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OCR for page 39
METHODOLOGICAL CONSIDERATIONS
IN EVALUATING THE Evidence
I he U S Environmental Protection Agency (EPA) charged
the committee responsible for this report with two primary
objectives:
1. To provide the scientific and technical basis for communi-
cations to the public on
asthma; and
lutants.
· the health impacts of indoor pollutants related to
· mitigation and prevention strategies to reduce these pol
2. To help determine what research is needed in these areas.
To help operationalize the first objective, EPA posed several
questions for the committee's consideration. The committee was
asked to evaluate the strength of the scientific evidence associat-
ing exposure to indoor pollutants with asthma, to discuss what
was known about how and in what way~s) various pollutants in-
fluence asthma, and to examine the risk for development or exac-
erbation of asthma associated with indoor exposures.
EPA asked for information on the characteristics of the indi-
viduals most at risk for these exposures and on the role of genetic
39
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40
CLEARING THE AIR
and other environmental factors in the occurrence of asthma. It
requested information about whether effective strategies to miti-
gate or prevent problematic exposures had been developed and
tested, whether these strategies had been shown to decrease
asthma as well, at what exposure levels such decreases had been
shown to occur, and whether the strategies were reasonable and
cost-effective for affected individuals to undertake.
The ensuing chapters of the report address these questions, to
the extent permitted by currently available science. They also
touch on issues identified by the committee as relevant to its
charge.
EVALUATING THE EVIDENCE
The evaluation of evidence involves several stages: (1) assess-
ing the quality and relevance of individual reports; (2) deciding
on the possible influence of error, bias, or confounding on the
reported results; (3) integrating the overall evidence within and
across diverse areas of research; and (4) formulating the conclu-
sions themselves. These aspects of a review require thoughtful
consideration of both quantitative and qualitative information-
they cannot be accomplished by adherence to a prescribed for-
mula.
The approach applied by the committee to this task evolved
throughout the process of review and was determined in impor-
tant respects by the nature of the evidence, exposures, and out-
comes at issue. Ultimately, the conclusions expressed in this re-
port are based on the committee's collective judgment. The
committee endeavored to express its judgments as clearly and
precisely as the available information allowed.
This section describes more fully how the evidence was evalu-
ated. It discusses the research approach used to develop informa-
tion, the methodologic considerations underlying the evaluation,
considerations in assessing the strength of the evidence, and the
categories of evidence used to summarize the committee's con-
clusions. The section is based on similar discussions in the Insti-
tute of Medicine (IOM) reports characterizing scientific evidence
regarding vaccine safety (IOM, 1991, 1993) and the health effects
of herbicides used in Vietnam (IOM, 1994, 1996, 1999), adapted to
the current task.
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METHODOLOGICAL CONSIDERATIONS
41
Research Approach
To answer the questions posed by the EPA, the committee
undertook a wide-ranging evaluation of the research on asthma
and indoor air. While it did not review all such literature an un-
dertaking beyond the scope of this report the committee at-
tempted to cover the work it believed to be influential in shaping
scientific understanding at the time it completed its task in mid
1999.
The committee consulted several sources of information in
the course of its work. For conclusions regarding asthma out-
comes, the primary source was epidemiologic studies. Most of
these studies examined general population exposures to indoor
agents at home, reflecting the focus of researchers working in this
field. A small number of studies of occupationally exposed indi-
viduals were also evaluated. Some clinical research for example,
that addressing challenge tests and animal studies were consid-
ered where appropriate. Engineering, architecture, and physical
sciences literature informed the discussions of building charac-
teristics, exposure assessment and characterization, indoor damp-
ness, pollutant transport, and related topics; public health and
behavioral sciences research was consulted for data on the effec-
tiveness of interventions to limit exposure to problematic indoor
agents. The committee also benefited from presentations of cut-
ting-edge research given during two workshops it held in early
1999. A listing of the participating researchers and their topics is
given in Appendix B.
The committee attempted to fairly consider and weigh all rel-
evant information in reaching its conclusions. The failure to cite a
particular study or research effort, however, does not necessarily
mean that the committee did not consider its results.
Methodologic Considerations in Evaluating the Evidence
Uncertainty and Confidence
All science is characterized by uncertainty. Scientific conclu-
sions concerning the result of a particular analysis or set of analy-
ses can range from highly uncertain to highly confident the
theoretical concept of "proof" does not apply in evaluating actual
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42
CLEARING THE AIR
observations. In its review, the committee evaluated the degree of
uncertainty associated with the results on which it had to base its
conclusions.
Statistical significance is a quantitative measure of the extent to
which chance that is, sampling variation might be responsible
for the observed exposure-adverse event association. The magni-
tude of the probability value or the width of the confidence inter-
val associated with an effect measure such as the relative risk or
risk difference is generally used to estimate the role of chance in
producing the observed association. This type of quantitative es-
timation is firmly founded in statistical theory on the basis of re-
peated sampling.
For individual studies, confidence intervals around estimated
results such as relative risks represent a quantitative measure of
uncertainty. Confidence intervals present a range of results that,
with a predetermined level of certainty, is consistent with the ob-
served data. The confidence interval, in other words, presents a
statistically plausible range of possible values for the true relative
risk. When it is possible to use meta-analysis to combine the re-
sults of different studies, a combined estimate of the relative risk
and confidence interval may be obtained.
