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THE COMMITTEE'S 10 HIGHEST-PRIORITY RESEARCH RECOMMENDATIONS

In this chapter, the committee identifies the 10 particulate-matter research needs that it judges to be of highest priority and describes general types of research that should be undertaken to address those needs. The research needs described herein are considered to be of equivalent importance. The committee evaluated approaches for obtaining such information within its framework linking source emissions to health responses (see Figure 3.1 in Chapter 3). The research priorities described below do not include the full universe of potentially useful research. Instead, in the committee's judgment, they are the 10 most critical scientific questions to be answered in pursuit of understanding the complex relationships that lead from particle sources (including formation of secondary particles from gaseous interactions) to ambient particulate-matter concentrations, actual human exposures, doses delivered to the lung, and, ultimately, to adverse health effects from the most biologically active constituents or characteristics of particulate matter.

The 10 particulate-matter research priorities identified in this chapter include some research activities that should be started immediately and others that should begin only after a better foundation is built from current or new research. Information obtained from approaches in one field can and should be used to advance methods and knowledge for other research needs. For example, epidemiological findings



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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio 4 THE COMMITTEE'S 10 HIGHEST-PRIORITY RESEARCH RECOMMENDATIONS In this chapter, the committee identifies the 10 particulate-matter research needs that it judges to be of highest priority and describes general types of research that should be undertaken to address those needs. The research needs described herein are considered to be of equivalent importance. The committee evaluated approaches for obtaining such information within its framework linking source emissions to health responses (see Figure 3.1 in Chapter 3). The research priorities described below do not include the full universe of potentially useful research. Instead, in the committee's judgment, they are the 10 most critical scientific questions to be answered in pursuit of understanding the complex relationships that lead from particle sources (including formation of secondary particles from gaseous interactions) to ambient particulate-matter concentrations, actual human exposures, doses delivered to the lung, and, ultimately, to adverse health effects from the most biologically active constituents or characteristics of particulate matter. The 10 particulate-matter research priorities identified in this chapter include some research activities that should be started immediately and others that should begin only after a better foundation is built from current or new research. Information obtained from approaches in one field can and should be used to advance methods and knowledge for other research needs. For example, epidemiological findings

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio that point to potentially susceptible subpopulations within the general population can be used as part of the basis to develop laboratory animal models and toxicological studies. Toxicological results, in turn, may help to identify biologically important constituents or characteristics of particulate matter or potentially susceptible subpopulations. This information can then be used to focus on human exposures to biologically important aspects of particulate matter. An iterative process involving interpretation of evidence from toxicological and exposure studies will lead to the selection of the metrics of exposure for designing future epidemiological studies on the health effects of particulate matter and other pollutants. The process should also lead to a better understanding of source-concentration-exposure-dose-response relationships through the application of successive generations of analytical tools for the most biologically important components or characteristics of particulate matter and gaseous copollutants. Although each of the research topics discussed below was evaluated individually, the committee recognized and addressed the fundamental interdependence of the individual elements. In the research investment portfolio presented in Chapter 5, the committee integrates these interdependent issues into a set of year-by-year timing recommendations and funding priorities for research. A truly integrated research strategy has rarely been used to investigate environmental problems, and it will require a major shift in current approaches to filling knowledge gaps and building toward a coherent understanding of the particulate-matter problem. In addition to their scientific value, the research priorities described below are also expected to strengthen the basis of evidence for establishing allowable emission rates for the chemical components and precursors of particulate matter that are biologically important. This evidence base will be essential for designing and implementing effective control strategies for particulate matter in outdoor air through state implementation plans and for developing other mitigation approaches, including educational activities, voluntary emissions reductions, and product improvements for reducing indoor particulate-matter emissions that are not currently regulated. Each research priority is presented with a description that includes

