EPA 600/R-10/064 | June 2010 | www.epa.gov/ord
    United States
    Environmental Protection
 Workshop on Optimizing Exposure Metrics
        for the National Children's Study
Sum maty of Workgroup Discussions and Recommendations
     ce of Research and Development
    National Exposure Research Laboratory


             EPA/600/R-10/064 June 2010 www.epa.gov/ord
Workshop on Optimizing Exposure Metrics for the
               National Children's Study
 Summary of Workgroup Discussions and Recommendations
           Nicolle S. Tulve, Linda S. Sheldon, and Roy C. Fortmann
                 National Exposure Research Laboratory
                  Office of Research and Development
                 U.S. Environmental Protection Agency
                  Research Triangle Park, NC 27711


The information in this document has been funded in part by the U.S. Environmental Protection Agency. It has been
subjected to the Agency's peer and administrative review and has been approved for publication as an EPA
document. Mention of trade names or commercial products does not constitute endorsement or recommendation
for use.


The workshop organizers thank the workgroup and workshop participants for their time and intellectual
contributions to this workshop. We also thank the NERL staff who provided administrative and logistical support
both before and during the workshop.


   Workshop  on Optimizing  Exposure  Metrics for the

                         National Children's Study
     Summary of Workgroup Discussions and Recommendations

                                     Organizational Sponsors
          U.S. Environmental Protection Agency, Office of Research and Development (ORD),
   National Institute of Environmental Health Sciences (NIEHS), and National Children's Study (NCS)

                         Co-Chairs: Nicolle Tulve and Linda Sheldon (ORD)
           Steering Committee: Sally Darney, Roy Fortmann, James Quackenboss (ORD);
                         Allen Dearry (NIEHS); and Michael Dellarco (NCS)

The National Children's Study (NCS) will examine the
relationships between environmental exposures and the
health and development of 100,000 children living in the
United States. The children will be followed from before
birth until age 21. This is a very large, complex, and
ambitious undertaking. Scientifically robust exposure
metrics that are both low cost and low burden are
needed to link environmental exposures to health
outcomes within this study. This workshop engaged
scientists from the exposure, epidemiology, and health
effects disciplines with the goal of identifying the most
promising and practical exposure metrics to use in a
study the size and scope of the NCS. Additionally, the
group discussed knowledge gaps and potential
exposure research that would fill these gaps and could
be used to develop and evaluate the most efficient and
effective metrics. The workshop results are intended to
provide operational input to NCS in the near term and to
stimulate research in the U.S. Environmental Protection
Agency's (EPA's) Office of Research and  Development
(ORD), the National Institute of Environmental Health
Sciences (NIEHS), and the exposure science
community to advance the national children's research

Prior to the workshop, three areas with clear chemical
exposure to health outcome linkages were selected for
discussion at the workshop: (1) air pollution and
asthma, (2) endocrine disrupting chemicals and
reproductive end points, and (3) insecticides and
cognitive development. Three interdisciplinary expert
workgroups, each consisting of a toxicologist, an
epidemiologist, and two exposure scientists, were
formed to address each of the three areas. The
workgroups were charged with identifying appropriate
target chemicals, time windows of susceptibility, and
exposure metrics. The problem statement and charge
given to the workgroups is attached,  along with the
workgroup memberships and their qualifications
(Attachments A and B). The workgroups were
challenged to review the current state of the science
and to recommend a suite of exposure metrics that they
considered most important for understanding the
relationships between environmental exposures and the
three health outcomes. Each workgroup met by
conference call before the workshop to develop
preliminary reports.

The workshop, held in Research Triangle Park, NC, on
April 12 and  13, 2010, included the workgroup
participants and invited scientists in the health  and
exposure fields from EPA, NIEHS, the NIEHS/EPA
Children's Centers, the NCS Program Office, and the
NCS Vanguard Centers (see Attachment C, Workshop
Attendee List). The workgroups presented overviews of
their discussions along with their recommendations
(Attachment D) to the larger workshop audience.
Workshop participants then discussed the workgroup
proposals and recommendations with regard to
scientific soundness, other schemes and options,
feasibility, costs, participant burden, etc. Following all
three workgroup presentations, opportunities for
leveraging exposure research to evaluate proposed
exposure metrics were discussed.

Concepts for Exposure Metrics

This section  provides a common definition for exposure
metric as it is used throughout this report. For
epidemiological studies, the exposure metric is a
summary variable used for exposure-response analysis.
Exposure metrics can be as simple as a single
measurement or they can combine or model information
from several measurements or other types of data.  In
many cases, the exposure metrics discussed in this
report will combine data from several sources rather
than relying on a single measurement. Selection of the
correct metric for a specific exposure/disease process

is crucial because misspecification of the metric can
introduce error into the analysis and bias the outcome
toward the null. The degree to which any exposure
metric is correlated with the "true exposure" will
determine how well it performs in conjunction with
analyses of health end points. Fundamentally, the "true
exposure" metric must capture the characteristics of
exposure that are associated with the damaging or toxic
effect being studied. However, identifying such a metric
is often difficult, especially with complex diseases that
have both genetic and environmental components.

Biologically relevant (BR) exposure recently was
defined  by Birnbaum (Environmental Health
Perspectives, 118(4), April 2010) as a metric that can
be directly associated with key events in a disease
process and an individual's exposure profile. During a
brief discussion at the workshop, it was proposed that
BR exposure during  the time window of susceptibility
could  be considered the "true exposure" metric. An
example using urinary biomarkers is used to clarify
these concepts. A biomarker in urine can serve  as an
exposure metric if it is correctly related to an exposure
to the exogenous chemical. It is a BR exposure metric if
that concentration also can be related to the
concentration of the  biologically active species that is
available to react with the target disease pathway. It is
the true exposure metric if it can be related to the
concentration that is available for reaction during the
entire period that the child would be most susceptible to
the health outcome. Although only limited discussion
occurred during the workshop around this concept,
identification of a true metric is fundamentally important
because it will provide the basis for evaluating proposed
metrics, for identifying science gaps associated with
proposed metrics, and for identifying the research
needed to fill the  most critical gaps.

Common Themes Throughout the Workshop

Although all three workgroups met independently
beforehand, they raised several common themes,
issues, and recommendations at the workshop.
A summary of these  themes is discussed first because
of their cross-cutting nature. Table 1 highlights the
common themes.

Time  Periods for Susceptibility and Exposure
Monitoring. All workgroups agreed that in utero and
through early childhood (up to ages 3 to 5 years) were
the time periods when children were most susceptible
and when exposure monitoring should be conducted. At
a minimum, all groups preferred to conduct monitoring
during three visits, one each during the  first trimester,
the third trimester, and the first year. There was
discussion but no general agreement about  when to
collect environmental samples and biological specimens
during pregnancy if only one visit could be conducted. It
is important to recognize that exposure variability over
time will depend, in part, on the persistence of a
chemical and the nature of the source. Thus, exposure
monitoring approaches should take into account the
nature of the sources, as well as the window of
susceptibility. Regardless of the time period selected, all
groups agreed on the need to demonstrate whether a
given sample taken at one time in pregnancy could be
used to estimate exposure at other times or windows of
susceptibility. In addition, all of the groups agreed that,
given the outcomes selected, fine time resolution
(<1  day) for exposure estimates was not important.
Again, the greater concern was whether a sample taken
during a short time period could adequately represent
exposure during the entire window of susceptibility,
which may be months or even years long. Although the
final recommendation was for two or three monitoring
visits from conception through the first year, there was
general agreement that
• urine samples were relatively low burden and should
  be collected more frequently, if possible;
• a blood sample should be collected from the mother
  while pregnant and from children once they are old
  enough to tolerate a blood draw; and
• additional monitoring should be conducted at the new
  residence if the participant moves.

Sample Matrices. All workgroups agreed that a
preference should be given to samples that could be
collected and archived for later analysis. There was also
consensus that it would be most cost effective to
analyze selected stored samples using a case/cohort
approach after the health outcomes have been
identified. Archived samples also can serve as a
resource to evaluate exposures to chemicals (and other
agents) that emerge as a concern in the future. Sample
matrices that require immediate analysis were given a
lower preference based on both logistical and cost
considerations. However, there was consensus that
research is needed to understand stability of archived

Biological Samples—For many chemicals, blood
(whole blood, serum, or plasma) would be the preferred
matrix. Collecting blood from the mother during
pregnancy and at birth already is planned. It was
recognized that there would only be very small volumes
of blood from the infant that would be in very  high
demand. It was considered unlikely that sufficient blood
would be available for conducting multiple exposure
measures. Recent advances in analyzing blood spot
samples from children should be further pursued.
Although urine is an alternative for some chemicals or
their metabolites, there are currently problems with
collecting urine from very young children. For many
chemicals, recovery of metabolites from commercial

Table 1. NCS Exposure Metrics Workshop—Summary Recommendations for Data Collection in Home Visits
Data Collection During Home Visits
Mother — Prenatal | Child
Visit 1
First Trimester
House Dust
Ambient Air Pollutants— Use
available ambient monitoring
data or modeled estimates
Indoor Air Pollutants— Subset
of homes
Air— Source proximity
Pesticides— Use, gated
pesticide questions,
dietary intake;
EDC— Product use and
CIS (ambient sources,
Visit 2
Third Trimester
House Dust
Ambient Air Pollutants— Use
available ambient monitoring
data or modeled estimates
Indoor Air Pollutants— Subset
of homes
Air— Source proximity
Pesticides— Use, gated
pesticide questions,
dietary intake;
EDC— Product use and
CIS (ambient sources,
Visit 3
First Year after Birth
Blood Sample as Early in Life
as Possible
House Dust
Ambient Air Pollutants —Use
available ambient monitoring
data or modeled estimates
Indoor Air Pollutants— Subset
of homes
Air— Source proximity
Pesticides— Use, gated
pesticide questions,
dietary intake;
EDC— Product use and
CIS (ambient sources,
Breast Milk (if available)
Annual Visits
Up to Age 5 Years and at
Blood, If Available
House Dust
Ambient Air Pollutants— Use
available ambient monitoring
data or modeled estimates
Indoor Air Pollutants— Subset
of homes
Air— Source proximity
Pesticides— Use, gated
pesticide questions,
dietary intake;
EDC— Product use and
CIS (ambient sources,

Archive for Analyses
Serum IgE, Persistent
Nonpersistent EDCs,
Insecticide Metabolites
Allergens, Endotoxins,
EDCs, Insecticides
PM2.5, NO2
PM2.5, NO2

EDCs, Insecticides

diapers may be poor. The diaper material contains
co-extracted material that interferes with the analysis of
some metabolites. Additionally, there are difficulties with
contamination with feces in the diaper sample. On the
other hand, urine bags are often difficult to use with very
young children. Research will be required to improve
methods for collecting and analyzing urine samples and
for minimizing exposure misclassification because of
variability or the presence of metabolites in
environmental  media.

Environmental Samples—All workgroups selected
house dust as the highest priority environmental matrix
and agreed that as much dust as possible should  be
collected. Dust provides an integrated sample overtime
and can be archived for later analysis. It was
recognized that there are many different types of dust
samples (e.g.,  vacuum, settled, surface and hand
wipes) and methods for collecting these samples. It is a
research priority to evaluate the current methods and
then select and optimize a method for collecting,
processing, and archiving dust samples for future
analysis. Understanding the relationship between  dust
concentrations and exposure is another high-priority
research need. Indoor surface wipe samples are not
recommended  because of the high variability of
concentrations within homes.

Utility of Questionnaires.  Except in a few cases,
current questionnaires, diaries, and inventories have
not been effective for predicting exposures. Many
questions asked historically have proven to have little
value—they have no variance, an "expected" answer, or
no correlation with an outcome. For specific sources,
selected questions may be  useful for classifying
exposure and for covering longer time periods than
represented by direct measurements. All workgroups
recommended  that questionnaires be kept very short to
reduce burden, and that research must be conducted to
evaluate the value and validity of each question. An
exposure question should be  asked only if it can be
used as, or directly related to, the development of a
specific exposure metric.

Geographic Information System (GIS) Land Use
Data. The  location of a participant's home, workplace,
ordaycare and the characteristics of the surrounding
environment are very important for understanding
exposure.  Currently,  some of these characteristics are
available through several internet links (e.g., Google
Earth). It was very strongly recommended that a plan
for archiving these data be developed immediately.

Exposure Variability. Exposure  metrics must be
capable of estimating exposure during the time periods
of susceptibility. Thus, samples collected over a short
time period must represent exposure over a much
longer period. For most chemicals,  very little is known
about the variability (either within day or between days)
of exposure or the exposure metric over the time period
of concern. It is a priority to evaluate this variability
either using existing data or collecting new data, if

Discussion by Workgroup

Asthma Workgroup Recommendations. Asthma is a
complex disease with known environmental  etiologies
and very high public health impacts. The workgroup
considered that the greatest uncertainties were
associated with understanding the onset of asthma, and
that this should be the highest priority for the NCS.
Progression  of asthma (atopy and gender differences)
also was considered important. Although, it is difficult to
diagnose asthma before age 4, the critical window for
exposures related to asthma onset is from in utero to
3 years of age. The time window for asthma
progression is 3 years and beyond.

The workgroup considered that the overall goal was to
minimize exposure misclassification for the NCS
participants.  Personal exposure measurements were
considered not to be feasible in such a large study.
Even with  personal measurements, methods would be
required to extrapolate the short-time measurement
(1 day to 1 week) to the window of susceptibility
(several months or years). Residential exposure metrics
that represented both the indoor component and the
ambient components of exposure were  considered the
most feasible. However, it also was considered
important to gather information about where participants
spent significant amounts  of time, such  as at work for
pregnant mothers  and at daycare centers or school for
children, allowing researchers to relate this information
to the GIS data.

