Children's Health Protection Advisory Committee
Committee Members:
Pamela Shubat, Ph.D., Chair
Environmental Health Division
Minnesota Department of Health
625 N. Robert Street
St. Paul, MN 55155-2538
Ph: 651/201-4925
Pamela.shubat@health.state.mn.us
Robert Amler, M.D.
Laura Andeiko, R.N., Ph.D.
Tyra Bryant-Stephens, M.D.
Gall Cynthia Christopher, D.N,
Nancy Clark, M.A., C.I.H., C.S.P.
Rochelle Davis
Janice Dhonau
Maida Galvez, M.D., M.P.H.
Janvier Gasana, M.D., Ph.D.
Peggy Nilsson Geimer, M.D.
David Jacobs, Ph.D., C.I.H.
Richard W. Janssen, Jr.
Lynda Knobeloch, Ph.D.
Amy D. Kyle, Ph.D., M.P.H.
Elise Miller, M.Ed.
Marie Lynn Miranda, Ph.D.
Curtis Munoz
Nsedu Obot-Witherspoon, M.P.H.
Jerome Paulson, M.D., F.A.A.P.
Jennifer D. Roberts, Dr.P.H., M.P.H.
Martha S. Sandy, Ph.D., M.P.H.
Sheela Sathyanarayana, M.D.,
M.P.H.
Barbara Sattler, R.N, Dr.P.H.,
F.A.A.N.
Anne T umer-Henson, R.N, D.S.N,
December 20, 2011
Lisa P. Jackson, Administrator
United States Environmental Protection Agency
1200 Pennsylvania Ave, NW
Washington, DC 20460
RE: ORD Research Strategies Supporting Sustainability
Dear Administrator Jackson: .
The Children's Health Protection Advisory Committee (CHPAC) has been
following the planning that the US Environmental Protection Agency
(EPA) Office of Research and Development (ORD) has undertaken to
restructure thirteen ORD research programs into six major program
areas. This letter summarizes CHPAC comments and questions
concerning the new research framework and includes specific requests
for more information from ORD staff in the coming year.
ORD personnel presented new ORD research strategies to the CHPAC
on July 20, 2011. At the July meeting, CHPAC learned that ORD is
incorporating the theme of sustainability into new research strategies and
research plans for these new program areas. CHPAC members reviewed
the strategies that ORD has publically shared1. In addition, at the
November 16, 2011, CHPAC meeting, members heard a presentation on
the 2011 National Academy of Sciences report "Sustainability and the US
EPA"2 from Dr. Bernard Goldstein; and learned about another advisory
committee's (EPA National Advisory Council for Environmental Policy and
Technology) focus on sustainability.
CHPAC recognizes the importance of the new research strategies as
they are intended to guide research and research funding decisions into
the future. CHPAC was pleased to hear from ORD staff that children's
environmental health is one of two cross cutting, fundamental strategies
of interest to ORD (the other being environmental justice).
It was clear from the July presentation that ORD does not intend to depart
from the values encompassed in the 2000 ORD strategy report that
described a program of children's environmental health research3. The
'take home' messages CHPAC heard from ORD echoed longstanding
1 Request to EPA Science Advisory Board and EPA ORD Board of Scientific Counselors
http://tfOsemite.epa.aov/sab/sabproduct.nsf/MeetinqCal/794564E427071DFA8525780F00656E3270penDocument
and ORD research frameworks
2 National Research Council Committee on Incorporating Sustainability in the U.S. Environmental Protection Agency.
(2011). Sustainability and the U.S. EPA. Washington, DC : National Academies Press, http://www.nap.edu/
http://www.epa.gov/ncea/pdfs/strat4resrch.pdf
Children's Health Protection Advisory Committee is a Federal Advisory Committee for the
U.S. Environmental Protection Agency under the Federal Advisory Committee Act
http://yosemite.epa.gov/ochp/ochpweb.nsffconteiit/whatweadvisorv.htm
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Administrator Jackson
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December 20, 2011
concerns expressed in CHPAC letters and recommendations to the agency. That is, that
protection from environmental hazards early in life is fundamental to children's health and that
health protection must be based on knowledge of the exposures and sensitivities that are
unique to early life stages. The ORD spokesperson described many laudable ORD program
achievements of which CHPAC has been very supportive. For example, CHPAC has advocated
for the Children's Environmental Health Centers research program4 and the National Children's
Study as ways to develop the data and tools necessary to guide health protection.
The ORD presenter inferred that children's health protection will be fully incorporated into all of
EPA's activities across each of the strategic goals of the Agency. With that in mind, interested
CHPAC members spent time outside of the July meeting to examine the research strategy
frameworks for Sustainable and Healthy Communities, Chemical Safety and Sustainability, and
Human Health Risk Assessment in order to understand how children's environmental health
(e.g., early life exposure research) would be addressed in the new strategies. The following
comments are a reaction to how ORD has addressed children's environmental health in the new
research strategies.
Overall:
CHPAC members note that there could not be any more powerful statement of sustainability
than the recognition that what we do today must protect and nurture future generations,
Sustainability can be defined by society's ability to preserve and improve the health and welfare
of communities over generations. This definition applies to ecosystems and communities, and
encompasses economic, societal, and environmental wellbeing. Protecting health during early
life stages is fundamental to the concept of sustainability. Given that infants and children are
often more sensitive and exposed to toxic substances than adults, a research focus on
children's health is essential to EPA's emphasis on sustainability.
EPA's goal of sustainability is laudable and CHPAC is supportive of the new research strategy
that is intended to integrate research areas that perhaps had previously been studied in
isolation. CHPAC is also supportive of the seemingly convergent communication strategy of the
ORD on the goal of reorganizing research around sustainability. Prior presentations to CHPAC
have focused on individual ORD offices or individual media. The messages delivered at the
July meeting were much more unified, coordinated, and cohesive. This trend of unification and
coordination needs to be incorporated into all aspects of EPA communications and outreach. All
of EPA should, as ORD has done, utilize the concepts of sustainability in EPA actions and
communications.
CHPAC members noted that EPA has sponsored or developed excellent scientific research on
children's environmental health in the past. However, findings from this research have not
always been shared outside of a narrow scientific community. CHPAC members encourage
EPA scientists and grantees to publish their work in scientific journals, government reports, and
government newsletters5. ORD should develop outreach strategies to make research findings
freely accessible to scientists, health care professionals, and community-based organizations,
including school communities, with the understanding that each target audience requires
different communication methods to assure that critical findings are shared in a timely manner.
4 http://vosemite.epa.gov/ochp/ochpweb nsf/content/7252007.htm/$file/7252007.pdf
6 For example, the EHS Bulletin (Environment, Health and Society research methods Bulletin) published by NCER
(National Center for Environmental Research) http://www.epa.gov/ncer/ehs/ehsfall2011 /ehs bulletin sept2011.pdf
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Administrator Jackson
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December 20, 2011
Evaluation of the success of the new strategies will need to be clearly described, The metrics for
sustainability are not obvious, and criteria for measuring the success of meeting the goals for
sustainability are needed (perhaps in research plans that are developed from the research
frameworks),
CHPAC would like to hear more from ORD on specific areas of the framework and strategies.
Areas of special interest to CHPAC follow,
A. Chemical Safety for Sustainability
At the July meeting, an ORD spokesperson for the Chemical Safety for Sustainability Research
Program (CSS) described program realignments that result in new research topic areas, such
as inherency, systems modeling, and life cycle considerations. The CSS framework6 contains
much more detail on strategies for sustainability, and the CSS research action plan7 provides
information useful to CHPAC members interested in knowing how children's environmental
health research will be advanced through the realignment.
By focusing on the populations and life stages most susceptible to harm, the health of the
general population may be protected and promoted. This may mean putting a high priority on
determining, for any particular chemical, whether hazards to early life stages have been
appropriately and adequately evaluated. While great strides have been made over the past
twenty years to ensure that life stage appropriate studies are conducted, most toxicological
studies that are being used to develop regulatory standards and assess chemical safety were
conducted using mature animals. While theses historical data are valuable, new studies must be
designed to assess potential effects on prenatal and early life stages.
High throughput testing, which has been promoted as a method to rapidly build a new data base
related to inherent chemical properties and cellular and molecular changes in response to a
chemical, falls within the scope of the CSS research action plan. This new method of toxicity
testing is expected to generate a large amount of data on early cellular and molecular changes
that are predictive of adverse effects on human health and development. Several CHPAC
members have expressed concerns that the potential for in vitro testing to predict chemical
effects on embryogenesis, neurodevelopment, endocrine and immune function during early
childhood is poorly understood at this time.
Members present at the July meeting raised the following points related to this research
strategy:
1. ToxCast seems to be intended as a predictive model as opposed to being part of a
tiered system of testing. There is a concern that if ToxCast rules out chemicals for
further testing, biological effects relevant to early life stages could be missed.