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio specific research tasks that are linked to individual steps and interactions among steps in the committee's framework. The value to scientific knowledge and the information needs of decisionmakers is also discussed. In addition, the feasibility, timing, and rough but informed collective-judgment estimates of the cost to conduct each recommended research task are discussed. RESEARCH PRIORITIES RESEARCH TOPIC 1 OUTDOOR MEASURES VS. ACTUAL HUMAN EXPOSURES What are the quantitative relationships between concentrations of particulate matter and gaseous copollutants measured at stationary outdoor air-monitoring sites, and the contributions of these concentrations to actual personal exposures, especially for potentially susceptible subpopulations and individuals? DESCRIPTION Several studies have identified associations between measures of particulate-matter mass concentrations and health responses in ambient air (Dockery and Pope 1994; EPA 1996; Wilson and Spengler 1996; Vedal 1997). However, the currently available information is not sufficient for general characterization of the relationships of ambient air concentrations of particulate matter and gases to actual human exposures that include the indoor environments. Personal exposures to certain air pollutants have consistently been found to differ from estimates based on corresponding outdoor concentrations. The differences are largely due to the variable contributions of outdoor air to indoor environments, the indoor fate of outdoor contaminants, and the substantial contribution of indoor sources and sinks to total personal exposures to particulate matter (Lioy et al. 1990). Most people spend the majority of their time indoors, exposed to a mixture of particles that penetrate from outdoors and those generated

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio indoors. Studies to date have found that a significant fraction (50-90%) of smaller indoor particles have outdoor origins (Koutrakis et al. 1992; Clayton et al. 1993; Thomas et al. 1993). Once indoors, particles may deposit on surfaces, or they can be altered through volatilization, as with ammonium nitrate, or through reactions with other pollutants present indoors, as with neutralization of sulfuric acid by ammonia. Indoor particles are further affected by the myriad of indoor particle sources, including cooking, resuspension, cleaning, tobacco smoking, pets, insects, and molds (lioy et al. 1990; Waldman et al. 1990; Koutrakis et al. 1992; Clayton et al. 1993; Thomas et al. 1993). The emission rates of most indoor-particle sources, however, have not been adequately quantified. Furthermore, factors that affect the contribution of outdoor particles to indoor concentrations have not been well characterized. Information is especially lacking on the relationship between particulate matter in outdoor air and personal exposure to particulate matter for subpopulations that may be particularly susceptible to the effects of particulate-matter exposures, such as the elderly, individuals with respiratory or cardiovascular disease, and children. That gap in knowledge needs to be addressed immediately. Investigations must be designed specifically to test hypotheses related to actual human exposures. These studies should not be deferred while waiting for further health-effects studies. Hypothesis-driven exposure studies must be designed to provide fundamental information on actual human exposure to particulate matter and gaseous pollutants (NRC 1991). The recommended studies will be used to determine the exposure metrics that are most suitable for establishing exposure-response relationships. The following specific research tasks are needed to attain these goals: Field studies that differentiate the contributions to personal particulate matter and gas exposures made by ambient air and by the penetration of ambient air indoors. These studies will require coordination and temporal resolution among measures of personal exposure and ambient concentrations of particulate matter and gases. Longitudinal panel studies, in which a group of individuals is studied at successive points in time, to examine interpersonal and intrapersonal

