Examining the influence of environmental exposures
on various health indices is a critical component of
the National Children’s Study (NCS), one that
will require determining a) the likely chemical
and biologic agents of interest, b) the most
cost-effective approaches to measure these chemicals
in environmental and biologic matrices, c) how
to best design and administer questionnaires, and d)
cost-effective statistical sampling strategies for
gathering the necessary environmental and personal
exposure-related information with minimum burden to
the participants. The Chemical Exposure Work Group
of the NCS has been evaluating the available information
on exposure monitoring in the context of an epidemiologic
study design. In this article we synthesize the recent
findings from this NCS-sponsored work group activity,
which is presented in a comprehensive white paper (NCS
2004a), regarding potential alternatives for assessing
subject-specific exposures in the context of an epidemiologic
study design.
In general, children and adults are exposed to a wide
variety of persistent and nonpersistent chemicals in
the environment, some of which are either known or suspected
to cause health effects and/or exacerbate health conditions.
The NCS hypotheses attempt to link certain types of exposures
with specific health effects. For example, one NCS hypothesis
holds that exposure to several indoor and outdoor air
pollutants, including particulate matter (PM), ozone,
and certain volatile organic compounds (VOCs), and bioaerosols
(including allergens, endotoxin, and mold) is associated
with an increased incidence of asthma in children. Much
of the epidemiologic asthma research to date has focused
on the acute effects of air pollution and aeroallergen
exposures and on housing and personal factors that may
trigger asthma attacks. For example, researchers have
shown that acute air pollution, including fine PM and
sulfur dioxide (SO2), exacerbates asthma and
also may increase its incidence (Dockery and Pope 1994;
Schwartz et al. 1993; Tolbert et al. 2000). Additionally,
children who live near a busy road and are exposed to
motor vehicle emissions have been shown to be at increased
risk of wheezing, a symptom of asthma (Venn et al. 2001).
Researchers have also shown associations between wheezing
or asthma incidence and exposure to indoor allergens
such as dust mites or cockroach-related allergens (Finn
et al. 2000; Platts-Mills et al. 2001). Chronic asthma
studies have shown increased prevalence of respiratory
symptoms for areas with higher air pollutant levels (Sunyer
2001). Because the long-term effect of these air pollutant
and allergen exposures on asthma incidence and severity
are not well understood, the NCS is planning to study
the effects of indoor and outdoor air pollution and allergen
exposures on asthma incidence after adjusting for potential
confounders. However, as discussed below, complete exposure
assessment to all these chemical and biologic agents
of concern is a complex task.
Recent studies have also shown associations between
prenatal exposures to ambient particulates and gases,
such as carbon monoxide (CO), SO2, and nitrogen
oxides (NOx), and adverse birth outcomes such
as preterm birth or fetal mortality (Bobak 2000; Pereira
et al. 1998; Ritz et al. 2002; Rogers et al. 2000; Xu
et al. 1995). In addition, prenatal exposures to residential-use
pesticides such as chlorpyrifos and diazinon have been
associated with undesirable birth outcomes, such as low
birth weight or size (Berkowitz et al. 2004; Whyatt et
al. 2004). Moreover, diagnoses of autism and attention
deficit disorder (ADD) have been on the rise in recent
years, prompting concern over potential relationships
between such neurobehavioral outcomes and exposures to
chemicals in the environment. Associations between exposures
to lead and IQ deficits in children have already been
documented (Bellinger et al. 1992; Koller et al. 2004;
Needleman 1995). Similarly, one NCS hypothesis holds
that repeated low-level exposure to nonpersistent pesticides in
utero or postnatally increases risk of poor performance
on neurobehavioral and cognitive examinations during
infancy and later in childhood, especially for those
with genetically decreased paraoxonase activity. Many
of the organophosphate and carbamate pesticides used
in agricultural and residential settings are neurotoxic
and are suspected to cause neurobehavioral deficits in
children. For example, members of the pyrethroid and
organophosphate classes of synthetic insecticides have
been identified as toxic to developing nervous systems
(Olson et al. 1998; Roy et al. 1998; Weiss 2000). The
ages during which children are most vulnerable to disruption
of their neural development because of exposure vary
by substance, dose of the substance, and mechanism of
action (Adams et al. 2000). In addition, animal toxicology
studies have shown that in utero and subsequent
exposures to environmental agents--such as bisphenol
A, atrazine, and Pb--can affect the endocrine system,
which has led to a hypothesis that children’s exposure
to these chemicals could lead to an altered age of puberty.
