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Asthma and Automotive E ~ missions PHILIP A. BROMBERG University of North Carolina Asthma: Definition, Demography, and Clinical Spectrum / 466 Definition / 466 Demography / 466 Clinical Spectrum / 467 Asthma: Pathogenesis / 468 Extrinsic and Intrinsic Asthma / 468 Early and Late Reactions to Allergens / 469 Bronchial Hyperreactivity / 469 Controlled Exposure Studies / 470 Normal Subjects / 470 Asthmatic Subjects / 471 Need for Further Research / 472 Asthma: Pathophysiology / 473 Assessment of Airways Size / 474 Distribution of Airflow Resistance Along the Airways / 474 Mechanisms of Bronchoconstriction / 475 Ozone Exposure / 478 Respiratory Epithelium: Asthma and Ozone / 481 Permeability / 482 Mucous Production and Secretion / 483 Ion Transport / 484 Mucociliary Clearance / 484 Experimental Models / 485 Human Studies / 485 Laboratory Animal Models / 485 Cells in Culture / 487 Summary of Research Recommendations: Discussion / 487 Summary of Research Recommendations: Priorities / 489 Air Pollution, the Automobile, and Public Health. (it) 1988 by the Health Effects Institute. National Academy Press, Washington, D.C. 465

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466 Asthma and Automotive Emissions Urban air pollution is characterized by in- creased levels of ozone (03) and nitrogen dioxide (NO2) resulting from photochem- ical reactions of automotive emissions. Lung damage caused by exposure to oxi- dant gases is well recognized. For instance, inhalation of 5(}100 parts per million (ppm) NO2 causes acute pulmonary edema in humans, and survivors may develop a chronic progressive obstructive bronchio- litis several weeks after~apparent recovery from the acute edema. O3 is also capable of producing acute pulmonary edema at a concentration of less than 10 ppm. Levels of NO2 and O3 in ambient air generally do not exceed 1 ppm. Therefore, the toxic effects of inhalation of high levels of these gases may not be relevant for low-level ambient exposures. Neverthe- less, several population surveys have found a relation between episodes of oxidant air pollution and adverse respiratory health effects including exacerbations of asthma. More chronic effects of oxidant air pollu- tion on respiratory function have also been suggested (see Bresnitz and Rest, this volume; U. S. Environmental Protection Agency 1986~. The notion that individuals with preex- isting respiratory disease might be espe- cially susceptible to effects of ambient air pollution has been strengthened by the relatively recent observation that, unlike normal subjects, asthmatic individuals with mild disease are highly susceptible to the experimental inhalation of low concentra- tions of sulfur dioxide (SO2) during exer- cise. During brief exposures, asthmatic subjects have developed acute, sometimes symptomatic, increases in specific airflow resistance (SRaW) attributed to bronchocon- striction (Sheppard et al. 1981; Bethel et al. 1983~. In this chapter, the clinical forms of asthma and their pathogenesis are de- scribed, and the results from controlled exposure studies of the effects of inhalation of pollutant gases relevant to automotive emissions on normal and asthmatic subjects are summarized. These findings are dis- cussed with respect to the mechanisms of asthma, and key questions about possible interactions between asthma and automo tive air pollution whose answers have so far been elusive are formulated. Asthma: Definition, Demography, ant! Clinical Spectrum DeJitzition Asthma is a common paroxysmal disorder of the airways but is difficult to define because of its complex pathogenesis, mul- tiple etiologic factors, and clinical overlap with other airway diseases. It is character- ized by recurrent episodes of diffuse air- ways obstruction associated with wheez- ing, coughing, and breathlessness (dyspnea). These episodes are largely reversible, espe- cially with pharmacological therapy, but an- atomic and physiological evidence of persist- ent diffuse airways disease can be found on careful investigation even during apparently quiescent periods. One important indication of persistent abnormality, even in asympto- matic asthmatics, is nonspecific bronchial hyperreactivity, that is, enhanced airways response to bronchoconstrictive stimuli that . .. . . are nelt per speailc antigens operating through immunologic mechanisms nor spe- cific chemicals in the occupational environ- ment (for example, toluene diisocyanate). Demography A 1970 U.S. Public Health Service survey of national health suggested that the prev- alence of asthma was about 3 percent (Wilder 1973~. Regional population surveys in Tecumseh, Michigan (Broder et al. 1962, 1974a, b), and Tucson, Arizona (Lebowitz et al. 1975), suggest a prevalence of 4-8 percent. In the Public Health Service sur- vey, three-fifths of the asthmatics had con- sulted a physician for asthma during the previous year, one-fifth had visited their physician at least five times during the year, and one-sixth felt the disease limited their activity (Bonner 1984~. Prevalence is highest among children (males >> females) and a second peak occurs in older adults (males > females). This later peak may include patients with

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Philip A. Bromberg 467 relatively irreversible airways obstruction. In young to middle-aged adults, women may be somewhat more at risk than men. In young children, asthma (wheezing) as- sociated with viral respiratory tract infec- tions is a common problem. This associa- tion (Busse 1985) and the demonstration of IgE-type antibody, particularly to respira- tory syncytial virus, in such patients (Wel- liver et al. 1986) suggest that respiratory tract infections can provoke an asthmatic state in some children. Of the various "types" of asthma, allergen-related (ex- trinsic) asthma occurs more commonly in somewhat older children and in young adults than does intrinsic (no identifiable allergen or specific antibody) asthma (Bonner 1984~. Intrinsic asthma increases in importance in older adults and is a form of the disease that can manifest increasingly irreversible airways obstruction even in the face of chronic treatment with large doses of corticosteroids. Clinical Spectrum The clinical severity of asthma (either the background level of airways obstruction or the intensity and the frequency of the epi- sodes) varies greatly, not only among af- fected individuals, but at different times in the same individual. Some asthmatic chil- dren seem to grow out of their disease. On the other hand, relatively asymptomatic asthma can flare so severely that it becomes life-threatening or even fatal. This variabil- ity is reflected in the intensity of therapy and the number of physician contacts. Some asthmatics use only an occasional inhalation of a bronchodilator aerosol; oth- ers use aerosols more frequently, either as required or on a regular basis. Other asth- matics use long-acting oral bronchodilators supplemented with one or more inhaled agents. Some affected individuals require intermittent or chronic corticosteroid ther- apy. Life-threatening, severe episodes re- quire hospitalization and often involve a period of assisted ventilation. Nonspecific Bronchial Hyperreactivity. Although patients with recently developed asthma may have normal airway reactivity between attacks, the presence of nonspe- cific bronchial hyperreactivity is considered an important, but not specific, feature of asthma (Hargreave et al. 1981~. Various stimuli have been used to elicit a broncho- constrictive response. Quantitative inhala- tion challenge with aerosolized histamine and methacholine has gained widespread acceptance and use as an investigative and diagnostic tool. Individual reactivities to histamine and methacholine challenge cor- relate well with the presence of clinically severe asthma as judged by degree of symptoms, medication requirements, oc- currence of spontaneous early morning in- crease in airflow obstruction, presence of more-or-less continuous airflow obstruc- tion, and general instability of the airways despite chronic use of multiple bronchodi- lator medications. Such unstable patients with exquisite nonspecific bronchial hyper- reactivity are at risk for life-threatening asthmatic crises. A sharp decrease in non- specific bronchial hyperreactivity correlates with clinical improvement (Hargreave et al. 1985b; Woolcock et al. 1985~. Inhalation of cold dry air is also com- monly used as a bronchoconstrictive stim- ulus, but its quantitation is more difficult, its mode of action is less well understood than that of specific drugs, and its effects are subject to the development of decreased response on repeated application (Har- greave et al. 1985a). Nonspecific bronchial hyperreactivity to various challenges is an index of the intrin- sic responsiveness of elements in the airway wall (smooth muscle, submucosal blood ves- sels and glands, afferent nerve endings and efferent nerve ganglia, mast cells, and possi- bly neuroendocrine cells), and presumably reflects or mimics certain events in "naturally occurring" asthma. Of course, multiple me- diators are involved in asthma. Even with respect to histamine or methacholine, the naturally occurring release of these autacoids probably causes changes in local concentra- tions at receptor sites that are not precisely mimicked by inhalation challenge. Other Obstructive Airways Disease. Dif- fuse airways disease associated with the impairment of forced expiratory flow rates

