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Principles of Exposure Assessment INTRODUCTION Since the early 1970s, when federal regulatory agencies first focused their attention on the association of cancer and other chronic diseases associated with human exposure to toxic agents, rapid advances in bioassay techniques and other test methods have made it possible to discern relations between particular agents and cancer and other health effects. Risk assessment is a method for estimating the likelihood that a given pollutant will have a given health effect. Risk assessment has four components: hazard identification, dose-response assessment, exposure assessment, and risk characterization (NRC, 1983a). Advances in hazard identification and dose-response assess- ment have been successfully incorporated into risk-assessment practice. Ad- vances in analytic instrumentation permit the detection of chemicals at lower and lower concentrations and these make it possible to detect the presence of chemicals that would have been missed earlier. Also, advances and improve- ments in mathematical and statistical manipulation of data have been major contributors to improvement in the practice of risk assessments. However, accurate data on exposure, i.e., contaminant concentrations at the boundary between a human and the environment and the duration of contact, are also crucial to valid risk assessment, but advances in exposure assessment have not been fully integrated into standard risk-assessment practice. Exposure assessment has seen important conceptual and practical advances. Perhaps the most fundamental has been the recognition that exposures to various contaminants can occur through contact of any tissue with any envi- ronmental medium at any time, and in all sorts of venues. That might seem obvious, but in major environmental regulations, exposures to contaminants have been-and to a large degree still are-thought of in the terms of 8-hour workplace exposures and 2lhour outdoor exposures of a "standard" 70-kg man. Such definitions assume the presence of a contaminant in a particular medium 17

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18 ASSESSING HUM4N EXPOSURE (or microenvironment) just as they assume the presence of the person and the contact with that medium in that microenvironment. In fact, indoor concen- trations of some pollutants can be higher than outdoor concentrations, most people spend far more time indoors than outdoors, and different population groups (e.g., young children and older persons) have different patterns of sensitivity and activity, which affect their likelihood of and responses to expo- sure. The national env~ronmental-policy implications of those findings could be enormous. For example, if indoor sources of airborne benzene were acknowl- edged, and it were determined that the average person's major exposure oc- curred indoors, rather than outdoors, the allocation of hundreds of millions of dollars for control of industrial emissions of benzene might appear less than optimal. The same could well be true of a number of other major elements (such as NO2 from stoves) of concern to national environmental policy associ- ated with substantial exposures. The Committee on Advances in Assessing Human Exposure to Airborne Pollutants was established by the National Research Council's Board on Envi- ronmental Studies and Toxicology to review important new developments in e~osure-assessment instrumentation and methods that have arisen in pollu- tion-related research, occupational medicine, and other disciplines over the last 10-15 years, especially as they apply to individual human exposures to airborne tome substances. The committee's work was sponsored by the Agen- cy for Toxic Substances and Disease Registry (ATSDR), whose mandate is to prevent or mitigate adverse human health effects and diminution in quality of life resulting from exposure to hazardous substances in the environment. In response to its charge and to national needs for improved understanding about exposures to environmental hazards, the committee has reviewed the new developments and developing technologies in exposure assessment, identified knowledge and technological gaps, and recommended research and develop- ment to fill those gaps. In this report, the committee also presents a concep- tual framework for the science of exposure assessment and illustrates, with a series of case studies, how exposure assessments can be (and have been) properly and improperly applied and conducted. However, it was not within the committee's charge to perform an exhaustive study on the proper applica- tion and further development of techniques to assess exposure to any specific contaminant. This chapter introduces the basic principles and definitions of exposure assessment. Chapter 2 presents the framework for conducting exposure as- sessments, the quantitative relationship among source and receptor character- istics, and the basic components of exposure assessment and how it may be employed. Sampling and physical and chemical measurements are discussed