A number of other important NCS hypotheses have also
recognized the contribution of personal activities and
exposures--such as dietary practices--as either
confounders or effect modifiers in the hypothesized environmental
factors resulting in various adverse health conditions
in children. Recording dietary intake and consumption
amounts is an integral part of assessing nutrition and
exposures to persistent and nonpersistent chemicals from
the dietary pathway. Accounting for changes in the dietary
intake and activities of children is a difficult but
important problem because these changes could be caused
by societal as well as lifestyle changes. Therefore,
the study has to integrate information collected at the
individual household level with community-level and other
broader-scope data for these variables.
As the preceding examples show, determining what to
measure and when to measure is a very complex issue for
consideration in the design of the NCS. Environmental
exposures can be quantified by three methods: direct
environmental or personal measurements, collection and
analysis of biologic samples (e.g., blood, urine, hair,
saliva), and indirect measurement--including questionnaires,
time-activity diaries, or geographic information systems
(GIS) techniques--often combined with environmental data
using existing exposure models. Choosing an
appropriate method can be daunting. Choices that might eliminate measurements
of certain chemicals might also mask the synergistic effects of the chemicals
on the fetus or developing body and lead to erroneous conclusions about the
outcomes of concern. Additionally, participant burden and the costs of sample
collection and analysis can have a major influence on method choice in a study
the size of the planned NCS. Examples of commonly used direct exposure measurement
approaches for pollutants of interest to the NCS include biomonitoring (e.g.,
blood, hair, or urine samples) for persistent pesticides, some nonpersistent
organics (e.g., organophosphate pesticides, phthalates), and metals, and indoor,
outdoor environmental, and personal monitoring of exposures to criteria pollutants
(e.g., PM, gaseous pollutants) and nonpersistent pesticides (e.g. organophosphate
and pyrethroid pesticides).
Before choosing the various measurement methods to
be used in exploring the NCS hypotheses and formulating
an exposure monitoring program for the NCS, study designers
must first identify the chemicals or chemical classes
and biologic agents of interest for each hypothesis and
then the key media, routes, and pathways of exposure
for each chemical type or class. However, the primary
sources and routes of exposures to chemicals and allergens
vary by age of the study subject, and the specific media
and routes of exposure that are of concern in children
start to change dramatically during the course of early
infancy and into the toddler stage. Young infants and
children exhibit considerable hand-to-mouth or object-to-mouth
behavior. Crawling on carpets and hard surfaces increases
the potential for dermal and nondietary ingestion of
pesticides, other household chemicals, and chemicals
in soil or dirt tracked in from outdoors. Exposures in
day care and school settings can become a concern for
children younger than 1 through 6 years. The NCS measurement
program should thus consider monitoring non-home environments
as well as residential environments to fully assess the
role of early childhood exposures in the development
of asthma and both neurobehavioral and other developmental
disorders. As children get older, they become more active
and mobile, and their activities and behaviors become
more variable. Consequently, identifying and monitoring
the different microenvironments in which young children
spend most of their daily waking hours become more difficult.
These children often engage in outdoor sports and episodic
eating behaviors at home, in school, or in local restaurants.
Inhalation and dietary ingestion exposure routes become
more significant for school-age children. During teenage
and young adult years, times spent in friends’ homes,
school, malls, movie theaters, other public places, and
commuting increase the diversity of locations and sources
that contribute to exposures of children older than 12
years. For example, a study of high school students in
New York City showed that for certain VOCs (e.g., benzene,
toluene, xylenes), urban motor vehicle emissions contribute
to personal exposures, whereas for several other air
toxics (e.g., aldehydes), concentrations in indoor environments
influence personal exposures of teenagers (Kinney et
al. 2002).
Identifying key media and routes of exposure will help
focus the design of the study’s exposure component
and will also allow for the dedication of valuable study
resources to the study of major sources and factors of
childhood exposures. For example, the exposure pathway
for many chemicals of concern for the nursing infant
is mother’s milk. Accordingly, mother’s milk
would be collected and analyzed during the nursing stage
of the infant. Characterization of most significant contributors
to children’s exposures to pollutants will enable
researchers to employ more extensive methods for measuring
these important exposures while administering less-detailed
measurements (e.g., integrated samples or measures with
lower precision, accuracy, and sensitivity) to quantify
secondary routes or pathways of exposures.