Exposure metrics for testing the asthma hypotheses
could  be both source-based (traffic, second-hand
smoke, indoor sources, and indoor swimming pools)
and pollutant-based (traffic component,  particulate
matter [PM] components, PM size fractions, nitrogen
dioxide [NO2], phthalates,  allergens, mold, and
endotoxins). Exposures for source-based pollutants can
be estimated primarily using proximity metrics based on
questionnaires, GIS, and geo-databases.  Pollutant-
based exposure metrics would include a combination of
measurements and models that evaluated exposures
for both ambient and indoor pollutants.

Exposure to  ambient pollutants (PM, ozone, and pollen)
can be estimated using ambient monitoring data where
available. Simple or more  complex modeling
approaches also can be used to estimate exposure or
refine the metrics based on ambient measures alone.
Where ambient data are not available, the workgroup
recommended that modeling be used, rather than

attempting to collect additional ambient measurements.
The workgroup recommended that modeling
approaches that could be used at all of the NCS
communities need to be developed and evaluated.

Exposure metrics for indoor pollutants will require
measurements at the  participant's home. The highest
priority is to collect house dust and indoor PM2 5
samples. House dust  provides an integrated
measurement for multiple pollutants of both indoor and
outdoor origin, including allergens and endotoxins.
House dust also can be used to identify exposures to
specific sources using pattern recognition techniques.
A medium  priority was given to NO2, which can be
monitored  using simple, low-cost methods. A low priority
was given  to measuring volatile organic chemicals
(VOCs) and carbonyls (i.e., formaldehyde, acrolein)
because of the cost of sample analysis, the requirement
to analyze samples immediately, and  variability of the
measurements in a single residence.

A number of published and  planned studies are
available that can be used to develop and evaluate the
exposure metrics. It is strongly recommended that
follow-up efforts finalize exposure modeling approaches
and evaluate them relative to these databases.

Hormonally Active Agents Workgroup
Recommendations. Workgroup recommendations
focused on health end points associated with
reproductive effects. They also included other health
effects, such as impaired neurological development,
which is related to thyroid disruption during pregnancy.
The critical windows of exposure for these end points
may be 8 to 10 weeks gestation for reproductive effects,
<20 weeks gestation for thyroid disruption effects, and
the third trimester for neurological effects. The work
group also felt that, for hormonally active compounds
and hormonal end points, additional monitoring should
be conducted close to the end point of interest. As an
example, prepubertal  monitoring is recommended at
ages 6 to 8 years for girls and 8 years for boys.

The chemicals for consideration spanned  a very large
set. To prioritize the list, the workgroup considered their
importance from a health perspective, along  with the
likelihood of exposure. The  final list also included
contaminants that act as confounders for neurotoxicity
(pesticides, organotins, lead,  mercury, and tobacco
smoke), as well as endocrine disrupters.  For each
group of chemicals, information was provided on
inclusion rationale, exposure  characteristics, and
exposure metric options. Exposure to most of these
chemicals  is through indoor sources or consumer
products that may not be well known to consumers
(which limits the validity of questions for these
chemicals). Thus, the workgroup recommended that not
only should the NCS consider the chemicals that are
currently in use and recent replacements, but that future
chemical replacements for specific uses be tracked for
potential inclusion into the study at a later date.

Chemicals can be placed into several categories based
on their physical and chemical properties and potential
exposure pathways.
• Persistent and bioaccumulative chemicals, including
  polybrominated diphenyl ethers (PBDEs),
  perfluorinated chemicals (PFCs), and polychlorinated
  biphenyls (PCBs). Once absorbed into the body,
  these chemicals have long half-lives and tend to
  accumulate in lipid compartments. Exposure is best
  estimated  by measuring levels of the chemical in
  serum or breast milk samples.  For prenatal exposure,
  the mother's serum levels measured at most anytime
  during pregnancy should represent the developing
  embryo's exposure. Alternatively, breast milk samples
  collected postnatally potentially may be used to
  model prenatal exposure in the child. For postnatal
  exposures during the first year, the workgroup
  recommended a house dust sample (vacuum,
  settled, surface, or hand wipe)  in lieu of infant serum.
  Although a blood sample would be ideal, it will be
  difficult to obtain. Research with PBDEs has
  demonstrated a relatively strong correlation between
  species found in vacuum dust  or hand wipe samples
  and serum samples.
• Chemicals that are metabolized rapidly in the body
  with metabolites that are excreted in the urine.
  - Phthalates, bisphenolA, other phenols, and
    triclosan/triclocarban all are  found in common
    indoor products. With the exception of the other
    phenols, urinary biomarkers  are available for these
    chemicals and are recommended as the exposure
    metric. For the other phenols, a house dust sample
    is recommended. Some limited questionnaire
    information may be useful for this group of
    chemicals but, again, the use of questionnaires
    must be evaluated.
  - Phytoestrogens are found in infant soy formula.
    Questions regarding the use of soy formula are
    recommended. A urinary biomarker is available
    and could be considered, but only for limited use.
  - Perchlorate is found in certain water sources and
    in some foods. The development of an exposure
    metric based on the combination of community
    water sample data and well water sample data is
    recommended. A urinary biomarker is available
    and could be considered, but only for limited use.
  - PAH exposures are primarily from traffic, cooking
    sources, and certain foods. CIS systems and
    questionnaires can be used  to evaluate exposures.
    Alternatively,  PAHs can be measured in house
    dust, but this is expensive and not currently

It was stressed that, if urinary biomarkers are used to
estimate exposure, it is crucial to evaluate variability of
biomarkers overtime to establish that a short-term
biomarker measurement can be used to
estimate/classify exposure over the entire time period of
susceptibility. It also should be considered that these
compounds show hormonal effects at very low levels,
thus analytical methods that can generate high-quality
data at these low levels are needed.

The primary exposure source of most of these
chemicals is consumer product use. However, most
adult participants cannot provide sufficiently accurate
information for classifying exposures based on product
use or activities.  On the other hand, it may be possible
to use questionnaires in developing exposure metrics
for very young children because of the limited number
of products that are used. Measurements were
recommended as the primary metric for most
chemicals. Where questionnaires are used, they need
to be very carefully evaluated, as noted above in the
"Utility of Questionnaires" section.

Diet is an additional source of exposure for the
phytoestrogens,  PFCs, PCBs, and, possibly, PBDEs. As
suggested above, exposure to phytoestrogens through
consumption of infant soy formula can be estimated
using questionnaires. Dietary exposure to the persistent
chemicals will be captured by biomonitoring, which
provides an aggregate exposure estimate for these

Insecticide Workgroup Recommendations. This
workgroup focused on the association between
insecticide exposures and poor neurological outcomes
in children.  Various time windows for neurological
development were considered, such as cell
proliferation, synapse development, myelination, etc.
Based on this information, time windows during the first
trimester of pregnancy and the first year of life were
considered most important for exposure assessment.
The second and  third trimesters of pregnancy and up
until 5 years of age were considered of high importance,
and ages 5 to 10 years were of moderate importance.

The chemicals of interest were the organophosphate,
pyrethroid,  carbamate, and fipronil insecticides, and the
synergist piperonyl butoxide. Most of these are current
or recent use pesticides, whereas others appear to
remain in homes at low levels long after their use has
been discontinued. Future active insecticide ingredients
need to be tracked and incorporated into the study
based on use and likely exposure. In the general
population, the primary sources for pesticide exposure
are food and residential indoor use. For some groups,
other sources may be important, including flea control,
residential outdoor use, occupational use, other building
uses (daycare, school, and workplace), proximity to
agriculture, and public health treatments. Potential
exposure to these latter uses may be informed by gated
questions that may lead to additional questionnaire or
measurement collection. Drinking water and ambient air
are not considered important exposure media for the
general population.

Developing exposure metrics for insecticides presents
several difficult challenges. There are multiple
pesticides, sources, and pathways that typically result in
low and often variable exposures to multiple pesticides.
Measuring pesticides in all important exposure media
can be both high burden and very expensive and is
generally not  considered feasible for large studies. This
is an especially difficult problem where diet is the major
route of exposure because of the extremely high
variability of pesticides in foods and high variability in
dietary exposures overtime. It is not feasible to collect,
store, and analyze the number of duplicate diet samples
that would be needed to evaluate exposure over a time
period of concern. Biomarkers provide an alternative to
environmental samples and provide the ability to
integrate exposure over multiple routes and pathways.
Unfortunately, biomarker interpretation  is often difficult
because of the short half-lives of biomarkers,
intermittent and variable pesticide exposures, and
presence of metabolites in the environments that can
give false positive results. Finally, questionnaire-based
approaches have limited predictive power for classifying
pesticide exposure and generally lack chemical

The workgroup  recommended that biological and
environmental sampling at critical time periods is
essential to estimate/classify exposures and to develop
an index of exposures for epidemiological analyses.
Core sample  collection (to be held for future analysis)
was recommended as follows: urine from key time
points (indicated above) for the mother and young child;
blood and  milk for the mother at key times and blood
from the child as feasible; and the best measure of
residential loading, most likely a house dust,  floor wipe,
or vapor/settled dust measurement. Several
nonmeasurement approaches also should be
considered: questions on outdoor residential pesticide
use, selected dietary questions (e.g., organic diet, fish
consumption) to place dietary exposure into a low or
high group, questions regarding the use of spray
pesticide products by the pregnant mother, gated
questions on  pets and occupations, geographical
information for residence to identify proximity to
agricultural or public health pesticide applications, and
time/activity location to provide information on other
places where the child or mother may spend substantial
amounts of time.

Given the many limitations associated with developing
exposure metrics for insecticides, the workgroup made
several strong recommendations for additional
• Current-use pesticide exposures often have a short-
  time frame, are intermittent, and are not persistent in
  the body, thus new methods are needed that can
  integrate exposures overtime.
• For environmental samples, alternative measures
  need to be evaluated to determine the "best"
  measure of long-term residential concentrations and
  of individual exposure. This could be a house dust,
  a vapor/settled dust sample, or other house loading
  measurement. This also could include protein or
  albumin adducts as biomarkers.
• Carefully evaluate the uncertainties associated with
  using short-term urinary biomarkers to estimate long-
  term exposures.  This includes understanding within-
  day, between-day, and over-season variability. It is
  also important to understand how much of the urinary
  metabolite is caused by exposure to pesticide
  metabolite in the environment rather than the
  pesticide itself. Again, the development of adduct
  biomarkers would overcome some of these problems.
• Understanding dietary exposure to specific pesticides
  and developing approaches to classify exposure in
  very broad classes based on questionnaires or
  diaries (e.g., to identify "high" or "low" consumers of
  foods likely to contain pesticide residues).
• Finally, intensive substudies were proposed to
  evaluate the ability of exposure metrics to estimate
  biologically effective exposure during the time
  window of susceptibility.

Areas for Future Research
Throughout the workshop, a number of knowledge gaps
were identified that could impact the usefulness of the
exposure metrics that were identified. Several areas
were discussed for which research is needed to fill
important gaps and reduce the uncertainty associated
with the use of various metrics. Both near-term and
longer term research needs were identified. The
following  list is presented according to the metrics
proposed by the workgroups. The highest priority
should be given to research  needed to implement the
recommendations of the workgroup related to house
dust methods, urine sample  collection, and air exposure

House Dust
• Development of methods for relating house dust
  loading and/or concentrations to exposure to
  effectively use house dust as an exposure metric in
  the NCS. Existing data should be analyzed from
  relevant studies.
• Evaluation of potential methods for estimating house
  dust loading of pesticides, other organic chemicals,
  allergens, and endotoxins. A single sample needs to
  be collected using a simple, but standardized
  method. Adequate sample needs to be collected to
  facilitate multiple analyses. Alternatives for
  consideration include vacuum dust,  settled dust, and
  passive sampler. Conduct literature  review, data
  analyses, and limited experimental testing. Develop
  protocols for sample collection for multiple analytes.
• Development of a method for the efficient and
  effective sampling, processing, and  storage of dust
• Development of protocols for documenting storage
  stability of dust samples for selected EDCs,
  pesticides, allergens, and endotoxins.

Air Exposure  Metrics
• Development of the protocols  and modeling
  approaches  proposed by the asthma workgroup for
  the exposure metrics for onset and exacerbation of
  asthma. Approaches  (e.g., land use regression
  modeling) should be developed and evaluated in
  ongoing studies.
• Development of a low cost, low burden method for
  collection of indoor PM.

• Development and evaluation of adduct techniques on
  blood spots to characterize infant exposures.
• Evaluation of storage stability  of blood for analyses of

• Evaluation of the relevance and applicability of short-
  term sampling for extrapolation to long-term
  exposures. Data are needed on the  within-day and
  between-day variability of urinary metabolite
  concentrations.  Approaches to estimate exposures
  during the critical windows of susceptibility need to be
  identified or  developed. Protocols for collection of
  urine samples for biomonitoring of nonpersistent
  chemicals need to be developed based on an
  improved understanding of urinary variability.
• Development of new and improved methods for
  collecting infant urine samples (improved diaper or
  bag methods). Multiple analytes need be analyzed in
  urine samples. Methods need  to address potential
  interferences and recovery.
• Development of alternative methods for biological
  sample collection for nonpersistent EDCs and

Nonmeasurement Methods—Questionnaires,
Inventories, GIS, etc.
• Development and evaluation of improved surveys for
  categorizing dietary exposures to pesticides.
• Evaluation of the use of questionnaires to categorize
  or estimate exposures to pesticides and EDCs.
  Analyze data from the EPA/NIEHS Children's Centers
  studies and other studies.
• Develop and evaluate alternative approaches for
  recording product use and inventories (e.g., bar code
  recording methods).
• Develop protocols for collecting and archiving GIS

Metric Evaluation
• Field studies or substudies should be conducted to
  evaluate the relationship between the proposed
  exposure metric and the true exposure metric.