2. Assurance that adverse effects relevant to early life are captured by testing systems
such as ToxCast (or at least not dismissed) is needed. This was expressed as a need to
validate the high throughput testing related to biological endpoints relevant to prenatal
development and children's health.
f'http://vosemite.epa.qov/sab/sabproduct.nsf/7807842B9AD880F7852578B00040D27E/$File/CSS+Framework+1+Ju
ne+2011 .odf
'http://vosemite.epa.qov/sab/sabproduct.nsf/23A995E7EDE63D26852578B20009D90B/$File/CSS+Draft+Research+
Action+Plan+v1 .pdf
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Administrator Jackson
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December 20, 2011
3. The similarities between high throughput screening for toxicity and testing that result in
screening out pharmaceutical chemicals was described. However, there is a
fundamental difference in the result of a pharmaceutical company's rejection of a
chemical for further development and developing a full understanding of what is "safe"
for human exposure. Many, many tiers of additional pharmaceutical testing and use trials
are necessary to demonstrate both efficacy and a lack of toxicity, while the current vision
for Tox21 is additional tiers of testing to demonstrate toxicity rather than safety.
4. Some CHPAC members expressed concern that ToxCast is reductionist. While the
conceptual approach for mixtures and multiple chemicals is understandable and
laudable, there is a basic concern that focusing on what might be relatively few changes
in protein expression or genomic change may not capture the potential range of
interactions in the human body.
5. EPA seems to have assumed the burden of proof of sustainability and safety in the CSS
research strategy. The contribution of industry is not apparent.
CHPAC members received an acknowledgement from ORD that EPA sees the issue of
capturing and validating early life endpoints in high throughput testing as a concern. ORD
described the new high-throughput assays as one guide to decision-making and explained that
the current focus is on developing priorities for further testing. CHPAC members are pleased
that Office of Children's Health Protection (OCHP) staff are providing input to EPA programs
conducting computational toxicology work (for example, the virtual embryo project8} so that early
life stages and developmental windows of vulnerability are comprehensively considered in the
research.
CHPAC would like to hear more explicitly what health effects related to early life stage exposure
and development (including prenatal and preconception exposure and development) will be
incorporated into high throughput screening (e.g., assay selection for neurodevelopmental
toxicity) and if specific health endpoint correlates are not included, what additional testing would
be required before screening out a chemical for further research.
ORD suggested that with the possibility of conducting 8,000 simultaneous assays EPA
anticipates a more comprehensive understanding of mixtures will emerge. CHPAC would like to
hear explicitly how a systematic study of the cumulative effect of mixtures will be conducted in
ways that can be correlated with whole animal studies. In addition, CHPAC would like to hear
about both plans and outcomes for incorporating metabolic activation into high throughput
research.
ORD is working on validation for testing that considers correlations, confounders, and
dependent and independent variables for specific types of studies and assays. CHPAC will be a
much more enthusiastic advocate of ToxCast and Tox21 testing once the potential for the new
testing strategies to predict effects on growth, development, and function have been proven.
CHPAC would like to see validation studies such as the recently published EPA computational
toxicity research project on prenatal developmental toxicity®. CHPAC would like to hear more
about plans for validating the relationship between in vitro and in vivo toxicity endpoints and see
the results of this validation work.
8 http://www.epa.gov/ncctA/-Embrvo/ focuses on early eye, vascular and limb developments and conducts
experiments using stem cells and zebrafish to generate data
9 Sipes, N.S. et al., 2011. Predictive Models of Prenatal Developmental Toxicity from ToxCast High-Throughput
Screening Data. Toxicological Sciences 124(1), 109-127
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Administrator Jackson
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December 20, 2011
CHPAC is concerned about translating this research, specifically in 1) explaining the complexity
of this work to scientists, medical professionals, and community members; and 2) using this
work to protect children by developing appropriate interventions based on this work and
measuring the success of such interventions, CHPAC would like to hear ORD plans for sharing
and using the results of the CSS work,
B, Sustainable and Healthy Communities
An ORD spokesperson discussed how the Sustainable and Healthy Communities Research
Program (SHC) integrates multiple programs throughout ORD to work toward sustainable and
healthy communities. This new strategy comprises aspects of the human health research
program, land program (Superfund), and the ecosystems services program. Major SHC themes
that relate to children's health research are related to tools and data collection, partner needs,
and communities (such as children's settings and built environment factors), ORD described the
SHC Children's Health Project, which has three tasks; 1) children's exposure factors (including a
study of determinants of exposure to chemicals in the environment for early life stages); 2)
health effects from early life exposures (and the latent or chronic effects resulting from early life
exposures); and 3) systems approach to community-based children's health10.
Members at the July meeting and subsequent discussions raised the following points related to
this research strategy:
1. CHPAC members suggest that the social determinants of health model Is a useful way
to address multiple critical factors (such as economic disparities and environmental
justice).
2. CHPAC did not hear a strong theme of addressing or acknowledging issues surrounding
environmental justice.
3. CHPAC expressed concern that EPA may not have sufficient staff with the appropriate
training and expertise (such as social scientists) for working with communities and their
needs.
4. Members encouraged EPA to partner with groups that focus on learning environments
across the childhood and adolescence trajectory, including child care and schools, and
suggested that EPA determine the types of community capacity building that are
successful and build on that knowledgebase.
5. It was not clear to members that EPA consistently includes preconception and prenatal
lifestages in strategies aimed at children's health.
6. Members commented that it is important for EPA to sustain capacity building programs
and that EPA should identify resources to sustain community efforts to improve
environmental health.
7. CHPAC members noted that it is important to ensure that the community groups asked
to participate in research programs and projects are actually part of the community, and
suggested that existing community organizations provide excellent communication
linkages to the community.
8. Members also suggest that Children's Environmental Health Centers integrate
community participatory research methodology into all research and involve more
10 Systems approach to community-based children's health; A research construct that interactions of factors,
stressors, and exposures may result in children's health disparities; with the result that interventions may need to be
just as complex and rooted in community environments.
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Administrator Jackson
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December 20, 2011
representatives from the residents of the community they serve in their decision-making
around research.
9. Members expressed some reservations about the concept of empowering communities
to conduct risk assessments, as experience has shown that communities do not have
the resources or expertise to conduct risk assessments, but expect state and federal
agencies to provide guidelines and regulations that will ensure the public's safety.
CHPAC is interested in how social determinants of health can be explicitly, and in a measured
way, incorporated into a systems approach to community-based children's health. CHPAC is
interested in EPA's plans to transfer or translate the science to community action. A concern
was expressed about the extent to which community and school based interventions have been
proven effective (i.e., are proposed interventions grounded in science?).
Measures of success are needed in order to determine whether SHC work results in healthier
and safer communities. CHPAC would like to hear ORD plans for measuring the progress of the
SHC work.
C. Human Health Risk Assessment
Human Health Risk Assessment (HHRA) topics described in the ORD power point presentation
included themes of dose response assessments (the Integrated Risk Information System);
Integrated Science Assessments for criteria air pollutants; community and technical support for
exposure and health assessments; and methods, models, and approaches to modernize risk
assessment for the 21st century.
Members raised the following questions and points related to this research strategy:
1. What are the major research goals, timelines, and outcome measures? What childhood
illnesses and developmental problems are being targeted and how are those associated
with environmental exposures? What exposures are targeted and what is known about
how those affect children's health? How will EPA measure its success or failure? Has
past research been successful in reducing illness rates? How do current asthma rates
compare with rates 10 and 20 years ago? Blood lead levels are lower, but attention
deficit disorders and other learning problems seem to be more common and college
entrance test scores are lower. Can the new research program explain these
contradictory trends?
2. Environmental health research is most likely to produce a useful outcome when it targets
a specific problem. CHPAC would prefer that EPA focus on improving children's health
by identifying and reducing exposure to harmful substances instead of studying the
effects of unabated exposures that are known or suspected to be hazardous.
3. CHPAC members have asked if additional children's exposure factors and risk
information should be developed. There is concern among CHPAC that allergens and
asthma triggers have not been assessed as rigorously as the approach used for
chemicals. The Integrated Risk Information System is used for chemicals, not biologicals
or pathogens, and work should be conducted to characterize risks from cockroach
antigens, molds, harmful algae, and complex mixtures.
4. The EPA-funded Near Roadways Exposure to Urban Air Pollutants Study (NEXUS), a
project of the University of Michigan, demonstrates that near roadway air pollution is a
very important metric for exposures to urban pollutants. The relationship between the
stage of pregnancy and level of exposure to pollutants is an important aspect of such
research.
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Administrator Jackson
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December 20, 2011
Questions were raised, as with other research areas, about measuring the result of HHRA
utilizing a new research strategy. It was noted that approaches to human health risk
assessment will continue to be used (that is, be sustainable) only if found useful. The question
was asked how EPA will know that the result of the new strategy is improvements in children's
health.
In addition to the three research strategies described above, CHPAC members discussed
issues related to Safe and Sustainable Water Resources. Current requirements for tests done
on drinking water and air are limited to a relatively small number of chemicals. When an
unregulated contaminant is found in a drinking water supply at a level that exceeds EPA's one-
day child health advisory, no action is required to be taken under the Safe Drinking Water Act. A
question was raised about whether the Safe and Sustainable Water Resources Research
Program will study children's exposure to unregulated contaminants of public drinking water,
and if so, members asked what contaminants will be assessed, how many children are
exposed, and what is the potential for an adverse health effect?
D. Research partners
In addition to discussing the individual strategies, CHPAC members expressed interest in the
theme of overlapping research communities. Members encouraged EPA to partner with other
agencies on research.