Exposure Measurement Considerations
As discussed above, the important locations, media,
and routes of exposures to environmental agents may vary
by chemical type and by the age of the child. Exposures
to some of these chemicals such as outdoor concentrations
of fine particulates or pollen are more widespread, but
concentrations of many other pollutants such as combustion-related
pollutants (e.g., NOx, air toxics from motor
vehicles) are higher near roadways or in cars or buses.
Exposures to pesticides are highly variable, depending
on the proximity to agricultural fields or during times
of indoor or outdoor residential application. Consequently,
concentrations of most of the chemicals may vary considerably
over time, geographic locations, and seasons. As a result,
quantifying exposures to short-term or intermittent acute
exposures requires a measurement system that incorporates
periodic monitoring (perhaps triggered by reported chemical
use, e.g., a residential-use pesticide or consumer products)
as well as more routine surveillance-type monitoring.
However, measurements collected as a result of a particular
event constitute a type of adaptive sampling, and those
data are likely to result in biased estimates of the
distribution of exposures if great care is not used to
analyze them properly (i.e., researchers need to consider
the frequency of use events over time as well as the
magnitude of exposure per event).
Environmental sampling methods vary by analytical sophistication
and level of precision. Unfortunately, increased sensitivity,
accuracy, precision, and temporal resolution often come
at the cost of more expense (including both instrumental
and operating costs) and larger instrument size. Personal
monitoring is not always possible for all the environmental
agents because of sample volume constraints dictated
by analytical requirements. Moreover, active personal
samplers are often heavy and bulky and are not suited
for use by children younger than 7 years. Passive samplers
such as the 3M (3M, St. Paul, MN) or Ogawa (Ogawa & Co.,
USA, Inc., Pompano Beach, FL) badges are lightweight
and may be used by small children for monitoring VOCs
and NOx or SO2, respectively. However,
all types of personal samplers require parental supervision
and collection of accurate activity and instrument use
information. Active or passive devices can be used for
fixed-site indoor or outdoor environmental monitoring
applications. Use of these sampling devices, especially
active samplers, requires technician visits to homes,
schools, and other selected microenvironments of the
study subjects. Less detailed measurements may be more
feasible to collect from many homes. Passive or active
devices could be shipped by mail or installed by a field
technician in homes. The parents of the study subjects
can return these devices on a prespecified schedule.
Results from the analysis of these monitors can then
be used to determine if additional more accurate or shorter-term
sampling is recommended for a given household. Many biologic
specimens will most likely be collected during technician
home visits or during checkups at doctors’ offices.
However, biologic measures collected in a noninvasive
manner (e.g., hair, nail, saliva, lost teeth, and perhaps
urine samples) could be collected directly by the parents
without a technician visit. Where and how these samples
are collected depend on the biologic sample, the chemical
of interest, and the age of the participant. Unfortunately,
there are still no practical low-cost technologies for
determining exposures to indoor allergens of concern
(e.g., dust mites, mold, endotoxin) that are linked with
the asthma hypothesis. Because indoor bioaerosol levels
of allergens and their viability can vary seasonally,
it is desirable to collect indoor air, dust, and furniture,
mattress, and stuffed toy samples frequently over the
course of a year. Ideally, quarterly samples, starting
with preconception and through 3 years of age, are recommended.
Fewer annual samples collected after 3 years of age may
be considered (NCS 2004a).
In addition to collecting environmental and biologic
measurements, collecting questionnaire and time-activity
diary data is also important. This information will be
used not only to augment any measurement data collected
but also can be used to estimate exposures in the absence
of direct monitoring data because of subsampling of participants
or time periods to be measured. In essence, such indirect
data may provide surrogate or indirect estimates of exposures
to environmental agents. Furthermore, questionnaires
will be used to obtain background information from the
study population cohort--so that inferences are
strengthened when subsampling is required--and to
adjust for item nonresponse. Questionnaire information
will also be cross-compared with other survey information
where appropriate to relate item response and generate
a measure of representativeness of the cohort (e.g.,
to compare participant and household characteristics
with census data).
