Epidemiology and Air Pollution (1985)

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ASSESSMENT OF HEALTH EFFECTS 37 2 ASSESSMENT OF HEALTH EFFECTS INTRODUCTION 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, biochemical, 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.1 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 relationship 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. 

ASSESSMENT OF HEALTH EFFECTS 38 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 availability 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 EFFECTS 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” 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, “exacerbation” generally refers to an increase in frequency or severity of symptoms, without any presumption of faster progression of an underlying disease. 

ASSESSMENT OF HEALTH EFFECTS 39 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 techniques, 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 treatment. 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 

ASSESSMENT OF HEALTH EFFECTS 40 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.131 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.82 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.52 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 contemporary studies have reported increased asthmatic attack rates with greater pollution, but others have found no such correlation. Whittemore and Korn used novel statistical methods for asthma epidemiology to analyze diaries kept by a panel of 443 asthmatics in the Los Angeles area during 1972-1975.173 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 

ASSESSMENT OF HEALTH EFFECTS 41 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 56 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.23 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 distribution; 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 COPD, or to severity of respiratory infection needs further exploration.69 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, O3, at low concentrations.99 151 However, SO2 at as low as 0.4 ppm and nitrogen dioxide, NO2, at as low as 0.3 ppm have induced symptoms or increased airway resistance in some asthmatics undergoing heavy exercise.14 100 Persons without respiratory disease generally do not show effects below 1 ppm.145 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 

ASSESSMENT OF HEALTH EFFECTS 42 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.36 Several recent studies have shown that current concentrations 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 nonrespiratory conditions at 79 hospitals in southern Ontario during January, February, July, and August in 1974, 1976, and 1978.13 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.172 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.116 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 48 77 118 Such 

ASSESSMENT OF HEALTH EFFECTS 43 lowering has been seen in mice exposed to NO2 at 0.5 ppm for 6 months (6 hours/day)38 and to O3 at 0.08 ppm for 3 hours.118 Exercised mice were more susceptible than nonexercised mice.77 These effects were seen at concentrations that humans might encounter, particularly 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.101 102 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.12 Avol et al. detected effects of O3 at 0.16 ppm with heavy exercise,6 and McDonnell et al. detected effects at 0.2 ppm.112 The acute response to O3 varies greatly among individuals. Horvath and co- workers reported that FEV1 decreased by 2-48% in 24 normal subjects exposed to O3 at 0.42 ppm for 2 hours while they performed intermittent moderate exercise.74 McDonnell and associates reported similar ranges.112 McDonnell and co-workers showed that this intersubject variability is apparently intrinsic, inasmuch as it persisted over periods of months.111 

ASSESSMENT OF HEALTH EFFECTS 44 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 pollution cause acute respiratory symptoms, including asthmatic attacks and increases in respiratory infection, especially among children. Transient decreases in pulmonary 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 RESPIRATORY EFFECTS Three chronic effects of air pollution of great concern are the set of disorders called chronic obstructive pulmonary 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: 

ASSESSMENT OF HEALTH EFFECTS 45 • Chronic mucus hypersecretion (used synonymously with “chronic bronchitis”), with hypertrophy of bronchial mucous glands and changes in small airways.156 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.68 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.119 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 diseases105 or as a result of the inhalation of irritants. It is thought to reflect the presence of inflammation in the respiratory bronchioles.126 Its importance as perhaps the earliest lesion in smoking-induced COPD has been recognized only recently.72 Considerable obstruction may be present in airways smaller than 2 mm in diameter before changes in FEV1 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 populations. Some persons have evidence of considerable irreversible damage to lung tissue before breathlessness, the cardinal symptom of COPD, appears. 

ASSESSMENT OF HEALTH EFFECTS 46 In view of these difficulties, COPD is defined operationally, rather than pathologically. A common definition is that COPD is present when FEV1 is less than 65% of the predicted value and the FEV1:FVC ratio is less than 80% of predicted68 when predicted values are based on age, sex, race, and height. Hence, COPD may be considered synonymous with chronic airflow limitation. The selection of airflow limitation as the defining feature of the syndrome also appears to be the appropriate public health definition, because the loss of expiratory airflow is a better predictor of long-term survival than the presence of coughing and sputum production. Survival and morbidity are heavily influenced by the susceptibility of persons with COPD to respiratory infections, such as influenza, and those infections are likely to be more serious in them than in persons with normal lung function. Much has been learned about the components of COPD since the early 1950s, when chronic bronchitis was recognized clinically, but not considered important. Diagnosis of emphysema was difficult and considered unimportant, because it could not be treated. Pulmonary function tests were used in only a few centers, and had not been studied in detail. The ease of carrying out pulmonary function tests and the use of FEV1 as an indicator of COPD progression led to the relatively rapid definition of etiologic factors in COPD. Established etiologic factors are cigarette smoking; some occupational exposures, such as to coal, cotton dust, and toluene diisocyanate; advanced age; high concentrations of SO2 and particles; and genetic factors, such as deficiency of α1-antiprotease, which occurs in a very small percentage of the population and increases susceptibility to emphysema. Some evidence supports a history of respiratory infection in childhood as another risk factor.144 Higgins and co-workers have developed useful models for predicting chronic airflow limitation on the basis of age, sex, smoking history, and initial FEV1.70 The hypothesis that current air pollution is important in the etiology of COPD is plausible, but has not been adequately assessed. Few of the available studies could examine overt clinical disease or separate recent from long-past, heavier exposures. Furthermore, the design of some studies did not permit a distinction between an 

