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Effects of Automotive Emissions on Susceptibility to Respiratory Infections JAMES E. PENNINGTON Brigham and Women's Hospital and Harvard Medical School The Hypothesis / 500 Background / 501 Determinants of Susceptibility / 501 Occurrence of Respiratory Infections / 501 Lung Defense Mechanisms / 502 Long-Term Effects of Infection / 503 Epidemiologic Approach / 503 Documentation and Measurement of Respiratory Infection / 503 Other Epidemiologic Variables / 505 Experimental Approach / 506 Experimental Infections / 506 Studies of Lung Defense Mechanisms / 507 Gaps in Knowledge and Research Recommendations / 508 Epidemiologic Study Design / 508 Experimental Studies / 510 Summary / 513 Summary of Research Recommendations / 514 Air Pollution, the Automobile) and Public Health. @) 1988 by the Health Effects Institute. National Academy Press, Washington, D.C. 499

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500 Effects of Automotive Emissions on Susceptibility to Respiratory Infections The Hypothesis Respiratory infection is the most common type of infection occurring in the United States. It is estimated that between 200 million and 600 million respiratory infec- tions occur in this country each year, re- sulting in a loss of more than 150 million work days (Monto and Ullman 1974; Ga- ribaldi 1985~. Costs associated with respi- ratory infections are enormous, with $10 billion expended each year for the common cold alone (Dixon 1985~. Mortality from most types of respiratory infections is low, with morbidity and economic factors the major concerns. However, Or pneumonia, which accounts for 1 to 2 percent of respi- ratory infections in adults (Garibaldi 1985), mortality also becomes an issue: pneumo- nia is currently the sixth most frequent cause of death in the United States (Gari- baldi 1985~. Thus, any factor that favorably or unfavorably influences the incidence or severity of respiratory infections is of enor- mous importance to our population. The hypothesis considered in this chap- ter is that exposure to automotive emis- sions can result in greater susceptibility to respiratory infections. This hypothesis is worthy of careful study for a number of reasons. First, if increased susceptibility to respiratory infection can be documented among populations heavily exposed to mo- bile source emissions (for example, traffic police, tollbooth attendants, mechanics), then specific vaccination programs, respi- ratory function monitoring, and occu- pational counseling for these high-risk individuals can be initiated. Second, if emissions are clearly linked to risk of infec- tion, then more extensive studies can be undertaken to identify the most hazardous components of automotive emissions; and, if specific components are identified, they could be taken into account in future engine design. Finally, short-term and long-term noninfectious sequelae have been linked to respiratory infections. For example, protracted bronchial hyperre- activity sometimes follows an acute epi- sode of influenza (Empey et al. 1976), and childhood respiratory infections have been linked to an increased risk of adult lung disease (Kattan 1979~. Thus, preven- tion of respiratory infections associated with automotive emissions might reduce subsequent noninfectious pulmonary dis- eases. In organizing a method for assessment of the basic hypothesis, a natural starting point is agreement about the constituents of automotive emissions and about the con- centration ranges relevant to human expo- sures; some components (for example, ni- trogen dioxide, acrolein) exist in low amounts in automotive emissions but in exceedingly high amounts elsewhere (for example, blasting areas, siloes, cigarette smoke). The emission components relevant to this discussion and their upper limits of exposure recommended by the National Ambient Air Quality Standards (NAAQS) of the U. S. Environmental Protection Agency, are listed in table 1. Recently, aldehydes have been added to this list in anticipation of future use of methanol fuel. In that case, acrolein, formaldehyde, and acetaldehyde would increase in importance as components of automotive emissions. However, on the basis of studies of Los Angeles smog, Tuazon and coworkers (1981) estimated that formaldehyde levels deriving from automotive emissions would be considerably less than 1 ppm, and levels of other aldehydes would be even lower. What methods, then, are available for analysis of the hypothesis that automotive emissions increase susceptibility to respira- tory infection? The approaches taken in- clude epidemiologic studies, and experi- mental studies using animal models. Although chamber studies using nitrogen dioxide (NO2), ozone (O3), and other rel Table 1. Major Pollutants Related to Automotive Emissions Component Air Quality Standard (ppm) ' 0.05/year Nitrogen dioxide (NO2) Ozone (03) Carbon monoxide (CO) Total suspended particulates (TSP) ' 0.12 (1-hr average) 9 ppm/8 hr 35 ppm/1 hr 260 ,ug/m3124 hr

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James E. Pennington 501 Table 2. Ambient Concentrations of NO2 Setting Concn. (ppm) Rural air Urban air Los Angeles freeway (usual) Los Angeles freeway, highest recorded (1962) Cigarette smoke exiting cigarette Mine shafts immediately after dynamite blast Siloes with advanced decomposition of ensilage 0.01 0.03-0.12 0.15-0.45 1.3 1.0-5.0 250 500 event gases on humans have been reported, those studies have been directed toward range finding for acute toxicity and effects on bronchial hyperreactivity (Ferris 1978~. Virtually no data on the relationship be- tween pollutants and the risk of infection have been published. The discussion that follows reviews epi- demiologic and experimental approaches to this problem. Since data on NO2 are exten- sive and the approaches taken in NO2 studies appear relevant to the question raised here, the background information presented below emphasizes findings with NO2 exposures. Table 2 lists ambient con- centrations of NO2 in various settings which may be useful in the experimental design of some of the studies discussed below. After the background discussion, gaps in our understanding are identified, and suggestions for future studies that might improve our ability to prove or disprove the basic hypothesis are presented. 1' Background Determinants of Susceptibility Frequency of infections as well as severity, as measured by physician visits, hospital- ization, absenteeism from work or school, and so on, should be considered relevant indicators of susceptibility. Health-impaired populations (for example, the immunosup- pressed or chronic lung disease patients) are important to consider, as are infants and the elderly, in whom developing or senescent lungs may be factors in susceptibility. Also to be considered is the specific type of infec- tion, that is, viral versus bacterial, especially as it relates to available vaccines. And certain anatomic locations in the lung and conduct- ing airways may be at greater risk of infec- tion than others. For example, is ciliary dys- function with associated bronchitis/sinusitis a major determinant, or is the alveolar paren- chymal region more prone to infection if stressed by automotive emissions? Naturally, if certain locations in the respiratory tract appear to be more susceptible, then research could be directed at analysis of the most relevant local defense mechanisms. Occurrence of Respiratory Infections In considering the contribution of emis . . . ,# . . . . s1ons to respiratory 1ntectlons, it IS worth- while to review the types of infectious agents that commonly cause respiratory tract infection in the United States. In a large prospective study over a 6-yr period, approximately 14,600 cases of respiratory infections were documented in 4,905 resi- dents of Tecumseh, Michigan (Monto and Ullman 1974~. Microbiological monitoring was carried out using throat cultures for Group A streptococcus, respiratory viral agents, and mycoplasma. Cultures were only obtained if available within 2 days after onset of symptoms. Of the isolates, 82 percent were viral, 13.3 percent were Group A streptococcal, and 4.7 percent were "other," which included mycoplasma. Res- piratory infections were far more frequent during childhood (five to six per year in newborns to 2-year-olds) and decreased steadily with age. By adulthood, one to two infections occurred per year. This study and others (for example, Garibaldi 1985) emphasize the predominance of upper res- piratory sites for infection, with bronchitis and pneumonia accounting for only 10 percent of the episodes. Although upper respiratory viral infec- tions are more common, the morbidity and mortality associated with bronchitis and pneumonia are far greater (Pennington 1983~. The major agents causing serious lower respiratory infection are Mycoplasma