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PRINCIPLES OF EXPOSURE ASSESSMENT 19 in Chapter 3, biological markers in Chapter 4, questionnaires and survey issues in Chapter 5, and modeling techniques and instruments in Chapter 6. Chapter 7 contains a number of airborne-contaminant case studies that illus- trate the application and misapplication of exposure assessment. The summa- ries of Chapters 1 and 2 contain general CQU~=iODS and recommendation The summaries of Chapters 3 through 6 contain conclusions and recommenda- tions relevant to the exposure assessment methods discussed in each chapter. Such methods can be incorporated into a study design to the extent practical and necessary to meet the specific objectives of the assessment. Conclusions presented at the end of each case study In Chapter 7 focus on broad implica- tions for the d~sapl~ne of exposure assessment, notable advances, and remain- ing needs. BACKGROUND Environmental contaminants found in the community or occupational set- tings long have been thought to be related to a wide range of adverse health and nuisance effects in humans. In the course of daily activities, humans are exposed to a variety of environmental contaminants through the air they breathe, water and beverages they drink, food they eat, and materials that contact their skin. These events occur in many settings-indoors (e.g., residen- tial, industrial, occupational, and transportation) and outdoors. An exposure to a contaminant is defined as an event that occurs when there is contact at a boundary between a human and the environment with a contaminant of a specific concentration for an interval of time. Thus, an exposure has units of concentration and time. This definition is consistent with definitions of expo- sure presented in other NRC reports and is discussed in greater detail in Chapter 2. Total human exposure accounts for all exposures a person has to a specific contaminant, regardless of environmental medium (air, water, food, and soil) or route of entry (inhalation, ingestion, and dermal absorption) (Lioy, 1990~. For media other than air, the time increment could be infinitesimal, such as that incurred flaring the act of drinking a glass of water. It is a necessary concept to carrying out risk assessments or health studies for a pollutant. Sometimes total exposure is used incorrectly to refer to exposure to all pollu- tants in an environment. Total exposure to more than one pollutant should be stated explicitly as such. Assessing the total exposure of an individual or population involves numer- ous techniques to identify the contaminant, contaminant sources, environmen- tal media of exposure, transport through each medium, chemical and physical

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20 ASSESSING HUAL4N EXPOSURE transformations, routes of entry to the body, intensity and frequency of con- tact, and spatial and temporal concentration patterns of the contaminant. An array of techniques can be employed, ranging from estimates of the number of people exposed and contaminant concentrations to sophisticated methodol- ogy employing contaminant monitoring, modeling, and measurements of hu- ~nan biological markers. The type of exposure-assessment methodology used largely determines the applicability of collected data to quantifying the rela- tionship between exposure and biological response. Whatever application or technique is employed, the fundamental concern is human health and comfort. In response to its charge, the committee focused on human exposure to airs borne contaminants that can be inhaled or absorbed through the skin and potentially cause adverse health or nuisance effects for an individual. The committee did not, nor was charged to, focus on exposure via other routes following deposition of airborne contaminants into other media (e.g., deposi- tion of airborne contaminants into food or ingestion of contaminated soil or water). Dose is the amount of a contaminant that is absorbed or deposited in the body of an exposed organism for an increment of time. Dose is not consid- ered in detail in this report, except in discussions of biological markers. The National Research Council's Committee on Biologic Markers has portioned dose into two components: internal dose and biologically effective dose (NRC, 1989~. Internal dose is the amount of a contaminant that is absorbed into the body over a given time. Biologically effective dose is the amount of contaminant or its metabolites that has interacted with a target site over a given period so as to alter a physiological function. Exposure assessment is central in environmental epidemiology, disease diagnosis and intervention, risk assessment, and risk management. In environ- mental epidemiology studies, exposure assessment historically has involved qualitative characterizations of whether contact was made with a contaminant rather than determination of actual concentrations, duration of human contact, and identification of all sources of the contaminant. Although a qualitative approach can provide order-of-magnitude estimates, it is unsatisfactory be- cause it can result in misspecification~ of exposure and can fail to account adequately for confounding factors (e.g., temperature affecting contaminant concentration). A qualitative approach can mask or overemphasize an actual exposure-response relationship. In some cases, if the pollutant and outcome are well defined, general indicator data can be used to describe important iMisspecification or misclassification of exposure occurs when a contaminant or the place of contact with a contaminant is incorrectly identified.