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio variability, as well as seasonal and temporal variability in particulate-matter exposure. These studies should assess how such variability affects the relationship between personal exposures and ambient exposure estimates from measurements at central outdoor-monitoring sites. The studies should be extended later to characterize simultaneous personal exposures to particulate matter and pollutant gases. Analyses of information collected from the field studies and longitudinal studies described above to determine the contributions of outdoor versus indoor sources for each pollutant, and to examine the degree to which the use of more accurate exposure information would, or would not, alter the findings of the epidemiological time-series studies concerning particulate matter and adverse health effects. The sampling of particulate matter should include measurements of both PM2.5 and PM10. SCIENTIFIC VALUE Most epidemiological studies of particulate matter to date have been based on outdoor measurements. Therefore, the investigation of relationships between actual personal exposures and outdoor air-particle concentrations is crucial for validating and interpreting the results of epidemiological studies by providing better estimates of actual human exposure. Results from preliminary studies suggest significant intrapersonal and interpersonal variability in exposures to particles (Lioy et al. 1990). The recommended exposure-assessment studies will generate large data sets that will make it possible to assess factors influencing actual personal exposure. The results of these studies can also be used to design new prospective epidemiological and toxicological studies by establishing better metrics of exposure. Using the data base of exposure measurements for particles and gaseous pollutants, we will be able to provide better metrics of personal exposure in terms of concentrations of chemical species and of other covarying pollutants to be used in epidemiological investigations that focus on particulate matter while controlling confounding effects of gaseous pollutants. Differences between personal exposures and ambient measures can be

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio characterized and incorporated into subsequent analyses. (Also see section on measurement error.) DECISIONMAKING VALUE Pollutant concentrations in outdoor ambient air often are very different from actual personal exposures. Understanding the relationship between particulate-matter mass concentrations measured at fixed outdoor sites and actual human exposure to particulate matter will help guide and improve decisions about ambient pollution control strategies (NRC 1991). From a public-health perspective, it is very important to characterize actual exposures of particularly susceptible subpopulations to ambient particles and gaseous pollutants. Understanding the origin and composition of such exposures and their relationships to various human activities is of paramount importance for developing and implementing risk-reduction strategies for ambient sources and for nonregulatory (e.g., educational or product-improvement) strategies for indoor sources. That can be accomplished by determining the relative contributions of different sources to personal exposures, as well as by investigating how these contributions are influenced by patterns of personal activity. FEASIBILITY AND TIMING Many of the sampling and analysis techniques needed for this type of research have already been developed and field tested. Such methods can be used to measure 12-hour or 24-hour integrated personal exposures to particles and criteria gaseous pollutants (e.g., ozone, sulfur dioxide, nitrogen oxides, carbon monoxide). In addition, pilot exposure-assessment studies have already established the feasibility of conducting personal monitoring on presumed susceptible subpopulations, such as persons with chronic obstructive pulmonary disease (COPD), the elderly, and children. Continuous and semicontinuous personal

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio monitors are under development and will be available within the next couple of years. The design and execution of a panel exposure-assessment study will take approximately 3 years. That includes subject recruitment, field measurements, collection of time-activity data, and data analysis. Therefore, it is feasible that panel exposure assessment studies be completed within a relative short period. Several such studies should be initiated almost immediately. These studies should examine different, potentially susceptible subpopulations in various geographical locations. COST A minimum of three studies in different parts of the United States will be needed to define ambient and personal exposures for populations at risk. Those studies should include at least one in the western United States, one in the northeast, and one in the southeast. The east-west differences will provide information on particulate-matter composition and variability, while the north-south studies will examine the effects of climate and living conditions. A possible design strategy might involve a study of 20 or more individuals for at least 15 days of sampling in the summer and winter. It would include members of presumed susceptible subpopulations, as well as representatives of the general population. Because of the complex aerometric measurements required, the three studies will require approximately $3.0 million per year for 3 years. Adding potentially susceptible subpopulations to such studies could increase that cost by a factor of 3 or more. RESEARCH TOPIC 2 EXPOSURES OF SUSCEPTIBLE SUBPOPULATIONS TO TOXIC PARTICULATE-MATTER COMPONENTS What are the exposures to biologically important constituents and specific

