Evaluation of a possible association of urban air toxics and asthma.

The prevalence of asthma, measured either as the frequency of hospital admissions or number of deaths attributed to asthma, has increased over the last 15 to 20 years. Rapid increases in disease prevalence are more likely to be attributable to environmental than genetic factors. Inferring from past associations between air pollution and asthma, it is feasible that changes in the ambient environment could contribute to this increase in morbidity and mortality. Scientific evaluation of the links between air pollution and the exacerbation of asthma is incomplete, however. Currently, criteria pollutants [SOx, NOx, O3, CO, Pb, particulate matter (PM10)] and other risk factors (exposure to environmental tobacco smoke, volatile organic compounds, etc.) are constantly being evaluated as to their possible contributions to this situation. Data from these studies suggest that increases in respiratory disease are associated with exposures to ambient concentrations of particulate and gaseous pollutants. Similarly, exposure to environmental tobacco smoke, also a mixture of particulate and gaseous air toxics, has been associated with an increase in asthma among children. In addition, current associations of adverse health effects with existing pollution measurements are often noted at concentrations below those that produce effects in controlled animal and human exposures to each pollutant alone. These findings imply that adverse responses are augmented when persons are exposed to irritant mixtures of particles and gases and that current measurements of air pollution are, in part, indirect in that the concentrations of criteria pollutants are acting as surrogates of our exposure to a complex mixture. Other irritant air pollutants, including certain urban air toxics, are associated with asthma in occupational settings and may interact with criteria pollutants in ambient air to exacerbate asthma. An evaluation of dose-response information for urban air toxics and biological feasibility as possible contributors to asthma is therefore needed. However, this evaluation is compounded by a lack of information on the concentrations of these compounds in the ambient air and their effects on asthma morbidity and mortality. Through an initial review of the current toxicological literature, we propose a tentative list of 30 compounds that could have the highest impact on asthma and respiratory health. These compounds were selected based on their ability to induce or exacerbate asthma in occupational and nonoccupational settings, their allergic potential and ability to react with biological macromolecules, and lastly, their ability to irritate the respiratory passages. We recommend better documentation of exposure to these compounds through routine air sampling and evaluation of total exposure and further evaluation of biological mechanisms through laboratory and epidemiological studies directed specifically at the role these substances play in the induction and exacerbation of asthma.


Introduction Urban Air Toxics
The Title III-Hazardous Air Pollutants portion of the 1990 Clean Air Act Amendment mandates the preparation of exposure standards for an initial list of 189 compounds within 6 years and a comprehensive strategy to control emissions from sources in urban areas within 5 years. The latter requires an identification of not less than 30 hazardous air pollutants that pre-sent the greatest threat to public health in the largest number of urban areas. Several health concerns are to be considered, with emphasis on carcinogenicity, mutagenicity, and teratogenicity. In the review that follows, we consider the possible relationship between these compounds and an additional disease, asthma. Asthma morbidity (emergency room visits, etc.) and mortality have steadily increased since the mid-I 970s, a situation that will require a better understanding of environmental risk factors.
Clean air is essential for life. Human commerce and recreation have led to the purification, development, and macroscale use of over 50,000 chemicals. Each can be considered toxic depending on the magnitude of exposure, the dose to target organ, and the biological response. Systematic evaluation and reevaluation of the toxicology of these chemicals is ongoing and may require many decades of effort to understand the relationships between environmental exposure and potential to cause or exacerbate human diseases. Faced with the immediate need to protect human health by providing recommendations for over 180 compounds (Table 1), referred to here as urban air toxics (UATs), we attempt to rank this substantial list of compounds (and groups of compounds). Any prioritization should be based on the likelihood and extent of human exposure and the severity of the response. Unfortunately, adequate scientific details are lacking for Environmental Health Perspectives of these compounds; therefore, we also present information on the current gaps in the toxicology literature and recommend research needs that may be useful in reducing the uncertainty of future evaluations of the health effects ofthese compounds.
Persons with Asma and Increased Susceptibility to Air Polution Air quality standards are designed to protect susceptible populations, and persons with asthma are clearly at increased risk from the adverse health effects of air pollution. Because asthma is a complex respiratory condition with varied definitions (1)(2)(3), it is helpful to develop an operational definition of this disease. Asthma is defined here as a respiratory disease with three primary features. The first is airway inflammation (associated with eosinophilic infiltration and altered T-cell lymphocytic function). A second feature is altered epithelial function (associated with thickening of the basement membrane, mucin hypersecretion, loss or altered ciliary structure, and altered cytokine and other inflammatory mediator production). The third and most predominate feature is recurrent airflow obstruction (presented in dual phases as decreased forced expiratory volume, bronchospasm, or airway hyperreactivity). Although the frequency of asthma is greater among atopic individuals (4), not all persons with asthma (e.g., more than half the adults with occupational asthma) (5) exhibit specific antigen-antibody responses. Instead, these individuals respond to many agents including dry air, hypo/hypertonic aerosols, acidic aerosols, and sulfur dioxide. Consequently, this condition is called nonspecific airway hyperreactivity, which many clinical investigators consider the hallmark of asthma (2,6).
Although asthma may persist for many years, the signs and symptoms are markedly erratic both in frequency and severity. In some ways, this intrinsic, sporadic nature contributes to the licentiousness of this disease. Severe, life-threatening asthmatic attacks can arise rapidly even after presentation of mild symptoms to which the victim is accustomed. Thus, patients and physicians may depend solely on selfadministered bronchodilators for therapy assuming relief is shortly in hand, only to be faced with a rapidly mounting array of irreversible changes (e.g. airway obstruction by mucus inspissation). Indeed, this lack of appreciation for this condition by patients and general practitioners has been cited as contributing to the recent increases in asthma mortality (7,8).
One factor that has been considered as having a possible role in the recent increases in asthma mortality is the use of bronchodilator therapy (9)(10)(11). Without recognition of the inflammatory and epithelial components of this disease, therapies directed solely at preventions of bronchospasm can leave a persistent inflammatory condition unchecked. In addition, patients relieved of symptoms may be more likely to put themselves in harm's way by not avoiding environmental exposures that increase epithelial injury and may hasten acute attacks. In addition, bronchodilation will alter the deposition pattern of subsequently inhaled irritant particles increasing their penetration to distal, small diameter airways and lengthening clearance times.