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468 Asthma and Automotive Emissions and increased airflow resistance is not lim- ited to asthma. In addition to at least 6 million asthmatics, it has been estimated that 7.5 million people in the United States have chronic bronchitis and 2 million have emphysema (U.S. Department of Health and Human Services 1979~. Etiologies vary among the obstructive airways diseases. Cigarette smoking is a major risk factor for chronic nonspecific bronchitis as well as for emphysema. Chronic airways infection with suppurative destruction of airway walls characterizes diffuse bronchiectasis. In some cases, a specific underlying reason, such as dysmotile cilia syndromes, immu- noglobin deficiencies, autoimmune dis- eases, cystic fibrosis, or hereditary defi- ciency of the c~-1-proteinase inhibitor can be identified. In others, the etiology is obscure and may be related to remote dif ~ . . . . . . ruse ung 1nJury or Injection occurring In childhood. Chronic airways obstruction generally is much less reversible in these diseases than in asthma, but to varying degrees. Airways obstruction associated with cystic fibrosis frequently manifests considerable reversi- bility in response to bronchodilators. Ob- struction is partially reversible with ,l3 ad . . . . . renerg1c or muscarln1c agonists In some patients with chronic bronchitis. Airways hyperreactivity to bronchoconstrictor drugs also occurs in some chronic bronchitics. Unusual reactivity to bronchodilators or bronchoconstrictors may be associated with relatively rapid deterioration of pul- monary function in chronic bronchitis (Barter and Campbell 1976~. An important unresolved question is whether there are specific risk factors for the development of irreversible obstructive airways disease in some asthmatics. In view of the extensive inflammation and epithelial damage that appears to be characteristic of asthma (see below), it is surprising that most patients with asthma retain the feature of substantial reversibility of airways ob- struction for long periods. Patients with chronic obstructive pulmo- nary disease (COPD) and increased airways reactivity may not be considered "asth- matics," but they should not be neglected in studies of the health effects of air pollu tion. Such disease groups would include patients with chronic nonspecific bronchitis with reactive airways, cystic fibrosis, and children with a history of bronchopulmo- nary dysplasia or of respiratory infections associated with wheezing. Asthma: Pathogenesis Extrinsic and Intrinsic Asthma The variability of the clinical features among different asthmatics and in a given individual at different times or periods of life has prompted efforts to classify the disease in a meaningful fashion. One ap- proach differentiates extrinsic asthma, in which antigens (allergens) affect tissue cells primarily mast cells sensitized by specific IgE antibody (see Chemical Medi- ators) from intrinsic asthma, which oc- curs without an identifiable antigen or a specific IgE antibody. Thus, extrinsic asthma occurs com- monly among allergic (atopic) individuals who have (usually) multiple specific IgE- class antibodies to airborne antigens associ- ated with pollens, mold spores, animal fur, or various insects (for example, mites found in house dust, cockroaches). The proclivity toward the development of IgE antibodies against common inhaled anti- gens (allergens) characterizes atopic indi- viduals and is importantly influenced by genetic factors. Asthma exacerbations are provoked by inhaled antigen (for example, laboratory workers handling certain an~- mals or insects) and tend, in the case of pollen and spore allergy, to be seasonal and regional. In many atopic individuals, clinical man- ifestations are limited to the skin or the nasal mucosa (allergic rhinitis) and the con- junctivae (allergic conjunctivitis). These patients often have some symptoms com- catible with asthma that are sufficiently mild to go unrecognized. They also may have a modest increase in nonspecific bron- chial reactivity to histamine or metha- choline. Indeed, Fish and Norman (1985) have found substantial hyperreactivity to inhaled pro s ta glandin (P G) F2~ in atopi c,