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio characteristics of particulate matter that cause responses in potentially susceptible subpopulations and the general population? DESCRIPTION As the database on particulate-matter constituents that induce health effects enlarges, and as specific chemical constituents or particle-size fractions are indicated as plausible causal agents, exposures to those constituents of particulate matter need to be quantified for both the general public and susceptible subpopulations. The process will be iterative, with information developed from earlier studies guiding the planning of later studies. Population-based field studies will provide information on the distribution and intensity of exposure of the general population to experimentally defined components and size fractions. The studies should be conducted for statistically representative groups of the general population, with some oversampling for potentially susceptible subgroups. The studies could be coupled to health outcome investigations, but they should be designed to determine the extent to which members of the population contact these biologically important constituents and size fractions of concern in outdoor air, outdoor air that has penetrated indoors, and air pollutants generated indoors. The following specific research tasks should be addressed after obtaining and interpreting results of studies and information from Research Topic 1: Measure population exposures to the most biologically important constituents and size fractions of particulate matter. These exposure studies should include members of the general population and potentially susceptible subgroups, using personal-monitoring studies and ambient stationary sites to examine the outdoor contributions to measurements of total personal exposure. Further refine the sampling and analysis tools developed in Research Topic 3 (below) to permit their routine application for the determination of biologically important chemical constituents and size ranges of particulate matter.

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio SCIENTIFIC VALUE This information will be vitally important in designing exposure assessments for critical particulate components as part of the prospective long-term epidemiological studies that will provide the basis for more accurate risk assessments. It is important to investigate through population-based studies the distribution of ambient particulate-matter exposures and doses for different susceptible subpopulations and to identify the differences between distributions and the exposures experienced by the general population. DECISIONMAKING VALUE Because these studies will focus on examining the actual exposures of individuals to the most biologically important components or characteristics of particulate matter, the results can be critical to the choice of the measured indicators that would be specified in the NAAQS and to standard setting for these critical indicators. At the same time, the identification of critical indicator species will help in the implementation of cost-effective strategies to protect individuals at high risk, because control resources will be devoted more efficiently to the sources of the specific causal agents of the health effects. FEASIBILITY AND TIMING Some population-exposure studies could be initiated soon, but a more targeted set of studies should await a better understanding of the physical, chemical, and biological properties of airborne particles responsible for the reported mortality and morbidity outcomes. This research in exposure should then be conducted expeditiously to affect decisions on source-reduction strategies. Focusing on the specific causal attributes of particulate matter will be essential to make population-exposure studies cost-effective. Sampling and analysis techniques similar to those that will be used

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio for the panel exposure-assessment studies could also be used for population-based studies. Additional techniques for measuring biologically important parameters, like the oxidative potential of particles, should be developed and tested before the initiation of the studies called for in Research Topic 3. Statistical analysis and participant recruitment methods developed over the past decade can be used to select cohorts that are representative of the total population. Finally, once sampling and analysis techniques are available, 3 to 5 years will be needed to complete these studies successfully. COST The committee estimates that at least five studies will be needed to cover the range of conditions that exist across the country. In the western United States, at least two cities should be studied. In the northeastern and southeastern United States, cities that represent climatic variations of the region will need to be studied. A city in the midwestern United States would provide geographical balance and establish exposure profiles for specific segments of the U.S. population. The studies would need to include at least 400 to 500 people per city. These studies are estimated to cost approximately $4.0 million per year for 5 years, depending on the indicators being measured. RESEARCH TOPIC 3 SOURCE-RECEPTOR MEASUREMENT TOOLS What are the advanced mathematical, modeling, and monitoring tools needed to represent source-response relationships more accurately? DESCRIPTION Determination of the constituents and characteristics of particulate matter that cause adverse human health effects will provide an opportunity