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PRINCIPLES OFE~OSURE ASSESSMENT 21 response-exposure relationships. Good examples of the use of this kind of data are the studies by Bates and Sitzo (1987), Bates et al. (1990), and Ostro and Rothschild (1989) of ozone and particulate irritants and acute respiratory response. media. Application of qu~titat~Ye techniques to all pertinent media and to all routes is desirable to account for the influence of confounding factors. Quan- titative methods also are important in defining subpopulations with the great- est potential for contracting a disease or exhibiting an adverse health effect. Exposure assessment can be important in disease diagnosis and treatment. With careful evaluation of the [actors that might have contributed to a specific disease, exposure assessment could be employed to define Me intervention necessary to reduce and control contact with a contaminant and provide a basis for further analysis of a larger population. Risk-assessment methods are widely used by federal, state, and local agen- cies, as well as industry, to determine whether various chemical substances in the environment might induce adverse health effects in humans. Exposure assessment provides fundamental information for describing the distribution (including the high and low extremes) of contaminant exposures within a population, for estimating the doses received from different media, and for determining routes of entry into the body. Use of appropriate exposure-as- sessment methodology in risk assessment reduces the error or uncertainty in the calculated risk. After risk assessment shows that a contaminant poses an adverse health risk, regulatory agencies develop risk management plans. Such a plan involves formulating cost-effective mitigation efforts to reduce the risk associated with exposure to a contaminant and to monitor progress toward risk reduction. Exposure assessment is an essential part of risk-management effort because it helps to determine the following: Concentration distributions in time and space for different environmental Populations or subgroups at high and low risk. Efficient, effective, and representative environmental monitoring pro- grams. Chemical and physical contributions of various sources to concentrations. Factors that control contaminant release into environmental media, routes of environmental transport, and routes of entry into humans. Effective mitigation measures. Compliance through mitigation measures to achieve health standards.

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22 ASSESSING HUMAN EXPOSURE Exposure-assessment efforts traditionally have focused on one route of entry through one environmental medium and microenvironment (EPA, 1988a). A microenvironment is a three-dimensional space with a volume in which contaminant concentration is spatially uniform during some specific interval (Sexton and Ryan, 1988~- A variety of microenv~ronments are en- countered in spaces in offices, homes, vehicles, stores, schools, athletic fields, parks, backyards, and city streets. Efforts directed at studying only one micro- env~ronment often have used unsophisticated techniques, such as question- naires with little or no information on spatial and temporal distributions of contaminant concentrations and the human contact with those contaminants. These efforts have resulted in difficulties identifying significant exposures and in developing effective mitigation measures for airborne compounds that have multiple sources in one or more microenvironments (EPA, 1988a). More effective methods were not used for many reasons, including technological limitations in environmental monitoring methods, lack of adequate concentra- tion-predictor models, unavailability of adequate human biological markers of exposure, limitations in available resources, inadequate understanding of media and routes of entry, and narrow public-health mandates of individual regulatory agencies. As a result, agencies responsible for regulating chemicals for indoor and outdoor environments (emissions, use, etc.) have often not adequately integrated exposure-assessment techniques and data into their regulatory actions. The Environmental Protection Agency (EPA) has developed exposure- assessment guidelines focusing on modeling (EPA, 1986a) and measurement (EPA, 1988b) to provide more accurate exposure assessments to use with risk assessments. The guidelines specify that an exposure assessment should in- clude an identification of the principal environmental pathway of exposure, including indoor settings. These guidelines, however, do not adequately ad- dress the need for indoor-air data on important sources of exposures for individual contaminants. Advances in indoor-air exposure studies have dem- onstrated the significant health effects from indoor emissions and exposures to contaminants that had been regulated only as outdoor pollutants (e.g., NO2) (Spengler and Sexton, 1983; Akland et al., 1985; Spengler et al., 1985; Leaderer et al, 1986; Wallace, 1986~. These demonstrations of high indoor- contaminant levels showed the importance of accounting for incremental exposures2 from microenvirorlments when making risk assessments for specif ~Incremental exposures are separate events of contact between an individual and a con- taminant; they can be summed, and their units are ~g-hr/m3.