Given the size and long-term duration of the NCS, questionnaires
are expected to be a key component of any planned exposure
study design for the NCS. They will be used to enroll
the participants and gain understanding about the family,
family structure and relationships, education, occupational
and residential history, type and nature of potential
exposures, activity and behavioral profiles, and medical
and health-related information. The content of the questionnaires
and the frequency and mode of administering them will
vary depending on the nature of the chemical or chemical
class, the hypothesis of concern, and the age of the
child (or fetus). Also, questionnaires may provide some
information on past exposures to the fetus, especially
during the first trimester when knowledge of conception
at least for part of the trimester is unknown to the
parent. Nevertheless, recruiting women before they are
pregnant and obtaining early pregnancy (e.g., first 20-30
days of gestation) exposure measures can be possible
under a national probability sample of households (NCS
2004b). Collecting both questionnaire information and
early pregnancy exposure and biologic measures for a
sample of women should also provide a way to check for
potential recall bias.
Questionnaires regarding the presence of, or contact
with, potential sources of exposures to chemicals in
homes, schools, and other key locations (e.g., to PM,
NO2, VOCs) where a child spends his or her
time each day have been used in various community health
studies. However, the reliability of these survey instruments
in predicting exposures to chemicals of concern in the
absence of actual exposure measurements is uncertain,
and they should be used cautiously. All survey instruments
in the NCS should be pilot tested and used in conjunction
with direct exposure-related measurements for a sample
of participants to obtain some measure of validity.
Technologic advancements may reduce the time burden
of obtaining questionnaire information. For example,
wireless-coupled infrared technologies [e.g., radio frequency
identification (RFID) chips or sensors) may provide information
on updated consumer source inventory or usage, by collecting
and transmitting product information via RF spectrum,
which would be more accurate and useful for exposure
modeling, and without participant burden. Greater use
of web-based technology may improve data collection and
data processing, generating savings for the participants
and the researchers. Accuracy and completeness of the
item response can be improved with automation of responses
via personal digital assistants (PDAs) or similar devices
because the data checking could be done very quickly.
Questionable responses could be verified in a timely
manner via human or machine interaction.
The discussion presented thus far has addressed the
important strengths and weaknesses of alternative exposure
measurement methods. However, an important operational
question for the NCS is how to determine an optimum strategy
for a measurement program (i.e., one that uses environmental
monitoring, personal monitoring, biomonitoring, questionnaires,
or other indirect methods in a most cost-effective, reliable,
and minimally burdensome manner) for the selected health
hypotheses. We have examined this complex issue and developed
a recommended approach for selecting an appropriate exposure
measurement method (or methods) for different classes
of chemicals and exposure situations.
Figure 1 provides an overview of the steps in selecting
the appropriate exposure measure(s). Initially, the researcher
must identify the chemical(s) and associated pathways
of exposures that need to be quantified (either as main
effects or as potential confounders or effect modifiers)
to test the study hypothesis. The life stage(s) at which
the exposure(s) need(s) to be measured should also be
determined. The initial step in selecting the exposure
measures will include an evaluation of whether the exposure
at the critical life stage can be reliably estimated
using only questionnaire data or another indirect low-cost,
low-burden measure of exposure (e.g., ambient monitoring
data, emissions inventories, time-activity logs,
consumer product use information) alone. When such indirect
methods exist and offer an acceptable measurement error
for testing a given hypothesis, they can then be used
with the aid of GIS tools because of lower potential
cost and participant burden. Prior epidemiologic studies
indicate that when relative risks are high and exposure
misclassification is not too high, questionnaire data
can be used as a surrogate for direct measures. Examples
include questionnaire-derived estimates of cigarette
smoking in relation to lung cancer and alcohol consumption
in relation to fetal alcohol syndrome. However, we again
recommend that, before using questionnaire-derived or
other indirect measures of the exposure, the NCS validate
the measure against more direct measures (e.g., biologic
or environmental monitoring). In many instances, questionnaire
data alone will not provide a reliable dosimeter for
the environmental chemicals of concern for the NCS and
may need to be supplemented with other direct measures
such as passive environmental sampling or biomonitoring.
Nevertheless, the questionnaire data might still be useful
in estimating the contact time (frequency and duration)
that an individual may have with the environmental media
that contains the chemical of interest or in identifying
changes in environmental/residential conditions and sources
over time. Therefore, questionnaire data will provide
a valuable addition to the direct measures.
