prevent effects.

The challenge facing the Agency is to evaluate emerging scientific  evidence and to fill  in gaps re-
quiring the identification of key environmental factors related to CEH, where the Agency can take
action. Specifically, what modifiable environmental factors are amenable to practical change using

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available technologies, policies, and preventive and public health measures? Within this context,
CEH research is conducted by ORD to inform, support, and evaluate regulatory decisions protec-
tive of children's health now and in the future; community decisions that protect and promote
children's health across generations; and, ecological decisions that provide sustainable healthy
environments for children. The goal is to enable and extend the Agency's ability to take actions
that minimize early-life exposures for optimal well-being across all developmental lifestages, from
preconception through puberty and into adulthood, recognizing that adverse consequences of
exposure may not manifest until later in life.

ORD is investing heavily in CEH research - intramural, extramural, and through strategic partner-
ships. Through its  National Research Programs, (Air, Climate, and Energy; Safe and Sustainable
Water Resources;  Sustainable and Healthy Communities; Chemical Safety for  Sustainability; Hu-
man Health Risk Assessment; and Homeland Security) ORD is collecting and compiling data on
children's exposures and providing access to information on exposure factors, human behavior,
chemical use, and developmental toxicity. Complex systems models of tissues and multi-organ
development are being constructed, as well as studies that combine epidemiologic and labora-
tory-based approaches to provide a holistic understanding of the relationship between early-life
environmental exposures and well-being during the lifespan. ORD is developing tools and  models
that can be used to access data, forecast exposures for thousands of chemicals, and evaluate
dosimetry of chemicals in the developing organism. ORD is also developing decision-support tools
to help States, local governments, and community organizations consider potential impacts of
environmental exposures in the context of decisions designed to protect and  promote children's
health.

Despite the many  contributions to CEH research by ORD over the last decade, important gaps
remain in actionable science and information required to understand, prevent, and mitigate im-
pacts to children from real-world exposures to potentially harmful air, water, and chemicals. ORD
leadership is required to bring together science generated inside and outside the Agency to build
predictive capacity to evaluate alternative actions and anticipate outcomes.

Working in conjunction with its partners  in the EPA regulatory program and other EPA
stakeholders, we identified four cross-cutting research areas required to address the critical
science challenges in CEH facing the Agency:

(1) Knowledge infrastructure to address the problem that information and data are distributed
    and difficult to access;
(2) Systems understanding of the relationship between environmental exposures and health
    outcomes across development;
(3) Methods and  models to evaluate early lifestage-specific risks and to support decisions
    protective of all lifestages; and
(4) Translational research and tools to support community actions and decisions.

Transforming the Agency's capacity for considering child-specific vulnerabilities requires that ORD
apply advanced systems science and integrate diverse emerging data and knowledge  in exposure,
toxicology, and epidemiology to improve understanding of the role of environmental exposure
during early life on health impacts that may occur at any point over the life course.

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This Children's Environmental Health Research Roadmap helps connect the dots among research
activities being implemented across the National Research Programs. Additionally, the vision
articulated in this roadmap serves to focus ORD investment in CEH research on areas where EPA
can play a significant leadership role and ensure that this cross-cutting research is integrated and
impactful.

The impact of integrated ORD research in CEH will be that the:

• Agency has the necessary data to evaluate risks:
  Information on early lifestage exposure and hazard is collated and organized to provide
  accessible data that can be used to estimate important CEH factors and to support evaluation of
  risks.

• Agency has scientific basis for action:
  Systems understanding of early life exposures and associated health outcomes is used to build
  predictive models that enable effective Agency actions to protect the health of children.

• Agency has tools to evaluate benefits of alternatives and to support decisions:
  Evaluated  and accessible tools enhance agency capacity to  adequately consider children's
  unique susceptibilities and vulnerabilities in Agency risk-based evaluations and sustainable
  public health  decisions.

• Agency can enable communities to take action;
  Information and translation tools are developed to support agency, state, tribal, and local
  decision makers with the knowledge needed to manage risks and to protect and promote CEH.

EPA has a unique mandate to understand the role of exposure to modifiable exogenous environ-
mental factors during early life in the context of important modifying factors (i.e., non-chemical
stressors) on health impacts during development. This roadmap presents ORD's vision for provid-
ing integrated and cutting-edge science on CEH to inform Agency decisions. This roadmap will
build stronger bridges to EPA partners and stakeholders who care about CEH issues. Resulting
research will provide the science required for EPA actions to promote children's environmental
health and well-being.

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Introduction
Background
The mission of the EPA is to protect human health and the environment. In addressing health
risks, the goal is not only to provide protection for the general population, but specifically for vul-
nerable individuals and groups, including children. In addition, the Agency expects that decisions
and actions designed to promote and protect children's health should do so sustainably.
That is, today's public policy for improving the health of individuals and communities should pro-
vide effective solutions without compromising the health and welfare of future generations.

In the Fiscal Year 2014-2018 EPA Strategic Plan, the Agency "recognizes [that] environmental jus-
tice, children's health, and sustainable development are all at the intersection of people and place.
These goals are not mutually exclusive. Throughout all our work to achieve more livable communi-
ties, EPA is committed to ensuring we focus on children's health and environmental justice." (U.S.
EPA, 2014h). As such, ORD has identified children's health as a cross-cutting research area.

Over the  last few decades, there have been a number of key legislative and policy initiatives that
have been crucial to EPA's mission to protect children's health. In response to concern about the
potential vulnerability of children to dietary exposure of pesticides, the U.S. Congress requested
that the National Academy of Sciences (NAS) study this critical public health issue. In 1993, the
NAS released a report titled Pesticides in the Diets of Infants and Children, which described sig-
nificant differences in toxicity and exposure of pesticides between children and adults (National
Academy of Sciences, 1993). The NAS report recommended that changes be made in regulatory
practice:  "Most importantly, estimates of expected total exposure to pesticide residues should
reflect the unique characteristics of the diets of infants and children and should account also for
all non-dietary intakes of pesticides. ... Determinations of safe levels of exposure should take into
consideration the physiological factors that can place infants and children at greater risk of harm
than adults."

The NAS report led Congress to enact the Food Quality Protection  Act (FQPA) in 1996, which sig-
nificantly amended the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal
Food,  Drug, and Cosmetic Act (FFDCA) and set a new risk standard of ensuring "reasonable cer-
tainty of no harm." Effective protection of children was emphasized through EPA's use of an extra
ten-fold children's safety factor when establishing tolerances unless data were available to  show
that a different factor was protective. The NAS report also provided the impetus for a series of ac-
tions to address the importance of assessing CEH  within EPA and across the federal government.

Since the 1990s, EPA has enacted a number of policies and strategies to protect children's health.
In 1995 (and reaffirmed in 2013), EPA released its Policy on Evaluating Health Risks to Children
(U.S. EPA, 1995) to consider the risks to infants and children consistently and explicitly as a part
of assessments generated during the decision  making process, including the setting of standards
to protect public health and the environment. In 2000, ORD released its Strategy for Research on
Environmental Risks to Children (U.S. EPA, 2000) to strengthen the scientific foundation of EPA
risk-based assessments and risk management decisions that support children's health and welfare.

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        In 2006, EPA prepared its Guide to Considering Children's Health When Developing EPA Actions:
        Implementing Executive Order 13045 and EPA's Policy on Evaluating Health Risks to Children
        (U.S. EPA, 2006). This guidance outlines the key steps to be considered when developing actions
        concerning children's health.

        Table 1 presents a summary of the major laws, policies, and guidance on the protection of
        children's health from environmental hazards. Policies of the U.S. government (executive
        and legislative branches); U.S. EPA and other federal agencies; U.S. States; and international
        organizations are considered.
Table 1.  Key governmental and international actions on children's environmental health
 Organization    Year   Title
                                                         Content
                                                U.S. Government
 Presidential
 Task Force
 [co-chaired
 by HHS and
 EPA)
1997   Presidential Executive Order 13045 - Protection of
       Children from Environmental Health Risks and Safety
       Risks and establishment of the Presidential Task Force
       on Environmental Health and Safety Risks to Children
       (http://www.gpo.gov/fdsvs/pkg/FR-1997-04-23/
       pdf/97-10695.pdf)
Requires all federal agencies to assign
a high priority to addressing health
and safety risks to children, coordinate
research priorities on children's health,
and ensure that their standards take into
account the special risks to children.
               2001  HUD Announces $67 Million in Grants to Fight
                      Childhood Lead Poisoning
                      (http://archive.hhs.gov/news/press/2001pres/200110
                      24a.html)
                                                         The task force's priority is to examine
                                                         programs that combat childhood lead
                                                         poisoning.
               2012  Released the Coordinated Federal National Action Plan
                      to Reduce Racial and Ethnic Asthma Disparities
                      (http://www.epa.gov/childrenstaskforce)
                                                         The goal is to reduce disparities in the
                                                         burden caused by asthma, particularly
                                                         among children.
               2013  Established a Federal Healthy Homes Workgroup and
                      released "Advanced Healthy Housing-A Strategy for
                      Action."
                      (http://www2.epa.gov/children/presidential-task-
                      force-environmental-health-and-safetv-risks-childrenl
                                                         The goal is to support research that
                                                         informs and advances healthy housing in a
                                                         cost-effective manner.
               2014  Established a Subcommittee on Climate Change, co-
                      chaired by NIEHS, EPA, and DHS.
                      (http://www2.epa.gov/children/presidential-task-
                      force-environmental-health-and-safetv-risks-childrenl
                                                         In July 2014, the Subcommittee hosted
                                                         an Expert Consultation on the Effects of
                                                         Climate Change on Children's Health to
                                                         explore these issues and to help inform
                                                         the ongoing U.S. Global Change Research
                                                         Program.
  106th U.S.
 Congress
2000  Children's Health Act (Public Law 106-310)
      (http://www.gpo.gov/fdsvs/pkg/PLAW-106publ310/
      pdf/PLAW-106publ310.pdf)
Directed NIH, NIEHS, CDC, and EPA to
conduct a National Children's Study.
 110th U.S.
 Congress
2007   Energy Independence and Security Act of 2007
       (http://www2.epa.gov/laws-regulations/summarv-
       energy-independence-and-securitv-act)
Required EPA to develop school siting
guidelines and environmental health
guidelines.

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Table  1. (continued) Key governmental and international actions on children's environmental health
 Organization   Year  Title
Content
                1995  Policy on Evaluating Health Risks to Children (U.S. EPA,
                      1995)
                      (http://www2.epa.gov/children/epas-policv-
                      evaluating-risk-childrenl
The risks to infants and children should
be considered consistently and explicitly
as part of risk assessments, including
the setting of standards to protect public
health and the environment.
                1996  National Agenda to Protect Children's Health from
                      Environmental Threats
                      (http://www2.epa.gov/children/epas-national-
                      agenda-protect-childrens-health-environmental-
                      threats)
All standards should be protective of
heightened risks faced by children;
develop a scientific research strategy
regarding child-specific environmental
threats; develop new policies regarding
exposures faced by children.
                1996   Enactment of The Food Quality Protection Act
                       (http://www.epa.gov/pesticides/health/children-
                       standards.html)
Improved the safety standards that
EPA uses in evaluating pesticide risks,
especially risks to children.
                1997  Creation of the Office of Children's Health Protection
                      (OCHP) (http://www2.epa.gov/children/historv-
                      childrens-environmental-health-protection-epal
Mission is to make the health protection
of children a fundamental goal of public
health and environmental protection.
                1997  Creation of the Pediatric Environmental Health
                      Specialty Units (PEHSUs) with ATSDR
PEHSUs translate research into public
health and clinical practice, educate
health providers, and consult on pediatric
environmental health issues.
                1998  Children's Environmental Health and Disease Research
                      Centers (CEHCs) (Jointly funded with NIEHS)
                      (http://epa.gov/ncer/childrenscenters/)
Explores ways to reduce children's health
risks from environmental contaminants.
                2005   New risk assessment guidance: Guidance on Selecting
                       Age Groups for Monitoring and Assessing Childhood
                2008   Exposures to Environmental Contaminants (U.S. EPA,
                       2005a)
                       (http://www.epa.gov/raf/publications/guidance-on-
                       selecting-age-groups.htm): Supplemental Guidance for
                       Assessing Susceptibility from Early-Life Exposure to
                       Carcinogens (U.S. EPA,
                       2005b)(http://www.epa.gov/raf/publications/cancer
                       guidelines/sup-guidance-earlv-life-exp-
                       carcinogens.htm): A Framework for Assessing Health
                       Risk of Environmental Exposures to Children (U.S. EPA,
                       2006b)
                       (http://cfpub.epa.gov/ncea/risk/recordisplav.cfm7d
                       eid=158363): Child-Specific Exposure Factors Handbook
                       (U.S. EPA, 2008)
                       (http://cfpub.epa.gov/ncea/risk/recordisplav.
                       cfm?deid=199243) (The latest information on child-
                       specific exposure factors can be found in the 2011
                       Exposure Factors Handbook)
Risk assessment guidance for assessing
CEH issues.

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Table 1. (continued) Key governmental and international actions on children's environmental health
 Organization    Year  Title
                                                         Content
                2010  "Working for Environmental Justice and Children's
                      Health" (part of EPA's Strategic Plan, 2011-15)
                      (http://nepis.epa. gov/Exe/ZvPDF.cgi?Dockev=P1008Y
                      OS.PDF)
                                                          Emphasis on development and use of
                                                          the latest science on children's unique
                                                          vulnerabilities.
                2013  Protections for Subjects in Human Subjects Research
                      with Pesticides
                      (http://www.epa.gov/oppfeadl/guidance/human-
                      test.htm)
                                                          Provides for additional protection of
                                                          susceptible subpopulations and prohibits
                                                          EPA-sponsored research involving
                                                          intentional exposures of pregnant
                                                          women or children to any environmental
                                                          substance. Implementation of this
                                                          guidance has broad implications for CEH
                                                          research.
                2013  ORD establishes six integrated, transdisciplinary
                      National Research Programs: Air, Climate, and Energy
                      (ACE); Safe and Sustainable Water Resources (SSWR);
                      Sustainable and Healthy Communities (SHC); Chemical
                      Safety for Sustainability (CSS); Human Health Risk
                      Assessment (HHRA); and Homeland Security (HS)
                      (http://www2.epa.gov/aboutepa/about-office-
                      research-and-development-ordl
                                                          Provides the scientific foundation,
                                                          methods, and tools that EPA needs to
                                                          fulfill its mission of protecting human
                                                          health and the environment.
                2013  EPA's 1995 Policy on Evaluating Health Risks to
                      Children is reaffirmed by the EPA Administrator
                      (http://www2.epa.gov/sites/production/files/2013-
                      11/documents/childrens enviromental health  risk 2
                      013 reaffirmation memorandum.pdf)
                                                          "This reaffirmation strengthens EPA's
                                                          commitment to leadership in children's
                                                          environmental health as well as the
                                                          leadership of the Office of Children's
                                                          Health Protection ... and continues to
                                                          encourage much needed research."
                2014  E PA's Report on the Environment
                      (http://www.epa.gov/roe/)
 NIH
                                                          Provides the best available indicators of
                                                          national trends in the environment and
                                                          human health and includes CEH metrics.
                          Other Federal Agencies, Countries, and International Organizations
2014   NIH announces a notice of intent to fund the
       Children's Health Exposure Analysis Resource
       (CHEAR): a National Exposure Assessment Laboratory
       Network
       (http://grants2.nih.gov/grants/guide/notice-
       files/NOT-ES-15-007.html)
Laboratories will provide a
comprehensive suite of laboratory-based
analytical services for samples from
children's health studies.
 FDA
2010  Advancing Regulatory Science for Public Health
      (http://www.fda.gov/downloads/scienceresearch/
      specialtopics/regulatorvscience/ucm228444.pdfl
Identifies improving child health as one
of the major areas in which advancement
in the field can improve public health.
 HUD
2009   The Healthy Homes Strategic Plan
       (http://portal.hud.gov/hudportal/HUD?src=/program
        offices/healthy homes)
Roadmap for the protection of the
health of children and other sensitive
populations in a comprehensive and cost-
effective manner.

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Table 1. (continued) Key governmental and international actions on children's environmental health
Organization
Year Title
Content
Other Federal Agencies, Countries, and International Organizations
Canada
European
Union
World Health
Organization
(WHO)


2010 National Strategic Framework on Children's
Environmental Health (http://www.hc-sc.gc.ca/ewh-
semt/Dubs/contaminants/framework children-
cadre enfants/index-eng.php#aO)
2013 The Helix Project (http://www.proiecthelix.eu/)
2004 Children's Environment and Action Plan for Europe
(http://www.euro.who.int/ data/assets/pdf file/000
6/78639/E83338.pdf)
2012 State of the Science of Endocrine Disrupting Chemicals
(http://www.who.int/ceh/publications/endocrine/en/)

2013 Guidance on identifying important lifestages for
monitoring and assessing risks from exposures to
environmental contaminants
(http://www.who.int/ceh/publications/exposures en
vironmental contaminants/en/1
Guides the development of action plans
for the protection of children living in
Canada from exposure to environmental
hazards.
A collaborative project using novel
tools and methods to characterize
early life exposure to a wide range of
environmental hazards and which will be
integrated and linked with data on major
child health outcomes.
Developed four regional priority goals
and committed the member states to
develop and implement national children's
environment and health action plans.
Presents scientific knowledge on exposure
to and effects of endocrine disrupting
chemicals.
Presents a harmonized set of age bins
for monitoring and assessing risks from
exposures to chemicals for global use
that focuses on preconception through
adolescence.
States
California
Washington
Minnesota
2001 Prioritization of Toxic Air Contaminants - Children's
Environmental Health Protection Act
(http://oehha.ca.gov/air/toxic contaminants/
SB25finalreport.html)
2008 Chemicals of High Concern to Children - Children's Safe
Product Act
(http://www.ecv.wa.gov/programs/swfa/cspa/)

2014 Chemicals of Special Concern to Children's Health
(http://www.health.state.mn.us/divs/eh/children/
chemicals.html)
Presents information on chemicals that
are identified as toxic air contaminants
that may cause infants and children to be
particularly susceptible to illness.
Presents information on chemicals that
are toxic and have either been found
in children's products or have been
documented to be present in human
tissues.
Presents information on chemicals that
may adversely affect children's health.

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Current Drivers for CEH Research

There are three key drivers that define the need for, and focus of, EPA-led CEH research:
1) EPA's 2014-2018 Strategic Plan,
2) EPA program office mandates, and
3) Recent and emerging scientific findings related to CEH issues.

(1)  EPA's 2014-2018 Strategic Plan

The EPA Strategic Plan released in early 2014 calls specifically for applied research in CEH in two of
the five strategic goals: Goal 3 (Cleaning Up Communities and Advancing Sustainable Development)
and Goal 4 (Ensuring Safety of Chemicals and Preventing Pollution).

In the area of cleaning up communities, research to enhance the ability to adequately consider
children's unique susceptibilities and vulnerabilities will provide the Agency, State, Tribal, and
local decision makers with the knowledge needed to make smart, systems-based decisions that
will inform a balanced approach to their cleanup and development needs. EPA's chemical safety
research will provide the scientific foundation to support safe and sustainable use of chemicals, in-
cluding the systems understanding needed to adequately protect the health of children and other
vulnerable groups.

Although there is no direct call for applied research in CEH under Goal 1 (Addressing Climate
Change and Improving Air Quality) or Goal 2 (Protecting America's Waters), Agency decisions and
actions to  meet these strategic goals require the information and tools to consider child-specific
vulnerabilities.

In addition, the EPA Strategic Plan emphasizes the importance of leveraging and building on ex-
isting partnerships to achieve strategic objectives. This includes partnering "with research orga-
nizations and academic institutions to focus and advance basic research and create models and
measures to expand the conversation on environmental and human health concerns to address
priority-focused, locally based problems, specifically including  ... children's environmental health
issues" (U.S. EPA, 2014h).

(2)  EPA Program Office Drivers

EPA program offices have a variety of different mandates to protect children from environmental
health risks. These mandates are based on authorities established under the environmental
statutes and on guidance specific to  each program  office.

Office of Children's Health Protection (OCHP):
EPA established OCHP in May 1997 to make the protection of children's health a fundamental goal
of public health and environmental protection in the United States. OCHP supports and facilitates
Agency efforts to protect children's health from environmental threats through participation in:
regulation and standards development; risk assessment guidance and policy development; re-
search planning; and outreach and partnerships with health care professionals, youth groups,
and community groups.  Important OCHP projects have  included: EPA's  Clean, Green, and Healthy

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Schools Initiative (http://www.epa.gov/schools/): increasing environmental health literacy of stu-
dents and educators; support of Pediatric Environmental Health Specialty Units (http://aoec.org/
pehsu/index.html): and publication, in partnership with the Office of Policy, of America's Children
and the Environment (http://www.epa.gov/ace/), which evaluates and communicates trends in
environmental contaminants that may contribute to childhood disease.

OCHP also provides children's health expertise in Agency rulemakings and other actions, including
the Integrated Risk Information System (IRIS) and many other programs across the Agency. Data
and analytical tools from ORD are valuable to OCHP's cross-cutting involvement in these priority
actions for children's health.

Office of Chemical Safety and Pollution Prevention (OCSPP):
The Toxic Substances Control Act (TSCA) provides EPA with the authority to require reporting,
record-keeping and testing requirements, and restrictions related to chemical substances and/
or mixtures. OCSPP carries  out these requirements by reviewing new and existing chemicals;
evaluating chemical hazards, including hazards relevant to  developmental and reproductive
toxicological endpoints; and exposure, including exposures of children to environmental
chemicals. EPA is currently  working with Congress, members of the  public, the environmental
community, and industry to reauthorize TSCA. EPA is working with these groups to modernize
and strengthen the tools available under TSCA to prevent harmful chemicals from entering the
marketplace and to increase confidence that remaining chemicals are safe and do not endanger
the environment or human health, especially for consumers, workers, and children.

Recently, as part of EPA's approach to enhance the Agency's existing chemicals management
program, OCSPP identified  83 chemicals (TSCA Work Plan Chemicals) for further assessment under
TSCA (http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html). The chemicals were
selected based on five criteria: hazard, exposure, persistence, bioaccumulation, and use, including
use in children's products.

OCSPP also regulates all use of pesticides in the U.S. based on legislative authority provided  under
FIFRA. EPA's current pesticide review processes also focus on ensuring that pesticide registrations
comply with the Endangered Species Act and achieve broader Agency objectives for water quality
protection. The review processes place emphasis on the protection  of potentially sensitive popula-
tions, such as children, by reducing exposures from pesticides used  in and around homes, schools,
and other public areas.

The 1996 Food Quality Protection Act directs EPA to develop a screening program, using appro-
priate validated test systems and other scientifically relevant information, to determine whether
certain substances including pesticides may have hormonal effects in humans. At the same time,
the 1996 amendments to the Safe Drinking Water Act authorize EPA to screen substances that
may be found in sources of drinking water for endocrine disruption  potential.  To carry out this di-
rective, OCSPP established  the Endocrine Disrupter Screening Program (EDSP), which uses a  two-
tiered screening and testing process to gather information  needed to  identify  endocrine-active
substances and take appropriate action, as mandated  by Congress. In  2005, EPA began screening
priority chemicals under this program including: pesticide active ingredients and high production
volume chemicals used as inert ingredients in pesticide formulation; drinking water contaminants,

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such as halogenated organic chemicals; persistent chemicals such as dioxins and flame retardants;
and chemicals found in plastics, Pharmaceuticals and personal care products (http://www.epa.
gov/endo/pubs/prioritvsetting/index.htm). In 2010, OCSPP announced plans to make better use
of computational toxicology tools in the EDSP and developed the EDSP21 Work Plan. This work
plan outlines an approach for using computational or in silico models and molecular-based high-
throughput assays to prioritize and screen chemicals to determine their potential to interact with
the estrogen, androgen, or thyroid hormonal systems,  (http://www.epa.gov/endo/pubs/edsp21
work plan  summary%20 overview final.pdf).

Office of Water (OW):
In the standard setting process for chemicals in drinking water, OW is required, under Section 103
of the 1996 Amendments to the Safe Drinking Water Act, to determine "the effects of the con-
taminant on the general population and on groups within the general population such as infants,
children, pregnant women, the elderly, individuals with a history of serious illness, or other sub-
populations that are identified as likely to be at greater risk of adverse health effects due to expo-
sure to contaminants in drinking water than the general population."
OW considers the effect of contaminants on children's  health in the standard setting process
by following EPA's guidance on children's health issues: Supplemental Guidance for Assessing
Susceptibility from Early Life Exposure to Carcinogens (http://www.epa.gov/raf/publications/
cancer guidelines/sup-guidance-earlv-life-exp-carcinogens.htm) and A Framework for Assessing
Health Risks of Environmental Exposures to Children (http://cfpub.epa.gov/ncea/risk/recordisplav.
cfm?deid=158363). OW uses these guidances in its qualitative assessment of the adverse health
effects of contaminants. For carcinogens, OW factors in age-dependent susceptibility in its dose-
response assessment.

Office of Air and Radiation (OAR):
In conducting risk assessments for air toxics, OAR routinely seeks to identify groups, such as
children, whose vulnerability to certain environmental  contaminants may be higher than that of
adults. Such assessments are conducted for all air toxics rulemakings, including National Emis-
sions Standards for Hazardous Air Pollutants (NESHAPS, otherwise known as Maximum Achievable
Control Technology, or MACT, standards) and Residual  Risk rules. During these assessments, OAR
specifically estimates risks to children and/or determines if children are disproportionately affect-
ed by their exposures and/or behavioral patterns. OAR uses dose-response values which specifi-
cally account for the differential sensitivity of children as compared to adults and has developed
exposure estimates for mutagenic carcinogens (e.g., vinyl chloride and polycyclic aromatic hydro-
carbons), which specifically account for the greater vulnerability of children to these compounds
during their developmental years, based on EPA's Supplemental Guidance for Assessing Suscepti-
bility from Early Life Exposure to Carcinogens.
OAR also carefully considers impacts on children's health as part of its periodic reviews of the
National Ambient Air Quality Standard (NAAQS),  in which the Agency must consider whether the
standards are requisite to protect public health, including the health of at-risk subgroups, with an
adequate margin of safety. Evaluating the effects of criteria air pollutants in children  has been a
central focus in several recent NAAQS reviews, including reviews of the lead, ozone, and particu-
late matter standards,  which resulted in revised standards to strengthen public health protection.

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Office of Solid Waste and Emergency Response (OSWER):
OSWER provides policy, guidance, and direction for the Agency's waste and clean-up programs,
emergency response, management of hazardous substances and waste, and redevelopment of
contaminated sites.  OSWER implements its mission under a variety of mandates, including the
Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), the Resource
Conservation and Recovery Act (RCRA), and the Small Business Liability Relief and Brownfields
Revitalization Act.  In addressing its mission, OSWER works to understand and protect the health
of populations, taking into account the unique susceptibilities and vulnerabilities of children.
OSWER directly considers potential impacts to sensitive subpopulations, including children, in its
risk assessment and  risk management actions. Consistent with the National Contingency Plan [40
CFR 430(e)(2)(i)(A)(10], OSWER's cleanup under Superfund actions ensures that exposures to the
human population, including sensitive groups, are without adverse effect during a lifetime or part
of a lifetime, and incorporate an adequate margin of safety. The Risk Assessment Guidance for Su-
perfund (RAGS) documents provide specific guidance on the incorporation of child-specific factors,
including body weight, timing of exposure, and unique exposure pathway considerations, such as
dust and soil intake rates.
Regional Offices: Each Regional Office has a Children's Environmental Health Coordinator who is
responsible for leading the CEH Program in their region, and to engage with other regional coor-
dinators, including Regional School Coordinators and risk assessors. These programs are based
on national and regional  strategies to protect CEH through a number of regulations and voluntary
programs. While exposures can occur in any number or variety of locations, the regions work with
decision makers to understand and reduce exposures in home, learning, and play environments.

(3) Scientific Drivers Related to Adverse  Health Outcomes

Recent and emerging research findings on the relationship of environmental contributions to
children's health outcomes are important drivers for EPA's CEH research. Evidence points to asso-
ciations between early life exposure to environmental contaminants and a  wide range of children's
health outcomes, including adverse birth outcomes, asthma, neurodevelopmental disorders,
metabolic disease, and childhood cancer.

Adverse birth outcomes: These include preterm birth, low birth weight, neonatal mortality, and
birth defects. Birth defects are seen in approximately 3% of births in this country and low birth
weights are observed in 11% of births. In 2012, black non-Hispanic women had the highest rate
of preterm birth of all racial groups (16.8%). Adverse birth outcomes are leading causes of infant
mortality and may presage long-term problems including motor, cognitive, visual, hearing, behav-
ioral, and social-emotional problems.
Birth outcomes have been associated with exposure to a variety of environmental contaminants
in utero and  early in  life,  including fine particulate matter (Dadvand et al., 2013; Fleischer et al.,
2014; Stieb et al., 2012) and chemicals such as arsenic (Boekelheide et al., 2012), organochlorine
pesticides, organic solvents,  and other air pollutants (Gorini et al., 2014).

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Asthma: The incidence and severity of childhood asthma continues to rise. In 2009, asthma af-
fected 7.1 million children (about 10% of children) in the United States. Asthma disproportionately
impacts minority children, especially in urban communities typified by low income, high levels
of air pollution, and poor indoor air quality (Akinbami et al., 2012). 12.2% of children in families
below the poverty line were reported to have asthma, compared to 8.7% of children in families
above the poverty line. A higher percentage of black non-Hispanic children (16%) and children of
"all other races" (12.4%) were reported to have asthma, compared to white non-Hispanic children
(8.2%).

More is known about environmental factors that exacerbate asthma severity than those that
cause asthma, but recent evidence implicates air pollution as a causative factor. Substantial evi-
dence has associated in utero or early life exposures to environmental tobacco smoke, ambient
and indoor air pollutants, and inhaled allergens (dust mites, pets and pollens) with asthma in-
cidence and/or severity in children (Dick et al., 2014; Selgrade et al., 2013). Genetic factors and
gene-environment interactions also play a role in asthma causation (Rigoli et al., 2011). Children
with specific gene variants were shown to be at increased rates of asthma associated with air
pollution (Macintyre et al., 2014). Environmental exposures may also impact asthma risk through
epigenetic mechanisms, an emerging area of study (Kabesch, 2014; Salam et al., 2012).

Neurodevelopmental disorders:  Developmental disabilities (DDs), including lower IQ, learn-
ing deficits and other indicators of poor cognitive function, and adverse effects on behavior,  are
common; about 1 in 6 children in the United States are affected.  Between 1997 and 2008, the
prevalence of DDs increased 17.1%, impacting about 1.8 million more children. The prevalence of
autism increased 289% while attention deficit hyperactivity disorder (ADHD) increased 33%. Again,
lower income children are disproportionally impacted by DDs. Children insured  by Medicaid had
nearly two-fold higher prevalence compared to those with private insurance.

Neurotoxicants that have been associated with developmental effects include lead, methylmer-
cury, PCBs, arsenic, toluene, manganese, fluoride, chlorpyrifos, and tetrachloroethylene (Grand-
jean and Landrigan, 2014). Limited evidence is emerging to suggest an association between
exposure to a range of environmental contaminants including air pollutants, organophosphate
pesticides, brominated flame retardants, phthalates, bisphenol A, and perfluorinated compounds
and adverse neurodevelopmental effects  (Bellinger, 2013; Choi et al., 2012; Rodriguez-Barranco et
al., 2013; Yim et al., 2014).

Recent children's cohort studies  implicate prenatal exposure to polycyclic aromatic hydrocarbons
(PAHs) from air pollution and bisphenol-A with attention problems, anxiety and  aggressive behav-
ior in boys (F. Perera et al., 2012; F. P. Perera et al., 2011). The possible link between environmen-
tal contaminants and increasing prevalence of ADHD and autism  is an area of active investigation.
In addition, potential for gene-environment interactions are being studied (Hu, 2012).

Metabolic Syndrome: Metabolic syndrome, a cluster of adverse health effects including obesity,
altered lipid levels,  and other metabolic abnormalities, is increasing globally. Prevalence of child-
hood obesity in the U.S. has recently stabilized at approximately 16%. 22% of Mexican-American
and 20% of black non-Hispanic children are obese, compared with 14% of white non-Hispanic chil-
dren. Prevalence of obesity is greater in children with family incomes below poverty level than in

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those above. The rise in obesity and related metabolic disease is of particular concern because the
risk of life-threatening diseases, such as diabetes, cardiovascular disease, and cancer, is increased
in persons with metabolic disease.

The possibility that environmental chemicals can influence childhood obesity is currently an area
of significant study. Chemicals that are under investigation include dioxins, PCBs, DDT, DDE, per-
fluoroalkyls, PBDEs, phthalates, bisphenol A, organotins, lead, air pollutants, polycyclic aromatic
hydrocarbons (PAHs), naphthalene, diethylstilbestrol, thiazolidinediones. Some of these chemicals
have been shown to increase obesity in laboratory animals and in vitro studies have shown cell
differentiation that may indicate an association between certain chemicals and obesity (Karoutsou
and Polymeris, 2012; La Merrill and Birnbaum, 2011; Scinicariello and Buser, 2014). Epigenetic
reprogramming is hypothesized to be a contributing factor in childhood obesity and metabolic
syndrome, and is an area of intense study (Janesick and Blumberg, 2011).

Developmental Origins of Disease:  More generally, an increasing number of studies are address-
ing the hypothesis that exposure in early life to environmental stressors may influence develop-
ment that impacts later health and disease risk. An area of intense interest involves epigenetic
modification resulting from exposures during critical windows of development. The support for
epigenetic change in early life comes from a large number of animal studies and a small number
of observational studies in humans (Saffery and Novakovic, 2014). Evidence has been published
for epigenetic changes including DNA methylation, histone modifications, and miRNAs in develop-
mental programming, leading to an increased risk of disease (Bernal and Jirtle, 2010; Hou et al.,
2012; Vaiserman, 2014). Environmental compounds being studied for their ability to cause epigen-
etic changes include asbestos, benzene, endocrine-disrupting compounds, and metals (Kim et al.,
2012; Vaiserman, 2014).


Purpose

Protecting children's health from environmental risks remains a critical and enduring part of EPA's
mission. EPA conducts and supports CEH research to inform regulatory decisions and to support
community decision making to promote sustainable healthy environments for children. Given
recent advances in the science of  risk assessment, it has now become an opportune time to re-
examine and update EPA's path forward for critical CEH research.

The purpose of this CEH Roadmap is to describe EPA's strategic vision for CEH research, building on
and extending the problems and needs identified in EPA's 2000 research strategy. This new vision
aims to use all science, particularly 21st century science and systems approaches to  improve our
understanding of how environmental factors affect children's health and contribute to the most
prevalent diseases and disorders;  incorporate basic human health research into the development
of innovative new approaches for assessing  risks associated with early lifestage exposures, includ-
ing prenatal and lactational exposures; and translate basic and applied research findings to inform
new ways by which the Agency and others can take action to prevent or reduce adverse CEH out-
comes and promote sustainably healthy environments in communities where children live, play,
and learn.

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The ORD cross-cutting Research Roadmaps are not intended to be new research strategies for
Strategic Research Action Plans (StRAPs). Rather, they take a cross-cutting look at existing and im-
minent ORD research portfolios and emerging StRAPs for each National Research Program (NRP)
and describe the focus of ongoing research and the direction of the planned research. They also
inform future research planning in relevant NRPs. As such, this cross-cutting Research Roadmap
has two important attributes: (1) the research needs described are "owned" by an  NRP and articu-
lated as either existing or planned (definitively or aspirationally) in a near-term timeframe; and (2)
research needs described are those for which EPA/ORD needs to play a transformative leadership
role.

This Roadmap is focused specifically on CEH research. There is a separate Roadmap for research
on environmental justice which will articulate research and needs specific to all lifestages, and
highlight research that addresses both CEH and environmental justice (health disparity) concerns.

