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Chapter 2 Assessment of Health Effects

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2 ASSESSMENT OF HEALTH EFFECTS I NTRODUCTION Epidemiologic studies usually seek to determine the relation between exposure and particular health effects. Epidemiologists use two types of measures to assess health effects: clinical data derived from medical diagnoses, often presented as rates of mortality or morbidity in established clinical diagnostic categories, such as chronic bronchitis and lung cancer; and data that reflect biologic changes that are not detected clinically. Data of the second type, sometimes called subclinical or early marker data, are obtained by measuring physiologic, bio- chemical, or morphologic features or by analyzing symptoms reported on questionnaires. We do not address the problem of determining exactly what constitutes an adverse health effect in an epidemiologic study, a topic recently analyzed by a Committee of the American Thoracic Society, with reference to the Clean Air Act.t Although annoyance or esthetic effects (such as odors or impaired visibility) undoubtedly affect human welfare, they are not discussed in this chapter, because they are not typical end points for epidemiologic study. Biologic models of diseases and of the relationship of exposure to pathologic response, whether implicit or explicit, underlie the selection of outcome measures in epidemiologic studies. The more accurately the available models can describe, for instance, the temporal relation- ship of exposure to response or the reasons for variation in susceptibility, the easier it is to choose health effects data that are valid and precise. 37

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This chapter reviews briefly some of the most important adverse health effects that might be associated with air pollution. It then discusses the various kinds of health effects data needed for future epidemiologic studies. After considering problems of data quality and availabil- ity and opportunities for improvement, it discusses how the use of these data is constrained by the incompleteness of knowledge of disease biology and by limitations in the instruments used to measure specific effects. Finally, it addresses the potential use in epidemiologic studies of biologic markers of respiratory health effects. HEALTH EFE ECTS OF CONCERN This chapter focuses on respiratory effects, because clinical and epidemiologic studies and animal experiments have shown that the major effects of air pollutants are on the respiratory system. Health effects are divided into four categories: acute respiratory effects, chronic respiratory effects, excluding cancer; lung cancer; and effects on other organ systems. Acute effects have a sudden onset and are relatively short-lived, lasting from a few minutes to a few days. Examples are an asthmatic attack and an exacerbation of symptoms of chronic obstructive pulmonary disease (COPD) Chronic effects persist over an extended time, generally years. Examples are a permanent respiratory loss from a decreased rate of lung growth in children and the syndrome COPD itself. These definitions of "acute. and "chronic n are somewhat arbitrary and do not provide information about the time course of antecedent exposures. For example, acute effects might be attributable to short-term fluctuations in pollutant concentrations or to cumulative exposures over an extended period. Similarly, although chronic effects are normally associated with long exposures, they can occur after single or small numbers of exposures. Some acute effects are discrete, and others are exacerbations of chronic conditions. In most instances, the relationship of acute events to the progression of chronic disease is not well understood. In this report, "exacerbations generally refers to an increase in fre- quency or severity of symptoms, without any presumption of faster progression of an underlying disease. 38

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Attempts to relate acute and chronic health conditions to air pollution have to overcome both shared and unique types of methodologic problems. Investigators of acute effects usually suspect and examine exposures that have occurred in the previous hours or days. However, many factors that can influence the risk of illness increase and decrease with pollution (for example, temperature and photochemical oxidants), making it hard to separate the effect of air pollution itself. Chronic effects are usually related to exposure that persists over many years; even with current sophisticated diagnostic tech- niques, it is virtually impossible to pinpoint the onset of disease and extremely difficult to identify persons with early stages of disease. The Committee has tried to answer two questions for each of the health effects discussed here: . How is the adverse health effect defined and categorized? The way in which a disease process is conceptualized or modeled and the existence of gaps in knowledge of its pathophysiology and natural history have important implications for the design and conduct of epidemiologic studies. What evidence links the health effect to air pollution and suggests that the link is a plausible concern for the future? The purpose is not to determine whether existing evidence is conclusive, but rather to determine whether it is sufficient to warrant further study. ACUTE RESPIRATORY EFFECTS Asthma and Airway HyperreactivitY Asthma is characterized by intermittent obstruction of airflow that reverts either spontaneously or with treat- ment. Physiologically, it is manifested by general narrowing of the air passages due to increased tone of the bronchial smooth muscle and by plugging of the airways with thick, excessive mucus. Clinical symptoms are paroxysms of shortness of breath, coughing, and wheezing. Asthma is usually an episodic disease, with acute attacks being interspersed with relatively symptom-free periods. Many asthmatics have abnormalities 39

