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Executive Summary This most excellent canopy, the air, look you, this brave overhanging firmament, this majestical roof fretted with golden fire--why, it appears no other thing to me than a foul and pestilent congregation of vapours. Hamlet, Act II, Scene 2 INTRODUCTION This report responds to a request by the Environmental Protection Agency (EPA) that the National Research Council consider the scientific feasibility of conducting epidemi- ologic investigations of the health consequences of current and future air pollution. In particular, the Research Council was asked to: Identify physiologic changes and adverse human health consequences (acute and chronic) that might be associated with air pollutants and that require additional study. Identify existing exposure monitoring methods that can be used in epidemiologic studies and situations for which such methods need to be developed or improved to permit epidemiologic studies to be more useful. Determine the types of epidemiologic studies and research strategies that are needed for assessing health effects of exposure to air pollutants. . Identify populations and exposure conditions that merit additional epidemiologic study to determine health effects of air pollution. To address those and related issues, the Research Council formed the Committee on the Epidemiology of Air Pollutants in the Board on Toxicology and Environmental Health Hazards of the Commission on Life Sciences. The Committee consists of professionals in a variety of fields, including epidemiology, toxicology, atmospheric 1

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science, clinical research, biostatistics, risk assessment, and economics. The sub ject of the Committee's report is epidemiology and its methods as applied to air pollution health effects. The primary goal of epidemiologic studies of air pollution is to relate health outcomes in human populations to quantities and types of contaminants in the air. During recent years, there have been major changes in the factors that influence such studies, such as the magnitude of the effects of exposure relative to background disease rates, the general magnitude of exposure to air pollution, and the strength of epidemi- ologic tools available. This report assesses the limits of available epidemiologic techniques for studying al r pollution problems and discusses opportunities for expanding these limits and for using epidemiologic studies effectively in an overall program of research on air pollution. Outdoor concentrations of many air pollutants--such as sulfur dioxide, particles, ozone, and lead--over most of the United States have decreased during the last 20 years. Widespread serious, even lethal, episodes of acute illness due to ambient air pollution were once common, but are no longer expected. In general, attendant health problems are likely to be less numerous and less severe--and therefore more difficult to detect--than in the past. However, the current picture also includes locally high concentrations, changing patterns of pollutant dispersion (due in part to recent control measures), and recognition of new pollutants, including those found indoors. Continued efforts to detect and describe the health effects of air pollution are needed, because small or infrequent effects spread over large populations can have important public health consequences, because air pollution sometimes acts in synergy with other agents to cause or exacerbate serious disease, and because the effects of past control measures are not a,1 well understood. Epidemiology as a discipline has a special rote in the formulation and evaluation of preventive strategies. It can detect hazards in populations under actual exposure conditions, determine the magnitude of their impact on public health, and provide direct guidance for interven- tion. One of the major challenges for future studies is 2

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to assess exposure, particularly to individual pollutants or classes of pollutants, with enough precision to permit quantitative estimation of risk. Such assessments must take into account indoor as well as outdoor exposure. Assessment of the health effects themselves poses tech- nical challenges, because each disease known to be caused by air pollute on has other causes as well. All the diseases of concern are believed to be multifactorial, and in most cases our knowledge regarding pathophysiology is sparse. Numerous factors other than air pollution can influence the risk of illness, and these must be accounted for if causal relationships between air pollution and disease are to be clearly established. Some new and better research techniques have been developed, and some are under development. These advances (and the advantages of experience) make it likely that future epidemiologic studies can contribute to further reduction of air- pollution-related illness. HEALTH EFFECT S The Committee finds that evidence from controlled human exposures, toxicology, and epidemiology is suf- ficient to warrant concern that current air pollution still produces substantial adverse health effects in some segments of the U.S. population. These effects include a variety of acute and chronic respiratory problems that have been linked with previous kinds and amounts of pollution. Acute respiratory effects of concern include an increase in the frequency of asthmatic attacks, transient deficits in pulmonary function, and increases in the frequency of respiratory disease in children and adults. Future pulmonary research to clarify the basis for individual variation in response and determine the relation between acute effects and long-term lung function will be particularly important in defining new opportunities for epidemiologic study of air pollution and acute effects. Chronic effects that warrant study include chronic obstructive pulmonary disease (COPD)--a broad term that encompasses emphysema, bronchitis, and some other conditions in which there is limitation of airflow in the lungs--and adverse changes in the rate of growth or reduction of lung function. Some of these effects in the U.S. population have been caused by heavy pollution