ASSESSMENT OF HEALTH EFFECTS 47 aggravating effect on existing disease and an etiologic effect. Chronic coughing and sputum production are commoner in areas with greater SO2 and particulate pollution than in less polluted areas,43 and some data suggest that increased oxidant pollution is associated with an increase in chronic wheezing.33 There is also inconclusive evidence of an increased occurrence of severe emphysema in more polluted cities.157 A recent study in several French cities found a higher prevalence of chronic respiratory symptoms in areas of greater SO2 pollution.60 Various lines of evidence from animal studies support the view that exposure to less severe air pollution can cause chronic lung disease. Researchers who have induced destruction of alveolar walls, the primary lesion in emphysema, by instilling proteolytic enzymes intratracheally have produced nearly identical lesions with long-term exposure to NO2 or O3.139 Chronic exposure to SO2 at very high concentrations (400-600 ppm) produces chronic bronchitis in rats and dogs,59 85 but the relation of this finding to human disease at ambient SO2 concentrations (the National Ambient Air Quality Standard is 0.03 ppm over a year) is unknown. Changes in Rate of Lung Function Growth and Decline Lung function normally develops at a predictable rate, reaching a plateau in the late teens and then decreasing at a relatively constant rate from the twenties onward.18 86 Various types of diseases result in deviations from this healthy function curve. Although an increase in the rate of loss of pulmonary function might indicate accelerated aging, its chief use is as an indicator of the risk of COPD. Similarly, the effects of retarded lung growth are not known, but young adults who achieve lower peaks of function presumably will have less reserve to resist the development of COPD. Lower rates of increase in lung function are not synonymous with retardation of lung growth, but the terms are sometimes used interchangeably because lung function is the only readily measurable indicator of the growth process. Recent analyses from the Harvard Air Pollution Health Study indicate that increased exposure to some indoor air pollutants contributes to slower lung development in children between the ages of 6 and 12.154 

ASSESSMENT OF HEALTH EFFECTS 48 For white males about 1.7 meters tall, normal is approximately 4,400 ml at the age of 25 and slowly declines to about 2,900 ml by the age of 70.161 Disability normally occurs when FEV1 is about 30% of the value expected at age 25.44 Smokers experience more rapid declines than nonsmokers. If smoking stops, the rate of decline becomes similar to that of nonsmokers, but the lost function is not recovered. An effect of pollution on the rate of decrease in FEV1, and thus presumably on the risk of COPD, can be inferred from cross-sectional data from Britain73 and, more recently, from France.60 In the latter study, average FEV1 in men was 3,600 ml in areas with SO2 concentrations averaging 10 µg/m3 and 3,400 ml in areas with SO2 averaging 100 µg/m3. A recent study of women who were long- term residents of an area of Los Angeles characterized by persistent photochemical oxidant pollution found a variety of chronic pulmonary function deficits after adjustment for smoking.84 A longitudinal study from the Netherlands found a faster decrease in FEV1 in a population near Rotterdam than in a rural population.168 Finally, on the basis of another longitudinal study, R. Detels et al. (unpublished manuscript) reported that current concentrations of air pollutants in Los Angeles are associated with measurable differences in the rate of change of some sensitive indexes of lung function. Summary Several factors make it particularly difficult to study the relationship of air pollution and chronic respiratory disease. Although the components of COPD can be more easily distinguished now than in the early 1950s, they still occur together often. Physicians often do not distinguish which components are present. And some causes of COPD, especially smoking, are more likely than ambient air pollution. The extent to which specific air pollutants interact with other factors, including smoking, to contribute to the various components of COPD or to abnormal rates of change of lung function has not yet been determined. Gaps in understanding of the natural history of lung diseases, especially COPD, constrain our ability to study 

ASSESSMENT OF HEALTH EFFECTS 49 the role of air pollution in causing them. We would like to know the relationship of long-term lung function to transient changes in lung function, to the presence of such symptoms as wheezing and coughing, to airway hyperreactivity (particularly because persons with hyperreactive airways generally have lower respiratory function than do normal persons), to respiratory infections in childhood, and to lower rates of lung growth in childhood. Why some smokers develop rapid deterioration in lung function while others with similar smoking patterns do not is a question of some relevance to air pollution epidemiology. The relationship of small-airway disease to COPD is also of great interest, in that small-airway disease can be an early lesion of pollution-induced COPD, as well as of smoking-induced COPD. Answers to these and related questions will have a critical effect on the development of better hypotheses and better methods for epidemiologic studies of air pollution, as well as on the definition of susceptible populations and the selection of appropriate measures of adverse health effects. LUNG CANCER Lung cancer is the most common form of malignancy among men in the United States, and it is becoming the most common among American women. In 1983, lung cancer caused approximately 120,000 deaths in the United States.165 Although operative mortality and the treatment of localized lung cancer appear to have improved slightly in recent years, the overall 5-year survival rate for lung cancer is still only 13%.148 The number of deaths caused by lung cancer must be reduced through prevention. Lung cancer has multifactorial origins and can result from interaction among several causal agents. Tobacco smoking is clearly the most important, followed by some occupational exposures.35 Passive smoking83 and indoor air pollutants (particularly radon gas and its decay products8) have also been strongly suggested to cause lung cancer. The proportion of lung cancers due to each of these factors is difficult to ascertain. Factors other than smoking account for smaller and more variable fractions of lung cancer than does smoking, and they sometimes seem 