                       Workshop on Optimizing Exposure Metrics for the
                                     National Children's Study
Workgroup Problem Statement

Currently, the NCS has seven Vanguard centers
recruiting participants and collecting multimedia
samples (e.g., environmental and biological samples)
and questionnaire information. These Vanguard centers
are serving a critical  need in regard to evaluating all
aspects of this large, longitudinal study. The protocol
developed for the NCS Vanguard centers includes an
array of environmental and  biological  measures that, in
combination with limited questionnaire data, were
intended to form the  basis for exposure classification for
many chemicals of interest  in the full study. However,
the cost and burden  of measuring all the environmental
and biological media and chemicals of interest at all
relevant time periods is high and may not be
supportable in the full NCS. Alternative approaches and
metrics are being considered for the classification of
exposures to chemical contaminants in the NCS cohort.
These approaches are intended to optimize the site visit
assessments and provide reliable exposure estimates
at critical lifestages at reduced cost and burden.
Approaches that may be considered include the use of
extant data where available, increased use of
questionnaire and other survey information, and
strategically targeted validation measurement studies to
assess core exposure classification approaches.
Experts in the fields of toxicology, epidemiology, and
exposure assessment can provide valuable guidance
for developing a resource-efficient study design that is
based on the selection of appropriate exposure metrics
and refined approaches for exposure classification in
the NCS.

Workgroup Charge

Three expert workgroups are being organized and
challenged to develop exposure classification metrics
and schemes associated with different chemical
exposures, critical time periods, and health outcomes.
The expert workgroups are being asked to address the
following specific questions.
• What environmental exposures for children, and at
  what lifestages, likely result in the health outcome?
• What metrics are needed to characterize the
  environmental exposures? If physical measurements
  are not available for all chemicals at all relevant time
  periods, what other metrics can best be used for all
  individuals in the cohort?
• What are the minimal metrics and approaches that
  can be employed for exposure classification?
• What is the best approach for employing these
  metrics cohort-wide for exposure classification?
• How should the proposed exposure classification
  approach be evaluated or verified?




                Workgroup 1—Exposure to Indoor and Outdoor Air Pollution,
                                 Aeroallergens, and Asthma Risk
Patrick N. Breysse, Ph.D., Johns Hopkins University
Dr. Breysse is a professor in the Department of
Environmental Health Sciences at the Johns Hopkins
Bloomberg School of Public Health. He conducts
research on air pollution exposure assessment,
including pollutant source characterization, exposure
measurement and interpretation, development, and use
of biomarkers of exposure/dose/effect, and evaluates
relationships between sources, exposure, doses, and
disease. A major focus of research in Dr. Breysse's
laboratory is on  exposure assessment for studies of
childhood asthma. This research includes evaluating in
home and ambient exposures to PM, ozone, NO2,
airborne nicotine, allergens, and endotoxins. This
research is conducted as a part of the multidisciplinary
Center for Childhood Asthma in the Urban Environment.
Dr. Breysse is also the Program Director for the
EPA-funded Johns Hopkins Particulate Matter Research

Michael Brauer, Sc.D., University of British
Dr. Brauer is a Professor in the School of
Environmental Health at the University of British
Columbia (UBC). He also holds associate appointments
in the Division of Respiratory Medicine and the School
of Population and Public Health at UBC.  Dr. Brauer
received bachelor's degrees in biochemistry and
environmental sciences from the University of
California-Berkeley  (1986) and a doctorate in
environmental health from Harvard University (1990).
He was a visiting scientist at the Institute of
Environmental and Occupational Medicine at  Arhus
University in Denmark (1991), at the Institute for Risk
Assessment Sciences at Utrecht University in the
Netherlands (2000-2001) and at the East-West Center
in Hawaii (2008). Dr. Brauer's research emphasis is  on
the assessment of exposure and health  impacts of air
pollution. He has evaluated associations between air
pollution and incidence of childhood asthma in birth
cohorts in the Netherlands and Canada. He is an
investigator in the recently launched Canadian Healthy
Infant Longitudinal Development birth cohort and is
currently investigating air pollution-genetic interactions
in relation to asthma initiation in a  combined analysis of
multiple birth cohorts. He has served on advisory
committees to the World Health Organization, the U.S.
National Academy of Sciences and Institute of
Medicine, the Royal Society of Canada,  and the
International Joint Commission. He is currently a
member of the outdoor air pollution expert working
group of the Global  Burden of Disease Project, the
International Scientific Oversight and Review
Committees of the Health Effects Institute and chairs
the external scientific advisory committee of the
Mesa-Air Study.

David Diaz-Sanchez, Ph.D., EPA, NHEERL
Dr. Diaz-Sanchez is a recognized expert in the area of
human asthma and allergy, as well as genes that
control susceptibility of humans to air pollution. Prior to
joining EPA in October 2007, he was a tenured
Associate Professor in the Department of Medicine at
the University of California, Los Angeles. He is currently
Chief of the Clinical Research Branch of NHEERL. He
is also the ORD representative for the Federal Liaison
on Asthma Group, as well as the National Asthma
Education and Prevention Program. He also serves on
several working groups at the NHEERL, ORD, and
Agency levels, including the Interagency Working  Group
on Climate Change and Health. In addition, he has an
adjunct position as Associate Professor in the
Curriculum of Toxicology at the University of North
Carolina. He has served on numerous  review
committees for national and international agencies,
including the National Academy of Sciences. He
recently was nominated to serve as a standing member
of the Infectious,  Reproductive, Asthma/Allergy, and
Pulmonary (IRAP) Conditions Study Section for NIH.
Recognition of his work has come in the form of multiple
requests to speak in different venues at national and
international conferences (SOT, AAAI, New Trends in
Allergy VII) and to different universities (e.g., Vanderbilt,
Johns Hopkins). He continues to have an active
research  program on factors determining susceptibility
to pollutants. His work has shown how specific
sensitivity factors, particularly diseases like asthma,
genes, and age can influence response to air pollutants.
His publications have ranged from a demonstration of
the role of diet in protection from air pollutants to the
first report of how environmental  pollutants can alter
epigenetic regulation (microRNAs) to identification of
novel biomarkers of air pollutant effects in  asthmatics.

Jack R. Harkema, D.V.M.,  Ph.D., D.A.C.V.P., Michigan
State University
Dr. Harkema received a B.S. (biology/chemistry) from
Calvin College, an M.S.  (mammalian physiology) and a
D.V.M. (veterinary medicine) from Michigan State
University (MSU), and a Ph.D. (comparative pathology)
from the University  of California-Davis (UCD). After
completing an NIH-sponsored research/residency
training program  in  comparative pathology and
toxicology at the UCD, Dr. Harkema joined the scientific
staff at the Lovelace Respiratory Research Institute in
Albuquerque,  NM, in 1985 as an  experimental and
toxicological pathologist.  He later became the institute's
project manager for pathogenesis research. In 1994,

Dr. Harkema joined the faculty of the Department of
Pathobiology and Diagnostic Investigation in the
College of Veterinary Medicine at MSU, where he is
currently a University Distinguished Professor. He is
Director of the Laboratory for Experimental and
Toxicological Pathology and the MSU Mobile Air
Research Laboratories. Also, he is a faculty member in
MSU's Center for Integrative Toxicology and the
MSU/NIEHS training program in Environmental and
Integrative Toxicological Sciences. Dr. Harkema's
research is in the areas of inhalation toxicology and
respiratory pathobiology.  His studies are designed
primarily to understand the cellular and molecular
mechanisms involved in the pathogenesis of airway
injury and remodeling caused by the inhalation of
airborne toxicants (e.g., ozone, PM, engineered
nanomaterials),  or other xenobiotic agents (e.g.,
bacteria, viruses, allergens) commonly found  in both
environmental and occupational settings. He is also a
recognized expert on laboratory animal models of
human cardiopulmonary diseases (e.g., asthma, COPD,
hypertension, atherosclerosis). Dr. Harkema has
authored or co-authored over 180 peer-reviewed
scientific publications and has served on numerous
national scientific advisory committees, including those
for the NIEHS, EPA, and  the MAS. Besides training
graduate students, residents, and postdoctoral fellows
in biomedical research, he also moderates courses in
advanced general pathology, integrative toxicology, and
pulmonary pathobiology.  Dr. Harkema is a diplomate of
the American College of Veterinary Pathologists and a
member of the Society of Toxicologic Pathologists, the
SOT, and the American Thoracic Society.

Lisa K. Baxter,  Sc.D., EPA, NERL
Dr. Baxter is currently an Environmental Health Scientist
in the EPA's NERL. She has a doctor of science degree
from the Harvard School  of Public Health. Her area of
interest is the improvement of human exposure
estimates for epidemiology studies. In large
epidemiological  studies, it is often impractical to collect
direct quantitative measures of exposure on all
subjects; therefore, reasonable proxies need to be
developed. For her doctoral research, Dr. Baxter
participated in the study design and collection of air
pollution data for a birth cohort study, as well as
developed models of air pollution exposure estimates.
The study investigated the development of asthma in
children because of environmental, genetic, and social
factors. Although much smaller in scale, this study
bears many similarities to the NCS. Her current
research activities continue along the same theme  of
developing and improving air pollution exposure
estimates for epidemiology studies. She has developed
exposure models identifying surrogates that can be
utilized when air pollution measurements on an entire
cohort are not available. This is germane to NCS in that
exposures for the entire cohort will need to be
estimated based on measurements from a subset of

Tim H. Watkins, EPA, NERL (Workgroup Facilitator)
Mr. Watkins is currently the acting director of the
Environmental Public Health Division in the EPAORD
NHEERL. Prior to this position, He served as the deputy
director of the Human Exposure and Atmospheric
Sciences Division in the EPA ORD NERL. Mr. Watkins'
expertise and interests lie in the area of air pollution
exposure assessment, including ambient air monitoring,
personal monitoring, source apportionment, and air
quality and exposure  modeling. He also has supported
some specific collaborative activities involving
monitoring and modeling. Most recently, he has
supported collaborative efforts between the EPA and
the Centers for Disease Control and Prevention (CDC)
toward the CDC's Environmental Public Health Tracking
program by providing air quality data from monitoring
networks, models, and satellites for use in surveillance
activities to track potential associations between air
quality and public health. In addition, Mr. Watkins also
served as the co-lead for the development of a cross-
EPA multimedia monitoring strategy for PBTs, which
focused primarily on monitoring emissions,
environmental concentrations, and exposures to
mercury, dioxin, and PCBs. He currently serves as the
co-chair of the Scientific and Technical Subcommittee of
the U.S.-Canada Air Quality  Committee and as the EPA
representative to the NARSTO Executive Steering
Committee. Mr. Watkins also participates in the Ambient
Monitoring Subcommittee of the National Association of
Clean Air Agencies. He has worked with the EPA since
1990. He received his M.S. in economics from the
University of North  Carolina at Chapel Hill and his B.A.
in economics and mathematics from Rollins College.

                          Workgroup 2—Nonpersistent Pesticides and
                           Poor Neurobehavioral and Cognitive Skills
P. Barry Ryan, Ph.D., Emory University
Dr. Ryan is Professor of Exposure Science and
Environmental Chemistry in the Department of
Environmental and Occupational Health, Rollins School
of Public Health, Emory University. He is jointly
appointed  in the Department of Chemistry at Emory
University. Prior to joining the faculty at Emory in 1995,
he was on the faculty at the Harvard School of Public
Health. He received a B.S. in chemistry from the
University  of Massachusetts, an M.S. in physical
chemistry from the University of Chicago, and a
doctorate in computational chemistry from Wesleyan
University. He has been active in the exposure
assessment field for more than 25 years publishing in
excess of 90 peer-reviewed manuscripts and book
chapters and making over 170 presentations of his work
to the scientific community. His work has included both
cross-sectional and longitudinal studies of community-
based exposure to multiple pollutants in multiple media.
Dr. Ryan is currently the PI on an EPA-funded STAR
grant designed to assess the effectiveness of biological
markers of exposure to organophosphate and
pyrethroid  pesticides. In addition,  he is a PI studying  the
impact on the  surrounding community of airport
emissions  of various airborne compounds and of a
retrospective study of exposure to perfluorooctanoic
acid  in a large area surrounding a manufacturing facility
using this compound. Recently, he began work
assessing  exposure to pesticides experienced by
individuals in a community in Northern Thailand.
Dr. Ryan is a member of the  Executive Committee of
the Emory/Battelle/Morehouse consortium for the NCS.
In the recent past, he was the PI on the EPA-funded
longitudinal study of exposures to pollutants known as
the National Human Exposure Assessment-Maryland
study, and he was co-Pi of a study on health-
compromised  individuals assessing the impact of PM
exposure on heart rate variability. He also was co-Pi  on
a study of the  impact of air pollution exposure on hiker
lung  health in the Great Smoky Mountains National
Park. Dr. Ryan is a member of the Board of Scientific
Counselors for EPA's ORD. Dr. Ryan also completed a
4-year term on the Federal Advisory Committee  for the
NCS being undertaken by the National Institutes of
Health. He has served on numerous advisory panels for
the EPA, most recently as an ad hoc member of the
FIFRA SAPs on CCA-treated wood products and
carbamate pesticides. Dr. Ryan also has served on
several National Academy of Science panels, most
recently on the panel producing the monograph
Managing Air Quality in the United States. Dr. Ryan is a
trained chemist and maintains a large laboratory facility.
His website is

Asa Bradman, Ph.D., DC Berkeley
Dr. Bradman is an environmental health scientist who
focuses on environmental exposures to pregnant
women and young children. In 1997, he helped found
the Center for Children's Environmental Health
Research in the UC Berkeley School of Public Health.
In this capacity, he helps direct multiple biomonitoring
and exposure studies investigating the relationship of
environmental exposures and health in children living in
the Salinas Valley, CA. Between 1987 and 1998,
Dr. Bradman participated in studies of lead exposure,
iron deficiency, pesticide exposure, and childhood
cancer with the California Department of Health
Services. He recently was appointed by Governor
Schwarzenegger to the Scientific Guidance Panel for
the California Environmental Contaminant
Biomonitoring Program and also serves on the Science
Advisory Council for the National Center for Healthy
Homes and the California Childcare Health Program
Advisory Committee, and has served on the Exposures
to Chemical Agents Working Group for the NCS.