The lifestage scope of the research described in this Roadmap specifically considers impacts as-
sociated with exposure during or across developmentally sensitive windows. Although many
references are made to children as a  "subpopulation" (e.g., 1996 SDWA amendments uses the
term "subpopulation" to describe groups with unique attributes, including those defined by age
or lifestage), since 2005 EPA has recognized the importance of distinguishing between population
groups that form a relatively fixed portion of the population (e.g., groups based on ethnicity) and
lifestages or age groups that are inclusive of the entire population. The term "lifestage" refers to
a distinguishable time frame in an individual's life characterized by unique and relatively stable
behavioral and/or physiological characteristics that are associated with development and growth.
Thus, childhood should be viewed as a sequence of lifestages, from birth, through infancy and
adolescence. EPA has official guidance defining early lifestage specific age bins which has been af-
firmed by WHO (Cohen Hubal et al., 2013; U.S. EPA, 2005).
                 The purpose of this roadmap is to describe and facilitate
                 integrated ORD CEH research that will provide the Agency
                 and stakeholders with scientific understanding, information,
                 and tools required to address early lifestage sensitivity,
                 susceptibility, and vulnerability for sustainable
                 decisions and actions.

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                                                                     I
                                                                     I  PrenatalNeonata|
                                                                        '      -•'-    Infant
                              Conception Birtn
                    Pre-conception  !IP
                                                 Toddler
        Adulthood
     Late
 Adolescence
                            CEH Roadmap
                              Lifestages
Early
  Childhood
                                                            Middle
                                                          Childhood
                        Early Adolescence
  E Preconception
  • 1st Trimester
  • 2nd Trimester
_ • 3rd Trimester
  • Birth to < 1 month
  • 1 to < 3 months
  • 3 to < 6 months
_ • 6 to < 12 months
  • 1 to < 2 years
[~ • 2 to < 3 years
L • 3 to < 6 years
  Q6to< 11 years
  • 11 to < 16 years
  • 16 to < 21 years
  • Adulthood
Figure  1 outlines these lifestages which are the specific focus for this Roadmap and cross-cutting
CEH research. Note that while exposures from preconception through adolescence are of primary
interest, impacts may extend throughout the lifecourse into adult lifestages and across generations.
Here, the lifecourse is depicted as a circle  to convey the concept of intergenerational impacts from
environmental exposures.

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Research Scope
Expanded Problem Statement
Sustainable decisions and actions are those that improve the health of individuals and communi-
ties today without compromising the health and welfare of future generations. The U.S. EPA and
stakeholders require scientific understanding, information, and tools to incorporate consider-
ation of early lifestage sensitivity, susceptibility and vulnerability for sustainable decisions and
actions.

Within the broad sphere of CEH, EPA has a unique mandate to focus on understanding the role
of exposure to modifiable xenobiotic environmental factors during early life, in the context of
important modifying factors (i.e., non-chemical stressors),  on health impacts over the course of a
lifetime. Specifically, applied research is required to enable and extend the Agency's ability to take
action. The science challenges associated with filling this unique niche in CEH research are signifi-
cant.

The Agency and stakeholders make decisions at several levels of organization, from  the individual
to community level all the way to the state and national level. ORD research will provide required
information and tools by considering the different types of decisions and actions required to sup-
port CEH. The CEH research translation framework presented in Figure 2 captures the important
science challenges addressed by ORD CEH research within  this context. Two general translation
routes are depicted: one focused on  providing cutting-edge science for effective public health
policy and efficient risk management at the national level;  the second at the community level.

Understanding of developmental biology, impacts to biological  pathways resulting from perturba-
tions at critical windows of development, and genetic and  environmental factors that may pro-
duce and/or modify these perturbations form the scientific basis for both translation routes. In
the first, identification of toxicity pathways coupled with identification of important environmental
factors (exposures) provides new opportunities to anticipate impacts by considering early indica-
tors of adversity and monitoring for emerging environmental contaminants. Information and tools
along this translation route will inform decision making and public health protection at the popu-
lation level. Decision support tools developed along this route may include: (1) biomarkers, met-
rics, and indicators for measuring and monitoring environmental exposures as well as providing
early indication of toxicological impacts; and (2) models for risk-based decision making, informed
by detailed understanding of relevant environmental stressors and associated perturbations to
toxicity pathways. In the second translational  route, knowledge of individual patterns of exposure
and disease predisposition resulting from the  full range of  community-level determinants provides
opportunities to develop community-based approaches to health promotion and risk manage-
ment. Here, information and decision support tools are developed to inform and support actions
by communities to manage risks and promote health by providing a clear understanding of impor-
tant exposures and how these can be locally controlled.

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Considerations of individual variation based on genetic susceptibility, lifestage, timing of expo-
sures, and interaction of non-chemical stressors is required context for both routes and for holis-
tic assessment of risk factors associated with complex environmental disease. By capturing the
science challenges of characterizing biologically relevant exposure, the framework presented in
Figure 2 facilitates translation of advances and findings in computational toxicology to information
that can be directly used to support risk-based decisions to improve public health. In addition, this
framework captures the challenge of addressing data gaps along all levels of biological organiza-
tion (i.e., from molecular through population levels) in a systems-based fashion to optimize de-
sign of future exposure and epidemiology studies. Such  a strategic implementation of toxicology,
exposure  and epidemiology research is required to ensure efficient use of resources committed to
children's health studies.
                                          Susceptibility
                                         (Genetic Variants /
                                            Epigenetic
                                          Modifications)
                            Biological Insights
                            (Developmentally-
                           Relevant Pathways)
                                                    Lifestage Specific
                                                     Vulnerabilities
                                                    and Community
                                                       Exposures
                             Environmental
                            Factors (Chemical
                            and Non-chemical)
              Key Perturbations,
            Targets, and Exposures
                                                                   Individual and
                                                               Community Risk Profile
                 Risk-Based
                  Decision
                  Support
                   Tools
Biomarkers
Indicators
 Metrics
Translation
Tools
Information for
  Decisions
Public Health
   Policy
 Community
   Health
 Promotion
  and Risk
Management _j
                 Figure 2.  Children's environmental  health research translation
                     framework (Adapted from Cohen Hubal et al., 2010).

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ORD research is designed and implemented through case examples that allow for demonstration
and evaluation of research products. ORD works with EPA program partners and regions through
its six National Research Programs to identify useful case examples, to develop and demonstrate
the research products fit-for-purpose, and to evaluate the value added of ORD  information and
tools to both inform decisions and to support measurement of impact resulting from those deci-
sions.


Children's Environmental Health  Research Areas

Working in conjunction with its partners in the EPA regulatory program and other EPA stakehold-
ers, EPA identified four cross-cutting research areas required to address the critical science chal-
lenges in CEH facing the Agency. To provide the science, information and decision support tools
required to promote and protect children's health and well-being, EPA's CEH research is designed
to address the following four priority research areas:

(1) Knowledge infrastructure to address the problem that information and data are distributed
and difficult to access;

(2) Systems understanding of the relationship between environmental exposures and health
outcomes across development;

(3) Methods and models to evaluate early lifestage-specific risks and to support decisions
protective of all lifestages; and,

(4) Translational research and tools to support community actions and decisions

For each of these research areas, this  Roadmap provides the general scope of the area, key
research questions, and specific research needed to provide the answers.

Research Area 1: Knowledge infrastructure to address the problem that
information and data are distributed and difficult to access

Information and data required to support Agency and stakeholder decisions and actions to pro-
mote and protect children are distributed and may be difficult to access. Much of these data are
generated outside the Agency but  are critical for evaluating emerging scientific evidence for role
of key environmental factors in CEH, identifying data gaps required to reduce uncertainties in
model predictions, and providing effective decision support tools. In all cases, the knowledge sys-
tems to facilitate integration and analysis of CEH data are required to identify and protect suscep-
tible lifestages.

Key research questions addressed  in this  research area:

• What data and information are most critical for characterizing early lifestage vulnerabilities
  and susceptibility in the areas of exposure, toxicokinetics, toxicodynamics, and disease etiology?

• What data and information are most critical for evaluating linkages between  early life
  environmental exposures and health outcomes, including those that may appear later in life?

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• What data and information are most critical for reducing early lifestage-related uncertainties in
  exposure and risk characterization to provide the basis for EPA's policy decisions?

Anticipated integrated impact:

The Agency has data it needs to evaluate risks. Information on early lifestage exposure and
hazard is collated and organized to provide accessible data that can be used to estimate important
CEH factors and to support evaluation of risks.

Research Area 2:  Systems understanding of the relationship between
environmental exposures and health outcomes across development

A holistic understanding of the factors that impact children's health, specific to each stage of de-
velopment, is needed in order to attribute, reduce, and eliminate risks specific to the environmen-
tal exposures over which EPA has regulatory authority. Systems-level understanding of the rela-
tionship between environmental exposures and health outcomes across development is required
to develop predictive models that enable effective Agency decisions and actions that protect
susceptible lifestages. EPA CEH research is designed to develop this understanding by considering
exposures to chemicals and chemical classes of concern as well as the influence  of non-chemical
stressors and the built environment on children's health outcomes. Toxicological and epidemiolog-
ical studies on exposure to chemical and non-chemical stressors are included in this research area.

Key research questions addressed in this research area:

• By what common biological pathways do  environmental contaminants contribute toward early
  origins of disease and to important childhood health outcomes, such as adverse birth
  outcomes, asthma, neurological disorders and metabolic syndrome?

• What are the key perturbations and biological targets associated with developmentally relevant
  adverse outcome pathways (AOPs)?

• What are the systems-level influences of the chemical and natural and built environments on
  these biological pathways and health outcomes?

• How can we  evaluate the individual and community risk profiles associated with exposures to
  chemical  mixtures including the contribution of non-chemical stressors across the course
  of development?

Anticipated integrated impact:

Agency has scientific basis for action.
Systems understanding of  early life exposures and  associated health outcomes is used to build
predictive models that enable effective Agency actions to protect the health of children.

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Specific research to provide biological systems understanding of the relationship between
environmental exposures and health outcomes across development:

• Identification of AOPS for chemicals that disrupt specific developmental processes.

• Evaluation of relevance/concordance of lab animal models for human health.

• Linkage of environmental exposures to health outcomes via AOPs including outcomes apparent
  at birth and those which contribute to later onset of disease in childhood or adulthood.

• Development and evaluation of systems models to understand and predict developmental
  toxicity.

• Systems level understanding of the complex interactions between  multiple chemical stressors
  and how these interact with non-chemical stressors (other environmental and socioeconomic
  factors), and genetics, including informing how those interactions may affect children's health.

Research Area 3: Methods and models to evaluate early lifestage-specific risks
and to support decisions protective of all lifestages

Risk assessors and risk managers need methods to measure lifestage specific exposure, toxicity
and health endpoints as well as models and tools to analyze and integrate the information to
adequately consider lifestage specific factors in sustainable decisions.

Key research questions:

• What methods, models, and decision support tools are needed to allow the Agency to use all
  available data to inform risk-based decisions?

• What methods, models, and decision support tools are needed to evaluate how and to what
  extent pregnant women and children are exposed to environmental stressors?

• What methods, models, and decision support tools are needed to evaluate how associated
  health outcomes vary by specific early lifestages and exposure patterns?

• What methods, models, and decision support tools are needed to  support analysis of potential
  risks associated with exposures to multiple chemicals in the context of other important
  environmental  stressors across development?

Anticipated integrated impact:

Agency has tools to evaluate benefits of alternatives and support decisions. Evaluated, acces-
sible tools  enhance agency capacity to adequately consider children's unique susceptibilities and
vulnerabilities in Agency risk-based evaluations and sustainable public health decisions.

Specific models and methods to evaluate early lifestage specific risks and support regulatory
decisions including:

• Efficient, cost-effective methods for monitoring children's exposures.

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• Tools for assessing exposure (timing and duration)-dose-response relationships in children
  including physiologically-based pharmacokinetic (PBPK) models that incorporate early life-stage
  specific parameters.

• Novel computational tools to incorporate estimates of developmental toxicity into risk
  assessments.

• Risk assessment tools for incorporating multiple exposures across multiple vulnerable stages to
  estimate risks that may accrue over time.

• Web-based tools that incorporate early lifestage-specific factors for predicting source-to-effects.

• Extend models and methods to estimate children's exposures at spatial and temporal scales
  relevant to the pollutant and health endpoint of concern.

Research Area 4: Translational research and tools to support community
actions and decisions

Federal, State, Tribal and local  governments  make decisions at multiple scales (national to local)
that impact children's health and well-being. Decision support tools that incorporate multiple
factors about the built and natural environments that contribute to children's health, along with
child-specific exposure and risk factors (including non-chemical stressors), can support informed
decisions that protect and promote children's health in the communities where they live, learn,
and play. Ideally, these tools should be developed through partnerships and active engagement
with affected communities and suitable for use across geographic scales.

Key research questions:

• What are the real-world environmental exposures to children in their homes, schools, and
  communities, and how do they contribute to children's health risks?

• How do social and economic factors, including those specific to place, influence lifestage-
  specific exposure and risk?

• What tools can provide communities with the  lifestage-specific information needed to support
  local decisions and actions?

• How can information regarding real-world environmental exposures to children inform
  community-based decisions  in key sectors (e.g., land use; buildings and infrastructure;
  transportation; waste and materials management) to meet community needs?

• What are the most effective  actions to prevent adverse environmental exposures and promote
  child well-being, how effective are these, and how can these be best communicated to
  communities and parents?

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Anticipated integrated impact:

Agency can enable communities to take action. Information and translation tools are developed
to support Agency, State, Tribal, and local decision makers with the knowledge needed to manage
risks and to protect and promote CEH.

Specific research and tools to inform community decisions designed to protect and promote
CEH:

• Methods and models for measuring or estimating exposures in pregnant women and children to
  environmental contaminants and potentially harmful substances in air, water, house dust,
  soil, and products encountered in their day-to-day lives.

• Models for estimating cumulative exposures and how they may vary in indoor vs. outdoor
  environments.

• Methods for measuring the sustainable benefits and costs of community decisions designed to
  promote CEH such as increasing green space or access to healthy foods.

• Community assessment tools (e.g., geographic information system (GIS) models) that identify
  sources of exposures as  well as health-promoting factors with respect to specific places where
  children live, attend school, or recreate.

• Approaches for incorporating CEH into Health Impact Assessments.

• Approaches and guidance for optimizing the built environment to sustainably protect and foster
  CEH.


Research Alignment  and Coordination

The four CEH Research Areas are cross-cutting to ORD's six National Research Programs. Currently,
one or more of the four Research Areas is contained within each of the following NRPs: Air, Cli-
mate, and  Energy (ACE); Chemical  Safety for Sustainability (CSS); Human Health Risk Assessment
(HHRA); Sustainable and Healthy Communities (SHC); and Safe and Sustainable Water Resources
(SSWR). Several of the NRPs conduct research in all four areas. Details of the research are de-
scribed in the individual NRP Strategic Research Action Plans.

Modifiable environmental  factors addressed by ORD research include chemicals/classes of cur-
rent and emerging focus where the Agency  has a role in setting policy or in developing regulatory
actions. These include manufactured chemicals and materials (pesticides, solvents, industrial
chemicals, nanomaterials); hazardous chemicals released to the environment through improper
waste disposal or accidental releases to the environment; environmental contaminants resulting
from human activities such as energy generation (air pollutants); and water disinfection. Across
the NRPs, research is focused  on providing systems understanding  of the role of modifiable envi-
ronmental factors to the childhood diseases and disorders prevalent today, including adverse birth

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outcomes, asthma, neurodevelopmental disorders, and metabolic outcomes. Table 2 summarizes
the individual NRP contributions to the 4 research areas in the context of these prevalent CEH
health outcomes.

In addition, to meet the Agency's mandate for protecting children, ORD relies heavily on strategic
partnerships with dozens of organizations ranging from other federal agencies, state governments
and international organizations, to academia, nongovernmental organizations and industry. All
of the strategic partners have an interest in promoting and protecting children's health. Strategic
partnerships are finalized through numerous types of agreements including STAR Grants, Coopera-
tive Research and Development Agreements, Materials Transfer Agreements, and Memoranda of
Understanding.

One of ORD's leading partners in CEH research is the National Institute of Environmental Health
Sciences (NIEHS). EPA, through its STAR Grants, and NIEHS jointly fund the Children's Environ-
mental Health and Disease Research Centers. Currently, there are 16 active centers conducting
research to increase understanding of how environmental factors affect children's health, and to
promote translation of basic research findings into intervention and prevention methods to pre-
vent adverse health outcomes. Other important partnerships include those of the Association of
Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control (CDC), the Depart-
ment of Health and Human Services (DHHS), the Food and Drug Administration (FDA), the Depart-
ment of Housing and Urban Development (HUD), and several institutes at the National Institutes
of Health (NIH). These partnerships are critical for conducting basic research on children's health
as well as for implementing research focused on  interventions that support CEH.
Table 2. CEH research efforts as distributed across the four research areas
CHILDREN'S HEALTH OUTCOMES
RESEARCH AREA
Knowledge
Infrastructure
Systems
Understanding
Methods & Models
Community
Decision Support
Adverse Birth
Outcomes
CSS
CSS, SHC, SSWR,
ACE
CSS, HHRA
SHC, ACE
Asthma
HHRA
SHC, ACE
ACE, HHRA
SHC, ACE
Neurodevelopmental
Disorders
CSS, HHRA
CSS, SHC, ACE
CSS, HHRA
SHC
Metabolic
Syndrome
CSS, HHRA
CSS, SHC
CSS, HHRA
SHC

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Cross-Cutting ORD  Research

Current ORD Research

This section summarizes ORD's current and recently completed research activities (2012-15) as
they are aligned with the four CEH research areas described in Section III. These research activi-
ties are implemented by ORD's NRPs according to their respective StRAPs (http://www.epa.gov/
research/research-programs.htm). Each activity addresses NRP-specific outputs and at the same
time contributes to achieving the CEH Roadmap objectives. The NRP with key responsibility for
each of the activities is provided in parentheses after the project name in this section.

See Appendix A for further details on the research activities outlined below, as well as information
on additional ORD research activities; Appendix B for a summary of ORD published research on
CEH outcomes from 2008 - 2014; and Appendix C for databases and tools that ORD has developed
that include CEH information.

Current ORD activities in  Research Area 1 (knowledge infrastructure) include the compilation
of data on exposure factors; human behavior; chemical usage; and childhood physiological pa-
rameters, and the development of databases that provide the results of high-throughput in vitro
assays and in vivo studies. Under Research Area 2 (systems  understanding), ORD is developing
bioinformatics-based, adverse outcome pathway, and simulation models to evaluate the toxicity
of environmental chemicals. In addition, Children's  Research Centers and place-based studies are
evaluating the relationship between exposure and a variety of health outcomes in children and
adolescents, leading to an increased understanding of how interactions among complex stressors
may increase the sensitivity of children.  Research Area 3 (methods  and models) includes the de-
velopment of exposure assessment tools and human exposure models for environmental chemi-
cals. ORD is developing dosimetry models and using new approaches to categorize lifestages and
to evaluate chemical mixtures. Under Research Area 4 (translational research), ORD is developing
decision support tools to enable communities to provide healthy environments for children. ORD
is also translating  research findings on children's health to inform communities and other local
groups as they develop environmental health related strategies that are sustainable.

Research Area 1: Knowledge infrastructure to address the problem that
information and data are distributed and difficult to access

Currently, knowledge resources are being developed under Research Area 1 in the following three
areas: (1) exposure information, (2) early lifestage  pharmacokinetic parameters, and (3) develop-
mentally relevant  hazard data. ORD's relevant research in each of these areas is summarized as
follows:

(1) Exposure Information
Exposure data are critical for characterizing children's environments and for evaluating
interactions of children with the environment across development.

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Exposure Factors Handbook (HHRA)
Data about children's exposures and exposure factors, such as lifestage specific modeled estimates
of soil and dust ingestion, is incorporated into EPA's Exposure Factors Handbook (U.S. EPA, 2011);
available at http://cfpub.epa.gov/ncea/risk/recordisplav.cfm?deid=236252. The exposure fac-
tors include: drinking water consumption; soil and dust ingestion; inhalation rates; dermal factors
including skin area and soil adherence factors; consumption of fruits and vegetables, fish, meats,
dairy products, and homegrown foods; human milk intake; human activity factors; consumer prod-
uct use; and building characteristics.

Consolidated Human Activity Database (CHAD)
ORD's Consolidated Human Activity Database (CHAD) is a compilation of data on human behavior
from 24 individual studies (U.S. EPA, 2014d); available at: http://www.epa.gov/heasd/chad.html.
This resource includes more than 50,000 individual data days of detailed location and activity data
and corresponding demographic data including age, sex, employment, and education level.  Data
are included for all ages, including infants and children.

ExpoCast Database (CSS)
ExpoCast Database (ExpoCastDB) was developed to improve access to human exposure data from
observational studies, including those funded by ORD. ExpoCastDB consolidates measurements  of
chemicals of interest in environmental and biological media collected from homes and child care
centers. ExpoCastDB is available as a searchable database (U.S. EPA, 2014g); available at: http://
actor.epa.gov/actor/faces/ExpoCastDB/Home.isp on EPA's Aggregated Computational Resource
(ACToR) system, an online data warehouse that collects data on over 500,000 chemicals from over
1000 public sources (U.S. EPA,  2014a); available at: http://actor.epa.gov/actor/faces/ACToRHome.
]Sฃ.

Chemical and Product Categories (CSS)
Chemical and Product Categories (CPCat) is a database of information on how chemicals are used
(U.S. EPA, 2014b); available at: http://actor.epa.gov/actor/faces/CPCatLaunch.isp. CPCat contains
information on the uses of chemicals (including use by children), products that  contain chemicals,
manufacturers of the products, and a hierarchy of consumer product "use" categories. It also
contains information on any regulations or studies in which the chemical has been considered
hazardous to children.

(2) Early Lifestage Pharmacokinetic Parameters
Pharmacokinetic and pharmacodynamic parameters for all lifestages are required to predict the
potential for health effects from exposures to environmental chemicals. Child-specific parameters
are used to characterize dose to the developing child in utero, after birth through lactational expo-
sure, and during early infancy through prepubertal ages.

Enzyme Ontogeny Database (CSS)
Chemicals are often biotransformed in the body by activating and/or detoxifying enzymes whose
expression changes over time from the developing embryo to adulthood.  Thus, metabolic capac-
ity based on the spectrum and relative quantity of critical enzymes at different  lifestages can play

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an important role in determining childhood susceptibility to environmental chemicals. ORD has
developed an enzyme ontogeny database that is useful for the development of PBPK models to
explore metabolism-based variability during early lifestages.

(3) Developmentally Relevant Hazard Data
Data from in vivo animal studies, screening assays, and other study types are needed in order to
carry out risk and hazard assessments on environmental chemicals. ORD has developed databases
that allow easy access to developmental hazard data that is being used to link environmental ex-
posures at early lifestages with health outcomes in children and later in life.

ToxCast Database (CSS)
ToxCastDB provides results of high-throughput in vitro assays. Biology covered in the large set of
assays include endpoints related to endocrine, reproductive, and developmental toxicity. A major
proportion of the assays are human-based cells or proteins. ToxCastDB is available as a searchable
database through the ACToR system (U.S. EPA, 2014i);  available at: http://actor.epa.gov/actor/
faces/ToxCastDB/Home.isp.

Toxicity Reference Database (CSS)
Toxicity Reference Database (ToxRefDB) contains data from thousands of in  vivo animal studies
and is available as a searchable database through the ACToR system (U.S. EPA, 2014J); available
at: http://actor.epa.gov/toxrefdb/faces/Home.isp. Developmental toxicity data includes results
from studies on more than 380 chemicals with 18 endpoints for both the rat and rabbit, while
the reproductive toxicity information is based on the results from multigenerational reproductive
studies on 316 chemicals, with 19 parental, reproductive, and offspring endpoints.

Adverse Outcome Pathway Wiki (CSS)
An Adverse Outcome Pathway (AOP) is a conceptual framework that portrays existing knowledge
concerning the linkage between a direct molecular initiating event and an adverse outcome. The
goal of an AOP  is to provide the framework to connect the two events. AOP Wiki is a wiki-based
tool that provides an interface for collaborative sharing of established AOPs and building  new
AOPs (Anonymous, 2014); available at: http://aopkb.org/aopwiki/index.php/Main Page.  AOP Wiki
uses templates to make it easier for users to include the  information needed for proper evaluation
of an AOP. Developmentally relevant AOPs are being incorporated. Currently, endocrine pathways
are well represented.

Research Area 2: Systems understanding of the relationship  between
environmental exposures and health outcomes across  development

Research Area 2 has been divided into the following two subgroups: (1) systems biology to predict
developmentally relevant outcomes, and (2) systems understanding of complex stressors. ORD's
relevant research in each of these areas is summarized as follows:

(1) Systems Biology to Predict Developmentally Relevant Outcomes
Systems models for tissues and multi-organ pathways specific to embryo-fetal and neonatal devel-
opment are being developed. These models increase the Agency's understanding of the biologic
mechanisms of chemical stressors that contribute to childhood health outcomes.

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Bioinformatics-Based Models (CSS]
As discussed on page 27, ToxCastDB uses high-throughput biochemical and cellular in vitro assays
to evaluate the toxicity of environmental chemicals. The development of predictive models is be-
ing carried out in phases, with the development and publication of first-generation (Phase I) Tox-
Cast predictive models for reproductive toxicity (M. T. Martin et al., 2011) and developmental tox-
icity (Sipes et al., 2011). Pathways for endocrine disruption (Reif et al., 2010), embryonic stem cell
differentiation (Chandler et al., 2011) and disruption of blood vessel development (Kleinstreuer
et al., 2011) have been linked to the Phase I ToxCast in vitro data. For the next approximately 700
compounds in Phase II, where animal toxicology is less well-characterized, ORD is developing plau-
sible model structures that deal with the possibility of additional relevant interactions and compo-
nents beyond those represented in the first-generation predictive models.

AOP Models (CSS)
ORD is developing AOP models, such as the vascular AOP model, with the aim of establishing the
predictive value of chemical  disruption of blood vessel development (vasculogenesis) during criti-
cal windows of embryonic and fetal development. A vasculogenesis model is being tested in zebra
fish embryos and in embryonic stem cells. As additional individual AOPs are developed, they can
be assembled into AOP networks that may aid the prediction of more complex interactions and
outcomes resulting from exposure to complex mixtures and/or chemicals with multiple modes of
actions.

Simulation Models (CSS)
Simulation models predict chemical toxicity using relevant biologic information,  such as the influ-
ence of subcellular pathways and networks on the development of tissues and organs. ORD is
developing the Virtual Embryo model, a simulation model of predictive toxicology of children's
health and development, which can be applied to prenatal or postnatal (including lactational)
exposures.

(2) Systems Understanding of Complex Stressors
Epidemiologic, animal studies, and in vitro assays  are being  used to develop a  systems understand-
ing of the relationship between environmental exposures as stressors and  lifestage-specific sus-
ceptibility and vulnerability.

Laboratory-Based Studies (CSS and SHC)
Intramural ORD research has used a variety of in vitro models to evaluate the effects of chemical
exposure in developmentally relevant systems.  Cell (e.g., human multipotent neuroprogenitors,
rodent embryonic stem cells, specific pathway-responsive modified hepatocytes), organ (e.g., hu-
man and rodent palatal shelves), and whole rodent embryo cultures, as well as whole organisms
(developing zebrafish) have been used to address issues of toxic response. Many of these models
have been developed, characterized, and refined to answer specific research questions. Several
model systems have been used to evaluate the effects of chemicals to aid in the translation of
high-throughput data in the  ToxCast assays. In vitro approaches using adipocyte  stem cells are also
being developed as potential predictors of obesity and to explore cellular mechanisms of action of
specific chemicals.

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Experimental research is also addressing causality in(longitudinal) lifecourse rodent studies where
effects of early life exposures on postnatal development and multiple health outcomes can be
evaluated under controlled laboratory conditions. These studies are also being used to examine
the extent to which modifying factors such as diet, exercise, and stress may alter sensitivity to
chemical stressors, a question relevant to diverse community settings and conditions.

Epidemiological Studies (SHC and ACE)
EPA-NIEHS Children's Environmental Health and Disease Prevention Research Centers (CEHC)
The EPA-NIEHS jointly funded Children's Environmental Health and Disease Prevention Research
Centers (CEHCs, or "Children's Centers") Program, ongoing since 1998, continues to generate
exposure and biomarker data in pregnant women and children, along with mechanistic data in
experimental models, in order to show relationships between exposure to chemical  contaminants
and a variety of children's health outcomes, and to identify critical windows of susceptibility
(U.S. EPA, 2014e); available at: www.epa.gov/ncer/childrenscenters: http://cfpub.epa.gov/
ncer abstracts/index.cfm/fuseaction/recipients.displav/rfa id/560/records per  page/ALL. The
long-range goals of this STAR Program  include understanding how environmental factors affect
children's health, and promoting translation of  basic research findings into intervention and
prevention methods to prevent adverse health  outcomes (Table 3).

Table 3. Current EPA/NIEHS Children's Environmental Health and Disease Prevention
Research Centers exploring associations between exposures and health outcomes in children
Institution- P.I.
Brown University
- Boekelheide
Columbia
University -
Perera
Dartmouth
College- Karagas
Duke University/
University of
Michigan -
Miranda
Duke University
- Murphy
Johns Hopkins
University -
Diette
National
Jewish Health -
Schwartz, Szefler
Chemical Exposures
and Other Stressors
Arsenic, EDCs (estra-
diol, BPA, genistein),
dietary restriction
Endocrine Disrupting
Compounds (BPA),
PAHs,
Arsenic in drinking
water and food
Environmental,
social and individual
susceptibility factors,
PM, Ozone
Environmental
tobacco smoke
Airborne pollutants
(particulate matter,
nitrogen dioxide),
allergens, urban diets
Air pollution (ozone,
PM, NO2), ambient
bacterial endotoxin
Outcomes
Fetal liver, lung and
prostate development;
prostate cancer in later life
Neurodevelopmental
disorders such as
problems with learning
and behavior; obesity and
metabolic disorders
Growth and development;
immune response
Disparities in birth
outcomes, respiratory
health in infants
ADHD, neurobehavioral
dysfunction
Asthma
Asthma, immune system
function, determinants of
host defense
Underlying Mechanisms
(molecular, genetic, social
factors)
Endocrine disruption; Epigenetic
changes in organ development
Endocrine disruption; Epigenetic
reprogramming and metabolic
syndrome
Epigenetic changes and influence
of gut microbiome
Social determinants of childhood
disease
Epigenetic modulation in fetal
and child development
Dietary contributions to asthma,
based on anti-oxidant and
anti-inflammatory impacts
on immune function and
inflammation
Host-immune responses and TL4
receptor function; interactions
between ozone and endotoxin

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Table 3. (continued) Current EPA/NIEHS Children's Environmental Health and Disease Prevention
Research Centers exploring associations between exposures and health outcomes in children
Institution -P.I.
University of
California at
Berkeley - Buffler,
Metayer
University of
California at
Berkeley -
Eskenazi
University of
California at
Berkeley -
Hammond,
Balmes, Shaw
University of
California at
Davis -
Van de Water
University of
California at
San Francisco -
Woodruff
University of
Illinois at Urbana-
Champaign-
Schantz
University
of Michigan
- Peterson,
Padmanabhan
University
of Southern
California -
McConnell
University of
Washington -
Faustman
Chemical Exposures
and Other Stressors
Pesticides, tobacco-
related contaminants,
chemicals in house
dust(PCBs, PBDEs)
Pesticides (DDT,
manganese), flame
retard ants
Ambient air
pollutants (airborne
PAHs), in utero
exposure to traffic-
related pollutants,
endotoxin
BPDEs, pyrethroid
insecticides,
perfluorinated
compounds, POPs
EDCs, PBDEs (BDE-
47), PFCs (PFOA),
psychosocial stress
EDCs (phthalates,
BPB), high fat diet
BPA, phthalates, lead,
cadmium
Near-roadway air
pollution including
elemental carbon,
PM2.5
Agricultural pesticides
Outcomes
Childhood leukemia
Neurodevelopment,
growth and timing of
puberty, obesity
Birth defects/preterm
birth, immune system
dysfunction (asthma/
allergies), obesity/glucose
dysregulation
Autism spectrum disorder
(ASD)
Placental and fetal
development, adverse
birth outcomes
Neurological and
reproductive development
Birth outcomes, child
weight gain, body
composition, activity
patterns, hormonal
levels, sexual maturation,
metabolomics and risk of
metabolic syndrome
Obesity, fat distribution,
metabolic phenotypes,
systemic inflammation
Altered neurodevelopment
Underlying Mechanisms
(molecular, genetic, social
factors)
Epigenetic and genetic
influences
Epigenetic reprogramming,
altered endocrine status
Gene variants in
biotransformation enzymes;
molecular mechanisms
e.g., altered T-cell function;
neighborhood factors
Immune dysfunction and
autoimmunity, genetic/epigenetic
contributions
Gene expression changes
via epigenetic mechanism,
contribution of psychosocial
stress
Endocrine disruption, oxidative
stress
Dietary influences; epigenetics
and gene expression changes;
oxidative stress
Expression of genes in metabolic
pathways, beta cell function,
oxidative stress;
Genetic susceptibility,
neurotoxicity, oxidative stress,
cellular pathways underlying
neurodevelopment

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Clean Air Research Centers (ACE)
ORD's Clean Air Research Centers Program includes a number of epidemiologic projects directly
relevant to CEH. Two currently active Children's Centers are producing new data and knowledge
on the relationship between air pollution and children's health, with final reports expected in
2015. The Children's Center at Emory University is generating "Novel estimates of pollutant mix-
tures and pediatric health in two birth cohorts/' and the Children's Center at Harvard University is
evaluating "Longitudinal effects of multiple pollutants on child growth, blood pressure and cogni-
tion." (U.S. EPA, 2012); available at: http://www.epa.gov/ncer/quickfinder/airqualitv.html.

Place-Based Studies (ACE and SHC)
ORD recognizes that combinations of stressors are often unique to a particular community setting
and that interventions to improve children's health must take this complexity into account. For ex-
ample, a STAR grant and ORD in-house project,  The Near-Road Exposures and Effects of Urban Air
Pollutants Study (NEXUS) (ACE), examined the influence of traffic related air-pollutants on respira-
tory outcomes in a cohort of 139 asthmatic children (ages 6-14) who lived close to major road-
ways in Detroit, Ml. Another place-based study, The Mechanistic Indicators of Childhood Asthma
(MICA) Study (SHC), was designed to pilot an integrative approach in children's  health research.
MICA incorporates exposure metrics, internal dose measures, and clinical indicators to decipher
the biological complexity inherent in diseases such as asthma and cardiovascular disease with eti-
ology related to gene-environment interactions. Additionally, grantees are conducting place-based
research exploring interactions among stress and air pollution in community settings; how school
conditions influence academic performance (SHC); and how to predict exposures for children liv-
ing near a Superfund site (ACE).

Research Area 3:  Methods and models to evaluate early lifestage-specific
risks and to support decisions protective of all lifestages

Research Area 3 has been divided into the following two subgroups: (1) exposure, and (2) dosim-
etry models. ORD's relevant research in each of these areas is summarized as follows:

(1) Exposure
ORD has developed tools to increase the usability and access to exposure data, models to predict
exposure by a variety of pathways and  routes, and approaches for categorizing  lifestage changes
and prioritizing chemical mixtures.

EPA ExpoBox (HHRA)
EPA ExpoBox is a  web-based compendium of over 800 exposure assessment tools that provides
links to exposure assessment databases, models, and references (U.S.  EPA, 2013c); available at:
http://www.epa.gov/ncea/risk/expobox/docs/archive/Expobox  Fact-Sheet  Novl3.pdf. It includes
approaches for exposure assessments; tiers and types of exposure assessments; chemical classes;
routes of exposure to chemicals, lifestages and populations; and exposure media. It also includes,
in a searchable and downloadable format, the full list of exposure factors from the Exposure Fac-
tors Handbook (see page 26).

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SHEDS-HT Model (CSS)
The Stochastic Human Exposure and Dose Simulation-HT (SHEDS-HT) model is a screening-level
human exposure model for chemicals. Exposure results can also be estimated for individual age-
gender cohorts. Exposure-relevant information specific to children included in SHEDS-HT includes
age-specific behaviors (such as hand-to-mouth contact and use of consumer products), time spent
in microenvironments, and food intakes.

ExpoCast (CSS)
ExpoCast is a rapid, high-throughput model using off-the-shelf technology that predicts exposures
for thousands of chemicals (U.S. EPA, 2014f); available at: http://epa.gov/ncct/expocast/. ORD
research is generating and incorporating new information about age-dependent exposures (e.g.,
product use) into ExpoCast to support risk-based decisions. This model can be more specifically
applied to capture children's unique vulnerabilities.