ASSESSMENT OF HEALTH EFFECTS 50 to exert their effects interactively with smoking or other factors. For example, lung cancer occurs 5 times more commonly among nonsmoking asbestos workers than in the general population, but 53 times more commonly among smoking asbestos workers than in the general population.63 It occurs 6 times more commonly among nonsmoking underground uranium miners exposed to radon than in the general population, but 10 times more commonly among smoking miners than in the general population.170 Laboratory rats that failed to develop bronchogenic carcinomas after inhaling the known chemical carcinogen benzo [a]pyrene alone developed this malignancy after inhaling the carcinogen plus SO2.93 A paradoxical consequence of these multiple interactions is that any attempt to add the proportions of lung cancer cases attributable to each separate factor will tend to produce a total greater than 100%. A particular case of lung cancer, such as a case in a smoking asbestos worker who resided in a heavily polluted neighborhood, could legitimately be attributed to as many as three causal factors (and might have been prevented if exposure to any of them had been reduced). Thus, simple addition and subtraction to determine the proportions of lung cancer attributable to various causal factors will not suffice. Perhaps for that reason, published estimates of the fraction of lung cancer attributed to ambient air pollution have varied widely.35 83 Despite these uncertainties about the magnitude of the effect, several lines of evidence support the hypothesis that ambient air pollution contributes to the etiology of lung cancer.35 83 93 153 • Chemical analyses show carcinogens in polluted urban air, including polycyclic aromatic hydrocarbons (such as benzo[a]pyrene), asbestos, and arsenic.35 61 63 97 103 152 • Toxicologic studies have shown that extracts of materials from polluted ambient air can cause tumors, including lung tumors, in mice, rats, and hamsters; chromosomal damage; and injury to DNA.128 • Epidemiologic studies--including geographic studies,45 58 67 128 171 studies of the urban-rural gradient,54 67 153 point-source 

ASSESSMENT OF HEALTH EFFECTS 51 studies,19 20 108 120 135 147 studies of time trends,12 67 and migrant studies37 142--have often suggested an association between lung cancer and air pollution. Nearly all these epidemiologic studies failed to collect information from individual members of study populations on such important, potentially confounding factors as age, social class, tobacco smoking, and occupational exposures.153 Furthermore, statistical adjustment for differences in demographic features or for aggregate tobacco consumption generally reduces the size of the reported associations.54 67 153 Those issues have been particularly carefully assessed with regard to the “urban factor” (observed urban-rural gradient).54 67 In summary, it is plausible that ambient air pollution causes some part of the lung cancer incidence in the United States, but the size of the fraction is still not known.83 153 NONRESPIRATORY END POINTS Although the Committee has elected to focus on respiratory end points, air pollution is either known or thought to be a causal factor in other major health problems, and epidemiologic studies will be necessary if these problems are pursued. These problems generate methodologic questions that are quite different from those emphasized in the remainder of the report. Lead, Neurobehavioral Effects in Children, and Essential Hypertension Lead is ubiquitous in the modern environment.122 It is found in air, soil, water, dust, and food. Current environmental concentrations of lead are several thousand times higher than those of the prehistoric era.121 Lead can be absorbed by inhalation or ingestion. Inhalation is the more efficient of the two. The dose- response relationship between air lead and blood lead has been evaluated extensively. In adults without prior exposure to lead, each 1-µg/m3 increase in ambient air lead content appears to increase the blood content by approximately 1 µg/dL. In children, each 1-µg/m3 

ASSESSMENT OF HEALTH EFFECTS 52 increase in ambient air lead content causes a mean increase in blood lead content of 2 µg/dL or more.92 A major source of environmental lead in the last 50 years has been the release into the atmosphere of several hundred thousand tons of lead particles each year from the combustion of leaded gasoline.122 Ambient concentrations of airborne lead vary widely.162 Immediately adjacent to primary lead smelters in the United States, annual mean air lead concentrations as high as 93 µg/m3 have been recorded.92 Concentrations elsewhere are lower; because they are affected principally by the combustion of leaded gasoline, these concentrations correlate with the density of motor-vehicle traffic.80 Air lead concentrations in the United States have decreased substantially,5 beginning in the mid-1970s and in parallel with the reduction in lead content of American gasoline.5 17 A major subject of study in recent years has been whether ambient lead at current concentrations causes subtle neurologic toxicity in apparently asymptomatic persons. Several carefully controlled studies have shown decrements in IQ of 3-7 points in asymptomatic children with modestly increased lead burdens. These decrements remained after socioeconomic status, perinatal history, child-rearing practices, and other sociologic variables were accounted for in the analyses.123 124 149 160 In a recent review of these epidemiologic studies, Yule and Rutter considered it “highly implausible” that the consistent differences in IQ score could have arisen by chance176 and estimated that the exposure of children to lead in ordinary modern urban environments causes a mean decrement in IQ score of 2-5 points. Needleman et al. have noted that a 4.5-point shift in mean IQ score is associated with a tripling in the number of children with IQ scores below 80 and with a significant reduction in the number with superior IQ scores (above 125).124 Data from the second National Health and Nutrition Examination Survey (NHANES II) indicate that 3.9% of American children (18.6% of urban poor black children) between the ages of 6 months and 5 years examined in 1976-1980 had blood lead concentrations of 30 µg/dL or more,4 the concentrations considered indicative of increased lead absorption. From those data, it can be 

