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 

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Notice 

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. 

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Acknowledgments 

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. 

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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) 

Background 

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 

agenda. 

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 

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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 

samples. 

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 

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Table 1. NCS Exposure Metrics Workshop―Summary Recommendations for Data Collection in 

Data Collection During Home Visits 

Mother―Prenatal Child 

Visit 1 Visit 2 Visit 3 Annual Visits 

First Trimester Third Trimester First Year after Birth 

Up to Age 5 Years and at 

Puberty 

Blood Blood Blood Sample as Early in Life 

as Possible 

Blood, If Available 

Urine Urine Urine Urine 

House Dust House Dust House Dust House Dust 

Ambient Air Pollutants―Use 

available ambient monitoring 

data or modeled estimates 

Ambient Air Pollutants―Use 

available ambient monitoring 

data or modeled estimates 

Ambient Air Pollutants ―Use 

available ambient monitoring 

data or modeled estimates 

Ambient Air Pollutants―Use 

available ambient monitoring 

data or modeled estimates 

Indoor Air Pollutants―Subset 

of homes 

Indoor Air Pollutants―Subset 

of homes 

Indoor Air Pollutants―Subset 

of homes 

Indoor Air Pollutants―Subset 

of homes 

Questionnaires: 

Air―Source proximity 

metrics; 

Pesticides―Use, gated 

pesticide questions, 

dietary intake; 

EDC―Product use and 

inventories; 

GIS (ambient sources, 

pesticides) 

Questionnaires: 

Air―Source proximity 

metrics; 

Pesticides―Use, gated 

pesticide questions, 

dietary intake; 

EDC―Product use and 

inventories; 

GIS (ambient sources, 

pesticides) 

Questionnaires: 

Air―Source proximity 

metrics; 

Pesticides―Use, gated 

pesticide questions, 

dietary intake; 

EDC―Product use and 

inventories; 

GIS (ambient sources, 

pesticides) 

Questionnaires: 

Air―Source proximity 

metrics; 

Pesticides―Use, gated 

pesticide questions, 

dietary intake; 

EDC―Product use and 

inventories; 

GIS (ambient sources, 

pesticides) 

― ― Breast Milk (if available) ― 
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 over time 

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, 

or daycare 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 

needed. 

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. Pollutantbased 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 

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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 disruptors. 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, bisphenol A, 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. GIS systems and 

questionnaires can be used to evaluate exposures. 

Alternatively, PAHs can be measured in house 

dust, but this is expensive and not currently 

recommended. 

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It was stressed that, if urinary biomarkers are used to 

estimate exposure, it is crucial to evaluate variability of 

biomarkers over time 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 

chemicals. 

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 over time. 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 

specificity. 

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. 

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Given the many limitations associated with developing 

exposure metrics for insecticides, the workgroup made 

several strong recommendations for additional 

research. 

• Current-use pesticide exposures often have a shorttime frame, are intermittent, and are not persistent in 

the body, thus new methods are needed that can 

integrate exposures over time. 

• 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 longterm exposures. This includes understanding withinday, 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 

metrics. 

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 

samples. 

• 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. 

Blood 

• Development and evaluation of adduct techniques on 

blood spots to characterize infant exposures. 

• Evaluation of storage stability of blood for analyses of 

EDCs. 

Urine 

• Evaluation of the relevance and applicability of shortterm 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 

pesticides. 

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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 

data. 

Metric Evaluation 

• Field studies or substudies should be conducted to 

evaluate the relationship between the proposed 

exposure metric and the true exposure metric. 
ATTACHMENT A

WORKGROUP PROBLEM STATEMENT AND CHARGE 

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11

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? 
12
ATTACHMENT B

WORKGROUP MEMBERS 

13
14
15

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 

Center. 

Michael Brauer, Sc.D., University of British 

Columbia 

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 NAS. 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 

participants. 

Tim H. Watkins, EPA, NERL (Workgroup Facilitator) 

Mr. Watkins is currently the acting director of the 

Environmental Public Health Division in the EPA ORD 

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 crossEPA 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.

16
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 communitybased 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 healthcompromised 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 

http://www.sph.emory.edu/eoh/faculty/ryan.html. 

Asa Bradman, Ph.D., UC 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 

17
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 

research. 

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 interagency 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 

studies.

18
Workgroup 3―Hormonally Active Environmental Agents and 

Reproductive Development 

Deborah Bennett, Ph.D., UC 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 UC 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 

Medicine 

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 

19
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 

Facilitator) 

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. 