(2) Dosimetry Models
ORD has developed a number of dosimetry models that assess exposure, predict dose, and de-
scribe the kinetics of environmental chemicals as related to children's health.

Empirical Models (CSS)
Persistent Bioaccumulative Toxicants
A statistical model was developed for predicting levels of polybrominated diphenyl ethers (PBDEs)
in breast milk, based on serum data from the National Health and Nutrition Examination Survey
(NHANES) (Marchitti et al.,  2013).  In this research, congener-specific linear regression partitioning
models were developed and applied to 2003-2004 NHANES serum data for U.S. women. These
models provide a sustainable method for estimating population-level concentrations of PBDEs in
U.S. breast milk and should improve exposure estimates in breastfeeding infants.
ORD is now applying this approach to other environmental chemicals (dioxins, perfluorinated
compounds (PFCs), polychlorinated biphenyls (PCBs), and organochlorine pesticides). ORD is also
working on developing a comprehensive quantitative structure-activity relationship (QSAR)-based
model for predicting milk:serum partitioning ratios for classes of chemicals where serum and milk
data are not available to construct regression models.
In vitro to In vivo Extrapolation
ORD has proposed an approach to link results from in vitro high-throughput studies with popula-
tion group-specific dosimetry for neonates, children,  and adults, and exposure estimates (Wet-
more et al., 2014). For nine ToxCast chemicals, pharmacokinetic models for multiple population
groups were constructed that predicted chemical concentrations in the blood at steady state.
These models have potential application to estimate chemical-specific pharmacokinetic uncertain-
ty factors and to estimate population group-specific oral equivalent dose values to aid in chemical
prioritization and identifying population groups with greater  susceptibility to potential pathway
perturbations.

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PBPK Models
Virtual Embryo Project (CSS)
ORD has developed a life-stage PBPK model, which has been incorporated into the Virtual Embryo
project. This model was developed to computationally investigate the relationship between chem-
ical exposure, tissue dosimetry, and in vitro markers of critical events related to AOPs. The model
includes time-changing physiological and biochemical descriptors related to a pregnant mother,
fetal growth, and child exposure through lactation.
Ethanol (ACE)
To supplement and complete PBPK models in the literature, ORD developed PBPK models to
describe the kinetics of ethanol in adult, pregnant, and neonatal rats for the inhalation, oral, and
intravenous routes of exposure (S. A. Martin et al., 2012).

Research Area 4: Translational research and tools to support community
actions and decisions

Research Area 4 has been divided into the following four subgroups: (1) decision support tools, (2)
problem driven research, (3) translational research, and (4) social determinants of health. ORD's
relevant research in each of these areas is summarized as follows:

(1) Decision Support Tools
ORD is developing decision support tools for State, Tribal, local governments, and other organiza-
tions in order to make sound decisions about both community development and healthful envi-
ronments, and to avoid unintended consequences.

Community-Focused Exposure and Risk Screening Tool (SHC)
ORD has developed the Community-Focused Exposure and Risk Screening Tool (C-FERST) (U.S. EPA,
2013a); available at: http://www.epa.gov/heasd/c-ferst/. which has been developed as a "toolkit"
for step-by-step community assessment guidance (e.g., Community Action for Renewed Environ-
ment (CARE) roadmap), GIS maps, reports, fact sheets, best practices, and potential solutions.
Children's health  issues in C-FERST currently include childhood lead exposure, childhood asthma,
and schools. Recently, C-FERST was used, along with other tools, to inform a Health Impact Assess-
ment (HIA) related to school renovation decisions in Springfield, Massachusetts.

EnviroAtlas (SHC)
EnviroAtlas, publicly released in May 2014, includes, at least for selected urban  areas, such
indicators as the locations of schools, recreational areas, factors relevant to health outcomes
(demographics, income), access to transportation routes, and indicators of ecosystem services
such as tree cover (related to heat, recreation, green-space accessibility). This tool also includes
an Eco-Health Relationship Browser (U.S. EPA, 2013b); available at: http://enviroatlas.epa.gov/
enviroatlas/Tools/EcoHealth RelationshipBrowser/introduction.html. Health outcomes currently
searchable in the browser of direct relevance to CEH include low birth weight and preterm birth;
asthma; ADHD; and obesity.

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(2) Problem-Driven Research
Studies are being conducted to further the understanding of linkages between human health and
environmental exposures. Communities are using results of these analyses to make decisions
concerning renovation of schools, location of recreational areas, and future development.

EPA Pilot Study Add-On to the Third Study Site of the Green Housing Study (SHC)
The Green Housing Study is a collaborative effort between HUD and CDC. In partnership with HUD
and CDC, ORD will collect additional multimedia measurements and questionnaire data from the
index children and a sibling(s) actively participating in the Green Housing Study in order to char-
acterize personal, housing, and community factors influencing children's potential exposures to
indoor contaminants at various lifestages.

Dust and Soil Ingestion (SHC)
ORD is using models to estimate different exposure parameters, such soil and dust ingestion rates,
in children. For example, ORD used the SHEDS-Soil/dust model to estimate soil and dust ingestion
rates for young children at two Taiwanese locations, and for simulations pertinent to U.S. children
in specific age categories (Glen et al., 2013).

Chemical and Non-chemical Stressors and Childhood Obesity (SHC)
ORD is currently completing a state-of-the-science literature review to identify chemical and
non-chemical stressors related to childhood obesity. Numerous chemical and non-chemical
stressors were identified and grouped into the following domains: individual, family, community,
and chemical. Data shows that there is not always a positive association between a stressor and
childhood obesity, and that there can be inconsistent correlations between the same stressors and
obesity. However, there is sufficient evidence to suggest the interactions of multiple stressors may
contribute to the childhood obesity epidemic.

Chemical and Non-chemical Stressors and Neurocognitive Health (SHC)
ORD is conducting research to examine stressors related to neurocognitive health in children,
ages 3-6 years. Key exposure factors were identified for each developmental lifestage from preg-
nancy to 3-6 years old. These elements were incorporated into a model and the results suggest
that some childhood exposures (e.g., socioeconomic status, parent-child interaction, diet, built
environment) not only present as key factors, but act as effect modifiers of stressors experienced
during pregnancy and infancy (e.g., lead, pesticides, prenatal stress).

Community Multi-scale Air Quality Model (ACE)
The EPA's Community Multi-scale Air Quality (CMAQ) Model is a powerful computational tool used
by EPA and states for air quality management that gives detailed information about the concentra-
tions of air pollutants in a given area. Comparison of data from the CMAQ model with  birth out-
comes or childhood hospital admissions for asthma has generated data on associations between
pollutant exposure (i.e., particulate matter (PM) or  ozone) and health outcomes (U.S. EPA, 2014c),
available at:  http://www.epa.gov/AMD/Research/RIA/cmaq.html.
See Appendix A for additional examples of problem-driven technical support and research on PCBs
in Schools (HHRA)  and Child-Specific Exposure Scenarios examples (HHRA).

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(3) Translational Research

Translational research involves translating the results from research on children's health into find-
ings that are useful to communities, neighborhoods, health care providers, or other groups as they
develop strategies to work on local environmental health issues.

EPA/NIEHS Children's Center Program (SHC)

As discussed on page 29, the EPA-NIEHS co-funded Children's Centers (CEHCs) Program is gen-
erating exposure and biomarker data in pregnant women and children, showing relationships
between exposure and a variety of children's health outcomes, and identifying critical windows of
susceptibility (U.S. EPA, 2014e); available at: www.epa.gov/ncer/childrenscenters. A critical and
unique component of the Children's Centers Program is the inclusion of Community Outreach and
Translation Cores. These  cores use a variety of innovative approaches to translate research find-
ings and  intervention strategies to community stakeholders (see Table 4).

Table 4.   EPA/NIEHS Children's Centers community outreach and translation -
community partners
 Institution -
 P.I.
 Brown
 University -
 Boekelheide
Study Site
Location(s)
Providence,
Rhode Island
Community Outreach and Translation -with Community Partners
Silent Spring Institute, Environmental Justice League of Rhode Island
 Columbia       New York City   Bronx Borough Presidents Office, Bronx Health Link, Columbia
 University-     (Northern      Community Partnership for Health, Columbia University Head Start,
 Perera          Manhattan and  Community Health Worker Network of NYC, Dominican Medical
                South Bronx),   Association, New York, Harlem Children's Zone Asthma Initiative,
                Poland, China   Harlem Health Promotion, Northern Manhattan Perinatal Partnership,
                              Nos Quedamos, WE ACT for Environmental Justice
 Dartmouth      Hanover, New   Dartmouth-Hitchcock Concord Clinic, Concord Hospital Family Clinic,
 College-        Hampshire     Concord Obstetrics and Gynecology Professional Associates, Concord
 Karagas                       Women's Care, Family Tree Health Care (Warner, NH), Dartmouth
                              Hitchcock Lebanon Clinic, Concord Hospital, The Family Place,
                              Dartmouth-Hitchcock Medical Center, New Hampshire Department
                              of Environmental Health Services, New Hampshire Birth Conditions
                              Program, University of New Hampshire Department of Molecular,
                              Cellular and Biomedical Sciences
 Duke           Durham, North  Durham Congregations, Associations, and Neighborhoods (CAN),
 University/      Carolina and    Triangle Residential Options for Substance Abusers (TROSA), Durham
 University of    Ann Arbor,      Affordable Housing Coalition, Partnership Effort for the Advancement
 Michigan -      Michigan       of Childrens Health/Clear Corps (PEACH), Durham People's Alliance,
 Miranda                      Durham County Health Department, Lincoln Community Health
                              Center, Duke University Nursing School Watts School of Nursing, City
                              of Durham Department of Neighborhood Improvement Services,
                              City of Durham Department of Community Development, Children's
                              Environmental Health Branch of NC Department of Environment and
                              Natural Resources, North Carolina Asthma Alliance, East Coast Migrant
                              Head Start, North Carolina Community Health Center Association,
                              North Carolina Rural Communities Assistance Project
 Duke
 University-
 Murphy
Durham, NC     DukeEngage Program, El Centro Hispano (local Latino community),
               Partnership for a Healthy Durham

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Table 4. (continued) EPA/NIEHS Children's Centers community outreach and translation -
community partners
Institution -
P.I.
Johns Hopkins
University -
Diette
National
Jewish Health
- Schwartz,
Szefler
University
of California
at Berkeley
- Buffler,
Metayer
University of
California at
Berkeley -
Eskenazi
University
of California
at Berkeley/
Stanford
University -
Hammond,
Balmes, Shaw
University of
California at
Davis -Van de
Water
University of
California at
San Francisco -
Woodruff
University
of Illinois
at Urbana-
Champaign -
Schantz
Study Site
Location(s)
Baltimore, MD
Denver, CO
Berkeley, CA
Berkeley and
Salinas, CA
Berkeley,
Palo Alto,
Bakersfield and
San Joaquin
Valley, CA
Davis, CA
San Francisco,
CA
Urbana-
Champaign,
IL, and New
Bedford, MA
Community Outreach and Translation -with Community Partners
Baltimore City Head Start Program, Baltimore City Health Department
Healthy Homes Program, Baltimore School Food Services Program,
Healthy Stores Program, Maryland Asthma Control Program, Women
Infants and Children (WIC) nutrition programs
Colorado Asthma Coalition, Colorado Clinical Guidelines Collaborative,
Colorado Department of Public Health and Environment, Denver
Public School System, Lung Association of Colorado, Rocky Mountain
Prevention Research Center, EPA Region 8, Alamosa Public School,
Denver Health, Colorado Public Health, Practice Based Research
Network, Regional Air Quality Council, Colorado Air Quality
Commission, Grand Junction Housing Authority, Western Colorado
Math & Science Center, Region 8 Pediatric Environmental Health
Specialty Unit (PEHSU)
Network of 8 clinical institutions in northern and central California
participating in the Northern California Childhood Leukemia Study (NC-
CLS), national community of pediatric health care professionals with an
interest in environmental health issues; national community of persons
interested in leukemia; California community of persons interested in
childhood leukemia; Region 9 Pediatric Environmental Health Specialty
Unit (PEHSU)
Clinica de Salud del Valle de Salinas, Natividad Medical Center, South
County Outreach Effort (SCORE), Monterey County Health Department,
California Rural Legal Assistance (CRLA) Program, Grower/Shipper
Association of Central California
Medical Advocates for Healthy Air; Fresno Metro Ministry; Center
on Race, Poverty, and the Environment; San Joaquin Valley Latino
Environmental Advancement Project (LEAP); El Comite para el Bienestar
de Earlimart; Coalition for Clean Air; San Joaquin Valley Cumulative
Health Impact Project (SJV-CHIP); Central California Environmental
Justice Network; Central Valley Air Quality Coalition; Californians for
Pesticide Reform
Families for Early Autism Treatment, Learning Disabilities Association,
Parents Helping Parents, San Francisco Bay Chapter of the Autism
Society of America, Alameda County Developmental Disabilities
Council, Cure Autism Now, State of California health/developmental
service providers, California Departments of Developmental Services
and Health Services, California Regional Centers and Office of
Environmental Health Hazard Assessment
American College of Obstetricians and Gynecologists (ACOG District
IX), Association of Reproductive Health Professionals, Physicians for
Social Responsibility (PSR) San Francisco Bay Area Chapter, WORKSAFE
(California Coalition for Worker Occupational Safety & Health
Protection), California Department of Health Occupational Health
Branch
Illinois Action for Children (IAFC), American Academy of Pediatrics
(AAP), Just-In-Time Parenting, Champaign-Urbana Public Health
Department, Great Lakes Center for Environmental Health, Cambridge
Health Alliance, Carle Foundation Hospital, Provena Covenant Medical
Center

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Table 4. (continued) EPA/NIEHS Children's Centers community outreach and translation -
community partners
Institution -
P.I.
University
of Michigan
- Peterson,
Padmanabhan
University
of Southern
California -
McConnell
University of
Washington -
Faustman
Study Site
Location(s)
Ann Arbor, Ml,
and Mexico
City, Mexico
Los Angeles,
CA
Yakima Valley,
WA
Community Outreach and Translation - with Community Partners
Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT),
National Institute of Public Health, Mexico City, Detroit Hispanic
Development Corporation
The Children's Clinic (Long Beach and South Bay), Asian and Pacific
Islander Obesity Prevention Alliance, East Yard Communities for
Environmental Justice, Digital Rain Factory, Los Angeles Parks
Foundation, The Trust for Public Land Center for Park Excellence,
Policies for Livable, Active Communities and Environments (PLACE) of
Los Angeles, Trade, Health and Environment Impact Project, Center
for Community Action & Environmental Justice (Riverside and San
Bernardino), Coalition for a Safe Environment (Wilmington), East Yard
Communities for Environmental Justice (Commerce and East LA.),
Long Beach Alliance for Children with Asthma, Outreach Program of
Southern California Environmental Health Sciences Center Los Angeles
(USC/UCLA), Urban & Environmental Policy Institute, Occidental College
Community members in the Yakima Valley, Farm Workers Union,
Growers' Association, Washington State Department of Health and
Department of Agriculture, Farm Workers' Union, Yakima Valley
Farm Workers Clinics, Radio KDNA (Spanish language), Washington
State Department of Labor and Industries, Columbia Legal Services,
Washington State Migrant Council, EPA Region 10
 (4) Social Determinants of Health (Place-Based Studies]
 ORD is carrying out research on the biological, environmental, and social conditions that may
 contribute to disparities in health outcomes in children.

 NIMHD Centers of Excellence on Environment and Health Disparities (SHC)
 Social determinants of health are a focus of research in the EPA and NIMHD Centers of Excellence
 on Environment and Health  Disparities (http://www.epa.gov/ncer/ehs/disparities/health-
 disparities.html). ORD, through an interagency agreement with the National Institute of Minority
 Health and Health  Disparities (NIMHD) (http://www.nih.gov/about/almanac/organization/
 NIMHD.htm) is supporting the establishment of transdisciplinary networks of excellence in health
 disparities research to achieve a better understanding of the complex interactions of biological,
 social, and environmental determinants of population health.
 One of these Center projects, "Analysis and Action on the Environmental Determinants of Health
 and Health Disparities" (University of South Carolina) is exploring six areas of health disparities
 that contribute disproportionately to premature death and morbidity found among poor and
 racial/ethnic minorities (e.g., infant mortality). Another project, "Environmental Health Disparities
 Research" (University of Texas) is exploring the individual- and neighborhood-level contributions
 to disparities in children's pulmonary health.

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Environmental and Community Factors Influence Effectiveness of Medical Treatments for
Asthma (SHC)
An ORD study, in collaboration with the University of North Carolina, Observational Assessment of
Baseline Asthma Control as a Susceptibility Factor for Air Pollution Health Effects in African-Amer-
ican Children with Persistent Asthma, is examining factors that contribute to asthma disparities in
adolescents. The study is following a cohort of African-American youth with moderate-to-severe
asthma and examining a variety of factors including air pollution, home environment, and com-
munity issues that may contribute to the high rate of asthma in this population and the relative
effectiveness of medical treatments.

Integrated Approaches to Sustain the Built and Natural Environment and the Communities They
Support (SHC)
In this study, researchers are using GIS tools and multi-layered mapping to examine relationships
between access to green space and birth outcomes. Analyses focus on associations between birth
measures across the greater Durham-Chapel Hill, North Carolina area and various measures of
green space around the home, including tree cover along busy roadways.

Summary of ORD CEH Research Partnerships

ORD has partnered with a  number of other Federal agencies and independent organizations to
further CEH research. One example where EPA reached out to leverage expertise and capacity
with partner federal agencies is on the topic of endocrine disruption.  Evidence is mounting that
some chemicals disrupt the endocrine system. The endocrine system  regulates biological pro-
cesses throughout the body and is sensitive to small changes in hormone concentrations. Some
of this  research  has identified dose-response relationships that have nonmonotonic curves. Non-
monotonic dose-response curves (NMDRs) are of concern because they do not follow the usual
assumption made in toxicology that as  dose decreases, the response also decreases. In addition,
more complex interactions and outcomes resulting from exposure to complex mixtures and/or
chemicals with multiple modes of action are not addressed well with  existing models and assess-
ment tools. Prenatal and early-life exposures are of particular concern and additional complexity
is associated with the fact  that these exposures may lead to health impacts across the lifespan. As
a result, there is a need to shift thinking about how potential for adverse impacts and ultimately
riskis evaluated. To comprehensively evaluate the evidence in this arena, EPA has formed a work-
ing group with experts from several EPA offices, FDA, NIEHS, and  NICHD to explore this issue and
to write a state-of-the-science paper.

Table 5 lists some of ORD's partner organizations and the CEH programs that are currently under-
way through these partnerships.

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Table 5.  ORD Partnerships and Activities
 Partners           Research
 NTP/NIEHS         Children's Environmental Health and
                   Disease Research Centers
                   (http://epa.gov/ncerchildrenscenters/)
                                       Description
                                       Research to increase understanding how
                                       environmental factors affect children's
                                       health and promote translation of basic
                                       research findings into intervention and
                                       prevention methods to prevent adverse
                                       health outcomes.
 NTP/NIEHS         Systematic review of progestin use during
                   pregnancy
                   (http://dx.doi.org/10.1289/ehp.13067111
                                       Systematic review of progestin use during
                                       pregnancy with interest on the effects in
                                       the mother and offspring after exposure
                                       during pregnancy/gestation.
 NTP/NIEHS &      National Children's Study (http://www.
 NICHD; CDC        nationalchildrensstudv.gov/Pages/
                   default.aspx)
                                       Multi-year research study examining the
                                       effects of environmental influences on the
                                       health and development of children.
ATSDR;
Association of
Occupational and
Environmental
Clinics
Pediatric Environmental Specialty Units
fhttp://aoec.org/pehsu/aboutus.htmll
Ten specialty units across the U.S. that are
a source of medical information and advice
on environmental conditions that influence
children's health.
 HUD; CDC          EPA Pilot Study Add-On to the Green
                   Housing Study
                                       Study that is collecting additional
                                       multimedia measurements and
                                       questionnaire data from the index children
                                       in the Green Housing Study and a sibling(s)
                                       in order to characterize personal, housing,
                                       and community factors influencing
                                       children's potential exposures to indoor
                                       contaminants at various lifestages.
 CDC
National Birth Defects Prevention Study
(http://www.nbdps.org/)
Population-based, case-control study
examining the causes of birth defects.
 NIH/National
 Institute of
 Minority Health
 and Health
 Disparities
STAR Centers of Excellence of
Environment and Health Disparities
(http://www.epa.gov/ncer/ehs/
disparities/health-disparities, htm I)
 Networks of excellence in health dispari-
ties research to achieve a better under-
standing of the complex interactions of
biological, social and environmental deter-
minants of population health.
 DHHS, FDA,
 Health Resources
 and Services
 Administration,
 NIH, Office of
 the Assistant
 Secretary for
 Health, HUD, DOJ,
 and DOT
Interagency Asthma Disparities
Workgroup (part of the President's Task
Force on Environmental Health Risks and
Safety Risks to Children) (www.epa.gov/
childrenstaskforce)
Workgroup with the goal of reducing the
burden caused by asthma, particularly
among minority children and children with
family incomes below the poverty level.
 CAAT DNT         Center for Alternatives to Animal Testing
 workshop 2014     (CAAT) workshop on developmental
                   neurotoxicity testing
                   (http://caat.ihsph.edu/programs/
                   workshops/DNT4/)
                                       Presented information on cutting-edge
                                       technologies being used to develop
                                       alternative tests for developmental
                                       neurotoxicity testing.

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Research Gaps  and Priority Research Needs


In the context of Agency mandates for CEH information (Section IIA), the decision context as pre-
sented in the Translation Framework (Figure 2), and a set of high visibility child health outcomes
(Appendix D) identified by ORD and Program Partner members of the CEH roadmap working
group, a gap analysis was conducted to identify and prioritize needs for ORD research in CEH.

The ORD portfolio of active and planned CEH research as described in the evolving NRP Strategic
Research Action Plans was reviewed. Here, a strong set of tools for addressing current regulatory
mandates was identified. Gaps remain around specific needs for science and information to incor-
porate consideration of early lifestage sensitivity, susceptibility, and vulnerability into these tools.
Building confidence that EPA decisions are fully considering lifestage  specific issues will require
incorporating extant data and developing targeted information to reduce uncertainties in model
predictions and risk-based assessments.

Emerging scientific understanding of CEH and the potential role of modifiable exogenous environ-
mental factors was reviewed for a set of high-visibility health outcomes. Prevalence and trends
were summarized, as was evidence pointing to associations between early life exposure to envi-
ronmental contaminants and the following children's health outcomes: adverse birth outcomes,
asthma, neurodevelopmental disorders, metabolic syndrome, and childhood cancer. In addition,
maturing scientific understanding of shared mechanisms for these complex environmental diseas-
es (e.g., endocrine disruption) was considered. Building evidence in support of the Developmental
Origins of Health and Disease hypothesis including implications of epigenetic effects (Saffery and
Novakovic, 2014) was also identified as an important scientific driver for research in CEH as part of
this gap analysis.

The scope of CEH research activities in other federal agencies was evaluated. NIH (including NIEHS
and NICD) is making significant investments in research to increase the understanding of funda-
mentally shared mechanisms of complex disease, genetic susceptibility across the lifespan to envi-
ronmental diseases, and a broad range of  other modifying factors, including psychosocial stressors
(NIEHS, 2012). Based on this gap analysis,  it is clear that rather than duplicate these investments,
ORD will need to leverage these efforts and identify pivotal leadership roles for EPA.

Clear gaps remain in actionable science and information required to  understand, prevent, and
mitigate impacts to children from real-world exposures to air, water,  and chemicals. ORD leader-
ship is required to bring together science generated inside and outside the Agency to build pre-
dictive capacity to evaluate alternative actions and anticipate outcomes. This section highlights
priority research needs identified for each of the four CEH Roadmap  research areas. The bullet
points present the strategic  research gaps and the discussion provides examples of research needs
and potential approaches to begin  to address these needs.

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Research Area 1: Knowledge infrastructure to address the problem that
information and  data are distributed and difficult to access

Early lifestage-specific data that could support Agency decisions are being generated at an increas-
ing pace both within EPA and across the wider children's health research community. However,
significant barriers remain to effectively access and mine relevant information to understand and
predict the role of exposures to environmental factors during early life on health impacts. Priority
Agency needs in this research area are for:

• Accessible data on critical lifestage-specific factors that influence children's vulnerability and
  resilience to environmental insults, including efficient links to access/collate knowledge and
  data about such factors from research conducted across the wider CEH research community;

• Accessible information on lifestage-specific  determinants of activities, behaviors, physiology
  and exposure;

• Accessible information on susceptibility to chemicals and other contaminants based on lifestage
  (absorption, distribution, metabolism, excretion (ADME), toxicity, and PBPK considerations);

• Associated data on genetic susceptibility and increased susceptibility due to health and
  nutritional status, including pre-existing diseases and  disorders;

• Accessible lifestage-specific data for non-chemical stressors linked to the built and natural
  environments, and to social and economic factors; and,

• Accessible data and information that shows the inter-relationships between chemical exposures
  and factors modifying those exposures.

ORD can begin to address these gaps by leveraging current activities within the NRPs to apply ad-
vanced approaches for curating and providing access to data through high-interest use-cases (i.e.,
research focused on addressing a gap in one or more of the other three research areas described
in this Roadmap). For example, ORD has multiple activities focused on  providing web-based infor-
mation resources and associated web services to efficiently access these data  (e.g., dashboards) as
inputs to design workflows and analysis tools.

ORD has also developed a novel semi-automated approach using bioinformatics and computation-
al techniques to mine the literature and facilitate systematic review. Using MeSH terms, ORD can
find articles of interest and search in a systematic way. First, articles of interest are captured into
a set database using specific MeSH annotations. The MeSH terms for this first pass are generally
related to chemicals, proteins, or adverse outcomes of interest, but may include any MeSH terms.
Second, this set of publications are queried using additional terms (e.g., proteins, cell-processes,
species) to find  articles where these terms are co-annotated. The  co-annotation of terms gives
plausible hypotheses about their associations, as well as the publication reference, without having
to manually search the literature. Once these  relationships and articles are identified, the article
can be manually evaluated for evidence of this association. This database and mining approach is
useful for identifying global hypotheses about associations of interest such as  chemical-protein,
chemical-cell process, or chemical-adverse outcome at all levels of biological complexity. These

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relationships can then be used to build AOPs, understand unappreciated connections, and identify
current data gaps.

These approaches can be applied in the context of NRP-specific and cross-cutting ORD CEH re-
search to amplify the impact of investments in studies, models, and decision support tools.

Research Area 2: Systems understanding of the relationship between
environmental exposures and health outcomes across development

The NIH (including NIEHS and NICHD) is currently investing significant resources in research to
increase the Agency's understanding of the fundamental shared mechanisms of complex disease,
susceptibility across the life span to diseases resulting from environmental factors, and links
between the totality of environmental exposures and biological pathways (NIEHS, 2012). EPA's
Strategic Plan translates this fundamental knowledge to provide a systems understanding that is
necessary to adequately protect the health of children. As such, ORD can provide leadership in
addressing priority gaps associated with using systems-based understanding of biology (from the
molecular, tissue, and organ level out to the individual and population) to predict the potential for
adverse impacts associated with development, chemical use, and environmental contamination.
To effectively provide this leadership will  require strategic implementation of ORD's STAR extramu-
ral grants program and leveraging partnerships of other cross-agency partnerships. Priority gaps in
this area are broad and include the need for:

• Improved understanding of critical environmental factors, and interactions, that impact
  children's growth and development at  EPA-defined early lifestages (U.S. EPA, 2005) and across
  the lifecourse;

• Understanding of the extent to which environmental stressors contribute to the childhood
  diseases and disorders prevalent today, including: abnormal birth outcomes (neonatal mortality,
  premature birth, morbidity, birth defects), metabolic and endocrine imbalance (associated
  with obesity and neurological outcomes), cognitive disorders related to neurodevelopmental
  dysfunction (learning problems, attention deficit hyperactivity disorder (ADHD), autism), and
  respiratory dysfunction such as asthma; and,

• Complex systems models that integrate key determinants to predict potential outcomes and
  impacts.

The Adverse Outcome Pathway (AOP) framework currently gaining traction in the toxicology and
risk assessment communities provides an opportunity to integrate ORD CEH  research across NRPs
to begin to address these key gaps in the context of high-priority assessment needs specific to
early lifestages. An AOP portrays existing knowledge of linkage between a direct molecular initiat-
ing event and an adverse outcome at a biological level of organization relevant to risk assessment
(i.e., actionable) (Ankley et al., 2010). These AOPs provide a framework for organizing and commu-
nicating existing knowledge concerning the linkages between molecular initiating events, interme-
diate key events along a toxicity pathway, and apical adverse outcomes traditionally considered
relevant to risk assessment and/or regulatory decision making. When developed and evaluated
in a rigorous manner, AOPs provide a scientifically-defensible foundation for  extrapolating from

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mechanistic data to predicted apical outcomes. Additionally, as individual AOPs are developed,
they can be assembled into AOP networks that may aid the prediction of more complex interac-
tions and outcomes resulting from exposure to complex mixtures and/or chemicals with multiple
modes of action. These AOP networks then afford the opportunity to integrate and evaluate the
potential for impacts associated with nonchemical stressors, in addition to chemical stressors.
By considering AOPs and AOP networks associated with important developmental processes, as
well as those associated with disease endpoints of concern, mechanistic toxicology information
and epidemiology insights can be brought together for model development and analysis of critical
knowledge gaps.

A major challenge is to translate AOP frameworks across scales of biological organization (mol-
ecules, cells, tissues, populations) and function, while incorporating critical windows of exposure,
dose, pharmacodynamics, and pharmacokinetics. Multiscale modeling and simulation is a power-
ful approach for capturing and analyzing biological information that is inaccessible or unrealizable
from traditional modeling and experimental techniques. For example, virtual tissue models (VTMs)
afford the opportunity to develop science without conducting studies in children. By simulating a
range of predicted effects, the earliest signs of adversity can be identified, and new testable hy-
potheses aimed at improving the accuracy of inferences from in vitro data. These same modeling
approaches can be applied to capture the complexity of children's interactions with the environ-
ment in their home, school, and community as well as to postulate key environmental determi-
nants of health.

ORD will continue to identify effective strategies for fostering emerging scientific understanding
and encouraging application of the latest science to inform Agency decisions. For example, the im-
portance of epigenetic changes, i.e., the alteration of birth outcomes and/or the reprogramming
of cells to  promote disease susceptibility and metabolic dysfunctions that could occur later in life,
is just beginning to be understood.  Some of the EPA/NIEHS Children's Centers are currently doing
work in this area and further research is needed, using both experimental and epidemiological
approaches, to help increase the understanding of the extent to which environmentally-induced
epigenetic changes can contribute both to future disease status and future resilience.

Research Area 3: Methods and models to evaluate early lifestage-specific risks
and to support decisions protective of all lifestages

As guidance for incorporating consideration of lifestage-specific risks into Agency decisions are
implemented, the need to incorporate a wide range of lifestage-specific information into work-
flows and  analytical tools to  support assessments has increased. Methods and tools are needed
to effectively address a growing range of considerations and factors where data may be limited.
Priority needs are for:

• Rapid, efficient methods to characterize children's total environments, including the built and
  natural environments, where pregnant women and children live, learn,  and play;

• Rapid, efficient methods for evaluating potential for developmental toxicity science-based
  tools to  support consideration of critical child-specific vulnerabilities for environmental and
  health policy decisions that promote and protect children's health.

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For example, there is currently only limited information on exposures and exposure factors for
infants and children  less than 6 years of age. In addition, even when there is information on ex-
posure levels from biomonitoring or other sources, there is little knowledge on the pathways of
exposure, i.e., whether the exposure is predominantly from air, food, water, or other sources. Such
information remains a  critical gap in EPA's Exposure Factors Handbook (U.S. EPA, 2011), a resource
that is widely used across the Agency and by other organizations to conduct chemical risk assess-
ments. Novel, ultra-low burden approaches are required to develop the exposure factor informa-
tion and data required to support these Agency assessments of risks in early life. There are also
important gaps in methods and approaches for characterizing potential exposures associated with
the home, school, and community environment required to assess risks associated with real-world
exposures to mixtures, as well as to characterize potential modifying factors for more holistic deci-
sions and solutions.

Another high-priority Agency research need is for continued development and evaluation of as-
says and testing schemes to identify the potential for developmental toxicity and human-relevance
across the full range of critical endpoints.  Assays that can be implemented  in  rapid, cost-effective
schemes are of particular priority to facilitate development of data for thousands of chemicals in
commerce that have not been evaluated for potential impacts to developmental pathways.

Research Area 4: Translational research and tools to support community
actions and decisions

A lifecourse approach to health considers  how an individual's current and future health may be
affected by the dynamic interaction among social, biological, and environmental influences over
time. It underscores the importance of multiple risk and protective influences and considers how
the presence or absence of these influences during critical and sensitive stages of development
may affect the health of individuals or selected populations (National Research Council,  2011).
There is expected to be significant investment by NIH to support public health in vulnerable popu-
lations and groups, including children. EPA leadership will be required to enable research that
meets targeted needs for translational tools incorporating lifestage-specific considerations to
provide local decision makers with the knowledge needed to inform a balanced approach to com-
munity cleanup and  development. Priority needs are for:

• Translational tools that can be  used by community decision makers to access and use quality
  data sources specific to promote children's healthy development,

• Research related to child-specific impacts of exposure to non-chemical and chemical stressors at
  the community level.

State, Tribal and local governments make decisions that impact children's health and well-being in
communities and settings (e.g., schools, daycare facilities, homes) where they live, work, and play.
In order to optimize  child (lifestage)-specific settings, community decision makers need access to
information on the health impacts of multiple factors in the built and natural environment that
contribute, in positive or negative ways, to children's health, and their importance relative to each
other. A lifecourse approach is needed to identify the types of decisions that focus on child- (or
lifestage-) specific environments. By taking a lifecourse approach and building such information

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into decision support tools, community decision makers can optimize features of the built and
natural environments so as to reduce (eliminate, prevent) risk and actively promote healthy devel-
opment and well-being.


Informing 2016-2019 ORD Research Planning

EPA's Office of Research and Development's National Research Programs (Air, Climate, and Energy;
Safe and Sustainable Water Resources; Sustainable and Healthy Communities; Chemical Safety for
Sustainability; Human Health Risk Assessment; and Homeland Security - http://www2.epa.gov/
epa-research/strategic-research-action-plans) are aligned on the core principle of sustainability
and are designed to provide the solutions the Agency and the nation need to meet today's com-
plex environmental and human health challenges. Inevitably, important scientific issues arise that
cut across these six programs. Rather than create additional research programs for every cross-
cutting issue, ORD is  developing Research Roadmapsto clearly identify the science questions and
associated research efforts that are ongoing in the six programs. These Roadmaps  identify scientif-
ic gaps that inform the National Research Programs in the development of their Strategic Research
Action Plans. As new, high priority, cross-cutting issues emerge, ORD expects to use this approach
to integrate existing research efforts and  identify needed work. Specific research products/deliver-
ables are not included in the Roadmap; these may change as a result of ORD's planning and bud-
geting each year. However, ORD will use the EPA's website to provide details regarding research
products associated with implementation of this Roadmap. Here, we elaborate on the objectives
of integrated ORD research in CEH and on the approach for enabling this research  through the
National Research Programs.

Objective: Apply advanced and emerging science to understand and predict the role of exposure
to xenobiotic environmental factors during early life, in the  context of important non-chemical
stressors, on health impacts across the course of development. Develop tools to address the com-
plexity of CEH and support decisions that promote health and well-being of children.

Conceptual Framework
Systems theory provides the required framework for linking exposure science, toxicology, and epi-
demiology to study, characterize, and make predictions about the complex interactions between
children and environmental stressors (both chemical and nonchemical) across the  course of de-
velopment (Figure 3). Multifactorial exposures to individuals, communities, and populations are
captured horizontally from left to right (source-to-dose response with feedback), while outcome
hierarchy is captured vertically from bottom to top (adverse outcome pathway). Kinetics and  dy-
namics of these complex systems processes are not depicted, but are critical to meet the objective
of moving toward development of predictive tools for supporting risk-based decisions.
The science developed will support consideration of multiple vulnerability and susceptibility fac-
tors for risk-based decisions. Exposure assessment and risk  assessment require population and
community-specific information or exposure factors that may vary significantly based on geogra-
phy and cultural practices. These factors have been reviewed and a framework has been described
to facilitate systematic consideration of these contextual factors for exposure and risk assessment
(see Table 6) (DeFur et al., 2007).