ASSESSMENT OF HEALTH EFFECTS 53 estimated that 675,000 young children have high blood concentrations. The Centers for Disease Control recently revised the definition of increased lead absorption in children from 30 µg/dL to 25 µg/dL; a substantially larger number of children would be classified as having high blood lead according to that new definition.160 The findings of NHANES II suggest that subtle, but irreversible, lead encephalopathy might be widespread among young American children. Although the NHANES II data show that children's blood lead decreased between 1976 and 1980, in parallel with reductions in the consumption of leaded gasoline,5 the Committee believes that the potential magnitude of the neurobehavioral problem warrants further epidemiologic study. Lead has long been recognized as toxic to the kidney.57 Prolonged high-dose exposure to lead both in children40 and in adults57 has been shown to produce nephropathy, which can lead to secondary hypertension. Hypertension, although not a constant finding, has been reported in association with occupational lead exposure30 34 41 in the absence of severe renal disease. A recent epidemiologic study based on data collected in NHANES II found that blood lead in American men aged 40-59 was significantly associated with increases in systolic and diastolic blood pressure.64 138 These findings are supported by low-dose feeding experiments in animals and warrant further epidemiologic study. Benzene and Leukemia Ambient air contains small amounts of many volatile organic chemicals that are known or suspected carcinogens. The data base for estimating the health effects of these exposures is far more extensive for benzene than for other substances. Epidemiologic studies of rubber workers78 143 and chemical workers130 have shown that benzene causes leukemia. These results have been corroborated by carcinogenesis bioassays106 107 150 and by studies of chromosomal damage in persons exposed to benzene.137 Recent epidemiologic risk assessments have suggested that the risk of death from leukemia is increased in industrial workers with mean annual exposure to benzene below 1 ppm 

ASSESSMENT OF HEALTH EFFECTS 54 (equivalent to 3,190 µg/m3) over a 40-year working lifetime.79 143 Benzene concentrations in ambient air in the United States range from 0 to 22 µg/m3 (annual arithmetic mean values), and quarterly means as high as 400 µg/m3 have been noted.76 Benzene at ambient concentrations has not been demonstrated to cause leukemia or other cancers, nor is it likely that such an association could ever be directly demonstrated by epidemiologic study, given the generally low exposures, the almost total lack of information on past exposures, and the poor definition of confounding variables that are typical of community populations. Carbon Monoxide and Ischemic Heart Disease Tissue hypoxia is the principal toxic effect of carbon monoxide, CO.62 Inhaled CO binds tightly to circulating hemoglobin, producing carboxyhemoglobin, COHb, and thus reducing the ability of the blood to transport oxygen.113 159 The heart and brain are the organs most severely affected by CO. Extensive evidence links low-concentration CO exposure to altered hemodynamics. In normal exercising adults, venous oxygen tension is decreased during exposure to CO, and heart rate, cardiac output, and coronary arterial blood flow are all increased.9 169 In persons with coronary arterial disease, a compensatory increase in coronary blood flow does not occur after exposure to CO,9 so such persons are at heightened risk of CO toxicity. Exercising subjects who have coronary disease develop angina and electrocardiographic abnormalities more rapidly when breathing air containing CO at 50 or 100 ppm than when breathing air without CO.3 Because cigarette smoke contains high concentrations of CO,159 similar toxic effects can be produced by smoking. In animal experiments, CO inhalation at relatively low concentrations has been associated with cardiac arrhythmias, including ventricular fibrillation.32 Visitors to high altitudes, fetuses and infants, and persons with peripheral vascular disease, COPD, or anemia also seem to be at heightened risk of CO toxicity.159 COHb concentration is an excellent example of a short-term biologic marker of exposure that can be a 

ASSESSMENT OF HEALTH EFFECTS 55 valuable tool in clinical and epidemiologic studies. NHANES II found that the national mean COHb concentration in nonsmokers in the United States was 0.77%, compared with 4.2% in smokers.141 The NHANES data also showed higher COHb concentrations in cities than in rural areas. This gradient was evident in children and in adults who had never smoked, as well as in smokers. The gradient was steeper in blacks than in whites, perhaps owing to heavier occupational exposure of blacks or residential proximity to traffic. Concentrations were higher in winter than in summer. Epidemiologic studies of cardiovascular disease in relation to ambient CO concentrations have so far been inconclusive. A study in Los Angeles28 found higher case-fatality rates for myocardial infarction in areas of “high” air pollution than in comparison areas, and the difference was observed only during periods of increased CO pollution. Weekly ambient CO concentrations were low, ranging from 5.1 to 14.0 ppm. However, a study in Baltimore found no correlation between CO exposure and sudden death from acute myocardial infarction.91 Volatile Organic Chemicals and Neurotoxicity Chronic exposure of industrial workers, such as painters, to volatile organic solvents is associated with a subtle and irreversible syndrome of chronic encephalopathy.7 98 146 The data are insufficient to determine whether exposure to volatile organic chemicals in the general environment is associated with chronic neurotoxicity. It appears prudent to define and measure the syndrome of solvent- induced encephalopathy in industrial workers with heavy exposures before trying to assess possible solvent-induced encephalopathies in the general population. Exceptions might be made for heavily exposed populations, such as persons living near point sources of emission. Priority in future evaluations should be given to the development of methods for improved assessment of exposure and improved quantitation of toxic neurologic effects.10 SOURCES OF HEALTH EFFECT DATA Many kinds of data can be used to determine health status in an epidemiologic study. Most of the data 