In selecting the direct measures, the researcher must
decide whether to collect a biologic or an environmental
measure or some combination of both. In addition to technical
factors, participant burden and cost are among the key
issues to consider in selecting one or both of these
sample types. Furthermore, regardless of which measure
is selected, timing of sample collection and the averaging
period represented need to be tailored to coincide with
critical life stages of vulnerability. Biologic measures
have the advantage over environmental measures of providing
an integrated dosimeter, reflecting exposures from all
sources and pathways. They also indicate intake/uptake
and absorption into the body across all routes. However,
biomarkers alone cannot normally be used if knowledge
of route of exposure is necessary for testing the study
hypothesis. Moreover, when associations are detected
between chemical exposure and health outcome, researchers
must determine how to mitigate or prevent the exposure,
which typically requires knowing the source and pathways
of the exposure related to the effect. Environmental
measures, on the other hand, can provide pathway and
source-specific exposure estimates for many of the agents
but can be burdensome or costly to collect or analyze
depending on the chemical or biologic agent of interest.
Often, biologic and environmental samples provide a snapshot
of exposures and may require repeat measurements when
exposure conditions are not stable over time. Combining
biologic and environmental measures allows comparison
of the relative contribution of different routes and
media to internal dose, facilitates the identification
of missing exposure measurements (e.g., locations that
were not sampled), and provides a link to identify locations
and sources of exposure, all of which help researchers
to determine how to reduce exposures and risks.
Table
1
|
In general, a biologic measure, for example, serum
levels of polychlorinated biphenyls (PCBs), could be
a dosimeter of choice for many of the persistent organic
pollutants and certain metals (e.g., Pb, mercury) measured
in blood (see Table 1 in Needham et al. 2005). In addition,
biologic measures can provide reliable dosimeters for
some of the nonpersistent compounds listed in Table
1 in Needham et al. (2005), particularly when exposures
are constant, intraindividual variability is low, and
pathway-specific information is not needed or exposure
occurs principally from one pathway, such as in the
measurement
of plasma or urinary cotinine as a dosimeter of cigarette
smoke exposure. In some instances, however, collecting
one or more types of biologic measures from a very
young child may not always be easy (e.g., from newborn
or young
infants). In some of these situations, questionnaires
and low-cost direct environmental measurements may
be used instead, when feasibility and other factors limit
the use of biomonitoring. For example, questionnaire
information has been shown to be a good indicator of
exposure for environmental tobacco smoke. There are
low-cost
methods for measuring cotinine on a filter that has
been shown to have very high association with biomarker
levels.
Also, depending on other information needed about the
environment or the exposure, researchers may choose
an alternative type of an environmental sampling approach.
For example, collection of dust samples (e.g., house
dust, carpet dust, attic dust) over 2-3 months
before removal and analysis or long-term passive monitoring
with existing or emerging technologies might provide
good indicators for a number of potential or historical
exposures to the infant/fetus, especially when concurrent
biologic or environmental measures are not available.
An environmental measure will be necessary when no
biologic measure is available, as is the case for most
of the criteria air pollutants and bioallergens. In addition,
an environmental sample may be the measurement of choice
for exposures that occur predominantly by one route.
For example, inhalation exposures to many of the VOCs
listed in Table 1 in Needham et al. (2005) may be measured
with the lowest cost and participant burden by using passive diffusion badges.
The internal dose is then estimated based on models. In general, whenever possible,
collection of both biologic and environmental measurements are encouraged because
together they provide a much more complete picture of media, routes, pathways,
and physiologic factors that influence exposures of a child.
Quantifying exposures to the nonpersistent compounds
listed in Table 1 in Needham et al. (2005) will be difficult,
particularly in instances of multimedia sources and sporadic
exposures such as the nonpersistent pesticides when exposures
are variable. These exposures can occur simultaneously
from multiple routes (dietary and nonintentional ingestion,
inhalation, and dermal absorption), can vary dramatically
within a particular group or across populations depending
on use patterns, and are difficult to quantify by questionnaires
only. These situations will likely require intensive
sampling and a repeat-measures design, and they may require
a combination of both environmental and biologic monitoring
supported by questionnaire information. Questionnaires
or checklists have been used in past exposure studies
to estimate/classify individuals by frequency of exposures
to household products.
Epidemiologic Study Design Considerations
In addition to determining what measurement methods
to use, NCS researchers must also determine optimum sample
sizes for obtaining measurement data. Sample size determinations
should be made on an epidemiologic basis. More common
health outcomes or relative risks > 1.3 can be readily
tested on a large portion of or on the full NCS cohort.
However, rarer outcomes (e.g., autism, certain birth
defects, or reproductive health outcomes) or exposures
that are unique to certain subgroups may be more efficiently
tested using a case-control or a nested case-control
study design involving fewer subjects. For example, in
studying the cases of autism, researchers might use a
nested case-control design in which a large screening
sample is used to identify the cases and a subsample
of the non-case sample members is selected for the control
sample. However, some environmental or exposure samples
must still be collected for the entire cohort because
case status will be unknown until later in the study.