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           Stressors
          (chemical and
          n on -chemical)
                                      Community
                                       (characteristics)
            Internal
            Exposure
           Tissue Dose)
     Disease      ^  Population
Incidence/PrevalenceJ'  Response
                                                                                       Organism
                                                                                       Response
                      Organ
                     Response
                                                                                       Cellular
                                                                                       Response
                                                                                       Macro-
                                                                                      Molecular
                                                                                      Interactions
                Figure 3.  Concept for integrated CEH research in ORD.

Conceptual Approach
EPA CEH Research will apply complex systems science to integrate the rapidly expanding body of
information on children's environments with advancing insights on developmental processes to
inform the understanding of key factors contributing to health outcomes. This understanding will
be translated and tools provided to support Agency decisions that promote and protect children's
health and well-being.
Studies will be model-driven to direct resources toward filling priority scientific gaps and to facili-
tate advancement of Agency capacity to be predictive of potential risks. This approach iteratively
measures, mines, models, and manipulates (4M's) to extract maximum understanding from extant
data and to provide tools that support holistic evaluation of the complex interactions that deter-
mine health impacts of early life exposures. To ensure short term impact in support of Agency
needs, the scope of the research will be targeted by implementing studies through case examples
focused on priority health outcomes and exposures as identified by ORD Program Office Partners
through the NRPs.

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Table 6.  Examples of specific vulnerability factors (Defur et al., 2007)
           Environmental Conditions
                (habitat quality)
 Location
     Geographic area
     Urban
     Rural
     Proximity to industrial sites
     Proximity to roads and traffic
     Time indoors, time outdoors
 Quality of setting
     Natural environment
        Air quality
        Water quality
        Climate, habitat
     Built environment
        Land use
        Housing quality
        Housing density
        Occupant density
        Sanitation
        Traffic density
        Noise
     Social environment
        Segregation
        Crime
        Chaos
        Conflict
        Social support
        Immigration/emigration
        Family or group stability
        Violence
        Racism
 Resources
     Social capital
     Wealth
     Employment opportunities
     Schools
     Medical care
     Food availability
     System complexity and redundancy
           Receptor Characteristics
         (individual or group quality)
Biological factors
    Genetics
       Gender
       Genetic diversity
       Genetic flux
       Susceptibility
    Developmental or lifestage
       Age
       Population structure
    Physical health status
       Low birth weight
       Chronic disease-obesity
       Compromised immune function
       Asthma
       Acute disease-exposure
       Infection
       Nutrition
       Injury
Psychological factors
    Mental/emotional health
       Depression
       Hostility
       Poor coping skills
    Temperament
       Adaptability
       Intensity
       Mood
       Persistence/attention span
       Distractibility
       Sensitivity
Activities/behaviors
    Physical activity
    Hygiene
    Diet
    Product use
    Smoking
    Substance abuse
    Religious practice
Social factors
    Race/ethnicity
    SES
    Population size
    Diversity
       Number of species
Other
    Marital status
    Educational status

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Measurement includes obtaining multi-dimensional information of the system through a variety
of methods including high-throughput data capture. This involves much of the same data capture
approaches that have been traditionally performed, but broadens the space through increasing
system complexity (e.g., cellular processes, metabolism, protein location, receptor binding, en-
zyme activation/inhibition, biomarkers of exposure, environmental concentrations) and efficiency
(e.g., rapid screening methods requiring fewer materials and increasing output).

Mining includes the organized compilation of the multi-dimensional data into usable databases,
and bioinformatics approaches which mine the database to develop plausible relationships provid-
ing systems-based hypotheses, including, for example, putative AOPs.

Modeling includes developing statistically-based signatures (i.e.,  metrics) and computational-
mechanistic models from the relevant information. These models are complex, nonlinear, and
interconnected, integrating the data beyond a linear process.

Manipulation includes functional studies to predict system-level behaviors in silico and to evalu-
ate model performance. An iterative process of prediction-validation is necessary to refine models
in order to adequately represent the human-environment system at important levels of organiza-
tion, whether the consequences  result in normal development and well-being or adverse conse-
quences to development and health.

This  approach calls for knowledgebase-driven methods to incorporate information from past and
current research, compilation of  plausible pathways and mechanism of exposure and toxicity,
models that can predict whether or not a chemical will elicit an adverse outcome, simulations that
can incorporate these models, validation models for checks and balances, and acceptance and
integration into current risk assessment paradigms, as well as integrating these data in new ways
to evaluate risk.

Application of this common approach to identify the most important environmental factors driving
early-life exposures and associated health outcome over the lifecourse will address key scientific
gaps required to support the Agency's mission and strategic goals for protecting and promoting
children's well-being.

Example 1: Birth Outcomes (Vascular VTMs)

The Virtual Tissue Modeling (VTM) project focuses on biologically-driven assembly to enable (in
vitro) and simulate (in silico) key  events in an AOP framework with respect to spatio-temporal
dynamics in human development. The overall goal is to advance the mechanistic understanding of
how chemical disruption  of cell lineage, fate, and behavior propagates to higher levels of biologi-
cal organization and adverse developmental outcomes. Genomic and environmental signals act
cohesively during successive windows of development. When disrupted, these changes can im-
pact aspects of maternal  or filial development, leading to an array of adverse birth outcomes (e.g.,
malformations, low birth weight).

Embryonic vascular network assembly is a complex process characterized by the formation of geo-
metric tubular networks (vasculogenesis). The early pattern is based on differential cell growth,
migration and survival  along a growth factor (VEGF-A)  gradient as well as differential cell adhesion

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and cell folding that connect the endothelial cell network and create a patent luminal channel,
respectively. Subsequent growth and remodeling of the primitive capillary network (angiogenesis)
is mediated by invasive angiogenic sprouting induced by local growth factors linked to oxygen
tension as well as shear-stress signals following establishment of blood flow (Perfahl et al., 2011;
Shirinifard et al., 2009). To understand and predict impacts of chemical exposures on this system,
computational systems models have been built that incorporate all of the systems biology frame-
work components (measurement, mining, modeling, manipulation). This provides a good example
for how the systems biology approach can be applied to a  particular developmental system.

Measurement: Data of chemical-biology perturbations came from the EPA's ToxCast program, as
well as from text mining the public literature. A number of ToxCast assays specifically related to
the vascular system were selected for incorporation into AOPs and computational simulation mod-
els. These assays and targets came from a human primary co-culture cell system with eight cell lin-
eages (e.g., endothelial, peripheral blood, coronary artery smooth muscle, fibroblasts) evaluating
protein secretion readouts (e.g., tissue factor, VCAM-1, MCP-1, uPAR, MMPs, TGFb, collagen); cell-
free assays evaluating protein  binding (e.g., VEGF, endothelin) and enzyme activity (e.g., caspase,
ephrin, MMPs, Tie2); and cell-based assays evaluating transcriptional regulation (e.g., RAR, VDR,
TGFb). A litany of MeSH terms was developed based on annotated genes, canonical pathways and
cellular processes that could be linked to  normal and abnormal vasculogenesis and angiogenesis
to identify relevant vasculature-related articles and co-annotated concepts and principles.

Mining: Mining techniques combined literature mining integration tools (eLibrary) and bio-
informatics approaches for making predictions about putative Vascular Disrupting Compounds
(pVDCs). Using the MeSH terms indicated above on the public literature domain limited the
articles to 100,000. These articles were organized in a way to assist in finding relevant relation-
ships described in the articles and annotated in the MeSH  terms. In the case of angiogenesis, for
instance, the relationship between angiogenesis and proteins is captured by extracting  co-annota-
tions for neovascularization  and proteins. Similarly, chemicals co-annotated  with neovasculariza-
tion are extracted into another sheet and organized by whether the chemical appears from the
MeSH annotations to have an adverse effect on neovascularization or to  have a therapeutic effect
on neovascularization. The protein annotations are further processed to  look at co-annotations
in the literature, which coarsely indicates a biological relationship. Although the exact nature of
the relationship is not identifiable from the annotations, the knowledge that two proteins are
co-annotated is a helpful starting point for more in-depth exploration and further research. These
associations are helpful in elucidating AOPs within the modeling section.

Chemicals were identified to be potential vascular disrupters, pVDCs, through identifying and
prioritizing the ToxCast HTS assays relevant to vascular development. Six broad  classes of as-
say targets (24 in total) were identified from the HTS assays, including receptor tyrosine kinases
(VEGFR2, TIE2), GPCR-based chemokine signals (CXCL10, CCL2), and the GPI-anchored signals from
matrix remodeling (PAH, uPAR), among others. Next, the chemical-assay target activities for each
chemical were used to rank the chemicals as least to most likely to affect the developing vascula-
ture system. This provided a list of potential chemicals to pursue in follow-up modeling and confir-
mation steps across 1060 chemicals in the ToxCast library.

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  Modeling: AOPs delineate the documented, plausible, and testable processes by which a chemical
  induces molecular perturbations and the associated biological responses that describe how the
  molecular perturbations cause effects at the subcellular, cellular, tissue, organ, whole animal,
  and population levels of observation. This concept identifies the pathway linking a molecular
  initiating event (MIE) to an adverse outcome. To identify potential MIEs, the gene ontology (GO)
  and mammalian phenotype (MP) browsers of the Mouse Genome Informatics database (http://
  www.informatics.iax.org/) were searched for terms affiliated with the disruption of vascular
  development. Terms for abnormal vasculogenesis [MP:0001622; 72 genotypes, 73 annotations]
  and abnormal angiogenesis [MP:0000260; 610 genotypes, 894 annotations] were captured into
  a table as well as the gene and protein and then both were linked to ToxCast assays. This list  had
  65 target genes with bona fide roles in vasculogenesis or angiogenesis, 50 of which had evidence
  of abnormal embryonic vascular development based on genetic mouse models (Knudsen and
  Kleinstreuer, 2011). The proposed AOP for embryonic vascular disruption is shown in Figure 4.
ProposedAOP: Embryonic Vascular Disruption
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                  Figure 4.  Proposed AOP for embryonic vascular disruption.

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An integrated understanding of the mechanisms and key events underlying embryonic vascular
disruption requires a modeling framework to link relevant information about molecular pathways
and cellular processes with the kinetics and dynamics of the system that describe the interactions
and functioning of those elements. A systems biology approach is required to extend traditional
conceptual linear models into computational models that are, ideally, quantitative or predictive. In
building a simulation model of this process, each simulated cell in the model, like a biological cell,
has an inherent capacity to process local information from the microenvironment and respond ac-
cording to its own genetic blueprint or history. The key molecular players and cellular behaviors of
concern were identified via the eLibrary,  AOP framework, and ToxCast assay data. By incorporating
these data and critical pathways and processes (e.g., extracellular matrix remodeling, chemokine
pathways, growth factor signaling), the model can test certain hypotheses on cell signaling interac-
tions and emergent vessel network topologies following chemical disturbance of specified growth
factors, cell-surface receptors, and breakdown of the extracellular matrix. Discrete cellular behav-
iors (growth, adhesion, proliferation, apoptosis, chemotaxis) and parameters (growth factor diffu-
sion, decay, secretion and uptake rates and cell size, motility, growth rate) were programmed into
the simulation. Model outputs (cell number, angiogenic index, average vessel length/diameter,
number of branching points) were compared to histological data for accurate representation.

Manipulation: Confirmation studies for the AOP and simulation model on vascular development
included several anti-angiogenic reference compounds: 5HPP-33 (thalidomide analogue), TNP-470
(Wnt inhibitor), PTK787 (VEGFR2 inhibitor), and AG1478 (EGFR inhibitor). The 5HPP-33 reference
compound was confirmed active in ToxCast Phase II assays across the AOP signature. In collabora-
tion with scientists  at the DOW Chemical Company, 5HPP-33 and TNP-470 were shown to interfere
with microvessel outgrowth in aortic explant assay and caused lethality (5HPP-33 > 15u.M) and
malformations (TNP-470 > 0.25 u.M) in rat whole embryo culture. Computer simulation with 5HPP-
33 predicted similar exposure-related morphological effects. RNA-Seq analyses were proposed
to aid in understanding the specificity of the vasculogenesis-disruption mechanisms and allow
identification of novel gene targets perturbed following chemical exposure. RNA-Seq analysis con-
ducted on rat embryos (GD10) exposed to 5HPP-33 and TNP-470 in vitro revealed concentration-
dependent effects on vasculogenesis genes (i.e., VCAM1, TNF, CASP8, HIF1A, AHR). These studies
provide evidence that the science is correctly understood within the context of this research and
that the predictions are plausible.

Example 2: Asthma (MICA Study)

Despite recent evidence suggesting that the very large increase in asthma incidence and preva-
lence  observed in recent years may be slowing (Akinbami et al., 2011), the global burden of this
complex disease remains at an all-time high. More than 20 million Americans have asthma, includ-
ing approximately 7 million children under the age of 18. The cost of treating asthma in children
under 18 in the U.S. is estimated at $3.2  billion per year. Prevalence of asthma in low-income and
minority children in the United States is disproportionately higher (Akinbami et al., 2011; von
Mutius and Hartert, 2013).

The Mechanistic Indicators of Asthma (MICA) Study was designed to investigate whether genomic
data (blood gene expression), viewed together with a spectrum of exposure, effects, and clinical
and susceptibility markers, can increase the sensitivity required to define exposure-response-
effects relationships and provide mechanistic insight for further hypothesis generation and testing.

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As such, this study provides an example of how a systems biology approach can support a more
holistic understanding of the multifactorial etiology of environmental disease (Gallagher et al.,
2011; George et al., 2015).

Measurement: A nested case-control cohort of 205 non-asthmatic and asthmatic children (9-12
years of age) from Detroit, Ml, were recruited. The integrated study design and framework for
MICA is shown in Figure 5. The MICA design focuses on environmental exposures, susceptibility,
asthma, and other health measures, including risk factors associated with obesity and cardiovas-
cular disease. Information on a wide range of risk factors relevant to asthma and asthma exacerba-
tions were characterized through collection of exposure metrics, lung function tests, and biological
and clinical indicators measured in blood, urine, and fingernails. The study includes environmental
measures (indoor and outdoor air, vacuum dust), biomarkers of exposure (cotinine, metals, total
and allergen specific Immunoglobulin E, polycyclic aromatic hydrocarbons, volatile organic carbon
metabolites) and clinical indicators of health outcome (immunological, cardiovascular and respira-
tory). In addition, blood gene expression and candidate SNP analyses were conducted. Selected
measurements are highlighted in Figure 5.
                            MICA Framework
                             Markers of Susceptibility
Nicotine, PAHs, etc.
      Genotypes at Candidate SNPs
      (HLA-DRB1. HLA-DQB1, FCER1B, ADAM33,
      CPU, IL4, IL13, GSTM1, GSTP1. GSTTt. THF-a)
                    Cotinine
                    PAH Metabolites
                    1-OHPyrene
                    Napthols, etc.
                             ปitinปf*iu!t\
                                                         Age, Gender,
                                                         Race/ethnicity
                   Secreted
                   Auto antibodies:
                   Neutrophils,
                   Eosinophils,
                   Monocytes
                       Metals:
                       Lead,
                       Mercury,
                       Arsenic, etc.
                    Inflammatory
                    Markers:
                    Cytokines,
                    Chemokines
                             Health status,
                             other risk
                             factors: BMI,
                             HDL, blood
                             chemistry
                                                             Lung
                                                             Function,
                                                             eNO,
                                                             eVOC
                                      Other Immune Markers:
                                      Total IgE, allergen specific
                                                         Respiratory
                                                         Symptoms
                                       Gene Expression
             Markers
srs of Expo
sure
Markers of Effect
Figure 5.  The overall MICA Study design includes exposure, biomarkers of exposure, clinical
  indicators, genomic data (blood gene expression and SNP) and health status indicators.

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Mining: Traditional analysis of complex disease considers one domain of data at a time to identify
associations between biomarkers or bioindicators and disease outcomes. The commonly em-
ployed methodologies used require a clearly defined phenotype representative of multiple un-
derlying disease processes for traditional supervised methods or a disease clearly identifiable by
genomic or clinical data for traditional unsupervised methods, neither of which is true of complex
disease. The large data sets that are now widely available can be mined to define novel, mecha-
nistically distinct disease subtypes (endotypes) in a completely data-driven manner.  Approaches
for maximizing the discovery potential of these data sets are still an area of significant research.
Alternative approaches for mining the MICA data were evaluated (e.g., Student's t-test, single data
domain clustering and the Modk-prototypes algorithm). To best exploit strengths and limitations
of the MICA data,  a novel multi-step decision tree-based method was developed to define endo-
types. This new method gave the best segregation of asthmatics and non-asthmatics, and it pro-
vided easy access to all genes and clinical covariates that distinguish the groups (Williams-DeVane
etal., 2013).

Modeling: As noted above, gene expression data were combined with hematologic, immunologic,
and cardiopulmonary covariates to define mechanistically distinct subtypes (or endotypes). A
novel method was used to integrate the clinical covariate data with gene expression, resulting in a
recursive partitioning tree that segregated individuals according to their asthma status. The result-
ing tree model assembled asthmatic subjects into purely data driven endotypes. These endotypes
were consistent with previous classifications, though the data suggest multiple mechanistically
distinct neutrophilic subtypes. Functional characterization of the genes and associated covariates
revealed a complex interaction among Th2 mediated lung inflammation, heightened systemic in-
nate immune response, and potentially metabolic syndrome in discriminating asthma endotypes.
These findings  support a prominent role for systemic inflammation due to heightened innate im-
mune responsiveness across the asthma syndrome and suggest that new biomarkers are needed
to better classify mechanistically distinct neutrophilic endotypes.

Manipulation: Characteristics of the data-driven derived endotypes from this study are consistent
with previously published endotypes based  solely on clinical diagnostic criteria, but this data-
driven  method provides mechanistic understanding that is not possible when using established
clinical markers alone. One theme that emerges from this analysis is the interplay between innate
and adaptive immune responses across endotypes.  Results also suggest a role for broad systemic
inflammation in addition to the localized hyperreactivity in the lung as a major driver for asthma.
The findings of this data-driven mining and modeling approach are consistent with studies demon-
strating that weight loss improves asthma symptoms without significant changes in markers of air-
way  inflammation. Of note, body mass index (BMI) alone is not a predictor of asthma in the MICA
Study, in contrast with other recent studies; this may be because MICA looks at asthma prevalence
in children rather than correlates of asthma onset. The MICA Study, among others, putatively iden-
tifies underlying mechanisms linking obesity and asthma through systemic inflammation related to
metabolic syndrome and increases the relevance and understanding of clinical findings.

The result of applying this holistic approach to the study of asthma in children is a better un-
derstanding of the various asthma endotypes and a scientifically defensible foundation for the
evaluation of the many environmental factors influencing each mechanistically distinct endotype.
Non-eosinophilic asthmatics likely fall into multiple mechanistically distinct subgroups or endo-

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types. Exacerbation of asthma by obesity and metabolic syndrome likely occurs through enhanced
systemic inflammation, which will not be detected by biomarkers reliant on airway inflammation.

Asthma biomarkers reliant on airway inflammation may miss endotypes driven by systemic inflam-
mation. The increasing incidence of asthma due to the rise in obesity will expand the proportion
of these endotypes.

Example 3: The Future of Cross-Cutting CEH Research

The traditional risk-based assessment paradigm supports decisions to minimize adverse impacts
associated with environmental exposures. Clearly, removing chemical/pollution stressors is a nec-
essary and essential component of children's health protection.  Community planning and devel-
opment decisions are designed from the holistic perspective of both minimizing risks while at the
same time providing an environment that supports and promotes healthy (optimal) child develop-
ment. Such a goal is an inherent property of sustainability. To support this goal, novel methods are
required to incorporate and consider the complexity associated with these decisions and to com-
pare alternatives and evaluate outcomes.

For example, the same agent-based modeling tools used by the ORD Virtual Tissues Modeling
project to simulate how chemical perturbations at the cellular level propagate to higher levels
of biological organization can potentially be applied to simulate population level interactions of
children in a community.  It has been suggested that health behavior research is a candidate for
application of complex systems modeling approaches to address empirical questions that can-
not be addressed using the regression approaches common to the field of social epidemiology
(Galea et al., 2009). Similarly, these approaches could provide the capacity to integrate the vast
array of information required to computationally test and evaluate community-level interventions
and public-policy decisions designed to improve CEH. By designing cross-cutting ORD research to
extend these approaches across all levels of organization, important gaps in data and understand-
ing can be efficiently identified for targeted study and data collection. The conceptual research
framework and approach  described in these three examples, implemented through case examples
of high priority to ORD program office and  regional partners,  will facilitate integrated research
required to support holistic and sustainable decisions in support of CEH.

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Summary
CEH research is conducted by the EPA to improve the scientific understanding required to support:
regulatory decisions protective of children's health now and in the future; community decisions
that protect and promote children's health across generations; and, ecological decisions that pro-
vide sustainable healthy environments for children. The overarching goal for EPA's CEH research
program is to provide the Agency and others with the information needed to incorporate consid-
eration of early lifestage susceptibility and vulnerability into decision making.

EPA's CEH research is designed to address four priority research areas: (1) knowledge infrastruc-
ture to provide early lifestage-specific data and information; (2) systems (biological) understanding
of the relationship between environmental exposures and health outcomes across development;
(3) methods and models fit for purpose to evaluate early lifestage-specific risks and to support de-
cisions protective of all susceptible and vulnerable early lifestages; and (4) translational research
and tools fit for purpose to support community actions and decisions.

EPA is currently carrying out research in each of these four areas and plans to build on this re-
search as it plans for the future. EPA will continue to partner with other Federal agencies and
independent organizations to further CEH research. Future research will apply complex systems
science to integrate the rapidly expanding body of information on children's health. This informa-
tion will be translated into tools and databases that will support Agency decisions that promote
and protect children's health and well-being. Model-driven studies will be used to direct resources
toward filling priority scientific research gaps and to advance the Agency goals of protecting hu-
man health and the environment.

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Appendix A: ORD's  Current  Research

Activities

This Appendix presents more information on the research activities that are presented in Section IV
of the document as well as information on additional research activities. The NRP with key respon-
sibility for each of the activities is provided in parentheses after the project name in this section.

•  ACE = Air, Climate, and Energy Research
•  CSS = Chemical Safety for Sustainability Research
•  HHRA = Human Health Risk Assessment Research
•  SHC = Sustainable and Healthy Communities Research
•  SSWR = Safe and Sustainable Water Resources Research

See Table Al for a summary of these research activities.

Table Al.  ORD's current research activities
Research Area 1. Knowledge Infrastructure to Provide Early Lifestage-Specific Data and
Information
Title Research Program
Description
Exposure Information
Exposure Factors Handbook
Consolidated Human
Activity Database
ExpoCast Database
Chemical and Product
Categories Database
HHRA
CSS
CSS
CSS
Databases and handbook with information
on children's exposures and exposure
factors; human behavior; amounts
of chemicals currently found in food,
drinking water, air, dust, indoor surfaces,
and urine; and chemical usage.
Early Lifestage Pharmacokinetic Parameters
Enzyme Ontogeny Database
CSS
Database that can be used as a
screening tool to explore metabolism-
based variability, based on enzyme
differences, during early lifestages.
Developmentally Relevant Hazard Data
ToxCast Database
Toxicity Reference Database
Adverse Outcome
Pathway (AOP) Wiki
CSS
CSS
CSS
Data from in vivo animal studies, screen-
ing assays and other study types are
included in these databases.
A wiki-based tool that provides an
interface for collaborative sharing of
established AOPS and building new AOPs.

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Table Al. (continued) ORD's current research activities
Research Area 2. Systems Understanding of the Relationship Between Environmental
Exposures and Health Outcomes Across Development
Title Research Program Description
Systems Biology to Predict Developmentally Relevant Outcomes
Bioinformatics-Based Models
AOP Models
Simulation Models
CSS
CSS
CSS
System models for tissues and multi-
organ pathways specific to embryo-fetal
and neonatal development. Examples
include: First-generation ToxCast
predictive models for reproductive and
development toxicity, the Vascular AOP
model, and the Virtual Embryo model.
Systems Understanding of Complex Stressors
Laboratory Based Studies
CSS, SHC, and SSWR
Includes in vitro models to evaluate
the effects of chemical exposure in
developmentally relevant systems, and
in vivo models with rodents studying
issues such as alterations in endocrine
function during fetal and early childhood
and its effect during and after puberty.
Epidemiologic Studies
EPA-NIEHS Children's
Environmental Health
and Disease Research
Centers (CEHC Program)
Clean Air Research Centers
Place-Based Studies
Co-Exposure to
Multiple Stressors
MICA Study
SHCandACE
ACE
ACE, SHC and SSWR
SHCandACE
CSS and SHC
Jointly funded by EPA and NIEHS through
the STAR grant program, the CEHC program
explores ways to reduce children's health
risks from environmental contaminants.
Health outcomes under investigation include
adverse birth outcomes, asthma, autism,
obesity, altered immune function, and cancer.
Studies investigating the relationship
between air pollutants and children's health.
Includes studies investigating housing quality,
traffic-related air pollutants, indoor air
pollutants, and water-related exposures and
their effect on children's health outcomes.
New methods for modeling and assessing
cumulative exposure and risk.
Study incorporates exposure metrics, internal
dose measures, and clinical indicators to
investigate gene-environment interactions
in asthma and cardiovascular disease.

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Table Al.  (continued) ORD's current research activities
Research Area 3. Methods and Models Fit for Purpose to Evaluate Early and Lifestage-Specific
Risks and to Support Decisions Protective of all Susceptible and Vulnerable
Title Research Program Description
Exposure
EPA Expo Box
SHEDS-HT Model
ExpoCast
Lifestage Categories for
Monitoring and Assessing
Exposures to Children
Biogeographical Approach for
Prioritizing Chemical Mixtures
HHRA
CSS
CSS
SHC
CSS
Tools to increase the usability and access to
exposure data, models to predict exposure
by a variety of pathways and routes, and
approaches for categorizing lifestage
changes and prioritizing chemical mixtures.
Dosimetry Models
Empirical Models
Persistent Bioaccumulative
Toxicants
In vitro to in vivo Extrapolation
Community Multi-scale
Air Quality Model
Pesticide Biomarker
Measurements in Children
CSS
CSS
CSS
CSS
Models that assess exposure and
predict dose based on measurements of
biomarkers and kinetic parameters.
PBPK Models
Virtual Embryo Project
Ethanol
CSS
CSS
PBPK models that investigate the relationship
between exposure, tissue dosimetry, and
kinetics of environmental chemicals.
 Research Area 4. Translational Research and Tools Fit for Purpose to Support Community
 Actions and Decisions
 Title
Research Program   Description
 Decision Support Tools
 Community-Focused Exposure
 and Risk Screening Tool
 EnviroAtlas
       SHC
       SHC
                   Tools that enhance access to information
                   for environmental health decision making.

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Table Al. (continued) ORD's current research activities
Research Area 4. (continued) Translational Research and Tools Fit for Purpose to Support
Community Actions and Decisions
Title Research Program
Description
Problem-Driven Research
EPA Pilot Study Add-On to
the Third Study Site of the
Green Housing Study
Dust and Soil Ingestion
Chemical and Non-
Chemical Stressors and
Childhood Obesity
Chemical and Non-
Chemical Stressors and
Neurocognitive Health
Community Multi-Scale
Air Quality Model
PCBs in School
Child-Specific Scenarios
Examples
SHC
CSSandSHC
SHC
SHC
ACE
HHRA
HHRA
Studies that increase the understanding
of the linkages between human health
and environmental exposures that will be
useful for community decision-making.
Translational Research
EPA-NIEHS Children's
Environmental Health
and Disease Research
Centers (CEHC Program)
SHC
Includes a Community Outreach and Transla-
tion Core that use a variety of approaches
to translate research findings and inter-
vention strategies to the community.
Social Determinants of Health
STAR Centers of Excellence
on Environment and
Health Disparities
Environmental and
Community Factors Influence
Effectiveness of Medical
Treatments for Asthma
Integrated Approaches
to Sustain the Built and
Natural Environment and the
Communities They Support:
Children's Health Example
Climate Change
SHC
SHC
SHC
ACE
Studies investigating the complex interactions
of biological, social, and environmental
determinants of population health.
Research on impacts of increased
ground level ozone and weather events
influencing allergic, chronic, waterborne,
and infectious disease risks.

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Research Area 1. Knowledge infrastructure to provide early lifestage-specific
data and information

Currently knowledge resources are being developed under Research Area 1 in the following three
areas: (1) Exposure Information, (2) Early Lifestage Pharmacokinetic Parameters, and (3) Develop-
mentally Relevant Hazard Data. ORD's relevant research in each of these areas is summarized as
follows:

(1) Exposure Information
Exposure data are critical for characterizing children's environments and for evaluating interac-
tions of the child with that environment across development.

Exposure Factors Handbook (HHRA)
Data about children's exposures and exposure factors, such as lifestage specific modeled estimates
of soil and dust ingestion is incorporated into EPA's Exposure Factors Handbook  (U.S. EPA, 2011);
available at http://cfpub.epa.gov/ncea/risk/recordisplav.cfm?deid=236252. This important re-
source is used by exposure assessors both inside and outside the Agency to obtain data on life-
stage specific exposure factors to calculate human exposure to environmental agents. These fac-
tors include:  drinking water consumption, soil and dust ingestion, inhalation rates, dermal factors
including skin area and soil adherence factors, consumption of fruits and vegetables, fish, meats,
dairy products, homegrown foods, human milk intake, human activity factors, consumer product
use, and building characteristics.

Consolidated Human Activity Database (CHAD)
ORD's Consolidated Human Activity Database (CHAD) is a compilation of data  on human behavior
from 24 individual studies (U.S. EPA, 2014d); available at: http://www.epa.gov/heasd/chad.html.
This resource includes more than 50,000 individual data days of detailed  location and activity data
and corresponding demographic data including age, sex, employment, and education level. These
data are used in human exposure and health studies and models  used for exposure and risk as-
sessment. Data are included for all ages, including children as young as infants. Recent information
added to CHAD for children includes data from the 2008 phase of the Child Development Supple-
ment of the University of Michigan's Panel Study for Income Dynamics (PSID).

ExpoCast Database (CSS)
ExpoCast Database (ExpoCastDB) was developed to improve access to human exposure data from
observational studies, including those funded by ORD. ExpoCastDB consolidates measurements of
chemicals of interest in environmental and biological media collected from homes and child care
centers. Data currently include the amounts of these chemicals found in food, drinking water, air,
dust, indoor surfaces, and urine. The current publicly released version of ExpoCastDB includes
data for 99 unique chemicals primarily consisting of active ingredients in pesticide products.
Chemical concentrations measured in samples collected for three observational studies are includ-
ed: the American Healthy Homes Survey (AHHS), the First National Environmental Health Survey
of Child Care Centers (CCC), and the Children's Total Exposure to Persistent Pesticides and Other
Persistent Organic Pollutants (both  CTEPP NC and CTEPP OH) studies.

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ExpoCastDB is available as a searchable database (U.S. EPA, 2014g); available at the link httc
actor.epa.gov/actor/faces/ExpoCastDB/Home.isp on EPA's Aggregated Computational Resource
(ACToR) system, an online data warehouse that collects data on over 500,000 chemicals from over
1000 public sources (U.S. EPA, 2014a); available at: http://actor.epa.gov/actor/faces/ACToRHome.
jsp. Controlled vocabularies are used to facilitate searching and analyses across datasets and to
encourage standardized reporting of observational exposure information. ExpoCastDB provides a
separate interface within ACToR to facilitate linkage of exposure measurement data with data on
toxicity, environmental fate, and chemical manufacturing and usage information.

Chemical and Product Categories (CSS)
Chemical and Product Categories (CPCat) is a database of information  on how chemicals are
used (U.S. EPA, 2014b); available at: http://actor.epa.gov/actor/faces/CPCatLaunch.isp. As with
ExpoCast, CPCat is available as a searchable database within ACToR. CPCat contains information
on the uses of chemicals; products that contain chemicals; manufacturers of the products; and a
hierarchy of consumer product "use" categories. Examples of the types of uses in this database
include uses in: consumer products; automotive products; agricultural chemicals; and pesticides.
It also contains information on use by children and lists any regulations or studies in which the
chemical has been considered hazardous to children.

(2) Early Lifestage Pharmacokinetic Parameters
Pharmacokinetic and  pharmacodynamic parameters for all lifestages are required to predict the
potential for health effects from exposures to environmental chemicals. Child-specific parameters
are used to characterize dose to the developing child in utero, after birth through lactational expo-
sure, and during early infancy through prepubertal ages.

Enzyme Ontogeny Database (CSS)
Chemicals are typically metabolized in the body sequentially by activating and detoxifying en-
zymes that change over time from the developing embryo to adulthood. Therefore, the availability
of certain enzymes at different lifestages could play an important role  in determining the suscepti-
bility of children, compared to adults, to environmental chemicals. ORD has developed an enzyme
ontogeny database that can be used as a screening tool to explore metabolism-based variability,
based on enzyme differences, during early lifestages.

(3) Developmental^ Relevant Hazard  Data
Data from in vivo animal studies, screening assays, and other study types are needed in order to
carry out risk and hazard assessments on environmental chemicals. ORD has developed databases
that allow for easy access to developmental hazard data that is being used to link environmental
exposures at early lifestages with health outcomes in children and  later in life.

ToxCast Database (CSS)
ToxCastDB provides results of high-throughput in vitro assays. Biology  covered in the large set
of assays include endpoints related to endocrine, reproductive, and developmental toxicity and
a major proportion of the assays are human-based cells or proteins. Information about the as-
say design, chemical dose, and experimental set-up are also provided in the database. ToxCastDB
is available as a searchable database through the ACToR system (U.S. EPA, 2014h); available at:
http://actor.epa.gov/actor/faces/ToxCastDB/Home.isp.

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Toxicity Reference Database (CSS)
Toxicity Reference Database (ToxRefDB) contains data from thousands of in vivo animal studies
and is available as a searchable database through the ACToR system (U.S. EPA, 2014i); available
at: http://actor.epa.gov/toxrefdb/faces/Home.isp. Information on study design, dosing, and treat-
ment-related effects from subchronic, chronic, cancer, developmental, and reproductive studies
are included in the database. The developmental toxicity information includes results from studies
on more than 380 chemicals with 18 endpoints for both the rat and rabbit, while the reproductive
toxicity information is based on the results from multigenerational reproductive studies on 316
chemicals, with 19 parental, reproductive, and offspring endpoints.

Adverse Outcome Pathway Wiki (CSS)
An Adverse Outcome Pathway (AOP) is a conceptual framework that portrays existing knowledge
concerning the linkage between a direct molecular initiating event and an adverse outcome. The
goal of an AOP is to provide the framework to connect the two  events. In developing information
on early lifestage toxicity, ToxCast provides the infrastructure to predict pathways of toxicity by
probing the fundamental nature of chemical interaction(s) with their potential molecular targets
and cellular consequences. However, since toxicity is an expression of  lesion propagation to higher
levels of biological organization, AOP models are needed to provide weight-of-evidence for biolog-
ical plausibility across the developmental linkages leading to observable endpoints in the newborn
or child. Multi-cellular interactions, such as between immune cells and endothelial cells during
angiogenesisfor example, play important roles  in utero-placental development, embryogenesis,
and other AOPs linked to childhood development. These AOPs can be used to integrate multi-
dimensional data with vast biological knowledge.
AOP Wiki is a wiki-based tool that provides an interface for collaborative sharing of established
AOPs and building new AOPs (Anonymous, 2014); available at: http://aopkb.org/aopwiki/index.
php/Main Page. AOP Wiki uses templates to make it easier for  users to include the information
needed for proper evaluation of an AOP.

Research Area 2. Systems understanding of the relationship between
environmental exposures and health outcomes across development

Research Area 2 has been divided into the following two subgroups: (1) Systems  Biology to Predict
Developmentally Relevant Outcomes and (2) Systems Understanding of Complex Stressors. ORD's
relevant research in each of these areas is summarized as follows:

(1) Systems Biology to Predict Developmentally Relevant Outcomes
Systems models for tissues and multi-organ pathways specific to embryo-fetal and neonatal
development  are being developed. These models increase our understanding of the biologic
mechanisms of chemical stressors that contribute to childhood  health outcomes.