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio for more effective protection of public health by permitting the control of the most important aspects of particles that cause health effects. In order to be able to utilize that information in effective strategies for monitoring and source emission control, new tools that link sources with ambient air quality will be needed. For example, a detailed knowledge of the specific nature of emissions (gases and particles) from sources, and the chemical reactions that these materials undergo in the atmosphere, will provide an inventory of the sources of potentially hazardous, airborne chemical substances that might be present at locations where people are exposed to ambient air. Because the development of a general capability to relate particulate-matter sources to the responses will take time, such an effort must begin as soon as possible. However, the implementation of source-response investigations should not begin until most of the biologically important components of particulate matter are believed to be identified. If source-response investigations were undertaken with the current limited knowledge, significant resources might be wasted by studying biologically unimportant components of particulate matter. That could also lead to false expectations about air-quality improvements relevant to health risks from particulate matter. Unlike other criteria pollutants that are completely defined by their chemical structure, particulate matter consists of a wide variety of chemical components and a wide range of particle sizes. Without knowledge of the biologically important components and particle sizes, it would be impracticable to apply source-receptor techniques to each of those components. Therefore, accurate and precise analyses are needed for representative samples from emissions and ambient air with respect to chemical compositions of particulate matter, especially PM2.5, and gaseous pollutants. It is possible that the organic carbon fraction of particulate matter contains compounds that are biologically important or would provide useful marker compounds to characterize various source emissions. For example, wood smoke and motor vehicle emissions have been found to contribute to the mutagenic activity of particulate-matter extracts (Lewis et al., 1988). However, the capability currently exists only to separate, identify, and quantify a small fraction of the organic species associated with particulate matter.

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio are required to complete this important task successfully so that appropriate animal models are available within the next 2-3 years. COST The development and validation of these animal models is expected to cost approximately $3.0 million per year for the first 6 years. 9b. IN VITRO STUDIES What are the appropriate in vitro models to use in studies of particulate-matter toxicity? DESCRIPTION In vitro studies with particulate matter have been performed to characterize specific cellular events and to determine underlying toxicological mechanisms. They are an important complement to studies in whole animals and humans. However, most in vitro studies have been executed without due consideration of doses administered to the cells. Therefore, it is important to use dose levels that are relevant to in vivo exposures. In vitro studies are useful to examine a specific hypothesis based upon results of in vivo studies and can be tested using target cells of the respiratory tract. However, the method of dosing has to be critically evaluated (e.g., via delivery of airborne particles or via particle suspension in the medium). Furthermore, the use of cell-lines versus primary cells or the use of cell co-cultures, as well as culture conditions, have to be carefully assessed. In general, in vitro studies should focus on specific mechanistic aspects of particulate-matter toxicity and might, therefore, be restricted to situations where results of in vivo studies indicate positive effects for a given particle type. Within this area, there is a need to test the usefulness of in vitro studies for investigating mechanistic events in cells that mimic those that occur in susceptible individuals (e.g., cells of old versus young organisms or sensitized cells).

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio SCIENTIFIC VALUE In vitro models can be used to examine cellular and molecular mechanisms of toxicity due to particulate-matter exposure, including the role of specific tissues and cell types in the induction of toxic responses. To be of most value, it is essential to relate tissue doses to levels of exposure (i.e., in vivo) and to ambient levels and components of particulate matter. This will permit calibration of cellular and molecular events to ambient exposures, and will facilitate the use of such in vitro data for risk-assessment purposes. Positive results from such studies should be pursued by whole animal or clinical studies. DECISIONMAKING VALUE The use of appropriate in vitro models will provide valuable indirect information to support other investigations of the mechanisms of particulate-matter toxicity, which will assist in the interpretation of epidemiological data that show associations between particulate-matter exposure and cardiorespiratory disease. Specifically, disease-related mechanistic information at the cellular and molecular level could add significantly to the weight of evidence regarding a causal relationship between particulate-matter exposure and human morbidity. This information can also be helpful in interpreting the results of animal and clinical toxicity studies conducted in support of the development of the NAAQS. FEASIBILITY AND TIMING Several toxicology laboratories are well equipped to conduct mechanistic studies on the cellular and molecular events involved in particulate-matter toxicity. Such studies should be designed and conducted in conjunction with whole-animal and clinical toxicity studies.