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PRINCIPLES OF EXPOSURE ASSESSMENT 23 ic contaminants. For many outdoor contaminants, significant emission reduc- tions have been achieved during the past few decades (e.g., sulfur dioxide). EPA's Science Advisory Board recognized the need to consider exposure- reduction strategies in media and situations that yield cost-effective benefits (e.~., indoor air) and recommended that EPA develop a 5-year program on exposure armament as one of ~ major new initiatives (EPA, 1988~. Exposure Assessment in Environmental Epidemiology During the past severe decades, expos~xre-assessment research }fax prm gressed most evidently in environmental epidemiology. This progress can be illustrated by tracing some of the major developmental steps in outdoor-air- pollution epidemiology and the accompanying air-monitoring efforts (Figure 1~1~. Early epidemiological methods for measuring the effects of outdoor-air pollution concentrated on the definition, measurement, and verification of disease outcomes and physiological changes that were indicative of disease development. Considerable efforts were made to improve the interpretation and standardization of death certificates, to standardize reporting of pulmo- nary symptoms and definitions of chronic lung disease (e.g., chronic bronchitis and emphysema), and to standardize the measurement, interpretation, and reporting of lung-function measurements. Concurrent efforts were made to develop and apply statistical methods to outdoor-air epidemiologic data bases. Early data on potential exposure to contaminated air were derived primari- ly from questionnaires that identified an indiv~dual's residence and indicated whether that individual had been exposed to a high level of air pollution. Categories of exposure to outdoor pollutants were assigned with little informa- tion on confounders, such as smoking status or occupation, which led to mis- classified exposure categories. In addition, when data were available on the spatial and temporal variations of the actual outdoor concentrations, they were for a very limited number of air contaminants. The factors affecting the accumulation of the measured outdoor concentrations (e.g., sources, meteorol- ogy, and chemical transformations) were poorly characterized or understood by the epidemiological investigators (Lippmarln and Lioy, 1985~. It commonly was assumed that the one or two routinely monitored contaminants or indica- tors (e.g., total suspended particles or sulfur dioxide) at fixed sites either were related to the health outcomes under study or were proxies for contaminants that posed a potential health threat. In time, ambient monitoring was expand- ed to cover a wider range of chemicals to better define the spatial and tempo- raI variability, as well as to gather better information on the factors influenc

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PRINCIPLES OF EXPOSURE ASSESSMENT 25 ing ambient levels. In addition, models that examined community source- receptor relationships were developed and improved to better identify sources and evaluate mitigation strategies. These efforts, however, still were directed toward determining outdoor concentrations and ignored the presence of many air contaminants in homes and other indoor locations (NRC, 198~. Further problems with identification of contaminant exposures remain since exposures continue to be considered as occurring from one media with one route of entry. Within the past 10 years, a~r-contaminant exposures have been recognized as taking place through many media and with different routes of entry. These multiple exposures need to be assessed by personal monitoring, biological monitoring, indirect measurement modeling, or combinations of monitoring methods. Recent advances in personal and passive monitoring instrumentation are examples of steps taken in this direction (Palmes et al., 1976; Geisling et al., 1982; Lewis et ale, 1985; Mulik and Williams, 1986; Hammond and Leaderer, 1987~. Meth- ods for air sampling and analysis have developed in parallel to air-pollution epidemiological methodology (ACGIH, 1988a; Lioy and Lioy, 1983~. When measures of internal dose or biological markers are available, attempts are being made to incorporate them into exposure-assessment research designs (NRC, 1988~. Increasingly, air-pollution exposure monitoring has been included as an integral part of environmental epidemiology. These data have indicated the potential importance of indoor sources of contaminants. For example, expo- sure and emissions studies published during the past 10 years successfully have tested the hypothesis that there are major indoor sources of NO2 (e.g., gas home appliances) and that concentrations and exposures in homes with these sources frequently yield higher N0' concentrations than outdoor levels (Lead- erer et al., 1986; Southern California Gas Co., 1986~. These studies have also shown that indoor NO2 concentrations in homes without these sources are about half the outdoor concentrations, personal exposures to NO2 are strongly associated with indoor levels (because people spend more time indoors than outdoors), and personal exposure is only weakly associated directly with out- door concentrations even for residences with no sources (Ott, 1988~. The advances in understanding exposure to NO2 are due in part to the develop- ment of inexpensive passive personal or microenvironmental monitors. As a result, measurement of personal exposures to NO2 with particular emphasis on indoor air is now used in the evaluation of health effects associated with NO: and in developing and specifying effective mitigation measures.