Bioinformatics-Based Models (CSS)
As discussed on page 65, ToxCastDB uses high-throughput biochemical and cellular in vitro assays
to evaluate the toxicity of environmental chemicals. ORD has developed bioinformatics-based
models using ToxCastDB in a two-step process:  (1) examining which assays were associated with

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chemicals having certain toxicity profiles, such as developmental or reproductive toxicity, and (2)
developing predictive models using these assay associations to predict the likelihood of repro-
ductive, developmental, or other types of toxicity of chemicals that had  not been tested in vivo.
The development of predictive models is being carried out in phases, with the development and
publication of first-generation (Phase I) ToxCast predictive models for reproductive toxicity (M. T.
Martin et al., 2011) and developmental toxicity (Sipes et al., 2011). These models anchored in vitro
data to in vivo endpoints for a set of approximately 300 data-rich chemicals. Pathways for endo-
crine disruption (Reif et al., 2010), embryonic stem cell differentiation (Chandler et al., 2011) and
disruption of blood vessel development (Kleinstreuer et al., 2011) have been linked to the Phase I
ToxCast in vitro data. For the next approximately 700 compounds in Phase II, where animal toxi-
cology is less well characterized, ORD is developing plausible model structures that deal with the
possibility of additional relevant interactions and components beyond those represented in the
first-generation predictive models.

AOP Models (CSS)
ORD is developing AOP models, such as the vascular AOP model, with the aim of establishing
the predictive value of chemical disruption of blood vessel development (vasculogenesis) during
critical windows of embryonic and fetal development. Using computer-based simulation tools,
vasculogenesis and its  disruption can be  visualized in the virtual absence and  presence of spe-
cific chemicals across a given dose range. This model is being tested in zebrafish embryos and in
embryonic stem cells and provides information for individual chemicals and chemical  families on
potential reproductive and developmental toxicity and susceptibility by developmental stage. As
additional individual AOPs are developed, they can be assembled into AOP networks that may aid
the prediction of more complex interactions and outcomes resulting from exposure to complex
mixtures and/or chemicals with multiple modes of actions.

Simulation Models (CSS)
Simulation models predict chemical toxicity using relevant biologic information, such as the influ-
ence of subcellular pathways and networks on the development of tissues and organs. ORD is
developing the Virtual  Embryo model, a simulation model of predictive toxicology of children's
health and development, which can be applied to prenatal or postnatal (including lactational) ex-
posures. This model uses cell-based systems and knowledge databases to generate and integrate
chemical, biological and toxicological information at all levels of biologic organization  (molecular,
cell, tissue, organ, and  organism) in order to enhance the predictive power to evaluate potential
chemical toxicity. The virtual model uses AOP models, such as the model for vasculogenesis (see
section above) and endocrine system models, as modules in the model.  Additional models for pal-
ate formation (predicting cleft palate), limb formation (predicting limb defects), eye development
(predicting retinal disease) and phallus development (predicting hypospadias) are under active
development.

(2) Systems Understanding of Complex Stressors
Epidemiologic, animal  studies, and in vitro assays are being used to develop a systems understand-
ing of the relationship  between environmental exposures as stressors and lifestage-specific sus-
ceptibility and vulnerability. A critical component of a systems approach is determining how inter-
actions among complex stressors - chemical and non-chemical (social, physical) - may increase
the sensitivity of children.

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Laboratory Based Studies (CSS, SHC, and SSWR)
Intramural ORD research has used a variety of in vitro models to evaluate the effects of chemical
exposure in developmentally relevant systems (CSS). Cell (e.g., human multipotent neuroprogeni-
tors, rodent embryonic stem cells, specific pathway-responsive modified hepatocytes), organ (e.g.
human and rodent palatal shelves), and whole rodent embryo cultures, as well as whole organ-
isms (developing zebrafish) have been used to address issues of toxic response. Many of these
models have been developed, characterized, and refined to answer specific research questions.
Several model systems have been used to evaluate the effects of chemicals to aid in the transla-
tion of high-throughput data in the ToxCast assays.
Intramural ORD research is also using in vivo, longitudinal study designs with rodents to explore
causation and characterize how in utero and neonatal environmental stressors may alter develop-
ment and thereby contribute to adverse health outcomes in adulthood (SHC). For example, ongo-
ing work is examining how alterations in endocrine function during fetal and early childhood may
impair adrenal and reproductive function during and after puberty. Researchers are also exploring
lifelong changes in physiology that may result from fetal and neonatal exposures  and predispose
an individual to metabolic syndrome (obesity, hypertension, diabetes), impaired neurological func-
tion, and altered immune responses. Molecular and epigenetic mechanisms are being explored
in these studies and companion in vitro models designed to identify toxicity pathways. Intramural
researchers are designing studies to address hypotheses generated by epidemiologic studies, such
as those being conducted by the Children's Centers (see next section below), in order to elucidate
mechanisms and characterize modifying factors such as prenatal stress.
Laboratory based studies are also examining the cumulative risk of mixtures of chemicals. For
example, ongoing studies are examining dose- and effect-additivity models for considering com-
bined impacts of endocrine disrupters that perturb reproductive tract development after in utero
exposures (SHC). Similarly, the combined impact of disinfection byproducts in drinking water on
developmental processes and children is being examined  (SSWR). In vitro and in vivo studies are
investigating the effects of cumulative exposure to disinfection byproducts in drinking water, com-
paring two common disinfection methods (chlorination and chloramination). These mixtures are
also being evaluated in mouse embryonic stem cells.

Epidemiologic Studies (SHC and ACE)
EPA-NIEHS Children's Environmental Health and Disease Prevention Research Centers (SHC)
The EPA-National Institute of Environmental Health Sciences (NIEHS) co-funded Children's
Environmental Health and Disease Prevention Research Centers (CEHCs, or "Children's Centers")
Program, ongoing since 1998, continues to generate exposure and biomarker data in pregnant
women and children in order to show relationships between exposure and a variety of children's
health outcomes, and to identify critical windows of susceptibility  (U.S. EPA, 2014e); available at:
www.epa.gov/ncer/childrenscenters; http://cfpub.epa.gov/ncer abstracts/index.cfm/fuseaction/
recipients.displav/rfa  id/560/records  per  page/ALL Jointly funded by EPA and NIEHS through
the STAR grant program, the long-range goals include understanding how environmental factors
affect children's health, and promoting translation of basic research findings into  intervention and
prevention methods to prevent adverse health outcomes. To achieve these goals, the program
fosters research collaborations among basic, clinical, and behavioral scientists with participation

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from local communities. The Children's Centers Program celebrated its 15th anniversary in 2013
with a meeting in Washington, D.C., including comments from EPA Administrator Gina McCarthy.
The Children's Centers are currently collecting exposure data on pesticides, bisphenol A (BPA),
phthalates, brominated flame retardants, metals such as arsenic, lead and manganese, and air pol-
lutants including polyaromatic hydrocarbons (PAHs) and environmental tobacco smoke. Collective-
ly, they are examining a wide range of health outcomes in cohorts of children including adverse
birth outcomes, asthma and respiratory dysfunction,  autism and other neurobehavioral problems
including ADHD, obesity and metabolic syndrome, altered immune function and childhood cancer
(Table A2). Increasingly, they are focused on potential epigenetic mechanisms by which exposures
during gestation and early life may reprogram gene expression and set the stage for a variety of
health conditions later in life.  Furthermore, several Centers maintain or have access to longitudi-
nal birth cohorts whose members are now entering puberty, making it possible to address multi-
factorial environmental public health questions relevant to adolescents.
Several Centers focus on childhood asthma as a common health outcome for which racial and
ethnic disparities exist. These studies approach asthma from multiple fronts including air pollution
from near-road exposures (as both causative and exacerbating), and the effectiveness of medical
and dietary interventions. These studies and other STAR and ORD in-house studies on asthma cau-
sation and intervention described later address place-based community scenarios and are contrib-
uting to meeting EPA commitments in the Coordinated Federal Action Plan to Reduce Racial and
Ethnic Asthma Disparities (President's Taskforce on Environmental Health Risks and Safety Risks to
Children, 2012).

Table A2.  Current children's environmental health and disease prevention research centers
exploring associations between exposures and health outcomes in  children
Institution- P.I.
Brown University
- Boekelheide
Columbia
University - Perera
Dartmouth College
- Karagas
Duke University/
University of
Michigan -
Miranda
Duke University-
Murphy
Chemical Exposures and
Other Stressors
Arsenic, EDCs (estradiol,
BPA, genistein), dietary
restriction
Endocrine Disrupting Com-
pounds (BPA), PAHs,
Arsenic in drinking water
and food
Environmental, social and
individual susceptibility
factors, PM, Ozone
Environmental tobacco
smoke
Outcomes
Fetal liver, lung and prostate
development; prostate cancer
in later life
Neurodevelopmental
disorders such as problems
with learning and behavior;
obesity and metabolic
disorders
Growth and development;
immune response
Disparities in birth outcomes;
respiratory health in infants
ADHD; neurobehavioral
dysfunction
Underlying Mechanisms
(molecular, genetic, social
factors)
Endocrine disruption; Epi-
genetic changes in organ
development
Endocrine disruption;
Epigenetic reprogramming
and metabolic syndrome
Epigenetic changes and in-
fluence of gut microbiome
Social determinants of
childhood disease
Epigenetic modulation in
fetal and child develop-
ment

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Table A2. (continued) Current children's environmental health and disease prevention
research centers exploring associations between exposures and health outcomes in children
Institution -P.I.
Johns Hopkins
University -
Diette
National Jewish
Health - Schwartz,
Szefler
University of
California,
Berkeley - Buffler,
Metayer
University of
California,
Berkeley -
Eskenazi
University of
California,
Berkeley -
Hammond,
Balmes, Shaw
University of
California at Davis
- Van de Water
University of
California, San
Francisco -
Woodruff
University of
Illinois, Urbana-
Champaign -
Schantz
University
of Michigan
- Peterson,
Padmanabhan
University
of Southern
California -
McConnell
University of
Washington -
Faustman
Chemical Exposures and
Other Stressors
Airborne pollutants (par-
ticulate matter, nitrogen
dioxide), allergens, urban
diets
Air pollution (ozone, PM,
NO2), ambient bacterial
endotoxin
Pesticides, tobacco-related
contaminants, chemi-
cals in house dust (PCBs,
PBDEs)
Pesticides (DDT, manga-
nese), flame retardants
Ambient air pollutants
(airborne PAHs), in utero
exposure to traffic-related
pollutants, endotoxin
BPDEs, pyrethroid insec-
ticides, perfluorinated
compounds, POPs
EDCs, PBDEs (BDE-47),
PFCs (PFOA), psychosocial
stress
EDCs (phthalates, BPB),
high fat diet
BPA, phthalates, lead,
cadmium
Near-roadway air pollu-
tion including elemental
carbon, PM 2.5
Agricultural pesticides
Outcomes
Asthma
Asthma; immune system
function; determinants of
host defense
Childhood leukemia
Neurodevelopment; growth
and timing of puberty; obe-
sity
Birth defects/preterm birth,
immune system dysfunction
(asthma/allergies), obesity/
glucose dysregulation
Autism spectrum disorder
(ASD)
Placental and fetal develop-
ment, adverse birth outcomes
Neurological and reproduc-
tive development
Birth outcomes; child weight
gain; body composition; activ-
ity patterns; hormonal levels;
sexual maturation; metabo-
lomics and risk of metabolic
syndrome
Obesity; fat distribution; met-
abolic phenotypes; systemic
inflammation
Altered neurodevelopment
Underlying Mechanisms
(molecular, genetic, social
factors)
Dietary contributions to
asthma, based on anti-
oxidant and anti-inflamma-
tory impacts on immune
function and inflammation
Host-immune responses
and TL4 receptor func-
tion; interactions between
ozone and endotoxin
Epigenetic and genetic
influences
Epigenetic reprogramming;
altered endocrine status
Gene variants in bio-
transformation enzymes;
molecular mechanisms
e.g., altered T-cell function;
neighborhood factors
Immune dysfunction and
autoimmunity; genetic/
epigenetic contributions
Gene expression changes
via epigenetic mechanism;
contribution of psychoso-
cial stress
Endocrine disruption;
oxidative stress
Dietary influences; epi-
genetics and gene expres-
sion changes; oxidative
stress
Expression of genes in
metabolic pathways; beta
cell function; oxidative
stress
Genetic susceptibility; neu-
rotoxicity; oxidative stress;
cellular pathways underly-
ing neurodevelopment

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Clean Air Research Centers (ACE)
ORD's Clean Air Research Centers Program (STAR) includes a number of epidemiologic projects di-
rectly relevant to children's environmental health. Two currently active Centers are producing new
data and knowledge on the relationship between air pollution and children's health, with final
reports expected in 2015. The Center at Emory University is generating "Novel estimates of pol-
lutant mixtures and pediatric health in two birth  cohorts/' and the Center at Harvard University is
evaluating "Longitudinal effects of multiple pollutants on child growth, blood pressure and cogni-
tion." (U.S. EPA, 2012); available at: http://www.epa.gov/ncer/quickfinder/airqualitv.html.

Place-Based Studies I ACE. SHC, and SSWR)
ORD recognizes that combinations of stressors are often unique to a particular community set-
ting and that interventions to improve children's  health must take this complexity into account.
For example, ongoing place-based studies are examining the contributions of housing quality and
mold to the severity of childhood asthma in children exposed to near-road air pollution  (ACE).
Other studies are showing that the social-economic status of a community can significantly alter
the response of resident asthmatics to wood smoke from nearby wildfires (SHC). These  studies are
designed to inform community intervention decisions and benefit community sustainability.
A STAR grant and ORD in-house project, "The Near-Road Exposures and Effects of Urban Air Pol-
lutants Study (NEXUS)" examined the influence of traffic related air-pollutants on respiratory
outcomes in a  cohort of 139 asthmatic children (ages 6-14) who lived close to major roadways in
Detroit, Michigan (ACE). An integrated measurement and modeling approach was used  to quanti-
tatively determine the contribution of traffic sources to near-roadway air pollution and predictive
models were used to estimate air quality and exposures for the children (Vette et al., 2013).

A STAR grant project, "Effects of Stress and Traffic Pollutants on Childhood Asthma in an Urban
Community," (SHC and University of Medicine and Dentistry of New Jersey)  is assessing  young
study participants (ages 9-14) with persistent asthma to correlate changes in asthma status with
changes in air pollution measures and incorporate the influence of stress (evaluated with behav-
ioral and biological indicators). In another STAR project, "Community Stressors and Susceptibility
to Air Pollution in Urban Asthma" (SHC and University of Pittsburgh), researchers are exploring
the interdependent and synergistic effects of community stressors and traffic-related air pollution
on asthma exacerbation among children (ages 5-17). They are applying variants  of spatial poisson
regression and multi-level time-series modeling using syndromic surveillance and hospitalization
databases by accessing emergency department visits and hospitalization records to examine the
association between exposure to air pollution and increases in asthma in children.
Geospatial tools are also being developed and deployed in place-based children's health research
to improve characterization of complex built and natural environments at various scales. For
example, STAR grantees from Texas State University, Texas A&M University, Texas Department of
State Health Services, and University of North Carolina-Charlotte are collaborating on a  project
called "Air Pollution-Exposure-Health Effect Indicators: Mining Massive Geographically-Referenced
Environmental Health Data to  Identify Risk Factors for Birth Defects" (SHC).  Using air pollution
exposure assessment methods, visual data mining tools, and epidemiological analysis procedures,
they are defining new environmental public health  indicators linking exposure metrics and birth
defects.

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Additional new knowledge about how the built environment, especially learning environments,
influence children's health and performance, potentially in both positive and negative ways, is also
being generated by STAR grantees. Currently, grantees from the New York Department of Health
are exploring linkages between school-related environments, children's school performance, and
environmental policies (report due in 2015) (SHC). More recently, a 2013 RFA solicited research
on "Healthy Schools:  Environmental Factors, Children's Health and Performance, and Sustainable
Building Practices" (SHC) (U.S. EPA, 2013d); available at: http://epa.gov/ncer/rfa/2013/2013  star
healthy schools.html. This research will investigate the impact of indoor pollutants, as well as
outdoor pollutants being drawn indoors in schools, on children's health and ability to learn. These
grants will be announced in 2014.
An ORD and EPA Region 6 study (SSWR) is examining water-related exposures and birth defects,
in a five-county area surrounding Corpus Christi, Texas. Previous studies noted an elevated rate of
birth defects in and around the Corpus Christi area. In this study, ORD is conducting analyses to
determine the extent and locations of clusters of birth defects and is examining the relationship
between these clusters to water and other environmental exposures.

Evaluating Impact of Co-Exposure to Multiple Stressors
Research is ongoing on new methods for modeling and assessing cumulative exposure and risk.
For example, "Estimation of Childhood Lead Exposure at the Census Tract  Level Based on Aggre-
gate Sources" (SHC) was a multi-factor analysis of cumulative lead exposure that increased the
knowledge base concerning lead exposure in children.
A STAR grant project called "Effects-Based Cumulative Risk Assessment in a Low-Income Urban
Community near a Superfund Site" (ACE and Harvard School of Public Health)  is leveraging data
from an ongoing birth cohort study and public databases to predict exposures  as a function of all
chemical stressors of interest. The resulting health risk characterization will include geospatial and
demographic variability and trends over time.

MICA Study fCSS and SHC)
The Mechanistic Indicators of Childhood Asthma (MICA) study was designed to pilot an integra-
tive approach in children's health research. MICA incorporates exposure metrics, internal dose
measures, and clinical indicators to decipher the biological complexity inherent in diseases such
as asthma and cardiovascular disease with etiology related to gene-environment interactions. A
cohort of 205 non-asthmatic  and asthmatic children  (ages 9 to  12) from Detroit, Michigan, was
recruited. The  study includes environmental measures (indoor and outdoor air, vacuum dust), bio-
markers of exposure (cotinine, metals, allergen specific IgE, PAH and volatile organic carbon (VOC)
metabolites) and clinical indicators of health outcome (immunological, cardiovascular and respi-
ratory). In addition, blood gene expression and candidate single nucleotide polymorphism (SNP)
analyses were  conducted. Based on an integrative design, the MICA study provides an opportu-
nity to evaluate complex relationships between environmental factors, physiological biomarkers,
genetic susceptibility and health outcomes (Gallagher et al.,  2011).

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Research Area 3. Methods and models fit for purpose to evaluate early
lifestage-specific risks and to support decisions protective of all susceptible
and vulnerable early lifestages

Research Area 3 has been divided into the following two subgroups: (1) Exposure, and
(2) Dosimetry Models. ORD's relevant research in each of these areas is summarized as follows:

(1) Exposure
Exposure factors and exposure data (page 64) need to be easily accessible to risk assessors in
order to assess the effects of environmental chemicals on children. ORD has developed tools to
increase the usability and access to exposure data, models to predict exposure by a variety of
pathways and routes, and approaches for categorizing lifestage changes and prioritizing chemical
mixtures.

EPA-Expo-Box (HHRA)
EPA-Expo-Box is a web-based compendium of over 800 exposure assessment tools that provides
links to exposure assessment databases, models, and references (U.S. EPA, 2013c); available at:
http://www.epa.gov/ncea/risk/expobox/docs/archive/Expobox  Fact-Sheet  Novl3.pdf. It includes
approaches for exposure assessments, tiers and types of exposure assessments, chemical classes,
routes of exposure to chemicals, lifestages and populations, and exposure media. It also includes,
in a searchable and downloadable format, the full list of exposure factors from the Exposure Fac-
tors Handbook (see page 64).

SHEDS-HT Model (CSS)
The Stochastic Human Exposure and Dose Simulations-HT (SHEDS-HT) model is a screening-level
human exposure model for chemicals. Pathways included in the model include near-field direct
and indirect use of chemicals in the home (e.g., use of personal care products, cleaning products,
and pesticides), emission of chemicals from building materials, and dietary consumption of con-
taminated foods. SHEDS-HT is a probabilistic model that produces population-level distributions of
exposures by the dermal, inhalation, and ingestion routes. Exposure results can also be estimated
for individual age-gender cohorts. Exposure-relevant information specific to children included  in
SHEDS-HT includes age-specific behaviors (such as hand-to-mouth contact and use of consumer
products), times spent in microenvironments, and food intakes.

ExpoCast (CSS)
ExpoCast is  a rapid, high-throughput model  using off the shelf technology that predicts exposures
for thousands of chemicals (U.S. EPA, 2014f), available at: http://epa.gov/ncct/expocast/. Expo-
Cast evaluated  1,763 chemicals for estimating exposure due to industrial releases and a simple
indicator of consumer product use. ORD research is generating and incorporating new information
about age-dependent exposures (e.g., product use) into ExpoCast so that this model can be more
specifically applied to capture children's unique vulnerabilities to support risk-based decisions.

Lifestage Categories for Monitoring and Assessing Exposures to Children (SHC)
ORD has developed a consistent set of childhood lifestage categories for researchers to use when
assessing childhood exposure and potential dose to environmental contaminants (Firestone et al.,

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2007). The standard lifestage categories are: birth to <1 month; 1 to <3 months; 3 to <6 months;
6 to <11 years; 11 to <16 years; and 16 to <21 years. These categories consider developmental
changes in various behavioral,  anatomical, and physiological characteristics that impact exposure
and potential dose. These lifestage categories were recommended by EPA to be used as stan-
dard age groups in exposure and risk assessments in the report titled "Guidance on Selecting Age
Groups for Monitoring and Assessing Childhood Exposures to Environmental Contaminants" (U.S.
EPA, 2005); available at: http://www.epa.gov/raf/publications/pdfs/AGEGROUPS.PDF.
In order to harmonize lifestage categories for monitoring and assessing risks from exposures to
chemicals for global use, the World Health Organization (WHO) recommended adapting ORD's
lifestage categories, as presented above (Cohen Hubal et al., 2013).

Biogeographical Approach for Prioritizing Chemical Mixtures (CSS)
In a study of the co-occurrence pattern of pesticides in child care centers (Tornero-Velez et al.,
2012). ORD used methods from the field of biogeography to investigate co-occurrence patterns in
chemicals. The results showed that the co-occurrence of pesticides in the child care centers was
not random but was highly structured, leading to the co-occurrence of specific combinations of
pesticides. ORD concluded that chemical mixtures arise,  in part through nonrandom processes
such as economic factors, engineered formulations, and differential degradation such that the
observed number of combinations tends to be less than the theoretical random number of com-
binations. The biogeographical approach will be highly useful for prioritizing chemical mixtures in
risk assessment and to calculate co-occurrence probabilities of mixtures of chemicals.

(2) Dosimetry Models
ORD has developed a number  of dosimetry models that assess exposure, predict dose, and de-
scribe the kinetics of environmental chemicals as related to children's health.

Empirical Models
Persistent Bioaccumulative Toxicants (CSS)
A statistical model was developed for predicting levels of polybrominated diphenyl ethers (PBDEs)
in breast milk, based on serum data from the National Health and Nutrition Examination Survey
(NHANES) (Marchitti et al., 2013). In this research, congener-specific linear regression partition-
ing models were developed and applied to 2003-2004 NHANES serum data for U.S. women. The
predictions of PBDE levels in breast milk were consistent with reported concentrations in 11  U.S.
studies.
ORD is now applying this approach to other environmental chemicals (dioxins, perfluorinat-
ed compounds (PFCs), polychlorinated biphenyls (PCBs), and organochlorine pesticides); it is
expected that these models will facilitate the use of available biomonitoring serum data (e.g.,
NHANES) to better characterize infant exposures. ORD is also working on developing a compre-
hensive quantitative structure-activity relationship (QSAR)-based model for predicting milk:serum
partitioning ratios for classes of chemicals where serum and milk data are not available to con-
struct regression models. This  QSAR model will predict the potential of an environmental chemical
to partition into breast milk and can be used to improve exposure and risk estimates for breast-
feeding infants.

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In vitro to In vivo Extrapolation (CSS)
ORD has proposed an approach to link results from in vitro high throughput studies with popu-
lation group specific-dosimetry for neonates, children, and adults, and exposure estimates. For
nine ToxCast chemicals, pharmacokinetic models for multiple subpopulations were constructed
that predicted chemical concentrations in the blood at steady state. These models have potential
application to estimate chemical-specific pharmacokinetic uncertainty factors and to estimate
subpopulation-specific oral equivalent dose values to aid in chemical prioritization and identifying
subpopulations with greater susceptibility to potential pathway perturbations (Wetmore et al.,
2014).

Community Multi-scale Air Quality Model (CMAQ)
The EPA's Community Multi-scale Air Quality (CMAQ) Model is a powerful computational tool used
by EPA and states for air quality management that gives  detailed information about the concentra-
tions of air pollutants in a given area. Comparison of data from the CMAQ model with birth out-
comes or childhood hospital admissions for asthma has generated data on associations between
pollutant exposure (i.e., particulate matter (PM) or ozone) and  health outcomes (U.S. EPA, 2014c),
available at: http://www.epa.gov/AMD/Research/RIA/cmaq.html.

Pesticide Biomarker Measurements in Children (CSS)
ORD is investigating the utility of various biomarkers for  determining exposure to environmental
chemicals in children. In a study consolidating the results from  several large- and small-scale ob-
servational studies on children's exposure to  pesticides,  ORD compared measurements of urinary
metabolites of select pesticides with the kinetic parameters of the pesticides (Egeghy et al., 2011).
The temporal variability of the metabolites detected, based on time of pesticide application, as
well as the relative importance of dietary exposure compared to the indirect ingestion, dermal,
and inhalation routes were examined. The results showed that urinary biomarker levels provided
only limited evidence of pesticide application and appeared to  be affected by differences in the
contribution of each exposure route to total intake.

PBPK Models (CSS)
Virtual Embryo Project
ORD has  developed a life-stage PBPK model,  as part of the Virtual Embryo project in the predic-
tive toxicology of children's health and development following prenatal or lactational exposure to
environmental chemicals. This model was developed to computationally investigate the relation-
ship between chemical exposure, tissue dosimetry and in vitro  markers of critical events related
to AOPs. The model includes time-changing physiological and biochemical descriptors related to a
pregnant mother, fetal growth, and child exposure  through lactation.

Ethanol
To supplement and complete PBPK models in the literature, ORD developed PBPK models to
describe the kinetics of ethanol in adult, pregnant,  and neonatal rats for the inhalation, oral, and
intravenous routes of exposure. The three models accurately predicted the  kinetics of ethanol,
including the absorption, peak concentration, and clearance across multiple datasets. This work
provides  comprehensive lifestage models of ethanol pharmacokinetics and  represents the first

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step in developing models for use with blends of ethanol and gasoline that are commonly used in
the United States. (S. A. Martin et al., 2012).

Research Area 4. Translational research and tools fit for purpose to support
community actions and decisions

Research Area 4 has been divided into the following four subgroups: (1) Decision Support Tools,
(2) Problem Driven Research, (3) Translational Research, and (4) Social Determinants of Health.
ORD's relevant research in each of these areas is summarized as follows:

(1) Decision Support Tools
ORD is developing decision support tools for state, tribal and local governments in order to make
sound decisions about both community development and healthful environments, and to avoid
unintended consequences.

Community-Focused Exposure and Risk Screening Tool (SHC)
ORD has developed the Community Focused Exposure and Risk Screening Tool (C-FERST) (U.S.
EPA, 2013a); available at: http://www.epa.gov/heasd/c-ferst/ to enhance access to information for
environmental health decision making. Developed in collaboration with several pilot communities,
and scheduled for public release in  2014 following external peer review, this Web-based tool pro-
vides a repository of information for >40 environmental issues. Children's health issues in C-FERST
currently include childhood lead exposure, childhood asthma, and schools. By providing a public
venue for communicating ORD science and  EPA guidance and solutions, C-FERST can empower
communities with information for prioritizing and addressing environmental issues. C-FERST will
soon provide data and maps of modeled childhood lead exposures for local impact estimates and
targeting enforcement activities. Future versions of C-FERST will incorporate additional research
results and features to help address children's environmental and cumulative risk issues.

Health Impact Assessment
Recently, C-FERST was used, along with other tools, to inform a Health Impact Assessment (HIA)
related to school renovation decisions in an environmental justice community. The HIA for the
Gerena Elementary School in Springfield, Massachusetts—one of EPA's first HIAs, and the first
school building focused HIA in the field—is a collaboration between EPA and stakeholders includ-
ing the Massachusetts Departments of Public Health and Environmental Protection, city, school,
and community groups. The purpose of this HIA is to provide and help process information to help
the City of Springfield narrow  down options for renovation and improvement at the Gerena School
to those that will best address environmental problems, reduce potential negative health impacts
such as asthma exacerbations, and enhance well-being of the school community. The school is
directly under a highway and adjacent to roadways and a railway, so the project is considering
transportation-related indoor air exposures as well  as those from flooding, moisture, mold and
other indoor environmental issues in the school.
In the process, EPA is learning how its science can be used in the HIA process and incorporating
HIA into its decision-support tools. A new HIA roadmap is being incorporated into C-FERST to
facilitate  broad access to  information, guidance, and best practices in conducting future HIAs. ORD

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led the assessment phase of the HIA for this elementary school, including indoor and outdoor air
monitoring, building systems evaluation, and data analysis.

EnviroAtlas (SHC)
EnviroAtlas, scheduled for public release in 2014 will include, at least for selected urban areas,
such indicators as the locations of schools, recreational areas and factors relevant to health
outcomes (demographics, income) and access to transportation routes and indicators of
ecosystem services such as tree cover (related to heat, recreation, green-space accessibility).
This tool also includes an Eco-Health Relationship Browser (U.S. EPA, 2013b), available at: http://
www.epa.gov/research/healthscience/browser/introduction.html (launched in 2012). It is a user-
friendly Web-based browser which illustrates linkages between human health and ecosystem
services, i.e., the benefits supplied by nature. Health outcomes currently searchable in the
browser of direct relevance to CEH include low birth weight and preterm birth, asthma,  ADHD,
and obesity. Expansion of the browser to more completely address children's health is being
considered.

(2) Problem-Driven Research
Studies have been conducted to further the understanding of linkages between human health
and environmental exposures. Communities are using results of these analyses to make decisions
concerning renovation of schools, location of recreational areas, and future development.

EPA Pilot Study Add-On to the Third Study Site of the Green Housing Study (SHC)
The Green Housing Study is a collaborative effort between the U.S. Department of Housing and
Urban Development (HUD) and the Centers for Disease Control and Prevention (CDC). Three main
goals of the Green Housing Study are to: (1) compare levels of certain chemical and biological
agents and non-chemical stressors in green versus traditional, multi-family, low-income  hous-
ing; (2) ascertain differences in the health of the residents in these homes; and (3) assess the
economic impacts of the "greening"  of housing—particularly those related to health. These goals
will be accomplished in ongoing building renovation programs sponsored by HUD. Green housing
includes strategies to reduce exposure to environmental contaminants, including but not limited
to the use of integrated pest management practices, the use of low/no volatile organic compound
(VOC) materials (e.g., paints, carpets), and improved insulation and ventilation practices. Briefly,
both the green-renovated and comparison (no renovation) homes will be from the same hous-
ing development or neighborhood to ensure homogeneity with regard to housing type and other
socioeconomic factors. Changes in environmental measurements (pesticides, VOCs, particulate
matter [i.e., PM2.5 and 1.0], indoor allergens, and fungi) over a one-year post-renovation period
will be compared to p re-re novation measurements, such that each home's measurements will be
compared with its own baseline measurements. This study design enables both a pre- and post-
renovation comparison as well as a comparison between green-renovated and control homes in
order to detect differences in exposure levels and asthma outcomes. Residents will participate for
one month prior to renovation, the time required for renovation of their home, and 12 months af-
ter completion of the renovation. The duration of participation for residents of comparison homes
is the same.

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 In partnership with HUD and CDC, ORD will leverage this opportunity to collect additional multi-
media measurements and questionnaire data from the index children actively participating in the
Green Housing Study and a sibling(s) in order to characterize personal, housing, and community
factors influencing children's potential exposures to indoor contaminants at various lifestages.
Additionally, by recruiting siblings of the index children, ORD will begin to examine how lifestage
affects children's exposures when children have the potential to be exposed to the same chemi-
cals in consumer products found in their environment.

Dust and soil ingestion (CSS and SHC)
ORD is using models to estimate different exposure parameters, such as soil and dust ingestion
rates, in children. These parameters are used in exposure and risk assessments to evaluate the
health outcomes of environmental chemicals in children. For example, ORD used the SHEDS-Soil/
dust model to estimate soil and dust ingestion rates for young children at two Taiwanese loca-
tions. One site was designated as the control, since the village in which the homes were located
was thought to be less likely impacted by the pollutants under investigation. The other site was
designated as a near road exposure site. Inputs were developed for both types of sites. In addi-
tion, similar SHEDS-Soil/dust simulations were conducted for U.S. children. The ages of the chil-
dren simulated ranged from 6 months up to (but less than) 36 months. The children were divided
into three age categories: 6 months to <12 months; 12 months to <24 months; 24 months to <36
months and soil and dust ingestion rates were  estimated through model simulation (Glen et al.,
2013).

Chemical and Non-Chemical Stressors and Childhood Obesity (SHC)
Childhood obesity has tripled in the last three decades and now affects 17% of children in the
U.S. In 2010, the percentage of obese children in the U.S. was nearly 18% for both 6-11 and 12-19
years of age. Recent evidence in the literature suggests that exposure to selected environmen-
tal chemicals may impact obesity. Socioeconomic status, ethnicity, and the built environment
may also impact obesity. Recent studies have also shown that poor quality food outlets in close
proximity to neighborhoods or schools increased the likelihood of poor quality food purchases.
While much research has focused on individual stressors impacting obesity, little research  has
emphasized the complex interactions of numerous chemical and non-chemical stressors affecting
a child's health and well-being.
ORD is conducting research in this area to (1) identify and characterize chemical and non-chemical
stressors that impact childhood obesity; (2) identify key stressors across a range of stressor do-
mains; and (3) characterize the interactions of these key stressors on children's health.
ORD is currently completing a state-of-the-science literature review to identify chemical and non-
chemical stressors related to childhood obesity. Using this information, a searchable database was
created and analyzed to identify  key stressors.  Numerous chemical and non-chemical stressors
were identified and grouped into the following domains: individual, family, community, and chem-
ical. Stressors were related to the child and their everyday environments (home and community)
and used to characterize child health and well-being. Data shows that there is not always a posi-
tive association with a  stressor and childhood obesity, and that there can be inconsistent correla-
tions between the same stressors and obesity. However, there is sufficient evidence to  suggest the
interactions of multiple stressors may be the cause of the childhood obesity epidemic.

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Chemical and Non-Chemical Stressors and Neurocognitive Health (SHC)
Early childhood (0-6 years old) is a time of significant brain growth and foundational skills devel-
opment essential for school readiness and academic achievement. Maximizing a child's learning
potential can be achieved only with complete knowledge of stressors that impact learning. Many
studies attempt to identify associations between individual exposure factors and neurocognitive
development. However, extending from pregnancy to a child's first day of school, numerous stress-
ors (e.g., chemicals, prenatal stress, behaviors, family violence) may influence children's neurocog-
nitive development and health and well-being. Additionally, community-level decisions related to
land use, transportation, buildings and infrastructure, and waste and materials management may
also influence a child's health and well-being by impacting their home and learning environments.
ORD is conducting research to examine stressors related to neurocognitive health in children
ages 3-6 years to (1) identify and characterize individual stressors associated with neurocognitive
development and (2) develop a conceptual model that identifies key stressors and their possible
interactions.
ORD completed a literature review across multiple databases (e.g., PubMed, Web of Science,
Psychlnfo) utilizing the search strings: neurodevelopment or cognition and children. Assessment
of the quality of the study and its applicability to the general population was conducted to identify
key stressors associated with neurocognitive health and to develop a conceptual model using a
multi-level systems approach.
Key exposure factors were identified for each developmental lifestage from pregnancy to 3-6 years
old. These factors were grouped three different ways according to (1) the type of occurrence (e.g.,
individual, home, school, community); (2) characterization as an individual health, social, environ-
mental or economic determinant; and (3) how decisions regarding land use, buildings and infra-
structure, waste and materials management, and transportation have impacted them. These ele-
ments were incorporated into the model and the results suggest that some childhood exposures
(e.g., SES, parent-child interaction, diet, built environment) not only present as key factors, but act
as effect modifiers of stressors experienced during pregnancy and infancy (e.g., lead, pesticides,
prenatal stress).