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio COST The cost of the recommended in vitro studies is estimated to be $3.0 million per year for the first 6 years. 9c. CLINICAL MODELS What are the appropriate clinical models to use in studies of particulate-matter toxicity? DESCRIPTION The association between particulate-matter exposure and adverse health effects reported from ecological epidemiology studies appears strongest for respiratory and cardiovascular deaths, especially in individuals 65-74 years of age and older. It is not clear if there are mortality effects in healthy individuals of any age, particularly those younger than 65 years of age. There is weak evidence for morbidity in children. Based upon epidemiological findings, the population subgroups potentially susceptible to particulate matter and, therefore, candidates for clinical studies, include the elderly with pre-existing respiratory conditions (e.g., COPD), the elderly with cardiovascular disease (e.g., previous myocardial infarction or arrhythmia), asthmatic children and adults, impaired and nonimpaired cigarette smokers, healthy children and healthy elderly (Utell and Drew 1998). Other aspects of life style (e.g., nutrition and activity) should also be considered in assessing potential susceptibility to particulate matter. Clearly, clinical models will focus on acute responses that often have implications for chronic effects. SCIENTIFIC VALUE Associations between exposure to generally low ambient particulate-matter levels and morbidity have been observed in susceptible

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio subpopulations. Controlled human studies provide an opportunity to examine responses to particulate matter in both healthy and susceptible subpopulations. Carefully designed clinical studies will provide information on symptomatic, physiological, and cellular responses in healthy and susceptible subpopulations, namely those with pre-existing cardiorespiratory conditions. Such studies can also provide much-needed information on particulate-matter uptake and retention in healthy and susceptible subpopulations. Preventive intervention trials within susceptible groups should be considered (e.g., an NIEHS trial). DECISIONMAKING VALUE Clinical studies have provided important information for other regulatory decisions. Elucidation of responses in humans is a key to defining critical effects levels and determining the nature of adverse health effects. Assessing acute responses in groups with chronic diseases will provide important leads on plausible mechanistic pathways. Moreover, it will provide crucially required information on relative differences in responsiveness between at-risk and healthy populations. Clinical research also aids decisionmaking on the complex issue of margin of safety. FEASIBILITY AND TIMING Research facilities exist for clinical studies that use environmental chambers and mouthpiece exposures. Studies could be initiated immediately and carried out in parallel with animal studies. COST The human studies are estimated to cost $3.5 million/year for six years due to the complexities and multidisciplinary teams required for the conduct of such studies.

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio RESEARCH TOPIC 10 ANALYSIS AND MEASUREMENT Several methodological advances are needed to facilitate understanding of health effects related to particulate matter. These range from the development of appropriate models to estimate the fate and deposition of inhaled particulate matter, to improved monitoring methods, exposure methods, and statistical tools to analyze collected data. 10a. STATISTICAL ANALYSIS To what extent does the choice of statistical methods in the analysis of data from epidemiological studies influence estimates of health risks from exposures to particulate matter? Can existing methods be improved? DESCRIPTION The statistical analysis of epidemiological data on particulate matter and human health presents several difficult methodological issues. Time-series studies require consideration of the appropriate dose-response time lag and long-term and short-term trends in health and exposure data (due to factors such as seasonal and day-of-the-week effects). Since observations taken at different points might be correlated, the nature of the serial correlation in time-series studies needs to be characterized, and autocorrelation needs to be adjusted for in subsequent analyses. Studies of long-term exposure require analyses of time-dependent exposure patterns to identify critical exposure-time windows. Identification of the unique effects of particulate matter or its constituents requires careful adjustment for simultaneous exposure to a complex mixture of copollutants. Extensive covariate adjustment is required to minimize the possibility of confounding factors. Exposure measurement error can have the effect of understating risk, as well as overstating the precision of risk estimates. Flexible exposure-response models including time-dependent covariates, are also needed to described accurately the nature of the exposure-response relationships observed in epidemiological studies of particulates.