In the past, controlled human exposures of persons with asthma indicate that these patients respond to bronchoconstrictive substances at lower concentrations than do healthy control subjects (12). Of the current criteria pollutants, SO2 (13,14), NO2 (15)(16)(17)(18), and acidic sulfates (19)(20)(21)(22)(23) can produce bronchoconstriction (or increase bronchial reactivity) at lower concentrations among asthmatic subjects. Clinical studies with ozone are more controversial (24)(25)(26), although a recent study by Molfino (27) suggests that 03 exposures can increase bronchial reactivity to subsequent antigen challenges in persons with airway hypersensitivity. Results from these studies qualitatively indicate that specific pollutants affect persons with asthma to a greater extent than healthy subjects. However, clinical findings are quantitatively disparate from epidemiological findings in that in clinical studies, the lowest effective concentration that produces bronchoconstriction is often higher than that noted to produce adverse pulmonary effects when subjects are exposed in free-roving environments. Because asthma varies in its severity, a selection bias of subjects with milder forms of the disease could be responsible for the difference noted between clinical and epidemiological studies.
In several recent epidemiological studies, associations between air pollution and the prevalence of respiratory symptoms characteristic of asthma have been noted throughout the world ( Table 2). When atopic and nonatopic patients were handled separately, the association with air pollution was unaffected (31,33,34). This suggests that both asthma subpopulations are affected equally by air pollution. Besides increases in symptoms, air pollution has been associated with decreases in pulmonary function, e.g., depressed forced expiratory volume-1 second (FEVy) or peak expiratory flowrate (PEF) (35,36).
Emergency department visits and hospital admissions for asthma have also been consistently associated with the amount of exposure to air pollution ( Table 3). The implicated air pollution variable differs among studies, with the most frequent being particulate, sulfate, and sulfur dioxide. In contrast, earlier studies failed to find similar associations with SO2 and hospital admissions for asthma (47). Several additional observations have been noted by the investigators of these studies. Although weather, pollen, and environmental tobacco smoke are important risk factors in asthma, each has been found to act independently of air pollution and thus do not explain the association between air pollution and asthma (32,41,44,(48)(49)(50). Local stationary sources are often associated with effects (31,38,45,(51)(52)(53)(54)(55)(56)(57). This observation, along with the observation that a variety of pollutants are associated with the same responses (Tables 2,3), suggests that the specific compounds measured may serve as indicators of a wider array of air pollutants (including UATs). By focusing on selected epidemiological studies that have been conducted in the last 5 years, emphasis is placed on the current effects of air pollution. All the reported associations have been noted during a period when criteria pollutants are either decreasing or maintaining levels noted in previous years (50,58). Last, because some recent studies are cross-sectional over short periods, it is unlikely that any recent changes in diagnostic criteria for asthma could explain these associations (59)(60)(61)(62). Together these studies indicate that air pollution is a complex mixture that can produce effects at current levels of exposure that are important to the etiology of asthma.  (33) "Particulate < 10 pm. Exposure is a primary issue regarding the culpability of UATs in the exacerbation of asthma. This is an extremely complex issue for this group of compounds. Ideally, existing air sampling networks could quantify hourly, daily, or yearly the ambient concentrations of all these 189 compounds. Evaluation of a massive data collection effort and its effectiveness in control-design strategies is well beyond the limited scale of this review. Nonetheless, appreciation for the magnitude of this problem and a preliminary understanding of exposure assessment is necessary to begin to evaluate whether such a future undertaking would have merit.
UATs can enter the environment by a complex array of pathways. Vaporization of gases is the primary route of entry and is often a consequence of fugitive emissions from stationary sources. This process depends on the intrinsic physical/chemical properties of each compound including vapor pressure and solubilities in various media (i.e., water, organic solvents, etc.) as well as certain attributes of the manufacturing and generating procedures (e.g., the temperature of the effluent). Highly volatile substances can more readily escape into the ambient air and thus have added concern. Emission inventories for UATs indicate that release into the air is the principal route through which these materials enter the environment ( Figure 1).
In addition to direct entry from stationary sources by volatilization, specific compounds can enter the urban air by mechanical dispersion or condensation, processes that dominate the formation of the urban aerosol. Urban aerosols have been chemically characterized to a limited extent in the past (64)(65)(66)(67)(68)(69)(70)(71). However, the past and current criteria pollutants, total suspended particulate (TSP), and particulate material < 10 pm (PMlo) overlap with specific UATs because particles in this size range and smaller are derived from anthropogenic sources, whereas larger particles (>10 pm) arise from natural sources (e.g., sea salt, soil, etc.). More details of the implication of the ambient levels of particulate matter to asthma are presented below.
A third source of atmospheric pollutants arises from secondary reactions in the atmosphere. Many reactive hydrocarbons (often with very short half-lives) can be formed and can accumulate in the atmosphere (72)(73)(74)(75)(76). This is particularly important for urban photo-oxidant plumes most often associated with ozone formation. Because ozone formation is dependent upon reactive hydrocarbon species (e.g., aldehydes), the continuous measurement of ozone concentrations could be useful in estimating the ambient concentrations of these compounds. Once inhaled, ozone is likely to react with unsaturated fatty acid in the airway lining fluid or the cell membrane to form aldehydes, hydroxyhydroperoxides, and hydrogen peroxide (77,78). These intermediates have recently been shown to activate mediator release from human airway epithelial cells in culture, thereby linking the biochemical outcomes of ozone with these compounds (79). Reductions in the emissions of ozone precursors (hydrocarbons and nitrogen oxides) are likely to limit indirectly the entry of certain UAT compounds into the atmosphere in the future. Urban activities of automobile transit, power generation, manufacturing, solvent use, wood burning, and even barbecuing have impact on the formation and release of these compounds.