For an overall judgment about an association between an ex-
posure and a disease outcome based on a whole body of evidence,
no quantitative method exists to characterize the uncertainty of
the conclusions. Thus, to assess the appropriate level of confi-
dence to be placed in the ultimate conclusions, it is useful to con-
sider qualitative as well as quantitative aspects.
Analytic Bias
Analytic bias is a systematic error in the estimate of associa-
tion between the exposure and the adverse event. It can be cat-
egorized under four types: selection bias, information bias, con-
founding bias, and reverse causality bias. Selection bias refers to
the way that the sample of subjects for a study has been selected
(from a source population) and retained. If the subjects in whom
the exposure-adverse event association has been analyzed differ
from the source population in ways linked to both exposure and
development of the adverse event, the resulting estimate of asso-
ciation will be biased. Information bias can result in a bias toward
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METHODOLOGICAL CONSIDERATIONS
43
the null hypothesis (no association between the exposure and the
adverse event), particularly when ascertainment of either expo-
sure or outcome has been sloppy, or it may create a bias away
from the null hypothesis through such mechanisms as recall bias
or unequal surveillance in exposed versus unexposed subjects.
Confounding bias addressed in greater detail below occurs
when the exposure-adverse event association is biased as a result
of a third factor that is both capable of causing the adverse event
and is statistically associated with the exposure itself. Finally, re-
verse causality bias can be a concern where it is possible that the
outcome in question might influence the probability of experienc-
ing the exposure being studied. It is not generally possible to
quantify the impact of such nonrandom errors in estimating the
strength of the association.
Confounding
In any epidemiologic study comparing an exposed to an un-
exposed group, it is likely that characteristics other than exposure
may differ between the two groups. For example, the group ex-
posed to a particular indoor pollutant may be of lower socioeco-
nomic status than the unexposed group. When the groups differ
with respect to factors that are also associated with the risk of the
outcome of interest, a simple comparison of the groups may ei-
ther exaggerate or hide the true difference in disease rates that is
due to the exposure of interest. In the example of socioeconomic
status, a simple comparison of asthma rates among the exposed
and unexposed would exaggerate an apparent difference in
asthma rates, since socioeconomic status is also thought to influ-
ence asthma incidence. If exposed individuals were of higher so-
cioeconomic status, the simple comparison would tend to mask
any true association between exposure and asthma by spuriously
elevating the risk of disease in the unexposed group. This phe-
nomenon, known as confounding, represents a major challenge
to researchers and those evaluating their work.
Publication Bias
An important aspect of the quality of a review is the extent to
which all appropriate information is considered and any serious
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44
CLEARING THE AIR
omission or inappropriate exclusion of evidence is avoided. A pri-
mary concern in this regard is the phenomenon known as publi-
cation bias. It is well documented (Beg" and Berlin, 1989; Berlin et
al., 1989; Callaham et al., 1998; Dickersin, 1990; Dickersin et al.,
1992; Easterbrook et al., 1991) in the scientific literature that stud-
ies with a statistically significant finding are more likely to be
published than studies with nonsignificant results. Where such
bias is present, evaluations of disease-exposure associations
based solely on published literature could be biased in favor of
showing a positive association. Other forms of bias related to re-
porting and publication of results have also been suggested. These
include multiple publications of positive results, slower publica-
tion of nonsignificant and negative results, and publication of
nonsignificant and negative results in non-English-language and
low-circulation journals (Sutton et al., 1998~. Several researchers
have addressed the specific topic of whether there is bias in the
publication of studies regarding the health impacts of exposure
to environmental tobacco smoke (Berg et al., 1994; Kawachi and
Colditz, 1996; Lee, 1998; Misakian and Bero, 1998~.
The committee did not in general consider the risk of publica-
tion bias to be high among studies of indoor air exposures and
asthma because
1. there were numerous published studies showing no posi-
tive association;
2. the committee was aware of the results of some unpub-
lished research; and
3. The committee felt that the interest of the research commu-
nity, public health professionals, government, and the general
public surrounding the issue of asthma is so intense that any stud-
ies showing no association would be unlikely to be viewed as
unimportant by investigators. In short, there would also be pres-
sure to publish "negative" findings.
Nonetheless, the committee was mindful of the possibility that
studies showing a positive association might be overrepresented
in the published literature.
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METHODOLOGICAL CONSIDERATIONS
Considerations in Assessing the Strength of
Scientific Evidence
Causality Definitions
45
The question of causality is of cardinal importance in health
research, clinical practice, and public health policy. Despite its
importance, however, causality is not a concept that is easy to
define or understand (Kramer and Lane, 1992~. Consider, for ex-
ample, the relation between a hypothetical exposure X and
asthma. Does the statement "X causes asthma" mean that (1) all
persons exposed to X will develop asthma, (2) all cases of asthma
are caused by exposure to X, or (3) there is at least one person
whose asthma was caused or will be caused by X?
The first interpretation corresponds to the notion of a suffi-
cient cause; X is a sufficient cause of asthma if all individuals ex-
posed to X develop the disease. X is a necessary cause of asthma if
the disease occurs only among those exposed to X, the second
interpretation above. The idea that a "proper" cause must be both
necessary and sufficient underlies the postulates of causality ar-
ticulated by Koch in the 1800s (Susser, 1973~. However, it is now
generally recognized that for most exposure-outcome relations, a
particular exposure need not be necessary or sufficient in order to
cause the outcome the third interpretation above. In other
words, most health outcomes of interest have multifactorial eti-
ologies.