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Philip A. Bromberg 469 nonasthmatic subjects. Atopic persons may constitute a useful population for study of the effects of exposure to air pollutants since the nasal epithelium is a good model for the large-airways epithelium. Basic im- munologic mechanisms in the allergic bronchial mucosa are also present in the nasal mucosa, which is readily accessible to experimental manipulation as well as to environmental exposures. Intrinsic asthma implies the absence of atopy, that is, no evidence of specific IgE- class antibodies against common airborne antigens in the patient's environment. These asthmatics have perennial rather than seasonal symptoms. Exacerbations seem to be triggered by poorly characterized respi- ratory tract infections, which on the basis of serologic evidence and in the absence of a bacterial infecting agent, are assumed to be viral. A subclass of these individuals has nasal polyps and demonstrates an unusual proclivity to precipitation of asthma shortly after ingesting acetylsalicylic acid (aspirin) or other nonsteroidal antiinflam- matory agents all of which inhibit cyclo- oxygenase activity and therefore affect cel- lular arachidonate metabolism. Asthma also can develop in workers (probably nonatopic) exposed to chemicals such as toluene diisocyanate, plicatic acid (western red cedar wood dust), and others. Exquisite airways sensitivity to inhalation of the specific offending agent is often present, although specific antibodies may not be demonstrable. Some of these indi- viduals develop chronic perennial asthma despite prolonged avoidance of the sensitiz- ing chemical. Such cases of asthma do not fit clearly into either the extrinsic or the . . . Intrinsic category. Early and Late Reactions to Allergens Recent descriptions of asthma pathophys- iology emphasize the discovery that tissues bearing IgE-sensitized mast cells, such as skin, nasal mucosa, and airways, display a complex series of responses to specific an- tigen (Gleich 1982; Cockcroft 1983~. A rapid, "early" response is dominated by local microvascular dilatation, edema, and in the airways, smooth-muscle contraction, all of which are mediated by substances released from sensitized mast cells as well as other sensitized cells. This reaction re- gresses spontaneously, or regression can be induced with ,B adrenergic agonists. Several hours later, a second local reac- tion occurs, again associated with broncho- spasm in the airway, but now with sub- stantial cellular infiltration by eosinophils, neutrophils, and basophils. These cells are thought to be attracted by chemotactic factors released by the activated mast cells. For reasons that are not clear, this "late" reaction is not reversed by ,~adrenergic agonists but can be diminished or pre- vented by pretreatment with corticoste- roids. Bronchial Hyperreactivity Late reactions following antigen challenge in asthmatic subjects are associated with enhancement of nonspecific bronchial hyperreactivity. Marked enhancement of bronchial hyperreactivity may last for weeks and is associated with the emergence of more severe clinical manifestations of asthma. The patient develops bronchocon- striction on exposure to a wide variety of stimuli. If no further exposure to the pro- voking agent (antigen or chemical) occurs, the bronchial hyperreactivity gradually re- cedes to baseline levels along with the clinical symptoms. The intensity of the late response to antigen correlates with the sub- sequent degree and duration of increased nonspecific bronchial hyperreactivity (Car- tier et al. 1982; Cockcroft 1983~. Airways inflammation constitutes a cen- tral feature of both the late reaction to specific antigens and the genesis of nonspe- cific bronchial hyperreactivity. The specific features of the inflammatory process re- quired for the development of hyper- reactivity are far from understood. For example, among patients with chronic bronchitis, only a fraction appear to exhibit nonspecific bronchial hyperreactivity al- though all presumably have some degree of airways inflammation. The prolonged state of bronchial hyper- reactivity provoked by a single exposure to

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470 Asthma and Automotive Emissions .. . . . a speailc antigen or to certain occupatlon- ally related chemicals suggests the possibil- ity that the airways of so-called intrinsic asthmatics may be sensitized to nonspecific stimuli in a similar fashion by intermittent exposure to some undefined specific agent(s). * The intensity of the bronchoobstructive response of a sensitized individual exposed to a particular antigen will therefore depend not only on the specific IgE-mediated dis- charge of mediators from local mast cells (and possibly other cells), but also on the degree of coexistent nonspecific bronchial reactivity (Cockcroft et al. 1979~. A corol- lary to this notion is that anv stimulus (for example, 03) that increases nonspecific bronchial reactivity should also enhance reaction to inhaled antigen, even in the absence of any change in immunologic status. Furthermore, to the extent that air pollutants can provoke bronchoconstric- tion in a "nonspecific" manner, highly bronchoreactive asthmatics should be more . . sensitive to suc 1 exposures. Controlled Exposure Studies While field studies and practical experience indicate an association between air pollu- tion and exacerbation of asthma, confirma- tion of the association and its physiological manifestations have been sought in con- trolled studies. The following section as- sesses the status of this research to date. Normal Subjects Ozone and Nitrogen Dioxide. Although NO2 and O3 are both classified as oxidants, and are relatively insoluble in aqueous me- dia and thus able to penetrate into the lower *Note, however, asthmatic children who are perenni- ally exposed to the relevant antigen, and who receive repetitive antigen injections in hyposensitization ther- apy, tend to outgrow their asthma and show a de- crease in IgE and IgG antibodies. In contrast, children who are intermittently (seasonally) exposed to another allergen, such as rye-grass pollen, continue to demon- strate seasonal asthma associated with rises in IgG and IgE antibodies (Hill et al. 1981). airways, their mechanisms of action on the airways may well be quite different. At concentrations < 1 ppm, effects of acute NO2 inhalation on the respiratory system of normal subjects have not been demonstrated. In contrast, acute (2-hr) ex- posure of exercising adults to levels of O3 as low as 0.12 ppm causes a reduction of mean vital capacity accompanied by cough (McDonnell et al. 1983~. Similar findings, which can be accounted for specifically by the O3 content of the air, have resulted from exposure of exercising adults to Los Angeles air pollution under controlled con- ditions (Avol et al. 1984), in active children exposed to about 0.10 ppm O3 in a summer camp (Lippman et al. 1983), and in children exposed to 0.12 ppm O3 in an environmen- tal chamber (McDonnell et al. 1985a). Decreases in vital capacity do not appear to be caused by changes in mechanical properties of the lung (Beckett et al. 1985; Hazucha et al. 1986), but are probably due to neurally mediated involuntary inhibition of inspiration. Bronchoconstriction is not a prominent feature of the response of nor- mal individuals to O3; nor does the degree of bronchoconstriction correlate with the vital capacity decrease (McDonnell et al. 1983~. In addition, inhaled atropine failed to prevent O3-induced changes in vital capacity (Beckett et al. 1985~. Unmyelin- ated airway sensory nerves (C-fibers), which contain and can release substance P and other physiologically active neuropep- tides, could mediate the inhibition of inspi . . . . . . ration, t ne subJectlve airway sensations, and a more shallow, rapid pattern of breathing. Since the stimulation of airway C-fibers in dogs also causes reflex broncho- constriction (Roberts et al. 1981; Coleridge and Coleridge 1986) as well as reflex tra- cheal gland secretion (Davis et al. 1982), the relative weakness of the human broncho- constriction response to inhaled O3 is sur- prising. Substance P or other neuropeptides may also provoke other features of the acute airways response to 03, such as mu- cous secretion (Coles et al. 1984) and in- creased epithelial permeability and ion transport (Al-Bazzaz et al. 1985~. Among a group of normal subjects, there is a substantial range of vital capacity re