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exposure over sustained periods in the past; evidence on possible chronic respiratory effects of current pollution is sparse, because of methodologic difficulties and a dearth of recent studies. As gaps in the natural history of chronic airflow obstruction are filled, some con- straints in studying the role of air pollution in that complex syndrome will be relaxed. The Committee also finds important research questions about the epidemiology of lung cancer. The contribution of air pollution to the lung-cancer burden and, in par- ticular, the interaction of air pollution with cigarette smoking require further exploration. Some of the nonrespiratory effects that warrant further epidemiologic study are the effects of lead on childhood neurobehavioral development and on blood pressure and the effects of carbon monoxide on ischemic heart disease. Possible carcinogenic, mutagenic, or neurotoxic effects of community exposures to benzene and other volatile organic substances are also of concern, but full-scale epidemiologic studies might not yet be feasible except in selected areas near point sources. Traditional tools for measuring health effects in epidemiologic studies of air pollution include routine collection of morbidity and mortality data, question- naires, and spirometry. The availability of FEV1 and other simple, noninvasive measures of pulmonary function has greatly benefited cross-sectional and longitudinal epidemiologic studies of respiratory disease. Refinements and standardization procedures in the use of these older tools can improve study sensitivity. Some newer tech- niques in pulmonary function testing, such as airway- reactivity challenge, expand the range of measurement capabilities and might provide important opportunities to study new end points. Biologic markers in such readily obtained biologic samples as blood, urine, and sputum can reveal evidence of exposure or disease in early stages and will find increasing application in epidemiologic studies of air pollution effects. These markers will be needed to provide information on biochemical changes that precede overt changes in lung function. Such markers could also identify susceptible persons. The protease-antiprotease hypothesis in emphysema offers the most promising terrain 4

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for the development of these new tools. Immunochemical methods are already capable of detecting extremely small quantities of connective-tissue breakdown products in biologic fluids. Current research on the sources of variation in these measurements and their predictive value will determine their feasibility for use in epidemiologic research on air pollution. EXPOSURE ASSESSMENT The assessment and measurement of exposure are impor- tant and difficult aspects of the design and conduct of epidemiologic studies of air pollution. meet" refers to a set of multidisciplinary activities that describes who is exposed to how much of what substances, for how long, and under what conditions. Whether based on direct measurements or on modeling, exposure assessment is a vital part of environmental epidemiology. Air pol- lutants do not occur independently, but rather as mixtures of natural, industrial, transportation, and residential exposures; hence, assessment of exposure to air pollutants is particularly complex. The Committee considered assess- ment of exposure relevant to human health and did not examine exposure relevant to potential environmental damage. "Exposure assess- Most epidemiologic studies of air pollution have assumed that exposure, however measured, constitutes an adequate surrogate of the dose of a given pollutant. Recent advances in toxicology and molecular epidemiology have emphasized some important distinctions: "exposure" refers to a concentration of a pollutant measured in the environment, n internal dose" is the amount of a substance or its metabolites in body tissues, and "biologically effective dose" is the amount of a substance that inter- acts with a particular target tissue or its surrogate. Information on internal dose and biologically effective dose is not generally available, but should be developed. In the interim, epidemiologic studies of air pollution will continue to rely on outdoor and indoor ambient exposure data, including data based on personal monitoring. Today, air pollution monitoring is a highly developed field of applied science, with sophisticated analytic devices for measuring many contaminants, both indoor and 5