Properly analyzing the exposure and outcome data from
this type of design will require considerable care.
The large sample size and longitudinal nature of the
NCS raise unique statistical issues, such as obtaining
sufficient samples to provide adequate statistical power
to detect health effects attributable to environmental
and personal exposures with a minimum amount of burden,
while still being cost-effective and staying within the
study’s overall budget. Rather than measuring the
full cohort for every hypothesis, researchers could draw
a sample randomly using a stratified or matrix sampling
approach to minimize overlap and burden. The sample could
then be assigned to subsamples covering critical life
stages targeted to answering specific hypotheses or having
common measurement requirements (e.g., hypotheses requiring
similar exposure measures, collected at similar time
points, might be grouped together). Unrestricted randomization
may not be practical for this purpose, but academic medical
centers, primary sampling units, or other geographic
sample areas can be randomly assigned to test specific
hypotheses or collect more detailed exposure measures
so that no sample household is overburdened with excessive
numbers of environmental measurements, biologic samples,
or questionnaire items.
In developing an exposure assessment strategy for the
NCS, researchers should carefully analyze each hypothesis
to determine the various appropriate measures of exposure,
including both basic (or core) and more detailed direct
measures, as well as indirect measures (e.g., ambient
monitoring data, time-activity diaries). The resulting
measurement design and statistical analysis plan should
consider cost, burden, and level of detail (i.e., accuracy,
precision, sensitivity, specificity, temporal resolution).
Given the measurement design, statistical analysis plan,
and the basic features of the sampling design for recruiting
participants (e.g., multistage probability-based sample),
researchers should determine the required sample size
for the full cohort and possibly for a subsample in which
more detailed measures are collected. If the full NCS
cohort is not required to answer the questions of interest,
researchers should develop a plan for random assignment
of NCS cohort members to a subsample to support the specific
hypothesis. With this main objective in mind, researchers
at the U.S. Environmental Protection Agency, Battelle,
and Harvard University have undertaken a project to develop
cost-effective statistical sampling strategies and optimal
design considerations for the NCS. The following material
regarding the design strategy for collecting exposure-related
information is derived from the recent Battelle/Harvard
report (Strauss et al. 2003).
The low-cost, low-burden methods such as questionnaires,
emissions inventories, and ambient pollution surveillance
data could easily be applied to a large cross section
of the NCS. However, these methods are not likely to
be sufficient for completely characterizing the participants’ actual
exposures, and even questionnaires do not have a low
burden unless they are very short, which is not likely
to be the case for the NCS. The lower level of detail
and quality (i.e., accuracy, precision, specificity,
and temporal resolution) associated with these methods
can be problematic in generating data across the entire
cohort. However, biologic samples or low-burden environmental
samples that can be collected in a noninvasive manner
(e.g., urine or passive air samples) may be appropriate
in some instances for the entire cohort. Participants
are more likely to understand the value of these measures,
and, for certain chemicals, these samples are likely
to be more informative than the survey data alone. In
general, questionnaire data should be restricted to items
directly related to exposures of interest, or they should
cover time periods that are not included in monitoring
(e.g., retrospective or changes over time between monitoring
visits). Surveys could include some core items and other
items that may be used only for subsamples addressing
specific hypotheses. In addition, if numerous questionnaire
items are relevant to certain hypotheses, a short version
for the primary sample and a long version for the subsample
participating in more detailed monitoring may be appropriate.
However, questionnaires and other surrogate exposure
assessment tools should be revised periodically to reflect
changes in lifestyle factors, sources, and societal conditions
over time.
Although recruiting study subjects may be difficult,
keeping them in the study throughout the full period
of 21 years may be even more difficult. Because of the
study’s length, both nonresponse over the course
of a monitoring period (i.e., wave nonresponse) and attrition
or dropout are concerns. Wave nonresponse refers to a
study subject missing data for one or more planned sampling
events but remaining in the study. Strauss et al. (2003)
evaluated the influence of both these factors on the
estimated study power, as did reports developed for the
NCS Sampling Workshop (NCS 2004b). Assuming reasonable
levels of attrition and wave nonresponse (ranging from
10 to 30%), Strauss et al. (2003) found that these factors
seem to have minimal effect on the resulting power and
efficiency of the substudy samples.