20
ATTACHMENT C

WORKSHOP ATTENDEE LIST 

21
22
Workshop on Optimizing Exposure Metrics for the National Children’s Study 

Attendee List 

Dana Barr 

Emory University 

Lisa Baxter 

EPA 

Debbie Bennett 

UC Davis 

Asa Bradman 

UC Berkeley 

Michael Breen 

EPA 

Patrick Breysse 

Johns Hopkins University 

Scott Collingwood 

University of Utah 

Gwen Collman 

NIEHS 

Lou D’Amico 

EPA 

Allen Dearry 

NIEHS 

David Diaz-Sanchez 

EPA 

Caroline Dilworth 

NIEHS 

Peter Egeghy 

EPA 

Michael Firestone 

EPA 

Roy Fortmann 

EPA 

Kim Gray 

NIEHS 

Jack Harkema 

Michigan State University 

Ross Highsmith 

EPA 

Jane Hoppin 

NIEHS 

Steven Kleeberger 

NIEHS 

Danelle Lobdell 

EPA 

Rob McConnell 

USC 

Larry McMillan 

EPA 

David Miller 

EPA 

Lucas Neas 

EPA 

Aaron Niman 

EPA 

Marcia Nishioka 

Battelle 

Halûk Özkaynak 

EPA 

Stephanie Padilla 

EPA 

Jim Quackenboss 

EPA 

Charles Rodes 

RTI 

P. Barry Ryan 

Emory University 

Pat Ryan 

University of Cincinnati 

Tim Shafer 

EPA 

Mike Shelby 

NIEHS 

Linda Sheldon 

EPA 

Heather Stapleton 

Duke University 

Dan Stout 

EPA 

Warren Strauss 

Battelle 

Kent Thomas 

EPA 

Nicolle Tulve 

EPA 

Eric Vigoren 

University of Washington 

Tim Watkins 

EPA 

Cliff Weisel 

UMDNJ 

Ron Williams 

EPA 

Vickie Wilson 

EPA 

23
Attendance via Webinar on April 12, 2010

Stephanie Engel 

Mt. Sinai 

Michael Dellarco 

NCS 

Marina Kleinhapel 

Michigan Department of Community 

Health 

Angela Galka 

Ellen Wells 

Case Western Reserve University 

Elizabeth Triche 

Karen Broski 

Michigan State University 

Margot Brown 

NCS 

Kelly Johnson 

Dean Baker 

UC Irvine 

Peter Weyer 

University of Iowa 

Kimberly McAllister 

NIEHS 

Bonny Specker 

South Dakota State University 

Doug Thompson 

David Camann 

SWRI 

Charles Weschler 

EOHSI 

Howard Wey 

South Dakota State University 

Roger Lewis 

Dan McCormack 

SouthDakota State University 

Chuck Shorter 

Tulane University 

Sastry Isukapalli 

EOHSI 

Alison Caviness 

Texas Children’s Hospital 

Xiaobin Wang 

Northwestern University 

Stephen Vesper 

EPA 

Michael Brauer 

UBC 

Ralph Delfino 

UC Irvine 

Lianne Sheppard 

University of Washington 

Natalie Thiex 

South Dakota State University 

Bill Griffith 

University of Washington 

Attendance via Webinar on April 13, 2010

Marina Kleinhapel 

Michigan Department of Community 

Health 

Stephen Vesper 

EPA 

Howie Duit 

James Starr 

EPA 

Stephanie Engel 

Mt. Sinai 

Vickie Wilson 

EPA 

Angela Galka 

Karen Broski 

Michigan State University 

Elizabeth Triche 

Peter Weyer 

University of Iowa 

Dean Baker 

UC Irvine 

David Camann 

SWRI 

Margot Brown 

NCS 

Kim McAllister 

NIEHS 

Dan McCormack 

South Dakota State University 

Howard Wey 

South Dakota State University 

Chuck Shorter 

Tulane University 

Nigel Fields 

EPA 

Ellen Wells 

Case Western Reserve University 

24
ATTACHMENT D

WORKGROUP PRESENTATIONS 

25
26
27 

1

Exposure Metrics for NCS 

Asthma Investigations

Summary and Recommendations from 

Workgroup 1

April 12, 2010

Overview

• Workgroup Information

– Members– Objectives– Approach

• Summary of Workgroup Discussions

– Time Window of Exposure – Hypotheses– Review of Measurement Protocol– Alternative Exposure Metrics– Exposure Algorithms– Recommendations

3

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 Objectiv

• Provide a conceptual model linking environmental e

critical time period(s) and health outcomes

• Provide recommendations for exposure classificatio

range from the simplest to the best metrics and appclassifying chemical exposures 

• Provide recommendations regarding the best data o

available to support the proposed metrics and approclassifying exposure

• Provide recommendations for research needed to u

develop the proposed approaches for classifying ex

• Provide recommendations where validation sub-stu

considered within the NCS and other children’s rese
28 

5

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 Workgro

Discussions

7

Time Window of Exposure

• Critical time window 

for Asthma Onset is from in-utero to 3 years

• Time window for 

asthma progression and exacerbation is year 3 and beyond 

Ober et al. Nature Reviews Genetics 9, 911-922 (December 2008)

Hypotheses:

Asthma Onset and Exace

• 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 

asthma?