This third form of causality is what is meant when scientists
say that cigarette smoking causes lung cancer. Not everyone who
smokes will develop lung cancer and not everyone who develops
Jung cancer smokes. However, individuals who smoke are more
likely to develop Jung cancer than those who do not, and the more
they smoke the more likely they are to develop it.
Types of Causal Questions
The causal relation between an exposure and a given adverse
event can be considered in terms of three different questions
(Kramer and Lane, 1992~:
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CLEARING THE AIR
1. Can It? (potential causality): Can the exposure cause the
adverse event, at least in certain people under certain circum-
stances?
2. Did It? (retrodictive causality): Given that an individual
who was subjected to the exposure developed the adverse event,
was the event caused by the exposure?
3. Will It? (predictive causality): Will the next person who is
subjected to the exposure experience the adverse event because
of the exposure? Equivalently, how frequently will those subjected
to the exposure experience the adverse event as a result of the
exposure?
The form of causality relevant to this report is the first of
these potential or "can it?" causality. In the section below, this
form of causality is discussed with reference to how it relates to
the committee's charges and how the committee attempted to an-
swer it.
Evaluation Criteria
Much of the epidemiologic literature on causality has focused
on potential causality, and a widely used set of criteria has
evolved for its assessment (Bradford Hill, 1965; Bradford Hill and
Hill, 1991; Susser, 1973; U.S. Public Health Service, 1964~. These
criteria are also often used to inform public health policy recom-
mendations and decisions (Weed, 1997~.
For each indoor air exposure for which evidence indicated
the presence of an association with asthma, the committee as-
sessed the applicability of each of five general considerations,
based on these criteria:
1. Strength of Association: Strength of association is usually ex-
pressed in epidemiologic studies as the magnitude of the mea-
sure of effect, for example, relative risk or odds ratio. Generally,
the higher the relative risk, the greater is the likelihood that the
exposure-disease association is "real" or, in other words, the less
likely it is to be due to undetected error, bias, or confounding.
Small increases in relative risk that are consistent across a number
of studies, however, may also provide evidence of an association.
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METHODOLOGICAL CONSIDERATIONS
47
2. Biologic Gradient (Dose-Response Relationship): In general,
potential causality is strengthened by evidence that the risk of
occurrence of an outcome increases with higher doses or frequen-
cies of exposure. In the case of asthma, however, this is compli-
cated by the central roles that susceptibility and sensitization play
in the disease. The same exposure may have very different effects
in susceptible and nonsusceptible, sensitized and nonsensitized
individuals. Thus, the absence of a dose-response effect might
not constitute strong evidence against a causal relation.
3. Consistency of Association: Consistency of association re-
quires that an association be found regularly in a variety of stud-
ies, for example, in more than one study population and with
different study methods. The committee considered findings that
were consistent across different categories of studies as being sup-
portive of an association. Note that the committee did not inter-
pret "consistency" to mean that one should expect to see exactly
the same magnitude of association in different populations.
Rather, consistency of a positive association was taken to mean
that the results of most studies were positive and that the differ-
ences in measured effects were within the range expected on the
basis of all types of error including sampling, selection bias,
misclassification, confounding, and differences in actual exposure
levels.
4. Biologic Plausibility and Coherence: Biologic plausibility is
based on whether a possible association fits existing biologic or
medical knowledge. The existence of a possible mechanism in-
creases the likelihood that the exposure-disease association in a
particular study reflects a true association. In addition, the com-
mittee considered factors such as evidence in humans of an asso-
ciation between the exposure in question and diseases known
to have causal mechanisms similar to asthma and evidence
that asthma outcomes are associated with occupational exposure
levels.
Considerations of biologic plausibility informed the com-
mittee's decisions about how to categorize the association be-
tween various indoor exposures and asthma, but the committee
.
recognized that research regarding mechanisms is still in its in-
fancy and did not predicate decisions on the existence of specific
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48
CLEARING THE AIR
evidence regarding biological plausibility. Chapter 4 addresses
the state of the science on asthma mechanisms.
5. Temporally Correct Association: If an observed association is
real, exposure must precede the onset or exacerbation of the dis-
ease by at least the duration of disease induction. Temporality
can be difficult to evaluate for some indoor agents because expo-
sure to them is recurrent and pervasive. If individuals are exposed
to an agent almost every day and in an environment where they
spend most of their time it can be difficult to discern a relation-
ship between exposure and effect. The lack of an appropriate time
sequence is thus evidence against association, but the lack of
knowledge about the natural history and pathogenesis of asthma
limits the utility of this consideration. The committee also consid-
ered whether the outcome being studied occurred within a time
interval following exposure that was consistent with current un-
derstanding of its natural history.
Other Considerations As noted above, it is important also to
consider whether alternative explanations error, bias, confound-
ing, or chance might account for the finding of an association. If
an association could be sufficiently explained by one or more of
these alternate considerations, there would be no need to invoke
the several considerations listed above. Because these alternative
explanations can rarely be excluded sufficiently, however, assess-
ment of the applicable considerations listed above almost invari-
ably remains appropriate. The final judgment is then a balance
between the strength of support for the association and the de-
gree of exclusion of alternatives.