Strauss et al. (2003) formulated a tentative design
approach for the environmental component of the NCS that
centers on hierarchical methods of sampling from the
NCS cohort. In this strategy, representative subsamples
drawn from the total NCS cohort are used for conducting
more focused and detailed environmental and exposure
measurements and for characterizing the relationship
between a) the basic (or core) measures of exposure
likely to be explored in the full cohort (e.g., low-cost,
low-burden measurements) and b) the more detailed
exposure measurements collected in subsamples. The studies
conducted on a small yet representative subsets of the
NCS cohort may also include additional repeated sampling
for biologic specimens to capture temporal variability
in biomarker chemical concentrations; concurrent analysis
of a subset of biologic and environmental samples to
measure VOCs, semivolatile organic compounds, and biologic
pathogens to characterize measurement error in questionnaires
and other methods used to act as surrogates for these
types of exposures; and higher-technology methods to
capture exposure-related behavior (e.g., global positioning
systems, accelerometer, or heart-rate monitor to capture
physical activity) with a higher degree of precision.
In most cases, according to Strauss et al. (2003), these
carefully designed subsamples provide adequate power
and precision for characterizing the relationship between
health outcomes and measures of exposure using sample
sizes in some cases as low as a few thousand respondents,
with exceptions typically occurring when the prevalence
of the health outcome is very low (e.g., autism) and
the relationship between the core and detailed measures
of exposure is very weak.
Because some of the efficient design options for linking
health outcomes to exposure metrics are outcome dependent,
collecting basic (or core) exposure measures from all
study subjects in a consistent manner with a sampling
plan that provides coverage across life stages will be
critical. Having exposure-related information available
for all study subjects at different stages of development
for the subject child will also be critical to support
health-outcome-oriented research in which the biologic
cause of disease is not well understood and the disease
is rare. The collection and archiving of biologic samples
(e.g., blood, hair, or urine) could serve as a foundation
for some but not all exposure-related research. To provide
coverage across exposures that cannot be assessed retrospectively
using archived environmental or biologic specimens, the
NCS will likely need to employ the prospective collection
of less-detailed exposure-related information, including
the use of questionnaires to capture exposure-related
behavior information on activity, diet, and consumer
product use; collection of house dust samples; abstraction
of medical records and/or diaries during pregnancy to
capture fever and exposure to biologic pathogens; and
reliance on independent data sources such as ambient
air monitoring data obtained from the U.S. Environmental
Protection Agency Aerometric Information Retrieval System
(AIRS).
The hypothesis on neurobehavioral or neurocognitive
health effects from exposures to environmental pesticides
highlights how combined biomarker, environmental, and
questionnaire information can be used in the NCS. Some
health effects might be related to long-term average
pesticide exposure, in which case an environmental measure
(e.g., a house-dust or passive air sample) might be an
appropriate measure of exposure for use in these studies.
Alternatively, if an adverse health effect is related
to an acute pesticide exposure event, questionnaire information
regarding consumer product use and other exposure-related
behavior combined with periodic biologic monitoring (e.g.,
for urinary pesticide metabolites triggered by the occurrence
of periodic events) might be better suited to estimate
the impact from these episodic events. Generally the
urinary metabolite measurements represent roughly only
a 24- to 72-hr exposure time frame, whereas dust or semipermeable
membrane diffusion would cover weeks or months.
One possible sampling strategy proposed in Strauss
et al. (2003) for the detailed exposure study is randomly
selecting and recruiting a subsample of participants < 10%
of the full cohort, say, about 1,000-5,000 participants
among women planning pregnancy or in early stages of
pregnancy. However, the actual sample size necessary
to provide detailed exposure assessment information to
the NCS and to serve as a basis for adjusting relationships
for measurement error in basic measures of exposure may,
in fact, be different than the 1,000-5,000 subjects
chosen here as an example at each stage of life. The
sample size and timing of detailed measurements will
be important topics of research, especially if the recommended
approach is adopted as part of the overall strategy for
exposure assessment. Of these 1,000-5,000 women
who participate in the aggregate exposure study during
this first stage (e.g., the first year of study), 40%
(or 400-2,000 women) could be selected at random
to participate in the aggregate exposure study during
the first two stages of vulnerability, and 16% (or 160-800
women) would be encouraged to participate in the aggregate
exposure study for the first three stages of vulnerability.