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502 Effects of Automotive Emissions on Susceptibility to Respiratory Infections pneumonias, Legionella species, influenza A and B. parainfluenza type 1, respiratory syncytial virus, and bacteria, especially Streptococcus pneumonias ("pneumococcus") and Hemophilus infuenzoe. In certain high- risk individuals such as alcoholics, diabet- ics, and the elderly, enteric gram-negative bacilli also may cause pneumonia. Thus, in selecting appropriate infectious agents for surveillance studies of respira- tory infection, a broad-based cultural and/or serologic approach is necessary. In selecting relevant infectious agents for use in animal models of respiratory infection, a wider range of infectious agents could be consid- ered. Lung Defense Mechanisms Requisite to an analysis of effects of inhaled pollutants on lung defenses against infec- tion is a thorough understanding of the respiratory defense system that is operative under normal conditions. Numerous reviews describe the lung's complex and remark- ably effective defense against infection (Green 1970; Kaltreider 1976~. Table 3 summarizes the basic components of this system. Specific defects in this defense sys- tem appear to predispose to specific types of infections (Reynolds 1983; Pennington Table 3. Host Defense Mechanisms in the Human Respiratory Tract Upper airways Nasopharyngeal filtration Mucosal adherence Bacterial "interference" Saliva (proteases, lysosome) Secretory IgA Epiglottis Lower airways and alveoli Cough reflex Mucociliary clearance Humoral factors Immunoglobulins Complement Cells and cell products Bronchus-associated lymphoid tissue Lymphocytes Alveolar macrophages Polymorphonuclear leukocytes Cytokines (interleukin-1, interleukin-2, interferons) 1984~. For example, impaired mucociliary clearance (which can occur with ciliary dyskinesia, cystic fibrosis, bronchiectasis) results in bacterial sinusitis and bronchitis, generally caused by encapsulated bacteria such as H. in1?uenzoe, and the pneumo- coccus. Local deficiency in immunoglobulins such as IgG2 and IgG4 are associated with recurrent bacterial bronchitis and broncho- pneumonia. Absent or impaired cough re- flex from neurological disease results in . . . asplratlon pneumonias. Cellular defenses are particularly impor- tant in the lower respiratory tract. For example, immunosuppressive drugs may reduce alveolar macrophage and local lym- phocyte function, resulting in opportunis- tic pneumonias, such as Pneumocystis carinii, and cryptococcal pneumonia (Pennington 1985~. Impaired polymorphonuclear leu- kocyte recruitment to the lungs during myelosuppression correlates with an in- creased risk for aerobic gram-negative ba- cillary pneumonia (Pennington 1985~. All of these relationships have been well de- scribed, and numerous other components of the lung defense system are now being investigated. For example, investigations undertaken by Bukowski et al. (1984) on the local importance of natural killer (NK) cells in antiviral activity and by Ennis et al. (1978) on the importance of other cytotoxic lymphocyte populations in lung defenses are being actively pursued. Likewise, the role of various cell-derived immune mod- ulators interleukin-1, interleukin-2, and interferons in local pulmonary defenses is a subject of great interest (Pinkston et al. 1983; Wewers et al. 1984; Robinson et al. 1985~. The functional integration of this com- plex system is not completely understood and in some cases is controversial. For example, some debate exists about the im- portance of alveolar macrophages versus neutrophils in bacterial defenses; alveolar macrophages appear to be critical resident phagocytes for the surveillance against low numbers of bacteria arriving in the lung, but recruitment of neutrophils into the lung is necessary for larger bacterial challenges. Furthermore, although secretory immuno- globin A (IgA) is generally considered the

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lames E. Pennington 503 primary humoral immunoglobulin in- volved in local respiratory defenses, recent information suggests that IgG is a more potent humoral factor in the lower respira- torv tract (Reynolds 19831. Finallv. the , ~ , . . . lymphocyte-directed cellular immune re- sponse has been traditionally viewed as the mainstay against facultative intracellular pathogens such as mycobacteria but of little importance against acute infection with pyogenic organisms such as Pseudomonas aeruginosa. Recent investigations, however, suggest that this distinction may not be clear-cut. It thus appears that for most infections, a combination of mechanical, secretory, and cellular defenses is needed for optimal lung defense. Long-Term EfJects of Infection Although most respiratory infections are not fatal, long-term adverse sequelae may result from childhood respiratory infec- tions (Burrows et al. 1977; Kattan 1979; Pullan and Hey 1982~. Long-term effects of infections may be particularly severe if in- fection-related lung injury occurs during infancy or early childhood- a critical pe- riod in lung development. Sequelae may take the form of asthma in children or adolescents or chronic airway obstruction in adults. However, a review of the rele- vant studies by Samet et al. (1983) suggests that evidence for these associations was incomplete and that many such studies suffer from recall bias. Nevertheless, the potential importance of such associations with childhood respiratory infections offers considerable incentive to pursue this anal- ys~s. Epidemiologic Approach The ideal method to test the hypothesis that links automotive emission exposure and increased susceptibility to respiratory infec- tions would be to document the frequency and/or severity of respiratory infections in individuals with greater exposure to emis- sions. Numerous epidemiologic studies have suggested that exposure to NO2 or other air pollutants increases the incidence of respiratory illness, and, in some cases, actual infection (discussed below). To date, no firm link between mobile source emis- sion exposures and respiratory infection has been established because of methodological difficulties including insufficient use of di- agnostic tests; unreliable techniques for col- lection of data (for example, recall, ques- tionnaires); and inaccurate measurements of ambient gas concentrations. Since expo- sure to air pollutants may cause respiratory irritation and increased bronchial hyper- reactivity, the use of symptoms such as cough, sputum production, sore throat, and wheezing as indicators of infection is much less accurate than viral or myco- plasmal serologies, or sputum and throat cultures. The use of questionnaires to record respiratory symptoms as a marker of infection is particularly problematic. Methodological problems must be taken into account in the design of future epide- miologic studies, even though some of the problems may prove insurmountable. The following discussion highlights important considerations in the design and implemen- tation of epidemiologic investigations that explore the link between emissions and infection (see also Bresnitz and Rest, this volume). Documentation and Measurement of Respiratory Infection Past Studies. Numerous epidemiologic studies have attempted to demonstrate an association between NO2 exposure and res- piratory illness. In some cases direct evi- dence of respiratory infection was sought, but in most cases infection was simply implied by association with cough, coryza (head cold, inflammation of nasal mucous membranes), or sore throat. In no studies were serologic assays performed, nor, with rare exception, were throat or sputum cul- tures obtained. Several of these studies illustrate this diagnostic difficulty. In one questionnaire- based study Speizer and Ferris (1973a,b) compared respiratory symptoms of a group of urban traffic police exposed to automo- tive emissions with symptoms of a group