Virginia Rauh, Sc.D., Columbia University
Dr. Rauh is Professor of Population and Family Health
at the Mailman School of Public Health, Columbia
University, and Deputy Director of the Columbia Center
for Children's Environmental Health. Her work focuses
on the adverse impact of exposure to air pollutants,
including secondhand smoke and pesticides on
pregnancy and child health, and the susceptibility of
disadvantaged populations to environmental hazards.
Dr. Rauh has been working in the field of perinatal
epidemiology since 1982. Her expertise is in the area of
low birth weight and preterm delivery, particularly with
respect to socioeconomically disadvantaged and
minority populations. She has been principal
investigator on numerous major research projects,
including studies of the impact of organophosphorus
insecticides and secondhand smoke on child
neurodevelopment and brain abnormalities, a
randomized intervention trial for low-birth-weight infants,
a multisite study of lifestyles in pregnancy, a study of
developmental outcomes of children born to inner-city
adolescent mothers, a multilevel analysis of the impact
of Head Start on New York City school children, a study
of the effects of air pollutants on pregnant women and
their children, and a study of links between race,
stressors, and preterm birth. She has worked with other
Columbia faculty to study the effects of the World Trade

Center disaster on pregnant women and newborns.
Dr. Rauh is currently principal investigator for the
Manhattan Site and co-investigator for the Queens
Vanguard Site  of the NCS. Dr. Rauh serves on
numerous national committees, including the Scientific
Advisory Board for the EPA.

Jane Hoppin,  Sc.D., NIEHS
Dr. Hoppin is a staff scientist in the Epidemiology
Branch at the NIEHS. Her research interests focus on
environmental  exposure assessment for environmental
epidemiology studies, with particular interest in
pesticides and  bioaerosols. She is one of the Pis of the
Agricultural Health Study (AHS), a prospective cohort
study in Iowa and North Carolina of 89,000 farmer
pesticide applicators, commercial pesticide applicators,
and spouses of private pesticide applicators. A critical
piece of the AHS is exposure assessment and
characterizing  exposure intensity to pesticides for
applicators and farm residents. Dr. Hoppin has
assessed the accuracy of self-reported pesticide use
information and contributed to the development of the
AHS exposure assessment algorithm and to the
modification of this algorithm based on field study data.
Dr. Hoppin currently  is conducting a case-cohort study
of asthma among 3600 participants in the AHS; this
study is collecting lung function measurements,
biological samples, and environmental samples (dust)
that will be integrated with the previously collected
exposure information. In addition to pesticide exposure
assessment and epidemiological analyses in the AHS,
since joining NIEHS  Dr. Hoppin has been involved with
helping develop protocols for biological sample
collection to assess environmental exposures in the
Norwegian Mother and Child Study cohort and with
development of environmental sampling protocols for
the Sister Study, a study of 50,000 women whose
sisters  had breast cancer. Specific to the topics of
interest to the NCS, Dr. Hoppin has assessed the
variability of urinary phthalate levels in women of
reproductive age and has assessed the reliability of a
detailed exposure questionnaire to  predict urinary
phthalate levels. She received her doctorate from the
Harvard School of Public Health in 1995 in
environmental  health and epidemiology. She has served
as a councilor for the International Society of Exposure
Analysis and as an associate editor of the American
Journal of Epidemiology. She has contributed to a
number of efforts to develop exposure materials that
can be applied in epidemiology studies, including the
NHGRI's PhenX project and the development of
standardized questionnaires for Parkinson's disease

Stephanie Padilla, Ph.D., EPA, NHEERL
Dr. Padilla is a  neurotoxicologist in the Integrated
Systems Toxicology Division of EPA's NHEERL,
Research Triangle Park, NC. Dr. Padilla received her
Ph.D. in Biochemistry from the Medical School of the
University of North Carolina at Chapel Hill. After
completing a staff fellowship with the National Institutes
of Health in Bethesda, MD, she joined the EPA in 1981.
Her research interests include acute and chronic toxicity
of anticholinesterases and developmental neurotoxicity,
specifically use of alternative species for screening
chemicals for toxicity. Dr. Padilla has received
numerous awards, including Scientific and
Technological Achievement Awards and Silver and
Bronze Medals for Commendable Service. In addition,
she is an Adjunct Professor in the Curriculum in
Toxicology, University of North Carolina at Chapel Hill.
Dr. Padilla has served on many professional review
boards, on the editorial board of the scientific journal
Neurotoxicology, and she also has served as an officer
in numerous scientific societies. Additionally, she has
authored numerous book chapters and reviews and
over 80 peer-reviewed publications.

Kent Thomas, EPA, NERL (Workgroup Facilitator)
Mr. Thomas is a research scientist at EPA's NERL. He
has extensive experience in the development and
implementation of human exposure measurement
methods for environmental contaminants. His
experience includes  complex multimedia and
multipathway studies of human exposure to VOCs,
pesticides, PAHs, metals, and particles. Mr. Thomas
has contributed to the development of sampling and
analytical methodology for contaminants in air, water,
food, dust, soil, blood, breath, and urine. Specific
research experience includes the Total Exposure
Assessment Methodology studies and being the field
study leader for the National Human Exposure
Assessment Survey  in Region 5, the Minnesota Child
Pesticide Exposure Study, and the Particle Total
Exposure Assessment Methodology Study. Additional
experience includes studies of building and residential
air pollutants and human exposures. He has led
research on methods for collecting personal dietary
samples and analysis of dietary samples for chemical
contaminants. Mr. Thomas is the EPA team leader for
the Agricultural Health Study (AHS) Pesticide Exposure
Study and serves as the EPA representative to the inter-
agency executive committee for the AHS. He was the
task leader for exposure and activity research areas
under ORD's Aging Initiative research and currently
contributes to the community cumulative risk and
biomonitoring research tasks. Mr. Thomas has served
as a government councilor for the International Society
of Exposure Science, was a member of the Exposure to
Chemical Agents Workgroup for the NCS, and serves
on the advisory panels for two NIEHS epidemiology

                Workgroup 3—Hormonally Active Environmental Agents and
                                   Reproductive Development
Deborah Bennett, Ph.D., DC Davis
Dr. Bennett is an associate professor in Environmental
and Occupational Health in the Department of Public
Health Sciences at the University of California, Davis.
Dr. Bennett's research focuses on the fate, transport,
and exposure of chemicals in both the indoor and
multimedia environments within the context of both
environmental risk assessment and environmental
epidemiology. Her work utilizes both modeling and
measurement techniques, bridging the gap between
these two lines of inquiry. Current research interests
include exposure to pesticides from indoor uses,
relating environmental measures to biological  measures
for flame retardants, exposures and resulting risks from
hazardous air pollutants, supporting exposure
assessments in autism studies, quantifying intake
fraction and exposures to agricultural workers.
Dr. Bennett received her doctoral degree in mechanical
engineering from DC Berkeley, worked as a scientist at
the Lawrence Berkeley National Laboratory, and was a
member of the faculty at the Harvard School of Public
Health. Dr. Bennett received the Early Career Award
from the International Society of Exposure Assessment
and was an EPA STAR Fellow. She has served on both
the EPA Science Advisory Board and Science Advisory
Panel, as well as on other EPA committees and was a
U.S. representative to OECD/UNEP Workshop on the
use of multimedia models. She served as the treasurer
for the International Society for Exposure Assessment.

Heather Stapleton, Ph.D., Duke University
Dr. Stapleton is an assistant professor of environmental
chemistry in the Nicholas School of the Environment at
Duke University. She received her Ph.D. in 2003 from
the University of Maryland at College Park and joined
the faculty at Duke University in 2005. Her research
interests are focused on understanding the fate and
transformation of emerging organic contaminants in the
environment and in measuring human exposure to
these contaminants in indoor environments. Her current
research focuses on characterizing the sources and
understanding the fate, biotransformation, and human
exposure, to flame retardant chemicals that are found in
consumer products (e.g., furniture, baby products, TVs,
computers, etc.). Dr. Stapleton is a member of the
advisory board for the U.S. CertiPur program,  and she
is on the editorial board for the journal Environment
International. Professional organizations in which she is
a member include the American Chemical Society and
the Society of Environmental Toxicology and Chemistry.
Stephanie Engel, Ph.D., Mt. Sinai School of
Dr. Engel earned an MSPH and Ph.D. in epidemiology
from the University of North Carolina at Chapel Hill. She
joined the Mount Sinai School of Medicine in 2003 as a
postdoctoral fellow and is currently a tenure-track
Associate Professor in the Department of Preventive
Medicine. Dr. Engel's research expertise is in molecular
perinatal epidemiology with a focus on immune, genetic,
and environmental risk factors for adverse pregnancy
outcomes and neurodevelopmental impairment. She
was a project PI of the Mount Sinai Children's
Environmental Health and Disease Prevention
Research Center and recently has published influential
articles in the area of prenatal environmental exposures
and child neurodevelopmental impairment.

Mike Shelby, Ph.D., NIEHS
Dr. Shelby founded the NIEHS/NTP Center for the
Evaluation of Risks to Human Reproduction in 1998
and served as its Director until mid-2009. In the past
12 years, he has participated in the evaluation of the
reproductive effects of over 20 substances, including
industrial chemicals, Pharmaceuticals, and
environmental contaminants. He has been at NIEHS
since 1977, serving in the office of the Associate
Director for Genetics, as head of the  Mammalian
Mutagenesis Section, as  head  of the Reproductive
Toxicology Group, and as Chief, Laboratory of
Toxicology. Prior to joining NIEHS, he was a research
associate at the Biology Division, Oak Ridge National
Laboratory. He received his B.S. in biology (1966) from
Central State College, Edmond, OK,  and his Ph.D. in
genetics (1973) from the University of Tennessee. His
graduate training was in radiation mutagenesis and
DNA repair. He has served as President of the
Environmental Mutagen Society, the  Genotoxicity and
Environmental Mutagen Society, and the NIEHS
Assembly of Scientists. He was an editor of Mutation
Research from 1980 through 2009.

Vickie Wilson, Ph.D., EPA, NHEERL
Dr. Wilson is a Research  Biologist and current Chief of
the Reproductive Toxicology Branch of the Toxicity
Assessment Division of EPA's NHEERL in Research
Triangle Park, NC. She has been with the Agency for
about 10 years. Dr. Wilson earned her B.S. degree from
Framingham State University in Framingham, MA, and
her Ph.D. in toxicology from North Carolina State
University in Raleigh, NC. Her research centers on the

cellular and molecular mechanisms of toxicant-induced
abnormal reproductive development utilizing in vitro,
ex vivo, and in vivo models. Her research focuses on
mechanisms through which environmental compounds
may impact the endocrine system and, specifically, how
those chemicals can impact offspring after in utero
exposure. Dr. Wilson has published nearly 60
publications in this area over the past 10 years. For her
work with endocrine disrupting compounds (EDCs), she
has been awarded nine EPA Science to Achieve
Results awards and three Bronze Medal awards from
EPA ORD. Dr. Wilson is an active member of several
professional societies, including SOT, the Society for
the Study of Reproductive Biology, the Triangle
Consortium of Reproductive Biology, and the Society of
Environmental Toxicology and Chemistry. She routinely
serves as a session chair, having organized several
symposiums at national meetings and on workgroups
within those organizations. She also routinely serves as
an ad hoc reviewer for several scientific journals, as
well as serving as a member of the Board of Reviewing
Editors for 4 years for the journal Biology of
Reproduction. Dr. Wilson also serves as a member of
the ORD-EDC workgroup, which provides technical
assistance and protocols to the program offices for their
endocrine screening program. She also routinely serves
on technical review panels for both OECD and NIH.

Nicolle S. Tulve, Ph.D., EPA, NERL (Workgroup
Dr. Tulve is  a research scientist in the EPA's NERL. Her
research focus includes understanding young children's
exposures to chemicals (e.g., pesticides,  PBDEs,
PFCs, etc.)  in their everyday environments. She has
had lead responsibility for several projects that were
collaborative efforts with academia and other
government organizations and for in-house EPA
research projects. She completed a detail (in 2002) with
the Office of Pesticide Programs that was developed to
promote collaboration between NERL researchers
involved in collecting multimedia measurements and the
regulatory staff in the program office. Currently,
Dr. Tulve is  the team lead for the  children's exposure
measurement research program in NERL. She
graduated from Clarkson University with a Ph.D. degree
in environmental engineering in 1999. She is a member
of the International Society of Exposure Science (ISES)
and the American Chemical Society. Dr. Tulve currently
serves as a government councilor for  ISES, as well as
chair of its membership committee.