Besides direct entry into the air and secondary formation, other chemicals can gain significant entry into the atmosphere through intermediate transport. In this case, chemicals that partition into water, soil, sediment, or biota can enter the atmosphere through evaporation from water or soil. For example, organic compounds with low or moderate solubility in water will partition to the air-liquid interface following an initial dispersion as an emulsion in a factory effluent stream. Thus, continuous and sole discharge into water can unexpectedly generate significant atmospheric concentrations. For example, recent fugacity models, e.g., Level III models by Mackay (80), predict that as much as 5% of naphthalene (a water-insoluble chemical with moderate volatility) will be distributed into the air when 100% is discharged into water. Although such a percentage seems low, the impact can be considerable. For example, dispersion of naphthalene solely into water at an emission rate of 1000 kg/hr (distributed throughout 100,000 km2 or about the area of Ohio) can yield atmospheric concentrations of 50 3 ng/m . This is approximately one quarter of the value achieved by 100% emission of the same amount directly into the air (210 ng/m3) when fugacity into other media is considered. This is somewhat remarkable and may partially explain why concentration estimates produced by airshed models that depend heavily on air emission inventories underpredict measurements made in the ambient air downwind from a point source (MA Marty, personal communication).
The movement of toxics from the air into other media and back again suggests an equilibrium can be achieved or predicted. However, uniform dispersion is unlikely in any compartment in real world situations. Furthermore, such models have uncertainty in estimating degradation rates in each compartment.
Degradation in the air itself can be appreciable and can even be sufficient to limit exposure. Naphthalene, the chemical used in the example above, is rapidly photolyzed. Based on the quantum yield for sunlight photolysis at latitude 400N at midday in the summer, the half-life of naphthalene can vary markedly from 71 to 550 days (81). In addition, photooxidation through reactions with hydroxyl radicals (often produced in urban plumes) can dramatically reduce the half-life of naphthalene to between 3 and 30 hr. Such variance in the environmental degradation rates can widely influence air concentrations. This latter situation presents another dilemma facing attempts to assess human exposure to UATs. Exposure to many of these compounds is likely to be dominated by proximity to point sources that produce intermittent, high concentrations as well as regional meterology, atmospheric dispersion, transport, and removal. Sourcereceptor analysis is therefore important. This attribute places significance on the identification of sensitive receptors in the population downwind from a point source.
Because persons with asthma constitute approximately 3.8 to 8.7% of the residents Environmental Health Perspectives of urban areas (82,83), this group represents an important target population and should be considered as such in evaluation of possible risks associated with exposure that could enter the neighborhoods of emission sources.
Exposure Assessment, Threshold Concentrations, and the Induction ofAsthma We have learned a great deal about the induction of chemically induced asthma from occupational experience. In this setting, exposure can still be difficult to quantify, but causal association can more readily be demonstrated. For example, polyisocyanate-induced asthma has clearly been ascribed to exposure in the workplace.
Historically, approximately 5 to 10% of all workers exposed to toluene diisocyanate, other polyisocyanates, and their monomeric precursors develop occupational asthma (5). Although host determinants (genetic factors) can modulate asthma, exposure to specific, identifiable agents is clearly associated with the development of asthma. This condition typically develops after several years of occupational exposure, indicative of a latency period when exposures are occurring while subjects are asymptomatic. Several of these compounds are included in the UAT list, and this selection of compounds of concern in the ambient environment draws from the experience in the occupational environment.
Current control strategies are designed to reduce occupational exposure concentrations below threshold limit values (TLVs). Exposures at these levels should ideally result in few or no adverse health effects. This approach from the occupational experience impinges directly on the method of application of risk assessment for noncancer health effects. However, although exposures have qualitatively been associated with occupational asthma, quantification of human exposure to a specific compound has been limited. Mathematical models of the relationship between dose (the concentration and duration of exposure) and occupational asthma have yet to be firmly established. Nonetheless, current occupational standards assume that a threshold dose can be established at which no additional cases of asthma will develop. However, this assumption may be flawed. For example, initiation of occupational asthma has been noted among workers wearing respiratory protective equipment and when exposures met current TLVs (5).
Induction of airway hyperre animals provides some insigh issue of threshold dose. For ex recently examined the induction reactivity in guinea pigs ex formaldehyde and acrolein (84 studies, the dose of acetylcholine to double pulmonary resistanc was measured after 2-and 8-hr Figure 2 shows that exposures e: 8 hr produced an effect greater predicted by the common est dose. After 8 hr of exposure tc formaldehyde, the percentage ED200 equaled 67 ± 4%. This is to the maximal effect produced exposure to either . 30 ppm fori or > 1.0 ppm acrolein. Thus the dose-response relationship for induced hyperreactivity after 1 exposure did not follow a simp tration x time relationship  respectively. (B) When exposures were E hr, a dose of 1.0 ppm formaldehyde produ equivalent to that following 30 ppm x 2 1 means ± SE of groups of five to seven Data from Swiechichowski (84). activity in equivalent response occurred after 1.1 ppm t into the x 8 hr = 8.8 ppm x hr that is nearly 7 ample, we times less than what would be predicted by 1 of hyper-31 ppm x 2 hours = 62 ppm x hr). These posed to findings suggest that low-level exposure of ). In these prolonged duration may be of greater cone necessary sequence than would be predicted by acute e (ED200) exposure. This would explain why some exposures. clinical studies with exposures of short extended to duration (< 4 hr) do not uncover effects at than that levels that are associated with pulmonary timates of effects in epidemiological studies. ) 1.1 ppm Induction of irritant-induced asthma change in without a latency period has also been equivalent reported extensively in the medical literature by 2 hr of and has been termed reactive airways dysmaldehyde function syndrome (RADS) (85). The estimated pathogenesis of this syndrome is speculative aldehydebecause reports are retrospective in nature. prolonged Typically, patients without pre-existing resile concen-piratory complaints develop airway hyperre-(i.e., an activity shortly after an accidental exposure or an exposure in an area with no or poor ventilation. Following this single exposure, 2-hr exposure hyperreactivity and abnormal bronchial epithelial biopsies persist for a year or longer (up to 12 years). Causative agents have varied greatly, but all are respiratory irritants HO and include chlorine (86)(87)(88), toluene diisocyanate (89-91), hydrazine (85), sulfur dioxide (92,93), acetic acid (94), and ammonia (95,96). This condition differs from typical occupational asthma because it lacks a preceding latent period and can be -,-,-,-,-,, initiated by a single exposure. Persons with 100 this syndrome often experience subsequent responses to a wide range of agents (non-8-hrexposure specific airway hyperreactivity) and workers report that symptoms are equivalent either at home or at work (97)(98)(99)(100). Because of a lack of exposure measurements during the initiating events, is it difficult to establish a threshold for this type of response; nonetheless, it is assumed that very high exposure levels are responsible for these cases.