– Gender differences

• Hypotheses related to 

exacerbation of asthma are of lower priority
9

Examples of Hypotheses to be Investigated

Source-Based Pollutant-Based

Asthma Onset

Traffic Traffic Components

Secondhand smoke PM Components

Indoor Sources PM Sizes

Indoor Swimming Pools NO2

Phthalates

Mold

Endotoxins

Asthma Progression/Exacerbation

Coarse and Fine Particles

SO2

Formaldehyde 

Establishing Exposure Gra

for Source-Based and Po

Based Hypotheses

Pollutant-Based

Source-Based

Measurements/

Models

Proximity metrics 

Source specific 

markers

Ques

Geo-

Marker m

Indo

Amb

Air 

Ex

29 

11

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

Personal

ResidentialUrban/Local

Regional

The Importance of Tracking Res

History and Time Spent in Oth

Microenvironments

• 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 geodatabases for historical 

reconstruction
13

Review of Environmental 

Measurement Protocol

Pollutant Priority

Indoor Measurements

PM2.5 High

NO2 Medium

Ozone Low

VOC Lower

Carbonyls Lower

House Dust High

Supplemental Community Measurements are 

a lower priority 

The Value of House D

• Highest priority indoor measurement• Integrated measurement that can provide in

potential exposure to multiple pollutants

– Indoor and outdoor origin

• Accumulative exposure metric• Measure allergens, endotoxin• Could possibly be used to identify exposure

sources 

– Examples

• Hopanes may be a unique indicator of exposure to traff• Nicotine is a measure of SHS exposure

• Collection Methods – vacuum, wipe• Archivable

15

Indoor Measurements versus Supplemental 

Community Measurements

• In general, indoor measurements 

are a higher priority than additional community-based measurement

– Ambient monitoring exist in many 

locations

– Ambient concentrations can be 

modeled

• Exception, community monitoring 

may be a priority if no existing measurements exist

– Particularly for source specific 

impacts

Alternative Exposure Me

Ambient Concentration

• Ambient Air Monitoring Networks

– Reliable source of ambient air 

data

– Possible near road monitoring 

network

• AirNOW

– Provides a semi-quantitative 

estimate of exposure based on Air Quality Index for entire country

– Need to validate for personal 

exposure

• Pollen Counts

– Should be collected from 

available sources

30 
31 

17

Alternative Exposure Metrics: 

Ambient Concentrations (2)

• Air Quality Modeling

– AQ modeling could be used in 

NCS, but needs to be validated

– AQ models should be 

related/linked to actual human exposure

• Land Use Regression

– Provides a more spatially 

resolved estimate of ambient concentrations

– Need measurements (40 min, 

passive) placed in key locations to capture characteristics that factor into variability

CMAQ PM2.5 2002

(Jerrett et al. Epidemiology 2005; 16: 727-736)

Alternative Exposure Me

Residential/Personal Expo

• Source Proximity

– Relative low cost estimate exposure 

obtained through various approaches including:

• Questionnaires• Modeling with GIS/Geo-databases• Archive geo-data to capture land use 

changes (e.g., roads, sources)

• Questionnaires

– 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

19

Alternative Exposure Metrics:

Residential/Personal Exposure (2)

• National Air Toxics Assessment 

(NATA)

– Census tract level estimate of 

exposure to air toxics

– NATA will eventually become 

National Air Pollution Assessment (NAPA) to include criteria pollutants.

• 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 application.

– NCS should allow for possible 

introduction at a later date.

GPS

GSM/GPRS

Wireless Sensors

Bluetooth

O3 Sensor #2

NOx Sensor

Temperature/Humidity

CO SensorO3 Sensor #1

(Source: M Jerrett & Intel Berkeley)

Trade-Offs

Ambient

Personal

No/Low

Added Cost

- Source Proximity- Questionnaires

- Indoor Measurem- Exposure Modelin- Air Quality Model- Land Use Regres- Community monit

-Existing AmbientMonitoring-AirNOW-NATA/NAPA
32 

21

Developing Exposure Algorithms

• 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 

Algorithms – Ongoing Re

• There is ongoing research relevant to the d

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 – Ambient concentration input (modeled or measure– Indoor air quality model– Individual level activity / housing characteristic data

23

An Integrative Approach to Estimating Chronic 

Exposure to Air Pollution: MESA-Air

Cohen et al. ES&T 2009 

Opportunities for Evalua

Exposure Metrics

• Databases

– Relationships of Indoor, Outdoor, and Personal – Detroit Exposure and Aerosol Research Study (– Children’s Total Exposure to Persistent Pesticid

Persistent Organic Pollutants (CTEPP)

• How does a dust sample relate to personal expos

• Planned Studies

– Near-road EXposures to Urban air pollutants Stu

• EPA Study in Detroit (with Univ of Mich) – Fall 20• Investigating role of near road exposures in childr• High Diesel / Low Diesel Impact• Exposure Metrics - Proximity, Measurements, Mo

– EPA RTP Near Road Study (Dates TBD)
33 

25

Summary Recommendations:

Source-Based Hypotheses

Source-Proximity

Exposure Gradient

Questionnaires *

Geo-Data

Validation

Observations

Questionnaire Follow-up

Archive Geo-Data

Track Residential/ME History

Indoor Measurements

* Note - Include source proximity questions in questionnaires 

Summary Recommenda

Pollutant-Based Hypoth

Pollutant 

Exposure Gradient

Indoor Measurements

Ambient Measurements

Ambient Modeling

Exposure Algorithms

Use existing n- Optional enh- Validate with Low-cost quaexposure estimfor validation- Priorities: du- Useful for va

27

Recommendations for Prioritization 

of Exposure Metrics

Existing Data Level 1 Level 2 Level 3

Ambient Networks

AirNOW

NATA/NAPA

Pollen Counts

Indoor - Dust

Source Proximity

Indoor – PM

Ambient

Air Modeling

Algorithms

Exposure Modeling

Supplemental 

Ambient 

Measurements

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 re• House dust is the highest priority indoor measureme• Source Proximity metrics can be obtained relatively 

should be strongly considered

– Track residential location history and locations of othe

microenvironments (daycare/school).