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26 ASSESSING HU1~4N EXPOSURE Exposure Assessment in Occupational Epidemiology and Risk Management Eyposure-assessment techniques have also evolved in the fields of occupa- tional epidemiology3 and occupational risk management. In early occupation- al epidemiology studies, exposure was determined principally by questionnaires and Implied contact with the contaminants of interest. This produced eypo- sure data that were based on job category, which made it difficult to compare studies of identical occupational contaminants. In addition, general categori- zation of exposure by job title tended to yield erroneous assignments of expo- sure categories, because each person's time-activity profile would be different. Daily movements of workers and variability in exposures could not be ade- quately identified, which made any exposure-response relationship difficult to define. Occupational epidemiology studies now use strategies that obtain more quantitative information on exposure. An industrial hygienist can deter- mine what to measure, how to measure, where to measure, whose exposure to measure, frequency of measurement, existence of possible confounding contaminants, and factors affecting contaminant exposures. As a result of more sophisticated exposure measurements, misclassification of subjects by exposure category is reduced, exposure-response relationships are more likely to be detected, and effective mitigation measures can be instituted. Occupa- tional epidemiology studies and occupational risk-management efforts are also beginning to incorporate measures of `1ose and biological markers (Lauwerys, 1983; ACGIH, 1988b). Conceptual Framework for Human Exposure Assessment Efforts to assess and reduce total human exposure to environmental con- taminants and relate exposure to acute and chronic health effects or nuisance effects4 must be guided by a theoretical framework or methodology. A gen- eral framework is shown in Figure 1.2 and is described in greater detail in 3For the terms "occupational epidemiology" and "environmental epidemiology" as used in this report, the committee considers "environmental" to include occupation- al settings with regard to exposure assessment. 4Nuisance effect is a subjectively unpleasant effect (e.g., headache) that occurs as a consequence of exposure to a contaminant; it may be associated with some physi- ological response, but it is not permanent.

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28 ASSESSING HUMAN EXPOSURE Lioy (1990~. Information on the doses that can cause effects associated with contaminant exposure is vital to the design of an exposure-assessment protocol (Calabrese, 1987~. It is difficult to identify a single effect associated with a single contaminant; it is even more difficult to determine a dose-response relationship. A health outcome often results from a complex situation that can include many factors such as health status, age, race, diet, personal habits, and occupation, as well as a variety of environmental contaminants emitted from several different sources. Generally, associations are explored among exposures to specific contaminants, general categories of contaminants or sources, and adverse biological responses, or health or nuisance effects. Con- founding variables must be controlled or accounted for simultaneously. Al- though this report emphasizes the direct inhalation route, it must be recog- nized that the approaches described are developed within the framework of total exposure, which accounts for all exposures a person has to a specific contaminant, regardless of environmental medium (air, water, food, and soil). This report focuses on exposure to airborne contaminants; however, exposure is a necessary event for there to be any health or nuisance effects from contact with contaminants in the other environmental media (see Figure 1.2~. Exposure assessments for airborne constituents must be considered in the framework of potential contributions from other media and adding the incre- mental exposures from other media when necessary. Furthermore, to achieve effective risk assessment, risk management, environmental epidemiology, and diagnosis and intervention, all media and routes of exposure must be assessed for the relative magnitude of their contributions before an assessment of one medium is conducted. Specification of a person's or a population's exposure to an environmental contaminant or categories of contaminants should take into account a time scale related to the biological response studied unless the exposure assessment is intended to provide data on the range of biological responses. Specification of biological response requires information on contaminant toxicity and quan- titative assessment of the exposures associated with the effects. Undcrstand- ing of the etiology of an effect is central to the application of exposure-assess- ment methodology. The impact caused by exposure to environmental contaminants ideally should be evaluated in terms of the dose of the contaminant or its metabo- lites, which the committee dcf~nes as follows: Dose is the amount of a con- taminant that is absorbed or deposited in the body of an exposed organism for an increment of time usually from a single medium. Total dose is the sum of doses received by a person from a contaminant in a given interval resulting from interaction with all media that contain the contaminant. Units of dose and total dose (mass) are often converted to units of mass per volume of