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outdoor. However, advances in measurement technology do not in themselves provide a valid rationale for a given study. Many studies that are possible might be unimportant or of unlikely productivity. With present knowledge, air pollutants can be divided into three categories of sources: outdoor, such as sulfates, ozone, and lead; outdoor and indoor, such as fine particles, nitrogen oxides, and carbon monoxide; and indoor, such as volatile organic compounds, radon and its progeny, formaldehyde, and woodsmoke. In reviewing the physical, chemical, and biologic characteristics of pollutants, the Committee noted that some emissions are "fresh" (from local sources) and some "aged" (from distant sources). The Committee identified and assessed some pollutants of concern, including "older" pollutants (some of which are regulated), such as acid aerosols, ozone, nitrogen dioxide, carbon monoxide, lead, and radon and its progeny. Emerging classes of pollutants that might require epidemiologic and exposure studies include volatile organic compounds and products of incomplete combustion. Documentation of the importance of indoor concentra- tions of pollutants is profoundly altering air pollution epidemiology. More than two-thirds of the time of the average U.S. citizen is spent indoors. Therefore, the presence of even moderate amounts of pollutants indoors can influence the classification of a person with regard to pollutant exposure. A goal of exposure assessment in epidemiologic studies of air pollution is to minimize the misclassification of study subjects by exposure magnitude or type. To this end, further development of integrated exposure assessment will be vital for air pollution epidemiology. The Committee recognizes that total personal exposure to an air pollutant is a conceptually important measure for epidemiology, in that it provides the most valid overall predictor of the risk of any air-pollution-related health effect. Several factors that can modify personal exposure might also be relevant in planning exposure assessment for epidemiologic studies, including activity, respiratory tract physiology, and weather patterns. Many of the established air pol- lution monitoring networks were not originally designed to represent personal exposure or to test explicit biologic models that considered such factors. 6

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Future epidemiologic studies of air pollution will often require selective use of more accurate quantitative measures of exposure (such as personal monitors) than have been used in the past, if they are to link exposure to disease. In particular, the usefulness of central monitoring station data to represent individual exposure will be limited. Where the effects studied are common and the risks of developing an effect are low but impor- tant, minimizing the misclassification of exposure will be necessary to increase the chance of finding differences between groups exposed to different extents. Research is needed to characterize pollutants and to validate the use of surrogate measures. Exposure assessment data can be used during study planning to improve several aspects of study design, including selection of study populations, specification of the relevant physical, chemical, or biologic characteristics of pollutants, and determination of needed sample size. CONCEPTS AND STRATEGIES IN PLANNING EPIDEMIOLOGIC STUDIES ON AIR POLLUTION Success in protecting the public from very high exposures to air pollution has fostered a situation in which both research questions and research strategies to address them must be more focused and more precise than in the past, when both exposures and effects were more apparent. Specification of the details of a research question--including type of exposure, temporal features, health effect of concern, population at risk, and known risk factors aside from air pollution--is a vital part of study planning. Several different types of research questions regarding air pollution can be addressed epidemiologically. Some pose greater inherent difficulty than others and neces- sitate more restricted answers. In general, questions involving dose-response relations at low doses or thresholds for chronic effects are the most severely constrained. Advances in these matters will depend largely on the development of more sensitive tools for measuring both exposure and effect. Questions that deal with attributable risk (the proportion of a given effect in a population that is due to air pollution) are uniquely appropriate for epidemiology and should play a larger part in future research. 7

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The importance of specifying research questions cannot be overemphasized. Furthermore, to provide credible estimates of low risks, epidemiologic studies will require attention at all stages to all potential sources of error; the Committee discussed a few concepts relevant to managing potential sources of error, with particular attention to air pollution studies. Another factor that has become an integral part of epidemiologic research planning concerns estimating the cost-effectiveness of various ways to answer specific questions. Epidemiologic methods that could be applied to air pollution questions include descriptive epidemiology or univariate studies; ecologic studies; cohort studies; case-control methods, including the nested case-control method; cross-sectional studies; and intervention studies Case-control studies are generally quicker and less expensive than longitudinal studies, but have been used only infrequently for air pollution effects, partly because it is difficult to reconstruct past exposures with adequate precision. Prospective longitudinal studies based on individual measurements of exposure and effect are likely to provide the strongest basis for epidemiologic inference on air pollution, but they might take years of observation, are generally expensive, and often require a tradeoff between sample size and duration of followup. Cross-sectional studies, in which exposure and effect data are collected concurrently during a single period, can also be useful for studying air pollution effects under some circumstances. Epidemiologists can develop productive studies on air pollution by taking advantage of several different types of special (and sometimes transient) situations. Analo- gous exposures in the workplace, migrant populations, pristine environments, and highly polluted areas overseas might provide opportunities to circumvent various methodologic constraints. Development of productive epidemiologic strategies in a difficult field like air pollution research will require time, organization, and patience. Necessary characteristics of the milieu for such research include opportunities for interaction among epidemiologists, clinicians, and toxicologists; provisions for training and career development of new scientists; opportunities for assembling multidisciplinary research groups; stable 8 .