1. CHPAC members wondered if the CSS research will be limited to currently regulated
chemicals and products. An emerging issue of interest to some members is the growing
use of nanosilver and other nanomaterials. CHPAC is interested in knowing how EPA
will work with other agencies to ensure the safety of these materials. Another group of
chemicals of interest are pesticide residues in foods, water, and the indoor environment,
which also may require collaboration with offices outside of ORD.
2. It was noted that more research is needed on endocrine disruption, childhood obesity,
Type I and Type I! diabetes, and developmental disorders including attention deficit and
hyperactivity disorders. EPA and Centers for Disease Control and Prevention (CDC)
could partner to identify the most prevalent childhood illnesses/disorders that seem to
have an environmental component and work together to study causes and design
interventions. CDC's Environmental Health Tracking Program and the National Institutes
of Health (NIH)/EPA funded Children's Health Study have shared goals of reducing
childhood illness and infant mortality and could work closely together.
3. CHPAC encourages ORD to compare research priorities among federal agencies (NIH,
CDC, Department of Defense, Department of Education) and identify potential
overlapping research and areas for collaboration.
In summary, CHPAC supports EPA's goal of sustainability and the integration and
reorganization of research around this goal. The research frameworks provide a starting point
for detailed research strategies, programs, and evaluation to achieve goals that include
protecting children from environmental hazards.
CHPAC has many questions related to how implementation of the new research strategies will
further our understanding of children's environmental health. The most pressing questions that
CHPAC would like to discuss further with ORD are:
1. How social determinants of health can be explicitly and quantitatively incorporated into
children's environmental health research;
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Administrator Jackson
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December 20, 2011
2. How health effects related to early life stage (including preconception and prenatal
periods) exposure and development will be addressed/incorporated into high throughput
screening; and
3. How the research that results from the new research strategies and ORD reorganization
be implemented into intervention strategies and evaluated {i.e., what metrics should be
used) to assess whether children's environmental health has improved as a result of
ORD's new research direction.
CHPAC will work with the Office of Children's Health Protection to request additional information
and updates on ORD research plans.
Thank you for your consideration of our interest in continuing to discuss with ORD how
sustainability and children's environmental health will be incorporated into the research of the
newly organized ORD program areas.
Sincerely,
/Signed/
Pamela Shubat, Ph.D.
Chair
Children's Health Protection Advisory Committee
cc: Paul T. Anastas, Assistant Administrator, Office of Research and Development
Kevin Teichman, Deputy Assistant Administrator for Science, Office of Research and
Development
Ramona Travato, Associate Assistant Administrator, Office of Research and
Development
Robert Kavlock, Director of the National Center for Computational Toxicology & Interim
Lead for Chemical Safety for Sustainability Program
Rick Linthurst, Interim Lead for Sustainable and Healthy Communities Program
Sally Darney, Associate interim National Program Director, Sustainable and Healthy
Communities Program
Stanley Barone, Jr., Assistant Center Director for Health, National Center for
Environmental Assessment, Office of Research and Development
Peter Grevatt. Director, Office of Children's Health Protection
B rend a Foos, Office of Children's Health Protection
Michael Firestone, Office of Children's Health Protection
Martha Berger, Office of Children's Health Protection
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Appendix
Additional responses and updates on specific issues and questions posed in Dr. Shubat's letter dated
December 21, 2011. Many of these will benefit from further discussion over time.
• General Issue: CUP AC emphasized the importance of synthesizing and communicating research
accomplishments, their usefulness, and their impact to a variety of different audiences (research
translation).
ORD response: Within the EPA, each ORD program has regular meetings with Program Office and
Regional partners to develop common program goals, report findings and prioritize new directions.
Continual communication with our partners is critical to the utility of the research products and their
impact on policy decisions and ultimately, the protection of public health. Specific to children's
health, ORD has established a cross-program Children's Health Work Group to foster coordination
of research relevant to children's health. This group includes the Office of Children's Health
Protection (OCHP) and other EPA partner participation in developing an integrated roadmap of
children's health research across ORD. We envision this roadmap to include an interactive visual
framework with links to various program components where more detailed information and points of
contact for each research component can be found. We also see value in building a children's
environment health protection "community of practice" to connect researchers working on children's
health issues both inside and outside the EPA. ORD's open approach to planning and implementing
research includes review of all research programs by ORD's Board of Scientific Councilors and
input from our Science Advisory Board as well as CHPAC. Our goal is to harness creative thinking
by the research and public health communities to advance knowledge about children's health and
chemical safety and apply it broadly to further children's health protection and promotion.
To make information available to the public in appropriate forms, we are translating our research
products into synthesis papers, fact sheets and multi-media "science notebooks" that convey
complex information in clear and public-friendly ways. We are also developing web-based tools to
enable public access to a wide variety of information. For example, efforts are underway to link age-
specific exposure factor data to databases and tools used by local governments and public health
authorities, health care providers and parent/educational advocacy groups. We hope to provide
highlights of ORD research and activities to OCHP for inclusion in their regular list-serve
communications which reach a broad readership that includes EPA regional scientists, school
coordinators, and pediatricians involved in the EPA-Agency for Toxics Release and Disease
Registry (ATSDR) Pediatric Specialty Units in each EPA Region.
Finally, we recognize the importance of communication and translation across the federal
government. For example, as a result of regular meetings with NIEHS on the EPA-NIEHS
Children's Centers program, a new factsheet that features descriptions of each active Center is
posted prominently under children's health on both the NIEHS and EPA websites
(http://www.epa.gov/ncer/childrenscenters/). This web site also includes links to currently funded
centers and final reports from others, and to a concise public-friendly synthesis of accomplishments
of the first ten years of the Centers Program (1998-2007). Most recently ORD's National Center for
Environmental Research (NCER) has launched a monthly webinar series about the Children's
Centers, featuring Center directors and Principal Investigators
http://www.epa.gOv/ncer/events/index.html#febcehc-webinar. This series is being advertised widely
within and outside the Agency and NIEHS. NIEHS is hosting the annual Children's Centers' grantee
4
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meeting (open to the public, March 6-7, 2012) at the National Institute of Health (NIH) Natcher
Center where a large audience can be accommodated. Finally, ORD is actively engaged with the
Federal Taskforce on Children's Health Protection (for which Peter Grevatt, OCHP is the lead for
the EPA) to define how the EPA can best contribute to national and international efforts.
• General issue: CHPAC emphasized the importance of having metrics by which to measure
whether we are reaching our sustainability and health protection/promotion goals.
ORD response: Sustainability metrics are considered essential for ORD to measure the effectiveness
of our research programs. Across ORD, each program has specific tasks to develop and validate
sustainability metrics, and these are being built into Agency performance measures related to the
EPA Strategic Plan. These include developing and improving indicators of children's health that can
facilitate public health tracking for childhood diseases and conditions. We expect this indicators
research to contribute to the EPA's America's Children and the Environment Report and the EPA's
Report on the Environment. The Air Climate and Energy Research Program (ACE), CSS and SHC
have initiated collaborative efforts with CDC in this regard and are working with community leaders
and decision-makers to test the usefulness of new public health and sustainability metrics gathered at
community and regional scales. We recognize the.need for metrics specific to children and their age-
specific health conditions, developmental stages and vulnerabilities. Thus, we concur that
meaningful metrics are essential for measuring the effectiveness of the EPA's policies, and for
justifying their costs and evaluating their benefits to the community with respect to economic, health
and ecological considerations.
• Chemical Safety for Sustainability Program (CSS)
CHPAC commented: At the July meeting, an ORD spokesperson for the Chemical Safety for
Sustainability Research Program (CSS) described program realignments that result in new
research topic areas, such as inherency, systems modeling, and life cycle considerations. The CSS
framework contains much more detail on strategies for sustainability, and the CSS research action
plan provides information useful to CHPAC members interested in knowing how children's
environmental health research will be advanced through the realignment.
By focusing on the populations and life stages most susceptible to harm, the health of the general
population may be protected and promoted. This may mean putting a high priority on determining,
for any particular chemical, whether hazards to early life stages have been appropriately and
adequately evaluated. While great strides have been made over the past twenty years to ensure that
life stage appropriate studies are conducted, most toxicological studies that are being used to
develop regulatory standards and assess chemical safety were conducted using mature animals.
While theses historical data are valuable, new studies must be designed to assess potential effects on
prenatal and early life stages.
High throughput testing, which has been promoted as a method to rapidly build a new data base
related to inherent chemical properties and cellular and molecular changes in response to a
chemical, falls within the scope of the CSS research action plan. This new method of toxicity testing
is expected to generate a large amount of data on early cellular and molecular changes that are
predictive of adverse effects on human health and development. Several CHPAC members have
expressed concerns that the potential for in vitro testing to predict chemical effects on
embryogenesis, neurodevelopment, endocrine and immune function during early childhood is poorly
understood at this time.
5
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ORD response; In the traditional testing paradigm, most data on developmental exposure(s) come
from studies that require large numbers of pregnant animals and their offspring. These studies are
too slow and costly to meet the efficiency needed to address the potential risks of thousands of new
and existing chemicals for which data are needed. The EPA and others in the research community
are continually working to improve our testing for developmental and other toxicants. We are
striving to increase the power of tests to detect effects while reducing the number of animals used. In
addition, we are seeking greater understanding of how chemicals perturb development in humans
with less reliance on extrapolation from animal models. Technical and biomedical achievements in
recent years have produced newer, more efficient, in vitro technologies that can be run quickly on
large numbers of chemicals and can provide mechanistic information, with less reliance on animal
usage.