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio Several analysis methods have been used to address these issues; to date there is no consensus about which method is preferable. Evaluation of alternative existing methods would be useful, along with the exploration of more innovative methods. The most important questions are What methods of removing the influence of long-term trends from parallel data on daily particulate-matter concentrations and population morbidity and mortality are most appropriate? Should time-series of health and/or environmental data be filtered before analysis? What filters are most appropriate for this type of data? What is the nature of the autocorrelation function in time-series studies? How should autocorrelation be taken into account in the analysis of time series data? How can the critical timing of exposure (e.g., frequency or duration) for particulate-matter-related morbidity and mortality be determined? How can the unique health effects of particulate matter and its biologically important constituents be determined in the presence of exposure to multiple copollutants? Are existing epidemiological data adequate to identify the most relevant timing characteristics of exposure? Is residual confounding a concern in particulate-matter epidemiological studies? What types of exposure-response models are most appropriate to describe the observed relationships between mortality and morbidity and exposure to ambient particulate matter? How can key covariates, including potential confounders and modifying factors, be best incorporated into risk models used to describe the effects of particulate matter on population health? How can the effects of long and short-term exposures to particulate matter on mortality, including reduction in life expectancy, best be estimated? Could the positive associations between particulate matter and adverse health outcomes, as observed in time-series studies, be false

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio positives resulting from multiple statistical tests using various regression models? SCIENTIFIC VALUE Analysis and evaluation of complex data on the health effects of particulate air pollution requires advanced statistical methods, including methods for the analysis of multivariate time series data. The application of such methods may involve a number of methodological choices during implementation, such as the method of detrending or filtering. With such complex analyses, it is important to ensure that the conclusions reached are not dependent on the choice of method used. Validation of the statistical methods used in the analysis of epidemiological data on particulate air pollution will increase the level of confidence that can be attributed to conclusions drawn from such studies. The development of optimal methods of analysis may also lead to greater sensitivity in the detection of subtle health effects, and reduce the uncertainty associated with estimates of human-health risks due to exposure to particulate matter. DECISIONMAKING VALUE Given the potential public health impact of particulate air pollution, and the large costs associated with reducing pollution levels, it is critical that the scientific evidence on which air quality standards are based not be subject to uncertainty due to methods of data analysis and evaluation. Validation of analytic methods will not only enhance the scientific value of epidemiological findings, but will strengthen the basis on which future regulatory actions are taken. FEASIBILITY AND TIMING Although analytic methods for the evaluation of data from epidemiological studies of the health effects of particulate air pollution are relatively

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio well established, there exists considerable need for further methodological development. Given the existing knowledge base, such development is highly feasible. To be most effective, methodological research on the evaluation of epidemiological data on particulate health effects should be conducted in a multidisciplinary manner. The development of statistical methods of analysis should be undertaken in collaboration with scientists with expertise in biostatistics, epidemiology, and exposure assessment, and validated under conditions corresponding to those likely to be encountered in practice. Methodological evaluation and development should be initiated immediately. This would enable the application of resulting methodological advances in the analysis of future epidemiological investigations initiated later, as well as in the reanalysis of previous epidemiological results. COST Methodological research is relatively inexpensive, compared to the costs of data acquisition. Methodological research could be established in the first year at a cost of $500,000. Subsequent development and application of methods could be undertaken by several multidisciplinary teams with an annual budget of $1 million per year for 6 years, including collection of data necessary to support this work. This program should include the conduct of focussed investigations designed to validate the methods used under conditions reflective of those encountered in practice. 10b. MEASUREMENT ERROR What is the effect of measurement error and misclassification on estimates of the association between air pollution and health? DESCRIPTION Some of the studies undertaken to estimate the association between