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Philip A. Bromberg 471 spouses to a given O3 exposure (McDon- nell et al. 1983~. In a single individual, however, the response to O3 exposure is relatively reproducible (McDonnell et al. 1985b). Whether this between-subject vari- ability is attributable to different tissue doses of O3 in different individuals under the same exposure conditions or to biolog- ical factors affecting individual responsive- ness remains to be determined. A feature of repeated daily experimental exposures to O3 is the initial enhancement (Hackney et al. 1977; Farrell et al. 1979; Bedi et al. 1985; Folinsbee and Horvath 1986) but eventual disappearance of the vital capacity response and the associated subjective sensations (Farrell et al. 1979; Folinsbee et al. 1980; Horvath et al. 1981~. Among the possible explanations for this phenomenon (often termed "tolerance" or "adaptation") is the depletion of neuropep- tides from repeatedly stimulated C-fibers. A more subtle feature of the response to 03, first described 20 years ago in guinea pigs (Easton and Murphy 1967), and then shown in dogs (Lee et al. 1977), sheep (Abraham et al. 1980), and humans (Gol- den et al. 1978), is a transient increase, lasting hours to perhaps a day in humans, in the bronchoconstrictive response to pa- renteral (Easton and Murphy 1967; Gordon and Amdur 1980; Gordon et al. 1984; Murlas and Roum 1985a) as well as inhaled histamine and cholinergic agonists (Lee et al. 1977; Golden et al. 1978; Holtzman et al. 1979; DiMeo et al. 1981; Holtzman et al. 1983; Roum and Murlas 1984~. This re- sponse also appears to undergo an adaptive suppression on repeated O3 exposure (Di- Meo et al. 1981~. Mixtures of Ozone and Other Pollut- ants. Synergy between O3 and other pol- lutants in causing respiratory effects during environmental chamber exposures has not been proven. Hazucha and Bates (1975) described synergism between SO2 and O3 in normal subjects, but other researchers were not able to duplicate their results (Bell et al. 1977; Bedi et al. 1979; Kleinman et al. 1981; Folinsbee et al. 1985~. Stacy and coworkers (1983) noted increased mean changes of respiratory parameters when low concentrations of acid aerosols were mixed with 0.4 ppm O3, but these differ- ences were not statistically significant. Us- ing a sequential rather than simultaneous exposure protocol, Kulle and colleagues (1982) found no effect of sulfuric acid (H2SO4) aerosol (100 ,ug/m3) following an exposure to 0.3 ppm O3. Recommendation 1. The uptake pro- file of pollutant gases in different regions of the airways should be measured by sam- pling and analyzing inspired air at different airway levels. Variables to be explored with such systems include concentration of pollutants, ventilatory parameters, dura- tion of exposure, and presence of disease (for example, asthma, chronic bronchitis). Recommendation 2. These data should be compared with the predictions of currently available mathematical models. ~ Recommendation 3. The uptake pro- files should be examined for their ability to account for some of the variability in vital capacity response to O3 exposure observed among individuals. Asthmatic Subjects Ozone. Controlled studies have yet to demonstrate that O3 dramatically affects lung function in asthmatic subjects, atopic nonasthmatic subjects, or patients with COPD. The most pertinent publications on asthmatics (Linn et al. 1978, 1980; Sil- verman 1979; Koenig et al. 1985), persons with smoking-related COPD (Linn et al. 1982, 1983; Solic et al. 1982; Hackney et al. 1983; Kehrl et al. 1983, 1985; Kulle et al. 1984), and atopic subjects (Holtzman et al. 1979) have been reviewed in the U.S. En- vironmental Protection Agency's (1986) most recent revision of the air quality cri- teria document for O3 and other photo- chemical oxidants. Unfortunately, deficiencies in the exper- imental design in some of these studies preclude making a definitive statement about the effects of O3 on pulmonary func- tion in asthmatic subjects. Among these deficiencies are incomplete characterization

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472 Asthma and Automotive Emissions of the nature of the obstructive airways proc- ess, little information on nonspecific bron- chial reactivity status and no testing of the effect of exposure on bronchial reactivity, absence of airflow resistance (RaW) measure- ments to assess airways response, no control of the use of medications by asthmatic sub- jects, possible investigator avoidance of sub- jects with severe asthma, and inadequate levels of ventilation (exercise) during the ex- posure (this was a critical variable in the demonstration of exquisite responsiveness of asthmatics to SO2 exposure). Furthermore, no studies of asthmatic subjects appear to have been performed using prolonged single exposures or repeated daily exposures. Nor has possible synergism between O3 and other relevant pollutants been studied in concur- rent or sequential exposure protocols. Nitrogen Dioxide. Orehek and cowork- ers (1976) were the first to claim that some asthmatics develop increased airways reac- tivity to inhaled bronchoconstrictor drug challenge after exposure to only 0.1 ppm NO2. An editorial by Dawson and Schenker (1979) provides a succinct evalu- ation of our understanding of the effects of NO2 inhalation as of the late 1970s. Since then, other groups have explored the effect of low levels of NO2 (<0.5 ppm) on lung function and bronchial reactivity in asth- mat~cs. Koenig and colleagues (1985) examined atopic asthmatic adolescents exposed to 0.12 ppm NO2 by mouthpiece for 1 hr at rest and found no changes in lung function during or after the exposure. Other re- searchers (Roger et al. 1985; Bauer et al. 1986) independently found evidence that bronchoconstriction in asthmatics follow- ing exercise was enhanced in the presence of 0.3 ppm NO2. In contrast, Linn and Hackney (1984) and Linn and others (1985) observed no effect on SRaW of exposure to 4 ppm NO2 (I) for 75 min with light or heavy exercise. The route of inhalation (oronasal versus oral), the duration of ex- posure, and the number as well as intensity of exercise stints may be significant varia- bles (Kulle 1982; Bauer et al. 1985~. Bylin and colleagues (1985) found enhanced non- specific bronchial reactivity to aerosolized histamine in asthmatics exposed to 0.5 ppm NO2 for 20 min. Kleinman and coworkers (1983) found no acute effect on respiratory mechanics after a 2-fur exposure, which included intermittent light exercise, to 0.2 ppm NO2. The enhancement of nonspe- cific bronchial reactivity to aerosolized methacholine was, however, borderline in terms of group means. Ahmed and col- leagues (1982) reported increased airways reactivity to aerosolized carbachol in rest- ing normal subjects as well as in asthmatics following a 1-fur exposure to 0.1 ppm NO2, despite the absence of any effects on baseline lung function. However, in a care- ful study, Hazucha and coworkers (1983) were unable to confirm the Orehek finding of increased airways reactivity following a 0.1-ppm NO2 exposure. In addition. --7 Roger and colleagues (1986) failed to dem- onstrate enhanced methacholine reactivity following exposure of exercising asthmat- ics to NO2 levels as high as 0.6 ppm. Finally, Ahmed and colleagues (1983) chal- lenged ragweed-sensitive asthmatic sub- jects with specific antigen immediately and 24 hr after a 1-fur exposure to 0.1 ppm. No effect of the exposure on specific bronchial reactivity was found, but the exposure con- ditions were extremely mild. None of the other studies cited above appear to have examined specific bronchial reactivity. Evidence suggests that the airways of exercising and perhaps even resting asth- matic subjects are affected by exposure to <0.5 ppm NO2. However, when all the reports are considered, a coherent picture fails to emerge. Even within a particular laboratory, there may be diff~culty in re- producing an observation (D. Horstman, personal communication). The reasons for this inconsistency are presently obscure. Some of the problems mentioned for O3 exposure studies may also apply to NO2. Needfor Further Research The preceding discussion suggests that, in contrast to the experience with SO2, initial controlled exposure studies have failed to demonstrate that asthmatics exhibit un- usual sensitivity to acute exposure to O3. Although the situation is less clear with respect to NO2, the effects claimed have been modest in extent. However, a conclu