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administrative and financial support; adequate overall funding; and an appropriate range of contact with government personnel. APPLICATION OF EPIDEMIOLOGY TO SELECTED RESEARCH QUESTIONS The Committee uses epidemiologic approaches to selected questions in air pollution research to illustrate the points made in its report. Using a framework that con- siders critical components of study strategy and design, the Committee addresses questions involving four health effects of concern: acute respiratory infection, chronic obstructive pulmonary disease (COPD), asthma, and lung cancer. The same framework is applied to the study of five types of pollutants likely to be of continuing con- cern in the United States: woodsmoke, nitrogen oxides, persistent ozone and acid aerosols, episodic ozone ana acid aerosol haze, and radon. The illustrated approaches use a range of study methods and several ways of measuring exposure and effect variables and identifying opportunities for study. For example, effects of air pollution on upper respiratory infections themselves in children under the age of 2 seem to lend to relatively straightforward prospective study; the end point is common, and the exposure history reasonably reliable, although the researcher needs to be especially concerned with indoor pollutants. Case-control studies of specific outcomes, such as acute bronchiolitis in infants. would not require prohibitively large numbers of subjects. Study of some acute effects or episodic exposures--such as asthmatic attacks, exacerbations or chronic lung disease, and exposure to ozone and acid aerosol haze--might be approached with small panels of subjects and individual regression models for each subject based on the probability of an adverse event on a given day. Research to understand air pollution and the origin of COPD will require great care and ingenuity. The occur- rence of new cases of COPD is relatively infrequent, so prospective studies of the role of air pollution in the etiology of this syndrome would be infeasible, owing to cost and time considerations. One could instead study the onset of COPD retrospectively or study the develop- 9

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ment of early physiologic or biochemical markers that presage the onset of the complete disease. The latter strategy is limited at present by gaps in our understand- ing of the natural history of COPD. All retrospective methods for studying this subject, however, will suffer from the lack of reliable, precise data on individual lifetime exposure to ambient pollutants. Rate of decline in such lung-function measurements as the FEV1 currently are the most sensitive relevant markers for COPD; in this approach, desirable samples for cohorts are smaller than might be expected, and small samples could be used to study persistent exposures to such pollutants as ozone and acid aerosol. Large multicenter case-control studies and the use of short-term indicators of mutagenic and carcinogenic effects are feasible, although not neces- sarily easy, for the study of the relation of air pollution and lung cancer. An unusually large cohort like that under study by the American Cancer Society might also present opportunities for prospective study. For studying the effects of woodsmoke, ecologic studies might be especially helpful initially, whereas indoor monitoring is crucial for studying the effects of nitrogen dioxide. In some studies of air pollution effects, it might be useful to eliminate direct smoking as a confounder by restricting study subjects to non- smokers; however, only by including smokers can inter- actions between air pollution and smoking be detected. CONCLUSIONS AND RECOMMENDATIONS Results of well-conducted epidemiologic studies can provide unique and valuable information about the health effects of air pollution. In view of the primary responsibility of the Environmental Protection Agency (EPA) for determining and acting on air quality in the United States, the Committee makes the following major recommendation: The Environmental Protection Agency should develop a long-term plan for research on air pollution; and population-based studies, in the form of a program in epidemiology, should be an integral part of that plan. 10

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CHARACTERISTICS OF A PROGRAM IN AIR POLLUTION EPIDEMIOLOGY To be productive and cost-effective, the epidemio- logic program should have the following four major characteristics: Maintenance of a capability to interpret and synthesize current knowledge about air pollution and, accordingly, to plan relevant short-term epidemiologic research and make appropriate changes in long-term research. . Inclusion of mechanisms for the creation of multidisciplinary teams to plan and conduct population-based epidemiologic research on the adverse health effects of air pollution. Means of ensuring stable, lonq-term epidemio- logic research in a context that supports the career development of the researchers and thus limits disruptive changes in personnel. . Exploration of collaboration with agencies that collect or could collect relevant data, after . careful consideration of overall long-term data needs. A productive epidemiologic research program must have a dual character with respect to sensitivity to outside forces. Part of the program must be dedicated to responding to rapidly changing conditions that offer important opportunities for study, to the varying concerns of regulators, and to new information from technologic development and parallel disciplines. In particular, toxicology, clinical research, and epidemiology should be viewed as parts of the same framework; advances in any one can drive new efforts in the others. Another part of the program, engaged in long-term research strategies or longitudinal studies, must remain relatively isolated and free from abrupt change, although the incorporation of new elements will sometimes be desirable. It is important that the EPA program staff at all levels include highly trained and experienced epidemiologists, regardless of whether research is conducted intramurally or extramurally. Continuous 11