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio particulate matter and human health relate population response to population exposures, whereas others are concerned with an individual's response to monitored particulate matter. To the extent that individual exposure measures are rarely available, most of the studies can be considered ecological in nature (Greenland and Robbins 1994; Kunzli and Tager 1997). The response of a given individual to environmental agents such as particulate matter depends upon that individual's exposure to the agents. In the case of particulate matter, it is a complex mixture. Several differences between individual exposure to a pollutant and the monitored value of that pollutant must be considered in analyses of exposure and response. The components of this difference include errors in the accuracy and precision of the monitoring instrument; differences in exposure due to the placement of the ambient monitor (related to the zones of representation for a monitor or to the spatial homogeneity of the environmental agent measured); differences between ambient concentrations used to characterize a pollutant exposure and the average personal exposure to that pollutant or, for particulate matter, its mass or the size fractions and chemicals of biological significance; and the differences between average personal exposure levels and the exposure of a given individual. Measurement error has several potential consequences. It can bias estimates of the association between a health end point and an environmental variable. (Usually the association is underestimated.) It can bias the estimated shape of any dose-response relationship between the health end point and environmental variable. Most often the bias is toward linearity; hence estimates of response thresholds can be obscured. In the context of a multivariate analysis, if the independent variables are correlated with each other and have relative differences in measurement error, then estimates of association can be biased. In general, associations between the health end point and those variables with smaller measurement error will be overestimated. The extent of the effect is determined very much by the type of analysis or statistical model used and by the nature of measurement error. For example, is the error linearly, nonlinearly, or multiplicatively related to the true measure? Is it systematic?

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio It is also possible for there to be misclassification error in the outcome variable. (For example, cause of death could be misclassified.) The effect of that type of misclassification will depend upon the nature of the misclassification and the statistical model used to analyze the data. For most of the models used to date, the effect of this error is not expected to be large. Other issues include How large are the various components of measurement error for each independent environmental variable (e.g., pollutants or weather)? How is the measurement error of one variable related to the measurement errors of other variables in the same model? What are the statistical distribution and types (e.g., Berkson or classical) of measurement error? What are the effects of measurement error on the estimated associations between particulate matter (or its size fractions and biologically important chemical constituents) and health? Does the presence of differential measurement errors in other variables in the model influence the estimate of association between a specific environmental agent and health? Is there any error or misclassification likely to be present in the outcome variable? Is that error likely to have any effect on the outcome of the statistical models used for analysis? Can methods of adjusting for the effects of exposure measurement error be used to mitigate the effect of exposure measurement error on risk estimates? Can spatial interpolation methods provide more accurate estimates of individual exposures to particulate air pollution? How would the use of measures of personal exposure improve estimates of the association between particulate matter and health? SCIENTIFIC VALUE Relatively little is known about the nature of exposure estimation error for the suite of criteria air pollutants. Effects of measurement error are known for a few classical situations when fixed assumptions

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Research Priorities for Airborne Particulate Matter: I Immediate Priorities and a Long-Range Research Portfolio are made about the nature of these errors. The validity of these assumptions needs to be ascertained. DECISIONMAKING VALUE Until the effects of measurement error are understood and taken into account, the association between exposures to ambient particulate matter (or its size fractions and biologically significant chemical constituents) and health effects cannot be estimated without acknowledging the source of uncertainty and its potential effect on risk estimates or particulate-matter reduction strategies. FEASIBILITY AND TIMING Data need to be collected to ascertain the nature of measurement error. Once that is understood, the effects can be ascertained and methods can be applied to correct for error. COST Much of the data required to address the issue of exposure measurement error will be collected through personal exposure studies conducted as part of the enhanced exposure monitoring component of the overall particulate research program. Nonetheless, additional studies designed to characterize distribution measurement error distributions will be needed. Such studies will involve replicate measurements under the same conditions, and are estimated to cost approximately $1.0 million annually for the first, second, third, and fourth years. Methodological development of exposure measurement error methods is recommended on an overlapping time frame, beginning with a workshop to identify methodological approaches ($100,000 in year 1), and followed by a five year program of methodological development and application, costing $500,000 per year.