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504 Effects of Automotive Emissions on Susceptibility to Respiratory Infections of suburban police. No differences in symptoms were noted, and the incidence of respiratory infections could not be deter- mined in either group. Similarly, a large- scale study was undertaken in groups of Chattanooga, Tennessee, schooich~uren residing in geographic areas with high ver- sus low levels of NO2 (Shy et al. 1970a,b). Respiratory symptoms were monitored by biweekly postcard survey, and positive re- sponses were followed up by direct ques- tioning. In addition, teams of parents using spirometers measured gas volumes of sec- ond-grade children in each locality. Initial analysis of these data suggested that chil- dren in the high-NO2 area experienced more frequent respiratory symptoms, were more prone (according to history) to "in- fluenza" when exposed during an epi- demic, and had lower FEVo75 values. A subsequent study in this area by Pearlman et al. (1971) also suggested that an increased incidence of childhood bronchitis was asso- ciated with increased NO2 exposure. Later analysis of study design and of the method used for NO2 measurements, however, rendered the findings from these studies less conclusive than originally thought (Ferris 1978~. Another relevant subject in investigating the health effects of NO2 exposure deals with the levels of NO2 inside homes with gas cooking appliances (Melia et al. 1977, 1979; Keller et al. 1979; Speizer et al. 1980~. In these studies, indoor exposure to NO2 was used as a method for isolated analysis of an ambient pollutant gas. Results of these studies conflict, again impaired by the use of questionnaires as well as the use of contemporary fuel exposures to assess past events. Practical suggestions for improving di- agnostic methods in future studies are more difficult to devise than might be imagined, because such methods of documenting and measuring respiratory infections generally suffer from insensitivity, impracticality, and expense. Personal History and Physical Examina- tion. A personal history taken during an acute respiratory illness is useful but ex- tremely time-consuming. Even with care ful questioning, differentiation between allergic and viral rhinitis or between asth- matic and infectious cough may be im- possible. The presence of fever, purulent sputum, pleuritic chest pain, and sore throat are informative but are absent in many cases of respiratory infection (Glezen and Denny 1973; Monto and Ullman 1974~. Of course, questionnaires, letters, infrequent telephone surveys, and patient recall are all even less accurate, although much less expensive, than personal histo- r~es. As with history taking, individual phys- ical examinations of patients with respira- tory complaints are labor and cost inten- sive. Also, symptoms of most bacterial infections are evident on examination (ex- udative pharyngitis, purulent sputum pro- ctuct~on, or even septic appearance), but viral or mycoplasmal infections may be difficult to differentiate from hypersensitiv- ity because of the similarity of symptoms (for example, coryza, erythematous throat, wheezing, tales). Thus, taken together a physical exami- nation and a personal history can provide useful concurrent diagnostic information. These data would clearly be superior to the data collected using questionnaire surveys, but the costs of these combined procedures may preclude their use for large-scale stud- ~es. ~ . Nonmicrobiological Laboratory Methods. Hematologic or radiographic tests do not provide conclusive evidence of respiratory infection. An elevated white blood cell count may suggest bacterial infection, and infiltrative patterns on chest x rays may suggest lung infection (among other possi- bilities). However, these tests are expensive and offer little diagnostic advantage over more specific microbiological tests discussed previously. If it is critical, however, that pneumonia be differentiated from bronchitis, then chest x rays would be necessary. Microbiological Methods. Although widely considered the methods of choice for diagno- sis of respiratory infections (McIntosh 1985), microbiological methods are surprisingly in- sensitive. For example, in large prospective

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James E. Pennington 505 studies of respiratory infections in pediatric practices, routine use of throat swab cultures for viral, mycoplasmal, and bacterial isola- tion yielded etiologic agents in less than 30 percent of the cases (Henderson et al. 1979; Murphy et al. 1981~. Similar results were reported in the Tecumseh study, in which throat cultures were collected from patients with symptoms for 2 days or less (Monto and Ullman 1974~. In several studies (re- viewed.by Pennington 1983) of adults who required hospitalization for community-ac- quired pneumonia, specific etiologic agents were found in only 60 to 70 percent of the cases. In attempts to define etiologies of respi- ratory infection, several studies used throat swab cultures to determine whether the pathogen was a virus, mycoplasma, or group A streptococcus (Glezen and Denny 1973; Monto and Ullman 1974; Henderson et al. 1979; Murphy et al. 1981), because respiratory infections caused by these agents are extremely common and because most infected patients cannot produce spu- tum for culture. But the use of throat cultures to isolate respiratory pathogens has certain drawbacks: first, most viral patho- gens are excreted for brief periods, early in infection, and often in low titers; second, viral, mycoplasmal, and chlamydial cul- tures require specialized and expensive methods, which are not available in most diagnostic laboratories; and third, in large population studies the logistics for obtain- ing proper specimens early in the illness may be difficult. Bacterial culture tech Table 4. Serologic Diagnosis of Common Respiratory Infections Agent Tests Viral Respiratory syncytial virus Influenza A and B Parainfluenza Adenovirus (group) Mycoplasma pneumonias Legionella sp. Chlamydia CF, IF CF, IF HI, IF CF, IF CF IFA, IF IFA NOTE: CF = complement fixation; HI = hemagglu- tination inhibition; IF = immunofluorescence (direct smear); IFA = indirect fluorescent antibody. niques are widely available, but most res- piratory infections are nonbacterial. Although serologic tests to detect most nonbacterial respiratory pathogens are available (table 4), these tests are expensive, require acute and convalescent specimens (except for direct immunofluorescent prep- arations), and may remain negative in in- fants with infection. Furthermore, anti- genic heterogeneity for rhinovirus, the most common cause of respiratory infec . . . . . . . tons, precludes serologic evaluation. in short, serologic diagnosis is expensive, time-consuming, and incomplete. Severity o/Respiratory Infections. In ad- dition to documenting the incidence of respiratory injections, a measurement of the severity of infection may be useful. Clinicians tend to measure severity in sub- jective as well as objective terms. For data collection, objective parameters are prefer- able. Measures such as duration of symp- toms and fever, time lost from work or school, time bedridden, whether sputum was produced, are all useful to gauge sever- ity. Questions such as how sore is your throat, how bad is your cough, are partic- ularly unreliable. In addition, some mea- sure of the overall effect of the respiratory infection may be useful in determining severity. Were physician visits needed, how much did the entire illness cost, were symptoms residual (for example, wheezing and coughing for weeks to months), can all be useful questions. Other Epidemiologic Variables Age. The highest risk of respiratory in- fection occurs during the first year of life and decreases steadily until adulthood (Monto and Ullman 1974~. On the other hand, risks of pneumonia and mortality from respiratory infection increase with advancing age (Pennington 1983~. Such variables may be useful in targeting groups for epidemiologic study. Season. Most studies indicate that the peak incidence of respiratory infections oc- curs during winter months (Glezen and Denny 1973~.