Community Multi-scale Air Quality Model (ACE)
The EPA's Community Multi-scale Air Quality (CMAQ) Model is a powerful computational tool used
by EPA and states for air quality management that gives detailed information about the concentra-
tions of air pollutants in a given area. Comparison of data from the CMAQ model with birth out-
comes or childhood hospital admissions for asthma has generated data on associations between
pollutant exposure  (i.e., particulate matter (PM) or ozone) and health outcomes (U.S.  EPA, 2014c),
available at: http://www.epa.gov/AMD/Research/RIA/cmaq.html.

PCBs in Schools (HHRA)
ORD research characterized sources of exposure to PCBs in school environments, showing that
both window caulking and light ballasts have contributed to exposures in older schools. Findings
from this research showed that caulk put in place between 1950 and 1979 can contain as much as
30% PCBs and can contaminate adjacent material such as masonry or wood. Fluorescent light fix-
tures that still contain their original PCB-containing light ballasts may rupture and emit PCBs. En-

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capsulation, a PCB containment method, was shown to be effective only when the PCB content in
the source was low. EPA used the results of this research to update its guidance to building owners
and school administrators on how to reduce exposures to PCBs that may be found in schools (U.S.
EPA, 2013e); available at: http://www.epa.gov/pcbsincaulk/caulkresearch.htm.

Child-Specific Exposure Scenarios Examples (HHRA)
The "Child Specific Exposure Scenarios Examples" is a companion document to the "Exposure
Factors Handbook: 2011 Edition" (EFH) (see page 64). The purpose of the "Child Specific Expo-
sure Scenarios Examples"  is to present childhood exposure scenarios using data from the "Child
Specific Exposure Factors Handbook" (U.S. EPA, 2008);  available at http://cfpub.epa.gov/ncea/
risk/recordisplav.cfm?deid=199243 and updated children's data from the EFH (U.S. EPA, 2011);
available at: http://cfpub.epa.gov/ncea/risk/recordisplav.cfm?deid=236252. These scenarios are
not meant to be inclusive of every possible scenario, but they are intended to provide a range
of scenarios that show how to apply exposure factors data to characterize childhood exposures.
The example scenarios were compiled from questions and inquiries received from users of the
earlier versions of the EFH on how to select data from the Handbook. The scenarios presented in
the report promote the use of the standard set of age groups recommended by EPA in the report
titled "Guidance on Selecting Age Groups for Monitoring and Assessing Childhood Exposures to
Environmental Contaminants" (U.S. EPA, 2005) (see page 73); available at http://www.epa.gov/
raf/publications/pdfs/AGEGROUPS.PDF.

(3) Translational Research
Translational research involves translating the results from research on children's health into find-
ings that are useful to communities, neighborhoods, or other groups as they develop strategies
to work on local environmental health issues. Many of the studies discussed on page 68 include
translational components, involving environmental health communication, community outreach,
and collaboration with local community groups.

CEHC Program (SHC)
As discussed on page 68, the EPA-NIEHS co-funded CEHC Program is generating exposure and
biomarker data in pregnant women and children, showing relationships between exposure and a
variety of children's health outcomes, and identifying critical windows of susceptibility (U.S. EPA,
2014e); available at: www.epa.gov/ncer/childrenscenters. Collectively they are examining a wide
range of health outcomes  in cohorts of children including adverse birth outcomes, asthma and
respiratory dysfunction, and other diseases.
A critical and unique component of the Children's Centers Program is the inclusion of a Commu-
nity Outreach and Translation Core. These cores use a variety of innovative approaches to trans-
late research findings and  intervention strategies to the community. As summarized in Table A3,
outreach and translation involves a wide variety of community  partners, including community
advocacy and environmental justice organizations, state and city health departments, state and
city environmental protection and natural resources departments, city governments, health care
providers, schools and  educational advocacy groups, and various  programs in universities. Thus,
research translation benefits environmental health broadly by influencing decisions at all  levels,
from health policy to personal choices.

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Table A3. EPA/NIEHS Children's Centers community outreach and translation -
community partners
 Institution-P.I.
 Brown University
 - Boekelheide
Study Site
Location(s)
Providence, Rl
Community Outreach and Translation -with Community Partners
Silent Spring Institute, Environmental Justice League of Rhode Island
 Columbia
 University -
 Perera
New York City
(Northern Man-
hattan and South
Bronx), Poland,
China
Bronx Borough Presidents Office, Bronx Health Link, Columbia Com-
munity Partnership for Health, Columbia University Head Start, Com-
munity Health Worker Network of NYC, Dominican Medical Associa-
tion, New York, Harlem Children's Zone Asthma Initiative, Harlem
Health Promotion, Northern Manhattan Perinatal Partnership, Nos
Quedamos, WE ACT for Environmental Justice
 Dartmouth       Hanover, NH
 College- Karagas
                  Dartmouth-Hitchcock Concord Clinic, Concord Hospital Family Clinic,
                  Concord Obstetrics and Gynecology Professional Associates, Concord
                  Women's Care, Family Tree Health Care (Warner, NH), Dartmouth
                  Hitchcock Lebanon Clinic, Concord Hospital, The Family Place,
                  Dartmouth-Hitchcock Medical Center, New Hampshire Department
                  of Environmental Health Services, New Hampshire Birth Conditions
                  Program, University of New Hampshire Department of Molecular,
                  Cellular and Biomedical Sciences
 Duke University/
 University of
 Michigan -
 Miranda
Durham, NCand
Ann Arbor, Ml
Durham Congregations, Associations, and Neighborhoods (CAN),
Triangle Residential Options for Substance Abusers (TROSA), Durham
Affordable Housing Coalition, Partnership Effort for the Advancement
of Childrens Health/Clear Corps (PEACH), Durham People's Alliance,
Durham County Health Department, Lincoln Community Health
Center, Duke University Nursing School Watts School of Nursing, City
of Durham Department of Neighborhood Improvement Services,
City of Durham Department of Community Development, Children's
Environmental Health Branch of NC Department of Environment and
Natural Resources, North Carolina Asthma Alliance,  East Coast Mi-
grant Head Start, North Carolina Community Health Center Associa-
tion, North Carolina Rural Communities Assistance Project
 Duke University   Durham, NC       DukeEngage Program, El Centro Hispano (local Latino community),
 - Murphy                          Partnership for a Healthy Durham
 Johns Hopkins    Baltimore, MD     Baltimore City Head Start Program, Baltimore City Health Depart-
 University -                        ment Healthy Homes Program, Baltimore School Food Services Pro-
 Diette                              gram, Healthy Stores Program, Maryland Asthma Control Program,
                                    Women Infants and Children (WIC) nutrition programs
 National
 Jewish Health -
 Schwartz, Szefler
Denver, CO         Colorado Asthma Coalition, Colorado Clinical Guidelines Collabora-
                  tive, Colorado Department of Public Health and Environment, Denver
                  Public School System, Lung Association of Colorado, Rocky Mountain
                  Prevention Research Center, EPA Region 8, Alamosa Public School,
                  Denver Health, Colorado Public Health, Practice Based Research
                  Network, Regional Air Quality Council, Colorado Air Quality Commis-
                  sion, Grand Junction Housing Authority, Western Colorado Math &
                  Science Center, Region 8 Pediatric Environmental Health Specialty
                  Unit(PEHSU)
 University of
 California at
 Berkeley -
 Buffler,  Metayer
Berkeley, CA       Network of 8 clinical institutions in northern and central California
                  participating in the Northern California Childhood Leukemia Study
                  (NCCLS), national community of pediatric health care professionals
                  with an interest in environmental health issues; national community
                  of persons interested in leukemia; California community of persons
                  interested in childhood leukemia; Region 9 Pediatric Environmental
                  Health Specialty Unit (PEHSU)

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Table A3.  (continued) EPA/NIEHS Children's Centers community outreach and translation -
community partners
 Institution-P.I.
 University of
 California at
 Berkeley -
 Eskenazi
Study Site
Location(s)
Berkeley and Sali-
nas, CA
Community Outreach and Translation -with Community Partners
Clinica de Salud del Valle de Salinas, Natividad Medical Center, South
County Outreach Effort (SCORE), Monterey County Health Depart-
ment, California Rural Legal Assistance (CRLA) Program, Grower/
Shipper
 University
 of California
 at Berkeley/
 Stanford
 University-
 Hammond,
 Balmes, Shaw
Berkeley, Palo
Alto, Bakersfield
and San Joaquin
Valley, CA
Medical Advocates for Healthy Air, Fresno Metro Ministry, Center on
Race, Poverty, and the Environment, San Joaquin Valley Latino Envi-
ronmental Advancement Project (LEAP), El Comite para el Bienestar
de Earlimart, Coalition for Clean Air, San Joaquin Valley Cumulative
Health Impact Project (SJV-CHIP), Central California Environmental
Justice Network, Central Valley Air Quality Coalition, Californians for
Pesticide Reform
 University of
 California at
 Davis -
 Van de Water
Davis, CA
Families for Early Autism Treatment, Learning Disabilities Association,
Parents Helping Parents, San Francisco Bay Chapter of the Autism
Society of America, Alameda County Developmental Disabilities
Council, Cure Autism Now, State of California health/developmental
service providers, California Departments of Developmental Services
and Health Services, California Regional Centers and Office of Envi-
ronmental Health Hazard Assessment
 University of
 California, San
 Francisco-
 Woodruff
San Francisco, CA
American College of Obstetricians and Gynecologists (ACOG District
IX), Association of Reproductive Health Professionals, Physicians for
Social Responsibility (PSR) San Francisco Bay Area Chapter, WORK-
SAFE (California Coalition for Worker Occupational Safety & Health
Protection), California Department of Health Occupational Health
Branch
 University
 of Illinois
 at Urbana-
 Champaign -
 Schantz
Urbana-Cham-
paign, ILand New
Bedford, MA
Illinois Action for Children (IAFC), American Academy of Pediatrics
(AAP), Just-In-Time Parenting, Champaign-Urbana Public Health
Department, Great Lakes Center for Environmental Health, Cam-
bridge Health Alliance, Carle Foundation Hospital, Provena Covenant
Medical Center
 University
 of Michigan
 - Peterson,
 Padmanabhan
Ann Arbor, Ml
and Mexico City,
Mexico
Early Life Exposures in Mexico to Environmental Toxicants (ELE-
MENT), National Institute of Public Health, Mexico City, Detroit
Hispanic Development Corporation
 University        Los Angeles, CA     The Children's Clinic (Long Beach and South Bay), Asian and Pacific
 of Southern                          Islander Obesity Prevention Alliance, East Yard Communities for Envi-
 California -                          ronmental Justice, Digital Rain Factory, Los Angeles Parks Foundation,
 McConnell                           The Trust for Public Land Center for Park Excellence, Policies for Liv-
                                     able, Active Communities and Environments (PLACE) of Los Angeles,
                                     Trade, Health and Environment Impact Project, Center for Commu-
                                     nity Action & Environmental Justice (Riverside and San Bernardino),
                                     Coalition for a Safe Environment (Wilmington), East Yard Communi-
                                     ties for Environmental Justice (Commerce and East L.A.), Long Beach
                                     Alliance for Children with Asthma, Outreach Program  of Southern
                                     California Environmental Health Sciences Center Los Angeles (USC/
                                     UCLA), Urban & Environmental Policy  Institute, Occidental College
 University of
 Washington -
 Faustman
Yakima Valley, WA
Community members in the Yakima Valley, Farm Workers Union,
Growers' Association, Washington State Department of Health and
Department of Agriculture, Farm Workers' Union, Yakima Valley Farm
Workers Clinics, Radio KDNA (Spanish language), Washington State
Department of Labor and Industries, Columbia Legal Services, Wash-
ington State Migrant Council, EPA Region 10

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(4) Social Determinants of Health

ORD is carrying out research on the biological, environmental, and social conditions that may con-
tribute to disparities in health outcomes in children. Although the scope of this research extends
well beyond a lifestage-specific focus, some specific activities are targeting children's environmen-
tal health.

STAR Centers of Excellence on Environment and Health Disparities (SHC)
Social determinants of health are a focus of research in the STAR Centers of Excellence on Envi-
ronment and Health Disparities (http://www.epa.gov/ncer/ehs/disparities/health-disparities.
html). ORD, in collaboration with the National Institute of Minority Health and Health Disparities
(NIMHD) (http://www.nih.gov/about/almanac/organization/NIMHD.htm), through an Interagency
Agreement, is supporting the establishment of transdisciplinary networks of excellence in health
disparities research to achieve a better understanding of the complex interactions of biological,
social and environmental determinants of population health. The collaboration promotes coordi-
nation efforts within the NIMHD Centers for Excellence in health disparities research, addressing
racial and socioeconomic disparities in environmentally mediated health outcomes and access to
healthy community environments.
One of these Center projects, "Analysis and Action on the Environmental Determinants of Health
and Health Disparities" (University of South Carolina) will explore six areas of health disparities
that contribute disproportionately to premature death and morbidity found among poor and
racial/ethnic minorities (e.g.,  infant mortality). This project is developing a relational database and
web portal for  integration of data on health outcomes, natural and built environment and social
environment. Another, "Environmental Health Disparities Research" (University of Texas) will ex-
plore the individual- and neighborhood-level contributions to disparities in children's lung health.

Environmental and Community Factors Influence Effectiveness of Medical Treatments for
Asthma (SHC)
An ORD study,  in collaboration with the University of North Carolina, "Observational Assessment
of Baseline Asthma Control as a Susceptibility Factor for Air Pollution Health Effects in African-
American Children with Persistent Asthma," is examining factors that contribute to asthma dispari-
ties in adolescents. The study is following a cohort of African American youth with moderate-to-
severe asthma and examining a variety of factors including air pollution, home environment, and
community issues that may contribute to the high rate of asthma in this population and the rela-
tive effectiveness of medical treatments.

Integrated Approaches to Sustain the Built and Natural Environment and the Communities
They Support:  Children's Health Example (SHC)
In this study, researchers are using GIS tools and multi-layered mapping to examine relationships
between access to green space and birth outcomes. Analyses focus on associations between birth
measures across the greater Durham-Chapel Hill, North Carolina area and various measures of
green space around the home, including tree cover along busy roadways.

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Climate change (ACE)
Young children may be disproportionately affected by climate change and would require specific
adaptations to respond to climate-related stressors. Research is using a multidisciplinary assess-
ment approach to identify those aspects of climate change to which vulnerable populations are
most sensitive, most likely to be exposed,  and most able to adapt, and determine how vulnerabil-
ity to climate change may interact with non-climate environmental stressors.
Current research is evaluating health effects associated with events expected to increase in
frequency during climate change, incorporating age-category-specific effect estimates. Where
possible, child-specific effects will be reported. Related research on climate change, relevant
although not necessarily specific to children's health, includes impacts of increased ground
level ozone and weather events influencing allergic, chronic, waterborne and infectious disease
risks. EPA recently awarded grants to six groups and institutions to study the health effects of
climate change on tribes. These grants will fund research on: improving air quality and reducing
environmental factors that trigger asthma; threats to food sustainability; coastal climate impacts
to traditional foods, cultural sites, and tribal community health and well-being; and food security
and tribal health.
(http://indiancountrvtodavmedianetwork.com/2014/07/23/epa-awards-5-million-research-
climate-change-and-tribal-health-156029).

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Reif, D. M.,  Martin, M. T, Tan, S. W., Houck,  K. A., Judson, R. S., Richard, A. M.,... Kavlock, R. J. (2010).
    Endocrine profiling and prioritization of environmental chemicals using ToxCast data.
    Environ. Health Perspect. 118(12), 1714-1720. doi: 10.1289/ehp.l002180
Sipes, N. S., Martin, M. T, Reif, D. M., Kleinstreuer, N. C., Judson, R. S., Singh, A. V.,...
    Knudsen, T. B. (2011). Predictive models of prenatal developmental toxicity from ToxCast
    high-throughput screening data. Toxicol. Sci. 124(1), 109-127. doi: 10.1093/toxsci/kfr220
Tornero-Velez, R., Egeghy, P. P., and Cohen Hubal, E. A. (2012). Biogeographical analysis of chemical
    co-occurrence data to identify priorities for mixtures research. Risk. Anal., 32(2), 224-236.
    doi: 10.1111/J.1539-6924.2011.01658.X

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U.S. Environmental Protection Agency. (2005). Guidance on selecting age groups for monitoring and
    assessing childhood exposures to environmental contaminants. (EPA/630/P-03/003F).
    Washington, D.C.: Retrieved from
    http://www.epa.Rov/raf/publications/Ruidance-on-selectinR-aRe-Rroups.htm.
U.S. Environmental Protection Agency. (2008). Child-specific exposure factors handbook
    (final report). (EPA/600/R-06/096F). Washington,  D.C.:  Retrieved from
    http://cfpub.epa.Rov/ncea/risk/recordisplav.cfm?deid=199243.
U.S. Environmental Protection Agency. (2011). Exposure Factors Handbook: 2011 Edition.
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U.S. Environmental Protection Agency. (2012). Air Quality and Air Toxics.
    Retrieved from http://www.epa.Rov/ncer/auickfinder/airqualitv.html.
U.S. Environmental Protection Agency. (2013a). Community-Focused Exposure and Risk
    Screening Tool (C-FERST). Retrieved from http://www.epa.Rov/heasd/c-ferst/.
U.S. Environmental Protection Agency. (2013b). Eco-Health  Relationship Browser Introduction.
    Retrieved from http://www.epa.Rov/research/healthscience/browser/introduction.html.
U.S. Environmental Protection Agency. (2013c). EPA-Expo-Box: A Toolbox for Exposure and Risk
    Assessors. Retrieved from http://www.epa.Rov/risk/expobox/docs/Expobox  Fact-Sheet Novl3.pdf.
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    Retrieved from http://actor.epa.Rov/actor/faces/ACToRHome.isp.
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    Retrieved from http://actor.epa.Rov/actor/faces/CPCatLaunch.isp.
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    Retrieved from http://www.epa.Rov/heasd/chad.html.
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    Retrieved from http://actor.epa.Rov/actor/faces/ExpoCastDB/Home.isp.
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    Thomas, R. S. (2014). Incorporating population variability and susceptible subpopulations
    into dosimetry for high-throughput toxicity testing. Unpublished.

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Appendix  B.  Literature Search
of ORD  CEH  Activities
A literature search of EPA-ORD children's environmental health activities was performed in EPA
Science Inventory using the following search conditions. The table lists individual hyperlinks to the
Science Inventory, where more information on each of the manuscripts may be found.
Search Boundaries
Search Terms


Total Results
2015
               Peer Reviewed Journals; Jan. 1, 2008 - March 25, 2015
               adolescence, adolescent, child, childhood, children, developmental,
               daycare, early life, epigenetic, fetal, in utero, infant, maternal, paternal,
               perinatal, postnatal, pregnancy, pregnant, prenatal, school, young adult
               341
                                         Publication
A Disadvantaged Advantage in Walkability: Findings from Socioeconomic and
Geographic Analysis of National Built Environment Data in the United States
2015
Air toxics and epigenetic effects: ozone altered microRNAs in the sputum of human subjects
2015
Cardiomyopathy confers susceptibility to particulate matter-induced oxidative stress,
vagal dominance, arrhythmia, pulmonary inflammation in heart failure-prone rats
2015
Ferrates: Greener Oxidants with Multimodal Action in Water Treatment Technologies
2015
Short-term variability and predictors of urinary pentachlorophenol levels in
Ohio preschool children
2015
The Effects of Perfluorinated Chemicals on Adipocyte Differentiation In Vitro
2014
A Short-term In vivo Screen using Fetal Testosterone Production, a Key Event in the
Phthalate Adverse Outcome Pathway, to Predict Disruption of Sexual Differentiation
2014
Applicability of the Environmental Relative Moldiness Index for Quantification
of Residential Mold Contamination in an Air Pollution Health Effects Study
2014
Assessing the bioavailability and risk from metal-contaminated soils and dusts
2014
Cellular Interactions and Biological Responses to Titanium Dioxide Nanoparticles
in HepG2 and BEAS-2B Cells: Role of Cell Culture Media
2014
Environmental Relative Moldiness Index and Associations with Home Characteristics
and Infant Wheeze
2014
Environmentally Relevant Mixing Ratios in Cumulative Assessments: A Study of the Kinetics
of Pyrethroids and Their Ester Cleavage Metabolites in Blood and Brain; and the Effect
of a Pyrethroid Mixture on the Motor Activity of Rats
2014
Exposures of 129 preschool children to organochlorines, organophosphates,
pyrethroids, and acid herbicides at their homes and daycares in North Carolina
2014
Exposure to fine particulate matter during pregnancy and risk of preterm birth
among women in  New Jersey, Ohio, and Pennsylvania, 2000-2005
2014
Flame Retardant Exposures in California Early Childhood Education Environments
2014
GPS-based Microenvironment Tracker (MicroTrac) Model to Estimate Time-Location
of Individuals for Air Pollution Exposure Assessments: Model Evaluation in Central
North Carolina

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2014
                                          Publication
High Throughput Heuristics for Prioritizing Human Exposure to Environmental Chemicals
       In Situ Formation of Pyromorphite Is Not Required for the Reduction of in Vivo Pb
       Relative Bioavailability in Contaminated Soils
2014
Immediate and long-term consequences of vascular toxicity during zebrafish development
       Influence of Urbanicity and County Characteristics on the Association between
       Ozone and Asthma Emergency Department Visits in North Carolina
       Modeling Spatial and Temporal Variability of Residential Air Exchange Rates for
       the Near-Road Exposures and Effects of Urban Air Pollutants Study (NEXUS)
       Neurophysiological Assessment of Auditory, Peripheral Nerve, Somatosensory,
       and Visual System Functions after Developmental Exposure to Ethanol Vapors
       Perchlorate exposure is associated with oxidative stress and indicators of serum iron
       homeostasis among NHANES 2005-2008 subjects
2014
Perfluorinated Compounds: Emerging POPs with Potential Immunotoxicity
       Phenotypic and genomic responses to titanium dioxide and cerium oxide nanoparticles
       in Arabidopsis germinants
       Relationships of Chemical Concentrations in Maternal and Cord Blood:
       A Review of Available Data
2014
Selective Cognitive Deficits in Adult Rats after Prenatal Exposure to Inhaled Ethanol
2014
Simvastatin and Dipentyl Phthalate Lower Ex vivo Testicular Testosterone Production
and Exhibit Additive Effects on Testicular Testosterone and Gene Expression Via
Distinct Mechanistic Pathways in the Fetal Rat
2014
The Citizen Science Toolbox: A One-Stop Resource for Air Sensor Technology
       Toward Quantitative Analysis of Water-Energy-Urban-Climate Nexus for Urban
       Adaptation Planning
2013
A Computational Model Predicting Disruption of Blood Vessel Development
       Comprehensive assessment of a chlorinated drinking water concentrate in a rat
       multigenerational reproductive toxicity study
       Controlled Exposures Of Human Volunteers To Diesel Engine Exhaust: Biomarkers
       Of Exposure And Health Outcomes
       Decreased Pulmonary Function Measured in Children Exposed to High Environmental
       Relative Moldiness Index Homes
       Effect of Treatment Media on the Agglomeration of Titanium Dioxide
       Nanoparticles: Impact on Genotoxicity, Cellular Interaction, and Cell Cycle
       Evaluation of iodide deficiency in the lactating rat and pup using a biologically based
       dose-response model
2013
Family and home characteristics correlate with mold in homes
2013
Harnessing genomics to identify environmental determinants of heritable disease
2013
Higher Environmental Relative Moldiness Index (ERMI) Values Measured in Homes
of Asthmatic Children in Boston, Kansas City and San Diego
       Higher environmental relative moldiness index values measured in homes of adults
       with asthma, rhinitis, or both conditions
2013
Human Exposures to PAHs: an Eastern United States Pilot Study

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                                          Publication
       Improving Infant Exposure and Health Risk Estimates: Using Serum Data to Predict
       Polybrominated Diphenyl Ether Concentrations in Breast Milk
       Lasting Effects on Body Weight and Mammary Gland Gene Expression in Female Mice
       upon Early Life Exposure to n-3 but Not n-6 High-Fat Diets
2013
Lead, Allergen, and Pesticide Levels in Licensed Child Care Centers in the United States
       Meta-analysis of toxicity and teratogenicity of 133 chemicals from zebrafish
       developmental toxicity studies
2013
Microbial content of household dust associated with exhaled NO in asthmatic children
2013
Release of silver from nanotechnology-based consumer products for children
       Stenotrophomonas, Mycobacterium, and Streptomyces in home dust and air: associations
       with moldiness and other home/family characteristics
       The Incredible Shrinking Cup Lab: An Investigation of the Effect of Depth and
       Water Pressure on Polystyrene
2013
Thermoregulatory deficits in adult long evans rat offspring exposed perinatally to the
antithyroidal drug, propylthiouracil
       Use Of High Content Image Analyses To Detect Chemical-Mediated Effects On Neurite
       Sub-Populations In Primary Rat Cortical Neurons
2012
Activation of mouse and human Peroxisome Proliferator-Activated Receptor-alpha
(PPARa) by Perfluoroalkyl Acids(PFAAs): Further investigation of C4-C12 compounds
2012
An In Vitro Assessment of Bioaccessibility of Arsenicals in Rice and the Use of this
Estimate within a Probabilistic Exposure Model
2012
Assessment of Circulating Hormones in and Nonclinical Toxicity Studies: General
Concepts and Considerations
       Biogeographical Analysis of Chemical Co-Occurrence Data to Identify Priorities
       for Mixtures Research
       Carbaryl Effects On Oxidative Stress In Brain Regions Of Adolescent And Senescent
       Brown Norway Rats
       Children's Exposure to Pyrethroid Insecticides at Home: A Review of Data Collected
       in Published Exposure Measurement Studies Conducted in the United States
       Combining continuous near-road monitoring and inverse modeling to isolate the effect of
       highway expansion on a school in Las Vegas
       Community duplicate diet methodology: A new tool for estimating dietary exposure
       to pesticides
       Comparison of Chemical-induced Changes in Proliferation and Apoptosis in Human
       and Mouse Neuroprogenitor Cells
       Comparison of Four Probabilistic Models (CARES, Calendex, ConsEspo, SHEDS) to Estimate
       Aggregate Residential Exposures to Pesticides
       Comparison of Work-related Symptoms and Visual Contrast Sensitivity between Employees
       at a Severely Water-damaged School and a School without Significant Water Damage
       Conference Report: Advancing the Science of Developmental Neurotoxicity (DNT)
       Testing for Better Safety Evaluation
2012
Development and Preparation of Lead-Containing Paint Films and Diagnostic Test Materials

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2012
                                           Publication
Development of Multi-Route Physiologically-based Pharmacokinetic Models for Ethanol
in the Adult, Pregnant, and Neonatal Rat
2012
Developmental Exposure to Valproate or Ethanol Alters Locomotor Activity and
Retino-Tectal Projection Area in Zebrafish Embryos
2012
Developmental Neurotoxicity Testing: A Path Forward
2012
Developmental Thyroid Hormone Disruption: Prevalence, Environmental Contaminants
and Neurodevelopmental Consequences
2012
Developmental Toxicity Evaluations of Whole Mixtures of Disinfection By-products using
Concentrated Drinking Water in Rats: Gestational and Lactational Effects
of Sulfate and Sodium
2012
Developmental Toxicity Evaluations of Whole Mixtures of Disinfection By-products using
Concentrated Drinking Water in Rats: Gestational and Lactational Effects
of Sulfate and Sodium
2012
Developmental Triclosan Exposure Decreases Maternal, Fetal, and Early Neonatal
Thyroxine: Dynamic and Kinetic Data Support for a Mode-of-Action
2012
Economic benefits of using adaptive predictive models of reproductive toxicity in the
context of a tiered testing program
2012
Effects of a Glucocorticoid Receptor Agonist, Dexamethasone, on Fathead Minnow
Reproduction, Growth, and Development
2012
Effects of perfluorooctanoic acid (PFOA) on expression of peroxisome proliferator-activated
receptors (PPAR) and nuclear receptor-regulated genes in fetal and postnatal mouse tissues
2012
Environmentally-Relevant Mixtures in Cumulative Assessments: An Acute Study of
Toxicokinetics and Effects on Motor Activity in Rats Exposed to a Mixture of Pyrethroids
                        and environmental exposures: Implications for prenatal care
2012
Fetal programming
and preterm birth
2012
Genomic biomarkers of phthalate-induced male reproductive developmental
toxicity: A targeted rtPCR array approach for defining relative potency
2012
GIS-modeled indicators of traffic-related air pollutants and adverse pulmonary health
among children in El Paso, Texas, USA
2012
Infant Origin of Childhood Asthma Associated with Specific Molds
2012
Iron accumulates in the lavage and explanted lungs of cystic fibrosis patients
2012
Magnetic Resonance Imaging and Volumetric Analysis: Novel Tools to Study Thyroid
Hormone Disruption and Its Effect on White Matter Development
2012
Maternal air pollution exposure induces fetal neuroinflammation and predisposes
offspring to obesity in adulthood in a sex-specific manner
2012
Maternal Diesel Inhalation Increases Airway Hyperreactivity in Ozone Exposed Offspring
2012
Metabolomic Response of Human Embryonic Stem Cell Derived Germ-like Cells after
Exposure to Steroid Hormones
2012
Nitric Oxide and Superoxide Mediate Diesel Particle Effects in Cytokine-Treated Mice and
Murine Lung Epithelial Cells - Implications for Susceptibility to Traffic-Related Air Pollution
2012
Perfluorooctanoic acid effects on ovaries mediate its inhibition of peripubertal mammary
gland development in Balb/c and C57BI/6 mice

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2012
                                           Publication
Perflurooctanoic Acid Induces Developmental Cardiotoxicity in Chicken Embryos and
Hatchlings
2012
Peroxisome Proliferator-Activated Receptorct (PPARct) Agonists Differentially
Regulate Inhibitor Of DNA Binding (Id2) Expression In Rodents And Human Cells
2012
PPAR involvement in PFAA developmental toxicity
2012
Predicting Later-Life Outcomes of Early-Life Exposures
2012
Quantifying Children's Aggregate (Dietary and Residential) Exposure and Dose to
Permethin: Application and Evaluation of EPA's Probabilistic SHED-Multimedia Model
2012
Rearing Conditions Differentially Affect the Locomotor Behavior of Larval Zebrafish,
but not Their Response to Valproate-lnduced Developmental Neurotoxicity
2012
Research Opportunities for Cancer Associated with Indoor Air Pollution
from Solid-Fuel Combustion
2012
Seasonality Of Rotavirus In South Asia: A Meta-Analysis Approach Assessing
Associations With Temperature, Precipitation, And Vegetation Index
2012
Some Chronic Rhinosinusitis Patients Have Significantly Elevated Populations
of Seven Fungi in their Sinuses
2012
Strategies for Evaluating the Environment-Public Health Interaction of Long-Term Latency
Disease: The Quandary of the Inconclusive Case-Control Study
2012
The Developmental Neurotoxicity Guideline Study: Issues with Methodology,
Evaluation and Regulation
2012
Toluene Effects on Gene Expression in the Hippocampus of Young-Adult, Middle-Age
and Senescent Brown Norway Rats
2012
Toluene effects on the motor activity of adolescent, young-adult, middle-age and
senescent male Brown Norway rats
2012
Transcriptional Ontogeny of the Developing Liver
2012
Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure
to Methylarsonous Acid During Gestation in CD1 Mice
2012
Zebrafish Developmental Screening of theToxCast™ Phase I Chemical Library
2011
Adverse Outcome Pathways During Early Fish Development: A Framework for
Identifying and Implementing Alternative Chemical Prioritization Strategies
2011
Age-related behavioral effects of methomyl in Brown Norway rats
2011
Age-related differences in acute neurotoxicity produced by mevinphos, monocrotophos,
dicrotophos, and phosphamidon
2011
Aging and the Environment: Importance of Variability Issues in Understanding Risk
2011
Air Pollution and Health: Emerging Information on Susceptible Populations
2011
Aktl protects against germ cell apoptosis in the post natal mouse testis following
lactational exposure to 6-N-propylthiouracil
2011
Allergens in household dust and serological indicators of atopy and sensitization
in Detroit children with history-based evidence of asthma
2011
Altered cardiovascular reactivity and osmoregulation during hyperosmotic stress in
adult rats developmentally exposed to polybrominated diphenyl ethers (PBDEs)

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2011
                                          Publication
An Assessment of the Exposure of Americans to Perflourooctane Sulfonate: A
Comparison of Estimated Intake with Values Inferred from NHANES Data
2011
Aroclor-1254, a developmental neurotoxicant, alters energy metabolism-and intracellular
signaling-associated protein networks in rat cerebellum and hippocampus
2011
Assessing Locomotor Activity in Larval Zebrafish: Influence of Extrinsic and
Intrinsic Variables
2011
Assessing the Quantitative Relationships between Preschool Children's Exposures
to Bisphenol A by Route and Urinary Biomonitoring
2011
Association between Perchlorate and indirect indicators of thyroid dysfunction
in NHANES 2001-2002, a Cross-Sectional, Hypothesis-Generating Study
2011
Booming Markets for Moroccan Argan Oil Appear to Benefit Some Rural Households
While Threatening the Endemic Argan Forest
2011
Combined retrospective analysis of 498 rat multi-generation reproductive toxicity
studies: on the impact of parameters related to Fl mating and F2 offspring
2011
Comparative pharmacokinetics of perfluorononanoic acid in rat and mouse
2011
Comparative sensitivity of human and rat neural cultures to chemical-induced inhibition
of neurite outgrowth
2011
Comparison of Wipe Materials and Wetting Agents for Pesticide Residue Collection
from Hard Surfaces
2011
Current Practices and Future Trends in Neuropathology Assessment for
Developmental Neurotoxicity Testing
2011
Development of a multiplex microsphere immunoassay for the quantitation of salivary
antibody responses to selected waterborne pathogens
2011
Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived
Neurotrophic Factor (BDNF) in Adults But Not in Neonates
2011
Developmental toxicity testing for safety assessment: new approaches and technologies
2011
Di-pentyl phthalate dosing during sexual differentiation disrupts fetal testis function and
postnatal development of the male Sprague dawley rat with greater relative potency
than other phthalates
2011
Disruption of Embryonic Vascular Development in Predictive Toxicology
2011
Dose-response assessment of fetal testosterone production and gene expression levels
in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate,
diisoheptyl phthalate and diisononyl phthalate
2011
Effect of maternal exposure to ozone on reproductive outcome and immune,
inflammatory, and allergic responses in the offspring
2011
Environmental Impact on Vascular Development Predicted by High Throughput Screening
2011
Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent
cell differentiation and cytotoxicity assay
2011
Evaluation of Genetic Susceptibility to Childhood Allergy and Asthma in an African
American Urban Population
2011
Feasibility of assessing the public health impacts of air pollution reduction programs
on a local scale: New Haven accountability case study