ASSESSMENT OF HEALTH EFFECTS 56 sources to be discussed in this report are specific to the respiratory effects discussed earlier, although some have broader applications. The different methods of obtaining data have different advantages and disadvantages with important implications for the design and ultimate sensitivity of a given study. Data come from a wide variety of sources, including clinical records, vital statistics, population-based surveys, data bases established for other reasons, and special inquiries. In many epidemiologic studies on air pollution, different kinds of data from different sources are used together. QUESTIONNAIRES The questionnaire is a common tool for measuring indicators of respiratory disease, especially chronic disease. It can be used either alone or (preferably) in conjunction with more objective measures. Like other instruments, questionnaires need to be standardized and calibrated to ensure that they measure the desired end points. Quality control of questionnaire data has been studied extensively.65 In 1960, the British Medical Research Council approved a standardized questionnaire to assess respiratory health, particularly chronic conditions.115 It has undergone several revisions, and the most recent (ATS-DLD-1978) was designed specifically to yield reproducible results, whether it is filled out by the subject without assistance or jointly with an interviewer. Detailed explanations of the testing procedures and the validity and reliability of items in the questionnaire are available in the literature.42 The revised version includes several items on asthma and pediatric respiratory diseases. Particular research applications might require the flexibility to alter some questions or to include more specific questions on some topics, such as occupational exposures. Although prospective studies on such end points as exacerbations of bronchitis, emphysema, and asthma often use daily or weekly diaries, such diaries have not been standardized. On balance, the continuing development of standardized questionnaires is valuable to epidemiologists, not only because it improves the utility of questionnaire data, but because it facilitates comparisons among different studies. 

ASSESSMENT OF HEALTH EFFECTS 57 Questionnaires have recognized limitations that have been summarized in review articles and need further methodologic research.96 One common problem is recall bias: sick people are more likely to recall possibly associated factors than healthy people, and exposed people are more likely to recall illness than nonexposed people. Thus, cancer patients might report their industrial exposures, or smokers their respiratory symptoms, more completely than well persons or nonsmokers. The reliability (reproducibility) of questionnaire responses of persons with chronic lung disease is also a matter of concern.136 Gandevia has recently discussed several innovative approaches to quantifying respiratory symptoms in epidemiologic studies of environmental inhalants.47 PULMONARY FUNCTION TESTING Pulmonary function tests of the mechanical aspects of airflow (spirometry) are noninvasive, quick, reproducible, sensitive, specific, and easy to perform in the field. These characteristics, in contrast with those of tests of renal or cardiac function, for example, have made it feasible to use respiratory function as an end point in epidemiologic studies and to define exposures and risk factors associated with deficits in pulmonary function. Although spirometry is the most commonly used technique, others are being developed and offer some promise of epidemiologic utility. The newer techniques generally measure quantities other than airflow. They include bronchial hyperreactivity testing, tests for particle deposition, and magnetopneumography to measure macrophage function and dust clearance. The use of a spirometer to analyze a single forced expiration is one of the most valuable techniques in the armamentarium of pulmonary function researchers. The subject inhales fully and then exhales as hard and as fast as possible into a mouthpiece. Test results are subject to many sources of variation, especially in large longitudinal studies that involve many instruments, technicians and sites.2 15 16 25 31 49, 50 and 51 75 140 177 All the instruments require extensive testing and calibration. Well-trained technicians, appropriate instructions to the subjects, and careful evaluation of the tests are also needed. A subject learns by performing the test, so the first measurement is usually 

ASSESSMENT OF HEALTH EFFECTS 58 lower than later ones. Problems in interpreting longitudinal data can arise from regression to the mean, extraneous exposure factors at some but not all test sessions, incomplete understanding of the normal curves for lung growth and decay, biologic variability among subjects, and lack of agreement as to the best methods of statistical analysis. The most useful spirometric measurement is FEV1, which is the maximal amount of air that the subject can exhale in 1 second. The peak expiratory flow rate, measures of flow at various lung volumes, and forced vital capacity are also used often. When carried out properly, spirometric tests are extremely sensitive. Thus, Ware et al. detected changes in FEV1 of less than 1%, or 10-20 ml of a total of about 2,000 ml, when they compared children of smoking and nonsmoking parents.172 Subjects with FEV1 values that vary excessively during a single test session are often discarded from studies, yet it was recently reported that such persons have more rapid decline in function over time than those who give repeat efforts within recommended limits.39 These kinds of problems are now receiving increasing attention. Several other measurements based on forced expiratory flow are more difficult to use than FEV1, but yield valuable information. These measurements, such as mid-expiratory flow rates, are more sensitive for some effects than FEV1, but are subject to wider normal variation, including a greater measurement error. Measurements of gas diffusion (diffusing capacity) in the lung with a portable single-breath device have recently been used in occupational survey work and are being applied in air pollution epidemiology.84 The development of portable peak flow meters that the subject can use to record repeated measurements might present opportunities for more extensive studies of respiratory function under varying conditions. FEV1 is related primarily to the function of the large airways. By the time large-airway effects are detectable, changes have usually occurred in the smaller airways. Researchers are therefore trying to devise simple tests that measure effects in small airways and can be used in the field. One measure of small airway function involves the single-breath nitrogen test, in which the subject takes one breath of pure oxygen and 