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506 Effects of Automotive Emissions on Susceptibility to Respiratory Infections Socioeconomic Status and Family Setting. The Tecumseh study (Monto and Ullman 1974) showed that the incidence of respira- tory infections increased with education but decreased with family income. Supe- rior reporting by well-educated subjects may partially account for this finding. In addition, larger families and rural life may increase the risk of infection (Glezen and Denny 1973~. Additional factors, such as crowded family quarters, parental smok- ing, and use of day-care centers, must be considered in evaluation of epidemiologic data. Underlying Diseases. Increases in inci- dence and/or severity of respiratory infec- tions have been well described for certain high-risk individuals (Pennington 1983~. These groups include individuals with chronic bronchitis, cystic fibrosis, alcohol- ism, malnutrition, or immunosuppressed states arising, for example, from organ transplants and cancer chemotherapy. Re- cent data suggest that bacterial pneumonia is more frequent in patients with acquired immune deficiency syndrome (AIDS) (Polsky et al. 1986~. If limited resources dictate studies of only selected, high-risk populations, these may be the best groups to study. Experimental Approach Experimental Infections A link between respiratory mucosal dam- age from inhalation of O3 and increased susceptibility to localized infections was postulated by Miller and Ehrlich (1958~. They reasoned that mucous membranes, known to be important in antiinfective defenses, might be damaged by O3 during high-altitude flight. To prove their hypoth- esis, they exposed mice in inhalation cham- bers to 4 ppm O3 for 3 hr and then moni- tored survival rates after exposures to aerosolized Klebsiella pneumonias. Mortality was significantly higher among the O3- exnosed mice than among nonexnosed but Ehrlich, as well as by others, examining the many variables that pertain to the effects of pollutant exposure and susceptibility to ex- perimental infection as measured by sur- vival rates. Later work using this model dealt with NO2 rather than O3 (Purvis and Ehrlich 1963; Ehrlich 1966; Ehrlich and Henry 1968~. Ehrlich and coworkers concluded that acute exposures (for example, 1 to 2 hr) to NO2 at levels below 3.5 ppm do not affect survival from Klebsiella challenge. In contrast, they found that chronic NO2 ex- posure (' 3 months) of 0.5 ppm increased mortality from Klebsiella challenge (Ehrlich 1966; Ehrlich and Henry 1968~. Recent attempts to duplicate these results have been unsuccessful. McGrath and Oyervides (1983, 1985) found that mice exposed for 3 or 8 months to 0.5 ppm NO2 were not significantly different from controls in their resistance to aerosol challenge with Klebsi- ella. In a subsequent study, they exposed mice to 0.5, 1.0, and 1.5 ppm NO2 for 3 months, and again no decrease in resistance to aerosolized Klebsiella challenges was found. Acute exposures (3 days) to 5 ppm NO2, however, did decrease survival rates (McGrath and Oyervides 1985~. These au- thors speculated that the older NO2 moni- toring devices previously used by Ehrlich and coworkers may have provided impre- cise data during their chronic exposure studies. Inhalation studies using squirrel mon- keys exposed to NO2 indicate that NO2 exposures in the 5- to 10-ppm range ad- versely affect lung resistance to Klebsiella (Henry et al. 1969) and influenza virus inocula (Henry et al. 1970~. However, in subsequent studies Fenters et al. (1973) found that the antiviral defenses of mon- keys exposed to 1 ppm NO2 for more than a year were not significantly impaired. Yet another system of analysis uses quan- titative bacteriological monitoring of lung tissues in animals exposed to inhaled gases. This methodology provides an in vivo evaluation of microbicidal function in res- piratory tissues. In one typical study by , ~Goldstein et al. (1973), mice were chal infected control groups. This work was the lenged with aerosolized Staphylococcus au first in a series of studies by Miller and reus and were then exposed to various

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James E. Pennington 507 concentrations of NO2 (0 to 14.8 ppm) for thr periods. Their lungs were removed and quantities of remaining viable bacteria were determined. Animals exposed to NO2 levels of 1.9 ppm killed pulmonary bacteria as well as control groups, but bactericidal capacity was reduced in groups exposed to -3.8 ppm NO2 The method of analysis survival rates or assays of intrapulmonary microbicidal capacity most indicative of the clinical setting is speculative. In either model sys- tem, exposure to rather high levels of NO2 or O3 is required before significant impair- ment of lung resistance to infection can be demonstrated. Thus, it might be concluded that NO2 only impairs lung defenses at levels at or above 1.0 ppm, and that auto- motive emissions probably do not impair resistance to infection. An equally valid possibility, however, is that these methods of evaluation are not sensitive enough to detect impairment of lung defenses that might occur during exposures to NO2 in lower concentrations. Several methodological concerns can be identified when reviewing past studies of animal models of experimental infection. First, in most cases, healthy animals were used for the exposure studies. If impaired hosts are involved, such as immunosup- pressed animals, lung-injured animals, or even neonatal or senescent animal hosts, adverse effects of pollutant gas exposure on lung defenses may occur at much lower concentrations. Second, in most animal studies, rather unusual respiratory patho- gens were used (for example, Klebsiella, S. aureus, Streptococcus pyogenes). More clini- cally relevant choices of bacterial pathogens might include S. pneumonias or H. inJqu- enzue. And, although some work using respiratory viruses has been reported (Henry et al. 1970; Fenters et al. 1973), far more emphasis on the use of viruses, My- coplasma, and Legionella sp. in animal models might produce more definitive con- clusions regarding the effects of inhaled gases on lung defenses. Furthermore, the combined or synergistic effects of viral plus bacterial infections, as described by Astry and lakab (1983), may be a more relevant method for analysis of emission effects on lung infection. Finally, it is quite possible that acutely overwhelming lungs with bac- terial challenges simply does not simulate the pathogenesis of most human lung in- fections, and that a more detailed analysis of various components of the lung defense apparatus would be necessary to detect adverse effects of realistically low gas con- centrations. Studies of Lung Defense Mechanisms Careful analysis of past studies describing the importance of specific lung defense components in resistance against specific types of infection is critically important to test the hypothesis that automotive emis- sions impair lung defenses. For example, careful epidemiologic studies such as those discussed above may demonstrate that in- dividuals working or living in urban areas with high levels of ambient NO2 have an increased risk for viral respiratory infection but not bacterial infections. In that case, investigative priorities could be placed on analyses of the effects of emission compo- nents on antiviral defense mechanisms such as NK cells, cytotoxic lymphocytes, and local and systemic interferon responses. In other words, the first clue regarding subtle but important effects of emissions on spe- cific components of lung defenses may be suggested indirectly rather than by directly analyzing the specific component. In the meantime, the effects of NO2 and O3 on alveolar macrophages and certain other components of lung defenses have been analyzed by Kavet and Brain (1975) and Green et al. (1977~. In general, these researchers first exposed animals to gas inhalants, and then collected bronchoalveo- lar cells and fluids by ravage. In a few instances, they exposed lung cells or tra- cheal tissues in vitro to gases. In consider- ation of future research recommendations, a review of these past findings is likely to be helpful. ' Using histologic methods, Freeman et al. (1968) found that 2-ppm NO2 exposures resulted in decreased ciliary integrity of the tracheal epithelium. Schiff (1977), on the other hand, found no morphologic damage to cilia in hamster tracheal explants after