At each subsequent stage of vulnerability covered by
the NCS, the aggregate exposure study would be replenished
to achieve a total sample size of 1,000-5,000 study
subjects by enrolling 600-3,000 study subjects
for the aggregate exposure study from a pool of available
NCS study participants who previously had not participated
in the aggregate exposure study. Of the 600-3,000
study subjects chosen for participation in each subsequent
stage or year, 240-1,200 would participate in two
consecutive phases, of which 160-800 would participate
in three consecutive phases. This hierarchical sampling
or recruitment strategy offers the advantage of both
samples (i.e., the core and the detailed samples) being
selected from the same finite study population. As a
result, a small number of study participants in both
samples can provide data to assess the assumption of
transferability of findings. Table 1 summarizes the required
number of subjects that would need to be recruited under
this rolling enrollment strategy for a hypothetical total
sample size of 1,000 subjects. Alternative but similar
recruitment and sampling strategies could also be considered.
Investigation of the associations between children’s
environmental exposures to chemical and biologic agents
and various health outcomes is an important component
of the planned National Children’s Study. The health
outcomes of interest to the NCS include such conditions
as asthma, neurobehavioral and neurocognitive disorders
(e.g., autism and ADD), adverse birth outcomes, and alteration
of age of puberty. Current epidemiologic evidence suggests
an important role of environmental and genetic factors
in the development or incidence of these conditions.
However, it has not yet been possible to identify the
nature and magnitude of exposures to specific pollutants
or allergens that could lead to these undesirable health
outcomes during critical life stages of either development
or vulnerability. Because of the large sample size of
the NCS study (~ 100,000 children), it is now feasible
to formulate and implement a study design that would
examine the influence of acute and chronic exposures
to many indoor and outdoor pollutants and bioaerosols
in the development of many of the health conditions noted
above. It is important, however, to recognize that the
study protocols for exposure measurement and analysis
have to be flexible enough to address changes in our
understanding of pollutants, personal factors, and societal
conditions that could play a role in influencing exposures
and health status of children. The magnitude and frequency
of potential exposures to children during various life
stages of concern (ranging from preconception to prenatal
and from postnatal to infancy) have to be considered
first. Technical and practical considerations dictate
that the NCS employ both direct and indirect (e.g., survey-based)
monitoring methodologies. Direct monitoring methods include
environmental and personal exposure monitoring methods
using either passive or active sampling techniques, or
biomonitoring of appropriate matrices, such as meconium,
placenta, blood, urine, saliva, hair, nail, tooth. Indirect
measurement methods may include household and personal
questionnaires, time-activity diaries, dietary
and consumer product surveys, and existing ambient pollution
and emissions surveillance databases, among others.
Figure 1. Selecting an appropriate exposure measure.
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In selecting the direct measures, the researcher must
decide whether to collect a biologic or an environmental
measure, or some combination of both, as summarized in
Figure 1. In addition to technical factors such as the
timing of exposures, participant burden and cost are
among the key issues to consider in selecting one or
both of these sample types. Ideally, whenever feasible,
collection of both environmental and biomonitoring samples
is recommended. Combining biomonitoring and environmental
exposure measurements allows for the comparison of the
relative contribution of different routes and media to
internal dose, facilitates the identification of missing
exposure measurements (e.g., locations that were not
sampled), and provides a link to identify locations and
sources of exposure, all of which help researchers to
determine how to reduce exposures and risks.
Given the large sample size and long duration of the
planned NCS and the potentially high costs and burden
associated with environmental sampling, collecting detailed
longitudinal exposure information across the cohort and
at all time periods to support multiple hypotheses relating
environmental exposure to potential adverse health outcomes
will be difficult. Well-designed substudies, however,
can be carried out within the NCS cohort--using
only a small fraction of the sample size (possibly < 10%
of the study sample)--to estimate and adjust for
exposure measurement errors, with sufficient power to
characterize the relationship between exposure and health
outcome for most hypotheses. We envision that low-cost,
low-burden methods, such as the use of questionnaires
and screening type environmental and/or biologic measurements,
may be employed across the entire (i.e., core) NCS cohort,
with smaller subsets of respondents (i.e., the detailed
study subcohort) undergoing more extensive environmental
exposure assessment using more expensive and detailed
environmental, biologic, and other sophisticated exposure
measurements. This strategy allows the exposure-response
relationship to be tested on the whole cohort, while
the detailed validation subsamples provide the relationship
between different exposure measures. Finally, the results
from these partially overlapping studies can then be
used for conducting more specific epidemiologic analyses
or for identifying optimum exposure mitigation strategies,
the ultimate aim of the planned NCS. |