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Philip A. Bromberg 473 sion that asthmatics do not constitute a sensitive subgroup in terms of possible adverse health effects of air pollution re- lated to automotive emissions would be premature and possibly incorrect. Reasons for this posture have already been alluded to and include: 1. Two types of field studies suggest that asthmatics do exhibit special sensitivity to ambient oxidant air pollution. In one, "panels" of asthmatic and control subjects have been selected and their health status monitored in relation to ambient air com- position over time; the best example is the analysis of Whittemore and Korn (1980~. In the other, the respiratory health of an entire community is assessed in terms of emer- gency room visits, hospital admissions, and physician visits, and correlated with envi- ronmental air quality. The best study of that type is the survey of almost 6 million individuals in southern Ontario who re- ceive medical care from a national health service with a computerized data base (Bates and Sizto 1983; Bates 1985~. 2. The known bronchoconstrictive pow- er of SO2 and H2SO4 aerosols in asthmatics supports the possibility that experimental exposure to certain combinations of pollu- tants, including oxidants, could demon- strate that asthmatics constitute an oxi- dant-susceptible population. The work of Bates and Sizto (1983), and of others, in which environmental air composition is analyzed should be invaluable in designing the types of multiple pollutant exposures that could be tested in controlled exposure chambers. ~1 ' 1 1 1 . 6. Severe asthmatics and chronic oron- chitics with reactive airways have under- gone little or no systematic study. 4. As previously noted, the clinical se- verity of asthma is related to the degree of nonspecific bronchial hyperreactivity. Ozone inhalation reproducibly causes an enhancement of bronchial reactivity and therefore may increase clinical manifesta- tions of an underlying asthmatic condition under the appropriate circumstances. 5. Despite inconsistencies, there is sig- nificant evidence suggesting increased sen- sitivity of asthmatics to the effects of NO2 inhalation. Additional support for the plausibility of significant interactions between oxidant air pollution and asthma may emerge from a more detailed comparison ofthe pathophys- iology of asthma and of the effects of oxidants, primarily O3 which has been studied more extensively than NO2, on the airway tissues. Before proceeding, however, it may be useful to anticipate some questions and issues relevant to the goals in this chapter. In extrinsic asthma, inhaled antigen must gain access to antibody-sensitized cells in the airways, particularly the submucosal mast cells. In order to reach underlying mast cells or immunecompetent cells, anti- gens must penetrate the epithelial barrier. Acute O3 exposure increases respiratory epithelial permeability and should enhance the ability of inhaled antigens to reach critical cells in the submucosa. Thus, acute or repeated oxidant pollutant exposures of sensitized individuals might modify the subsequent early and/or late airways re- sponses to specific challenge. In addition, increased epithelial permeability would al- low egress of submucosal albumin onto the airways surface where it could alter the viscoelastic properties of the surface liquid and impair mucociliary clearance. Some important effecter mechanisms in asthma involve stimulation of sensory nerves and neurally mediated reflexes; re- lease of chemical mediators, including ara- chidonate metabolites, from mast cells and possibly other cells; recruitment of inflam- matory cells to the airways; and damage to airways epithelium. Ozone is known to have all of these effects. In addition, some extracellular defense mechanisms against proteolytic enzymes, for example, c'-1- proteinase inhibitor, are oxidant sensitive. By causing such overlapping effects in the same tissue, short-term oxidant exposure could lead to some acute enhancement of asthma mechanisms. Asthma: Pathophysiology The hallmark of acute asthma is widespread decrease in the diameter of airway passages, due, in part, to contraction of circularly

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474 Asthma and Automotive Emissions arrayed airways smooth muscle. There is also edema of the submucosal tissues, and airway lumens are often plugged by tena- cious, albumin-rich secretions containing mucins, intact and degenerating inflamma- tory cells, and sheets of airways epithelium. Eosinophils are prominent among the in- flammatory cells (Hog" 1985~. Assessment of Airways Size Descriptions of the caliber or geometry of the airways are, at best, incomplete. The conducting airways are a complex branch- ing structure that includes over 20 branch points before a fully alveolated region of lung parenchyma is reached. In addition, the caliber of the airways is affected by lung elastic recoil which is a function of lung volume and is continually changing during . . resplratlon. Several techniques are available that can be used to estimate airway size. The simul- taneous measurement of the pressure gra- dient between the alveoli and the airway orifice and of airflow either during sponta- neous breathing or panting allows an em- pirical measurement of RaW, which is de- fined as the ratio between pressure gradient and flow. This relation varies with lung volume and depends on airflow rate. Nev- ertheless, this ratio is commonly used as a descriptor of overall airways geometry. Another indirect approach to assessing airways caliber is the forced expiratory spirogram (volume expired versus time) which is equivalent in informational con- tent to the flow-expired volume relation. Since the inspiration that precedes the forced expiratory maneuver may tempo- rarily dilate constricted airways or, in asth- matics, provoke increased bronchocon- striction, the size of the inspiration can be reduced and partial forced expiratory maneuvers performed in order to avoid these confounding factors. The quantitative changes observed with RaW and spirometric measurements in patients with airways nar- rowing may be poorly correlated. Thus, careful attention to selection of measure- ment techniques is necessary when probing for relatively small effects on airways func- t~on. l he direct relation between lung volume (and lung elastic recoil) and intrathoracic airways caliber is well known. Recent re- ports suggest that the dose/response rela- tion of the airways to inhaled bronchocon- strictors is quite sensitive to the lung volume at which RaW measurements are made (Martin et al. 1986~. This factor will need to be considered in assessing bronchial reactivity. Distribution of Airflow Resistance Along the Airways The longitudinal distribution of the pres- sure changes between the airway opening and alveoli is complex. The larynx repre- sents a significant problem in clinical stud- ies whereas an endotracheal tube poses problems in intubated experimental ani- mals. During quiet breathing or panting, a major pressure drop occurs in the larynx and the large airways of normal individuals or mild asthmatics. In normal adults, the small airways contribute little to total air- flow resistance but become a major com- ponent of the elevated airflow resistance in persons with diffuse airways disease. In addition, changes in the small airways are particularly important in the pathogenesis of COPD. Significant pathological changes in the very small airways have been de- scribed in primates chronically exposed to moderate levels of O3 (Tyler et al. 1985~. The caliber of the upper airways and the trachea can be measured with radiological or acoustic reflection techniques. Using tantalum dust as an experimental contrast material, researchers have obtained good visual resolution of the intrapulmonary bronchi (Hahn et al. 1976; Smith et al. 1979; Shioya et al. 1987~. A variety of approaches have been devised to fractionate resistance between the "large" and "small" airways. Some of these (for example, anal- ysis of the frequency dependence of respi- ratory impedance using random-noise forced oscillation, analysis of the gas-den- sity dependence of forced expiratory flow) are noninvasive. A more direct, though invasive, approach uses a wedged broncho- scope to isolate smaller airways. This tech- nique has been applied to the study of O3