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508 Effects of Automotive Emissions on Susceptibility to Respiratory Infections daily in vitro exposures to 2 ppm NO2 for up to 3 weeks, although decreased ciliary beat frequency as well as increased suscep- tibility of tissues to influenza A viral inoc- ulations were observed. Effects of gas exposures on alveolar mac- rophages have also been studied. For exam- ple, Vassallo and coworkers (1973) found that alveolar macrophages obtained from rabbits exposed to 10 ppm NO2 demon- strated reduced phagocytosis of bacteria, and Gardner et al. (1969) found that higher NO2 levels resulted in reduced numbers of pulmonary macrophages. Others have shown that O3 exposure reduces alveolar macrophage hydrolases and other antibac- terial metabolic functions (Hurst et al. 1970; Gardner et al. 1971; Hurst and Coffin 1971~. In another series of studies, Valand et al. (1970) and Acton and Myrvik (1972) acutely exposed rabbits to 25 ppm NO2, and then evaluated alveolar macrophages for antiviral defenses. In healthy rabbits, the alveolar macrophages obtained after parainfluenzal challenges produced inter- feron; however, NO2 exposures sup- pressed this normal response. Williams et al. (1972) found that NO2 exposures sup- pressed uptake of virus by macrophages. Voisin and coworkers (1977) observed that after 30-min in vitro exposures to 0.1 ppm NO2 alveolar macrophages showed re- duced bactericidal capacity as well as re- duced cellular adenosine-triphosphate. The relationship between in vitro NO2 concen- trations and the in viva situation, however, remains speculative. Finally, in more recent work, Greene and Schneider (1978) ex- posed baboons to 2 ppm NO2 for 8 hr/day, 5 days/week for 6 months and then ob- tained alveolar macrophages by ravage. They found that the capacity for alveolar macrophage response to a lymphokine (mi- gration inhibition factor) generated from autologous lymphocytes was decreased among NO2-exposed animals. In sum- mary, the recurrent finding resembles that in the infectivity studies: exposure to levels of NO2 or O3 above 2 ppm is necessary for adverse effects to be observed. Effects of inhaled gas exposure on sys- temic humoral antibody response have also been studied. Holt et al. (1979) exposed mice to 10 ppm NO2 daily for 30 weeks. At various intervals during the 30-week expo- sure period, they monitored serum anti- body response to a T-cell independent an- tigen (polyvinyl pyrrolidone) and a T-cell dependent antigen (red blood cells), finding that antibody response to red blood cells, but not to polyvinyl pyrrolidone, was blunted after prolonged NO2 exposure. In contrast, Fenters et al. (1973) found slight increases in serum antibody response to influenza virus in squirrel monkeys ex- posed to 1 ppm NO2/day for over 1 year. Fujimaki and Shimizu (1981) found that exposure to 5 ppm NO2 for 12 hr did not decrease antibody responses to red blood cells in mice, but exposures to 20 ppm and 40 ppm did reduce antibody-forming capa- bility. Thus, it appears that animals ex- posed to NO2 levels far above those ex- pected to result from automotive emissions have a reduced capacity for primary anti- body response to certain antigens. Studies of the effects of gas exposure on local antibody production by pulmonary tissues have not been reported. Gaps in Knowledge and Research Recommendations Epidemiologic Study Design Diagnostic Specificity. The epidemio- logic information currently available is not suff~cient either to prove or disprove the hypothesis that exposure to automotive emissions increases susceptibility to respi- ratory infection. The most direct method to prove this hypothesis would be to dem- onstrate clearly that individuals exposed to higher levels of automotive emissions experience more frequent and/or more se- vere respiratory infections than individuals exposed to lower levels. Reliance on symp- toms (cough, sore throat, "colds going to chest," sputum production) rather than on specific diagnostic methods as indica- tors of respiratory infection should be avoided. Diff~culties encountered in such studies

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James E. Pennington 509 may include lack of availability of certain serologic tests in local laboratories, poor patient compliance in collection of paired (acute and convalescent) serologic speci- mens, high costs of such a meticulous diagnostic approach, and a high incidence of false-negative cultures reported for community-acquired respiratory infections. These problems may require that larger rather than smaller populations be studied. They may also dictate that more specific target groups be identified for prospective study. High-Risk Populations. An attempt has been made to analyze special respiratory risks to children during NO2 exposures (reviewed above), but a much broader view of high-risk populations should be taken. For example, the difficulty in finding con- sistent data in the childhood studies re- ported to date may be related to the fact that school-aged children are not among the groups more sensitive to low-level NO2 exposures. The elderly or infants may, in fact, be far more susceptible to inhaled air pollutants. Likewise, patients whose immune systems are compromised because of drug therapy or AIDS may be especially vulnerable to low levels of NO2, 03, carbon monoxide (CO), or aldehyde. It is noteworthy that the lung is the most frequent target organ for infectious compli- cations among immunocompromised pa- tients, regardless of underlying disease (Pennington 1985~. Further susceptibility to respiratory infections for such patients residing in congested urban areas with high traffic density would be meaningful to doc- ument. Other high-risk groups deserving study would include patients with chronic lung diseases (for example, cystic fibrosis, chronic bronchitis, emphysema) or even other chronic medical ailments. Even if an epidemiologic survey in a general popula- tic~n is not economically feasible using the diagnostic methods described above, an analysis in these high-risk populations would be worthwhile. Difficulties that might be encountered in this type of study include rapid patient attrition due to underlying illness, multiple concurrent illnesses, and alterations in med . . . r Cations colnclc sing Wlt n 1ntectlous epi- sodes. Recommendation 1. Epidemiologic survey in high-risk populations exposed to varying levels of automotive emissions should be conducted. These surveys should adhere to the fol- lowing minimum set of requirements: a. Use of population with defined expo- sure. Prospective and accurate ambient air analysis should document elevated levels of relevant emission components in the environment for study. b. Use of defined group. Cost consider- ations argue for selection of specific study groups of persons at high risk for respira- tory infection, in particular the elderly, infants, patients with chronic lung diseases, and immunocompromised patients. One problem to be expected with groups suf- fering from chronic lung disease is the high rate of chronic symptoms not associated with, but potentially confused with, acute . , . ntectlon. c. Use of adequate history. Retrospective questionnaires should not be used. Rather, prospective and frequent telephone sur- veys, followed up by visits to the clinic for symptomatic patients, are recommended. d. Use of diagnostic tests for infection. At a minimum, throat swabs for respira- tory viral cultures and bacterial cultures should be collected within 2 days of onset of illness. In addition, acute and convales- cent sera should be evaluated for Myco- plasma pneumonias and Legionella sp. anti- body titers. If sputum is produced, it should be cultured. These methods can be expected to yield specific diagnoses in 20 to 30 percent of cases. Although considerably more expensive, viral serologies could also be done (see table 4), increasing diagnoses by at least another 20 to 30 percent. e. Measures of severity. Factors dis- cussed above dealing with severity of infec- tion and overall impact of illness (that is, duration of symptoms and fever, absentee- ism from work or school, time bedridden, sputum production, need for physician vis