Exposure Assessment and the Exacerbation ofAsthma 100 In addition to scientific uncertainties associated with the establishment of threshold of acrolein doses for chemicals that induce asthma, the I) on airway levels of occupational exposure necessary to )ur exposures cause the persistence of sensitization or to d a maximal elicit responses upon reexposure have yet to enous acetylbe established. Often the exposure concen-maonda3y ppsmtration necessary to produce a multi-phasic extended to 8 response of diminished lung function in iced an effect persons already sensitive to a compound can hr. Values are be exquisitely low, well below the concenguinea pigs. tration that will cause bronchoconstriction in nonsensitized persons exposed in clinical Volume 103, Supplement 6, September 1995 257 experiments. However, epidemiological data of doseresponse relationships in occupational settings are lacking and limited to anecdotal case histories. For example, one worker sensitive to ampicillin reportedly developed asthmatic bronchospasm the night after (delayed allergic response) a visit to the town where the factory that produces ampicillin is located. In another case, a toluene diisocyanate-sensitive patient was so reactive that he responded when walking in the neighborhood of a factory (101). Another cololphony (rosin)-sensitive worker became reactant to pine trees and even unheated colophony or turpentine (102). In addition, broncoprovocation tests have been positive in previously sensitized workers after exposure at concentrations as low as the current limit of chemical detection, i.e., 7 pg/mi3 toluene diisocyanate (103,104).
These histories indicate that once initiation of hypersensitivity has occurred, elicitation of response can be evoked upon minimal reexposure at extremely low concentrations. Thus, for these individuals any environmental exposure should be considered hazardous, and any attempt to set threshold doses for this susceptible population (that could provide a margin of safety) must be regarded as extremely tenuous.

Exposure Assessment fiom Probability-Based Sampling Procedures
Because exposure assessment for UATs is currently incomplete, several strategies must be developed to reduce uncertainty. One approach is to use probability-based survey sampling procedures that combine questionnaires with multimedia and multipathway monitoring to estimate total personal exposure. A recent example is a study by Whitmore et al. (105) in which nonoccupational exposure to 32 pesticides was assessed (Table 4). Air monitoring was performed outside and inside each home, and drinking water, food, and dermal routes of exposure were analyzed. Ten of these pesticides are on the UAT listing, and other studies have found associations between the use of pesticides and asthma (106). Inhalation exposure exceeded dietary exposure for four of these substances (chlordane, dichlorovos, heptachlor, and propoxur) with the concentrations being approximately 7 to 20 times greater indoors than outdoors. Dietary exposures were greater for five other UAT/pesticides (captan, carbaryl, DDT and related compounds, hexachlorobenzene, and methoxychlor), and the relative level of exposure for one substance (y-BHC) was undeterminable.
Based on these estimates of personal exposure, risk assessments for air exposure were presented assuming a constant exposure over a 70-year lifetime and reference doses from the Integrated Risk Information System (IRIS) and other sources. The inhalation risks were estimated to be negligible (< I x 106) for all compounds except chlordane (Table 4). However, these authors noted that these estimates are potentially high because of the discontinuation of use of these compounds and variable degradation in the environment. The data were considered insufficient to support risk assessment for food, dermal contact, or house dust exposure. Because indoor exposure may be due to past use in the home, it is also important to consider the possible risk due solely to outside exposure. For chlordane in Jacksonville, Florida, the estimated outside air exposure levels equaled about 22 ng/m3 (compared to 197 ng/m3 indoors), or about 10% of that used in the above risk assessment estimate. Thus, because exposure to other UATs also may be greater indoors than outdoors, accurate exposure assessment requires detailed analyses that involve total exposure evaluations. In addition, the above study is limited to only two locations, and these findings may not be readily generalized to other regions and climates.
Possible Eposure Concentrations ofUATs Indoors Assessment of possible human exposure for these compounds clearly requires consideration of exposure in the indoor environment.  (107). bOdor thresholds are lowest value reported.
Environmental Health Perspectives Recently, the U.S. EPA compiled a database of concentrations of volatile organic compounds (VOC) measured indoors (107). Based on reports from 1979 through 1990, information on over 220 compounds ranging from 30 to 446 Daltons molecular weight was recorded.  (108), determining the concentrations of 20 VOCs in personal air, outdoor air, expired breath, and drinking water. The median concentrations in air and breath of 10 of the more prevalent compounds are presented in Table 7. Each is included on the list of urban air toxics (Table 1). Personal concentrations often exceeded outdoor concentrations by a factor of 2 or greater in New Jersey, and by a factor of 5 to 10 in North Carolina and North Dakota. This suggests that indoor VOC sources are likely to be of greater significance than outdoor sources. In addition, the distributions of the measurements were skewed, with geometric standard deviations ranging from 2.5 to 3.5, which means the range of the concentrations usually exceeded a factor of 100 to 1000. Proximity to point sources (defined as 1.5 km from a suspected source) was stratified and had little influence on air or breath measurements. In contrast, personal activities including occupation, smoking or living with a smoker (increasing expired benzene, styrene, ethylbenzene and other aromatic hydrocarbons), filling a gas tank (doubling expired benzene), and visiting a dry cleaner or wearing dry-cleaned clothing (increasing expired trichloroethylene with a half-life of > 20 hr) significantly contributed to the levels of certain compounds measured in expired breath.