• If additional resources are available, alternative exp

should be considered.

– Air quality modeling– Exposure algorithms
34 

1

Insecticide Exposure Assessment in the National Children’s Study

Workgroup 2 Summary and RecommendationsApril 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 R

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

3

Acknowledgement of Prior Work

NCS Exposure to Chemical Agents Workgroup

- White Paper on Environmental Exposure Assessment- Journal articles on exposure assessment, including pesticides (EHP MiniMongraph)

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)

Overview

 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 Ne Survey-Based Exposure Metrics and Research Ne Measurement Sub-Sampling Other Considerations Final Workgroup Recommendations References
35 

5

Need for Insecticide Exposure Classification in NCS

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. 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.

HypothesisCurrent NCS Meta-hypothesis

Repeated, low-level exposure to non-persistent including carbamates, organophosphates, and putero or post-natally increases risk of poor perfoneurobehavioral and cognitive examinations durchildhood.

7

Workgroup Goals

Provide recommendations regarding insecticide measurement 

approaches, considering cost/burden issues

Consider non-measurement approaches for insecticide exposure 

classification

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 

NCS

Chemicals of Interest

Organophosphate InsecticidesPyrethroid InsecticidesCarbamate InsecticidesFipronil InsecticidePiperonyl Butoxide (synergist)Future active ingredients

Exposure assessment and exposure classification individual active ingredients should be a goal for tAssumes persistent chemicals, including organocinsecticides, PCBs, and others will be evaluated ublood biomarker measurements.
36 

9

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

Ingestion

DermalInhalatio

FoodResidential and Other Building UsesPetsOccupationalPara-occupationalProximity toAgriculture

Activity Mediation

11

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 InExposure Assessment

T2 T3

1 2 3 4 5 6 7 

T1

MotherPregnancyTrimester

ChildAge

VH H

VH-H H H H H M M 

VH = very high importance for exposure H = highM = moderateL = low
37 

13

Pesticide Exposure Classification Challenges

Multiple pesticides, sources, and exposure pathwaysTypically low concentrations in food and environmental mediaShort-term variability in exposuresLimited information on relationships between activities and 

exposures

Lack of chemical specificity in non-measurement approachesLimited predictive power (low R2) for survey data

Short biological half-lives for current-use pesticidesExposure to metabolites in environmental media confounding 

biomarker interpretation

Workgroup Summary RecommendMeasurements

Biological and environmental samples are essentCore Sample Collection

- Collect cohort-wide core samples, hold for futur

- Urine from key time points for mother and young c

- Blood & milk from mother at key times; from child - Best measure of residential loading (wipe, dust, o

- Additional research needed to support use for e

classification

Sub-Sampling Measurements

- Random sub-sample with oversampling for som

high/low exposure categories using multi-medapproaches (validation)

- Consider targeted sampling based on survey in

15

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 

Core Sample Collection

Urine for insecticide biomarker analysis

- Collect from mother at T1 and end of T2 or early T3 tim- Collect from child as often as possible through age 5- Collect entire FMV void volume; collect previous and c- Store for future analysis

Other biological samples

- Blood for parent compound and other biomarkers, stor

- 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/s- 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 (- Store for future analysis 
38 

Research Needs – Residential Loa

What is likely to be the best residential metric with reoverall residential “loading”? Predicting exposure? What type of sample has lowest cost/burden and can information on other chemicals of interest? 

- Assess extant research examining this issue for OP

pyrethroid and carbamate insecticides (AHHS, CTECenters, others?)

- Analysis of Vanguard Center data- Lessons learned from application of PUF indoor vap

sampling effort and possible further assessment

- Assess the temporal variability in residential loading - Develop a participant-based sample collection and m

17

Research Needs - UrineGiven the short-term variability in urine biomarker concentrations, will urine samples allow adequate exposure classification over longer time periods?

- 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 

intervals 

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

19

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.However, there are major limitations in the use of non-measurement insecticide exposure classification approaches in the general population.