SUMMARIZING CONCLUSIONS REGARDING THE EVIDENCE
Categories of Association
The committee summarized its conclusions using a common
format, described below, categorizing the strength of the scien-
tific evidence in two areas:
1. health effects: the association between exposure to an indoor
agent and asthma development or exacerbation; and
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METHODOLOGICAL CONSIDERATIONS
49
2. exposure reduction strategies: the effectiveness of exposure
mitigation and prevention measures.
The five categories described below were adapted by the
committee from those used by the International Agency for Re-
search on Cancer (IARC, 1977) to summarize the scientific evi-
dence for the carcinogenicity of various agents. Similar sets of
categories have been used in National Academies' reports char-
acterizing scientific evidence regarding vaccine safety (IOM,
1991, 1993) and the health effects of herbicides used in Vietnam
(IOM, 1994, 1996, 1999~. The distinctions reflect the committee's
judgment that an association would be found in a large, well-
designed study of the outcome in question in which exposure
was sufficiently high, well characterized, and appropriately mea-
sured on an individual basis.
For health effects, the categories relate to the association be-
tween exposure to the agent and asthma, not to the likelihood
that any individual's health problem is associated with or caused
by the exposure.
Each of the categories describes the strength of the scientific
evidence regarding the relationship between an action and an out-
come related to indoor exposures and asthma. Table 2-1 gives ex-
amples of these.
Sufficient Evidence of a Causal Relationship
Evidence is sufficient to conclude that a causal relationship
exists between the action or agent and the outcome. That is, the
TABLE 2-1 Examples of Actions and Outcomes Usecl in Categories of
Eviclence
Category Action Outcome
Exposure reduction
strategies
Health effects Exposu re to an indoor
agent
Implementation of a strategy
to avoid or reduce
exposure to an indoor agent
Asthma development or
exacerbation
Actual reduction of
exposure or reduction of
asthma incidence
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CLEARING THE AIR
eter, low-density pollen grains to penetrate and deposit in the
Jung. Once deposited in the lungs, airborne agents may react with
biomolecules, be absorbed into the blood, or be cleared from the
lungs. From the viewpoint of asthma development or exacerba-
tion, the relevant sites and nature of interactions between inhaled
agents and human body remain uncertain, limiting our ability to
define biologically effective dose in this context. In the case of
allergens, however, the measurements of serum IgE and allergen
skin test reactivity represent surrogates for biologically effective
dose. It is important to note that all measures of dose, like those of
exposure, can be viewed as surrogates for the theoretical risk-rel-
evant dose measure.
Exposure Assessment for Specific Agents
Considered in This Report
Table 2-2 lists the exposure and dose surrogates that have been
used in past studies of agents with possible links to asthma devel-
opment or exacerbation. The text that follows addresses issues
related to assessing exposures to some of the agents addressed in
this report. More detailed information on these agents and others
evaluated in the report is given in Chapters 5 through 10.
House dust mite (HDM) exposure is associated primarily
with inhalation of mite fecal pellets and aggregates (Chapman
and Platts-MilIs, 1980; Tovey et al., 1981~. Most allergen-related
particles are in the size range from 10-25 ,um and are thought to
become airborne primarily via active disturbance of allergen res-
ervoirs in beds, soft furniture, and carpets (Tovey et al., 1981~.
Because of their large size, HDM allergen-related particles remain
airborne for relatively short time periods (on the order of min-
utes). As such, area sampling of air concentrations has not proven
a useful method of exposure assessment. Personal sampling is
theoretically possible but requires further development. The cur-
rently accepted method for routine characterization of HDM ex-
posures is to assay concentrations of group 1 allergens in dust
samples collected by vacuuming, preferably in the bed or bed-
room. Allergen concentrations are usually expressed in units of
,ug HDM/gram of dust collected. A theoretical advantage of
dustborne allergen sampling is the presumed time-integration
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METHODOLOGICAL CONSIDERATIONS
TABLE 2-2 Exposure and Dose Surrogates Usecl in Asthma Research
57
Agent
Exposure Surrogates Dose Surrogates
House dust mite (HDM)
allergen
Dust mite count in bedroom dust HDM IgE
HDM allergen in bedroom dust HDM skin test
HDM allergen in other dust
Cockroach (CR) allergen CR counts by trapping CR IgE
CR allergen in bedroom dust CR skin test
CR allergen in kitchen dust
Animal (dog, cat, etc.)
allergen
Self-reported animal
Pet allergen in dust
Pet allergen in air
Pet-specific IgE
Pet-specific skin test
Fungal allergen Mold odor Fungal-specific IgE
Moisture problems Fungal-specific skin test
Visual evidence
Culturable fungi
Spore counts
Pollens and plant Pollen counts in air Pollen-specific IgE
allergen Allergen concentration in air Pollen-specific skin test
Environmental tobacco Self-reported household smoking Cotinine in urine, blood,
smoke (ETS) PM2 5 sampling saliva
Airborne nicotine or other ETS
markers
Nitrogen dioxide Self-reported gas appliances None
(NO2) Area monitoring for NO2 in air
Personal monitoring for NO2 in air
Volatile organic Self-reported material presence Exhaled-breath VOCs
compounds (VOCs) (e.g., freshly painted surfaces) Blood VOCs
Area monitoring for VOCs in air concentrations
Personal monitoring for VOCs in air
Formaldehyde Self-reported material presence None
Area or personal air sampling
Pesticides Self-reported use Blood concentrations
Concentrations in dust
Concentrations in air
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CLEARING THE AIR
that occurs in the deposition of allergen particles on surfaces over
time.