In similar investigations of indoor air quality, Molhave and associates (109)(110)(111)(112) measured the concentrations of several VOCs in Denmark. Using these data, the authors presented the concept of total VOC exposure in which the concentration of a mixture of 22 compounds is weighted by their relative concentrations in the environment. This group of compounds excludes carcinogens and includes 10 substances most frequently present in the atmosphere in new homes and 10 substances in greatest concentrations in nonindustrial buildings in which complaints had been recorded about quality of the indoor air ( Table 8). Because of the exclusion of carcinogens, this list differs from the lists in Tables 5 through 7. The relative amount of each compound is in proportion to a single concentration as measured by a flame ionization detector calibrated with a single reference compound, toluene. The concentrations of total VOCs measured in older dwellings (200-1700 pg/mi3) were typically lower than in new homes (500-19,000 pg/m3), with complaints   Table 1).
being more frequent when levels exceed 1700 pg/mr.
To investigate whether these compounds influenced pulmonary functions among persons with asthma, controlled 1.5 hr exposures were performed at concentration of total VOC of 2.5 and 25 mg/mi3 (113). At the end of the 25 mg/m3 exposure, subjects developed bronchoconstriction, with the FEV1 decreasing about 10% from pre-exposure control. Individual responses varied, with bronchoconstriction more pronounced in individuals with the greatest baseline airway hyperreactivity. The effect of 2.5 mg/m3 was not distinguishable from control. Subjective measures of discomfort (odor, and eye, nose, or throat irritation) first increased and then diminished during exposure suggesting acclimatization, and these responses were similar in magnitude to those noted in previous studies with healthy subjects (111). Using a similar VOC mixture, Koren and Delvin (114) also noted an increase in nasal inflammatory cells in lavage fluid immediately and 18 hr after a 4-hr exposure to 25 mg/n3. From these studies, Molhave has offered tentative guidelines for exposure to these compounds in nonindustrial settings. At total VOC levels of < 200 pg/mi3, no discomfort from odor, eye, nose, or throat irritation, or headache is likely, whereas above 3000 pg/Mi3, complaints have occurred in most investigated buildings; above 5000 pg/mr3 objective measures of upper respiratory tract irritation increase markedly.
Epidemiologic information on the respiratory effects of environmental VOC exposure is limited. One recent study, conducted in Kanawha Valley, West Virginia, found an association between exposure and respiratory symptoms among schoolchildren (third and fifth graders) (115).
Kanawha Valley was selected because it contains several chemical manufacturing plants within a valley topography that can confine atmospheric mixing. Exposures were categorized by school location (in or out of the valley and near or far from an industrial site) and by the sum of the concentrations of 5 petroleum-related chemicals or 10 manufacturing process-related chemicals. The concentrations of these chemicals were measured at the elementary schools and are presented in Table 9. When exposure was characterized by either proximity to sources or by concentrations, a positive association with the incidence of chronic lower respiratory symptoms was noted. Moreover, children enrolled in schools within the valley had higher rates of doctor-diagnosed asthma. Importantly, other potentially confounding variables including parental smoking and familial socioeconomic status had weak associations with health outcomes and proximity to sites. Nevertheless, these analyses adjusted for these variables and the association of chronic airway responses important to asthma and exposure was still evident.
Although the Kanawha Valley is somewhat unusual in that it has several chemical manufacturing sources, the levels of air pollutants in this area are not extremely different from those in other sites in the United States. Table 10 presents the mean and maximum concentration of 10 VOCs (5 petroleum-related and 5 process-related compounds) as measured in the Kanawha Valley and four other locations. At each location, the mean values are typically 0.1 to 0.5 of the maximal values. This suggests that the concentrations of each substance vary greatly within a location. The between-location variability is also large. For example, mean benzene concentrations in Kanawha, Houston, and San Jose have In addition, several differences exist between the findings from VOC exposure in the controlled human experiments and those in the epidemiologic Kanawha Valley Health Study. First, and most obvious, is the difference in the concentrations at which responses were noted. In the controlled exposure study, no acute responses   symptoms and diagnosed asthma), and the length of exposure (90 min vs continuous) are all different. In addition, the composition of the mixture (by a necessity that the controlled exposure excluded carcinogens) and the relative ratios varied in the total mixture. It also should be noted that the VOC compounds used in the controlled exposure studies (e.g., alkanes, xylene, benzene, or toluene) are not particularly irritating to the respiratory mucosa. Nonetheless, the clinical study supports the biological feasibility of the associations noted in the epidemiological study.

Health Effects Assessment Criteria Pollutants and Mortality
Air pollution has been linked to adverse health effects. Increased mortality from cardiopulmonary disease and cancer has been noted in areas with elevated air pollution concentrations. Similarly, increased morbidity has been associated with environmental exposure (117,118). The latter includes increases in respiratory symptoms (e.g., shortness of breath, wheezing, coughing, chest tightness), decreased pulmonary function (e.g., depressed FEVI or PEF, increased use of bronchodilators, absence from school or work, and increased hospital admissions). As noted above, most previous analyses of these associations have focussed on criteria pollutants because much less has been reported for other pollutants. Because air pollution is a complex mixture, several investigators have postulated that any single exposure variable cannot solely be responsible for observed adverse effects (50,69,(119)(120)(121). Thus, measurements of criteria pollutants also may serve as exposure surrogates for a complex mixture of criteria pollutants and UATs. In the past, epidemiologic studies in several cities throughout the United States have examined the relationship between mortality and the current criteria air pollutants. Observations from these studies have relevance to this assessment of the role of UAT in asthma. As mentioned above, one constant finding is the presence of covariables that might explain the observed associations. Weather, cigarette smoking, migration, and ethnic/socioeconomic variables impact mortality; however, these variables act independently of specific pollutants in these analyses. Numerous studies have consistently observed associations between air pollution and mortality in different populations, in different areas, and at different times of the year (37,42,50,60,122,123).
A second constant finding is the influence of local sources on mortality. Although this question has not been evaluated rigorously and long-range transport is recognized to influence ambient concentration, local sources can have strong influences on the association of air pollutants with mortality. A good example is the Harvard Six Cities study in which local, stationary sources in Steubenville, Ohio, and St. Louis, Missouri, dominate air pollution concentrations (50,124). Importantly, these cities have higher mortality than Watertown, Massachusetts, and Kingston/ Harriman, Tennessee. The latter cities have moderate air pollution levels that are attributable largely to long-range transport processes of pollutants into these airsheds from other regions upwind of these communities rather than from local sources.