The challenges in utilizing this information for a chemical management program are significant, not
least of which is the difficulty of recapitulating in vitro the complexity of a biological system during
its development and interactions with maternal and childhood factors.
CSS is geared to meet this challenge. It brings together researchers with broad technical expertise in
exposure modeling, systems biology, computer sciences, and computational toxicology. Much of the
work to advance understanding of how chemicals interact with important biological processes inside
the embryo, pregnant mother, or developing child is described in CSS Systems Models. This research
theme aims to generate, utilize, and integrate chemical, biological, and toxicological information at
various levels of biological organization (e.g., molecule, cell, organ, and organism), such that the
potential toxicity of a chemical can be evaluated with enhanced predictive power. Using innovative
technologies such as automated high-throughput screening (HTS), informative data on the biological
effects of a large number of chemicals and their associated adverse outcome pathways (AOPs) are
being compiled. These groundbreaking approaches have quickly produced results that are being used
to help prioritize chemicals for further testing and to help build "virtual tissue" models capable of
integrating and encoding data from many sources, informing potential effects of developmental
exposure(s) during prenatal and early life stages.
Production of tools for evaluating cross-species conservation of molecular targets and/or key events
is a means to predict the relative sensitivity or susceptibility to chemical exposure(s). Outcomes
from CSS Systems Models research will synergize with CSS Biomarkers, guiding researchers toward
diagnostic biomarkers that are relevant to developmental exposure(s) or indicative of key events for
AOPs associated with embryogenesis, neurodevelopment, endocrine, and immune function. This
synergism can promote a more effective utilization of public biomonitoring data (e.g. NHANES) to
inform which compounds are of concern and metrics to follow for evaluations (e.g., reductions in
levels of lead and perfluorinated chemicals in blood) and improved methodologies for early
lifestage-specific risk assessment (e.g., problem scoping and analysis). It can also guide
experimental designs in SHC's Enhancing Children's Health project that aim to characterize in
utero factors (e.g., chemicals, diet, stress) influencing developmental health and disease in
susceptible life stages and groups, and in community settings.
CHPAC commented: Members present at the July meeting raised the following points-
related to this research strategy:
1. ToxCast seems to be intended as a predictive model as opposed to being part of a tiered system
of testing. There is a concern that ifToxCast rules out chemicals for further testing, biological
effects relevant to early life stages could be missed.
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ORD response: ToxCast was initially designed as an HTS chemical prioritization research
program. It is well underway toward providing information on 1060 chemicals across -600
assays. A new implementation of ToxCast known as the "EDSP21 Work Plan" was
developed by OSCP/OCSPP with input from ORD scientists
(http://www.epa.gov/endo/pubs/edsp21 work plan summarv%20 overview final.pdf).
"EDSP21" describes an approach for using computational in silico models and molecular-
based in vitro HTS assays to prioritize and screen chemicals to determine their potential to
interact with the estrogen, androgen or thyroid hormonal systems and steroidogenesis
(EATS). This is part of a multi-year transition of the Endocrine Disruptor Screening
Program (EDSP) to validate and more efficiently use computational toxicology methods
and HTS. This would enable the Agency to more quickly and cost-effectively assess
potential chemical toxicity. The EPA also intends to prioritize industrial chemicals for
review and possible action under the Toxic Substances Control Act (TSCA). For example,
ToxCast HTS data tools could be used to prioritize a chemical for review or targeted testing
based on qualified predictive models for reproductive or developmental toxicity.
2. Assurance that adverse effects relevant to early life are captured by testing systems such as
ToxCast (or at least not dismissed) is needed. This was expressed as a need to validate the high
throughput testing related to biological endpoints relevant to prenatal development and
children's health,
ORD response: Profiling environmental chemicals by biochemical and cellular in vitro
assays raises important concerns about the means by which this information can be
translated into lifestage-specifie risk assessment. First-generation (Phase I) ToxCast
predictive models have now been published for reproductive toxicity [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 -300 data-rich chemicals. 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 -700 compounds in Phase II, where animal toxicology is
less well-characterized, CSS will develop plausible model structures that deal with the
possibility of additional relevant interactions and components beyond those represented in
the first-generation predictive models. Fact sheets on these ToxCast models are available
from the ORD/NCCT homepage:
http://www.epa.gov/ncct/download files/factsheets/ToxCast%20Models%20Fact%20Sheet
-Nov%2010%202011 .pdf.
A longer-term challenge is to extend these predictive models into what we call dynamic
multi-scale simulations of developing tissues and physiological processes. These
simulations can, in a sense, be viewed as a translation of statistically meaningful
(mathematical) relationships into biological context. The computer simulations use
information from various databases and attempt to reconstruct, in a visually simple way, the
development of embryonic structures such as a limb-bud or blood vessels. The user can then
add a stressor such as a chemical exposure and watch as the computer predicts and shows
with computer generated graphics how that chemical could change development. CSS
Systems Models is tasked with the design, development and implementation of such virtual
tissue models for the liver, embryo, and endocrine system. For example, sophisticated
computer models of embryonic blood vessel development in the Virtual Embryo task (CSS
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2.2.2) or interactions between hypothalamic-pituitary-testis in the Virtual Endocrine task
(CSS 2.2.3) are built from vast scientific knowledge of complex biological systems. These
models can potentially be used in toxicological assessments relevant to children's health by
simulating what might happen when the mother or child is exposed to different chemical
exposure scenarios.
Challenges for virtual tissue science and technology development are being facilitated by
academic collaborations through the EPA's STAR program, such as the Texas-Indiana
Virtual STAR Center (TIVS), which is devising strategies to reconstruct detailed in silico
models of complex developmental processes and toxicities. ORD/NCER is also in the
process of awarding 8 additional grants that will probe toxicity pathways of concern for
developmental toxicity, with the goal of moving these into HTS assays to broaden our
coverage of biological space.
3. The similarities between high throughput screening for toxicity and testing that result in
screening out pharmaceutical chemicals were described. However, there is a fundamental
difference in the result of a pharmaceutical company's rejection of a chemical for further
development and developing a full understanding of what is "safe" for human exposure. Many,
many tiers of additional pharmaceutical testing and use trials are necessary to demonstrate both
efficacy and a lack of toxicity, while the current vision for Tox21 is additional tiers of testing to
demonstrate toxicity rather than safety.
ORD response: CSS recognizes that 'drug discovery and attrition' is geared toward the efficacy of
the product and is intolerant of false positives (for reasons of time and money invested), whereas
'chemical risk management' is intolerant of false negatives (to avoid missing potential health risks).
The testing strategy adopted in ToxCast Phase I has proven to be conservative overall (false
positives » false negatives) with good to excellent balanced accuracy (70-80%). Currently, we are
prospectively evaluating the predictiveness of these models through Phase II of ToxCast. An
important CSS concept is the integration of large amounts of screening-level data with additional
tiers of toxicity information. Program-specific CSS "Dashboards" are web-accessible, customized
graphical user interfaces that link and translate information and knowledge to regulatory decision-
makers. Using customized dashboards, stakeholders can seamlessly access summary information
derived from data, publications, decision-rules, predictive models, and so forth. Through CSS,
'Lifestage-specific dashboards' could, for example, be developed in collaboration with OCHP to
provide access to information and models relevant to embryogenesis, neurodevelopment, endocrine,
and immune function.
4. Some CHPAC members expressed concern that ToxCast is reductionist. While the conceptual
approach for mixtures and multiple chemicals is understandable and laudable, there is a basic
concern that focusing on what might be relatively few changes in protein expression or genomic
change may not capture the potential range of interactions in the human body.
ORD response: ToxCast probes the fundamental nature of chemical interaction(s) with their
potential molecular targets and cellular consequences. Importantly, this covers a broad range of
concentrations. As such, dose-response relationships can be directly evaluated across literally
hundreds of assays. CSS recognizes that toxicity is an expression of the propagation of lesions into
more complex tissues and that cellular interactions, such as between immune cells and endothelial
cells during angiogenesis for example, play important roles in utero-placental development,
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embryogenesis, and other AOPs linked to childhood development. CSS also recognizes the need for
predictive hierarchical models spanning several scales from molecular networks to tissue- and
organism-level phenotypes. For example, the Virtual Embryo task integrates multi-dimensional data
with vast biological knowledge and translates this information into multi-scale, multi-cellular models
that can simulate outcomes following specific chemical perturbations. Whereas ToxCast provides
the infrastructure to predict pathways of toxicity, virtual tissue models may translate these
predictions into simulations that reconstruct the potential range of interactions inside the embryo,
fetus, infant or child.
As ORD's computational toolbox continues to evolve, we see the inclusion of additional lifestage
related effects to the broader context of developmental programming (functional deficits, latent
manifestations); this will move the science beyond severe outcomes (low birth weight,
malformations). As we come to better understand AOPs, and how these pathways interact with each
other, our virtual tissue models will be able to perform "what if' questions about exposures to
multiple chemicals. This will someday allow us to flag combinations that pose the highest levels of
hazard.