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Philip A. Bromberg 475 effects on peripheral lung airflow resistance and histamine reactivity in dogs by Menkes and his colleagues (Gertner et al. 1983a,b,c). Little or no attempt has been made in ' studies of pollutant effects in asthmatic subjects to fractionate airways resistance changes or, more specifically, to examine small airways function. --r Mechanisms of Bronchoconstriction Fundamental mechanisms intrinsic to smooth muscle that regulate its contraction and relaxation have been reviewed by Kamm and Stull (1985), Rasmussen (1986), and Russell (1986~. However, it is not known whether asthma is associated with changes in these mechanisms. It is, for example, conceivable that the hypertro- phied smooth muscle in the airways of severe asthmatics might show differences in composition of one or more of the mole- cules in the contractile or regulatory appa- ratus, or in properties of membrane cal- cium channels, or in the quantity or type of membrane receptors. Such abnormalities, and others, could produce an abnormal contractile response to normal stimuli. More attention has been focused on ab- normalities of mechanisms exogenous to the muscle cells that might stimulate exces- sive contraction and/or impair relaxation of normally functioning smooth muscle. These mechanisms fall into two broad classes: neural and chemical. Neural Mechanisms. The airway wall el- ements, including smooth muscle, are in- nervated by several different kinds of nerves (for review, see Nadel and Barnes 1984~. Best known are the postganglionic parasympathetic fibers. These fibers are cholinergic and depolarize the muscle membrane by reaction of acetylcholine re- leased from the nerve endings with specific muscarinic muscle membrane receptors. Normal individuals exhibit parasympathet- ically mediated airways smooth-muscle tone which can be blocked by atropine or ipratropium bromide, resulting in a signif- icant decrease in airways resistance. The preganglionic fibers in the airway wall are also cholinergic, but their synapse with the postgangi~onic nerve cell bodies is nicotinic (rather than muscarinic) and can be blocked by agents such as hexamethonium. The ganglion cells are subject to other neural and chemical influences that also influence their excitability. Detailed study of the anatomy and physiology of these impor . . . . . . . . tent tissue gang. pa Is Just beginning. There appears to be little sympathetic innervation of the airways despite the abundance of adrenergic receptors on vari- ous cellular elements in the airway walls. On smooth muscle, these receptors are normally of the beta type, and their activa- tion causes muscle relaxation. Under some circumstances, however, a-adrenergic con- strictive responses have been demonstrated which can be blocked by appropriate inhib- itors. An abnormality of adrenergic recep- tor function, in particular ,~adrenergic blockade, was proposed 20 years ago by Szentivanyi (1968) as an important mecha- nism underlying asthma. Asthmatic pa- tients often exhibit extraordinary sensitiv- ity to orally or even topically (ocularly) administered ,~adrenergic blockers which can precipitate a serious exacerbation of the asthmatic state. On the other hand, non- asthmatic individuals fail to develop bron- chial hyperreactivity or asthma when treated chronically with ,~adrenergic blocking agents. Less well understood is the nonadrener- gic, noncholinergic inhibitory system (see Barnes 1984) whose neurotransmitter~s) remained) to be firmly identified. Vasoac- tive intestinal peptide (VIP) is an attractive candidate for this role. Airway smooth muscle preparations from appropriate spe- cies including humans, when electrically stimulated, develop a transient relaxation followed by constriction. Constriction can be blocked by atropine pretreatment; this unveils a relatively prolonged relaxation that cannot be prevented by ,~adrenergic blockade. The neural nature of this re- sponse is shown by its blockade by the neuronal sodium ion channel blocker, te- trodotoxin. It is possible that the postgan- glionic cholinergic fibers are also VIP- ergic, with the polypeptide transmitter modulating the effect of the "classical"- that is, acetylcholine transmitter. Re

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488 Asthma and Automotive Emissions sponges. It therefore seems necessary to continue phenomenological or "descrip- tive" studies in the expectation that clear- cut findings that can be correlated with data from ongoing field studies will emerge. Asthmatic subjects and persons with other diseases associated with bronchial hyper- reactivity should be tested using NO2 as well as O3. With regard to field studies, it may be useful to digress and present several sug- gestions despite the fact that this general area is addressed by Bresnitz and Rest (this volume). In studies of large populations (for example, Bates and Sizto 1983) careful attention to the air quality measurements is required. In addition to quantifying ambi- ent gaseous and inorganic particulate pol- lutants, as well as temperature and relative humidity across a substantial area, it Is necessary to ensure that all pollutant spe- cies are examined and that the measure- ments are frequent enough to assess the pattern of fluctuation of each component of interest. Indeed, these air quality mea- surements may point the way to develop- ing controlled exposure protocols. In addi- tion, if asthma is the health effect of concern, it is desirable to quantify common airborne particulate antigens. The possible presence of confounders, such as epidemics of respiratory infections, must also be con- sidered. If not prohibited by considerations of privacy and ethics, one should identify individuals within the study population whose respiratory health status "drives" any overall population correlations ob- served between asthma and air quality. Such individuals could be invited to join a panel of asthmatics for a prospective study. They could also be clinically characterized in depth to define the features of a puta- tively sensitive subpopulation. Finally, they might serve as subjects for controlled exposures. In studies of panels of asthmatics, air quality monitoring might include personal monitors and home monitors in an effort to obtain the most precise exposure data. Again, common airborne allergens should be measured and evidence of respiratory tract infection sought. The respiratory sta tus of panel members should be character- ized in detail. In addition to descriptive studies, studies aimed at enhancing our understanding of the mechanisms underlying the multiple airways effects of oxidant pollutants, espe- cially 03, should be considered. Such in- vestigations should clarify the relation of automotive air pollution to relevant patho- physiological mechanisms in asthma and related diseases. Even if no relation to asthma were to emerge, a better under- standing of this issue is essential to a ratio- nal health policy. Some of these mechanistic studies can be performed in human subjects (for example, mucociliary clearance, airways surface liq- uid composition and volume, analysis of bronchial washes or of bronchoalveolar ravage samples for mediators and macro- molecules). The nasal mucosa can serve as a model for the airways. However, to the extent that invasive procedures are required (bronchoscopy), there will be obvious lim- itations, especially in asthmatic subjects. Sensitive and specific analytical techniques for certain cellular secretory products will be needed, and their development may have to await further progress in lung biology. Some investigations may be better suited by animal models, or by cultured cells, human as well as animal. For example, the bioelectric properties of respiratory epithe- lium are being explored in considerable detail using cultured cells as well as in vivo techniques. Macromolecular secretion can also be studied in cultured epithelial cell layers. Alveolar macrophages are particu- larly abundant in bronchoalveolar ravage liquid and can be cultured and exposed to air pollutants. Excised perfused lungs allow for control of the composition of the perfusate as well as of the inspired gas or airways fluid. The neural elements are disrupted, however, and the bronchial circulation is absent. In situ isolated lobe preparations are therefore preferable to study permeability effects of O3 exposure for various probe molecules including specific antigens. Intact animal models of used for a effects. antigen-induced asthma can be variety of studies of pollutant