It is worth noting one limitation of the common practice of
reporting concentrations of allergen in settled dust samples in
units of mass of allergen per gram of dust collected. By dividing
by total dust collected, this expression of exposure does a poor
job of characterizing the total allergen burden in a dwelling. For
example, two homes A and B could have the same amount of
allergen per gram of house dust by the conventional measure,
whereas home A might have 10 times more house dust than home
B. resulting in a 10-fold higher average exposure to occupants of
home A. A high priority research need is the development of im-
proved sampling methods that enable better standardization for
area sampled than is possible using current methods.
Like HDM, cockroach allergens are thought to be associated
primarily with larger particles that become airborne during and
immediately after active disturbance of dust reservoirs. Thus, the
same measurement issues apply here as for HDM. In contrast to
HDM, which thrive primarily in bed, furniture and carpet materi-
als, cockroach populations are usually concentrated in kitchens
and bathrooms due to the availability of water and food sources.
As a result, dust concentrations of cockroach allergen (,ug/g) are
often an order of magnitude higher in kitchen samples than in
bedrooms (Sarpong et al., 1996~. Even so, bedroom concentrations
are generally thought to represent a better measure of human ex-
posure to cockroach allergen for most individuals, due both to
the duration of time spent in the bedroom and the likelihood of
allergen disturbance there (Eggleston et al., 1998; Rosenstreich et
al., 1997~. For very young children who craw! or toddle on the
floor, dustborne cockroach allergen on floors throughout the
home may be relevant to exposures.
The principal cat allergen Fe! `1 I is produced by salivary, seba-
ceous, and anal glands (De Andrade et al., 1996~. Fe! ~ I can be
quantified in dust and air samples and also by specific IgE. A
significant portion of airborne Fe! ~ I is associated with particles
less than 5 ,um dae which remain airborne for extended periods
and therefore tend to be distributed widely within interior spaces
(Custovic et al., 1998~. Fe! ~ I also can be transported between
locations via adherence to and resuspension from clothing, lead
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METHODOLOGICAL CONSIDERATIONS
59
ing to measurable concentrations not only in homes with cats but
also in schools, offices, vehicles, and homes with no cats. Because
of this, home-based Fe! ~ I concentrations often represent only
one component of total human exposure. Dog and other animal
allergen exposures have been studied less extensively; however,
the basic parameters of exposure appear to be similar to those
discussed above for cats (Custovic et al., 1997~.
While several methods currently exist for measuring and
characterizing fungal populations, methods for assessing human
exposure to fungal allergens remain poorly developed at present,
and represent a high priority research need. Part of the difficulty
relates to the large number of fungal species that are measurable
indoors, and the fact that fungal allergen content varies across
species and across morphological forms within species (Cruz et
al, 1997; Fade! et al., 1992~. In addition, the most common meth-
ods for fungal assessment, counting cultured colonies and the
identification and counting of spores, have variable and uncer-
tain relationships to allergen content. Exposure surrogates based
on questionnaire or inspection such as water damage and vis-
ible fungal growth also have very uncertain relationships with
exposure to airborne fungal allergens. Although it is clear that
individuals can be allergic to fungi, measurements of fungal al-
lergen concentrations are very rarely included in epidemiological
studies.
Indoor concentrations of airborne pollens occur via penetra-
tion of outdoor pollens into interior spaces, rather than emissions
indoors. Penetration efficiency depends primarily on the size and
shape of openings through which air enters the building open
windows versus small cracks, for example and on aerodynamic
particle diameter. Pollen grains often have large physical diam-
eters but relatively small dae due to their low densities, favoring
penetration. This allows pollens to remain airborne for long peri-
ods outdoors and be widely distributed by winds, as well as to
penetrate indoors. Allergens from some plants, such as grass and
birch, are located within particles that are much smaller than pol-
len grains (see Chapter 10~. Indoor concentrations of particles
from outdoors depend on the rate of depositional losses to indoor
surfaces, the building ventilation rate, and the particle penetra-
tion efficiency.
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CLEARING THE AIR
Environmental tobacco smoke (ETS) is a complex mixture of
submicron particles and gases produced by the combustion of to-
bacco products (Daisey et al., 1994; U.S. EPA, 1992~. ETS remains
airborne for long periods after emission, allowing time for dis-
persion and spread throughout interior spaces. Removal mecha-
nisms include deposition onto interior surfaces and dilution by
building ventilation. Significant ETS concentrations typically oc-
cur only indoors.
Questionnaire-based assessment of indoor smoking patterns
has been used in many studies as an exposure surrogate. An im-
portant advantage of this approach is the potential it offers to cap-
ture long-term average indoor ETS emission patterns, which is
less feasible to do with airborne measurements. A limitation of
questionnaire-based exposure assessment is the potential for dif-
ferential self-reporting of smoking patterns as a function of edu-
cation and cultural attitudes.
