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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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46 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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56 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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58 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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60 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

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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.

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