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Philip A. Bromberg 489 Summary of Research Recommendations: Priorities Descriptive Studies HIGH PRIORITY Recommendation 9 Exposure chamber atmospheres that mimic the acid sulfate content and particle size distribution in ambient pollution should be created. First, it will be necessary to analyze in greater detail the composition of ambient atmospheres associated with increased symptomatology in patients with asthma and other respiratory diseases. Recommendation 10 Asthmatic subjects should be exposed to such chamber atmo spheres, with monitoring of airways caliber. The study of atmo spheres containing more than one pollutant will greatly complicate the design of such experiments and will require some choices to be made of concentrations of the pollutants, time course of the concentration of each pollutant, and particle size range of a particulate pollutant (for example, acid sulfate aerosol). Recommendation 11 Response of airways of extrinsic asthmatics to pollutants, espe ciallv NOB. should be assessed in the Presence versus the absence of , ,, ~ chronic low-level exposure to specific allergens. Recommendation 16 The effect in allergic rhinitis patients or in extrinsic asthmatics of experimental pollutant exposures on postexposure nasal or bron chial reactivity ("early" and "late" phases) to specific antigen challenge should be ascertained. MEDIUM PRIORITY Recommendation 7 Exercising asthmatics should be exposed to relevant O3 and NO2 levels for periods up to 8 hr. with monitoring of airways cali ber. Recommendation 13 The effect of experimental pollutant exposures on airways func tion should be measured in patients with COPD (for example, nonspecific chronic bronchitis, cystic fibrosis), in whom increased bronchial reactivity is present. Recommendation 15 The effect of oxidant pollutant exposures of asthmatics on bronchial reactivity to stimuli such as SO2, cold dry air, noniso tonic aerosolized solutions, and certain mast cell-derived mediators should be explored. LOW PRIORITY Recommendation 8 Asthmatics should be exposed experimentally for 8 hr to O3 or NO2 for two or three consecutive days, with monitoring of airways caliber.

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490 Asthma and Automotive Emissions Recommendation 12 The effect of experimental pollutant exposures on nonspecific airways reactivity in asthmatic subjects selected to display a range of baseline reactivities should be measured. Recommendation 14 Pollutant effects on airways should be measured in extrinsic asthmatics in whom a transient state of marked bronchial hyper reactivity has been induced by a single antigen inhalation challenge. Individual subject responses could then be assessed over time at several levels of baseline bronchial reactivity. Mechanistic Studies H I G H P R I O R I T Y Recommendation 1 The uptake profile of pollutant gases in different regions of the airways should be measured by sampling and analyzing inspired air at different airway levels. Variables to be explored with such systems include concentration of pollutants, ventilatory parame ters, duration of exposure, and presence of disease (for example, asthma, chronic bronchitis). Recommendation 2 These data should be compared with the predictions of currently available mathematical models. Recommendation 3 The uptake profiles should be examined for their ability to account for some of the variability in vital capacity response to O3 exposure observed among individuals. Recommendation 4 Specific neuropeptides should be assayed in airways surface liquid after O3 exposure, and the phenomenon of"tolerance" to the O3 effect on vital capacity should be explored along these lines. Highly sensitive neuropeptide assays will be required, and rapid inhibition of peptidase activity may also be necessary to prevent hydrolysis of peptides in the sample. Recommendation 6 Animals prepared so as to render their airway C-fiber systems nonfunctional should be used to examine the role of this sensory system in O3 effects on epithelial permeability, mucous secretion, epithelial ion transport, bronchial reactivity, and airways inflam mation. MEDIUM PRIORITY Recommendation 5 O3 responsiveness in human subjects should be compared to the responses to known stimulants of the airway C-fibers, such as . . capsalcln. Recommendation 17 The effects of exposure to 037 or O3 plus other air pollution components, on respiratory epithelial cell function should be probed in greater detail. These functions include mucociliary clearance, permeability to molecules including albumin and anti

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Philip A. Bromberg 491 gens, secretion of mucins and of other specific macromolecules, airway surface liquid composition and volume control, and release of mediator substances. Recommendation 18 Direct measurements of pollutant uptake (that is, covalent chem ical reaction) by cells or tissues can be attempted using "labeled" gases such as ~ O3. Cultured pulmonary endothelial cells, alveolar macrophages, and epithelial cells could be used. Such studies would be particularly useful if they could be correlated to specific pollut ant effects on the system under study. Recommendation 19 Although not a good representative of the conducting airways, the pulmonary alveolar macrophage, as obtained by bronchoalveo lar ravage following in viva pollutant exposure, may exhibit functional changes that could be correlated with in vitro dose/re sponse studies of cultured alveolar macrophages. Such data would provide some information on parenchymal tissue dosimetry. References Abraham, W. M., Januszkiewicz, A. J., Mingle, M., Welker, M., Wanner, A., and Sackner, M. A. 1980. Sensitivity of bronchoprovocation and tracheal mu- cous velocity in detecting airway responses to O3,J. Appl. Physiol. 48(5):789-793. Abraham, W. M., Yerger, L., Marchette, B., and Wanner, A. 1983a. The effect of ozone on antigen- induced bronchospasm in allergic sheep, In: Ad- vances in Modern Environmental Toxicology, Vol. 5 (S. D. Lee, M. G. Mustafa, and M. A. Mehlman, eds.), Vol. 5, pp. 193-203, Princeton Scientific Publ. Inc., Princeton, N.J. Abraham, W. M., Delehunt, J. C., Yerger, L., and Marchette, B. 1983b. Characterization of a late phase pulmonary response after antigen challenge in allergic sheep, Am. Rev. Respir. Dis. 128(5):839- 844. Abraham, W. M., Stevenson, J. S., Chapman, G. A., Yerger, L. D., Codias, E., Hernandez, A., and Sielczak, M. W. 1984. Ozone induces late bronchial responses after antigen challenge in allergic sheep, Physiologist 27:239 (abstr.). Ahmed, T., Marchette, B., Danta, I., Birch, S., Dougherty, R. L., Schreck, R., and Sackner, M. A. 1982. Effect of 0.1 ppm NO2 on bronchial reactivity in normals and subjects with bronchial asthma, Am. Rev. Respir. Dis. 125:A152. Ahmed, T., Danta, I., Dougherty, R. L., Schreck, R., and Sackner, M. A. 1983. Effect of NO2 on specific bronchial reactivity to ragweed antigen in subjects with allergic asthma, Am. Rev. Respir. Dis. 127: A160. Correspondence should be addressed to Philip A. Bromberg, Center for Environmental Medicine, School of Medicine, The University of North Caro lina, Chapel Hill, NC 27514. Al-Bazzaz, F. J. 1986. Regulation of salt and water transport across airway mucosa, Clin. Chest Med. 7(2):259-272 (Review). Al-Bazzaz, F. J., Kelsey, J. G., and Kaage, W. D. 1985. Substance P stimulation of chloride secretion by canine tracheal mucosa, Am. Rev. Respir. Dis. 131(1):8~89. Alink, G. M., Rietjens, I. M. C. M., van der Linden, A. M. A., and Temmink, J. H. M. 1983. Biochem- ical and morphological effect of ozone on lung cells in vitro) In: Advances in Modern Environmental Toxi- cology (S. D. Lee, M. G. Mustafa, and M. A. Mehlman, eds.), Vol. 5, pp. 449 158, Princeton Scientific Publ. Inc., Princeton, N.J. Avol, E. L., Linn, W. S., Venet, T. G., Shamoo, D. A., and Hackney, J. D. 1984. Comparative respiratory effects of ozone and ambient oxidant pollution exposure during heavy exercise, J. Air Pollut. Control Assoc. 34(8):804-809. Barnes, P. J. 1984. The third nervous system in the lung: physiology and clinical perspectives, Thorax 39:561-567. Barter, C. E., and Campbell, A. H. 1976. Relation- ship of constitutional factors and cigarette smoking to decrease in 1-second forced expiratory volume, Am. Rev. Respir. Dis. 113:305-314. Basbaum, C. B. 1986. Regulation of airway secretory cells, Clin. Chest Med. 7(2):231-235. Bates, D. V. 1985. The strength of the evidence relating air pollutants to adverse health effects, Carolina Environmental Essay Series VI, Institute for Environmental Studies, University of North Carolina, Chapel Hill. Bates, D. V., and Sizto, R. 1983. Relationship be- tween air pollution levels and hospital admissions in Southern Ontario, Can. J. Public Health 74:117-133. Bauer, M. A., Utell, M. J., Morrow, P. E., Speers, D. M., and Gibb, F. R. 1985. Route of inhalation influences airway responses to 0.30 ppm NO2 in asthmatic subjects, Am. Rev. Respir. Dis. 131 :A171.