ASSESSMENT OF HEALTH EFFECTS 59 then the distribution of nitrogen exhaled in the next breath is determined. In a normal lung, the percent of nitrogen is relatively constant during most of the breath; if small-airway disease is present, the percent of nitrogen increases substantially during the end of the breath. Lippmann and co-workers have been adapting, for field use, a sensitive laboratory technique to measure the dispersion of a nontoxic aerosol in exhaled air as an index of the overall distribution of ventilation in remote areas of the lung.110 Airways are tested for reactivity by having the subject inhale a substance, such as methacholine or cold air, that induces airway narrowing. People vary greatly in the amount of material needed to induce a specific decrease in spirometric measures.24 26 Hyperreactivity testing is now an epidemiologic tool, inasmuch as rapid and convenient techniques have become available in the last 4 years and have been applied to populations in the field.174 The ability of the lungs to clear dust and other small particles is another measurable lung function. This characteristic is receiving increased attention, because inhaled dust and smoke can cause or aggravate lung disease by damaging clearance mechanisms. Short-term clearance can be measured with safe, rapidly decaying radioactive materials, but long-term clearance is more difficult to measure. One promising laboratory technique for studying dust clearance requires that the subject inhale nontoxic magnetic particles. The location and clearance of these particles are then followed over a period of months. In one such experiment, approximately 50% of the dust remained in the lungs of three smokers after 11 months, whereas only about 10% remained in the lungs of nine nonsmokers.27 Further research is needed to reduce the cost of this technique and to explore the relationship of clearance to deficits in other pulmonary functions. MORBIDITY AND MORTALITY RECORDS Death certificates are the standard source of mortality data, but sources and types of routinely collected morbidity data are varied. They include such end points as 

ASSESSMENT OF HEALTH EFFECTS 60 hospital admissions, visits to emergency rooms, numbers of days lost from work or school, and numbers of visits to physicians. Whatever methods are used to determine morbidity and mortality for an epidemiologic study, determinations of health end points are subject to many errors in diagnosis, reporting, coding, and recordkeeping. In addition, hospitals and physicians vary within the acceptable range of practice. If a study extends over many years, techniques of diagnosing and treating diseases can change, as can definitions of diseases. In respiratory diseases, there is an increasing trend toward use of “COPD,” rather than the more specific “emphysema” or “chronic bronchitis,” in hospital records and on death certificates; this is due in part to the decreasing rate of autopsy. Thus, apparent trends or geographic differences in COPD mortality might reflect changes in terminology or diagnostic practices. Even if the reliability of morbidity data were to remain the same, availability of such data on entire, defined populations would constitute a major advance for air pollution epidemiology. The epidemiologic approach, comparing disease rates in large groups, can sometimes use diagnostic data whose validity on an individual basis is lower than the standard of validity required for clinical medicine. The appearance of health care financing based on diagnosis-related groups (DRGs) will increase the availability of population-based data on hospitalization, although detail might be seriously limited and biases substantial. The National Center for Health Statistics conducts various population-based surveys of morbidity, such as the National Health Interview Survey and the National Ambulatory Care Survey (in which physicians report on various demographic characteristics and medical problems of office patients); the use of these surveys is discussed in Chapter 4. Centralized population-based registries of specific diseases are another source of information. The National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) program has improved understanding of both cancer incidence and cancer mortality.163 Several difficulties impede the linkage of routinely collected morbidity data to potential causal factors, such as air pollution. The role of social and economic 

ASSESSMENT OF HEALTH EFFECTS 61 factors in determining the likelihood that a person with a given illness will seek health care is not yet well understood and could cause substantial bias in routinely collected morbidity data. Without population-based health services, it is not easy to link separate health records on a person so that the researcher will have complete information. Record-linkage studies also require a high degree of sensitivity to concerns about privacy and confidentiality. Death certificates are a crucial part of many epidemiologic studies. With the development of the National Death Index, researchers can now ascertain the fact and location of death from a central repository before requesting death certificates from individual states.166 Although mortality data are most useful for studies of lung cancer, they do provide a few important opportunities for studying the relationship of air pollution to other respiratory diseases when large data sets are available. The extent and nature of these opportunities have not been fully explored. Death certificates are not always a source of accurate information about cause of death, particularly for diseases that are difficult to diagnose or code.133 Autopsies are the surest mechanism for confirming whether the cause of death on a certificate is correct, but the overall rate of autopsies has been decreasing and was only approximately 14% in this country in 1982.164 BIOLOGIC MARKERS OF RESPIRATORY EFFECTS Biologic markers can be categorized as exposure markers, effect markers, or susceptibility markers. Exposure markers indicate that exposure to a substance of concern has occurred and sometimes allow estimation of absorbed dose and dose to target tissues. Effect markers show early results of interaction between substances of concern and cellular or molecular targets in the host. Susceptibility markers indicate that some characteristic of the host, independent of the exposure, increases the chance that disease will occur; an enzyme deficiency is an example. Whether a marker is considered an effect marker or an exposure marker can depend on how a researcher uses the information in a particular study. This discussion primarily concerns effect and susceptibility markers. 

