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1 Introduction Breathing fulfills the vital function of exchanging the gases of oxygen and car- bon dioxide. With oxygen, breathing brings in common toxic air pollutants, such as nitrogen dioxide, sulfur dioxide, ozone, carbon monoxide, and particulate matter. Because of concern for the poten- tial impacts of these and other pollutants on public health, the National Heart, Lung, and Blood Institute, the Office of Health Research of the Environmental Protection Agency (EPA), the National Institute of Environmental Health Sciences, and the Agency for Toxic Substances Disease Re~is- try asked the Board on Environmental Studies and Toxicology (BEST) in the National Research Council's Commission on Life Sciences to conduct a study of the scientific basis, potential use, and cur- rent state of development and validation of biologic markers in the respiratory system. BEST organized the Committee on Biologic Markers to examine the use of biologic markers in environmental health research. Three specific biologic systems or fields of research were chosen for study: the reproductive system, the respiratory system, and the immune sys- tem. This is the report of the Subcom- mittee on Pulmonary Toxicology, which was charged to review potential biologic mark- ers in the respiratory tract. 11 Biologic markers, broadly defined, are indicators of variation in cellular or biochemical components or processes, structure, or function that are measurable in biologic systems or samples. For most purposes in environmental health re- search, the reason for interest in biologic markers is a desire to identify the early stages of disease and to under- stand basic mechanisms of exposure and response in research and medical practice. The growth of molecular biology and bio- chemical approaches to medicine has re- sulted in the rapid development of markers for understanding disease, predicting outcome, and directing treatment. Many diseases are now defined, not by overt signs and symptoms, but by the detection of biologic markers at the subcellular or molecular level. For example, liver and kidney diseases are often diagnosed by measuring enzymes in blood or proteins in urine; lead poisoning can be diagnosed on the basis of blood lead concentrations and such biologic changes as increases in heme biosynthesis components in red cells and urine; and many inborn errors of metabolism, such as phenylketonuria, are diagnosed on the basis of cell biochem- ical findings, rather than expressed dys- functions. The identification, valida- tion, and use of markers in medicine and

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12 biology depend fundamentally on increased understanding of mechanisms of action and the role of molecular and biochemical proc- esses in cell biology. It is important to recognize that markers represent signals on a continuum between health and disease and that their defini- tions might shift as knowledge of the fun- damental processes of disease progression increases. That is, today's markers of exposure might become tomorrow's markers of early biologic effect. What are per- ceived at first to be early signals of risk could come to be considered health impair- ments themselves because the predictive relationship is so strong; i.e., an early signal could represent an effect at a stage in the progression at which it is difficult to prevent a disease. Thus, biologic mark- ers can be valuable in the prevention, early detection, and early treatment of disease. There is growing interest in the use of biologic markers to study the health ef- fects of exposure to environmental toxi- cants in clinical medicine, epidemiology, toxicology, and related biomedical fields. Clinical medicine uses markers to allow earlier detection and treatment of disease; epidemiology uses markers as indicators of exposure, internal dose, or health effects; toxicology uses mark- ers to help determine underlying mechan- isms of diseases, develop better estimates of dose-response relationships, and im- prove the technical bases for assessing risks at lower levels of exposure. TYPES OF BIOLOGIC MARKERS The Biologic Markers Committee has de- fined the following concepts related to biologic markers. Biologic markers are indicators of events in biologic systems or samples. It is useful to classify bio- logic markers into three types-markers of exposure, of effect, and of suscepti- bility-and to describe the events peculi- ar to each type. A biologic marker of ex- posure is an exogenous substance or its metabolite or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured in a com- partment within an organism. A biologic hL9R=RS IN PULMONARY TOXICOLOGY marker of effect is a measurable biochemi- cal, physiologic, or other alteration within an organism that, depending on mag- nitude, can be recognized as an established or potential health impairment or disease. A biologic marker of susceptibility is an indi- cator of an inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to a specific xenobi- otic substance. Biologic markers of sus- ceptibility are discussed in this report only insofar as they can also serve as mark- ers of exposure or effect. Once exposure has occurred, a continuum of biologic events can be detected. These events may serve as markers of the initial exposure, administered dose (circulating peak or cumulative dose), biologically effective dose (dose at the site of toxic action, dose at the receptor site, or dose to target macromolecules), altered struc- ture or function with no ensuing pathologic effect, or potential or actual disease. Even Bet ore exposure occurs, biologic differences among humans might cause some individuals to be more susceptible to en- vironmentally induced disease. Thus, biologic markers are tools that can be used to clarify the relationship, if any, be- tween exposure to a xenobiotic substance and disease. c Markers of Exposure Exposure is the sum of xenobiotic mater- ial presented to an organism, whereas dose is the amount of the material that is ac- tually absorbed into the organism or reaches a target tissue or organ. Blood flow, capillary permeability, transport into an organ or tissue, the num- ber of receptor sites, and route of admin- istration (which determines the path of the parent material or its metabolites in the body) all can influence absorbed dose or biologically effective dose. An inhaled carcinogen might produce tumors in the lung; if the same material were in- gested and eliminated via the kidney, renal tumors might be produced. If the parent material is responsible for the observed toxicity, the amount of metabo- lite that reaches the target might be of no importance. If metabolites are respon