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2011
                                          Publication
Fetal Programming of Adult Disease: Implications for Prenatal Care
       Generation and Characterization of Neurogeninl-GFP Transgenic Medaka for High
       Throughput Developmental Neurotoxicity Screening
2011
Geographic Distribution of Environmental Relative Moldiness Index (ERMI) in U.S. Homes
       Gestational Atrazine Exposure: Effects on Male Reproductive Development and
       Metabolite Distribution in the Dam, Fetus, and Neonate
       Hepatic Xenobiotic Metabolizing Enzyme Gene Expression Through the Life Stages
       of the Mouse
       High environmental relative moldiness index during infancy as a predictor of asthma
       at 7 years of age
       Identifying developmental toxicity pathways for a subset of ToxCast chemicals using
       human embryonic stem cells and metabolomics
2011
ILSI/HESI Maternal Toxicity Workshop Summary: Maternal Toxicity and its Impact on
Study Design and Data Interpretatio
2011
Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain
Development and Function
       In Vitro And In Vivo Approaches For The Measurement Of Oral Bioavailability
       Of Lead (Pb) In Contaminated Soils: A Review
2011
In Vitro Assessment of Developmental Neurotoxicity: Use of Microelectrode Arrays
to Measure Functional Changes in Neuronal Network Ontogeny
2011
Influence on Transfer of selected synthetic pyrethroids from treated Formicaฎ to Foods
2011
Investigating the American Time Use Survey from an Exposure Modeling Perspective
2011
Marginal Iodide Deficiency and Thyroid Function: Dose-response analysis for quantitative
pharmacokinetic modeling
       Maternal Influences on Epigenetic Programming of the Developing
       Hypothalamic-Pituitary-Adrenal Axis
       Mechanistic Indicators of Childhood Asthma (MICA): piloting an integrative design
       for evaluating environmental health
       Methodologies for Estimating Cumulative Human Exposures to Current-Use
       Pyrethroid Pesticides
2011
microRNAs: Implications for Air Pollution Research
2011
Modeled Estimates of Soil and Dust Ingestion Rates for Children
       Monoclonal Antibodies to Hyphal Exoantigens Derived from the Opportunistic Pathogen
       Aspergillus terreus
2011
Mortality in the Agricultural Health Study: 1993 - 2007
       Mysid Population Responses to Resource Limitation Differ from those Predicted
       by Cohort Studies
       Neurochemical Changes Following a Single Dose Polybrominated Diphenyl Ether 47
       in Mice
2011
On the Use of a PM2.5 Exposure Simulator to Explain Birthweight
2011
Pesticides on Household Surfaces May Influence Dietary Intake of Children
2011
PPARs and Xenobiotic-lnduced Adverse Effects: Relevance to Human Health

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                                           Publication
       Predictive models of prenatal developmental toxicity from ToxCast high-throughput
       screening data
       Pregnancy loss and eye malformations in offspring of F344 rats following gestational
       exposure to mixtures of regulated trihalomethanes and haloacetic acids
       Recommendations for Developing Alternative Test Methods for Screening and
       Prioritization of Chemicals for Developmental Neurotoxicity
2011
Review of Pesticide Urinary Biomarker Measurements from Selected US EPA Children's
Observational Exposure Studies
       Silver Nanopartilces After Zebrafish Development and Larval Behavior: Distinct Roles
       for Particle Size, Coating and Composition
       Spore trap analysis and MSQPCR in evaluating mold burden: a flooded gymnasium
       case study
2011
Streptomycetes in house dust: associations with housing characteristics and endotoxin
       Temporal Evaluation of Effects of a Model 3B-Hydroxysteroid Dehydrogenase Inhibitor
       on Endocrine Function in the Fathead Minnow
       The effects of prenatal exposure to atrazine on pubertal and postnatal reproductive
       indices in the female rat
2011
The Promise of Exposure Science
       The Reliability of Using Urinary Biomarkers to Estimate Human Exposures to
       Chlorpyrifos and Diazinon
       Thyroid-stimulating Hormone (TSH): Measurement of Intracellular, Secreted, and
       Circulating Hormone in Xenopus laevis and Xenopus tropicalis
2011
Tobacco Smoke Exposure and Altered Nasal Responses to Live Attenuated Influenza Virus
       Toluene effects on Oxidative Stress in Brain regions of Young-adult, Middleage, and
       Senescent Brown Norway Rats
2011
Toxicity and recovery in the pregnant mouse after gestational exposure to the
cyanobacterial toxin, cyl
       Traditional Mold Analysis Compared to a DNA-based Method of Mold Analysis with
       Applications in Asthmatics' Homes
       Use of Genomic Data in Risk Assessment Case Study: II. Evaluation of the Dibutyl
       PhthalateToxicogenomic Dataset
       Use of high content image analysis to detect chemical-induced changes in
       synaptogenesis in vitro
       Windsor, Ontario Exposure Assessment Study: Design and Methods Validation of
       Personal, Indoor and Outdoor Air Pollution Monitoring
2011
Zebrafish - As an Integrative Model for Twenty-first Century Toxicity Testing
2010
A Different Approach to Validating Screening Assays for Developmental Toxicity
       A Meta-Analysis of Children's Object-to-Mouth Frequency Data for Estimating Non-
       Dietary Ingestion Exposure
2010
Acute Neuroactive Drug Exposures alter Locomotor Activity in Larval Zebrafish
       Age, Dose, and Time-Dependency of Plasma and Tissue Distribution of Deltamethrine
       in Immature Rats

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                                          Publication
       Aging And Susceptibility To Toluene In Rats: A Pharmacokinetic, Biomarker, And
       Physiological Approach
2010
Aging-Related Carbaryl Effects In Brown Norway Rats
       Altered Health Outcomes in Adult Offspring of Sprague Dawley and Wistar Rats
       Undernourished During Early or Late Pregnancy
       An Evaluation of the Mode of Action Framework for Mutagenic Carcinogens Case
       Study II: Chromium (VI)
2010
Are Developmentally-Exposed C57BL/6 Mice Insensitive to Suppression of TDAR by PFOA?
2010
Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential
       Changes in mitogen-activated protein kinase in cerebeller granule neurons by
       polybrominated diphenyl ethers and polychlorinated biphenyls
       Characterization of Thyroid Hormone Transporter Protein Expression during Tissue-
       specific Metamorphic Events in Xenopus tropicalis
       Concentration, Chlorination, and Chemical Analysis of Drinking Water for Disinfection
       Byproduct Mixtures Health Effects Research: U.S. EPA's Four Lab Study
       Developmental Effects of Perfluorononanoic acid in the Mouse Are Dependent on
       Peroxisome Proliferator-Activated Receptor-alpha
       Developmental Exposure to a Commercial PBDE mixture, DEป71: Neurobehavioral,
       Hormonal, and Reproductive Effects
2010
Developmental Triclosan Exposure Decreases Maternal and Offspring Thyroxine in Rats
2010
Early Temporal Effects of Three Thyroid Hormone Synthesis Inhibitors in Xenopus laevis
       Effects of prenatal diesel exhaust inhalation on pulmonary inflammation and
       development of specific immune responses
       Effects of Prenatal Exposure to a Low Dose Atrazine Metabolite Mixture on pubertal
       timing and prostrate Development of Male Long Evans Rats
       Evaluation of Deltamethrin Kinetics and Dosimetry in the Maturing Rat using a
       PBPK Model
2010
Feasibility of Community Food Item Collection for the National Children's Study
       Fetal malformations and early embryonic gene expression response in cynomolgus
       monkeys maternally exposed to thalidomide
2010
Field Turbidity Methods for the Determination of Lead in Acid Extracts of Dried Paint
       Gene Expression Changes in Developing Zebrafish as Potential Markers for Rapid
       Developmental Neurotoxicity Screening
       Gene Expression Profiling In Wild-Type And Ppara-Null Mice Exposed To Perfluorooctane
       Sulfonate Reveals Ppara-lndependent Effects
2010
Hypoxia and the Edema Syndrome: Elucidation of a Mechanism of Teratogenesis
2010
In utero and lactational exposure to bisphenol A, in contrast to ethinyl estradiol, does
not alter sexually dimorphic behavior, puberty, fertility, and anatomy of female LE rats
       In Utero Exposure To An AR Antagonist Plus An Inhibitor Of Fetal Testosterone Synthesis
       Induces Cumulative Effects On Fl Male Rats
       Investigation of Reagent Gases for the Positive Chemical lonization of Select
       Polybrominated Diphenyl Ethers

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2010
                                          Publication
       Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference
       points for developmental neurotoxicity testing
2010
       Modeling the interaction of binary and ternary mixtures of estradiol with bisphenol A
       and bisphenol A F in an in vitro estrogen mediated transcriptional activation assay
       (T47D-KBIuc)
       Moderate Developmental undernutrition: Impact on growth and cognitive function in
       youth and old age
       Neural Progenitor Cells as Models for High-Throughput Screens of Developmental
       Neurotoxicity: State of the Science
2010
       Neuroendocrine Actions of Organohalogens: Thyroid Hormones, Arginine Vasopressin,
       and Neuroplasticity
2010
       Neuronal models for evaluation of proliferation in vitro using high content screening
       Organophosphorus and Pyrethroid Insecticide Urinary Metabolite Concentrations
       in Young Children Living in a Southeastern United States City
2010
       Participant-Based Monitoring of Indoor and Outdoor Nitrogen Dioxide, Volatile Organic
       Compounds, and Polycyclic Aromatic Hydrocarbons among MICA-Air Households
2010
       Peroxisome Proliferator Activated Receptors Alpha, Beta, and Gamma mRNAand protein
       expression in human fetal tissues
       Phenotypic and physiologic variability in nasal epithelium cultured from smokers and
       non-smokers exposed to secondhand tobacco smoke
2010
       Quantitative assessment of neurite outgrowth in human embryonic stem cell derived
       hN2 cells using automated high-content image analysis
2010
       The CAESAR models for developmental toxicity
2010
       The Effects of Simazine, a Chlorotriazine Herbicide, on Female Pubertal Development
       The Etiology of Cleft Palate: a 50 year search for mechanistic and molecular
       understanding
       The Hemimelic extra toes mouse mutant: Historical perspective on unraveling
       mechanisms of dysmorphogenesis
       Visually Observed Mold And Moldy Odor Versus Quantitatively Measured Microbial
       Exposure In Homes
       What do we need to know prior to thinking about incorporating an epigenetic evaluation
2010   .
       into safety assessments
       A high sensitivity of children to swimming associated gastrointestinal illness (response to
       letter by Linn)
       A participant-based approach to indoor/outdoor air monitoring in Community Health
       Studies
       *JLUUIC3

       Age, strain, and gender as factors for increased sensitivity of the mouse lung to inhaled
       n?nnp
2009
       ozone
2009
       Analyses of School Commuting Data for Exposure Modeling Purposes
       Analysis of PFOA in Dosed CD1 Mice Part 1: Methods Development for the Analysis
       of Tissues and Fluids from Pregnant and Lactating Mice and Their Pups
       Analysis of PFOA in Dosed CD-I Mice Part 2: Disposition of PFOA in Tissues and fluids
       from pregnant and lactating mice and their pups

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                                          Publication
       Characterization of Ontogenetic Changes in Gene Expression in the Fathead Minnow
       Pimephales promelas
       Childhood Asthma and Environmental Exposures at Swimming Pools: State of the Science
       and Research Recommendations
       Concentration and persistence of tin in rat brain and blood following dibutyltin exposure
       during development
2009
Contact with beach sand among beach-goers and risk of illness
       Correlation between ERMI values and other moisture and mold assessments of homes in
       the American Healthy Home Survey
       Cumulative and antagonistic effects of a mixture of the antiandrogrens vinclozolin and
       iprodione in the pubertal male rat
       Cumulative Effects of in Utero Administration of Mixtures of "Antiandrogens" on Male
       Rat Reproductive Development
2009
Current Development in Reproductive Toxicity Testing of Pesticides
       Developmental exposure to polychlorinated biphenyls (PCBs) interferes with experience-
       dependent dendritic plasticity and ryanodine receptor expression in weanling rats
       Developmental Profile and effects of perinatal PBDE exposure in Hepatic Phase I, II, III and
       deiodinase I gene expression involved in thyroid hormone metabolism in male rat pups
       Developmental toxicity of perfluorooctane Sulfonate (PFOS) is not dependent on
       expression on peroxisome proliferator activated receptor-alpha (PPAR-alpha)in the mouse
       Effects of maternal and pre-weaning undernutrition in rat offspring: Age at
       reproductive senescence and intergenerational pup growth and viability
       Effects of Perfluorooctanoic Acid on Mouse Mammary Gland Development and
       Differentiation Resulting from Cross-Foster and Restricted Gestational Exposures
       Gene Expression Profiling in the Liver and Lung of Perfluorooctane Sulfonate-Exposed
       Mouse Fetuses: Comparison to Changes Induced by Exposure to Perfluorooctanoic Acid
       Impact of lifestage and duration of exposure on arsenic-induced proliferative lesions and
       neoplasia in C3H mice
2009
Locomotion in Larval Zebrafish: Influence of Time of Day, Lighting and Ethanol
       Longitudinal Mercury Monitoring Within the Japanese and Korean Communities (United
       States): Implications for Exposure Determination and Public Health Protection
2009
Maternal drinking water arsenic exposure and perinatal outcomes in Inner Mongolia,
China, Journal
2009
Methodological issues in studies of air pollution and reproductive health
       Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of
       Triazole Antifungals
       Neighborhood deprivation and small-for-gestational-age term births among non-Hispanic
       whites and non-Hispanic blacks in the United States
2009
Peroxisome proliferator-activated receptor alpha (PPARalpha) agonists down-
regulate alpha2-macroglobulin expression by a PPARalpha-dependent mechanism
       Pharmacokinetic Modeling of Perfluorooctanoic Acid During Gestation and Lactation in
       the Mouse

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2009
                                          Publication
Phenotypic Dichotomy Following Developmental Exposure to Perfluorooctanic Acid
(PFOA) Exposure in CD-I Mice: Low Doses Induce Elevated Serum, Leptin, Insulin, and
Overweight in Mid-Life
2009
Polyfluoroalkyl Chemicals in the Serum and Milk of Breastfeeding Women
2009
Predicting Residential Exposure to Phthalate Plasticizer Emitted from Vinyl Flooring - A
Mechanistic Analysis
2009
Predicting Virulence of Aeromonas Isolates Based-on Changes in Transcription of c-jun
and c-fos in Human Tissue Culture Cells
2009
Predictive Models for Carcinogenicity and Mutagenicity: Frameworks, State-of-the-Art,
and Perspectives
2009
Profiling the activity of environmental chemicals in prenatal developmental toxicity
studies using the U.S. EPA'sToxRefDB
2009
Protein Nutrition of Southern Plains Small Mammals: Immune Response to Variation in
Maternal and Offspring Dietary Nitrogen
2009
Retrospective performance assessment of the draft test guideline 426 on developmental
neurotoxicity
2009
Review of the expression of Peroxisome Proliferator Activated Receptors alpha (PPARct),
beta (PPAR 3), and gamma (PPARv) in rodent and human development
2009
Screening Tools to Estimate Mold Burdens in Homes
2009
Selenium and mercury interactions with emphasis on fish tissue
2009
Spatial Analysis and Land Use Regression of VOCs and NO2 from School-Based Urban Air
Monitoring in Detroit-Dearborn, USA
2009
Speciation And Distribution Of Arsenic And Localization Of Nutrients In Rice Grains
2009
The Developmental Effects Of A Municipal Wastewater Effluent On The Northern Leopard
Frog, Rana pipiens
2009
The Effects of In Vivo Acute Exposure to Polychlorinatedbiphenyls on Free and Total
Thyroxine in Rats
2009
The herbicide linuron reduces testosterone production from the fetal rat testis both in
utero and in vitro
2009
Tobacco and Pregnancy
2009
Toxicogenomic Effects Common to Triazole Antifungals and Conserved Between Rats and
Humans
2009
Transgenerational Effects of Di(2-ethylhexyl) Phthalate in the SD Male Rat
2009
Use of Single Fiber Electromyographic Jitter to Detect Acute Changes in Neuromuscular
Function in Young and Adult Rats
2008
A Genomic Analysis of Subclinical Hypothyroidism in Hippocampus and Neocortex of the
Developing Brain — JN
2008
A mixture of five phthalate esters inhibits fetal testicular testosterone production in a
cumulative manner consistent with their predicted reproductive toxicity in the Sprague
Dawley rat
2008
A mixture of seven antiandrogens induces reproductive malformations in rats

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2008
                                          Publication
Acute Postnatal Exposure To Brominated Diphenylether 47 Delays Neuromotor Ontogeny
And Alters Motor Activity In Mice
2008
Acute Respiratory Health Effects Of Air Pollution On Asthmatic Children In US Inner Cities
2008
Adult And Children's Exposure To 2,4-D From Multiple Sources And Pathways
2008
Air pollution, airway inflammation and lung function in Mexico City school children
2008
AJE invited commentary: Measuring social disparities in health - what was the
question again?
2008
Assessment of chemical effects on neurite outgrowth in PC12 cells using high content
screening
2008
Black-white preterm birth disparity: a marker of inequality
2008
Building a scientific framework for studying hormonal effects on behavior and on the
development of the sexually dimorphic nervous system
2008
Chronic particulate exposure, mortality and cardiovascular outcomes in the nurses health
study
2008
Comparative Absorption and Bioaccumulation of Polybrominated Diphenyl Ethers
following Ingestion via Dust and Oil in Male Rats
2008
Comparative hepatic effects of perfluorooctanoic acid and WY 14,643 in PPARa-knocked
out and wild-type mice
2008
Comparison Of Gestational Age At Birth Based On Last Menstrual Period And Ultrasound
During The First Trimester
2008
Coordinated Changes in Xenobiotic Metabolizing Enzyme Gene Expression in Aging
Male Rats
2008
Cytotoxic effects of propiconazole and its metabolites in mouse and human hepatoma
cells and primary mouse hepatocytes
2008
Development of a high-throughput screening assay for chemical effects on proliferation
and viability of immortalized human neural progenitor cells
2008
Development of glucocorticoid receptor regulation in the rat forebrain: Implications for
adverse effects of glucocorticoids in preterm infants
2008
Developmental exposure to perchlorate alters synaptic transmission in hippocampus of
the adult rat: in vivo studies
2008
Developmental neurotoxicity testing in vitro: Models for assessing chemical effects on
neurite outgrowth
2008
Diverse mechanisms of anti-androgen action: impact on male rat reproductive tract
development
2008
Environmental factors and puberty timing: Expert panel research needs
2008
Examination Of U.S. Puberty Timing Data From 1940 To 1994 For Secular Trends:
Panel Findings
2008
Exhaled breath malondialdehyde as a matter of effect of exposure to air pollution in
children with asthma
2008
Fetal alcohol syndrome (FAS) in C57BL/6 mice detected through proteomics screening of
the amniotic fluid

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2008
                                          Publication
Fifteen years after "Wingspread"- Environmental Endocrine Disrupters and human and
wildlife health: Where we are today and where we need to go
2008
Focusing On Children's Inhalation Dosimetry And Health Effects For Risk Assessment: An
Introduction
2008
Gene expression profiles following exposure to a developmental neurotoxicant,
Aroclor 1254: Pathway analysis for possible mode(s) of action
2008
Gene expression profiles in the cerebellum and hippocampus following exposure to a
neurotoxicant, Aroclor 1254: Developmental effects
2008
Gestational and Lactational Exposure to Ethinyl Estradiol, but not Bisphenol A, Decreases
Androgen-Dependent Reproductive Organ Weights and Epididymal Sperm Abundance in
the Male Long Evans Hooded Rat
2008
Higher Environmental Relative Moldiness Index (ERMISM) Values Measured In Detroit
Homes Of Severely Asthmatic Children
2008
Identification And Interpretation Of Developmental Neurotoxicity Effects: A Report From
The ILSI Research Foundation/Risk Science Institute Expert Working Group On
Neurodevelopmental Endpoints
2008
In Vitro Effects Of Environmentally Relevant Polybrominated Diphenyl Ether (PBDE)
Congeners On Calcium Buffering Mechanisms In Rat Brain
2008
Integrated Disinfection Byproducts Mixtures Research: Comprehensive Characterization
Of Water Concentrates Prepared From Chlorinated And Ozonated/Postchlorinated
Drinking Water
2008
Integrated Disinfection By-Products Research: Assessing Reproductive and
Developmental Risks Posed by Complex Disinfection By-Product Mixtures
2008
Lack Of Alterations In Thyroid Hormones Following Exposure To Polybrominated
Diphenyl Ether 47 During A Period Of Rapid Brain Development In Mice
2008
Maternal exposure to water disinfection by-products during gestation and risk
of hypospadias
2008
Mercury Exposure From Fish Consumption Within The Japanese And Korean Communities
2008
Modeling Approaches For Estimating The Dosimetry Of Inhaled Toxicants In Children
2008
Mold Species in Dust from the International Space Station Identified and Quantified by
Mold Specific Quantitative PCR
2008
Mold Species in Dust from the International Space Station Identified and Quantified by
Mold Specific Quantitative PCR - MCEARD
2008
Nasal Contribution to Breathing and Fine Particle Deposition in Children Versus Adults
2008
Neighborhood deprivation and preterm birth among non-Hispanic black and white
women in eight geographic areas in the United States
2008
Neonatal Exposure To Decabrominated Diphenyl Ether (Pbde 209) Results In Changes
In Biochemical Substrates Of Neuronal Survival, Growth, And Synaptogenesis
2008
Of mice and men (and mosquitofish): Antiandrogens and androgens in the environment
2008
Perfluoroctane sulfonate-induced changes in fetal rat liver gene expression
2008
Pharmacokinetics and dosimetry of the anti-androgen vinclozolin after oral
administration in the rat

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2008
                                          Publication
Predicting Maternal Rat and Pup Exposures: How Different Are They?
2008
Protein Biomarkers Associated With Growth And Synaptogenesis In a cell culture model
of neuronal development
2008
Pyrethroid Pesticides and Their Metabolites in Vacuum Cleaner Dust Collected from
Homes and Day-Care Centers
2008
Quantifying Fungal Viability in Air and Water Samples using Quantitative PCR after
Treatment with Propidium Monoazide (PMA)
2008
Rapid New Methods for Paint Collection and Lead Extraction
2008
Research Issues Underlying the Four-Lab Study: Integrated Disinfection Byproducts
Mixtures Research
2008
The balance between oligodendrocyte and astrocyte production in major white matter
tracts is linearly related to serum total thyroxine
2008
The Effect of Environmental Chemicals on Human Health — CJA
2008
The Effects of Triclosan on Puberty and Thyroid Hormones in Male Winstar Rats
2008
The Induction Of Hepatocellular Neoplasia By Trichloroacetic Acid Administered In The
Drinking Water Of The Male B6C3F1 Mouse
2008
The relationship of maternal and fetal toxicity in developmental toxicology bioassays
with notes on the biological significance of the "no observed adverse effect level"
2008
Thyroid hormone status and pituitary function in adult rats given oral doses of
perfluorooctanesulfonate (PFOS)
2008
Tobacco and Pregnancy: Overview of exposures and effects
2008
Traffic And Meteorological Impacts On Near-Road Air Quality: Summary Of Methods And
Trends From The Raleigh Near-Road Study
2008
Undertaking Positive Control Studies As Part Of Developmental Neurotoxicity Testing: A
Report From The ILSI Research Foundation/Risk Science Institute Expert Working Group
On Neurodevelopmental Endpoints
2008
Use of (l-3)-3-D-glucan Concentrations in Dust as a Surrogate Method for Estimating
Specific Mold Exposures
2008
Use of electrostatic dust cloth for self-administered home allergen collection

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Appendix C. CEH Tools and Databases
Name & Type Acronym
Brief Description
Databases
Consolidated Human -UAT
Activitv Database
Exposure Forecaster
ExpoCast
Database
Aggregated
Computational ACToR
Toxicology Resource

Physiological
Parameters Database
for PBPK Modeling

Chemical and Product
Categories Database

Ontogeny Database
on Enzymes

Toxicity Forecaster
ToxCast
Database
Toxicity Reference
ToxRef
Database
Adverse Outcome
AOP Wiki
Pathway Wiki

Virtual Tissues
VT-KB
Knowledeebase

Exposure Toolbox Expo-Box

Compiled, detailed data on human behavior
from 19 separate studies
Automated model to predict exposures
for thousands of chemicals
Data warehouse of all publicly available chemical
toxicity data, including chemical structure, physico-
chemical values, in vitro assay data
and in vivo toxicology data.
Includes physiological parameters such as alveolar
ventilation, blood flow, tissue volumes, and
glomerular filtration rate used for Physiologically-
Based Pharmacokinetic (PBPK) modeling
Database containing information on the uses
of chemicals, products that contain chemicals
and manufacturers of the products
Database that can be used as a screening tool
to explore metabolism-based variability, based
on enzyme differences, during early lifestages
Builds computational models from HTS data to
forecast the potential human toxicity of chemicals
Captures thousands of in vivo animal toxicity
studies on hundreds of chemicals
Provides an open-source interface for rapid
and collaborative sharing of established
AOPs and building new AOPs
A human and machine readable knowledgebase
developed by extracting and organizing relevant
facts from the scientific literature and other
sources of information in to central database
Web-based compendium of over 800 exposure
assessment tools that provides links to exposure
assessment databases, models, and references
Handbooks
Exposure Factors
Summary of the available statistical data on various
factors used in assessing human exposure

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Name & Type Acronym
Brief Description
Models
Stochastic Human
Exposure and
SHEDS-HT
Dose Simulations-
HT Model
Stochastic Human
Exposure and Dose SHEDS-
Simulation Model Multimedia
for Multimedia

Community-Focused
Exposure and Risk C-FERST
Screening Tool
EnviroAtlas

Eco-Health
Relationship Browser

Environmental
Quality Index
A probabilistic human exposure model that produces
population-level distributions of exposures by
the dermal, inhalation, and ingestion routes
A physically-based, probabilistic model, that can
simulate multiple- or single-chemical exposures
over time for a population via residential and
dietary exposure routes for a variety of multimedia,
multipathway environmental chemicals
A community mapping, information access, and
assessment tool designed to help assess risk and
assist in decision making with communities
Collection of tools and resources that provides
geospatial data, maps, research, and analysis on the
relationships between nature, people, health,
and the economy
Interactive tool that illustrates scientific evidence
for linkages between human health and
ecosystem services
Estimates environmental quality at the county
level used to assess effects on health outcomes

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Appendix D:  Environmental Stressors

and Childhood Disorders

The following is a summary of information on five childhood disorders: childhood cancer, asthma,
adverse birth outcomes, autism, and metabolic syndrome, including the current state of scientific
knowledge on the contribution of environmental stressors to the causation of the disorders.
Information on prevalence, trends, and research activities across the Federal Government on each
of the five disorders is also presented.

Childhood Cancer

Definition
• Childhood cancer is not a single disease but a variety of malignancies in which abnormal cells
  divide in an uncontrolled manner (U.S. EPA, 2013).
• The most common childhood cancers are leukemias (cancers of the white blood cells) and
  cancers of the brain or central nervous system (U.S. EPA, 2013).
• Other less common childhood cancers include neuroblastoma, Wilms tumor,
  rhabdomyosarcoma and osteosarcoma (Congressional Childhood Cancer Caucus, 2014).

Prevalence
• Childhood cancer is the leading cause of death (other than injuries) in U.S. children ages 1 to 14
  (U.S. EPA, 2013).
• It is estimated that 15,780 children (up to 19 years of age) will be diagnosed with cancer, and
  1,960 will die of the disease in 2014  (NCI, 2014).
• As of 2010, there were approximately 380,000 survivors of childhood cancer in the U.S
  (NCI, 2014).

Trends
• Over the past 20 years, there has been some increase in the incidence of children diagnosed
  with all forms of cancer, from 11.5 cases per 100,000 children in 1975 to 14.8 cases per 100,000
  children in 2004 (Congressional Childhood Cancer Caucus, 2014).
• Death rates from childhood cancer have declined in the past 20 years, with the 5-year survival
  rate increasing; for all childhood cancers combined the survival rate increased from 58.1% in
  1975-77 to 79.7% in 1996 - 2003 (Congressional Childhood Cancer Caucus, 2014).
• Increased survival rates have been especially dramatic for acute lymphoblastic leukemia (ALL),
  which is the most common childhood cancer, from a 5-year survival rate of <10% in the 1960's
  to about 90% in 2003-2009 (NCI, 2014).

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Causes
• Genetic syndromes such as Down Syndrome, exposure to high levels of ionizing radiation, and
  certain pharmaceutical agents used in chemotherapy are known risk factors for childhood
  cancer, but these explain only a small percentage of childhood cancer cases (NCI, 2014).
• Critical genes and processes regulating development are being studied for their association with
  childhood cancer, with certain genes associated with an increased risk of ALL and other types of
  childhood cancer (Evans et al., 2014).
• Different types of cancer affect children at different ages, and recent studies suggest that
  susceptibility to some cancers in adulthood may be determined  by prenatal exposures
  (U.S. EPA, 2013).
• Environmental factors are under investigation for their association with childhood cancer
  (U.S. EPA, 2013).
• Research suggests that childhood cancer may be caused by a combination of genetic
  predisposition and environmental exposure (U.S.  EPA, 2013).

Evidence for Environmental Risk Factors
• Pesticides
- A meta-analysis of 31 studies reported a significant association between prenatal maternal
  occupational pesticide exposure (but not paternal occupational pesticide exposure) and
  childhood leukemia (Wigle et al., 2009).
- In a meta-analysis of 13 case-control studies, Bailey et al. (2014a) reported a significantly
  increased risk of acute myeloid leukemia (AML) in children with maternal exposure to
  pesticides during pregnancy and a slightly increased risk of ALL in children with paternal
  exposure around conception.
- Research suggests that parental, prenatal, and childhood exposure to pesticides may be
  associated with a higher risk of brain tumors  in children (U.S. EPA, 2013).
• Hazardous air pollutants (HAPs)
- Reynolds et a I. (2003) found an increased risk for childhood leukemia in census tracts where
  children were exposed to a group of 25 potentially carcinogenic HAPs.
- A meta-analysis of 9 studies (Soothe et al., 2014)  on residential traffic exposure and childhood
  leukemia reported that childhood leukemia is associated with residential exposure during the
  postnatal period, but not during the prenatal period.
- Some studies have found an association between leukemia and traffic density and vehicle
  density (surrogate measures of exposure to motor vehicle exhaust) while others did not find an
  association, with review studies concluding that the overall evidence is inconclusive
  (U.S. EPA, 2013).
• Environmental Tobacco  Smoke
- The U.S. Surgeon General concluded that there is suggestive evidence that prenatal and
  postnatal exposure to environmental tobacco smoke can lead to leukemia and brain tumors in
  children (U.S. DHHS, 2006).

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• Paint
- Bailey et al. (2014b), a meta-analysis of 13 studies, did not report an association between
  parental occupational exposure to paint and childhood leukemia.
• Indoor Air Pollution
- Gao et al. (2014) found an increased risk for ALL with indoor air pollution consisting of nitrogen
  dioxide and 17 types of VOCs.
- Deziel et al. (2014) reported an increased risk for ALL with increasing concentrations ofpolycyclic
  aromatic hydrocarbons (PAHs) in household dust.
• Power  Lines
- Some studies have found an association between exposure to power lines and childhood cancer
  and other studies have not found an association (U.S. EPA, 2013).
- A variety of national and international organizations have concluded that the link between
  exposure to very low frequency electromagnetic fields and cancer is controversial or weak
  (U.S. EPA, 2013).
• Radiation and Radon
- Some studies have reported an association between radon and childhood leukemia, while others
  have not reported an association (U.S.  EPA, 2013).
- Kendall et al. (2012) reported an association between naturally occurring gamma radiation
  and childhood leukemia.
Research Activities Across the Federal Government
• EPA-NIEHS Children's Environmental Health and Disease Prevention Research Centers
  www.epa.gov/ncer/childrenscenters
- A study at the University of California at Berkeley is investigating the association of pesticides,
  tobacco-related contaminants, and chemicals in house dust and childhood leukemia.

Asthma
Definition
• Asthma is a disease of the lungs in which the airways become blocked and cause breathing
  difficulties (Asthma and Allergy Foundation of America, 2014).
• Asthma is commonly divided into two types: allergic (extrinsic) asthma and non-allergic
  (intrinsic) asthma (Asthma and Allergy Foundation of America, 2014).
• Asthma triggers are substances or conditions that cause asthma symptoms to appear
  (Asthma and Allergy Foundation of America, 2014).
Prevalence
• In the year 2009, asthma affected 7.1 million (about 10%) of children in the U.S (U.S. EPA, 2013).
• 10.7% of boys, compared to 8.0% of girls, were reported to have asthma in 2009 (a statistically
  significant difference) (U.S. EPA, 2013).

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• In 2009, children living in families below the poverty line, 12.2% were reported to have asthma
  compared to 8.7% of children living in families above the poverty line (a statistically significant
  difference) (U.S. EPA, 2013).
• In 2007-2010, a higher percentage of black non-Hispanic children (16%) and children of "all
  other races" (12.4%) were reported to have asthma, compared to white non-Hispanic children
  (8.2%) (U.S. EPA, 2013).

Trends
• The percentage of children with asthma increased substantially from 1980 to 1996 and remains
  at high rates today (U.S. EPA, 2013).
• The proportion of children reported to have asthma increased from 8.7% in 2001 to 9.4% in
  2010 (U.S. EPA, 2013).
• In 2010, 5.7% of all children were reported to have had one or more asthma attacks in the
  previous 12 months (U.S. EPA, 2013).

Causes
• Researchers believe genetic and environmental factors may interact to cause asthma, probably
  early in life. These factors include: inherited factors that increase the risk of developing
  allergies; parents who have asthma; certain respiratory infections during childhood; and contact
  with airborne allergens or viruses during early childhood (NIH, 2014).
• Known asthma triggers include: exercise; weather; secondhand smoke; dust mites; molds;
  cockroaches and pests; pets; nitrogen dioxide; chemical irritants; outdoor air pollution; and
  wood smoke (U.S. EPA, 2014).
• Recent research suggests that epigenetic mechanisms may play a role in the development of
  asthma (Kabesch, 2014).

Evidence for Environmental Risk Factors
• Outdoor air pollutants
- Particulate matter, ozone, nitrogen dioxide, carbon monoxide, and sulfur dioxide have been
  associated with increased asthma symptoms in children (U.S. EPA, 2013).
- Long-term ozone exposure may be a contributing factor in the development of asthma,
  particularly among children who frequently exercise outdoors (McConnell et al., 2012).
- Hazardous air pollutants being studied for their possible association with asthma include
  acrolein, formaldehyde, nickel, and chromium (Leikauf, 2002).
- Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) (hazardous air pollutants found in
  diesel exhaust, secondhand smoke, and wood smoke),  has been associated with the
  development of asthma in children (Rosa et al., 2011).
- Many studies have found an association between traffic-related air pollution (i.e., living close to
  busy roads) and the occurrence of new cases of asthma or exacerbation of existing asthma
  symptoms (U.S. EPA, 2013).

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• Indoor air pollutants
- McGwin et al. (2010), a meta-analysis of 7 studies, concluded that there was a significant
  association between exposure to formaldehyde (a chemical released from carpet and furniture)
  and increased asthma symptoms in children.
- Volatile organic compounds (VOCs) released in the home have been associated with the onset
  and exacerbation of asthma (Chin etal., 2014).
- Biological sources such as pets, mold, dust mites, cockroaches, and other pests have been shown
  to increase existing asthma symptoms in children (Dales et al., 2008; Apelberg et al., 2001;
  Breysse et al., 2010; Portnoy et al., 2008; Douwes and Pearce 2003; Fisk et al., 2007).
- The Institute of Medicine (2000) concluded that exposure to dust mites can cause asthma in
  susceptible children, and exposure to cockroaches may cause asthma in young children.
• Environmental Tobacco Smoke
- The U.S. Surgeon General concluded that exposure to environmental tobacco smoke results in
  more severe asthma symptoms in children (U.S. DHHS, 2006).
• Green infrastructure
- Urban tree cover was shown to significantly reduce ambient concentrations ofparticulate
  matter, ozone,  carbon monoxide, sulfur dioxide, and nitrogen dioxide (Nowak et al.,  2006).
- Lovasi et al. (2008) reported that asthma was negatively correlated with
  urban street trees in New York City; an increase in tree density of 343 trees/km2 was associated
  with a 29% lower asthma prevalence in 4- and 5-year-old children.
- Dadvand et al. (2014) reported that proximity to forest land, percent tree cover and percent
  green space around the home were linked to reduced asthma, while proximity to parks was
  correlated with increased asthma and allergies. The authors hypothesized that trees generally
  buffer air pollutants that can exacerbate asthma, but there may be more exotic species planted
  in parkland that produce airway irritants.
- Dales et al. (1991) reported that the odds of asthma for children were increased 29% when
  dampness and/or mold were present in the home. Green infrastructure can mitigate asthma risk
  in low-lying neighborhoods, because trees, wetlands, and other vegetated land cover absorb
  stormwater, reducing the extent and duration offloads.

Research Activities Across the Federal Government
• Coordinated Federal Action Plan to Reduce Racial and Ethnic Asthma  Disparities - HHS, EPA,
  HUD. www.epa.gov/childrenstaskforce
- Presents a framework across the federal government to accelerate actions to reduce disparities
  in asthma.
• EPA-Funded Research
- A study at the University of North Carolina is examining factors that contribute to asthma
  disparities in children.
- A study at the University of Medicine and Dentistry of New Jersey is correlating changes in
  asthma status  with air pollution and stress in children with persistent asthma.