5. EPA seems to have assumed the burden ofproof of sustainability and safety in the CSS research
strategy. The contribution of industry is not apparent.
ORD response: The Toxic Substance Control Act (TSCA) puts the burden of proof on the EPA.
CSS research will support the Office of Chemical Safety and Pollution Prevention (OCSPP) in its
mission by developing better chemical prioritizing and testing methods for use by the Agency and
industry. In addition, partnerships with industry, such as voluntary actions to reduce/prevent
pollution are often motivated and informed by CSS research.
Industry also contributes to CSS research through Material Transfer Agreements (MTA) between
ToxCast and industry partners. In some cases, the MTA partnership entailed a donation of 'failed
drugs' to Phase II. Other cases entailed pilot studies to qualify predictive toxicology of ToxCast
signatures or virtual tissue simulations for developmental effects. The ExpoCast program in CSS
Systems Models has catalyzed a limited research initiative by industry to support development of
exposure models and metrics for improved exposure-based chemical prioritization. ORD/NRMRL
has a number of industry partnerships relevant to the CSS Life Cycles research theme.
ORD welcomes the opportunity to work with industry, especially in the alignment of a research
strategy toward capturing and validating early life endpoints in high throughput testing approaches
and developing metrics that can be applied by external organizations to improve the sustainability of
their products. The ORD HTS program is one key tool in this effort.
CHPAC commented: CHPAC members received an acknowledgement from ORD that the EPA sees
the issue of capturing and validating early life endpoints in high throughput testing as a concern.
ORD described the new high-throughput assays as one guide to decision-making and explained that
the current focus is on developing priorities for further testing. CHPAC members are pleased that
Office of Children's Health Protection (OCHP) staff are providing input to EPA programs
conducting computational toxicology work (for example, the virtual embryo project) so that early
life stages and developmental windows of vulnerability are comprehensively considered in the
research.
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ORD response: Cross-training has been ongoing in CSS between OCHP and the CSS Virtual
Embryo team. ORD welcomes the chance to work with CHPAC and would be interested in a new
'Children's Health Community-of-Practice in Children's Health' (CH-COP), similar to one hosted
by CSS in computational toxicology [http://www.epa.gov/ncct/communities of practice.html]. The
purpose of the CompTox COP is to provide regular updates to stakeholders interested in research
progress. It serves as an effective forum for discussing plans for the advancement and utilization of
exposure science and computational toxicology to address the EPA's needs for chemical screening,
prioritization and toxicity testing. The CompTox COP is composed of more than 300 people who
have an interest in encouraging computational toxicology usage and exposure science in helping to
implement the EPA's mission of protecting human health and the environment. Anyone can join the
COP and members include staff from the EPA, other federal agencies, industry, academic
institutions, professional societies, nongovernmental organizations, environmental non-profit groups,
state environmental agencies and more. We would be pleased to add interested members of CHPAC
to the stakeholder database. You will then receive updates about the Communities of Practice and
announcements about research progress.
A focused CH-COP could serve as a focal point for cross-training activities and could open the door
to further discussion between ORD, OCHP, CHPAC, and the broader community. CH-COP would
foster the shared vision across diverse communities focusing on public health, toxicology, basic
science, and technology development. For example, cross-training can delve into why a pathway-
based risk assessment is needed and the problem being addressed; how we are addressing the
problem using contemporary developmental biology; and how a systems-based approach can be used
in a new risk assessment paradigm (e.g., CSS is developing NextGen Risk Assessment case studies
for phthalates).
CHPAC commented: CHPAC would like to hear more explicitly what health effects related to early
life stage exposure and development (including prenatal and preconception exposure and
development) will be incorporated into high throughput screening (e.g., assay selection for
neurodevelopmental toxicity) and if specific health endpoint correlates are not included, what
additional testing would be required before screening out a chemical for further research.
ORD response: Much of the data generation in the research program relevant to developmental
processes and toxicities will come from assays residing in CSS Systems Models. For example, HTS
data is being collected on a variety of assay platforms designed to identify a range of pathways that
contribute to normal embryo and fetal development, and for which alterations in the pathway are
predicted to result in both specific and general development deficits from early embryo and fetal
loss, to birth defects, to health conditions related to abnormal hormone signaling, defects in organ
formation as may be secondary to inadequate blood supply during development, and behavioral
deficits due to altered development of the brain and nervous system. Accordingly, exploratory
platforms include mouse embryonic stem cell differentiation; human pluripotent stem cells (derived
from adult tissues); neural cell differentiation and neural crest biomarkers from neuronal cell lines;
vasculogenesis/angiogenesis assays for blood vessel formation and growth; zebrafish embryogenesis
for early steps in embryo development; and cell lines relevant to studies on the hypothalamic-
pituitary-gonadal and thyroid-brain axes. Specific health endpoints are represented in a computable
manner in the ToxRefDB database [http://actor.epa.gov/toxrefdb/faces/Home.jsp]. ToxRefDB
includes over 30-years of registrant-submitted animal studies worth >$2-billion for chronic/cancer in
two-year bioassays in rats and mice; multigeneration reproductive toxicity in rats; and prenatal
developmental toxicity in pregnant rats and pregnant rabbits. It has been expanded recently to
include data on developmental neurotoxicity in rats and may in the future include data on
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developmental immunotoxicity. ToxRefDB provides a resource to anchor the newer pathway-based
paradigm, in which toxicity is predicted from in vitro signatures, to a more traditional outcomes-
based paradigm that focuses on observational endpoints. ORD can provide details and progress to
CHPAC during regular meetings, CH-COP webinars, and scientific publications.
CHPAC commented: ORD suggested that with the possibility of conducting 8,000 simultaneous
assays EPA anticipates a more comprehensive understanding of mixtures will emerge. CHPAC
would like to hear explicitly how a systematic study of the cumulative effect of mixtures will be
conducted in ways that can be correlated with whole animal studies. In addition, CHPAC would
like to hear about both plans and outcomes for incorporating metabolic activation into high
throughput research.
ORD response: The aim of CSS Cumulative Risk research is to identify, predict, and assess the
potential human health and environmental outcomes that may occur due to multiple and continuous
exposures to chemicals, with a focus on those chemicals found in consumer products. We would
welcome the chance to convey our progress to CHPAC on the following topics in more detail. For
example, researchers are assessing the cumulative risk of perfluorinated chemicals (PFCs) that have
been tested in ToxCast. HTS datasets can now be mined for molecular targets or pathways
potentially affected by PFCs. Virtual tissue models can be used to generate 'mixed effects models'
for specific developmental processes (e.g., angiogenesis) and the models can be qualified against
empirical data from targeted experiments or a high throughput mixtures study.
Methods are also being developed to identify testing priorities based on potential for children's
exposure to chemical mixtures in their home environment, for potential follow-on work in the CSS
Cumulative Risk [Tornero-Velez et al. 2011].
In terms of incorporating metabolic activation into high-throughput research, CSS Extrapolation and
Systems Models projects are utilizing physiologically-based dose response (PBPK) models to
integrate exposure with internal dose; reverse-PBPK models to compare the oral equivalent doses
with human exposure estimates from the in vitro data; and virtual tissue models for cell-level
microdosimetry and transport. The latter is considered in detail for hepatic microdosimetry in the
Virtual Liver task in metabolically-competent HepRG cells, and for pregnancy (transplacental) and
infantile (translactational) exposures in the Virtual Embryo task. Continued refinement of the in vitro
assays to better reflect in vivo adverse effects and special considerations for developmental
exposure(s) will eventually allow us to move beyond hazard-based prioritization to early lifestage
specific risk assessment.
CHPAC commented: ORD is working on validation for testing that considers correlations,
confounders, and dependent and independent variables for specific types of studies and assays.
CHPAC will be a much more enthusiastic advocate of ToxCast and Tox21 testing once the potential
for the new testing strategies to predict effects on growth, development, and function have been
proven. CHPAC would like to see validation studies such as the recently published EPA
computational toxicity research project on prenatal developmental toxicity'" CHPAC would like to
hear more about plans for validating the relationship between in vitro and in vivo toxicity endpoints
and see the results of this validation work.
ORD response: Again, ORD welcomes additional engagement with CHPAC on matters of critical
importance to prenatal exposures and early lifestage research. Below is a selection of 2010-2012
publications regarding first-generation predictive models utilizing ToxCast HTS data to
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acknowledge the strong activity toward use of the new testing strategy in issues relevant to
children's health protection. ORD would be happy to offer fact sheets and presentations to CHPAC
on these various topics.