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of pulmonary function even while symptom-free; a few, considered chronic asthmatics, are essentially always symptomatic. No standard definition of asthma for epidemiologic purposes has been established. Approximately half of patients with asthma have atopic (allergic) asthma, which depends on an antibody response to a specific, identifiable antigen. Once sensitivity (the formation of antibodies) has developed, even minute amounts of the antigenic material induce symptoms. Many different inhalants have been identified as primary sensitizers in asthma, including large complex proteins, such as ragweed and animal dander, and low-molecular- weight synthetic chemicals, such as toluene diisocyanate.i 3 ~ Asthma that does not appear to be due to allergy to specific substances can arise from a complex set of genetic and environmental factors. Whatever its origin, asthma is often exacerbated by a variety of nonspecific stimuli, including respiratory infection, exercise, cold air, and emotional stress. Asthmatics vary greatly in their responses to these factors, as well as in their responses to conventional forms of therapy. This heterogeneity must be considered by epidemiologists. _ _ _ , _ ,, The precision of studies will advance as groups with particular response characteristics are identified. For instance, there is evidence that some asthmatics develop prolonged responses due to inflammatory cells in the airways.8 2 There is reason to believe that clarification of distinct categories will result from current breakthroughs in the understanding of biochemical mediators of airway response, such as the arachidonic acid metabolites.5 2 Air pollution can increase the risk of an attack in persons with established asthma, but it is not known whether air pollution itself is a cause of asthma. Little research has focused on the latter question. Some con- temporary studies have reported increased asthmatic attack rates with greater pollution, but others have found no such correlation. Whittemore and Korn used novel statis- tical methods for asthma epidemiology to analyze diaries kept by a panel of 443 asthmatics in the Los Angeles area during 1972-1975.~7 3 The most significant predictor of attacks was the presence of an attack on the previous day. However, on the average, panelists also tended to have increased numbers of attacks on days with high 40

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oxidant and particulate pollution, on cool days, and during the first 2 months of the study. In contrast, Goldstein and co-workers found that visits to the emergency room for asthma in New York City were more common in autumn and on Sundays and Mondays, but were not correlated with concentrations of outdoor sulfur dioxide, SO2, or particles. They suggested that indoor exposures trigger the attacks.55 s 6 Bronchial hyperreactivity is an abnormal degree of airway narrowing in response to a stimulus that causes little or no change in normal airways. It is always present in asthma, and followup studies of workers who develop asthmatic reactions to chemicals in the workplace have demonstrated persistent bronchial hyperreactivity even after the overt symptoms of asthma ceased.2 3 When apparently normal persons inhale a nonspecific broncho- constrictor, such as methacholine, some are hyperreactive without meeting the clinical criteria for asthma.53 Airway reactivity seems to have a unimodal distribu- tion; within a population, there appears to be a continuum from the most reactive to the least reactive persons, rather than a group of hyperresponders and a separate group of normal responders.26 The health implications of airway hyperreactivity without asthma are not known, and the relationship of this state to development of other diseases, such as COPO, or to severity of respiratory infection needs further exploration. 6 9 In controlled-exposure studies, somewhat surprisingly, volunteers with asthma or with COPD (subjects who, according to current disease models, would be expected to have increased airway reactivity) did not seem to be more susceptible than healthy volunteers to the effects of ozone, 03, at low concentrations.99 use However, SCk at as low as 0.4 ppm and nitrogen dioxide, N02, at as low as 0.3 ppm have induced symptoms or increased airway resistance in some asthmatics undergoing heavy exercise.~4 t Persons without respiratory disease generally do not show effects below 1 ppm.~.s Good animal models of chronic human asthma do not exist, although acute episodes of bronchoconstriction can be induced in animals by inhalation of ambient air pollutants.59 41

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Respiratory Infections and Related Effects Upper respiratory infections include colds, influenza, and sore throats; almost all upper respiratory infections are caused by viruses. Lower respiratory infections include pneumonia and acute bronchitis, which are often caused by bacteria. Early studies clearly demonstrated a link between high concentrations of reducing pollutants-- e.g., SO2 and total suspended particles (TSP)--and respiratory infection in children.3 6 Several recent studies have shown that current concen- trations of specific pollutants might also be associated with increases in respiratory infections and symptoms in exposed populations. For example, Bates and Sizto studied hospital admissions for nine respiratory and six nonrespi- ratory conditions at 79 hospitals in southern Ontario during January, February, July, and August in 1974, 1976, and 1978. t3 Admission data were compared with pollutant concentrations at 15 air sampling stations in the area. The strongest correlation was between concentrations of sulfates and total respiratory admissions, and the significant correlation with sulfates remained when asthma admissions were excluded from analysis. Evidence of a relationship between acute respiratory infection and exposure to NO2 from gas cooking stoves is suggestive, but inconsistent and inconclusive. An early report from the Harvard Air Pollution Health Study indicated an increased risk of respiratory infection before the age of 2 associated with exposure to gas cooking in the home. A later analysis, based on a larger sample, showed this risk to be still present, but no longer statistically significant. 7 2 In another series of studies, Melia and co-workers found a higher prevalence of respiratory infection in children aged 5-10 living in homes with gas stoves than in homes with electric stoves. This effect persisted after adjustment for parental smoking. Results of animal studies suggest that low, and sometimes brief, exposures to pollutants increase susceptibility to infection. The animal infectivity model appears to be extremely sensitive for demonstrating pollution effects. Numerous reports have shown that low concentrations of NO2 and O3 lower resistance of animals to bacterial infection.38 .8 7 7 ~ ~ ~ Such 42