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510 Effects of Automotive Emissions on Susceptibility to Respiratory Infections its, cost of illness, residual symptoms) should be routinely recorded. Experimental Studies Animal Versus Human Studies. Before discussing areas where specific experimen- tal studies could provide more useful infor- mation regarding effects of inhaled gases on lung defenses, it is important to point out the lack of relevant data derived from hu- man studies. In recent years a methodology has been developed to collect cells and fluids from the human lower respiratory tract safely and rapidly with the flexible fiberoptic bronchoscope (Hunninghake et al. 1979~. Much valuable information is now available regarding normal bronchoalveolar cell populations and the fluid-phase constitu- ents of lower respiratory secretions (Hun- ninghake et al. 1979~. Further analyses using specimens obtained bronchoscopically from patients with lung diseases such as sarcoid, idiopathic interstitial pneumonitis or asthma have identified cell population alterations that correlate with specific diseases and with the status of disease activity (Weinberger et al. 1978; Hunninghake et al. 1979; Pinkston et al. 1983; Rankin et al. 1984~. To date, bronchoscopic analysis has not been used in humans to evaluate the effects of inhaled gases on various components of the lung defense system. Ethical consider- ations have, perhaps, slowed acceptance of this approach because the risks attendant with inhalation chamber exposures to NO2 or O3 in humans are unknown. But, nu- merous chamber studies have been per- fon~ed to develop guidelines for air quality recommendations (reviewed by Ferris 1978~. Those using low-level, short-term exposures appear to be safe and may be considered favorably by human studies committees. On the other hand, it could be argued that until the basic hypothesis has been disproved, it may not be wise to expose humans even to low levels of in- haled pollutants. After all, a basic premise of such investigations is that low-level ex- posure induces subtle but important defects in local defenses, and that such defects will be detected only by careful analytical meth- odology. Yet another method of human study might use experimental viral infections in association with inhalant exposures. The use of healthy subjects for experimental viral infections such as influenza and respi- ratory syncytial virus is an accepted prac- tice (see, for example, Bell et al. 1957; Johnson et al. 1961; Feery et al. 1979), particularly to evaluate vaccine efficacy. Combining chamber exposures with ex- perimental viral infections may be a useful method to evaluate the effects of emissions on respiratory pathogenicity of these agents. For example, the effect of inhalants on severity and duration of infection, and on minimum size of infective inoculum, could be determined. Again, ethical consid- erations must be addressed in designing such studies. Furthermore, the dose range maintained for inhaled gas exposures should be low enough to address the issue of relevance to automotive emissions. In summary, studies should be designed for human subjects as well as animal mod- els. Although dose-response studies can be carried out over much broader ranges of pollutant concentration in animals, the more direct clinical relevance of human data argues for strong consideration of at least some analyses being carried out in human subjects. Ideally, subjects exposed to high levels of automotive emissions could be compared with subjects from rural or other areas of low-level exposure, but, if this is not possible, chamber exposure methods could be used. Infectivity Models. Despite the large body of information regarding susceptibil- ity to infection in animals exposed acutely or chronically to inhaled NO2 or O3, ques- tions regarding lung defenses during exper- imental infection remain unanswered. For example, little or no information exists about defenses against several extremely common respiratory pathogens, including mycoplasma, respiratory syncytial virus, Legionella s p., S. pneumonias, and H. inf u- enzoe. Experimental models of infection with each of these pathogens have been reviewed by Pennington (1986) and could be used for analyses similar to those for Klebsiella and influenza virus.

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James E. Pennington 511 Recommendation 2. Perform experi- mental studies in animals using common respiratory pathogens. Altered-Host Studies. ~1 ~1 The influence of altered-host status on lung susceptibility to infection after exposure to components of automotive emissions is poorly under- stood. Ethical considerations preclude bronchoscopic analyses in high-risk pa- tients exposed to pollutant gases, but nu- merous animal models of immunosuppres- sion (Pennington 1985), chronic lung damage (Snider et al. 1986), or extremes of age (Sherman et al. 1977; Esposito and Pennington 1983) exist from which valu- able information may be obtained. ~ ~ , Recommendation 3. Animal models should be used to determine whether al- tered-host status or extremes of age influ- ence the lung's susceptibility to infection after exposure to automotive emission components. Survival or lung clearance during experimental infections could be evaluated as well as the additive influences of gas exposure plus underlying host defect on lung defense components (for example, alveolar macrophages, inflammatory reac- tion in airways after infection, bacterial adherence to respiratory mucosa). Antiviral Defense Mechanisms. fudging from current epidemiologic data, the most likely source for increased infection in in- dividuals exposed to high levels of automo- tive emissions is viral. As discussed above, this conclusion is by no means proven, but sore throat, coryza, and cough without sputum are the symptoms most frequently noted in such studies. As such, high prior- ity must be placed on analysis of the effects of inhaled emission components on antivi- ral defenses in the respiratory tract. Some early data suggested that NO2 exposure suppresses interferon production by alveo- lar macrophages (Valand et al. 1970; Acton and Myrvik 1972) and decreases lung resis- tance to influenza (Henry et al. 1970) or parainfluenza (Williams et al. 1972~. The NO2 levels used in those studies, however, were high (5 to 25 ppm). Using the more sophisticated methodologies now available for analysis of antiviral activities (Sissons and Oldstone 1985), it may be possible to detect adverse effects on lung defenses at levels of gas exposure relevant to ambient concentrations. Such studies may be ideal for human subjects because low levels of gas (for example, NO2) could be used in chamber exposures, followed by collection of large numbers of cells by bronchoscopic ravage. This approach may be especially useful because obtaining enough of the appropriate cell population (for example, NK cells, K cells, cytotoxic T cells) may be impossible in small animals but feasible in humans (Pinkston et al. 1983; Robinson et al. 1984~. Naturally, animal studies of antiviral de- fense mechanisms also could be carried out in experimentally exposed groups, allow- ing more convenient dose-response studies. If mice are used, pooling of lung specimens would probably be necessary to obtain enough cells for well-controlled, replicate assays. If larger animals such as guinea pigs and rabbits are used, difficulties in obtain- ing appropriate reagents for analysis (for example, monoclonal antibodies for NK cells) may be encountered. Especially important in these studies would be the analysis of numbers and function of pulmonary NK cells (Stein- Streilein et al. 1983; Bukowski et al. 1984), cytotoxic T lymphocytes (Ennis et al. 1978), antibody-dependent cellular cyto- toxicity (using alveolar macrophages and K cells) (Hunninghake and Fauci 1977; Kohl et al. 1977), and interferon cat, ,l3, and fly production by lung cell populations (Rob- inson et al. 1985~. Since available data show no viral antibody responses in animals ex- posed to relevant levels of NO2, it is less likely that studies of antibody response will be helpful. Analysis of pulmonary secretory antibody levels may be useful, however. Recommendation 4. Components of respiratory antiviral defense mechanisms should be analyzed with respect to impair- ment from exposure to automotive emis- sion products. Immunologic Modulators (Cytokines). A rapid expansion has occurred recently in