Cohen Hubal E.A., Richard A.M., Shah I.A., Gallagher J., Kavlock R.J., Blancato J.N., and
Edwards S.W. (2010) Exposure science and the US EPA National Center for Computational
Toxicology. J Expo Sci Environ Epidemiol 20: 231-236
Reif D., Martin M.T., Tan S.» Houck K.A., Judson R., Richard A.M., Knudsen T.B., Dix D.J. and
Kavlock R.J. (2010) Endocrine profiling and prioritization of environmental chemicals using
ToxCast data. Environ Hlth Persp 118, 2-8
RotrofTD.M., Wetmore B.A., Dix D.J., Ferguson S.S., Clcwell H.J., Houck K.A., LeCluyse E.L.,
Andersen M.E., Judson R., Smith C.M., Sochaski M.A., Kavlock R.J., Boellmann F., Martin
M.T., Reif D., Wambaugh J.F. and Thomas R.S. (2010) Incorporating human dosimetry and
exposure into high-throughput in vitro toxicity screening . Toxicol Sci 117, 348-358
Sipes M.S., Martin M.T., Reif D.M., Kleinstreuer N.C., Judson R.S., Singh A.V., Chandler K.J.,
Dix D.J., Kavlock R.J. and Knudsen T.B. (2011) Predictive models of prenatal developmental
toxicity from ToxCast high-throughput screening data. Toxicol Sci 124, 109-127
Martin M.T., Knudsen T.B., Reif D.M., 1 louck K.A., Judson R.S., Kavlock R.J. and Dix D.J.
(2011) Predictive model of rat reproductive toxicity from ToxCast high throughput screening.
Biol Reprod 85, 327-339
Chandler K.J., Barrier M., Jeffay S., Nichols II.P., Kleinstreuer N.C., Singh A.V., Reif D.M.,
Sipes N.S., Judson R.S., Dix D.J., Kavlock R.J., Hunter E.S. Ill and Knudsen T.B. (2011)
Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell
differentiation and cytotoxicity assay. PLOS One 6(6), p. el 8540
Sipes N.S., Padilla S. and Knudsen T.B. (2011) Zebrafish, as an integrative model for twenty-
first century toxicity testing. Birth Defects Res C 93, 256-267
Kleinstreuer N.C., Judson R.S., ReifD.M., Sipes N.S., Singh A.V., Chandler K.J., DeWoskin R„
Dix D.J., Kavlock R.J. and Knudsen T.B. (2011) Environmental impact on vascular development
predicted by high throughput screening. Environ Health Perspect 119,1596-1603
Kleinstreuer N.C., Smith A.M., West P.R., Conard K., Fontaine B., Weir-Hauptman A.M.,
Palmer J., Knudsen T.B., Dix D.J., Donley E.L, and Cezar G.G. (2011) Identifying
developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic
stem cells and metabolomics. Toxicol Appl Pharmacol 257, 111-121
Padilla S., Coram D., Padnos B., Hunter D.L., Beam A., Houck K.A., Sipes N., Kleinstreuer N.,
Knudsen T., Dix D.J. and ReifD.M. (2012). Zebrafish Developmental Screening of the ToxCast
Phase I Chemical Library. Reprod Toxicol (in press), doi: 10.1016/j.reprotox.2011.10.18
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Tornero-Velez R., Egeghy P. and Cohen Hubal E.A. (2011). Application of biogeographical
methods to chemical co-occurrence data to identify priorities for mixture research. Risk Analysis
doi: 10.1111/j.l 539-6924.2011.01658.x
Joubert B.R., Reif D., Edwards S., Leiner K.A., Hudgens E., Egeghy P., Gallagher J. and Cohen
Hubal E. (2011) Evaluation of genetic susceptibility to childhood allergy and asthma in an
African American urban population. BMC Medical Genetics 12: 25.
http://www.biomedcentral.eom/l 471 -2350/12/25
Gallagher J.E., Hudgens E.E., Williams A.H., Inmon J., Rhoney S., Andrews G., Reif D.M.,
Heidenfelder B.L., Neas L.M., Williams R., Johnson M.M., Ozkaynak H., Edwards S.W. and
Cohen Hubal E.A. (2011) Mechanistic Indicators of Childhood Asthma (MICA) Study: piloting
an integrative design for evaluating environmental health. BMC Public Health 11: 344.
doi: 10.1186/1471-2458-11-344
Egeghy P.P., Cohen Hubal E.A., Tulve N., Melnyk L., Morgan M., Fortmann R. and Sheldon L.
(2011) Review of Pesticide Urinary Biomarker Measurements from Selected US EPA Children's
Observational Exposure Studies. Int. J. Environ. Res. Public Health 8(5), 1727-1754
Knudsen T.B. and Kleinstreuer N.C. (2012) Disruption of embryonic vascular development in
predictive toxicology. Birth Defects Res C 93, 312-323
Judson R.S., Mortensen H.M., Shah I., Knudsen T.B. and Elloumi F. (2012) Using pathway
modules as targets for assay development in xenobiotic screening. Mol BioSyst 8, 531-542
Wetmore B.A., Wambaugh J.F., Ferguson S.S., Sochaski M.A., Rotroff D.M., Freeman K.,
Clewell H.J. Ill, Dix D.J., Andersen M.E., Houck K.A., Allen B., Judson R.S., Singh R.,
Kavlock R.J., Richard A.M. and Thomas R.S. (2012) Integration of dosimetry, exposure and
high-throughput screening data in chemical toxicity assessment. Toxicol Sci 125: 157-174
CHPAC commented: CHPAC is concerned about translating this research, specifically in 1)
explaining the complexity of this work to scientists, medical professionals, and community
members; and 2) using this work to protect children by developing appropriate interventions based
on this work and measuring the success of such interventions. CHPAC would like to hear ORO
plans for sharing and using the results of the CSS work.
ORD response: The ORD research programs are in the process of developing a communications
strategy to guide how research will be shared with external audiences. The purpose of the
communications strategy will be to increase audiences' awareness, interest and usage of ORD
research. The communications strategy will include goals, objectives, target audiences,
communication strategies and a timeline. As mentioned already, we are developing cross-training
programs with OCHP and different levels of outreach to the public and children's centers. Public
communities of practice were described above. Fact sheets are developed on a continuous basis, and
ORD would be pleased to provide copies of relevant fact sheets as they are generated.
• Sustainable and Healthy Communities Research Program (SHC)
CHPAC commented: An ORD spokesperson discussed how the Sustainable and Healthy
Communities Research Program (SHC) integrates multiple programs throughout ORD to work
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toward sustainable and healthy communities. This new strategy comprises aspects of the human
health research program, land program (Superfund), and the ecosystems services program. Major
SHC themes that relate to children's health research are related to tools and data collection, partner
needs, and communities (such as children's settings and built environment factors). ORD described
the SHC Children's Health Project, which has three tasks: 1) children's exposure factors (including
a study of determinants of exposure to chemicals in the environment for early life stages); 2) health
effects from early life exposures (and the latent or chronic effects resulting from early life
exposures); and 3) systems approach to community-based children's health.
Members at the July meeting and subsequent discussions raised the following points related to this
research strategy:
1. CHPAC members suggest that the social determinants of health model is a useful way to address
multiple critical factors (such as economic disparities and environmental justice).
2. CHPAC did not hear a strong theme of addressing or acknowledging issues surrounding
environmental justice.
3. CHPAC expressed concern that EPA may not have sufficient staff with the appropriate training
and expertise (such as social scientists) for working with communities and their needs.
ORD Response, items 1-3:
SHC is conducting research about social determinants of health in two projects which were not
covered in depth at the CHPAC meeting last July. In the SHC StRAP a topic area called "Improving
Human Health and Well-being for Community Sustainability" includes projects on "Securing and
Sustaining Environmental Justice (EJ)," and "Enhancing Community Public Health," along with the
project on "Enhancing Children's Health."
The EJ project consists of a series of tasks designed to address the goals of the EPA's Plan EJ 2014
(http://www.epa.gov/compliance/ei/resources/policv/plan-ei-2014/Dlan-ei-201 l-09.pdf). Scientists
from SHC and OEJ will be describing this research in more detail at the upcoming CHPAC meeting
this spring. Briefly, this project includes:
o Research on the fundamental determinants of environmental inequity (conducted by grantees
in Centers of Excellence in Environmental and Health Disparities developed in collaboration
with NIMHD);
o STAR research examining how social and economic factors can exacerbate the impacts of
environmental chemical exposures and methods for evaluating this complexity using multi-
factorial approaches;
o Development and application of tools communities can use to evaluate their specific
problems, identify inequities and their causes, and weigh the costs and benefits of proposed
solutions;
o Development of guidance for the EPA to use in order to better evaluate the impact of its
policies and actions with respect to potential environmental inequities;
o Capacity building activities and training for ORD staff in the area of EJ and for communities
in how to work with governmental and other groups toward common goals.
The Public Health project also considers social determinates in its plans to:
o Identify and characterize key public health conditions and their causes relative to the
environment (e.g. asthma);
o Develop and verify public health indicators that can be used to track the benefits and
effectiveness of risk management actions (working with CDC);
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o Develop and apply (in case studies collaboratively with at risk communities) tools for
community public health assessment and remediation (including Tribal science grants).
Consideration of environmental equity and children's unique vulnerabilities is inherent in all this
research, and in other ORD programs. The EPA is working to leverage our existing resources in the
social sciences. Current and new STAR grants in the EJ and Community Public Health tasks will
add much needed social science expertise in the near term as ORD takes steps to increase its in-
house capacity. ORD's Science Advisory Board has made this recommendation as well.
4. Members encouraged EPA to partner with groups that focus on learning environments across
the childhood and adolescence trajectory, including child care and schools, and suggested that
EPA determine the types of community capacity building that are successful and build on that
knowledgebase.