       Workshop on Optimizing Exposure Metrics for the National Children's Study
                                         Attendee List
Dana Barr
Emory University

Lisa Baxter
Jack Harkema
Michigan State University

Ross Highsmith
Pat Ryan
University of Cincinnati

Tim Shafer
Debbie Bennett
UC Davis
Jane Hoppin
Mike Shelby
Asa Bradman
UC Berkeley

Michael Breen

Patrick Breysse
Johns Hopkins University

Scott Collingwood
University of Utah

Gwen Collman
Steven Kleeberger

Danelle Lobdell

Rob McConnell

Larry McMillan

David Miller
Linda Sheldon

Heather Stapleton
Duke University

Dan Stout

Warren Strauss

Kent Thomas
Lou D'Amico
Lucas Neas
Nicolle Tulve
Allen Dearry

David Diaz-Sanchez

Caroline Dilworth
Aaron Niman

Marcia Nishioka

Eric Vigoren
University of Washington

Tim Watkins

Cliff Weisel
Peter Egeghy
Stephanie Padilla
Ron Williams
Michael Firestone
Jim Quackenboss
Vickie Wilson
Roy Fortmann
Charles Rodes
Kim Gray
P. Barry Ryan
Emory University

Attendance via Webinaron April 12, 2010
Stephanie Engel
Mt. Sinai

Michael Dellarco
                                  Peter Weyer
                                  University of Iowa

                                  Kimberly McAllister
Marina Kleinhapel                   Bonny Specker
Michigan Department of Community   South Dakota State University
                                  Doug Thompson

                                  David Camann

                                  Charles Weschler

                                  Howard Wey
                                  South Dakota State University

                                  Roger Lewis

                                  Dan McCormack
                                  SouthDakota State University

                                  Chuck Shorter
                                  Tulane University
Angela Galka

Ellen Wells
Case Western Reserve University

Elizabeth Triche

Karen Broski
Michigan State University

Margot Brown

Kelly Johnson

Dean Baker
UC Irvine
Sastry Isukapalli

Alison Caviness
Texas Children's Hospital

Xiaobin Wang
Northwestern University

Stephen Vesper

Michael Brauer

Ralph Delfino
UC Irvine

Lianne Sheppard
University of Washington

Natalie Thiex
South Dakota State University

Bill Griffith
University of Washington
Attendance via Webinaron April 13, 2010

Marina Kleinhapel                   Angela Galka
Michigan Department of Community

Stephen Vesper

Howie Duit

James Starr

Stephanie Engel
Mt. Sinai

Vickie Wilson
                                  Karen Broski
                                  Michigan State University

                                  Elizabeth Triche

                                  Peter Weyer
                                  University of Iowa

                                  Dean Baker
                                  UC Irvine

                                  David Camann

                                  Margot Brown
Kim McAllister

Dan McCormack
South Dakota State University

Howard Wey
South Dakota State University

Chuck Shorter
Tulane University

Nigel Fields

Ellen Wells
Case Western Reserve University




     Exposure Metrics for NCS
       Asthma Investigations

    Summary and Recommendations from
                Workgroup 1

                April 12,2010
       Workgroup Members

Lisa Baxter (US EPA, ORD/NERL)

Michael Brauer (University of British Columbia)

Patrick Breysse (Johns Hopkins University)

David Diaz-Sanchez (US EPA, ORD/NHEERL)

Jack R. Harkema (Michigan State University)

Tim Watkins (US EPA, ORD/NERL) - Facilitator
Workgroup Information
 -  Members
 -  Objectives
 -  Approach

Summary of Workgroup Discussions
 -  Time Window of Exposure
 -  Hypotheses
 -  Review of Measurement Protocol
 -  Alternative Exposure Metrics
 -  Exposure Algorithms
 -  Recommendations
      Workgroup  Objectives
Provide a conceptual model linking environmental exposures with
critical time period(s) and health outcomes

Provide recommendations for exposure classification schemes that
range from the simplest to the best metrics and approaches for
classifying chemical exposures

Provide recommendations regarding the best data or literature
available to support the proposed metrics and approaches for
classifying exposure

Provide recommendations for research needed to understand or
develop the proposed approaches for classifying exposure

Provide recommendations where validation sub-studies could be
considered within the NCS and other children's research programs

                           Workgroup Approach
                    Identified Asthma Onset as top priority (versus Exacerbation)
                     - Critical Time Window

                    Reviewed Environmental Measurement Protocol to prioritize relative to
                    Asthma onset

                    Discussed additional pollutants with potential to exacerbate asthma

                    Discussed differences in Source-based and Pollutant-based hypotheses
                     - Importance of residential information

                    Reviewed alternative exposure metrics
                     - Routinely available
                     - Modeling
                     - Low cost / novel approaches

                    Discussed opportunities for validation

                    Developed overall recommendations for exposure metrics
                                     Summary of Workgroup
                       Time  Window of Exposure
                                           Asthma Phenotypes in Children
                    Critical time window
                    for Asthma Onset is
                    from in-utero to 3

                    Time window for
                    asthma progression
                    and exacerbation is
                    year 3 and beyond
                                Asthma Onset and Exacerbation
NCS hypotheses should focus on
environmental factors leading to
onset of asthma
 -  Source-based
 -  Pollutant-based
 -  Atopic versus Non-atopic

Hypotheses relating to the
progression of asthma should also
be investigated
 -  Why do some children grow out of
 -  Gender differences

Hypotheses related to
exacerbation of asthma are of
lower priority

                    Examples of Hypotheses to be Investigated
Asthma Onset
Secondhand smoke
Indoor Sources
Indoor Swimming Pools

Traffic Components
PM Components
PM Sizes
Asthma Progression/Exacerbation

Coarse and Fine Particles
Establishing Exposure Gradients
for Source-Based and Pollutant-
          Based  Hypotheses


Indoor Measurements
Ambient Measurements
Air Quality Modeling
Exposure Modeling
                                                                                                                     Geo-data bases
                                                                                                                  Marker measurements
                               Scale  of Exposure
                     Goal is to minimize misclassification of
                     exposure for NCS subjects

                     Personal exposure measurements for all
                     subjects are not feasible

                     Residential exposure metrics are the most
                     realistic option for NCS subjects
                      - Indoor component
                      - Ambient component (including infiltration)

                     Ambient exposure metrics are useful
                      - Characterizing pollutant gradients in
                        residential setting
                      - Estimating infiltration into residence

                     The appropriate scale for the ambient
                     metric will depend upon the source/pollutant
                      - Regional / Urban / Local
 The Importance of Tracking Residential
   History and Time Spent in Other Key
Imperative to accurately track
residential location history

Also, important to track location of
microenvironments where
subjects spend significant
amounts of time
 - Work (pregnant mothers)
 - Daycare/School

The information is fundamental for
developing source proximity
metrics and for estimating the
pollutant concentration gradients
most relevant to the NCS subject
 - Need to capture archived geo-
   databases for historical

                         Review of Environmental
                           Measurement Protocol
Indoor Measurements
House Dust
Supplemental Community Measurements are
a lower priority
     The Value of House Dust

Highest priority indoor measurement
Integrated measurement that can provide information on
potential exposure to multiple pollutants
 - Indoor and outdoor origin
Accumulative exposure metric
Measure allergens, endotoxin
Could possibly be used to identify exposures to specific
 - Examples
    • Hopanes may be a unique indicator of exposure to traffic pollutants
    • Nicotine is a measure of SHS exposure
Collection Methods - vacuum, wipe
                   Indoor Measurements versus Supplemental
                            Community Measurements
                    In general, indoor measurements
                    are a higher priority than additional
                    community-based measurement
                     - Ambient monitoring exist in many
                     - Ambient concentrations can be

                    Exception, community monitoring
                    may be a priority if no existing
                    measurements exist
                     - Particularly for source specific
  Alternative Exposure Metrics:
    Ambient Concentrations (1)
Ambient Air Monitoring Networks
 -  Reliable source of ambient air
 -  Possible near road monitoring
 - Provides a semi-quantitative
   estimate of exposure based
   on Air Quality Index for entire
 - Need to validate for personal
                                                                             Pollen Counts
                                                                             - Should be collected from
                                                                               available sources
Ore™ to Wu« by Mi on

    Alternative Exposure  Metrics:
     Ambient Concentrations (2)
 Air Quality Modeling
  - AQ modeling could be used in
    NCS, but needs to be
  - AQ models should be
    related/linked to actual human
 Land Use Regression
  - Provides a more spatially
    resolved estimate of ambient
  - Need measurements (40 min,
    passive) placed in key
    locations to capture
    characteristics that factor into
                      Alternative Exposure  Metrics:
                  Residential/Personal  Exposure (1)
                                 (Jerrett et al. Epidemiology 2005; 16: 727-736)

                   Source Proximity

                    - Relative low cost estimate exposure
                      obtained through various approaches
                       •  Questionnaires
                       •  Modeling with GIS/Geo-databases
                       •  Archive geo-data to capture land use
                         changes (e.g., roads, sources)


                    - Provide valuable information, including:
                       •  Where people are
                       •  What they are doing
                       •  What was around them
                       •  Source proximity - sources of ambient and
                         indoor air pollutants

                    - Validation is important
                       •  Self reporting may not be reliable,
                         especially with negative responses
    Alternative Exposure  Metrics:
Residential/Personal  Exposure (2)
 National Air Toxics Assessment
  - Census tract level estimate of
    exposure to air toxics
  - NATA will eventually become
    National Air Pollution Assessment
    (NAPA) to include criteria

 Human Exposure Modeling
  - Should also be considered, but
    reliable input data is needed.

 Novel Sensor Technologies
  - Technology is evolving quickly,
    but not ready for immediate
  - NCS should allow for possible
    introduction at a later date.

CO Sensor

O3 Sensor #1
                              (Source: M Jerrett & Intel Berkeley)
                               - Source Proximity
                               - Questionnaires
                   Added Cost
-Existing Ambient
                 - Indoor Measurements
                 - Exposure Modeling
                            •*• Additional
- Air Quality Modeling
- Land Use Regression
- Community monitoring

                        Developing  Exposure Algorithms
Algorithms - Ongoing Research
                        It may be possible to develop an "algorithm" using readily available
                        information to provide an exposure metric

                        Possible Approaches
                        - Ambient Adjustment
                            • Use housing characteristics (e.g., age, square footage, AC, normalized
                             leakage) obtained from property assessment data
                               - Works relatively well in winter, but not as well in summer when windows are used
                        - Weighted Metric
                            • Identify activities that impact exposure and assign weights to develop an
                             exposure metric
                            • Traffic Example - Assign weights to various traffic related metrics (e.g.,
                             distance from road, traffic counts, amount of diesel traffic, commuting time)
                             to created an overall traffic exposure metric
                        - Exposure Modeling
                            • Use ambient metric combined with either person specific or census based
                             information to model personal exposure estimates
  There is ongoing research relevant to the development
  of exposure algorithms

   - Ambient Adjustment
      • Normalize Leakage (LBNL)
      • Property Assessment Data (Univ of Victoria)

   - Exposure Modeling
      • EPA's Exposure Model for Individuals (EMI)
          - Provides person specific exposure estimate for use in cohort studies
          - Ambient concentration input (modeled or measured)
          - Indoor air quality model
          - Individual level activity / housing characteristic data
                        An Integrative Approach to Estimating Chronic
                              Exposure to Air Pollution:  MESA-Air
      Opportunities for  Evaluating

               Exposure Metrics

   - Relationships of Indoor, Outdoor, and Personal Air (RIOPA)
   - Detroit Exposure and Aerosol Research Study (DEARS)
   - Children's Total Exposure to Persistent Pesticides and Other
     Persistent Organic Pollutants (CTEPP)
      • How does a dust sample relate to personal exposure?

  Planned Studies
   - Near-road Exposures to Urban air pollutants Study (NEXUS)
      • EPA Study in Detroit (with Univ of Mich) - Fall 2010 start
      • Investigating role of near road exposures in children's asthma
      • High Diesel / Low Diesel Impact
      • Exposure Metrics - Proximity, Measurements, Modeling
   - EPA RTP Near Road Study (Dates TBD)
                                                      Cohen et al. ES&T2009

                       Summary Recommendations:
                         Source-Based Hypotheses
                                                  Summary Recommendations:
                                                   Pollutant-Based Hypotheses
                          Exposure Gradient
                            Questionnaires *
             Questionnaire Follow-up
               Archive Geo-Data
            Track Residential/ME History
              Indoor Measurements
                                                Exposure Gradient
                                                                                Ambient Measurements
                                                                                  Ambient Modeling
                                                                                 Exposure Algorithms

                                                                                 Indoor Measurements
                                                                                                             Use existing networks
                                                               - Optional enhancement
                                                               - Validate with ambient data

                                                               Low-cost qualitative/semi-quantitative
                                                             -> exposure estimate, research needed
                                                               for validation

                                                             _^ - Priorities: dust and PM
                                                               - Useful for validation
                 * Note - Include source proximity questions in questionnaires
                   Recommendations for Prioritization
                              of Exposure Metrics
                   Existing Data
                 Ambient Networks



                   Pollen Counts
 Indoor - Dust

Source Proximity
  Indoor- PM

  Air Modeling


Exposure Modeling

Indoor- Other
          Overall  Summary

Asthma onset is highest priority hypothesis
 - Critical time window of exposure - in utero to 3 years

Residential level exposure estimate are the most realistic for NCS

House dust is the highest priority indoor measurement.

Source Proximity metrics can be obtained relatively easily and
should be strongly considered
 - Track residential location history and locations of other key
   microenvironments (daycare/school).

If additional resources are available, alternative exposure metrics
should be considered.
 - Air quality modeling
 - Exposure algorithms

                         Insecticide Exposure Assessment
                         in  the  National Children's Study

                         Workgroup 2
                         Summary and Recommendations

                         April 13,2010
                                                                                       Workgroup Members
 Asa Bradman
    School of Public Health, UC Berkeley
 Jane Hoppin
    National Institute of Environmental Health Science
 Stephanie Padilla
    U.S. EPA National Health Effects and Environmental Research Laboratory
 Virginia Rauh
    School of Public Health, Columbia University
 P. Barry Ryan
    Rollins School of Public Health, Emory University
 Kent Thomas (Workgroup Facilitator)
    U.S. EPA, National Exposure Research Laboratory
                     Acknowledgement of Prior Work

                     NCS Exposure to Chemical Agents Workgroup
                        - White Paper on Environmental Exposure Assessment
                        - Journal articles on exposure assessment, including pesticides (EHP Mini-
                     NICHD, EPA, and NIEHS Sponsored Research
                        - Lessons learned from Children's Center research
                        - Design and Pilot Studies
                             - Low cost/low burden sample collection
                             - Validation sub-sampling
                        - Workshops and White Papers
                     NCS Program Office, Vanguard Centers, Coordinating Center
                        - Environmental measurements committee
                        - Development of draft research study design
                        - Development of Vanguard Center protocol
                         -Development of Questionnaires and Survey Instruments
                        - Development of Dietary Intake Instruments (with input from EPA/ORD and OPP)
 •  Hypothesis
 •  Workgroup Goals
 •  Pesticides of Interest
 •  Important Time Windows of Exposure
 •  Important Sources and Exposure Pathways
 •  Insecticide Exposure Assessment Challenges
 •  Summary Recommendations
 •  Measurement Exposure Metrics and Research Needs
 •  Survey-Based  Exposure Metrics and  Research Needs
 •  Measurement Sub-Sampling
 •  Other Considerations
 •  Final Workgroup Recommendations
 •  References

                      Need for Insecticide Exposure Classification
                      Assessing exposures to specific insecticides in the NCS
                      is important -

                          The potential association between insecticide exposure and poor
                          neurological outcomes in children remains an important public
                          health question.