- 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

Non-Measurement Approaches

Some survey information will need to be collected for timportant sources and pathwaysProposed areas of information collection are described several slidesThe following slides discuss research that is needed to information most highly associated with insecticide exCurrent questionnaires and instruments will need to be 
39 

21

Non-Measurement Approaches:Residential Use Information

Collect basic pesticide residential use information from all participantsFocus 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 treatmentsProduct inventories may have some analytic value; need to assesstime/burden for information collection

Non-Measurement Approaches:Dietary Information

Collect dietary intake information from all participants purposes in NCS as well)Ensure that good information is collected for

- Potential highly exposed (high consumers of specific 

contain residues)

Potential low exposed (primarily organic fruits and vegConsider alternate approaches

- Collect some information outside of food instruments 

details, gardening, local farmers markets)

- Community dietary sample collection and analysis- Market basket sample collection and analysis

23

Non-Measurement Approaches:Pet Use Information

Collect Qx information about presence of pets; use as gateway question for additional pesticide use information collectionCollect 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 classification

Non-Measurement ApproachesOther Uses to Consider

Lice treatmentsUse of impregnated materials (e.g. bedding liners for etc.)
40 

25

Non-Measurement Approaches:Occupational Information

Collect information about parent occupational use of, or exposures to, pesticidesUse 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

Non-Measurement Approaches:Time/Location/Activity Information

Exposures are affected by time spent in environments residues and interaction with those environmentsGeneral information on time spent in different microenneed to be collected for multiple purposes in NCSAt this time we have limited ability to apply simple actifor improving pesticide exposure assessment 

27

Non-Measurement ApproachesGeographical Information

General geographic region may be informative regarding exposures in one NCS PSU relative to others (higher pesticide uses in some regions) Archival of satellite photos over time (every 2 years?)In rural areas, information regarding proximity to agricultural pesticide use should be collected

- GIS approaches where supported by extant data- Participant questions regarding proximity to ag use

Analyses will be limited by lack of specificity of active ingredients in most locations

Research Needs forNon-Measurement Approaches

Systematic evaluation of extant literature, recent studistudies is needed to assess predictive power of questother survey information regarding associations with eassociations with outcomes.Evaluation and assessment of questionnaires and othdiverse communities is needed to ensure that people accurate, comparable, and consistent information.
41 

29

Research Needs forNon-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- NHANES- Other recent research?

Issues

AvailabilityFundingShort time frame to complete work 

Research Needs forNon-Measurement Approaches

A possible model for systematic analysis of exposure data at Children’s Centers

Center 1 Center 2 Center 3 Center 4Center 1 Center 2 Center 3 Center 4

StatisticianExposure SpecialistEpidemiologist

Funding mechanism for PI or Post-docs at Centers? E

31

Research Needs forNon-Measurement Approaches

Near-term analyses of NCS Vanguard Center data are neededQuestions 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 

term?

- 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 forNon-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 PD

It is recommended that EPA devote time and resourcfund analyses in near term that can inform predictive data for the NCS
42 

33

Validation Sub-Sampling Measurements

Purpose

- 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 areaBy residence typeBy socio-economic statusBy agricultural proximity

Sample Size

- Cost, burden, power factors- Use of Battelle/Harvard tool

Targeted Sub-Sampling Measurem

Purpose

- Provide measurement data for improved outcome as

Recommended Approach

- Use initial survey data on pesticide use and diet to se- 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

35

Sub-Sampling Measurement Plan

The workgroup did not develop a detailed set of recommendations for the types of samples and the sub-sampling strategyMeasurements 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 somemedia

Exposure Algorithm or IndexDevelopment of an exposure algorithm or index for epiinsecticide exposure classification in the general populdifficult, time consuming task. The workgroup discusseconsiderations 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, po

cumulative exposures)

- Decisions on continuous (numerical) or categorical ind- Peer review- Ability to assess or validate inside or outside of NCS
43 

37

Co-ExposuresChemical 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? 

Lawn Care ChemicalsHerbicides are widely used, and insecticides and fungisometimes used, in lawn care products and treatment Concerns have been raised regarding the use of lawn and children’s health.While the workgroup was asked to consider exposure ainsecticides and neurological outcomes, the NCS could to more broadly examine lawn care chemical use and hNCS information collection and chemical analyses woubroadened to include lawn care products and herbicide

39

Final Workgroup RecommendationsWorkgroup 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.
44 

1

ENDOCRINE DISRUPTING

COMPOUNDS: EVALUATION FOR

NCS

Deborah Bennett, Stephanie Engel, Mike

Shelby, Heather Stapleton, Vickie Wilson

Workgroup Facilitator: Nicolle Tulve

2

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

3

Health Endpoints In addition to reproductive effects, it is 

important to include other health effects related to hormonally active compounds

 Thyroid disruption during pregnancy impacting 

neurological development

 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

4

Goals To present a method for classifying ex

endocrine disrupting compounds in th

 Context – Environmental samples may 

be available for analysis & may not be 

optimal exposure assessment for all c

 In some cases sample size will be sma

be practical to measure biological and

environmental samples within a case‐design

 In some cases sample size will be large 

not be practical to provide measurem
45 

5

Process for selecting compounds List of compounds taken from early NCS 

materials 

 How important from a health perspective and 

how much exposure there was likely to be 

 We also considered whether or not another 

group would be addressing the compounds

 Concerned with co-exposure to neurotoxins We ultimately prioritized the list to some 

degree

6

Compounds Considered Phthalates PBDEs Bisphenol‐A Phytoestrogens PFCs Perchlorate Triclosan/Triclocarban Other phenols Other Flame Retardants PCBs PAHs

 Co‐exposur Pesticides Organotins Cotinine Mercury Lead Compounds  TCDD/Fs Limited agri

pesticides

7

Challenges We have a very large set of compounds 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