ORD response: New research is being solicited in FY12 as STAR grants and as a new "formative"
center in the Children's Center Program to address child care environments and school
environments/school buildings. This is a proposed topic for future CHPAC discussions. Input on
writing teams for these RFAs was provided by OCHP, Office of Air and Radiation, and the Regional
children's health coordinators to help respondents understand how research can help inform Agency
policies and guidance in these settings across the childhood and adolescence trajectory.
5. It was not clear to members that EPA consistently includes preconception and prenatal life
stages in strategies aimed at children's health.
ORD response; The EPA has long considered preconception and prenatal exposures essential
considerations for risk assessment as articulated in its Guidelines for Reproductive Risk Assessment
Guidelines, 1996 (www.epa.gov/raf/publications/pdfs/REPRQ51 .PDF ), Guidelines for
Developmental Toxicity Risk Assessment, 1991
(http://www.epa.gov/raf7publications/pdfs/DEVTOX.PDF ) and Cancer Guidelines and
supplemental guidance (http://www.epa. gov/ cancer guidelines/ and
http://www.epa.gov/cancerguidelines/guidelines-carcinogen-supplement.htm'). These guidelines are
integral to considerations in human health assessments in the HHRA program including IRIS,
provisional peer reviewed toxicity values (PPRTVs), and integrated science assessments (ISAs).
ORD recognizes the growing concern that chemical exposures, nutrition and other factors may
operate through epigenetic mechanisms to alter the programming of gamete and embryo
development with potential new implications for children's health. Prenatal development is an area
of major focus in CSS's Virtual Embryo project described earlier. SHC's Children's Health project
includes a task developing and using animal models to evaluate the impact of early exposures on
later health impacts. In addition, many STAR grantees in the Children's Centers Program are
evaluating levels of priority chemicals in pregnant women and potential health impacts and body
burdens in children born to these women. ORD's commitment to the Children's Centers Program
over the last 14 years has fostered ground-breaking research using this longitudinal approach in
defined cohorts. Information gained from these studies as well as lessons learned with respect to
study design and exposure metrics will not only be valuable to the EPA but also to the National
Children's Study (NCS) funded by NIH (www.nationalchildrensstudv.gov). A STAR grantee
meeting in March 2012 will report results of research focused on early indicators of childhood
disease; this workshop is being held on the NIH campus so that staff from the NCS can attend.
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Consideration of maternal health and nutrition in all these studies provides insights into the
importance of preconception health.
6. Members commented that it is important for EPA to sustain capacity building programs and that
EPA should identify resources to sustain community efforts to improve environmental health.
ORD response: Resources are being prioritized to insure that progress can be made in capacity
building for EJ and for participatory research with communities. Pilot studies are being conducted to
develop and evaluate the usefulness of tools for improving environmental health in community and
tribal settings and in collaboration with community members as well as State, Tribal and local
decision-makers. We expect to report significant progress on these objectives over the next five
years.
7. CHPAC members noted that it is important to ensure that the community groups asked to
participate in research programs and projects are actually part of the community, and suggested
that existing community organizations provide excellent communication linkages to the
community.
ORD response: This is a central premise of community-based, participatory research, and a key
element of ORD's "path forward" operating principles.
8. Members also suggest that Children's Environmental Health Centers integrate community
participatory research methodology into all research and involve more representatives from the
residents of the community they serve in their decision-making around research.
ORD Response: Previous and current Requests for Applications (RFAs) for the Children's Center
Program, developed with NIEHS, specify that all full Centers must have an outreach and/or
community participatory research "core." The currently funded Centers are partnering with a variety
of groups such as medical providers, educators, and community organizations/parent groups. More
information can be found at http://www.epa.gov/ncer/childrenscenters/ and will be provided in the
new monthly Children's Centers webinar series mentioned earlier.
9. Members expressed some reservations about the concept of empowering communities to conduct
risk assessments, as experience has shown that communities do not have the resources or
expertise to conduct risk assessments, but expect state and federal agencies to provide guidelines
and regulations that will ensure the public's safety.
ORD Response: We did not intend to imply that communities conduct risk assessments in the
regulatory sense. State and local governments have decision making authority with respect to
enforcing federal regulations, setting policies for land use and zoning, and taking local public
actions. The emphasis of the SHC program is to provide improved tools for these local decision
makers and provide greater transparency for communities to participate in and contribute their input
to the decision making process. SHC is developing tools that will help communities access and
synthesize information and data on a wide variety of environmental stressors and use that
information to better define their environmental and health problems and options while evaluating
the advantages and potential adverse consequences of various decisions (or "alternative futures").
We are working on tools and interactive spatial displays that could be accessed by the public (web-
based and user-friendly) and that provide "one stop shopping" for exposure data of various sorts,
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ecosystems services data, policies, and other resources. ORD will work with community
partners/decision-makers on how to use these tools and continually modify them as needed. The goal
is to help community decision-makers make decisions that promote sustainability and health while
avoiding unanticipated consequences.
10. CHPAC commented: CHPAC is interested in how social determinants of health can be
explicitly, and in a measured way, incorporated into a systems approach to community-based
children's health. CHPAC is interested in the EPA'splans to transfer or translate the science to
community action. A concern was expressed about the extent to which community and school
based interventions have been proven effective (i.e., are proposed interventions grounded in
science?). Measures of success are needed in order to determine whether SHC work results in
healthier and safer communities. CHPAC would like to hear ORD plans for measuring the
progress of the SHC work.
ORD response: A major goal of SHC is to identify, develop and improve ways to measure and
weigh the social determinants of health, including children's health at all developmental stages. In
addition to in-house and STAR efforts mentioned above, we expect research funded by new RFAs
on childcare and school environments to help address this question. "How do we show that various
interventions improve children's health, development and performance?"
• Human Health Risk Assessment Program (HHRA)
CHPAC commented: Human Health Risk Assessment (HHRA) topics described in the ORD power
point presentation included themes of dose response assessments (the Integrated Risk Information
System); Integrated Science Assessments for criteria air pollutants; community and technical
support for exposure and health assessments; and methods, models, and approaches to modernize
risk assessment for the 21st Century.
ORD response: We would like to expand the conversation with CHPAC on HHRA at an upcoming
CHPAC meeting where we can clarify the many objectives and activities in HHRA that support
modernization of risk assessment.
Suggested topics could include: How will HHRA respond to the recommendations of the "next
generation" risk assessment, as conceived in the NAS "Silver Book" Science and Decisions,
Advancing Risk Assessment (2009), and Phthalates and Cumulative Risk Assessment Task Ahead
(2008)?
Members raised the following questions and points related to ORDs research programs:
1. What are the major research goals, timelines, and outcome measures? What childhood illnesses
and developmental problems are being targeted and how are those associated with
environmental exposures? What exposures are targeted and what is known about how those
affect children's health? How will EPA measure its success or failure? Has past research been
successful in reducing illness rates? How do current asthma rates compare with rates 10 and 20
years ago? Blood lead levels are lower, but attention deficit disorders and other learning
problems seem to be more common and college entrance test scores are lower. Can the new
research program explain these contradictory trends?
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ORD response: ORD will address these questions broadly since they apply across ORD programs.
The StRAPs for all our programs and the children's health roadmap will help clarify goals, timelines
and outcome measures. Timelines are specific to various projects within the ORD StRAPs, need to
be flexible and can change as a result of changing resources. Ongoing engagement with CHPAC will
enable ORD to address these questions as research questions are answered and new priorities arise.
Answers to questions about changing trends in such childhood conditions and disease burdens such
as asthma prevalence and neurodevelopmental disorders will require combined efforts of HHS as
well as the EPA and other public health partners as these are complex societal and health issues.
SHC and ACE are actively exploring opportunities for collaborative projects with CDC that would
help integrate public health tracking and biomonitoring data into community-based exposure models,
tools and public health intervention approaches. We expect that SHC research on public health
indicators will contribute to these efforts and also be useful in the conduct of Health Impact
Assessments. ORD is an active partner with CDC and other Agencies in a workgroup that recently
developed a National Action Plan for Reducing Racial and Ethnic Asthma Disparities (part of the
Federal Task force on Children's Health Protection and Safety), and is conducting research in support
of that action plan, particularly on intervention strategies and asthma causation. This action plan
should be publically accessible in the near future. Research related to asthma, lead, and neuro-
developmental deficits, being implemented in SHC and ACE, includes both in-house and STAR
research in several of the Children's Centers in SHC and Clean Air Centers in ACE. In turn, the
HHRA uses data and information derived from ORD and other research to assist the Agency in
evaluating risks associated with certain exposures, and thereby supports the regulatory and
enforcement roles of the Agency.
2. Environmental health research is most likely to produce a useful outcome when it targets a
specific problem. CHPAC would prefer that EPA focus on improving children's health by
identifying and reducing exposure to harmful substances instead of studying the effects of
unabated exposures that are known or suspected to be hazardous.
ORD Response: CSS research helps the Agency identify evaluate and predict the risks of potentially
harmful exposures to chemicals and other materials. HHRA helps the Agency understand, evaluate
and remediate risks of such exposures. Research in HHRA will contribute to improved risk
assessment approaches and guidance for Agency use. Beyond this attempt to clarify the scope of
HHRA research distinct from the EPA's overall mission, ORD is happy to engage in dialog with
CHPAC to better understand this concern.