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lowering has been seen in mice exposed to NO2 at 0.5 ppm for 6 months (6 hours/day) 3 8 and to O3 at 0.08 ppm for 3 hours. Exercised mice were more sus- ceptible than nonexercised mice.77 These effects were seen at concentrations that humans might encounter, par- ticularly during peaks of exposure. Thus, the findings could be relevant to epidemiologic studies that show more respiratory infections in areas of greater air pollution, although such infections in humans are most often viral, rather than bacterial. Animal models for studying the effect of air pollutants on susceptibility to viral agents have not yet been developed. Transient Changes in Pulmonary Function Pollution can cause transient changes in pulmonary function in humans both in the laboratory and under natural conditions. Changes measured in children at a summer camp include reduction in the maximal volume of air expired in 1 second (FEV1), the peak expiratory flow rate (PEFR), and the forced vital capacity (FVC). Decrements of a few percent were found on days when O3 concentrations were higher, particularly above 100 ppb, and an exposure-response relationship between O3 and degree of transient change in pulmonary function tests was reported.~t t02 Transient effects of short-term exposures have also been demonstrated in clinical studies with healthy volunteers. O3 has shown effects at concentrations likely to be attained in polluted air. For example, O3 at 0.3 ppm produced symptoms of irritation of the respiratory tract and decreases in pulmonary function during 2-hour exposures of normal volunteers. Avol et al. detected effects of O3 at 0.16 ppm with heavy exercise,. and McDonnell et al. detected effects at 0.2 Pam. 2 m e acute response to O3 varies greatly among individuals. Horvath and co-workers reported that FEV decreased by 2-48% in 24 normal subjects exposed to O3 at 0.42 ppm for 2 hours while they performed intermittent moderate exercise. 7 4 McDonnell and associates reported similar ranges. 12 McDonnell and co-workers showed that this intersubject variability is apparently intrinsic, inasmuch as it persisted over periods of months. 43

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The basis for this variation among normal subjects is unknown, but it shows that some "normal" persons can be especially sensitive to O3 and that this sensitivity is detectable in repeated measurements. This finding has implications for the design of epidemiologic studies of air pollution, in which accurate definition of the population at risk is important. Summary Various components and patterns of current air pol- lution cause acute respiratory symptoms, including asthmatic attacks and increases in respiratory infection, especially among children. Transient decreases in pul- monary function have been seen in sensitive or exercising people exposed to O3 and SO2 at low concentrations. Further study is needed to understand the basis of individual variation in response and to determine whether these acute effects have a long-term impact on lung function. Whether airway hyperreactivity is related to accelerated decrease in lung function or to impairment in lung growth has not been determined. The resolution of these questions will have a direct impact on possibilities for and design of epidemiologic studies of air pollution and acute health effects. CHRONIC ~SPI=TORY EFFECTS Three chronic effects of air pollution of great concern are the set of disorders called chronic obstructive pul- monary disease (COPD), diminished growth of lung function in children, and accelerated decrease in pulmonary function with age. Chronic Obstructive Pulmonary Disease The general use of the convenient, but imprecise, term chronic obstructive pulmonary disease and the widespread application of a single test of lung function, FEV1, combine to give a false impression of simplicity to the study of this disease. The syndrome of COPD has several main components: 44

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Chronic mucus hypersecretion (used synonymously with "chronic bronchitisn), with hypertrophy of bronchial mucous glands and changes in small airways.ls 6 Its leading symptom is a chronic productive cough. Chronic bronchitis is usually ascertained in epidemiologic studies when a productive cough (one that produces sputum or phlegm) is present for at least 3 consecutive months per year for at least 2 years, provided that it is not attributable to other lung or heart disease .6 ~ Only in some people does chronic bronchitis lead to clinically important COPD, manifested by recurrent pulmonary infection, chronic airflow limitation, or both. Alveolar destruction, or emphysema. The chief symptom is breathlessness without a cough. The essential pathophysiologic element in emphysema--breakdown of alveolar walls--is apparently caused by proteolytic enzymes released by macrophages or polymorphonuclear leukocytes.~9 At present, this irreversible change in lung structure can be diagnosed with certainty only at autopsy. 157 Small-airway disease. This condition is seen most often as a component of COPD, but it also occurs in other diseases or as a result of the inhalation of irritants. It is thought to reflect the presence of inflammation in the respiratory bronchioles. 2 6 Its importance as perhaps the earliest lesion in smoking- induced COPD has been recognized only recently. 7 2 Considerable obstruction may be present in airways smaller than 2 mm in diameter before changes in FEV are detected.29 Thus, small-airway disease plays a major role in a current disease model that might be applicable to air pollution studies. Some persons with COPD also have airway hyperreactivity and bronchospasm; many of these are long-term asthmatics who have developed a degree of fixed airway obstruction. These components can exist alone or in any combination Widespread use of the term COPD came about because it is difficult for clinicians to separate the roles of the separate components in individual patients or in popula- tions. Some persons have evidence of considerable irreversible damage to lung tissue before breathlessness, the cardinal symptom of COPD, appears. 45

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