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512 Effects of Automotive Emissions on Susceptibility to Respiratory Infections our understanding of how various immu- nologic cell populations communicate and modulate cellular responses to infectious (and other antigenic) agents. Researchers have shown that interleukin-1 (Wewers et al. 1984), interleukin-2 (Pinkston et al. 1983), and various interferons (Robinson et al. 1985), are produced by pulmonary cells and may be affected by various disease states, including infection (Lamontagne et al. 1985) and sarcoidosis (Pinkston et al. 1983; Wewers et al. 1984; Robinson et al. 1985), or by immunosuppressive drugs (Salomon et al. 1985~. Little is known regarding the effects of automotive emis- sion exposure on these important cyto- kines. Recommendation 5. Animal and/or hu- man lung cell populations should be eval- uated for the effect of inhaled gases on the production of interleukin-1 by alveolar macrophages, interleukin-2 by T lympho- cytes, and the production of various in- terferons by alveolar macrophages and lymphocytes. Availability of enough bron- choalveolar lymphocytes may be a limiting factor, and, for that reason, human speci- mens may be especially valuable. Alveolar Macrophage Functions. Infor- mation on alveolar macrophage functions with regard to the viral defense mecha- nisms and cytokines discussed above has increased considerably in recent Years (Hunninghake et al. 1979, 1985~. For ex- ample, expression of the type 2 histocom- patibility antigen determinant on the mac- rophage surface is now known to be critical for alveolar macrophage processing of an- tigenic and infectious challenges (Mason et al. 1982~. In fact, the role of alveolar mac- rophages in accessory cell functions is be- coming increasingly clear (Toews et al. 1984~. Also, the capacity of interferon By treatment to activate alveolar macrophages for microbicidal activity has been closely associated with their defense function (Schaffner 1985~. Furthermore, the capacity for respiratory burst (for example, super- oxide anion production) is known to be directly related to alveolar macrophage mi- crobicidal capacity (Hoidal et al. 1979; Pen nington 1985~. Other metabolic activities, such as the production of chemotactic leu- kotrienes (leukotriene B4) (Martin et al. 1984), as well as complement components (Pennington et al. 1979), and a low-molec- ular-weight neutrophil-activating factor (Pennington et al. 1985), have been identi- fied for alveolar macrophages. Finally, the intrinsic motility of alveolar macrophages (Pennington and Harris 1981), plus their capacity to produce neutrophil chemotactic factors (Merrill et al. 1980), clearly relate to lung defense activities. It is safe to say that virtually no information is available regard- ing the effects of automotive emission com- ponents on these important alveolar mac- roph.age products and functions, so the possibility exists that one or more of them may be significantly impaired by low and relevant levels of air pollutants. Recommendation 6. The effects of au- tomotive emission components on alveolar macrophage function should be determined. Mucosal Binding. Several studies already mentioned in the Background section have described morphologic and functional de- fects in mucociliary apparatus of airway mucosa in intact animals or explanted tis- sues exposed to NO2. These defects might adversely affect mucociliary clearance of potential infectious agents, but another mechanism altered mucosal binding properties might also predispose to infec- tion. Increased mucosal binding aff~nity for pathogenic bacteria occurs under a number of stress conditions including surgery (Woods et al. 1981a), necessity for intensive care unit management (Woods et al. 1981b), and malnutrition (Niederman et al. 1984~. Increased adherence of gram-nega- tive bacilli to airway mucosa predisposes to subsequent respiratory infections in certain individuals (Johanson et al. 1972~. The impact of emission exposures on binding affinity of airway mucosa for potential pathogenic infectious agents is unknown. The adherence properties of airway cells obtained from animals or humans experi- mentally exposed to relevant levels of au- tomotive emission components should be studied. Such assays could be performed by

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James E. Pennington 513 using radiolabeled, gram-negative bacilli and quantitating their binding affinity for buccal or tracheobronchial cells removed by scraping and placed into tissue cultures (Niederman et al. 1984; Woods et al. 1981a, b), or tracheal explant cultures (Ramphal and Pyle 1983~. These assays are relatively insensitive due to high background radio- activity, and it may be impossible to detect very subtle alterations in mucosal binding properties. ~ Recommendation 7. Mucosal cell bind- ing affinity for respiratory pathogens should be studied after exposure to relevant concentrations of emission components. Summary The basic hypothesis under consideration is that exposure to automotive emissions re- sults in increased susceptibility to respira- tory infections. The rationale for exploring this hypothesis is that if it is true, then special programs for vaccination, clinical monitoring, and occupational counseling of high-risk groups should be undertaken. Current data are insufficient to test this hypothesis, but numerous studies suggest that it may be true. For operational pur- poses, the components of automotive emis- sions of interest include nitrogen oxides (especially NO2), CO, 03, and particu- lates. In addition, interest in aldehydes has increased in expectation that methanol fuel sources may be used in the near future. Two basic research approaches have been used in past studies to explore this hypoth- esis. One approach has involved epidemi- ologic surveys of populations exposed to varying levels of known components of automotive emissions. Frequency and se- verity of respiratory symptoms, as well as performance on spirometry testing, were monitored and compared but results are conflicting. Outdated methods for moni- toring ambient gas levels, as well as lack of serologic or cultural tests for diagnosing infection, are justified criticisms of these . studies. Future epidemiologic studies should take these problems into account. Also, future studies may wish to identify and focus attention on high-risk popula- tions such as chronic lung disease patients, the immunosuppressed, and the elderly. The second approach has been to expose animals to inhaled gases, commonly NO2 or 03, and then to study the effects of exposure on lung defenses against infection. Numer- ous studies have demonstrated decreased sur- vival from experimental bacterial or viral infection and decreased capacity to kill bac- teria in the lungs of animals exposed to pollutant gases. Levels of NO2 ' 0.5 ppm (often much higher), however, were re- quired to demonstrate these adverse effects. Infectivity studies with animal models may not be sufficiently sensitive to identify more subtle defects in lung defense which might result from lower levels of gas exposures. To address this possibility, individual components of the lung defense system have been evaluated in specimens obtained from exposed animals. To date, most stud- ies have focused on alveolar macrophages, although some studies have examined mor- phologic effects of gases on mucociliary tissues and effects on systemic antibody responses. As in the infection models, im- paired defenses have been identified only after high (that is, - 2.0 ppm) and often prolonged NO2 exposure. It is fair to point out, however, that newer assays have been developed (for example, NK cell function, interleukin-1 and -2 production, cell migra- tion) that may be better suited to detect subtle, yet potentially important, defects in lungs exposed to low-level emission com- ponents. Furthermore, it is now safe and ethical to obtain human lung specimens using the flexible fiberoptic bronchoscope. Thus, future chamber studies with human subjects could be followed by an evaluation of bronchoscopic specimens. In planning such studies, it should be kept in mind that adverse effects on one component of lung defense might be compensated for by aug- mented activity of other defense systems. The complexity of this type of analysis cannot be overstated.

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514 Ejects of Automotive Emissions on Susceptibility to Respiratory Infections Summary of Research Recommendations HIGH PRIORITY On the basis of current information, the following studies are most likely to yield useful data and, given limited funding re- sources, most highly recommended. Recommendation 1 Epidemiologic survey in high-risk populations exposed to vary ing levels of automotive emissions or components. The design of such surveys should include populations with defined exposure, specific study groups, adequate histories, diagnostic tests for infec tion, and measures of severity. Recommendation 4 Evaluation of components of respiratory antiviral defense mech anisms. This analysis could be done in humans or animals exposed to emission components under controlled conditions. Studies most likely to yield useful new information would be numbers and function of pulmonary NK cells and cytotoxic lymphocytes; interferon production by alveolar macrophages and lymphocytes; and antibody-dependent cellular cytotoxic activity of Fc receptor bearing lung cells (that is, alveolar macrophages and K lympho cytes). MODERATE PRIORITY Studies that include recent developments in methodology may allow detection of more subtle defects, particularly at relevant emission exposure levels. Recommendation 5 Assays of immunologic modulator production by alveolar mac rophages (interleukin-1, interferon) and pulmonary lymphocytes (interleukin-2, interferon). As before, chamber studies with human subjects or animal models could be used. - Recommendation3 Altered-host infection models. The influence of altered-host status on lung susceptibility to emission components is important. Animals at extremes of age, immunosuppressed, or with experi mentally induced chronic lung damage, should be studied to evaluate the effects of low-level exposures on lung defenses against infection. Recommendation 6 Specialized alveolar macrophage functions, such as chemotaxis, production of complement and chemotactic factors, accessory cell function, and capacity for respiratory burst. Chamber studies with human subjects or animal models could be used. LOW PRIORITY These studies are similar to studies already performed which have shown negative results at low emission levels (infection model), or utilize relatively insensitive methodologies. However, if