Methods now exist for airborne measurements of chemical
markers of the gaseous and particle phases of airborne ETS; how-
ever, the relationship between these marker compounds and the
concentrations of the broader mixture of ETS constituents is still
under investigation. While ETS is a major source of indoor PM2 5
concentrations, PM2 5 iS not specific to ETS. For example, airborne
nicotine concentrations are often used as a specific marker for the
gaseous constituents of ETS. (Samet, 1999~. Nicotine is a semi-
volatile organic component of ETS.
Little data exist on the temporal variability of indoor ETS con-
centrations and it is not known what averaging time is adequate
for characterizing long-term airborne ETS exposure of building
occupants. Personal sampling represents an attractive approach
in terms of sampling location; however, to be valid, the averaging
time must be sufficiently long to estimate the long-term average
exposure. Sampling with area monitors (i.e., nicotine sampler in
bedroom or main activity room) enables more convenient and
extensive sampling of long-term ETS exposures (e.g., over 1-2
weeks duration), and is thus recommended for epidemiology
studies.
Biomarkers of ETS exposure also play an important role in
research on ETS exposure and health. Cotinine, a biological me-
tabolite of nicotine, can be measured in urine, blood, and saliva
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METHODOLOGICAL CONSIDERATIONS
61
(Benowitz, 1996~. An important attribute of biomarkers such as
cotinine is that they reflect exposures from all routes and loca-
tions such as cotinine concentration in urine reflects not only
ETS exposure in the home but also at work, in school or daycare,
while shopping, in vehicles, and the like. This may be an advan-
tage or disadvantage depending on the context. A limitation of
cotinine for long-term exposure assessment is its relatively short
biological half-life, on the order of several hours. Thus, cotinine
measurements provide a measure of recent exposure, with sig-
nificant modification by time since last exposure and individual
metabolism rate. Because of these limitations, a single measure-
ment of cotinine in urine or blood provides a good indication of
whether recent exposure has occurred, but is generally not an ac-
curate measure of long-term exposure levels.
Nitrogen dioxide (NO2) is an irritant gas produced by high
temperature combustion. Indoor sources include gas stoves and
unvented space heaters. Indoor NO2 levels are also influenced by
the penetration of outdoor NO2, which is elevated in urban areas
where motor vehicles are the dominant source. Factors that influ-
ence concentrations of indoor NO2 include frequency and dura-
tion of combustion appliance usage, emission rates of individual
appliances, and home ventilation rate (Samet et al., 1987~. High
ventilation rates act to reduce NO2 levels generated indoors, but
conversely to increase penetration of NO2 of outdoor origin.
Available measures of indoor NO2 exposures include question-
naire-based self-reporting of gas appliance presence or usage, en-
vironmental area sampling of airborne NO2 levels, and personal
sampling of airborne NO2 levels. Questionnaire-based assessment
is logistically simple but does not account well for variations in
emission and ventilation rates. The sampling methods inherently
account for these factors, as well has being specific for NO2. How-
ever, as with most sampling methods, area and personal sampling
characterizes only a snapshot in time, which may or may not be a
good surrogate for long-term average indoor NO2 levels.
Given the variety and complexity of indoor volatile organic
compound (VOC) emission sources and rates, there is in general
no reliable method for characterizing indoor VOC levels other
than air sampling. A number of methods exist for both area and
personal sampling of airborne VOCs. Of particular interest are
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62
CLEARING THE AIR
recently developed passive diffusion badges that can measure
VOC levels in the ,ug/m3 range with sampling duration of 48
hours or more (Stock et al., 1996~. Internal dose assessment is pos-
sible based on both exhaled breath and blood sampling; however,
both methods address only recent exposures (e.g., within the pre-
vious 24 hours).
OTHER CONSIDERATIONS
The committee did not fee! that there was sufficient evidence
to generate confident quantitative estimates of the asthma risk
associated with indoor air exposures. It is not possible to make
general statements about the relative risk of various exposures
because this is highly dependent on the characteristics of a par-
ticular environment and its occupants. House dust mites, for ex-
ample, are a very common exposure in temperate and humid re-
gions such as the southeastern United States but do not typically
present a problem in cooler and drier climates such as northern
Europe. Cockroaches, which also thrive in temperate and humid
regions, are an important exposure in some urban environments.
Fungi are ubiquitous and can be the primary source of allergen in
some arid climates. Endotoxins may be found in humidifiers in
urban settings or in organic dusts that infiltrate rural homes from
outdoors. Occupant choice has a major role in determining in-
door exposure to animals, plants, environmental tobacco smoke,
indoor combustion sources, and chemicals used in cleaning and
other activities. Indoor chemical exposures also result from out-
door infiltrates and certain building materials and furnishings.
Much of the literature regarding indoor exposures and asthma
outcomes focuses on single agents, and the report thus has this
same focus. Real indoor environments, however, are complex.
They subject occupants to multiple exposures that may interact
physically or chemically with one another and with the other
characteristics of the environment like humidity, temperature,
and ventilation levels. Synergistic effects that is, interactions
among agents that result in a combined effect greater than the
sum of the individual effects may also take place. Information
on the combined effects of multiple exposures and on synergistic
OCR for page 63
METHODOLOGICAL CONSIDERATIONS
63
effects among agents is cited wherever possible. However, rather
little data are available on this topic and it remains an area of
active research interest.