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access to both advice and review from scientists outside the institution will also be needed. Given the constraining and difficult nature of today's questions about air pollution, stable research teams with expertise in several critical fields will be most productive. Epidemiologists in the teams should collaborate with atmospheric scientists, statisticians, and health effects scientists in all phases of research, from study design through inter- pretation. The present structure of many universities and government research agencies often makes it difficult to arrange such collaboration. Financial and administrative mechanisms that encourage develop- ment of these teams must be implemented; and the EPA program staff itself must have a multidisciplinary composition. The program should assess the value of large data systems developed for reasons other than air pollution studies (such as the National Health and Nutrition Examination Survey, the National Health Interview Survey, and the National Ambulatory Medical Care Survey) as resources in air pollution research. Some of them might be modified and linked to air pollution exposure data to develop a feasible and cost-effective research approach that affords very large samples. Modification in the routinely collected air sampling data alone might be appropriate, to facilitate use of these data in some types of epidemiologic studies. THE FOCUS FOR RESEARCH - For the immediate future, the epidemiologic research program should focus on the following exposures and effects of concern: . - Persistent air pollution problems, including the-health effects of acid sulfate particles, ozone, nitrogen dioxide, carbon monoxide, lead, and radon. It should be flexible enough to address emerging problems, such as the health effects of products of incomplete combustion and volatile organic chemicals. Lung disorders in which air pollution might play a role, including chronic obstructive pulmonary 12

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disease, asthma, decreased rate of lung growth or increased rate of lung decline with anion, and increased susceptibility to acute respiratory infections. . The Quantitative contribution of air nol- lutants to lung cancer in human populations. For this purpose, it could take advantage of the existing funding arrangement between EPA and the National Cancer Institute for the support of epidemiologic studies of this problem. Many important questions about the n traditional" pollutants remain unanswered. For example, the acute and chronic respiratory effects of acid aerosol and ozone exposures, which might result only from outdoor sources, are not well understood. A large population, perhaps in excess of 100 million, is exposed to ambient ozone at high concentrations during the spring and summer. Shifts in coal combustion to the south central states will result in an increase in the area and population exposed to acid aerosols. No systematic epidemiologic study has been designed to assess either the acute or chronic effects of this type of shift in exposure. Exposures to acid aerosols are likely to increase more in rural areas than in urban areas, so consideration should be given to locating baseline and followap studies in rural areas. As new automotive fuels, new industries, new fuel sources, new commercial products for the home, and new building ventilation patterns are introduced, they might yield new pollutants and pollution patterns that require epidemiologic evaluation. These changes will result in increased exposures to volatile and particulate organic compounds, radon, carbon monoxide, and other potentially hazardous materials. Indoor air pollution can be a major factor--in some instances the principal factor--in determining total personal exposure (averaged and acute) to air pollutants. Epidemiologic studies must therefore consider indoor or outdoor concentrations, or both, depending on the health response and pollutant being examined. For example, average and peak exposures to nitrogen dioxide are determined primarily by the presence of unvented indoor combustion sources. Peak 13

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exposures higher than those in most urban outdoor environments occur often in residences that use unvented gas or kerosene as a cooking or heating fuel. Therefore, to assess the health effects of nitrogen dioxide, EPA should study respiratory infection, pulmonary function changes, and, as soon as possible, biochemical indicators in association with indoor exposures and simultaneous outdoor exposures. There have been important advances in air monitor - ing instruments and inferential data analysis tech- niques. Air pollution is a complex mixture of gases, vapors, and particles; epidemiologic studies will often benefit from detailed characterization of its components. For instance, the chemical composition and acidity of size-fractionated particles should be characterized where appropriate. In some cases, new techniques for biologic characterization are also appropriate. Detailed characterization can help to determine the air pollution components most closely associated with health outcomes, potential con- founders, and the relative contributions of various sources. The most readily observed health effects of air pollution are in the respiratory system. The pro- portion of the overall disease burden from common respiratory diseases that are attributable to air pollution has not yet been established. This part of the disease burden includes both the development of disease de nova and the exacerbation of pre-existing disease. Air pollution might have nonrespiratory effects that, although not emphasized in this report, also deserve study. These include neurobehavioral deficits and essential hypertension related to lead exposure, ischemic heart disease related to carbon monoxide, and carcinogenesis and mutagenesis related to various volatile hydrocarbons. Respiratory cancers, which are the most common cause of cancer death in men and will soon be in women, are attributable largely to cigarette smoking. However, attempts to assign proportions of this disease burden to separate causal agents, such as air 14