The third constant finding is the order of the relative strengths of the associations between mortality and specific criteria pollutants. Although controversial, these pollutants can be ranked from strongest to weakest as follows: PM2.5 > PM10 > SOX > H+ 2 03 > NOX (30,37,41,50,115,121,(125)(126)(127)(128). In most recent studies, particulate matter, a complex mixture containing several UATs, is the dominant pollutant (50,68,120,129). The strength of this relationship is remarkably consistent across studies (128,130). In addition, association with mortality has been reported for exposures at concentrations well below the current PM10 standard (150 pg/mi3). A recent estimate of the total population exposed to ambient PM10 levels in counties and cities not in attainment with this standard is over 41 million, of which approximately 1 million adults and 625,000 children have asthma (131). Because of the extent of human exposure and the strength of PM10 (a complex mixture) as an associated risk factor, it is important to consider the chemical composition of this pollutant.
Detailed chemical analyses of PM10 vary significantly from location to location and data are limited (65,69,132,133).
Although apportionment of PM10 may be site specific, typically particles in the 2.5to 10-pm size range consist of re-entrained road dust [soil particles, engine oil including metals, tire particles, sulfate (6% of <10 pm), and nitrate (7% of <10 pm)], Volume 103, Supplement 6, September 1995 and construction and wind-blown dust (mostly soil particles). Fine particles less than 2.5 pm are derived primarily from combustion, condensation, and coagulation of gases and ultrafine particles; thus, particles in this smaller size range are derived predominantly from anthropogenic sources. Preliminary and tentative analyses of the effect of including particle source on mortality estimates suggest that the least significant indicator is soil, whereas auto and oil sources are intermediate and metal industry and coal combustion sources are more significant contributors to mortality (28,60).

Environmental Tobacco Smoke, UATs, and Asthma
Environmental tobacco smoke (ETS) has recently been associated with an increase of asthma in children (134)(135)(136). Maternal smoking is associated with an increase in severity and frequency (additional episodes) of asthma in children with the disease. Importantly, this exacerbation of asthma and symptoms related to asthma may occur at low doses.
ETS is a complex mixture of over 4000 chemicals from exhaled mainstream and sidestream smoke. ETS contains several human respiratory carcinogens (including benzo[a]pyrene, benz[a]anthracene, other polycyclic aromatic hydrocarbons, 4-aminobiphenyl, and nitrosadi-methylamine) and irritants (including formaldehyde, acrolein, other aldehydes, cadmium, and other metals) (136,137) (Table 1 1). Twenty-nine of the 49 major components in ETS are UATs (compare Table 1 with Table 11). Each is a complex mixture of chemicals in both gas and particle phase. Because of these similarities, it is relevant to compare and contrast ETS and UATs in asthma.
ETS exposure has been assessed by measurement of a number of its constituents in air. Nicotine, respirable suspended particulate (RSP = PM < 2.5 prm), benz[a]pyrene, benzene, formaldehyde, toluene, carbon monoxide, 4-aminobiphenyl, and other chemicals have been used to assess ETS exposure. Of these, nicotine and RSP have the widest application, and these two variables correlate reasonably XRSP = 17.9 ± 10.8 nicotine; each in pg/mr) (138). Either measure has been used as ETS exposure surrogates, and when measured together can accurately represent the frequency, duration, and magnitude of ETS exposure (136).
Because nicotine is not suspected of inducing asthma and is not a UAT, and because RSP contains many compounds that affect asthma and are UATs, a preliminary evaluation of the magnitude of RSP exposure associated with increased asthma is worthwhile. The amount of RSP produced in the breathing zone of a child will vary with the number of smokers, proximity to the smokers, ventilation, and other variables. Nonetheless, average room RSP concentrations (obtained from 2 4 hr samples) are typically elevated by 2 to 5 pg/m3 per cigarette smoked in an average size room (138). Background indoor RSP levels vary depending on other indoor aerosol sources and the amount of penetration of the ambient aerosol [this can be substantial (50-80%) for particles in this size range], and typically are 15 pg/mr3 [ (138)(139)(140).
Increases in the incidence and prevalence of asthma among children have been noted when mothers smoke 10 or more cigarettes per day (141,142). Applying the findings of Leaderer et al. (138), we calculate that 10 cigarettes would generate an atmosphere containing 20 to 50 pg/mr3 RSP above background and result in total exposure to approximately 35 to 65 pg/mr3 RSP. Exposures in this range have been estimated to induce 8000 to 26,000 new cases of asthma annually (based on estimates of maternal smoking). It is feasible that UAT exposures, when mixed with the respirable particulate load in this range, also could adversely impact persons with asthma. This level of particulate exposure is     well below the current PM10 ambient air standard of 150 pg/m3. Other studies have examining the relationship between ETS generated by mothers and respiratory symptoms (wheeze, etc.) associated with asthma in children. The data in Figure 3 suggest an association with an increase in symptoms with an increase in maternal smoking (143). Again, an adverse response was noted at relatively low levels of exposure of 1 to 4 and 5 to 14 cigarettes per day smoked by the mother. Applying the estimates of RSP produced by these exposures yields estimated concentrations of added particulate of 2 to 20 pg/mi3 and 17 to 35 pg/mi3 above background. Similarity, Lebowitz and Quakenboss (144) reported that exposures to 2 20 cigarettes/day (or 40-100 pg/mi3) produces 3.6 times more bronchial hyperreactivity, a characteristic sign of asthma.
Several factors are uncertain in these comparisons, however. First, because maternal smoking has a greater effect than paternal smoking, it also may influence the development of asthma in utero by limiting lung development (145)(146)(147). In addition, average concentrations of room air samples may underpredict the levels in a child's breathing zone because small children are often held by their mothers. This proximity could result in complex exposure patterns of intermittent high-level exposures of short duration. Conversely, older children spend less time at home or in a room with a parent who smokes. Exposure patterns to UATs also may be intermittent, with wide variances in concentration. Thus, it is important to obtain time-activity information to predict personal exposures by combining microenvironmental concentration information with duration of exposure obtained from time-activity analyses.