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PRINCIPLES OF EXPOSURE ASSESSMENT 29 physiological fluid or mass per mass of tissue, e.g. blood-lead levels in g/DL. Potential dose is the exposure multiplied by a contact rate (e.g., rates of inhalation, ingestion, or absorption through the skin) and assumes total ab- sorption of the contaminant. Internal dose refers to the amount of the env~- tc~nmental contaminant absorbed in body tissue (Dens and Grossman, 1982) or interaction with an organ's membrane surface (e.g., asbestos deposited on the lung surface). Biological markers are being used increasingly as indicators of the internal effective dose of contaminants or metabolites (e.g., blood-lead levels, cotinine in urine or blood, and DNA adJucts). The biologically effec- tive dose is the amount of the deposited or absorbed contaminant that reaches the cells or target site where an adverse effect occurs (Davis and Gusman, 1982) or where that contaminant interacts with a membrane surface. Few indicators of biologically effective dose of environmental contaminants are well characterized. These definitions of internal dose and biologically effective dose are consistent with those given in recent NRC reports: Biologic Markers in Pulmonary Toxicology and Biologic Markers i': Reproductive Toxicology. Physico-pharmacokinetic models are used to describe or calculate a rela- tionship between exposure and target-tissue concentrations of environmental contaminants. Such models can be simple with one compartment (Rappaport, 1985), or complex, with multiple compartments (Kjellstrom and Nordberg, 1978~. Pharmacodynamic models describe the dynamic processes that relate the target tissue concentrations and tissue effects to the ultimate health ef- fects. These models typically present a mathematical relationship between biologically effective dose and a health outcome. For risk assessment, the models are based upon toxicological data; contaminant exposures from differ- ent media; and the biologically effective dose, internal dose, or a health out- come. Data on biologically effective dose are useful for exposure assessment when a contaminant has only one significant route, and the metabolic pathway is well understood. For example, carboxyhemoglobin levels are a good measure of the dose received from CO exposures and are directly related to exposure, because inhalation of CO in air is the most significant cause of elevated levels of carboxyhemoglobins. However, the levels can be influenced by methylene chloride, whose metabolism will release CO that can bind to the hemoglobin. Biologically effective dose is not practical in assessing the overall effect of exposure to an environmental contaminant because of limitations of knowl- edge; for example, uptake, distribution, metabolism, and site and modes of action of contaminants in humans are neither well understood nor easily measured. Moreover, information on biologically effective dose cannot be used directly to assess sources, environmental conditions, or location of human

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30 ASSESSING HUMAN EXPOSURE receptors, which affect the accumulation of contaminants in the environment; the uptake of contaminants, including physical characteristics of the contami- nants; and the physiological characteristics and activity levels of exposed per- sons. The exposure-assessment methodology employed must consider a wide range of aspects, including: Contaminant and potential biological response. Specification and selection of the target population. Available technology for personal environmental and biological marker sample collection and analysis. Spatial and temporal variability of concentration distribution patterns. Selection of the sampling period in appropriate relationship to the time scale of biological effect. Frequency and intensity of exposure. Precision and accuracy requirements. Costs and available resources. Types of Studies The development of exposure-assessment methodologies has involved nu- merous professions and organizations. Such groups have employed different approaches although the general goals might have been similar, for example, to understand individual or population exposures to various contaminants within specific environments. Data from previous assessments on the magni- tude of physical, chemical, and biological impacts and the routes of transport and entry into the body have aided in the identification of mitigation methods. Unfortunately, some data did not accurately address public health priorities, because the environments studied did not include those in which the most significant exposures would occur (EPA, 1988a). For example, exposure investigations conducted for various volatile organic compounds have shown that emissions in outdoor-air environments might not accurately reflect the major sources of exposure, because significant exposures occur in indoor environments, especially for certain contaminants, such as benzene and tetra- chloroethylene (Wallace, 1987~. An accurate assessment of exposure used to test initial hypotheses can be employed with health data to establish relationships between exposure and health response. The type of exposure assessment and the acceptable level of uncertainty in the data vary according to whether the assessment is designed to generate or test hypotheses about exposure, test instruments, make risk