Current NCS Meta-hypothesis

      Repeated, low-level exposure to non-persistent pesticides,
      including carbamates, organophosphates, and pyrethroids, in
      utero or post-natally increases risk of poor performance on
      neurobehavioral and cognitive examinations during infancy and
                          The NCS provides the best opportunity to assess multiple
                          chemical and non-chemical exposures, genetic susceptibility
                          factors, and neurological outcomes.

                          It may not be possible to fully evaluate neurological outcomes in
                          the NCS without information on multiple risk factors, including
                          insecticide exposures.
                      Workgroup Goals
Chemicals of Interest
                       Provide recommendations regarding insecticide measurement
                          approaches, considering cost/burden issues

                       Consider non-measurement approaches for insecticide exposure

                       Recommend research that would be needed for:
                          - Improving measurement approaches and interpretation
                          - Assessing predictive power of non-measurement metrics
                          - Improving non-measurement exposure assessment

                       Provide recommendations for measurement sub-studies within the
                                                                                                          Organophosphate Insecticides
              Pyrethroid Insecticides
              Carbamate Insecticides
              Fipronil Insecticide
              Piperonyl Butoxide (synergist)
              Future active ingredients
         Exposure assessment and exposure classification of
         individual active ingredients should be a goal for the NCS.

         Assumes persistent chemicals, including organochlorine
         insecticides, PCBs, and others will be evaluated using
         blood biomarker measurements.

                     Sources of Exposure
                      In the general population, the primary sources of exposure are from:
                         - Residential indoor use
                         - Foods

                      For some parts of the population, other sources may be important
                         - Pet uses
                         - Residential outdoor use
                         - Occupational (direct use by parent and take-home)
                         - Proximity to agriculture
                         - Other building uses (day care, school, workplace)
                         - Public health treatments

                      Sources generally not as important for insecticides
                         - Drinking water
                         -Ambient air
Insecticide  Exposure Pathways
     Residential and
     Other Building Uses
     Proximity to
                    Time Windows for Neurological Development
                     Fig 2 in Rice and Barone. 2000. Critical periods of vulnerability for the developing
                     nervous system. Environ Health Perspect 108:511-33.
Importance of Time Windows for Insecticide
Exposure Assessment
                                                                                     Pregnancy I T1 I T2 I T3
                                                                                     Trimester '	'	'	
                                                                                                        VH-H  HHHHMMMMM
4   5
                                                                                                     VH = very high importance for exposure assessment
                                                                                                     H  = high
                                                                                                     M  = moderate
                                                                                                     L  = low

                      Pesticide Exposure Classification

                       Multiple pesticides, sources, and exposure pathways
                       Typically low concentrations in food and environmental media
                       Short-term variability in exposures
                       Limited information on relationships between activities and
                       Lack of chemical specificity in non-measurement approaches
                       Limited predictive power (low R2) for survey data
                       Short biological  half-lives for current-use pesticides
                       Exposure to metabolites  in environmental media confounding
                         biomarker interpretation
Workgroup Summary Recommendations:
  Biological and environmental samples are essential

  Core Sample Collection
      - Collect cohort-wide core samples, hold for future analysis
        - Urine from key time points for mother and young child
        - Blood & milk from mother at key times; from child as feasible
        - Best measure of residential loading (wipe, dust, or settled dust?)
      - Additional research needed to support use for exposure

  Sub-Sampling Measurements
      - Random sub-sample with oversampling for some possible
        high/low exposure categories using multi-media and longitudinal
        approaches (validation)
      - Consider targeted sampling based on survey information
                     Workgroup  Summary Recommendations:
                     Non-Measurement Approaches
                       - Collect residential pesticide use information
                       - Collect dietary intake information most appropriate for dietary
                         intake assessments
                       - Gated questions on pets and occupation
                       - Geographical information for residence
                       - Some time/activity/location information will probably be needed
                       - Additional research
                          - Focused research needed in near term to assess predictive power
                            of survey information; use Children's Center, Vanguard, and other
                            recent research study data
                          - Revise and focus current survey instruments - evaluate how well
                            they result in accurate, useful information
                          - Assess predictive power for outcomes as well as exposures        15
 Core Sample Collection
 Urine for insecticide biomarker analysis
     - Collect from mother at T1 and end of T2 or early T3 times
     - Collect from child as often as possible through age 5
     - Collect entire FMV void volume; collect previous and current void times
     - Store for future analysis

 Other biological samples
     - Blood for parent compound and other biomarkers, store for future
        - Mother at T1, child when feasible for sufficient volume
     - Mother's milk; store for future analysis

 Collect an appropriate residential "loading" sample
     - Select best approach:  house dust, floor wipes, vapor/settled dust
     - Collect at mother T1, child age 6 months or 1 year
     - Collect new sample with change in residence
     - If feasible, collect additional samples through age 10 (mail-in?)
     - Store for future analysis

           Research Needs - Urine

           Given the short-term variability in urine biomarker concentrations, will
           urine samples allow adequate exposure classification over longer time

               - Assess extant research examining this issue for OPs, and especially for
                 pyrethroid and carbamate insecticides

               - If needed,  collect sufficient longitudinal samples from mothers and young
                 children to evaluate variability over 3-month (and 1 -year ?) time

           Urinary metabolites of pesticides may also appear as pre-formed
           degradates in food and environmental media; will these potentially
           confound exposure classification?

               - Assess extant research examining this issue for OPs, pyrethroid, and
                 carbamate insecticides

               - If needed,  perform measurement study to collect food, house dust, floor
                 wipe samples and analyze for metabolites concurrently with collection
                 of urine from home residents
                                                                         Research Needs - Residential Loading

                                                                           What is likely to be the best residential metric with regard to predicting
                                                                           overall residential "loading"? Predicting exposure?

                                                                           What type of sample has lowest cost/burden and can provide the best
                                                                           information on other chemicals of interest?

                                                                               - Assess extant research examining this issue for OPs, and especially for
                                                                                 pyrethroid and carbamate insecticides (AHHS, CTEPP, Children's
                                                                                 Centers, others?)

                                                                               - Analysis of Vanguard Center data

                                                                               - Lessons learned from application of PUF indoor vapor/deposition
                                                                                 sampling effort and possible further assessment

                                                                               - Assess the temporal variability in residential loading measures

                                                                               - Develop a participant-based sample collection and mail-in approach
Non-Measurement Approaches
 Questionnaire and other survey data collected cohort-wide could,
 potentially, be used as low-cost/low-burden metrics for generic
 insecticide exposure classification in the NCS cohort.
Non-Measurement Approaches

 Some survey information will need to be collected for the most
 important sources and pathways
                        However, there are major limitations in the use of non-measurement
                        insecticide exposure classification approaches in the general

                            - Pesticide use information from questionnaires has not been shown to be
                              highly predictive of insecticide exposures in general, and for individual
                              active ingredients in particular

                            - Exposure - activity relationships are still not well-defined, particularly for
                              very young children

                            - Systematic analyses of survey data and exposure across recent studies
                              are lacking

                            - For much of the population, dietary intake of insecticides is difficult to
                              classify using consumption and residue information due to the
                              infrequent occurrence of residues, variability of residue concentrations,
                              and diet variability
                                                                          Proposed areas of information collection are described in the next
                                                                          several slides
                                                                          The following slides discuss research that is needed to identify the
                                                                          information most highly associated with insecticide exposures

                                                                          Current questionnaires and instruments will need to be refined

                     Non-Measurement Approaches:

                     Residential  Use Information

                      Collect basic pesticide residential use information from all participants

                      Focus on (in priority order):
                         - Recent use
                         - Frequency of use
                         - Duration of use
                         - Indoor use locations
                         - Outdoor pesticide and lawn chemical use
                         - Purpose of use

                      Collect information about flea and termite treatments

                      Product inventories may have some analytic value; need to assess
                      time/burden for information collection
                                                                  Non-Measurement Approaches:
                                                                  Dietary Information
                                                                   Collect dietary intake information from all participants (needed for other
                                                                   purposes in NCS as well)

                                                                   Ensure that good information is collected for
                                                                      - Potential highly exposed (high consumers of specific foods likely to
                                                                        contain residues)

                                                                   Potential low exposed (primarily organic fruits and vegetables in diet)

                                                                   Consider alternate approaches
                                                                      - Collect some information outside of food instruments (organic diet
                                                                        details, gardening, local farmers markets)
                                                                      - Community dietary sample collection and analysis
                                                                      - Market basket sample collection and analysis
Non-Measurement Approaches:
Pet Use Information
 Collect Qx information about presence of pets; use as gateway
 question for additional pesticide use information collection

 Collect Qx information for
    - Use of flea collars
    - Use of spot-on treatments
    - Use of shampoos or powders
    - Treatment of bedding or outdoor areas
    - Whether pets spend time indoors and outdoors

 It is not clear whether enough data are available to define useful
 human/pet interaction activity information for improving exposure
Non-Measurement Approaches
Other Uses to Consider
                                                                                       Lice treatments

                                                                                       Use of impregnated materials (e.g. bedding liners for mites, clothing,

Non-Measurement Approaches:
Occupational  Information
 Collect information about parent occupational use of, or exposures to,
Non-Measurement Approaches:
Time/Location/Activity Information
 Exposures are affected by time spent in environments with pesticide
 residues and interaction with those environments
 Use gateway question for collection of additional information
    - Specific occupational use(s) or exposure(s)
    - Whether location is same as home location (e.g. farm, nursery)
    - Duration and frequency of uses or exposures
    - Hygiene information (changing clothes/shoes after work, etc.)

 Analyses likely to be limited  by lack of chemical specificity
 General information on time spent in different microenvironments will
 need to be collected for multiple purposes in NCS

 At this time we have limited ability to apply simple activity information
 for improving pesticide exposure assessment
Non-Measurement Approaches
Geographical Information

General geographic region may be informative regarding exposures in
one NCS PSU relative to others (higher pesticide uses in some

Archival of satellite photos over time (every 2 years?)

In rural areas, information regarding proximity to agricultural pesticide
use should be collected
    - CIS approaches where supported by extant data
    - Participant questions regarding proximity to ag use
Research Needs for
Non-Measurement Approaches
 Systematic evaluation of extant literature, recent studies, and current
 studies is needed to assess predictive power of questionnaires and
 other survey information regarding associations with exposures and/or
 associations with outcomes.

 Evaluation and assessment of questionnaires and other survey tools in
 diverse communities is needed to ensure that people can provide
 accurate, comparable, and consistent information.
Analyses will be limited by lack of specificity of active ingredients in
most locations

Research Needs for

Non-Measurement Approaches

Literature Review
    - Associations between survey information and environmental levels
    - Associations between survey information and exposures
    - Associations between survey information and outcomes

Analysis of Extant Data
    - NCS Vanguard Centers
    - EPA/NIEHS Children's Centers
    - American Healthy Homes Survey
    - Other EPA STAR grant studies
    - EPA data including CTEPP, Jacksonville pilot, NHEXAS
    - Other recent research?

    Short time frame to complete work
Research Needs for

Non-Measurement Approaches

 A possible model for systematic analysis of survey and
 exposure data at Children's Centers
                                              Centers report
                                              types & amounts
                                              of survey and
                                              Exposure data
                                              Central organization
                                              designs data analysis
   Center 1
Exposure Specialist
Center 2

Center 3
Centers perform
analyses and report
and publish results
    Funding mechanism for PI or Post-docs at Centers? EPA or NIH?
Research Needs for

Non-Measurement Approaches

Near-term analyses of NCS Vanguard Center data are needed

Questions regarding NCS Vanguard Center data

    - Will urine and environmental samples be analyzed for pesticides or
      biomarkers in near term?
    - Will questionnaire and dietary data be prepared for analysis in the near
    - Will measurements and survey data be made available for analyses that
      could inform insecticide exposure assessment approaches?

    - When would information be available?
    - Who will perform analyses?
Research Needs for

Non-Measurement Approaches

  Other Data Sources and Analyses

     - American Healthy Homes Survey (EPA/HUD)

     - Other STAR Grant Recipients

     -EPA Study Results

     - EPA analysis of NHANES dietary intake data and POP pyrethroid data

  It is recommended that EPA devote time and resources to perform or
  fund analyses in near term that can inform predictive value of survey
  data for the NCS

Validation  Sub-Sampling Measurements
Targeted  Sub-Sampling Measurements
     - Evaluate how well core measures and survey data predict exposures
       (validation, exposure misclassification assessment)
     - Potentially, use results for analytical adjustments

 Recommended Approach
     - Random sample across NCS cohort
     - Consider oversampling selected sub-groups, potentially including higher
       and lower exposure groups:
        By geographic area
        By residence type
        By socio-economic status
        By agricultural proximity

 Sample Size
     - Cost, burden, power factors
     - Use of Battelle/Harvard tool
     - Provide measurement data for improved outcome assessment

 Recommended Approach
     - Use initial survey data on pesticide use and diet to select participants

     - Based on likely higher or lower exposures
        - Reported residential pesticide use
        - High or low dietary intake category
        - Other use or proximity information
        - Outcome susceptibility information??