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Relationship between airway hyperreactivity and hyperpermeability in Ascaris-sensitive monkeys, J. Allergy Clin. Immunol. 64(3) :197-201. Boucher, R. C., Johnson, J., Inoue, S., Hulbert, W., and Hogg, J. C. 1980. The effect of cigarette smoke on the permeability of guinea pig airways, Lab. Invest. 43(1):94-100. Boucher, R. C., Stutts, M. J., Bromberg, P. A., and Gatzy, J. T. 1981. Regional differences in airway surface liquid composition, J. Appl. Physiol. 50(3): 61~620. Boushey, H. A. 1985. Role of the vagus nerves in bronchoconstriction in humans, Chest 87:197S- 201S. Boushey, H. A., Holtzman, M. J., Sheller, J. R., and Nadel, J. A. 1980. Bronchial hyperreactivity, Am. Rev. Respir. Dis. 121 (2) :389-413 (Review). Brink, C., Duncan, P. G., and Douglas, J. S. 1981. The response and sensitivity to histamine of respi- ratory tissues from normal and ovalbumin-sensi- tized guinea pigs: effects of cyclooxygenase and Asthma and Automotive Emissions lipoxygenase inhibition, J. Pharmacol. Exp. Ther. 217(3):592-601. Broder, I., Barlow, P. P., and Horton, R. J. M. 1962. The epidemiology of asthma and hay fever in a total community, Tecumseh, Michigan, [. Allerg. 33: 51~523, 520531. Broder, I., Higgins, M. W., Mathews, K. P., and Keller, J. B. 1974a. Epidemiology of asthma and allergic rhinitis in a total community, Tecumseh, Michigan. III. Second survey of the community, J. Allergy Clin. Immunol. 53(3):127-138. Broder, I., Higgins, M. W., Mathews, K. P., and Keller, J. B. 1974b. Epidemiology of asthma and allergic rhinitis in a total community, Tecumseh, Michigan. IV. Natural history, J. Allergy Clin. Immunol. 54(2):10~110. Bromberg, P. A. 1987. Mechanism of effects of ozone inhalation on lung function: a hypothesis, In: Fourth Health Effects Institute Annual Conference, p. 37 (abstr. ), Health Effects Institute, Cambridge, Mass. Bromberg, P. A., Ivanick, M., and Ranga, V. 1984. Effect of ozone (03) on airways epithelial perme- ability to polar solutes: demonstration of adaptation following repeated exposure, Physiologist 27:276 (abstr.). Buckle, F. G., and Cohen, A. B. 1975. Nasal mucosal hyperpermeability to macromolecules in atopic rhi- nitis and extrinsic asthma, J. Allergy Clin. Immunol. 55(4):21~221. Busse, W. W. 1985. The precipitation of asthma by upper respiratory infections, Chest 87:44S-48S. Bylin, G., Lindvall, T., Rehn, T., and Sundin, B. 1985. Effects of short-term exposure to ambient nitrogen dioxide concentrations on human bron- chial reactivity and lung function, Eur. J. Respir. Dis. 66(3) :205-217. Cartier, A., Thomson, N. C., Frith, P. A., Roberts, R., and Hargreave, F. E. 1982. Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber, J. Allergy Clin. Immunol. 70(3):17~177. Cockcroft, D. W. 1983. Mechanism of perennial allergic asthma, Lancet 2(8344):253-256. Cockcroft, D. W., Ruff~n, R. E., Frith, P. A., Cartier, A., Juniper, E. F., Dolovich, J., and Hargreave, F. E. 1979. Determinants of allergen-induced asthma: dose of allergen, circulating IgE antibody concentration, and bronchial responsiveness to in- haled histamine, Am. Rev. Respir. Dis. 120(5): 1053-1058. Coleridge, H. M., and Coleridge, J. C. G. 1986. Reflexes evoked from tracheobronchial tree and lungs, In: Handbook of Physiology, Section 3, The Respiratory System. Vol. II. Control of Breathing, Part 1, Chap. 12. (N. S. Cherniack and J. G. Widdicombe, eds.), pp. 395-429, American Physi- ological Society, Bethesda, Md. Coleridge, H. M., Coleridge, J. C. G., and Luck, J. C. 1965. Pulmonary afferent fibers of small diameter stimulated by capsaicin and by hyperinfla- tion of the lungs, J. Physiol. London 179:24~262. Coleridge, H. M., Coleridge, J. C., Baker, D. G.,

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