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PRINCIPLES OF EXPOSURE ASSESSMENT 31 assessment decisions, or make regulatory enforcement decisions. At some point, however, exposure assessments must focus on the interrelationship of human activity patterns within segments of the general population and single or multiple contaminants suspected of contributing to acute or chronic effects. Exposure assessments vary si~fi~tly' depending on the interest and training of the individuals or organizations conducting the studies. Some of the more common applications of exposure assessment include the following studies; the order of these studies does not imply rank. Community Studies Community studies involve segments of the general population and quantifi- cation of single-medium or total exposure to individual contaminants or com- plex matures. If the significant microenvironments or personal activities are identified, the significant biological effects can be determined or estimated through risk assessment (Johnson and Paul, 1981, 1983; Wallace, 1986; Lioy et al., 1988; Wallace et al., 1988~. These studies can also include the results of clinical case studies to focus on the biological effects of specific contami- nants (Pfaffenberger, 19879. Epidemiological Studies Direct or indirect population exposure data are used in conjunction with measures of adverse health outcomes to try to establish cause-and-effect relationships. These studies quantify human health impacts based on the assumption that the nature and extent of exposure can be adjusted for con- founding factors and quantified for individual compounds or compound mix- tures (MacMahon and Pugh, 1970; NRC, 1985~. Epidemiological studies are conducted by industry, National Institute for Occupational Safety and Health (NIOSH), EPA, Occupational Safety and Health Administration (OSHA), ATSDR, state agencies, National Institutes of Health, and universities to identify causative agents when occupational or environmental health effects are suspected. The hypotheses tested in these studies are that contaminants are responsible for the health effects, and monitoring of the workplace or community can identify contaminants and sources or define exposure-effect relationships.

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32 ASSESSING HUMAN EXPOSURE Industrial Hygiene Studies Microenvironmental-, biological-, and personal-monitoring studies are made In the workplace to quantify occupational exposure. The results are compared with health criteria developed by government agencies (e.g., OSHA) and organizations (e.g., American Conference of Governmental Industrial Hygien- ists), based on the assumption that knowing the actual exposures will allow prediction or quantification of biological effects, and subsequent reduction of exposure by personal protection or process control will lower such effects (Patty, 1978~. Industrial hygiene studies are conducted by industrial firms to check for compliance with EPA and OSHA regulations and to define mitiga- tion methods for actual or potential exposures. Those studies that employ personal sampling assume that the exposures can be traced to the sources and that those sources can be controlled. Clinical Case Studies Medical personnel identify health outcomes that are potentially related to environmental or occupational contaminants. Exposure assessments assist in quantifying the exposure-response relationship or focusing on diagnosis, treat- ment, or intervention. Clinical case studies are conducted by state agencies, industry, NIOSH, and OSHA to identify causative agents when occupational or environmental health effects are identified or suspected. Engineering Studies Models that estimate the intensity of exposure from chemicals emitted by various sources at outdoor downwind receptors may be used in conjunction with fixed site monitors. Their use is based upon the assumptions that the exposure estimates of a plume impact represent actual exposures, and the results can be used to predict biological impacts using health criteria devel- oped by other studies (Schroy, 1981; Fenstermacher and Ottinetti, 1987; Lip- ton and Lynch, 1987~. EPA conducts engineering studies under the Clean Air Act, the Federal Insecticide, Fungicide and Rodenticide Act, and the Toxic Substances Control Act (TSCA). OSHA, NIOSH, the Nuclear Regulatory Commission, state agencies, and industry groups also conduct engineering studies. EPA (under TSCA) uses such studies to define exposure levels in the workplace and ambient environment for the Remanufacture notice process before permitting introduction of a new chemical into commerce. It is as

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PNNCIPLES OF EXPOSURE ASSESSMENT 33 sumed that potential exposures can be defined by using exposure models for populations that will work with or use the chemical. OSHA uses engineering studies for evaluating workplace-exposure criteria and effectiveness of engineering controls. The studies of workplace-emissions mutrols evaluate the emission rates defined for classes of equipment =d apply results to all equipment in that class. The Nuclear Regulatory Commission uses engineering studies to define the most appropriate design alternatives for new or modified nuclear power plants. The assumption for these studies is that providing the rigorous con- trols to prevent atmospheric emissions will protect the population around the plant. An example of state agencies' use of engineering studies is for state imple- mentation plans for permitting emission sources. Industries use engineering studies to determine the most appropriate design alternatives for production and transportation facilities. The general assump- tion for these studies is that reduction in emissions results in reduction in exposure. Industries also use engineering studies to help identify causative agents when occupational or environmental health effects are identified, as well as to check for compliance with EPA and OSHA regulations and to define mitiga- tion methods for actual or potential exposures. Animal Studies Animals exposed to contaminants in actual environments can be used as exposure sentinels. The animals are assumed to represent acceptable models for humans. Also, experimentally defined exposure-response relationships are assumed to identify biological effects similar to those that will occur in hu- mans (Calabrese, 1987~. Pharmacokinetic and Pharmacodynamic Studies These studies link actual human-exposure measurements (personal or microenvironmental) to measurements of biological markers of internal or effective dose and biological response. The modeling could include whole- animal responses, based on the physiology of the species, and the toxicological data from molecular biological studies. For predicting human response to a contaminant the assumption is made that molecular biological processes stud- ied on a cellular level can be translated to human responses by using models