8

Challenges with Biological  Blood Limited in early

childhood due tosmall blood volumes

 Limited by parent

refusal and samplecollection failure

 Urine Interferen

diapers

 Low perce

samples cthere are 

using urin

 Bags are t

preferenc
46 

9

Approach 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

 We went over all the chemicals one by one,

challenging ourselves to come up with other ideasand trying to come to a general consensus for each

compound

10

Approach Some compounds can easily be classif

questionnaire data or biological samp

available and low cost – Easy Compou

 Other compounds provide additional c

 Justification Exposure Routes by Time Period Samples Needed Exposure Metrics

11

Phthalates – Justification for Inclusion

 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

 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

12

Phthalates – Exposure Routes

 Prenatal

 Phthalates cross the placenta Direct effect on maternal prenatal thyro

 Postnatal

 Exposure from breastmilk (0‐1y) Exposure from housedust (0‐4y) Exposure from consumer products acros

lifecourse
47 

13

Phthalates – Samples Needed

 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

 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?

 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

14

Phthalates – Exposure Metric

 Pregnancy – Concentration in maternal urine, ideally more 

 For brominated phthalate need dust Variability in metabolites over time makes single spot 

 Early Childhood – Ideally childhood urine, one per year.

 For brominated phthalate need dust Possibly can extrapolate 6‐12

m dust sample back to p

 Lack of child urine will make classification impossible

 Later Childhood – Concentration in child’s urine Non‐Physical Estimations :Product‐use questionnaire unlik

quantify exposure

 Piloting needs

 Comparison of 6‐12

m dust with pregnancy dust

 Ongoing

& published studies have quantified urinary pht

variability over pregnancy

15

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

between:

 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)

16

PBDEs – Exposure Routes

 Prenatal

 PBDEs cross the placenta, exposure from 

 Postnatal

 Exposure from breast milk (0‐1 yr) Exposure from house dust (0‐4 yr) While diet is also a source of exposure, 

to estimate exposure from diet as levels 

variable and not specific to food types
48 

17

PBDEs – Samples Needed

 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)

 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)

 Questionnaires not practical

18

PBDEs – Recommendations

 Collect house dust and hand wipes

 Some PBDEs have short half‐lives in the bod

cannot be characterized for these congene

 Both are needed to differentiate exposur

milk

 Justification for use of hand wipes

 Better metric for quantifying exposure to d

used to evaluate exposure to other compou

dust

 Easy to collect and store (relatively inexpen Significant PBDE residues have been measu

wipes collected from adults and children (S

2008)

19

PBDE – Exposure Metrics

 Pregnancy – Concentration in mother’s blood Early Childhood – Environmental concentration, modify

with breastfed or not, breast milk concentration

 Later Childhood – Concentration in child’s blood Non‐Physical Estimations – There are no non‐physical

methods for evaluating this compound with the

exception of substituting mother’s blood concentrationfor breast milk concentration

 Piloting needed – Available studies looking at blood/

dust correlation

20

Bisphenol A – Justification fo

 Metabolites detectable in 90% of the 

 Biomonitoring suggests higher exposure

minority groups, children, and women

 NTP‐CERHR expert panel noted a vary

concern for:

 Neural or behavioral effects resulting fro

infant, or childhood exposure

 Accelerated puberty resulting from pren

childhood exposure

 Bulk of exposure coming from dietary 
49 

21

Bisphenol A – Samples Needed

 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

 Environmental samples ‐ None required 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

22

Biphenol A – Exposure Metric

 Pregnancy – Concentration in maternal urine, id

 Variability in BPA metabolite level over time

 Early Childhood – Ideally childhood urine one pe

 Lack of child urine will make classification im

 Later Childhood – Concentration in child’s urine Product‐use questionnaire unlikely to reliably qu

 Can ask about use of canned food, polycarbo

sippy cups. Without knowing plastic number 

contains BPA.

 Piloting needs

 Ongoing & published studies have/will quant

metabolite variability over pregnancy

23

Phytoestrogens Widespread exposure through dietary intake, especially

through soy formula in infancy

 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)

 Biological Samples ‐ urine (short half‐life, modest reproducibility

in metabolite levels across spot urines)

 Compound can be evaluated well by questionnaire/biological

samples!

 Exposure Metrics – questions on use of soy formula

24

Perfluorinated Chemicals (PFCs) –

Justification for Inclusion

 Includes perfluorooctanoic acid (PFOA); perfluo

acid (PFOS); perfluorohexane sulfonic acid (PFH

perfluorooctane sulfonamide; perfluorinated te(e.g., 6:2, 8:2, and 10:2 FtOH)

 Detected at high frequencies (>99%) in US serum 

2007)

 Detected in US house dust (Strynar and Lindstro Developmental and thyroid effects observed in 

exposures (Lau et al., 2004; Yu et al., 2009)
50 

25

PFCs – Exposure Routes

 Prenatal

 Likely crosses to fetus via bloodstream (support from

rat study by Yu et al., 2009)

 Postnatal

 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)

26

PFCs – Samples Needed

 Biological samples

 Top choice: serum

 Prenatal (3rd trimester) Postnatal (cord blood, 6 m, 2 yr)

 Breast milk not recommended as we kn

about partitioning between blood and b

 Physical/Environmental samples

 House dust (collected at 6 m, 1 yr, and 2  Hand wipes (collected at 6 m, 1 yr, and 2 

 Questionnaires

 Not validated although there are ideas a

what could be asked

27

PFCs – Exposure Metrics Pregnancy – Concentration in mother’s blood Early Childhood – Environmental concentration Later Childhood – Concentration in child’s blood Non‐Physical Estimations

 Questionnaires have not been developed for this

compound

 Piloting needed

 None

28

Perchlorate

 Water samples should be collected an

by water distribution system.