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INTRODUCTION sible, however, metabolism in the liver, in another target organ, or elsewhere as a result of metabolic cooperation between several tissues is an important determin- ant of absorbed dose and biologically ef- fective dose. Markers of Effect For present purposes, the effects of an exposure on an organism (the responses of an organism to an exposure) are consid- ered in the context of the relationship of exposure to disease or to the probabili- ty of disease. An effect is defined as a health impairment, a precursor that indi- cates a likelihood of health impairment, or an event peripheral to any disease proc- ess, but correlated with one and thus pre- dictive of development of disease. A biologic marker of an effect or re- sponse, then, can be any change that is qualitatively or quantitatively indica- tive of health impairment or potential impairment (disease process) associated with exposure. Biologic markers are also useful to identify endogenous components or system functions that are considered to signify normal health. It is important to recognize, however, that the magnitude of such a component or function represents points on a continuum. Therefore, the boundaries between health and disease can change as knowledge increases. Markers of Susceptibility Some biologic markers indicate individ- ual or population differences that affect the biologically effective dose of or the response to environmental agents indepen- dentlY of the characteristics of a particu lar exposure. An intrinsic genetic or other characteristic or a pre-existing disease that results in an increase in the absorbed dose, the biologically effective dose, or the target-tissue response after an exposure can be a marker of increased susceptibility. Such markers include inborn differences in metabolism, varia- tions in immunoglobulin concentrations, low organs reserve capacity, and other identifiable genetically determined or environmentally induced variations in 13 absorption, metabolism, and response to environmental agents. Other factors that can affect individual susceptibilities include the nutritional status of the or- ganism, the role of the target site in con- trolling overall body function, the condition of the target tissue (whether disease is or was present), and compensa- tion by homeostatic mechanisms during and after exposure. The reserve capacity of an organ to recover from an insult at the time of exposure can play an important role in determining the extent of an impairment. VALIDATION OF BIOLOGIC MARKERS The usefulness of a biologic marker must be validated by establishing the existence of a relationship between an environmental exposure and the biologic change of inter- est. Two characteristics of assessment determine the validity of a marker: sen- sitivity and specificity. Sensitivity is the extent to which a biologic marker indicates that a particular characteris- tic is present when it is present. If sen- sitivity is high, the probability of ob- taining false-negative results is low. Specificity is the extent to which a bio- logic marker indicates that a particular characteristic is absent when it is absent. If specificity is high, the probability of obtaining false-positive results is low. It is desirable for a marker to be as spe- cific and as sensitive as possible. Speci- ficity is needed to be able to associate a biologic marker with exposure to a speci- fic pollutant. Sensitivity is required because many environmental exposures are airborne pollutants at low concentra- tions. The ideal biologic marker of an environmental exposure would be pollu- tant-specific, available for analysis with noninvasive techniques, detectable in trace concentrations or at very low activities, inexpensive to detect, and quantitatively relatable to the degree of exposure. Very rarely will all those qualities be available in a biologic marker. Most markers discussed in this report lack at least one of the attributes. Furthermore, many, if not most, diseases