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James E. Pennington 515 funding is available, the indicated modifications of study may provide new information. Recommendation 7 Mucosal binding affinity. Human or animal respiratory cell binding affinity for respiratory pathogens should be studied after exposure to relevant concentrations of emission components. Recommendation 2 Infection models using common human pathogens. Studies using viral agents, mycoplasma7 Legionella sp., S. pneumoniae, and H. in.f uenzoe for experimental infections in exposed animals might over more relevant information than the numerous past studies using Klebsiella and S. aureus. References Acton, J. D., and Myrvik, Q. N. 1972. Nitrogen dioxide effects on alveolar macrophage, Arch. Envi- ron. Health 24:4~52. Astry, C. L., and Jakab, G. J. 1983. The effects of acrolein exposure on pulmonary antibacterial de- fenses, Toxicol. Appl. Pharmacol. 67:49-54. Bell, J. A., Ward, T. G., Kapikian, A. Z., Shelokov, A., Reichelderfer, T. E., and Huebner, R. J. 1957. Artificially induced Asian influenza in vaccinated and unvaccinated volunteers, J. Am. Med. Assoc. 165:1366-1373. Bukowski, J. F., Woda, B. A., and Welsh, R. M. 1984. Pathogenesis of murine cytomegalovirus in- fection in natural killer cell-depleted mice, J. Virol. 52:119-128. Burrows, B., Knudson, R. J., and Lebowitz, M. D. 1977. The relationship of childhood respiratory illness to adult obstructive airway disease, Am. Rev. Respir. Dis. 115:751-760. Dixon, R. E. 1985. Economic costs of repiratory tract infections in the United States, Am. ]. Med. 78(Suppl. 6B):4~51. Ehrlich, R. 1966. Effect of nitrogen dioxide on resis- tance to respiratory infection, Bacteriol. Rev. 30: 604-614. Ehrlich, R., and Henry, M. C. 1968. Chronic toxicity of nitrogen dioxide. I. Effect on resistance to bac- terial pneumonia, Arch. Environ. Health 17:860-865. Empey, D. W., Laitinen, L. A., Jacobs, L., Gold, W. M., and Nadel, J. A. 1976. Mechanisms of bron- chial hyperreactivity in normal subjects after upper respiratory tract infection, Am. Rev. Respir. Dis. 113:131-139. Ennis, F. A., Wells, M. A., Butchko, G. M., and Albrecht, P. 1978. Evidence that cytotoxic T cells are part of the host's response to influenza pneumo- nia,J. Exp. Med. 148:1241-1250. Esposito, A. L., and Pennington, J. E. 1983. Effects of aging on antibacterial mechanisms in pneumonia, Am. Rev. Respir. Dis. 128:662~67. Correspondence should be addressed to James E. Pennington, Clinical Research Department, Cutler Laboratories, P.O. Box 1986, Berkeley, CA 74701. Feery, B. J., Evered, M. G., and Morrison, E. I. 1979. Different protection rates in various groups of vol- unteers given subunit influenza virus vaccine in 1976,J. Infect. Dis. 139:237-241. Fenters, J. D., Findlay,J. C., Port, C. D., Ehrlich, R., and Coff~n, D. L. 1973. Chronic exposure to nitro- gen dioxide. Immunologic, physiologic, and patho- logic effects in virus-challenged squirrel monkeys, Arch. Environ. Health 27:8~89. Ferris, B. G. 1978. Health effects of exposure to low levels of regulated air pollutants. A critical review, J. Air Pollut. Control Assoc. 28:482-497. Freeman, G., Crane, S. C., Stephens, R. .J., and Furiosi, N. J. 1968. Environmental factors in em- physema and a model system with NO2, Yale J. Biol. Med. 40:566-575. Fujimaki, H., and Shimizu, F. 1981. Effects of acute exposure to nitrogen dioxide on primary antibody response, Arch. Environ. Health 3:114-119. Gardner, D. E., Holzman, R. S., and Coff~n, D. L. 1969. Effect of nitrogen dioxide on pulmonary cell population,J. Bacteriol. 98:1041-1043. Gardner, D. E., Pfitzer, E. A., Christian, R. T., and Coff~n, D. L. 1971. Loss of protective factor for alveolar macrophages when exposed to ozone, Arch. Intern. Med. 127:107~1084. Garibaldi, R. A. 1985. Epidemiology of community- . acquired respiratory tract infections in adults, Am. J. Med. 78(Suppl. 6B):32-37. Glezen, W. P., and Denny, F. W. 1973. Epidemiology of acute lower respiratory disease in children, N. Engl. J. Med. 288: 498~505. Goldstein, E., Eagle, C., and Hoeprich, P. D. 1973. Effect of nitrogen dioxide on pulmonary bacterial defense mechanisms, Arch. Environ. Health 26: 202-204. Green, G. M. 1970. TheJ. Burns Amberson lecture In defense of the lung, Am. Rev. Respir. Dis. 102: 691-703. Green, G. M., Jakab, G. J., Low, R. B., and Davis, G. S. 1977. Defense mechanisms of the respiratory membrane, Am. Rev. Respir. Dis. 115:479-514. Greene, N. S., and Schneider, S. L. 1978. Effects of NO2 on the response of baboon alveolar macro- phages to migration inhibitory factor, J. Toxicol. Environ. Health 4:869-880.

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516 Effects of Automotive Emissions on Susceptibility to Respiratory Infections Henderson, F. W., Collier, A. M., Denny, F. W., Semor, R. J., Sheather, C. I., Conley, W. G., and Christian, R. M. 1979. The etiologic and epidemi- ologic spectrum of bronchiolitis in pediatric prac- tice,J. Pediatr. 95:183-190. Henry, M. C., Ehrlich, R., and Blair, W. H. 1969. Effect of nitrogen dioxide on resistance of squirrel monkeys to Klebsiella pneumonias infection, Arch. Environ. Health 18:580-587. Henry, M. C., Findlay, J., Spangler, J., and Ehrlich, R. 1970. Chronic toxicity of NO2 in squirrel mon- keys. III. Effect on resistance to bacterial and viral infection, Arch. Environ. Health 20:56~570. Hoidal, R. ]., Fox, R. B., and Repine, J. E. 1979. Defective oxidative metabolic responses in vitro of alveolar macrophages in chronic granulomatous disease, Am. Rev. Respir. Dis. 120:613018. Holt, P. G., Finlay-Jones, L. M., Keast, D., and Papadimitrou, J. M. 1979. 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