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34 ASSESSING HUMAN EXPOSlJRE that have been validated on a variety of other animals (Andersen et al., 1987 Smith, 1987; Saltzmarl, 1988a). Behavioral Studies The quantification of changes in human behavior is an indirect approach to measure the effects of physically, chemically, and biologically active contam- inants. This is based on the assumption that biological stress results in behav- ;oral change (e.g., as from inhalation of mercury vapor) that can be compared with the intensity of directly or indirectly determined exposure. One or more of the above types of studies require measurements or esti- mation of exposure, because humans are constantly exposed to a broad range of synthetic and naturally occurring contaminants. Unfortunately, it is usually difficult to distinguish the effect of one or more contaminants from the ambi- ent environmental mixture of contaminants. In addition, for long-term, low- level exposure, the evidence usually is inconsistent or inconclusive as to which contaminants shorten or end human life. Naturally occurring toxic contami- nants often provide defense against predators of the animal or plant that produce them. Such agents are almost always biologically active in humans (Ames et al., 1987~. Therefore, when designing exposure assessments, the intensity of exposure from contact with natural and anthropogenic contami- nants must be defined qualitatively or quantitatively to help identify the impor- tant epidemiological and clinical applications. The nature of exposure might vary with a specific health effect and might require special exposure-measurement methods for each assessment. For instance, when a health effect is sudden death or obvious illness, gross or short-term exposure measurements that highlight recent or instantaneous changes in exposures might be adequate to identify the cause-and-effect rela- tionships. More subtle long-term measurements of exposures are required when the outcome is a subtle change in the human biological or behavioral system. Development of disease and death due to low-level, long-term expo- sure is very diff~cuIt to relate to specific contaminants using morbidity and mortality studies because of multiple intervening exposures. Identification of the specific contaminant causing the exposure-response relationship of concern e IS essentla . Inferences might be made more clearly in prospective studies because complicating factors can be measured or held constant. An example of a prospective study is an engineering study designed to forecast workplace expo- sures for proposed production units. Obtaining accurate previous exposure

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PNI`JCIPLESOFEXPOSUREASSESSMENT 35 and health histories or testing any hypothesis is difficult for retrospective studies. SUMMARY Exposure assessment is an integral and essential component of en~ronmen- ta] epidemiology, risk assessment, risk management, and diagnostic and inter- vention efforts. It is a multidisciplinary endeavor that usually requires the combined expertise of engineers, environmental and industrial hygienists, toxicologists, epi;demiolog;~ts, chemists, physicians, mathematicians, and social scientists. Exposure-assessment methodology employs various direct and indi- rect techniques, including environmental measurements, personal monitoring, biological markers, questionnaires, and modeling. Exposure assessments for airborne constituents must be considered in the framework of potential contributions from other media and adding the incre- mental exposures from other media when necessary. Furthermore, to achieve effective risk assessment, risk management, environmental epidemiology, and diagnosis and intervention, all media and routes of exposure must be assessed for the relative magnitude of their contributions before an assessment of one medium is conducted. To maximize opportunities for risk management, exposure assessments should obtain information on the sources and environmental factors affecting the exposures to ensure that effective and appropriate mitigation measures can be formulated. The plan developed to gather data for an exposure assessment should take into account the time scale related to the biological response being studied. Exposure assessment is an equal partner with toxicology in defining human health risk and identifying exposure-response relationships and should be funded by government programs according to priorities commensurate with the importance of exposures to environmental contaminants. Because the features of exposure assessments range from the straightfor- ward to the complex, it is necessary to provide and maintain avenues for professional-societyinteraction, training, continuing education, publication, and education. Only in this way can the current state of research and applications discussed above continue to grow and address societal and technical concerns.

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