 Well water samples should be collecte

limited)

 Compound that can be evaluated well 

block

 A biomarker is available for individual  Exposure metric – Census level well w

concentrations
51 

29

Triclosan and Triclocarban – Justification for

Inclusion

 Detected in US urine (Calafat et al., 2008) Detected in house dust (Canosa et al., 2007; Geens

et al., 2009)

 Known effects on thyroid (Veldhoen et al., 2006;

Crofton et al., 2007; Paul et al., 2010)

30

Triclosan and Triclocarban – Exposur

 Prenatal

 Likely crosses to fetus via bloodstream

 Postnatal

 primary exposure from treated product

toothpaste, hand soaps/gels (age 1‐adu

 Exposure from breast milk (0‐1 yr) Exposure from house dust (0‐4 yr)

31

Triclosan and Triclocarban – Samples Needed

 Biological samples

 Top choice: urine (3rd trimester, 6 m, 2 yr, 4 yr) Second choice: serum (detected, easier to collect

urine)

 Environmental samples

 Not adequately characterized Hand wipes may be a good choice for measuring

residues

 Non‐physical measures ‐ Add questions to

survey/questionnaire regarding use of

antibacterial toothpastes and soaps/lotions/gels,

32

Triclosan and Triclocarban – Exposur

 Pregnancy – antibacterial product 

concentration in mother’s urine

 Early Childhood – antibacterial pro

concentration in child’s urine

 Later Childhood – antibacterial pro

concentration in child’s urine

 Piloting needed None
52 

33

Nonyl/Octyl Phenols – Justification for Inclusion

 4‐nonylphenol/nonylphenol ethoxylates – used in

plastics, resins/hardeners, cleaners, cosmetics

 4‐tert‐octylphenol – used in paints, plastics, floor

polish

 2,6‐Di‐tert‐butylphenol – used as a UV stabilizer

and antioxidant in petrochemicals and plastics

 Residential dust samples may be most efficient

and cost‐effective for assessing exposures

 Unlikely that a questionnaire would be informative

about exposures

34

Nonyl/Octyl Phenols – Exposure  Pregnancy and Childhood – analys

samples

 Non‐Physical Estimations – There a

physical methods for evaluating th

compounds

 Questionnaires would not be infor Piloting needed

None

35

Alternate Current‐Use Flame Retardants –

Justification for Inclusion

 Includes hexabromocyclododecane (HBCD), decabromodiphenyl

ethane (DBDPE), triphenyl phosphate (TPP), tetrabromobenzoate

(TBB), tetrabromophthalate (TBPH), tris(1,3‐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)

36

Other Flame Retardants – Expos

Routes

 Prenatal

 Likely crosses to fetus via bloodstream; 

evaluated

 Postnatal

 Exposure from breast milk (0‐1 yr) Exposure from house dust (0‐4 yr) While diet is also a source of exposure, 

to estimate exposure from diet as levels 

variable and not specific to food types
53 

37

Other Flame Retardants – Samples

Needed

 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

 Physical/Environmental samples

 House dust (collected at 6 m, 1 yr, 2 yr) Hand wipes (collected at 6 m, 1 yr, 2 yr)

 Questionnaires not practical

38

Other Flame Retardants –

Recommendations

 Collect house dust and hand wipes

 Questionnaires not practical Some have short half‐lives in the body and 

cannot be characterized using serum

 Justification for use of hand wipes

 Better metric to quantify exposure to dust Can be used to evaluate all flame retardant Easy to collect and store (relatively inexpen Significant residues of HBCD, TBB, TBPH, TP

have been measured in hand wipes collecte

and children (Webster and Stapleton, work 

39

Other Flame Retardants – Exposure Metrics

 Pregnancy – Concentration in mother’s blood for

some, environmental concentration

 Early Childhood – Environmental concentration Later Childhood – Concentration in child’s blood for

some, environmental concentration

 Non‐Physical Estimations – Non‐physical measures

are not practical, potentially substitute one time

period for many

 Piloting needed

 Some research becoming available

40

PCBs

 Questionnaire – fish consumption, age  Biomarker available May want environmental sample in so

housing stock
54 

41

PCBs – Exposure Metrics Pregnancy – Concentration in mother’s blood Early Childhood – Use concentration in child’s

blood from later time period

 Later Childhood – Concentration in child’s blood Non‐Physical Estimations:

 Pregnancy – Fish Consumption Childhood – Fish Consumption/ potentially need

environmental measurement for participants in older

housing stock

 Piloting needed ‐ None

42

PAHs Exposure primarily from traffic, cookin

and certain foods

 Traffic exposure can be evaluated thro Exposure to foods and cooking metho

addressed by questionnaires

43

Co‐Exposures Considered

 Organotins – Can be measured in blood but not a standard

method, found in the home so can be measured in dust

 Cotinine – Questionnaire – Cigarette use and exposure to

second hand smoke, biomarker also available

 Mercury – Questionnaire – Fish consumption, biomarker

also available

 Lead – Questionnaire – Age of home, condition of paint,

low cost biomarker available

 Indoor Pesticides – Consult with pesticide group

44

Agricultural Pesticides

 There may be additional pesticides of c

terms of endocrine disruption by distanand use on fields should be able to be c

each Census block and not on an individ

 Compounds that can be evaluated well 

block
55 

45

Environmental Sampling Conclusions Critical time window that cannot be captured by

biological samples and/or questionnaires is 0‐12

months

 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) Organotins Nonyl/octy phenols

46

Biological Sample Research N Develop a diaper or an insert that can 

easily by participants and that does no

interference problems

 Critical for determining exposure in fir

life to:

 Phthalates Bisphenol‐A Helpful for Triclosan/Triclocarban

47

Compounds Considered

 Phthalates – urine, dust PBDEs – blood, dust Bisphenol‐A  ‐ urine, Q Phytoestrogens ‐ Q PFCs – blood, dust Perchlorate – Regional Triclosan/Triclocarban – Q, urine Other phenols ‐ Dust Other Flame Retardants ‐ Dust PCBs ‐ Q PAHs – Q, GIS

 Co‐exposures of concern Pesticides Organotins ‐ dust Cotinine – Q, biomarker Mercury – Q, biomarker Lead – Q, biomarker Compounds not discussed TCDD/Fs Limited agricultural pesticides

48

What Sort of Environmental S Dust Wipe Hand Wipe Recommend collect and store to le

future grant support if funds are li
56 

49

Evaluating Environmental Measures Correlation with biological sample % of samples likely to be above LOD Sample can be evaluated with multiple extraction

methods

 Stability of sample

50

Dust Methods HVS3: Pro: Uniform sample collection, pow

collects sample quickly

 Con: Heavy and awkward

 Mighty Mite: Pro: Easy to carry

 Con: Often overheats, can be time cons

 Participant Vacuum: Pro: Easy to Collect

 Con: Not all people have vacuums, no u

 Provided Vacuum: Pro: semi‐uniform, avoi

 Con: Not sure all participants will collect 

uniform

51

Dust Collection Evaluation Need to collect dust samples through multiple methods

in conjunction with biological samples and determine

which method has the best correlation

 Samples Available: 1) EPA analyzing HVS3 and participant vacuum cleaner

bags and CDC is analyzing biological samples, waiting for

analytical results.

 2) UC Davis has 25 co‐located HVS3 and Mighty mite

samples with biological samples from within a couple of

months. Analysis not planned.

52

Household Wipes Collection from hard flooring is proble

potential high loading for phthalates

 David Camann is experimenting with d

wipes
57 

53

Employing Hand Wipes for Measuring Exposure

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

54

What Compounds to Analy Ideally we would like to include a wide 

compounds – this adds costs

 One idea: Two Dimensional Gas Chrom

with Time‐of‐Flight Mass Spectrometry 

MS)

 Response factor quantification based o

approaches can be considered for new 

 Significantly enhanced chromatographi

limits interferences

 Detection limits similar to conventional 

55

Cumulative Exposure We acknowledge that in a perfect world, we would be able to

sum across all the compounds based on the toxicity

 Only limited data is available to do this in an effective way 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.)

 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

56

Biological/Environmental S Goal: Is dust representative of exposu

childhood?

 Stapleton Study – 60 kids, 12 – 30 mo

handwipe, blood, PBDE and other flam

 Webster Study – Better correlation be

blood/handwipes than blood/dust for 

 Bennett Study – 100 kids 3‐6 years, bl

and participant vacuum dust, PBDE an

 Hertz‐Picciotto Study – 33 bloods @ 1 

month dust – Analysis not planned
57

Variability in Dust Concentrations Goal: Can we say dust collected at 6 months is

representative of dust collected during pregnancy?

 Bennett Study – 50 HVS3 samples 1 year apart

being analyzed for PBDEs, houses with young kids

 Hertz‐Picciotto – 25 samples from pregnancy visit

and 6 month visit – Analysis not planned

58

Variability during Pregnanc Goal: How representative is spot urin Engel Study: Phthalate and phenol me

(BPA, TRCS, 2,5‐DCP, BP3) measured i

women enrolled with 3 urines per wo

Amniotic fluid being processed.

 Hertz‐Picciotto Study: 65 woman with 

samples, 40 more with 4 or more. At 

hour sample per woman. Analysis not 

59

Integration with Vanguard Centers 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

 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

60

Conclusions

 Potential limitations with biological samp

early childhood coupled with the lack of 

physical measures support need for envi

sample/hand wipe in early childhood

 Environmental analysis methods should 

to get as many compounds as feasible in 

effective way

 Note that samples may be able to be sto Develop a urine collection method that w

acceptable and limit interference

58