Exposures in the indoor environment are not the only factor
that may influence asthma outcomes, and interventions that con-
sider only indoor factors may miss important opportunities to
improve health. This report touches on the roles that genetics and
socioeconomic status may play, although these subjects are not
addressed in detail. Research has also examined the possible in-
fluence of several other factors, including antibiotic use (von
Mutius et al., 1999), breastfeeding (Oddy et al., 1999) and other
aspects of diet (Kimber, 1998; Weiss, 1999), low birth weight
(Shaheen et al., 1999), number of siblings (Ponsonby et al., 1999),
and obesity (Luder et al., 1998~.
REFERENCES
Begg CB, Berlin JA. 1989. Publication bias and dissemination of clinical research.
Journal of the National Cancer Institute 81~2~:107-115.
Benowitz NL. 1996. Cotinine as a biomarker of environmental tobacco smoke
exposure. Epidemiologic Reviews 18~2~:188-204.
Berlin JA, Begg CB, Louis TA. 1989. An assessment of publication bias using a
sample of published clinical trials. Journal of the American Statistical
Association 84:381-392.
Bero LA, Glantz SA, Rennie D.1994. Publication bias and public health policy on
environmental tobacco smoke. Journal of the American Medical Association
272~2~:133-136.
Bradford Hill A. 1965. The environment and disease: association or causation.
Proceedings of the Royal Society of Medicine 58:295-300.
Bradford Hill A, Hill ID. 1991. Bradford Hill's Principles of Medical Statistics
(Twelfth Edition). London: Hodder & Stoughton.
Callaham ML, Wears RL, Weber EJ, Barton C, Young G. 1998. Positive-outcome
bias and other limitations in the outcome of research abstracts submitted to a
scientific meeting. Journal of the American Medical Association 280~3~:254-
257. [Published erratum appears in JAMA 1998 280~14~:1232.1
Chapman MD, Platts-Mills TA. 1980. Purification and characterization of the
major allergen from Dermatophagoides pteronyssinus-antigen P1. Journal of
Immunology 125~2~:587-592.
Chew GL, Higgins KM, Gold DR, Muilenberg ML, Burge HA. 1999. Monthly
measurements of indoor allergens and the influence of housing type in a
northeastern US city. Allergy 54~10~:1058-1066.
Cruz A, Saenz de Santamaria M, Martinez J. Martinez A, Guisantes J. Palacios R.
OCR for page 64
64
CLEARING THE AIR
1997. Fungal allergens from important allergenic fungi imperfect) [Review].
Allergologia et Immunopathologia 25~3~:153-158.
Custovic A, Green R. Fletcher A, Smith A, Pickering CA, Chapman MD,
Woodcock A. 1997. Aerodynamic properties of the major dog allergen Canf I:
distribution in homes, concentration, and particle size of allergen in the air.
American Journal of Respiratory and Critical Care Medicine 155~1~:94-98.
Custovic A, Simpson A, Pahdi H. Green RM, Chapman MD, Woodcock A. 1998.
Distribution, aerodynamic characteristics, and removal of the major cat
allergen Fel d I in British homes. Thorax 53~1~:33-38.
Daisey JM, Mahanama KRR, Hodgson AT. 1994. Toxic volatile organic
compounds in environmental tobacco smoke: Emission factors for modeling
exposures of California populations. A133-186; California Air Resources
Board, Sacramento, CA.
De Andrade AD, Birnbaum J. Magalon C, Magnol JP, Lanteaume A, Charpin D,
Vervloet D. 1996. Fel d I levels in cat anal glands. Clinical and Experimental
Allergy 26~2~:178-180.
Dickersin K. 1990. The existence of publication bias and risk factors for its
occurrence. Journal of the American Medical Association 263~10~:1385-1389.
Dickersin K, Min YI, Meinert CL. 1992. Factors influencing publication of research
results: follow-up of applications submitted to two institutional review
boards. Journal of the American Medical Association 267~3~:374-378.
Easterbrook PI, Berlin JA, Gopalan R. Matthews DR. 1991. Publication bias in
clinical research. Lancet 337~8746~:867-872.
Eggleston PA, Rosenstreich D, Lynn H. Gergen P. Baker D, Kattan M, Mortimer
KM, Mitchell H. Ownby D, Slavin R. Malveaux F. 1998. Relationship of indoor
allergen exposure to skin test sensitivity in inner-city children with asthma.
Journal of Allergy and Clinical Immunology 102~4 Pt 1~:563-570.
Fadel R. David B. Paris S. Guesdon JL. 1992. Alternaria spore and mycelium
sensitivity in allergic patients: in vivo and in vitro studies. Annals of Allergy
69~4~:329-335.
IARC (International Agency for Research on Cancer). 1977. Some Fumigants, The
Herbicides 2,4-D and 2,4,5-T, Chlorinated Dibenzodioxins and Miscellaneous
Industrial Chemicals. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Man, Vol. 15. Lyon: IARC.
ICRP (International Commission on Radiological Protection). 1994. ICRP 66:
Human Respiratory Tract Model for Radiological Protection. Annals of the
ICRP 24~13~.
IOM (Institute of Medicine). 1991. Adverse Effects of Pertussis and Rubella
Vaccines. Washington, DC: National Academy Press.
IOM. 1993. Adverse Events Associated with Childhood Vaccines: Evidence
Bearing on Causality. Stratton KR, Howe CJ, Johnston RB, eds. Washington,
DC: National Academy Press.