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- A study at the University of Pittsburgh is exploring the effects of community stressors and traffic-
  related air pollution on asthma in children.
• EPA-NIEHS Children's Environmental Health and Disease Prevention Research Centers
  www.epa.gov/ncer/childrenscenters
- A study at Johns Hopkins University is investigating the association between outdoor air
  pollutants, including particulate matter and nitrogen dioxide, and asthma in children.
- A study at the National Jewish Health Center is investigating the relationship between air
  pollution and the development of asthma in children.
• NIEHS Funded Research
  http://www.niehs.nih.gov/research/supported/recoverv/critical/childhealth/
- A study at Johns Hopkins University is investigating the impact of indoor air pollutants and the
  incidence of asthma in children.
- A study at Children's Hospital Medication Center, Cincinnati, OH, is studying diesel exhaust and
  its role in the development of asthma in children.
• NIH - National Asthma Control Initiative
  http://www.nhlbi.nih.gov/health-pro/resources/lung/naci/
- Multi-component, mobilizing and action-oriented effort to engage diverse stakeholders who are
  concerned about or involved in improving asthma control with the ultimate aim of
  bringing the asthma care that patients receive in line with evidence-based recommendations.
- NIH - National Asthma Education and Prevention Program
  httD://www.nhlbi.nih.aov/about/ora/naeDD/index.htm
- Ultimate goal of the program is to enhance the quality of life for patients with asthma and
  decrease asthma-related morbidity and mortality.

Adverse Birth  Outcomes

Definition
• Adverse birth outcomes include preterm birth (births before 37 weeks of pregnancy), low birth
  weight, neonatal mortality, and birth defects (U.S. EPA, 2013).
• Preterm and low birth weight infants are at a greater risk for infant death  and complications
  involving effects on the respiratory, gastrointestinal, immune, and central  nervous systems
  (U.S. EPA, 2013).
• Longer-term problems of preterm birth include motor, cognitive, visual, hearing, behavioral, and
  social-emotional problems (U.S. EPA, 2013).
• Birth defects consist of a range of structural and chromosomal abnormalities that occur before
  birth (U.S. EPA, 2013).

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Prevalence
• Birth defects are the leading cause of infant death in the first year of life in the U.S.
  (U.S. EPA, 2013).
• From 2004 to 2006, approximately 3% of births in the U.S. were affected by birth defects, with
  the highest number of cases reported for Down Syndrome, cleft lip, and cleft palate
  (CDC, 2014).
• Effects from preterm birth and low birth weight are the second leading cause of infant death in
  the U.S (U.S. EPA, 2013).
• The preterm birth rate varies depending on the age of the mother, with women ages 20 to 39
  having the lowest rate of preterm birth, compared to women under 20 years old and women
  40 years and older  (U.S. EPA, 2013).
• Multiple birth babies are five times more likely to be born preterm than singleton babies
  (U.S. EPA, 2013).

Trends
• The rate of preterm birth showed an increasing trend  between 1993 and 2006, ranging from
  11% in  1993 to its highest value of 12.8% in 2006. Since that time, the rate has declined to
  11.5% in  2012 (U.S. EPA, 2013; March of Dimes, 2014).
• In 2012, black non-Hispanic women had the highest rate of preterm birth of all racial groups
  (16.8%), although it decreased from a high of 18.5% in 2006 (U.S. EPA, 2013).
• It is difficult to identify national trends for birth defects, since there is no unified national
  monitoring system; available information comes from state birth defects monitoring systems
  and birth certificates (U.S. EPA, 2013).

Causes
• Increases in maternal age, rates of multiple births, use of early Cesarean sections and labor
  inductions, changes in neonatal technology, assisted reproductive technologies, chronic
  maternal health problems,  maternal smoking, use of alcohol or illicit drugs, maternal and fetal
  infections, placental problems, inadequate maternal weight gain, and socioeconomic factors
  have been associated with  preterm birth and low birth weight (U.S. EPA, 2013).
• Some birth defects are inherited. In addition, alcohol use, smoking, and insufficient folate in a
  woman's diet are known causes of birth  defects (U.S. EPA, 2013).
• A variety of environmental  factors are under investigation for their association with adverse
  birth outcomes (U.S. EPA, 2013).

Evidence for Environmental Risk Factors
• Outdoor air pollutants
- Stieb et al. (2012), a meta-analysis of 62 studies, concluded that particulate matter, nitrogen
  dioxide, and carbon monoxide are associated with adverse birth outcomes, including low birth
  weight and preterm birth.

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- A number of studies have reported associations between airborne polycyclic aromatic
  hydrocarbons (PAHs) and reduced birth weight and fetal growth restriction (U.S. EPA, 2013).
- Several studies have reported associations between residential proximity to traffic during
  pregnancy and an increased risk ofpreterm birth; however the Health Effects Institute (2010)
  reviewed the existing studies and concluded that there is inadequate and insufficient
  evidence to infer a causal relationship.
- Wigle et al. (2008), a literature review, concluded that nitrogen dioxide, sulfur dioxide, and
  particulate matter are associated with certain cardiac birth defects.
• Indoor air pollutants
- Smoke from traditional cookstoves, fueled by wood, coal, or dung, has been associated with an
  increase in low birth weight and other adverse health effects (NIEHS, 2014).
• Hazardous Waste Sites
- Multiple studies have reported an association between residence near hazardous waste sites
  and an increased risk of birth defects, particularly neural tube defects and congenital heart
  disease (U.S. EPA, 2013).
- Yauck et al. (2004) and Brender et al. (2008) reported an association between hazardous waste
  sites that emit heavy metals or solvents and birth defects.
- Currie et al. (2011) reviewed birth records of children born to mothers living near any of the 154
  Superfund sites and reported an overall reduced incidence of birth defects.
• Environmental Tobacco Smoke
- The U.S. Surgeon General concluded that exposure of pregnant women to environmental
  tobacco smoke causes a small reduction in mean birth weight,  and that the evidence is
  suggestive (but not sufficient to infer causation) of a relationship between maternal exposure to
  environmental tobacco smoke during pregnancy and preterm delivery (U.S. DHHS, 2006).
• Pesticides
- Many studies have reported an association between maternal  and paternal exposure to
  pesticides and an increased risk of birth defects in children; however Wigle et al. (2008),
  in a review of the literature, concluded that the data are inadequate to confirm an association
  between pesticide exposure and the risk of birth defects.
• Endocrine Disrupting Chemicals
- Several studies have reported an association between endocrine disrupting chemicals and
  urogenital malformations in newborn boys, such  as cryptorchidism and hypospadias
  (U.S. EPA, 2013).
• Solvents
- McMartin et al. (1998), a meta-analysis of a number of studies of women's occupational
  exposure to organic solvents, reported an increased risk of birth defects and oral cleft palates in
  children born to women exposed to these solvents.
- Wigle et a I. (2008), in a review of the literature, concluded that the evidence linking paternal
  exposure to solvents to neural tube defects was suggestive of an association, but not strong
  enough to make conclusions about a causal relationship.

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• Phthalates
- Several studies have reported associations between prenatal exposure to some phthalates and
  preterm birth, shorter gestational length, and low birth weight; however one study reported
  that longer gestational length and increased risk of Cesarean section delivery were associated
  with phthalate exposure (U.S. EPA, 2013).
• Disinfection By-Products
- Several studies have reported associations between disinfection by-products and an increased
  risk of birth defects, particularly neural tube defects and oral clefts; however  Wigle et al.
  (2008), in a review of the literature,  concluded that the evidence is too limited to make
  conclusions about an association between disinfection by-products and birth  defects.
- Studies on disinfection by-products and preterm birth have shown conflicting results
  (U.S. EPA, 2013).
• Polychlorinated biphenyls (PCBs)
- Baibergenova et al. (2003) reported that increased exposure to PCBs from fatty fish
  consumption was associated with lower birth weights, while Longnecker et al. (2005) did not
  observe an association between PCB exposure and low birth weight or preterm delivery.
• Perfluorinated compounds
- Some studies have reported an  association between perfluorinated compounds, particularly
  perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) and adverse birth
  outcomes including low birth weight, decreased head circumference, reduced birth weight, and
  smaller abdominal circumference (U.S.  EPA, 2013).
• Health Promotion: engagement with nature
- Increasing tree cover near a mother's home by 10% can have a marginal decrease on small-for-
  gestational-age births, lowering them by 1.42 per 1,000 births. Potential causal mechanisms
  include increased physical activity, stress reduction as a result of contact with green space, and
  improved social contacts (Donovan et al., 2011).
- Dadvand et al. (2012) reported that higher levels of greenness near maternal residences
  were associated with higher birth weight and infant head circumference, particularly in
  participants with low/moderate education levels. Potential mechanisms include decreased
  personal exposure to air pollution and increased physical activity.

Research Activities Across the Federal Government
• EPA-Funded Research
- A joint study between Texas State University,  Texas A & M University, Texas Dept. of State
  Health Services, and the University of North Carolina at Charlotte is defining new public health
  indicators linking exposure metrics and birth  defects.
- EPA is examining water-related exposures and birth defects in a five-county area in Texas.
• EPA-NIEHS Children's Environmental Health and Disease Prevention  Research Centers
  www.epa.gov/ncer/childrenscenters

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- A study at the University of California at Berkeley is investigating the association between air
  pollutants, including airborne PAHs, and birth defects and preterm birth.
- A study at the University of California at San Francisco is studying the role of endocrine
  disrupting compounds, perfluorinated compounds, and other chemicals in fetal development
  and adverse birth outcomes.
- A study at the University of Michigan is investigating the association between phthalates, lead,
  cadmium, and other compounds and adverse birth outcomes.
• Pregnancy Health Interview Study/Birth Defects Study- NIH, FDA, Private companies, others
  http://www.bu.edu/slone/research/studies/phis/
- Multicenter case control study began in 1976 and is investigating a wide range of environmental
  exposures in pregnancy that may be associated with  birth defects and other adverse birth
  outcomes.
• NIEHS Research on Cookstoves http://www.niehs.nih.gov/research/programs/geh/cookstoves/
- NIEHS funded research in Guatemala, Ecuador, Nepal, Pakistan, Ghana and the U.S. on the
  health effects, including low birth weight, of smoke from cookstoves.
• CDC Birth defects research and tracking
  http://www.cdc.gov/ncbddd/birthdefects/research.html
- CDC tracks birth defects, researches factors that might increase or decrease the risk of birth
  defects, and identifies community or environmental concerns or other factors that need more
  study.

Autism

Definition
• Autism spectrum disorder (ASD) is a group of developmental disabilities that can cause
  significant social, communication and behavioral challenges  (Landrigan et al., 2012;
  NIEHS, 2014).
• A diagnosis of ASD  now includes several conditions that used to be diagnosed separately:
  autistic disorder, pervasive developmental disorder not otherwise specified (PDD-NOS),
  and Asperger syndrome (NIEHS,  2014).

Trends
• Change in percentage of children ages 5 to 17 years old in the U.S. reported to have ever been
  diagnosed with autism has increased from 0.1 percent in 1977 to 1.0 percent in 2010 (U.S. EPA,
  2013).
• Globally,  after accounting for methodological variations, there is no clear evidence of a change
  in prevalence for ASD between 1990 and 2010. (Baxter et al., 2014).

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Prevalence
• The CDC estimates ASD affects roughly 1 in 68 children in the U.S. (8 years-of-age, during the
  year 2010) (CDC, 2014).

• ASD is almost 5 times more common among boys (1 in 42) than among girls (1 in 189)
  (CDC, 2014)
• Globally, the prevalence of ASD is estimated to be 1 in 132 persons (Baxter et al, 2014).

Causes
• Emerging understanding suggests a complex, dynamic system of metabolic and immune
  anomalies involving many organ systems, including the brain, in association with environmental
  exposures (U.S. EPA, 2013).
• Evidence points to pregnancy and the early postnatal period as critical windows of vulnerability
  (IACC, 2013).
• Understanding of the role of genes has been significantly refined in  recent years. Data suggest
  that approximately 40-60% of ASD risk can be attributed to inherited, common variation (SNPs)
  (Sandinetal., 2014).

Evidence for Environmental Risk Factors
• Outdoor Air Pollutants
- Several studies suggest that there is an increased risk of ASD from air pollution exposure during
  gestation and/or early infancy (Becerra et al., 2013; Volk et al; 2013; Von Ehrenstein et al.,
  2014).
- Volk et al. (2014) reported that children with both a specific genotype and high air pollutant
  exposures were at increased risk of ASD compared to children who had the same genotype
  and lower pollutant exposures.
- Allen et al. (2014) investigated the mechanism by which exposure to ultrafine particulate matter
  from air pollution adversely affects central nervous system development in mice.
• Pesticides
- Shelton et al. (2014) showed an increased risk of ASD for children of mothers that lived within
  1.5 km of an agricultural pesticide application during pregnancy.
- Roberts et al. (2007) reported an increased risk for developing ASD with increasing poundage
  oforganochlorine pesticide applied and decreased with distance from the pesticide application
  sites.
• Brominated Flame Retardents
- In a literature review, Messer (2010) suggests that polybrominated diphenyl ethers) PBDEs
  may be a risk factor for ASD, while a case-control study that measured 11 PBDE congeners
  showed no difference in PBDE levels  congeners in children with ASD  compared to controls
  (Hertz-Picciotto et al., 2011).

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Research Activities Across the Federal Government
• Interagency Autism Coordinating Committee (IACC)
- Established in accordance with the Combating Autism Act of 2006, reauthorized 2011
  (Public Law 112-32)
- Federal Members of IACC include Director NIH, Director NIEHS, Director NICHD, FDA, DOD, HHS,
  DOEd
- Strategic Plan, 2009, updated April 2014, objectives associated with elucidating causes ofASD
  emphasize:
  • Understanding how environmental risks may differ in vulnerable subgroups
  • Applying emerging science in epigenetics,  the microbiome, animal models ofASD, and
    bioinformatics
• GAO report May 20, 2014, on coordination of federal autism activities
- The GAO found that a part from federal agencies' participation on the IACC, there were limited
  instances of agency coordination.
- 1,206 autism research projects funded by  12 federal agencies.
- Five Agencies fund a total of 159 research activities focused on elucidating causes of autism.
  Primarily NIH followed by DOD and CDC. EPA included under category "other agencies" with one
  activity.
• BRAIN Initiative
- June 5, 2014 NIH released a scientific vision for $4.5 billion investment over 10 years beginning
  in 2016.
- Early results include application of 3-D map collating activity of genes in 300 brain regions
  during mid-prenatal development to demonstrate relationship between genetic risk
  factors for ASD and early brain development.

Metabolic  Syndrome

Definition
• Metabolic syndrome incorporates a cluster of adverse health effects, including obesity,
  hypertension, altered lipid levels, and other metabolic abnormalities, that appear to be caused
  by common biological mechanisms (U.S. EPA, 2013).
• Obesity, defined as a high range of weight for an individual of given height that is associated
  with adverse health effects, is measured based on set cutoff points directly related to  an
  individual's body mass index (BMI) (U.S. EPA, 2013).
• Obesity has been associated with cardiovascular disease, cancer, psychological stress,  asthma,
  and diabetes in childhood and later in life  (U.S. EPA, 2013).

Prevalence
• The prevalence of childhood obesity in the U.S. has been increasing for several decades,
  although it has stabilized at approximately 16% over the past few years (U.S. EPA, 2013).

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• In 2005-2008, 22% of Mexican-American and 20% of black non-Hispanic children were obese,
  compared with 14% of white non-Hispanic children and 14% of children of "Other Races/
  Ethnicities" (U.S. EPA, 2013).
• Among children in the U.S., the prevalence of obesity is greater in children with family incomes
  below poverty level than in those above poverty level (U.S. EPA, 2013).

Trends
• In 1976 - 1980, 5% of children in the U.S. were identified as obese; this rate rose until it reached
  a high of 16% in 2007 -2008 (U.S. EPA, 2013).

Causes
• Obesity is  primarily due to an imbalance between caloric intake and activity (U.S. EPA, 2013).
• A number of animal  and cellular studies suggest that environmental chemical exposures may
  contribute to obesity and  diabetes (U.S. EPA, 2013).
• Studies show that obesity is largely programmed during early life, including the prenatal period
  (Janesickand Blumberg, 2011).

Evidence for Environmental Risk Factors
• Outdoor air pollutants
- Several studies have reported that obesity may result in greater susceptibility to the adverse
  effects of air pollutants, such as particulate matter and ozone, including airway inflammation,
  cardiovascular effects and increased particle deposition in  the lungs (U.S. EPA, 2013).
• Endocrine Disrupting Chemicals
- Studies suggest that some endocrine disrupting chemicals, such as bisphenol A, phthalates,
  diethylstilbestrol, and endogenous steroids may be associated with  obesity in children
  (Choi et al., 2014; Karoutsou and Polymeris, 2012).
- Janesick and Blumberg (2011) hypothesized that individuals exposed to certain endocrine
  disrupting chemicals early in life might be predisposed to increased fat mass and obesity.
• Other Chemicals
- Smink et al. (2008) reported that prenatal exposure to high levels of hexachlorobenzene was
  associated with increased weight and BMI in children at 6.5 years old.
- Verhulst et al. (2009) reported that prenatal exposure to DDE (the main metabolite of DDT) was
  associated with increased BMI and exposure to PCBs was associated with increased BMI in early
  childhood.
- Scinicariello and Muser (2014) found an association between total urinary PAH metabolites
  and naphthalene metabolites and higher BMI, obesity, and waist circumference in children ages
  6-11 years of age.
• Health Promotion: Physical Activity
- Children who lived in greener neighborhoods were less likely to increase their BMI scores over
  2 years compared to those who lived in less-green neighborhoods. The lower BMI scores were
  likely due to increased physical activity or time spent outdoors (Bell et al 2008).

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- Wolch et al. (2011) reported that children who had parks and/or recreation programs close to
  their homes had lower measured BMIs at age 18 than those without such programs. The
  authors concluded that this may be because children with better access to parks and
  recreation programs spend more time in physical activity and thus have reduced BMIs.
- Models based on the results from  Wolch et al. (2011) suggest that if all children in the sample
  were to have average access to parkland and recreation programs near their homes, over 9.5%
  of boys and 8.3% of girls would move from overweight to normal BMIs, and approximately
  2% of obese children would move  down to overweight.

Research Activities Across the Federal Government
• EPA Funded Research
- EPA is conducting a state-of-the-science literature review to identify chemical and nonchemical
  stressors related to childhood obesity.
• EPA-NIEHS Children's Environmental Health and Disease Prevention Research Centers
    www.epa.gov/ncer/childrenscenters
- A study at the University of California at Berkeley is investigating the association between
  pesticides  and flame retardants and obesity.
- Another study at the University of California at Berkeley is studying the effects of air pollutants
  on obesity and glucose dysregulation.
- A study at the University of Michigan is investigating bisphenol A, phthalates, lead, and
  cadmium and the risk of metabolic syndrome.
- A study at the University of Southern California is studying near-roadway air pollution and its
  contribution to obesity and metabolic phenotypes.
• NIH Obesity Research http://www.obesitvresearch.nih.gov/
- NIH seeks  to identify genetic, behavioral, and environmental causes of obesity; to understand
  how obesity leads to type 2 diabetes, cardiovascular disease, and other serious health
  problems; and to build on basic and clinical research findings to develop and study innovative
  prevention and treatment strategies.
• CDC-Overweight and Obesity: Childhood Obesity Facts
  http://www.cdc.gov/obesitv/data/childhood.html
- Presents facts about the prevalence of childhood obesity in the U.S.
• CDC - National Collaborative on Childhood Obesity Research (NCCOR)
  http://www.cdc.gov/obesitv/data/surveillance.html
- CDC's Catalogue of Surveillance Systems reviews, sorts, and compares more than 75 surveillance
  systems with data related to childhood obesity research.
- CDC's National Collaborative on Childhood Obesity Research (NCCOR)  Measures Registry is
  a database of diet and physical activity measures used in childhood obesity research.

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References for Childhood Cancer

Bailey, H. D., Fritschi, L, Infante-Rivard, C., et al. (2014a). Parental occupational pesticide
    exposure and the risk of childhood leukemia in the offspring: findings from the
    Childhood Leukemia International Consortium. Int. J. Cancer. 135(9):2157-72.
Bailey, H. D., Fritschi, L, Metayer, C., et al. (2014b). Parental occupational paint exposure
    and risk of childhood leukemia in the offspring: findings from the Childhood Leukemia
    International Consortium. Cancer Causes and Control. 25(10):1351-67.
Boothe, V. L, Boehmer, T. K., Wendel, A. M., et al. (2014). Residential traffic exposure and
    childhood leukemia: a systematic review and meta-analysis. Am J Prev Med. 46(4): 413-22.
Congressional Childhood Cancer Caucus. Facts and Figures.
    http://childhoodcancer-mccaul.house.gov/resources/facts-and-figures
Deziel, N. C., Rull, R. P., Colt, J. S., et al. (2014). Polycyclic aromatic hydrocarbons in residential dust
    and risk of childhood acute lymphoblastic leukemia. Environ. Res. 133:388-95.
Evans, T. J., Milne, E., Anderson D. et al. 2014. Confirmation of childhood acute lymphoblastic leukemia
    variants, ARID5B and IKZF1, and interaction with parental environmental exposures.
    PLoSOne. Oct. 13; 9(10):ell0255.
Gao, Y, Zhang, Y, Kamijima, M., et al. (2014). Quantitative assessments of indoor air pollution and
    the risk of childhood acute leukemia in Shanghai. Environ. Pollut. 187:81-9.
Kendall, G. M., Little M. P., Wakeford R., Bunch K. J., Miles J. C., Vincent T. J., Meara J.R., and Murphy M. F.
    (2012). A record-based case-control study of natural background radiation and the incidence of
    childhood leukaemia and other cancers in Great Britain during 1980-2006.
    Leukemia, doi: 10.1038/leu.2012.151.
National Cancer Institute (NCI). Fact Sheet: Cancer in Children and Adolescents.
    http://www.cancer.gov/types/childhood-cancers/child-adolescent-cancers-fact-sheet
Reynolds,  P., Von Behren, J., Gunier, R. B., Goldberg, D. E., Hertz, A., and Smith, D. F.. (2003).
    Childhood cancer incidence rates and hazardous air pollutants in California: an exploratory analysis.
    Environ. Health Perspect. lll(4):663-8.
U.S. Department of Health and Human Services. (2006). The Health Consequences of Involuntary
    Exposure to Tobacco Smoke: A Report of the Surgeon General. Atlanta, GA: Centers
    for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center
    for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
    http://www.surgeongeneral.gov/librarv/secondhandsmoke/report/index.html.
U.S. Environmental Protection Agency (EPA). 2013. America's Children and the Environment.
    3rd Edition. EPA-240-R-13-OOa. http://www.epa.gov/ace/pdfs/ACE3 2013.pdf
Wigle, D. T., Turner, M. C., and Krewski, D. (2009). A systematic review and meta-analysis of childhood
    leukemia and parental occupational pesticide exposure. Environ. Health Perspec. 117(10):1505-13.

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References for Asthma

Apelberg, B. J., Aoki, Y., Jaakkola, J. J. K. (2001). Systematic review: Exposure to pets and risk
    of asthma and asthma-like symptoms. J. Allergy Clin. Immunol. 455-460.
Asthma and Allergy Foundation of America. (2014). Asthma Overview.
    http://www.aafa. org/displav.cfm?id=8
Breysse, P. N., Diette, G. B., Matsui, E. C., Butz, A. M., Hansel, N. N., McCormack, M. C. (2010). Indoor
    air pollution and asthma in children. Proceedings of The American Thoracic Society. 7:102-104.
Chin, J. Y, Godwin, C., Parke, E., Robins, T, Lewis, T, Harbin, P., Batterman, S. (2014). Levels and
    sources of volatile organic compounds in homes of children with asthma. Indoor Air. 2494:403-15.
Dadvand, P., Villanueva, C. M.,  Font-Ribera, L, et al. Risks and Benefits of Green Spaces for
    Children: Across-Sectional Study of Associations with Sedentary Behavior, Obesity,
    Asthma, and Allergy. Environ. Health Perspect. in press, http://dx.doi.org/10.1289/ehp.1308038.
Dales R. E., Zwanenburg, H., et al. (1991). Respiratory health effects of home dampness
    and molds among Canadian children. American J. of Epidemiology.  134(2): 196-203.
Dales, R., Liu, L, Wheeler, A.J., and Gilbert, N.L (2008). Quality of indoor residential
    air and health. Canadian Medical Association Journal. 179(2): 147-52.
Douwes, J. and Pearce, N. (2003). Invited Commentary: Is indoor mold exposure a risk
    factor for asthma? doi: 10.1093/aje/kwgl49 Am. J. Epidemiol. 158:203-206.
Fisk, W.J., Lei-Gomez, Q., Mendel, M. J. (2007). Meta-analyses of the associations of respiratory
    health effects with dampness and mold in homes. Indoor Air. 17(4), 284-296.
    doi:10.1111/j.l600-0668.2007.00475.x
Institute of Medicine. (2000). Clearing the Air: Asthma and Indoor Air Exposures.
    Washington DC: National Academy Press, http://books.nap.edu/catalog/9610.html.
Kabesch, M. (2014).  Epigenetics in asthma and allergy. CurrOpin Allergy Clin Immunol, 14(l):62-68.
    doi:10.1097/aci.0000000000000025
Leikauf, G. D. (2002). Hazardous air pollutants and asthma. Environ. Health Perspect. 110 Suppl 4:505-26.
Lovasi G. S., Quinn, J. W., et al.  (2008). Children living in areas with more street trees have lower asthma
    prevalence. J.  of Epidemiology and Community Health. 62:647-9.
McConnell, R., Berhane, K., Gilliland, F., London, S.J., Islam, T, Gauderman, W. J., Avol, E., Margolis, H.G.,
    and Peters, J.M. (2002). Asthma in exercising children exposed to ozone: a cohort study. Lancet.
    359 (9304):386-91.
McGwin, G., Lienert, J., and Kennedy, J.I. (2010). Formaldehyde exposure and asthma in children:
    a systematic review. Environ. Health Perspect. 118(3):313-7.
National Institutes of Health. National Heart, Lung, and Blood Institute.  2014. What Causes Asthma?
    www.nhlbi.nih.gov/health/health-topics/topics/asthma/causes.html
Nowak, D. J., Crane, D. E., et al. (2006). Air pollution  removal by urban trees and shrubs in the United States.
    Urban Forestry & Urban Greening. 4(3-4): 115-123.
Portnoy, J. M., Barnes, C. S., Kennedy, K. (2008). Importance of mold allergy in asthma mold. Curr. Allergy
    Asthma Rep. 8(l):71-8.
Rosa,  M. J., Jung, K. H., Perzanowski, M. S., Kelvin, E. A., Darling, K. W., Camann, D.  E., Chillrud, S. N.,
    Whyatt, R. M., Kinney, P. L, Perera, F. P., et al. (2011). Prenatal exposure to polycyclic
    aromatic hydrocarbons, environmental tobacco smoke and asthma. Respiratory Medicine.
    105(6):869-76.
U.S. Department of Health and Human Services (DHHS). (2006). The Health Consequences of
    Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. Atlanta, GA: Centers for
    Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for
    Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
    http://www.surgeongeneral.gov/librarv/secondhandsmoke/report/index.html.
U.S. Environmental Protection Agency (EPA). (2013). America's Children and the Environment.
    3rd Edition. EPA-240-R-13-OOa. http://www.epa.gov/ace/pdfs/ACE3  2013.pdf
U.S. Environmental Protection Agency (EPA). (2014). Asthma Triggers.
    http://www.epa.gov/asthma/triggers.html

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References for Adverse  Birth Outcomes

Baibergenova, A., Kudyakov, R., Zdeb, M., and Carpenter, D.O. (2003). Low birth weight and residential
    proximity to PCB-contaminated waste sites. Environ. Health Perspect. lll(10):1352-7.
Brender, J. D., Zhan, F. B., Langlois, P. H., Suarez, L., and Scheuerle, A. (2008). Residential proximity to waste
    sites and industrial facilities and chromosomal anomalies in offspring.
    Int. J. of Hygiene and Environ. Health. 211(l-2):50-8.
Centers for Disease Control (CDC). (2014). Birth Defects, Data and Statistics.
    http://www.cdc.gov/ncbddd/birthdefects/data.html
Currie, J., Greenstone,  M., and Moretti, E. (2011). Superfund cleanups and infant health.
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Donovan G.H., Y.L. Michael, et al. 2011. Urban trees and the risk of poor birth outcomes.
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Health Effects Institute. (2010). HEI Panel on the Health Effects of Traffic-Related Air Pollution: A Critical
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    http://pubs.healtheffects.org/view.php?id=334
Longnecker, M. P., Klebanoff, M. A., Brock, J. W., and Quo, X. (2005). Maternal levels of polychlorinated
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McMartin, K.  I.,  Chu, M., Kopecky, E., Einarson, T. R., and Koren, G. (1998). Pregnancy outcome following
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National Institute of Environmental Health Sciences (NIEHS). (2014). Cookstoves and Indoor Air.
    http://www.niehs.nih.gov/research/programs/geh/cookstoves/
Stieb, D. M., Chen, L., Eshoul, M., and Judek, S.  (2012). Ambient air pollution, birth weight and  preterm
    birth: a systematic review and meta-analysis. Environ. Res. 117:100-11.
U.S. Department of Health and Human Services (DHHS). (2006). The Health Consequences of
    Involuntary Exposure to Tobacco Smoke: A  Report of the Surgeon  General.
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U.S. Environmental Protection Agency (EPA). (2013). America's Children and the Environment.
    3rd Edition. EPA-240-R-13-OOa. http://www.epa.gov/ace/pdfs/ACE3 2013.pdf
Wigle, D. T, Arbuckle, T. E., Turner, M.  C., Berube, A., Yang, Q., Liu, S., and Krewski, D. (2008).
    Epidemiologic evidence of relationships between  reproductive and child health outcomes  and
    environmental chemical contaminants. J. of Tax. and Environ. Health Part B: Crit. Reviews.
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Yauck, J. S., Malloy, M.  E., Blair, K., Simpson, P. M., and McCarver, D .G. (2004). Proximity of  residence
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    older women. Birth Defects Research. Part A, Clinical and Molecular Teratology.  70(10):808-14.

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References for Autism

Allen J. L, et al. (2014). Early postnatal exposure to ultrafine participate matter air pollution: persistent
    ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice.
    Environ. Health Perspect. 122(9):939-945.
Baxter, A. J., Brugha, T. S., Erskine, H. E., Scheurer, R. W., Vos, T., Scott, J. G. (2014). The epidemiology and
       global burden of autism spectrum disorders. Psychol. Med. 11:1-13.
Becerra T. A., Wilhelm, M., Olsen, J., Cockburn, M.,  Ritz, B. (2013). Ambient air pollution and autism in
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Centers for Disease Control (CDC). (2014). Autism Spectrum Disorder.
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Hertz-Picciotto, I., Bergman, A., Fangstrom, B., Rose, M., Krakowiak, P., Pessah, I., Hansen, R., Bennett, D. H.
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Landrigan, P. J., Lambertini, L., and Birnbaum, L. S. (2012). A research strategy to discover the environmental
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Messer, A. (2010). Mini-review: polybrominated diphenyl ether (PBDE) flame retardants as potential
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National Institutes of Environmental  Health Sciences (NIEHS). (2014). Autism.
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Roberts E. M., English, P. B., Grether, J. K., Windham, G. C., Somberg, L, Wolff, C. (2007). Maternal
    residence near agricultural pesticide applications and autism spectrum disorders among
    children in the California Central Valley. Environ. Health Perspect. 115(10):1482-9.
Sandin, S., Lichtenstein, P., Kuja-Halkola, R., Larsson, H., Hultman, C. M., and Reichenberg, A. (2014).
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Shelton, J. F., Geraghty, E. M., Tancredi, D. J., Delwiche, L D., Schmidt, R. J., Ritz, B., Hansen, R.  L,
    Hertz-Picciotto, I. (2014). Neurodevelopmental Disorders and Prenatal Residential Proximity to
    Agricultural Pesticides: The CHARGE Study. Environ. Health Perspect. doi:  10.1289/ehp.1307044.
    (EPA supported)
U.S. Environmental Protection Agency (EPA). (2013). America's Children and the Environment.
    3rd Edition. EPA-240-R-13-OOa. http://www.epa.gov/ace/pdfs/ACE3 2013.pdf
Volk, H. E., Lurmann,  F., Penfold, B., Hertz-Picciotto, I., McConnell, R. (2013). Traffic-related air  pollution,
    particulate matter, and autism. AMA Psychiatry. 70(l):71-7.
Volk, H. E., et al, 2014. Autism  Spectrum Disorder: Interaction of Air Pollution with the MET Receptor
    Tyrosine Kinase Gene. Epidemiology. 25(l):44-47. (EPA supported)
Von Ehrenstein, O. S., et al. (2014). In Utero Exposure to Toxic Air Pollutants and
    Risk of Childhood Autism. Epidemiology. Jul 22 (Epub ahead of print)

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References  for Metabolic Syndrome

Bell J. F., Wilson, J. S., Liu, G. (2008). Neighborhood greenness and 2-year changes in body mass index of
    children and  youth. Amer. J. of Preventive Med. 35(6): 547-53.
Choi, J., Eom, J., Kim, J., Lee, S., and Kim, Y. (2014). Association between some
    endocrine-disrupting chemicals and childhood obesity in biological samples of young girls:
    a cross-sectional study. Environ. Toxicol. Pharmacol. 38(l):51-7.
Dadvand P., de Nazelle, A., et al. (2012). Green space, health inequality and pregnancy.
    Environment International. 40(0):110-115.
Dadvand P., Sunyer, J., et al. (2012). Surrounding Greenness and Pregnancy Outcomes
    in Four Spanish Birth Cohorts. Environ. Health Perspect. 120 (10):1481-1487.
Donovan G. H., Michael, Y.L, et al. (2011). Urban trees and the risk of poor birth outcomes.
    Health & Place. 17:390-393.
Ellaway A., Macintyre, S.,  et al. (2005). Graffiti, greenery, and obesity in adults: secondary analysis of
    European cross sectional survey. BMJ. 331(7517):611-612.
Janesick, A. and Blumberg, B. (2011). Endocrine disrupting chemicals and the developmental
    programming of adipogenesis and obesity. Birth Defects Res C Embryo Today. 93(1):34-50.
Karoutsou, E. and Polymeris, A. (2012). Environmental endocrine disrupters and obesity.
    Endocr. Regul. 46(1):  37-46.
Lovasi G. S., Bader, M. D. M., et al. (2012). Body Mass Index, Safety Hazards, and Neighborhood
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Scinicariello, F. and Buser, M.C.  (2014). Urinary polycyclic aromatic hydrocarbons and childhood obesity:
    NHANES (2001-2006). Environ. Health Perspect. 122(3):299-303.
Smink, A., Ribas-Fito, N., Garcia, R., Torrent, M., Mendez, M.A., Grimalt, J.O., and Sunyer, J. (2008).
    Exposure to  hexachlorobenzene during pregnancy increases the risk of overweight in children
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Tudor-Locke, C.,  Brashear, M. M., Johnson, W., Katzmarzyk, P. (2010). Accelerometer profiles of physical
    activity and  inactivity in normal weight, overweight, and obese U.S. men and women.
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U.S. Environmental Protection Agency  (EPA). (2013). America's Children and the Environment.
    3rd Edition. EPA-240-R-13-OOa. http://www.epa.ROV/ace/pdfs/ACE3 2013.pdf
Verhulst, S. L., Nelen, V., Hond, E. D., Koppen, G., Beunckens, C.,Vael, C., Schoeters, G., and  Desager, K.
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    first 3 years  of life. Environ. Health Perspect. 117(l):122-6.
West S. T, Shores, K. A.,  et al.  (2012). Association of Available Parkland, Physical Activity, and
    Overweight  in America's Largest Cities. J. of Pub. Health Management and Practice. 18(5): 423- 30.
Wolch J., Jerrett, M., et al. (2011). Childhood obesity and proximity to urban parks and recreational
    resources: A longitudinal cohort study. Health Place. 17(1):207-14.

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