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pollution, are frustrated by the multifactorial and interactive etiology of these cancers. It is par- ticularly important to understand the role of air pollutants in lung cancer, inasmuch as interactive effects might multiply the number of cases that could be prevented by reducing exposures. The limits of an epidemiologic research program depend on the questions under consideration. Only by considering each research question carefully can one understand the limits of investigative methods and discuss them productively. In general, studies of chronic health effects are more difficult than studies of acute effects. The major problems include uncer- tainties in measurements of long-term exposure, the relative rarity of chronic diseases (which strains statistical power), and limitations in our under- standing of the biology underlying the gradual evolution of chronic damage. Epidemiologic studies can show whether exposure to a complex pattern of polluted air increases the risk of adverse health effects in human populations, but studies are often limited in their ability to delineate the quanti- tative relationships between concentrations or sources of specific air pollutants and health. Such delineation requires interpretation of epidemiologic data in conjunction with toxicologic and clinical research. Susceptibility to the effects of air pollution varies widely; studies that focus on sensitive subgroups, necessary in themselves, are an important part of strategies to detect and measure the effects of air pollution in the general population. The sensitive-subgroup approach to increasing the effectiveness of air pollution epidemiology must be furthered by broad-based efforts (toxicology, clinical research, and epidemiology) to clarify the precise nature and degree of sensitivity of such groups as the young, the elderly, those with increased airway reactivity, and those with particular pre- existing diseases. Opportunities for carrying out epidemiologic studies on populations exposed to unusual magnitudes or patterns of air pollution must be specifically sought. By circumventing various methodologic constraints, these studies might provide information that would not otherwise be easily 15

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obtained. The opportunities include the use of occupational cohorts exposed to high concentrations, groups living in pristine environments or in highly polluted environments, and groups subjected to marked temporal changes in pollution. Collaboration with researchers in other countries might be necessary. NEW RESEARCH TOOLS AND OPPORTUNITIES Some constraints in air pollution epidemiology could be removed by complementary research to develop and explore the application of new tools for measuring exposure and effect. Such research and development is especially needed in two categories: . New methods for assessing personal exposure and response to air Pollution to be selectively incorporated into epidemiologic studies, with attention to the cost-effectiveness of these methods. , . Epidemiologic studies designed to determine the characteristics and the Predictive value of potentially useful physiologic biochemical, and morphologic markers of subclinical effects. Personal exposure monitoring and modeling are sometimes needed in epidemiologic research to define study populations, optimal sample sizes, relationships of surrogate measures to exposures, and the extent of exposure misclassification associated with the use of central monitoring data. Depending on the design of a given study, only a sample of the study population might require such detailed monitoring; various strategies need to be explored and their performance documented. Markers of physiologic, biochemical, and cellular morphologic changes will be increasingly important in air pollution studies. FEV1, a physiologic test of lung function, has been used successfully to measure differences related to air pollution between popula- tions. Serial measurement of FEV1 has also proved to be sensitive and effective in following the growth and decline of lung function in large populations. In adults, a more rapid than normal decline in FEV predicts premature death from pulmonary failure. 16

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Although FEV1 is a simple and highly reproducible test, its interpretation in terms of organ or cellular pathology is complex and subject to some judgment. Some biochemical indicators of air pollutant exposure or early effects--such as blood lead and carboxyhemoglobin concentrations, urinary mutagens, and indexes of genotoxic damage--have already been successfully applied in population studies. other biochemical indicators, designed to detect early pathologic processes in the lung, have recently shown promise and require further development and valida- tion. Insights into the pathogenesis of emphysema have been particularly fruitful in opening pos- sibilities for biochemical markers related to the breakdown of connective tissue in the lung. Develop- ment of biochemical markers for epidemiologic studies requires particular attention to constraints imposed by the need to study large groups of relatively healthy people. 17

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