Second, the physical and chemical properties of ETS differ from those of the ambient mixture of gaseous and particulate UATs. Although several main irritants are contained in both, the levels of most are greater in ETS than in urban air. The particle size also may differ in that ETS is < 1.0 pm [sidestream smoke is typically 0.001-1.0 pm and mainstream smoke is 0.1-1.0 pm in diameter (148)], whereas the cutoff diameter of PMIO in the ambient aerosol containing UATs is 10 pm. Besides mass concentration (i.e., pg/mi3), certain aspects of particulate toxicity depend on the number of particles (149)(150)(151). Because mass depends on particle volume, small increases in diameter in this range can have large influences on the reduction number of particles. Thus, particles between 1.0 to 10 pm add greatly to the mass estimates of UATs in air. Nonetheless, ambient fine (< 2.5 pmr particulate between 11 and 30 pg/m and inhalable (< 10 pm) particulate between 18 and 47 pg/mi3 has been associated with increase in cardiovascular and respiratory disease (50).

An Evaluation of Human Exposure and Its Relationship to Asthma
Identification Criteria for UATs Likely to Impact Asthma Reversible, acute airflow obstruction (indicated by diminished expiratory flow that can be reversed by adrenergic therapy) produced by direct exposure in a clinical setting has become a useful operational definition for the evaluation of chemically induced asthma (5,101). Through direct bronchoprovocation with a series of compounds, certain chemicals have been identified to produce marked responses. Common asthmagens identifiable by this method include metals (chromium trioxide, chromates, nickel sulfate, and platinum compounds). Such an approach is particularly useful in diagnosis of occupational asthma and is aided by knowledge of the chemicals present in the workplace and the reversal of symptoms upon their removal from the workplace. Although much can be learned by this diagnostic strategy, it may be impractical to apply this approach to future evaluations of the toxicity of over 189 compounds.
Further, certain known occupational asthmagens act by an immunologic mechanism in some persons, but not in others. These compounds include polyisocyanates, acid anhydrides, and aldehydes. In these cases, the threshold concentration needed to produce bronchospasm is likely to below that necessary to induce nonimmunospecific irritation. Other substances (acting like sulfur dioxide and perhaps ozone) do not produce antigenic responses but can provoke bronchoconstriction in persons with asthma at concentrations that are lower than those that are bronchoconstrictive in healthy subjects. These chemicals may act as an irritant and have an ability to induce airway epithelial injury and inflammation, effects that can be barely perceptible at doses in the range occurring in the environment. Released from stationary sources, such UATs can mix with other toxic chemicals in the urban air and add to the irritant load presented to persons with asthma in the general population.
Many UATs have insufficient scientific data to evaluate their immunologic potential, however. Because of this situation, because it is difficult to limit the definition of asthma to antigenic responses, and because of difficulties in ascertaining whether each chemical by itself causes or Volume 103, Supplement 6, September 1995  (152), the broader chemical to their effects in occupational settings. properties of UATs need to be considered.
Other UATs share a portion of these Properties that are important to this ques-properties, but it is unclear whether they tion include respirability, irritancy, and can induce persistent asthma. Adding to skin antigenicity. the difficulty of this situation are the Several compounds identified as UATs uncertainties created by the gaps in the litshare these properties and can clearly be erature regarding the human toxicity of classified as suspected human asthmagens. each compound. Nonetheless, to develop These compounds are listed in Table 13. logical strategies to assess possible links These compounds have had documented between environmental exposure to these reports in the medical literature associating compounds and asthma, the limited human exposure with asthma (either as human experience must be considered. inducers or exacerbaters). This includes This second group of compounds (Table  polyisocyanates, aldehydes, anhydrides, 14) includes skin allergens (compounds and metals-compounds with wide accep-producing allergic contract dermatitis) with chemical properties that suggest inhalation as a route of exposure (153,154). This includes hydrazine, pphenylenediamine, nickel, and chromium compounds. In addition, other compounds known to react covalently with proteins or DNA include polycylic aromatics/aryl epoxides, bis-chloromethyl ether, dimethyl carbonyl chloride, dimethyl sulfate, and 0propiolactone. These compounds can act directly by forming specific immunoglobulin complexes or indirectly by forming haptens or other antigenic determinants to produce adverse responses in the airways (155)(156)(157)(158). Carcinogenic compounds can cause irritation and inflammation at sites of exposure and are often antigenic (159)(160)(161)(162)(163)(164). Last, potent respiratory irritants with wide-scale usage are included in this list. Substances such as cadmium compounds, chlorine, hydrochloric acid, hydrogen fluoride, phosgene, phosphine, and hydrogen sulfide are known irritants to the respiratory tract, and in some cases have been responsible for community air pollution episodes involving accidental emissions (e.g., rail car derailments).
Noticeably not included on these lists are UATs that are also VOC compounds listed in Tables 5 through 8. As noted above, these compounds have been associated with increased asthma symptoms in controlled human studies (111,113,114) and epidemiologic studies (165). However, because these studies measured exposures to mixtures and because many of the compounds listed have not been associated with asthma or other respiratory effects, these compounds have not been included in this tentative list. Investigations of human exposures to these compounds separately and as mixtures are likely to yield additional insights into their possible role in inducing asthma and therefore will be worthwhile.