IOM. 1994. Veterans and Agent Orange Health Effects of Herbicides Used in
Vietnam. Washington, DC: National Academy Press.
OCR for page 65
METHODOLOGICAL CONSIDERATIONS
65
IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National
Academy Press.
IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National
Academy Press.
Kawachi I, Colditz GA. 1996. Invited commentary: confounding, measurement
error, and publication bias in studies of passive smoking. American Journal of
Epidemiology 144~10~:909-915.
Kimber I. 1998. Allergy, asthma and the environment: an introduction. Toxicology
{A {J 1
con
Letters 28~102-103~:301-306.
Kramer MS, Lane DA. 1992. Causal propositions in clinical research and practice.
Journal of Clinical Epidemiology 45~6~:639-649.
Lee PN. 1998. Difficulties in assessing the relationship between passive smoking
and lung cancer. Statistical Methods in Medical Research 7~2~:137-163.
Luder E, Melnik TA, DiMaio M. 1998. Association of being overweight with
greater asthma symptoms in inner city black and Hispanic children. Journal
of Pediatrics 132~4~:699-703.
Misakian AL, Bero LA. 1998. Publication bias and research on passive smoking:
comparison of published and unpublished studies. Journal of the American
Medical Association 280~3~:250-253.
National Research Council (NRC). 1991. Human Exposure Assessment for
Airborne Pollutants. Washington, DC: National Academy Press.
Oddy WH, Holt PG, Sly PD, Read AW, Landau LI, Stanley FJ, Kendall GE, Burton
PR. 1999. Association between breast feeding and asthma in 6 year old
children: findings of a prospective birth cohort study. British Medical Journal
319~7213~:815-819.
Ponsonby AL, Couper D, Dwyer T. Carmichael A, Kemp A. 1999. Relationship
between early life respiratory illness, family size over time, and the
development of asthma and hay fever: a seven year follow up study. Thorax
54~8~:664-669.
Rosenstreich DL, Eggleston P. Kattan M, Baker D, Slavin RG, Gergen P. Mitchell
H. McNiff-Mortimer K, Lynn H. Ownby D, Malveaux F. 1997. The role of
cockroach allergy and exposure to cockroach allergen in causing morbidity
among inner-city children with asthma. New England Journal of Medicine
336~19~:1356-1363. [Comment in N Engl J Med 1997. 336~19~:1382-1384 and
337~11~:791-792.]
Samet JM, Marbury MC, Spengler ID. 1987. Health effects and sources of indoor
air pollution. Part I. American Review of Respiratory Disease 136~6~:1486-
1508.
Samet JM. 1999. Workshop summary: assessing exposure to environmental
tobacco smoke in the workplace. Environmental Health Perspectives
107(Suppl 2~:309-312.
Sarpong SB, Wood RA, Eggleston PA. 1996. Short-term effect of extermination
and cleaning on cockroach allergen Bla g II in settled dust. Annals of Allergy,
Asthma, and Immunology 76~3~:257-260.
Sexton K and Ryan PB. 1988. Assessment of Human Exposure to Air Pollution:
Methods, Measurements, and Models. In Air Pollution, the Automobile, and
OCR for page 66
66
CLEARING THE AIR
Public Health, AY Watson, RR Bates, and D Kennedy, editors, pp. 207-238.
Sponsored by the Health Effects Institute, Cambridge, MA. Washington, DC:
National Academy Press.
Shaheen SO, Sterne JA, Montgomery SM, Azima H. 1999. Birth weight, body
mass index and asthma in young adults. Thorax 54~5~:396-402.
Stock TH, Morandi MT, Afshar M. 1996. A Modified Diffusion Sampler for
Measuring 24-Hour VOC Concentrations in Personal, Indoor and Community
Air, in Proceedings of the 7th International Conference on Indoor Air Quality and
Climate, Vol. 2, S Yoshizawa, K Kimura, K Ikeda, S Tanabe, T Iwata, Eds.,
Indoor Air '96, Nagoya, Japan, pp. 73-77.
Susser M. 1973. Causal Thinking in the Health Sciences: Concepts and Strategies
in Epidemiology. New York: Oxford University Press.
Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. 1998. Systematic reviews
of trials and other studies. Health Technology Assessment 2~19~:1-276.
Tovey ER, Chapman MD, Platts-Mills TA. 1981. Mite faeces are a major source of
house dust allergens. Nature 289~5798~:592-593.
U.S. EPA (U.S. Environmental Protection Agency). 1992. Respiratory Health
Effects of Passive Smoking: Lung Cancer and Other Disorders. EPA/600/6-
90/006F. Washington, DC.
U.S. Public Health Service, U.S. Department of Health, Education, and Welfare.
1964. Assessing Causes of Adverse Drug Reactions with Special Reference to
Standardized Methods. Venulet J. Ed. London: Academic Press.
von Mutius E, Illi S. Hirsch T. Leupold W. Keil U. Weiland SK. 1999. Frequency of
infections and risk of asthma, atopy and airway hyperresponsiveness in
children. European Respiratory Journal 14~1~:4-11.
Weed DL. 1997. On the use of causal criteria. International Journal of
Epidemiology 26~6~:1137-1141.
Weiss ST. 1999. Gene by environment interaction and asthma. Clinical and
Experimental Allergy 29(Suppl 2~:96-99.
Representative terms from entire chapter:
publication bias