     - Sampling with known probability is recommended
Sub-Sampling  Measurement Plan

 The workgroup did not develop a detailed set of recommendations for
 the types of samples and the sub-sampling strategy
 Measurements should be designed to assess the important sources
 and pathways
    - Residential dust, surfaces, soil
    - Dietary intake
    - Activity levels, activities types, locations
    - Urine
    - Dermal
    - Consider some air/inhalation measures
 Frequency and duration of sampling are critical and should be based
 on information on variability in environmental and biological media;  a
 repeated measures design will likely be needed for at least some
Exposure Algorithm or Index

Development of an exposure algorithm or index for epidemiological
insecticide exposure classification in the general population will be a
difficult, time consuming task. The workgroup discussed some of the
considerations for developing an algorithm:
    - Expert workgroup
    - Feasibility assessment
    - Selection of key parameters or variables
    - Evaluation of supporting data
    - Combining dissimilar information
    - Level of specificity needed for active ingredients (or, potentially for
      cumulative exposures)
    - Decisions on continuous (numerical) or categorical indicator
    - Peer review
    - Ability to assess or validate inside or outside of NCS

                      Chemical stressors other than insecticides, and other non-chemical
                      exposures, may also result in or contribute to adverse neurological
                      outcomes. Multiple risk factors must be considered in the NCS
                      epidemiologic analyses.

                      The workgroup has not considered exposure assessment for other
                      chemical and non-chemical stressors.  Some of the important stressors
                      may include:

                          - Persistent chemicals (OC pesticides, PCBs, Pb, Hg) these need to be
                            measured in blood (or hair for Hg)

                          - Non-persistent chemicals not considered by this workgroup; may need to
                            measure in biological and environmental samples

                          - Other exposures or conditions
                             - Maternal alcohol and drug use
                             - Nutrition (pre-  and post-natal)
                             - Social environment
                             - Others?                                              37
Lawn Care Chemicals

Herbicides are widely used, and insecticides and fungicides are
sometimes used, in lawn care products and treatment programs.
Concerns have been raised regarding the use of lawn care chemicals
and children's health.
While the workgroup was asked to consider exposure assessment for
insecticides and neurological outcomes, the NCS could offer a platform
to more broadly examine lawn care chemical use and health.

NCS information collection and chemical analyses would need to be
broadened to include lawn care products and herbicides.
                                                          Final Workgroup Recommendations

                                                          Workgroup members emphasize the need for retaining biological and
                                                          environmental measurements at critical time periods for insecticide
                                                          exposure assessment in the NCS.

                                                          Exposure assessment and classification of individual insecticides
                                                          should be a study goal.

                                                          Sub-sampling strategies and internal and/or external research can
                                                          improve insecticide exposure interpretation and classification.
                                                         The ability to use non-measurement information for general insecticide
                                                         exposure classification, and particularly for individual chemicals, has
                                                         not been adequately demonstrated. More research is needed in the
                                                         near term to improve survey questions and tools.


    Deborah Bennett, Stephanie Engel, Mike
    Shelby, Heather Stapleton, Vickie Wilson
    Workgroup Facilitator: NicolleTulve
Health Endpoints

n In addition to reproductive effects, it is
  important to include other health effects
  related to hormonally active compounds
n Thyroid disruption during pregnancy impacting
  neurological development
n Critical window to capture will depend on the
  exposure and outcome of interest:
    Thyroid < 20 weeks' gestation possible sensitive window
    Surge in brain development starting 3rd Trimester
    Repro tox: starting 8-10 weeks' gestation

a Health Endpoints
a Process
n Compound List
n Guidance by chemical
a Decisions still needed to be made
a Available and needed research

n To present a method for classifying exposure to
  endocrine disrupting compounds in the NCS
n Context - Environmental samples may or may not
  be available for analysis & may not be required for
  optimal exposure assessment for all chemicals
n In some cases sample size will  be small and it will
  be practical to measure biological and
  environmental samples within a case-control
n In some cases sample size will  be large and it will
  not be practical to provide measurement values

                 Process for selecting compounds
                                                   Compounds Considered
                 n List of compounds taken from early NCS
                 n How important from a health perspective and
                   how much exposure there was likely to be
                 n We also considered whether or not another
                   group would be addressing the compounds
                 n Concerned with co-exposure to neurotoxins
                 n We ultimately prioritized the list to some
                                                   n Phthalates
                                                   n PBDEs
                                                   n Bisphenol-A
                                                   n Phytoestrogens
                                                   n PFCs
                                                   n Perchlorate
                                                   n Triclosan/Triclocarban
                                                   n Other phenols
                                                   n Other Flame Retardants
                                                   n PCBs
                                                   n PAHs
n Co-exposures of concern
n Pesticides
n Organotins
n Cotinine
n Mercury
n Lead
n Compounds not discussed
n Limited agricultural

                 n We have a very large set of compounds
                 n Primary source of exposure is through indoor
                   sources and consumer products that may not be
                   well known to consumer and are not tied to
                   ambient levels
                                                   n Blood
                                                   n Limited in early
                                                     childhood due to
                                                     small blood volumes
                                                   n Limited by parent
                                                     refusal and sample
                                                     collection failure
 n Urine
 n Interference with
 n Low percentage of
   samples collected if
   there are difficulties
   using urine bags
 n Bags are the

                   a We each created a table listing our level of
                    concern over health effects, relevant routes of
                    exposure by time period, and recommended
                    methods for evaluating exposure
                   a We went over all the chemicals one by one,
                    challenging ourselves to come up with other ideas
                    and trying to come to a general consensus for each
                                                        n Some compounds can easily be classified by
                                                          questionnaire data or biological samples are
                                                          available and low cost - Easy Compounds
                                                        n Other compounds provide additional challenges
                                                            Exposure Routes by Time Period
                                                            Samples Needed
                                                            Exposure Metrics
Phthalates -Justification for Inclusion
Phthalates - Exposure Routes
                  Phthalate metabolites have been detected in a wide range of body
                  tissues including urine, blood, semen, amniotic fluid and breast milk
                  .] Phthalate exposures are ubiquitous and high internationally and
                    across all age ranges
                  j At least 10 metabolites are commonly detected; median levels in
                    urine range from 1-500 ug/L (4-4000 nmoles/L)
                  Animal studies demonstrate reproductive toxicity and thyroid
                  hormone antagonism
                  Recent human health studies demonstrate associations with
                  anogenital distance in male babies, sexually dimorphic behaviors,
                  and neurobehavioral problems
                                                       j Phthalates cross the placenta
                                                       j Direct effect on maternal prenatal thyroid hormone
                                                       j Exposure from breastmilk (0-ly)
                                                       j Exposure from housedust (0-4y)
                                                       j Exposure from consumer products across the

 Phthalates-Samples  Needed
D Urine (best option)
     Short half-life, modest reproducibility across spot urines
     Prenatal, ideally 1 per trimester
     Postnatal, 6m, 1 per year thereafter
     Unable to quantify exposure without urine specimen,
     difficult in early childhood
D Environmental samples - Brominated  phthalate (potentially
  some additional traditional ones as well)
     House dust or hand wipes (6-12 m)
     Possible to extrapolate back to pregnancy?
D Consumer product questionnaire
     Composition of  products changes over time
     General questions (i.e., use of scented products) may be
     able to crudely rank for some phthalates, but significant
     concerns about  accuracy of self-reporting
Polybrominated Diphenyl Ethers (PBDEs)
Justification for Inclusion
  PBDEs are bioaccumulative and persistent
    Levels in US population 10X higher than other countries
    Detected in >95% of population (Sjodin et al., 2008)
    Levels in children significantly higher than adults (from breast
    milk and dust exposure)
  Animal studies demonstrate effects on thyroid
  homeostasis and on neurodevelopment (Review:
  Birnbaum and Staskal, 2004)
  Recent human health studies demonstrate associations
    Body burdens and fecundability in women (Harley et al., 2010)
    Neurodevelopmental outcomes in children ages 1-6 years at
    environmentally relevant levels (Herbstman et al., 2010)
Phthalates - Exposure Metrics

Pregnancy- Concentration in maternal urine, ideally more than one
   For brominated phthalate need dust
   Variability in metabolites over time makes single spot urine undesirable
Early Childhood - Ideally childhood urine, one per year.
   For brominated phthalate need dust
   Possibly can extrapolate 6-12 m dust sample back to pregnancy
   Lack of child urine will make classification impossible
Later Childhood - Concentration in child's urine
Non-Physical Estimations :Product-use questionnaire unlikely to reliably
quantify exposure
Piloting needs
   Comparison of 6-12 m dust with pregnancy dust
   Ongoing & published studies have quantified urinary phthalate metabolite
   variability over pregnancy
PBDEs -  Exposure  Routes
    PBDEs cross the placenta, exposure from mother
    Exposure from breast milk (0-1 yr)
    Exposure from house dust (0-4 yr)
    While diet is also a source of exposure, it is impossible
    to estimate exposure from diet as levels in food are
    variable and not specific to food types

                   PBDEs-Samples Needed
                                                         PBDEs - Recommendations
                   n Biological samples
                       Top choice: serum
                       » Prenatal (3rd trimester)
                       « Postnatal (cord blood, 6 m, 2 yr)
                       Second choice: breast milk (higher brominated PBDEs
                       do not partition well into breast milk)
                   n Physical/Environmental samples
                       House dust (collected at 6 m, 1 yr, and 2 yr)
                       Hand wipes (collected at 6 m, 1 yr, and 2 yr)
                   n Questionnaires not practical
                                                         D Collect house dust and hand wipes
                                                             Some PBDEs have short half-lives in the body and exposure
                                                             cannot be characterized for these congeners using serum
                                                             « Both are needed to differentiate exposure from breast
                                                         D Justification for use of hand wipes
                                                             Better metric for quantifying exposure to dust and can be
                                                             used to evaluate exposure to other compounds found in
                                                             Easy to collect and store (relatively inexpensive)
                                                             Significant PBDE residues have been measured in hand
                                                             wipes collected from adults and children (Stapleton et al.,
PBDE - Exposure Metrics
Bisphenol A-Justification for Inclusion
                 D  Pregnancy-Concentration in mother's blood
                 n  Early Childhood - Environmental concentration, modify
                    with breastfed or not, breast milk concentration
                 n  Later Childhood - Concentration in child's blood
                 n  Non-Physical Estimations -There are no non-physical
                    methods for evaluating this compound with the
                    exception of substituting mother's blood concentration
                    for breast milk concentration
                 n  Piloting needed - Available studies looking at blood/
                    dust correlation
                                                         n Metabolites detectable in 90% of the population
                                                             Biomonitoring suggests higher exposures in certain
                                                             minority groups, children, and women
                                                         n NTP-CERHR expert panel noted a varying level of
                                                           concern for:
                                                             Neural or behavioral effects resulting from prenatal,
                                                             infant, or childhood exposure
                                                             Accelerated puberty resulting from prenatal, infant, or
                                                             childhood exposure
                                                         n Bulk of exposure coming from dietary ingestion

                     Bisphenol A - Samples Needed
                                                                Biphenol A- Exposure Metrics
                     D  Urine (best option)
                          Short half-life, modest reproducibility in metabolite levels
                          Prenatal, ideally 1 per trimester
                          Postnatal, 6 m, 1 per year thereafter
                          Unable to quantify exposure without urine specimen,
                          difficult in early childhood
                     D  Environmental samples - None required
                     D  Consumer product questionnaire
                          Composition of products changes over time
                          General questions (i.e., use of canned foods,
                          polycarbonate products) may be useful, and significant
                          concern over accuracy of self-reporting
                          Unclear how many polycarbonate products such as sippy
                          cups will still be in use
                                                              D Pregnancy - Concentration in maternal urine, ideally multiple
                                                                   Variability in BPA metabolite level over time
                                                              D Early Childhood - Ideally childhood urine one per year.
                                                                   Lack of child urine will make classification impossible
                                                              D Later Childhood - Concentration in child's urine
                                                              D Product-use questionnaire unlikely to reliably quantify exposure
                                                                   Can ask about use of canned food, polycarbonate plastics,
                                                                   sippy cups. Without knowing plastic number hard to tell if
                                                                   contains BPA.
                                                              D Piloting needs
                                                                   Ongoing & published studies have/will quantify urinary BPA
                                                                   metabolite variability over pregnancy
Perfluorinated  Chemicals (PFCs) -
Justification for Inclusion
                     D Widespread exposure through dietary intake, especially
                       through soy formula in infancy
                     D Questions regarding use of soy formula in infancy- should take
                       into account amount, timing, and patterns of usage (i.e.,
                       supplementing breast milk or exclusive use)
                     D Biological Samples - urine (short half-life, modest reproducibility
                       in metabolite levels across spot urines)
                     D Compound can be evaluated well by questionnaire/biological
                                                              D  Includes perfluorooctanoic acid (PFOA); perfluorooctane sulfonic
                                                                 acid (PFOS); perfluorohexane sulfonic acid (PFHxs);
                                                                 perfluorooctane sulfonamide; perfluorinated telomer alcohols
                                                                 (e.g., 6:2, 8:2, and 10:2 FtOH)
                                                              D  Detected at high frequencies (>99%) in US serum (Calafat et al.,
                                                              D  Detected in US house dust (Strynar and Lindstrom, 2008)
                                                              D  Developmental  and thyroid effects observed in laboratory
                                                                 exposures (Lau et al., 2004; Yu  et al., 2009)
                        Exposure Metrics - questions on use of soy formula

                  PFCs - Exposure Routes
                                                       PFCs-Samples Needed
                      Likely crosses to fetus via bloodstream (support from
                      rat study by Yu et al., 2009)
                      Exposure from breast milk (0-1 yr)
                      Exposure from house dust and treated products in
                      home (e.g., furniture, carpets, etc.) (0-4 yr)
                      Diet/food packaging (age 1-adult)
                                                       n Biological samples
                                                           Top choice: serum
                                                           » Prenatal (3rd trimester)
                                                           » Postnatal (cord blood, 6 m, 2 yr)
                                                           Breast milk not recommended as we know nothing
                                                           about partitioning between blood and breast milk
                                                       n Physical/Environmental samples
                                                           House dust (collected at 6 m, 1 yr, and 2 yr)
                                                           Hand wipes (collected at 6 m, 1 yr, and 2 yr)
                                                       n Questionnaires
                                                           Not validated although there are ideas available on
                                                           what could be asked
PFCs - Exposure Metrics
                  n Pregnancy-Concentration in mother's blood
                  n Early Childhood - Environmental concentration
                  n Later Childhood - Concentration in child's blood
                  n Non-Physical Estimations
                       Questionnaires have not been developed for this
                  n Piloting needed
                                                       n Water samples should be collected and analyzed
                                                         by water distribution system.
                                                       n Well water samples should be collected (will be
                                                       n Compound that can be evaluated well by Census
                                                       n A biomarker is available for individual classification
                                                       n Exposure metric-Census level well water