ASSESSMENT OF HEALTH EFFECTS 62 Future studies are likely to make increasing use of subclinical data, including effect markers, for several reasons. First, current ambient air pollution in the United States is unlikely to produce statistically significant changes in clinical outcomes unless very large numbers of persons are studied; early markers of disease will constitute surrogate end points that generally will be more common than the ultimate disease and thus will allow detection of relationships with fewer subjects. Second, early markers can be detected sooner than clinical effects and so reduce the time needed for observing populations in followup studies. Third, the use of sensitive indicators might improve researchers' ability to classify individual subjects correctly as affected or unaffected. Finally, research on detecting adverse effects of air pollution at an early subclinical stage has the potential to provide clinicians with opportunities to prevent clinical disease. Further development is needed before biologic markers are ready for routine use in epidemiologic studies of air pollution. Their accuracy in measuring what they are intended to measure, their value in predicting health impairment or premature death, and their applicability to various demographic groups are not yet fully established. Regardless of the extent to which markers fulfill their promise, clinical data will continue to be used in air pollution epidemiology. To be useful in epidemiologic research, markers must be validated. The procedures and techniques used to measure a marker must generally be noninvasive, precise, sensitive, specific, easy to use, and inexpensive. Although biologic markers are commonly used in clinical research and in epidemiologic studies of infectious diseases, they have seldom been used for studying pulmonary effects. One reason is that spirometry has been extraordinarily useful in measuring pulmonary function. Second, the complex cellular and biochemical processes of the lung, the heterogeneity of cell types, and the changes that occur in disease have only recently begun to be understood. Third, lung tissue and fluids are not easily obtained noninvasively--an important factor when large and relatively healthy groups are under study. 

ASSESSMENT OF HEALTH EFFECTS 63 Urine, blood, sputum, saliva, and nasal mucosa are readily accessible for noninvasive detection of functional, biochemical, or structural changes in the respiratory system. Bronchoalveolar lavage (BAL) is a major advance for clinical and toxicologic research, but it is not appropriate for most large-scale epidemiologic studies, because it is invasive and expensive. It is possible, however, that pathology specimens of cells or tissue from BAL, biopsies, or even autopsy could be used in special types of epidemiologic studies. Specimens from patients without interfering disease can be selected (for instance, from a tissue bank) and retrospective exposure histories obtained. For example, studies examining alveolar inventory and fine structure in populations free of clinical lung disease (e.g., coroner's cases) are feasible. Specimens from Sputum and Nasal Mucosa Sputum cytology has been used in studying nonneoplastic bronchopulmonary disorders.125 Nobutomo compared the sputum cytology of nonsmoking residents of two towns, one of which had sulfur oxide (SOx) and particle concentrations several times higher than the other.129 Increased numbers of inflammatory cells were found in sputum of residents of the more polluted town, and these findings preceded development of such signs of respiratory disease as increased phlegm. Investigators from Norway recently reported standardization of a new technique for counting expectorated alveolar macrophages in workers exposed to dust and gaseous irritants.127 Further development of the method might permit more convenient evaluation of this important effector cell, which is believed to have a fundamental role in several pathogenic processes in the lung. Biochemical tests on sputum, such as measurement of antiproteases, might also provide important leads. For example, sensitive enzyme-linked immunoassays on sputum have identified a low- molecular-weight anti-protease (bronchial protease inhibitor) that is active in the bronchial areas of the lung.88 Use of sputum for studying COPD and other respiratory diseases warrants further research. Problems in the use of sputum samples in population studies include difficulties in standardizing the methods for obtaining reliable samples, particularly from healthy subjects, and in 

ASSESSMENT OF HEALTH EFFECTS 64 interpreting findings, in that cells and other substances found in sputum reflect not only secretions from both upper and lower respiratory tracts, but also materials from the mouth. Some important biochemical and cellular features of nasal mucosa can also be investigated with nasal brushing, a new noninvasive technique.104 This technique might be useful in epidemiologic research, because the nasal mucosa is vulnerable to the effects of pollutants and can reflect damage to more critical areas in the lower respiratory tract. For example, it has been shown that ciliary beat frequency can be measured with a simple photoelectric device and that results obtained on samples from nasal mucosa are highly correlated with results from bronchoscopy.104 A recent study has shown that repeated nasal-brush sampling (even in children) is feasible and can be used to describe the evolution of changes in ciliary morphology before, during, and after acute viral infection or short-term exposure to O3.21 22 Blood and Urine Markers for COPD A task force of the National Institute of Environmental Health Sciences167 recently reported on investigations to determine early markers of COPD. The task force concentrated on emphysema, because recent breakthroughs in understanding its biochemical basis might permit the development of several markers for use in clinical research and epidemiology. The disease involves changes in the alveolar walls, and research has focused on changes in the elastin and collagen that make up these walls. Researchers now believe that the connective tissue matrix of the alveolar wall in the healthy lung is protected from destruction by a balance of protease and antiprotease. In the development of emphysema, however, a net excess of proteolytic activity leads to destruction of the matrix. Measurable elements (reactants or products) in the protease- antiprotease balance could be valuable markers. Various environmental factors, including cigarette smoking and exposure to oxidants, increase the release of protease and endogenous oxidants from neutrophils and macrophages and decrease antiprotease activity. Protease concentrations and activity can be measured in bronchoalveolar 