3. CHPAC members have asked if additional children's exposure factors and risk information
should be developed. There is concern among CHPAC that allergens and asthma triggers have
not been assessed as rigorously as the approach used for chemicals. The Integrated Risk
Information System is used for chemicals, not biologicals or pathogens, and work should be
conducted to characterize risks from cockroach antigens, molds, harmful algae, and complex
mixtures.
ORD Response: In contrast to specific chemicals of concern, cockroach antigens and molds (and
harmful algae) arc complex in composition and often undefined. Some research has identified
components of these antigenic materials that may be the proximate toxicant/stressor and could be
approached in a fashion similar to that for chemical risk assessment. However, these naturally
occurring substances are not regulated at present. Rather, guidance developed by EPA Programs for
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identifying and removing harmful mold, and for understanding and avoiding asthma triggers is
provided to the public on the EPA's website.
The association between cockroach antigens and certain molds and allergies is well-known.
Children's Center research has previously demonstrated the health (and economic) benefits of
applying "Integrated Pest Management" which includes improved cleaning methods to remove such
allergens, as has been used by public housing authorities to protect children's health. Within current
budgetary limitations, in-house research is evaluating better methods for identifying specific molds
and the extent to which they may cause or exacerbate asthma.
ORD is also interested in the long term impacts of climate and climate change on the types and
distribution of aeroallergens including potential for improving public health alerts. STAR grantees
funded under ACE are actively investigating the implications of climate change and aeroallergens.
Additionally, the National Center for Environmental Assessment provides a recent report on this
issue: http://www.epa.gov/ord/gems/scinews aeroallergens.htm.
4. The EPA-funded Near Roadways Exposure to Urban Air Pollutants Study (NEXUS), a project of
the University of Michigan, demonstrates that near roadway air pollution is a very important
metric for exposures to urban pollutants. The relationship between the stage ofpregnancy and
level of exposure to pollutants is an important aspect of such research.
ORD Response: Research in several of the Children's Centers is also exploring prenatal air
pollution impacts. In addition, the University of Michigan research, which is ongoing in ACE,
includes evaluation of a cohort of asthmatic children to better characterize potential near-roadway
impacts on existing disease. Further, ORD's NEXUS program in ACE also includes new near-road
research in North Carolina.
5. Questions were raised, as with other research areas, about measuring the result of HHRA
utilizing a new research strategy. It was noted that approaches to human health risk assessment
will continue to be used (that is, be sustainable) only if found useful. The question was asked how
EPA will know that the result of the new strategy is improvements in children's health.
ORD response: As mentioned at the start, ORD welcomes the opportunity to discuss in more detail
the metrics we are planning to develop and use as part of the "NextGen" risk assessment efforts in
HHRA and with the EPA's Risk Assessment Forum.
• Safe and Sustainable Water Resources (SSWR)
CHPAC commented; In addition to the three research strategies described above, CHPAC
members discussed issues related to Safe and Sustainable Water Resources. Current requirements
for tests done on drinking water and air are limited to a relatively small number of chemicals. When
an unregulated contaminant is found in a drinking water supply at a level that exceeds the EPA's
one-day child health advisory, no action is required to be taken under the Safe Drinking Water Act.
A question was raised about whether the Safe and Sustainable Water Resources Research Program
will study children's exposure to unregulated contaminants ofpublic drinking water, and if so,
members asked what contaminants will be assessed, how many children are exposed, and what is the
potential for an adverse health effect?
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ORD response: There are no specific tasks in SSWR that uniquely address issues of children's
exposure or potential health consequences to unregulated contaminants in public drinking water.
However, SSWR has established linkages with CSS where adverse effects of unregulated drinking
water contaminants are being addressed. Two hundred and seventeen compounds on the EPA Office
of Water's Chemical Contaminant Lists (CCL1, CCL2, CCL3 and PCCL,
http ://www. water.epa. gov/scitech/drinkingwater/dws/ecl/) are being evaluated as part of the
ToxCast Phase II chemical library. The complete information on the identity of compounds included
in this library is available at
http ://www.epa, gov/ncct/toxcast/files/T oxCast%20Chemical%20Summary%2014Dec2010.pdf
Information on specific assays being used to evaluate the effects of these compounds and the
specific assay results is and will be available at: http://www.epa.gov/ncct/toxcast/.
Research to translate specific cellular and molecular effects in the in vitro ToxCast assays designed
to enhance our understanding the potential impacts of exposure to children will also be addressed in
specific research tasks in CSS such as CSS "Systems Models" tasks for data collection and
computational modeling for the Virtual Embryo (CSS 2.2.2), which is focused on the predictive
toxicology of children's health and development following prenatal or lactational exposure to
environmental chemicals.
• Research partners
CHPAC commented: In addition to discussing the individual strategies, CHPAC members
expressed interest in the theme of overlapping research communities. Members encouraged EPA
to partner with other agencies on research.
I. CHPAC members wondered if the CSS research will be limited to currently regulated chemicals
and products. An emerging issue of interest to some members is the growing use of nanosilver
and other nanomaterials. CHPAC is interested in knowing how EPA will work with other
agencies to ensure the safety of these materials. Another group of chemicals of interest are
pesticide residues in foods, water, and the indoor environment, which also may require
collaboration with offices outside of ORD.
ORD response: CSS Systems Models has a major project focusing on the toxicology of
nanomaterials, and a number of nanomaterials are being tested across -600 assays in ToxCast Phase
II. Working with an interagency consortium of 25 agencies, ORD has helped develop the
Interagency National Nanotechnology Initiative's Strategic Plan (2011). In turn, the CSS
"Nanomaterial-Specific Inherency Issues" project, developed in partnership with OCSPP, is
responsive to the needs articulated in this national plan. This close partnership will insure that
appropriate research priority is placed on individual chemicals and groups of chemicals of highest
importance to the Agency with respect to exposure (including through food) and effects data needs
(such as dose response data for limit-setting) to ensure that ORD contributes scientific expertise and
data to the timely assessment of risks for regulatory and enforcement actions and reviews of
registrations. Also, as part of the Federal Taskforce for Children's Health Protection, ORD is
working with OCHP, OCSPP, NIEHS, CPSC and other Agencies to identify chemicals in products
that children are most likely to come into contact with in order to develop strategies for avoiding
exposures and risks.
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2. It was noted that more research is needed on endocrine disruption, childhood obesity, Type I and
Type II diabetes, and developmental disorders including attention deficit and hyperactivity
disorders, EPA and Centers for Disease Control and Prevention (CDC) could partner to identify
the most prevalent childhood illnesses/disorders that seem to have an environmental component
and work together to study causes and design interventions. CDC's Environmental Health
Tracking Program and the National Institutes of Health (NIH)/EPA funded Children's Health
Study have shared goals of reducing childhood illness and infant mortality and could work
closely together.
ORD response: ORD is working on these important outcomes and towards these necessary ends
with CDC, NIEHS and other Agencies. CSS and SHC ("Enhancing Children's Health" project)
retain a major emphasis on endocrine disruptors, including their potential long term impacts over the
various stages of development and for adult human health. Both CSS and SHC offer expertise to
NCS through research and participation on the NCS Interagency Coordinating Committee.
3. CHPAC encourages ORD to compare research priorities among federal agencies (NIH, CDC,
Department ofDefense, and Department of Education) and identify potential overlapping
research and areas for collaboration,
ORD response: ORD is working with many Federal partners (as well as State and local
governments and Tribes) with the common goal of protecting and promoting children's health and
development. Goals of the Federal Taskforce for Children's Health Protection (on which the EPA is
participating) include elimination of overlap and promotion of synergy by combining expertise
across agencies for the benefit of children's health. Partners include the U.S. Department of
Education, U.S. Department of Housing and Urban Development, the Centers for Disease Control
and Prevention (CDC), and other arms of the U.S. Department Health and Human Services including
the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National
Heart Lung and Blood Institute and NIMIID. ORD is represented on the subcommittee which has
proposed a National Action Plan for Reducing Racial and Ethnic Asthma Disparities which is due to
be released in 2012, and on the subcommittee proposing strategies for evaluating products and
chemicals with which children are most likely to come into contact. Peter Grevatt is the lead for the
EPA on this Federal Taskforce and can provide updates for CHPAC as its agenda progresses. As
mentioned earlier, SHC plans to support a 2012 RFA to solicit research on how school buildings and
practices can be optimized to promote children's health and performance; this RFA was developed
in collaboration with the Department of Education. ORD and OCHP are active members of the
Interagency Coordinating Committee for NCS and meet regularly with members from CDC, NIEHS
and NICHD to help insure that NCS meets the needs of all partner Agencies and is positioned to
achieve its overarching goal of understanding environmental impacts (defined broadly) on children's
health and development. SHC is working with HUD and the EPA's Office of Sustainable
Communities (in additional to national sustainability organizations and community development
groups) to develop and apply tools for smart and sustainable community development that promotes
health and protects ecosystem services in economically viable and socially equitable ways. CSS is a
partner and collaborator in the broader Tox21 partnership between the EPA, NIH Chemical
Genomics Center, NIEHS/National Toxicology Program and the U.S. Food and Drag
Administration.
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