                  Triclosan and Triclocarban -Justification for

                  a Detected in US urine (Calafat et al., 2008)
                  a Detected in house dust (Canosa et al., 2007; Geens
                    eta I.,2009)
                  n Known effects on thyroid (Veldhoen et al., 2006;
                    Crofton et al., 2007; Paul et al., 2010)
Triclosan and Triclocarban - Exposure Routes

a Prenatal
    Likely crosses to fetus via bloodstream
a Postnatal
    primary exposure from treated products such as
    toothpaste, hand soaps/gels (age 1-adult)
    Exposure from breast milk (0-1 yr)
    Exposure from house dust (0-4 yr)
                  Triclosan and Triclocarban -Samples Needed
Triclosan and Triclocarban - Exposure Metrics
                  n Biological samples
                      Top choice: urine (3rd trimester, 6 m, 2 yr, 4 yr)
                      Second choice: serum (detected, easier to collect
                  a Environmental samples
                      Not adequately characterized
                      Hand wipes may be a good choice for measuring
                  a Non-physical measures - Add questions to
                    survey/questionnaire regarding use of
                    antibacterial toothpastes and soaps/lotions/gels,
n Pregnancy-antibacterial product use,
  concentration in mother's urine
n Early Childhood - antibacterial product use,
  concentration in child's urine
n Later Childhood - antibacterial product use,
  concentration in child's urine
n Piloting needed
n None

                    Nonyl/Octyl Phenols -Justification for Inclusion
                                                            Nonyl/Octyl Phenols- Exposure Metrics
                    a 4-nonylphenol/nonylphenol ethoxylates - used in
                      plastics, resins/hardeners, cleaners, cosmetics
                    n 4-tert-octylphenol - used in paints, plastics, floor
                    a 2,6-Di-tert-butylphenol - used as a UV stabilizer
                      and antioxidant in petrochemicals and plastics
                    n Residential dust samples may be most efficient
                      and cost-effective for assessing exposures
                    a Unlikely that a questionnaire would be informative
                      about exposures
                                                            n Pregnancy and Childhood - analysis of dust
                                                            n Non-Physical Estimations -There are no non-
                                                              physical methods for evaluating these
                                                            n Questionnaires would not be informative
                                                            n Piloting needed
Alternate Current-Use Flame Retardants -
Justification for Inclusion
                      Includes hexabromocyclododecane (HBCD), decabromodiphenyl
                      ethane (DBDPE), triphenyl phosphate (TPP), tetrabromobenzoate
                      (TBB), tetrabromophthalate (TBPH), tris(l,3-dichloroisopropyl)
                      phosphate (TDCPP), tris (2-chloroethyl) phosphate (TCEP)
                      All detected at high frequencies in US house dust (Stapleton et al.,
                      2008, 2009)
                      DBDPE primary replacement for DecaBDE
                      TPP, TBB, and TBPH present in Firemaster 550/600 which is a primary
                      replacement for PentaBDE
                      TCEP and TDCPP are prominent replacements for PBDEs detected in
                      furniture products imported from China
                      HBCD affects thyroid regulation (Palace et al., 2008); TCEP is a
                      carcinogenic compound and TDCPP is a neurodevelopmental toxicant
                      (Dishaw et al., 2010, work in progress)
                      Recent human health studies found negative associations between
                      TDCPP and hormone levels in men (Meeker and Stapleton, 2010)
Other Flame Retardants - Exposure


n Prenatal
    Likely crosses to fetus via bloodstream; not full

n Postnatal
    Exposure from breast milk (0-1 yr)
    Exposure from house dust (0-4 yr)
    While diet is also a source of exposure, it is impossible
    to estimate exposure from diet as levels in food are
    variable and not specific to food types

                  Other Flame Retardants - Samples

                  a Biological samples
                      Top choice: serum
                      « Prenatal (3rd trimester)
                      « Postnatal (cord blood, 6 m, 2 yr)
                      Breast milk not recommended as we know nothing
                      about partitioning between blood and breast milk
                  n Physical/Environmental samples
                      House dust (collected at 6 m, 1 yr, 2 yr)
                      Hand wipes (collected at 6 m, 1 yr, 2 yr)
                  a Questionnaires not practical
                                                        Other Flame Retardants -

                                                        n Collect house dust and hand wipes
                                                           Questionnaires not practical
                                                           Some have short half-lives in the body and exposure
                                                           cannot be characterized using serum
                                                        n Justification for use of hand wipes
                                                           Better metric to quantify exposure to dust
                                                           Can be used to evaluate all flame retardants found in dust
                                                           Easy to collect and store (relatively inexpensive)
                                                           Significant residues of HBCD, TBB, TBPH, TPP, and TDCPP
                                                           have been measured in hand wipes collected from adults
                                                           and children (Webster and Stapleton, work in progress)
Other Flame Retardants - Exposure Metrics
                 n Pregnancy-Concentration in mother's blood for
                   some, environmental concentration
                 n Early Childhood - Environmental concentration
                 n Later Childhood - Concentration in child's blood for
                   some, environmental concentration
                 n Non-Physical Estimations-Non-physical measures
                   are not practical, potentially substitute one time
                   period for many
                 n Piloting needed
                      Some research becoming available
                                                        n Questionnaire - fish consumption, age of home
                                                        n Biomarker available
                                                        n May want environmental sample in some older
                                                         housing stock

                  PCBs - Exposure Metrics
                  a Pregnancy-Concentration in mother's blood
                  n Early Childhood - Use concentration in child's
                    blood from later time period
                  a Later Childhood - Concentration in child's blood
                  a Non-Physical Estimations:
                      Pregnancy- Fish Consumption
                      Childhood - Fish Consumption/ potentially need
                      environmental measurement for participants in older
                      housing stock
                  a Piloting needed - None
a Exposure primarily from traffic, cooking sources,
  and certain foods
n Traffic exposure can be evaluated through CIS
n Exposure to foods and cooking methods can be
  addressed by questionnaires
                  Co-Exposures Considered
                  i Organotins - Can be measured in blood but not a standard
                   method, found in the home so can be measured in dust
                 n Cotinine - Questionnaire - Cigarette use and exposure to
                   second hand smoke, biomarker also available
                 n Mercury - Questionnaire - Fish consumption, biomarker
                   also available
                 n Lead - Questionnaire - Age of home, condition of paint,
                   low cost biomarker available
                 n Indoor Pesticides - Consult with pesticide group
Agricultural Pesticides

a There may be additional pesticides of concern in
  terms of endocrine disruption by distance to fields
  and use on fields should be able to be collected for
  each Census block and not on an individual level
a Compounds that can be evaluated well by Census

                  Environmental Sampling Conclusions
                                                       Biological Sample Research Needs
                    Critical time window that cannot be captured by
                    biological samples and/or questionnaires is 0-12
                      Sample collected in the home during this time
                      frame is strongly recommended
                    This sample would serve as the primary means of
                    classifying the following compounds:
                      PBDEs (high priority)
                      Other flame retardants (high priority)
                      PCFs (high priority)
                      Nonyl/octy phenols
                                                      n Develop a diaper or an insert that can be used
                                                        easily by participants and that does not have
                                                        interference problems
                                                      n Critical for determining exposure in first 2 years of
                                                        life to:
                                                          Helpful for Triclosan/Triclocarban
Compounds Considered
What Sort of Environmental Sample?
                D Phthalates-urine, dust
                D PBDEs-blood, dust
                D Bisphenol-A - urine, Q
                D Phytoestrogens - Q
                D PFCs-blood, dust
                D Perchlorate-Regional
                D Triclosan/Triclocarban -Q, urine
                D Other phenols-Dust
                D Other Flame Retardants - Dust
                D PCBs-Q
                D PAHs-aGIS
                            Co-exposures of concern
                            Organotins- dust
                            Cotinine - Q, biomarker
                            Mercury - Q, biomarker
                            Lead -Q, biomarker

                            Compounds not discussed
                            Limited agricultural pesticides
n Dust
n Wipe
n Hand Wipe

n Recommend collect and store to leverage for
  future grant support if funds are limited


                   n Correlation with biological sample
                   n % of samples likely to be above LOD
                   n Sample can be evaluated with multiple extraction
                   n Stability of sample
n HVS3: Pro: Uniform sample collection, powerful suction
  collects sample quickly
    Con: Heavy and awkward
n Mighty Mite: Pro: Easy to carry
    Con: Often overheats, can be time consuming
n Participant Vacuum: Pro:  Easy to Collect
    Con: Not all people have vacuums, no uniformity
n Provided Vacuum: Pro: semi-uniform, avoids staff time
    Con: Not sure all participants will collect sample, semi-

                   a  Need to collect dust samples through multiple methods
                      in conjunction with biological samples and determine
                      which method has the best correlation
                   n  Samples Available:
                   n  1) EPA analyzing HVS3 and participant vacuum cleaner
                      bags and CDC is analyzing biological samples, waiting for
                      analytical results.
                   a  2) DC Davis has 25 co-located HVS3 and Mighty mite
                      samples with biological samples from within a couple of
                      months. Analysis not planned.
n Collection from hard flooring is problematic due to
  potential high loading for phthalates
n David Camann is experimenting with door frame

                  Employing Hand Wipes for Measuring Exposure
                                                           to              For?
                             Wipe Top of Hand
Wipe Bottom of Hand
                    -Methods based on those published by Stapleton et al., 2008 for measuring PBDEs
                     in hand wipes
                    -Uses sterile gauze pads and isopropyl alcohol (relatively inexpensive)
                    -Can be collected by participants
                    -Collects most organic residues on hands
                    -Analysis in extracts by Mass Spectrometry methods

                    -Can be evaluated for several chemical classes; collect sequential wipes from a sub-
                     population of individuals to assess recovery from first wipe collection
n Ideally we would like to include a wide range of
  compounds - this adds costs
n One idea: Two Dimensional Gas Chromatography
  with Time-of-Flight Mass Spectrometry (GCxGC TOP-
n Response factor quantification based on surrogates
  approaches can be considered for new compounds
n Significantly enhanced chromatographic resolution
  limits interferences
D Detection limits similar to conventional GC/MS/SIM
                    a We acknowledge that in a perfect world, we would be able to
                      sum across all the compounds based on the toxicity
                    n Only limited data is available to do this in an effective way
                    n Research on phthalates and other anti-androgens indicates
                      that compounds which impact the same pathway or endpoint
                      will act in a dose additive manner (Hotchkiss et. al. 2004, Biol Repro;
                      Howdeshell et. al. 2007, Tox Sci; Howdeshell et. al. 2008, Tox Sci; Rider et. al.
                      2008 Int J Androl; Rider et. al. 2010 Int J Androl.)
                    n These studies  argue for combining exposure assessments for
                      some compounds (such as those phthalates known to be
                      reproductive toxicants) as a better indicator of risk

                                D Goal: Is dust representative of exposure in early
                                n Stapleton Study - 60 kids, 12 - 30 months, dust,
                                  handwipe, blood, PBDE and other flame retardants
                                D Webster Study-Better correlation between
                                  blood/handwipes than blood/dust for adults
                                D Bennett Study- 100 kids 3-6 years, blood, HVS3
                                  and participant vacuum dust, PBDE and RFC
                                n Hertz-Picciotto Study - 33 bloods @ 1 year w/ 6
                                  month dust-Analysis not planned

                 Variability in Dust Concentrations
                                                    Variability during Pregnancy
                 n Goal:  Can we say dust collected at 6 months is
                   representative of dust collected during pregnancy?
                 n Bennett Study - 50 HVS3 samples 1 year apart
                   being  analyzed for PBDEs, houses with young kids
                 n Hertz-Picciotto - 25 samples from pregnancy visit
                   and 6  month visit - Analysis not planned
                                                    n Goal:  How representative is spot urine?
                                                    n Engel Study: Phthalate and phenol metabolites
                                                      (BPA, TRCS, 2,5-DCP, BP3) measured in 100
                                                      women enrolled with 3 urines per woman.
                                                      Amniotic fluid being processed.
                                                    n Hertz-Picciotto Study: 65 woman with 6 or more
                                                      samples, 40 more with 4 or more.  At least one 24
                                                      hour sample per woman. Analysis not planned.
Integration with Vanguard  Centers        Conclusions
                 n Dust collection and hand wipe methods are
                   developed and could be integrated into Vanguard
                   centers to test for acceptability and potentially
                   compare with biological samples
                 n Although  a "special" diaper is not yet developed,
                   vanguard centers could provide  a regular diaper
                   and ask that participants use that diaper to
                   determine if participants remember to use the
                   specified diaper
                                                    n Potential limitations with biological samples during
                                                      early childhood coupled with the lack of practical non-
                                                      physical measures support need for environmental
                                                      sample/hand wipe in early childhood
                                                    n Environmental analysis methods should be developed
                                                      to get as many compounds as feasible in a cost
                                                      effective way
                                                    n Note that samples may be able to be stored
                                                    n Develop a urine collection method that will be
                                                      acceptable and limit interference


     United States
     Environmental Protection
   PERMIT NO. G-35
     Office of Research and Development (8101R)
     Washington, DC 20460

     Official Business
     Penalty for Private Use
                               Recycled/Recyclable Printed on paper thai contains a minimum o
                                  50% poslconsumer fiber content processed chrorirte free