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14 can be due to multiple causative agents, only some of which are environmental. Nevertheless, biologic markers provide valuable information that can improve our ability to determine the extent of environ- mentally induced respiratory disease. Before many markers can be used for large epidemiologic field studies, efforts must be directed toward both the miniaturiza- tion of laboratory techniques and the pre- servation and banking of appropriate spe- cimens. Those efforts initially must be carried out by laboratory scientists de- veloping new biologic markers and-because of the intensity of the developmental ef- forts-will usually be of only second- order interest. DelaYs in taking the new _ techniques from the laboratory and apply- ing them to population-based field studies will be inevitable. A useful approach to the validation of biologic changes as markers is to use ex- perimental studies in animals and clinical (human) studies to develop a matrix of information that enables one to make es- timates for humans (Table 1-1~. For ex- ample, markers of acute effects of short- term, low-concentration exposures to a pollutant can be detected in both animals and humans. A comparison of this informa- tion with markers of chronic effects re- sulting from long-term exposure of animals to the same pollutant could lead to the development of markers that are more pre- dictive of health effects in chronically exposed humans (McClellan, 1986~. Numerous instances of clinical research and animal toxicology studies have both used and provided validation of biologic MARKERS IN PULMONARY TOXICOLOGY markers. Analysis of bronchoalveolar- lavage fluid is used to detect markers of an inflammatory response in the respira- tory tract (Hunninghake et al., 1979b; Henderson et al., 1985a; Utell et al., 1985; Reynolds, 1987~. Those markers have proved useful in diagnosing, staging, and planning therapeutic approaches to pul- monary disease in humans (Reynolds, 1987~; in screening for pulmonary toxicity of inhaled pollutants in animals (Henderson et al., 1 985a); and in detecting human responses to inhaled pollutants in short- term clinical studies (Utell et al., 1985~. From such studies has come information on potential biologic markers of both the magnitude and the respiratory effects of environmental exposure. It is important to distinguish between physiologic responses that represent normal defense mechanisms and responses that are predictive of disease. An organ- ism might have a continuum of responses to a noxious agent-from responses that lead to removal of the agent or repair of initial injury to responses that indicate that irreversible damage has occurred or is destined to occur. Markers are needed to indicate where a given response lies on the continuum. USE OF BIOLOGIC MARKERS IN THE RESPIRATORY TRACT The potential usefulness of markers applies to all organ systems and tissues. In this report, discussion is limited to use of markers in the respiratory tract. The respiratory tract, as a portal of TABLE 1-1 Example of a Matrix for Determining the Validity of a Biologic Marker Nature of External Internal Health Species Exposure Exposure Dose Effect A Acute X X X Chronic X X X B Acute X - X Chronic Human Acute X X X Chronic ? ? ? X = Marker determined. - = Marker not yet determined. ? = Not yet tested.

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INTRODUCTION entry for airborne pollutants into the body (and as a route of exit of some materi- als), should be advantageous for detecting pollutant-specific markers. If tissues or cells of the respiratory tract react chemically with an inhaled pollutant, it might be possible to detect reaction prod- ucts in the lumen of the respiratory tract or in cells washed from it. Gaseous pol- lutants or the volatile metabolites of pollutants might be detected in the exhaled breath of exposed people. A disadvantage of attempting to assess toxicant-induced changes in the respira- tory tract, with respect to potential bio- logic markers of effects of environmental exposures, is the lack of specificity of pulmonary responses in relation to etio- logic agents. The lung can respond to in- haled toxic materials in only a few ways: Altered breathing patterns and airway constriction. Altered breathing patterns are receptor-mediated responses; airway constriction can result from the direct action of a variety of stimuli or be mediat- ed through neurogenic reflexes. Besides pollutants, potential stimuli include such agents as various antigens (in sen- sitized persons), infection, exercise, cold, and psychogenic factors. Cell injury leading to inflammation. The inflammatory response is character- ized by an influx of inflammatory cells and an increased permeability of the al- veolar-capillary barrier, which might lead to edema. Such an inflammatory re- sponse can also be induced by immunologic responses in a sensitized lung or by infec- tious agents. Persistent alteration of lung struc- ture, such as fibrosis, chronic obstruc- tive pulmonary disease (such as chronic bronchitis or emphysema), granulomatous disease, or neoplasia. None of these con- ditions or responses has a specific etiolo- gy; each can be a response to a variety of causative agents or conditions. 15 Thus, although biologic markers, such as changes in respiratory function, can be used to detect some structural altera- tions, it is not readily possible to as sociate a single functional alteration with a single causative agent. In the same manner, it might be easy to detect an in- flammatory response in the respiratory tract by analyzing bronchoalveolar-lavage fluid or nasal-ravage fluid, but without additional information it is not easy to associate inflammation with a particular environmental exposure. The following chapters discuss poten- tial biologic markers of environmentally induced pulmonary disease. Some of the markers represent new techniques made possible by recent technologic advances. Others represent new uses of technique or procedures that have been used in other fields of research. STRUCTURE OF THE REPORT Chapter 2 examines markers of exposure. The deposition and clearance of inhaled material is discussed. New methods for monitoring inhaled material are reviewed as well as clinical techniques for assess- ing exposure. Chapter 3 examines current methods for assessing respiratory func- tion. In addition, methods for assessing airway hyperactivity and injury to alveo- lar and vascular tissues are described. Chapter 4 discusses methods for structural assessment of whole lung, airways, and parenchyma. Chapter 5 describes the mechanisms of inflammatory and immune response in the respiratory system and the associated markers. Chapter 6 continues the discus- sion developed in Chapter 5 but focuses on the cellular and biochemical responses observed as the lung responds to chemical insult. Finally, Chapter 7 provides the recommendations of the Subcommittee on Pulmonary Toxicology.

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