ASSESSMENT OF HEALTH EFFECTS 65 lavage fluid, but these measurements have not yet been extended to blood or urine. Antiprotease can be measured in blood, since the landmark discovery of α1-antiprotease deficiency by Laurell and Eriksson in 1963.95 Persons with this genetic deficiency are especially susceptible to emphysema,46 but variations in total serum antiprotease among normal persons and persons who are heterozygous for the enzyme do not seem to reveal much about the risk of emphysema. α1-Antiprotease, the major antiprotease in humans, is damaged in a highly specific way by endogenous or exogenous oxidants.81 The damage involves cleavage of the protein backbone at a specific methionine-serine linkage in the molecule. The recent development of extremely sensitive assays for the detection of damaged antiprotease fragments has opened the possibility of their use as markers of exposure or effect.158 Among the various proteases, elastases might be critical in the pathogenesis of emphysema. Elastase has been assessed by measuring elastin fragments in serum with the use of antibodies to the various peptide fragments.114 Elastin- derived peptides were detected in the serum of dogs that had been exposed to an elastase-containing aerosol to induce emphysema-like lesions. More recent clinical research has suggested that serum concentrations of these peptides are distinctly different between people with COPD and normal people and between heavy smokers without disease and nonsmokers.89 Assays for these fragments in urine have not yet been as successful.132 Detection of elastin fragments in serum might therefore provide the basis of an early biologic marker for emphysema that could be tested soon. Recent advances in understanding the role of factors measurable in plasma, such as ceruloplasmin and catalases, which protect the lung from injury by oxidants and free radicals, might lead to other markers of susceptibility that could be used in epidemiologic studies. Ceruloplasmin, for instance, “is the major antioxidant of plasma” and might be a particularly important determinant of lung defense in persons chronically exposed to oxidants.155 Studies of other rare genetic diseases of connective tissue in humans and animals could increase our understanding of COPD etiologies and the identification of 

ASSESSMENT OF HEALTH EFFECTS 66 markers relevant to the disease. Examples include Marfan's syndrome and lysyl oxidase deficiency, a genetic disease that specifically decreases the cross-linking of collagen fibers. Changes in lung collagen have also been proposed as markers of chronic pulmonary disease. Collagen constitutes 6-20% of the dry weight of the lung, and elastin 3-5%. The ratio and distribution of distinct types of collagen vary as a consequence of several disease states, and chronic lung disease induced in animals by long-term O3 exposure is associated with an increase in total lung collagen content.94 The specific collagens can be detected with immunochemical procedures.11 Furthermore, Michaeli and Fudenberg found that 70% of patients with emphysema had antibodies to denatured collagen in their serum, compared with 9% of control subjects.117 Antibody titers were also higher for the emphysema subjects. The amino acid hydroxyproline might also serve as an indicator of the status of lung connective tissue. Hydroxyproline is found almost exclusively in collagen, and lung collagen has a higher ratio of hydroxyproline to proline than does collagen in other tissues.90 Studies in guinea pigs have indicated that long- term exposure to NO2 increases the urinary excretion of hydroxyproline.87 Matsuki and colleagues have measured the ratio of hydroxyproline to creatinine in urine in several types of human subjects, including smokers and COPD patients.109 175 In the only epidemiologic studies to use this marker so far, they found increases in urinary hydroxyproline with increased exposure to NO2 and with passive smoking (in children).109 Although these results are of great interest, more fundamental research is needed to identify the determinants of intra- individual and interindividual variation in hydroxyproline excretion and to understand the clinical meaning of observed changes. Markers of Genetic Toxicity Carcinogenesis is a multistep process, and years are presumed to intervene between the early steps and eventual disease manifestation. If researchers could detect early stages of the disease process, followup studies of groups would be more feasible, and further exposure might be 

ASSESSMENT OF HEALTH EFFECTS 67 preventable. Many carcinogens cause mutations or other genetic damage, and researchers have developed several tests for possible markers of cancer risk.134 Such tests would be applied in two ways in air pollution epidemiology: to determine degree of exposure, and to identify persons especially sensitive to genetic damage by particular agents. The relative importance of exposure and susceptibility can be influential in interpreting results. The use of these assays as indicators of exposure is discussed in Chapter 3. Genetic toxicity is detectable soon after exposure, so the option of taking steps to prevent further exposure or to continue monitoring might be available. Genotoxicity tests have been used in various occupational settings and among populations known to be exposed to low concentrations of toxic environmental chemicals, such as ethylene oxide and benzene. Future studies are needed to clarify further the relationship of these end points to development of disease. REFERENCES 1. American Thoracic Society. Guidelines as to what constitutes an adverse respiratory health effect, with special reference to epidemiologic studies of air pollution. Am. Rev. Respir. Dis. 131:666-668, 1985. 2. American Thoracic Society. Respiratory care position paper. ATS News 4(6), 1976. 3. Andersen, E.W., R.J. Andelman, J.M. Strauch, N.J. Fortuin, and J.H. Knelson. Effects of low-level carbon monoxide exposure on onset and duration of angina pectoris: A study in ten patients with ischemic heart disease. Ann. Int. Med. 79:46-50, 1973. 4. Annest, J.L., and K.R. Mahaffey. Blood Lead Levels for Persons 6 Months-74 Years, United States, 1976-1980. Vital and Health Statistics, Series 11, No. 233. DHHS Publication No. (PHS) 84-1683. Hyattsville, Md.: National Center for Health Statistics, 1981. 61pp. 

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