Our literature review of other UATs listed in Table 1 suggests that they may be of lesser concern. It is appreciated that these compounds also may contribute (particularly as mixtures) to other serious health outcomes, and therefore inclusion of compounds with high enough priorities for more immediate consideration should be based on these effects. (Examples include benzene and 1,3-butadiene.) Estimates ofthe Magnitude ofExposure to As The extent of human exposure must be considered in the evaluation of the role of UAT in asthma. Because air sampling is Environmental Health Perspectives not routinely performed on each of these compounds, the lack of scientific information requires caution. One approach is to consider the extent of occupational exposure as an indication of possible sources of emissions. Recently, Seta and coworkers (166) estimated that over 6 million workers are potentially exposed to chemical or metal asthmagens at industrial settings throughout the United States. (Potential exposure to polyisocyanates alone exceeded 110,000 workers.) At a minimum, this suggests that several point sources exist that can potentially contribute to community air pollution. Historic levels reported in occupational settings are presented in 'Values are estimates from U. S. EPA (167). bAssumes no overlap in usage (may be an overestimate if more than one compound is used).  (167). Tables 13 and 14. Information on the level of current exposures is limited and requires additional study. Another approach to estimate the extent of exposure is to consider the emission inventories recently compiled by the U.S. EPA. Table 15 lists UAT compounds that are known or suspected asthmagens and presents the number of facilities and the total amounts estimated to be released into the air. These values are for the amounts released directly into the air and do not include estimates of intermedia transport or other pathways that might result in inhalation exposures in the ambient air. Styrene (168)(169)(170), formaldehyde (171), and acetaldehyde (172) are the three chemicals with the greatest number of reporting sources and with the greatest amount of release. In 1990, the total estimated release into the air of these 16 asthmagens was over 55 million pounds.
Release inventories for other UATs that might influence the respiratory health of persons with asthma are listed in Table 16. The highest levels of release are reported for chlorine and hydrochloric acid, two respiratory tract irritants. The estimated release of respiratory carcinogens is low. Estimates of the release of polycyclic aromatic hydrocarbons, however, are unlikely to be accurate because this value does not include amount produced by combustion. In addition, emission inventories are, at best, only qualitative and may serve as indications of the magnitude of point sources. These estimates have not been validated by air sampling near point sources. Furthermore, recent studies in California suggest that models of air toxic exposures using inventories often underestimate the actual measured concentrations downwind from stationary sources (MA Marty, personal communication). Nonetheless, the large number of possible point sources indicates that extensive human exposure is possible.
In addition, predictions of ambient concentrations require applications of air quality dispersion models of chemical-specific data. It is unclear whether inventory data have enough fidelity for such applications. Another important gap in the literature is whether cumulative effects result from multiple acute exposures at high levels. Release inventories only present estimates of annual averages and therefore lack detail for modeling elevated acute exposures.

Gurrnt Exosure Guidelines
Tables 17 and 18 present concentration guidelines for occupational and nonoccu-pational exposure. Included in these tables are the current ACGIH-TLVs (threshold limit values from the American Conference of Governmental Industrial Hygienists) for time-weighted averages for occupational exposures for a normal 8-hr workday and a 40-hr workweek, to which nearly all workers can be repeatedly exposed, day after day, without adverse effects. Importantly, bronchoprovocation challenges typically start at these concentrations, and occupational asthma is often defined by a decrease in lung function occurring at or below these values. Consequently, these values are unlikely to provide an adequate margin of safety for the general population. In addition, a comparison of the lowest odor threshold presented in Tables 5 and 6 and the TLVs presented in Tables 17 and  18 indicates that odor thresholds are often above recommended exposure limits, suggesting that when odor is detected, significant exposure can occur.
Also presented in Tables 17 and 18 are guidelines for exposure in the ambient air. Ambient air level goals (AALG) were obtained from a monograph by Calabrese and Kenyon (174). These guidelines are based on calculation from no observed effects level (NOEL) or lowest observed effects level (LOEL) corrected for lifetime exposure and divided by appropriate multiplicative uncertainty factors (as much as 1000 over the NOEL). When animal toxicity data are used, adjustments are made for the equivalent human breathing rates using species-specific equations and absorption factors.
Also presented in Tables 17 and 18 are the current reference exposure levels (RELs) developed for California (175). Exposure to each substance independently at or below these values is not expected to result in adverse (noncancer) health effects following estimated 1-hr maximum concentrations (acute) or annual average (chronic) for inhalation. To compare these values with the cancer unit risk, the latter must be multiplied by an exposure estimate (concentration x number of persons exposed). A major difference between these two values is that cancer unit risks are derived by linear extrapolation, assuming no threshold. In contrast, RELs assume a threshold (based on the NOEL presented by IRIS and other sources). One way to compare these values is to assume lifetime exposure of one million people to a concentration (in pg/mi3) equal to the cancer unit risk. For example, if a community of one million is exposed to 2.7 pg/mi3 Volume 103, Supplement 6, September 1995   Table 17 that have both a cancer unit risk and chronic REL value (formaldehyde, cadmium, chromium, nickel, toluene diisocyanate, and hydrazine), exposure is to be limited based more on the chronic noncancer effects. It is noteworthy that IRIS or other documentation of these values does not consider the possibility of induction or exacerbation of asthma specifically as a basis for chronic noncancer effects. NOEL for these compounds are primarily selected by the estimates of respiratory irritation. For example, formaldehyde's ACGIH-TLV and IRIS values are based on the data obtained on irritation, and not on potential to induce asthma or animal carcinogenesis data (173). Because the diagnosis of occupational asthma involves pulmonary responses that are reported at or below the TLV, exacerbation of asthma can occur at doses of these compounds below those that induce irritation. Therefore, the TLV and NOEL do not always account for the exacerbation of existing asthma. Inasmuch as sensitization is of more relevance when considering safeguarding a heterogeneous general population compared to an occupational population, these exposure guidelines should be considered tentative until further information can be obtained on the relationship between levels that produce irritation and asthma in industrial settings, and asthma in the nonoccupational settings.

Future Research Priorities
Exposure Assessment Future scientific investigations are needed to evaluate the possible links between UATs and asthma. Currently, little information exists on human exposure to these compounds. In particular, emission release inventories have yet to be validated by environmental sampling. Another unsettled issue specific to these compounds is the relative extent of indoor exposure. Because these compounds are in ETS, involuntary exposures are likely to be frequent. Aldehydes have several other indoor sources including wood fires and release from building materials, personal care products, and clothing (171). Initially, field investigations could assess total exposures to aldehyde and metal asthmagens Environmental Health Perspectives using probability-based sampling. One exposure aspect that is important in the induction of asthma is that the magnitude of peak concentrations and ambient air samples should include variant sample times if possible. Last, this group of compounds is ideal for future investigation of fugacity models and it would be helpful to know the amount of intermedia transport for these compounds, particularly the less volatile organic compounds.

Health Effcs Assessment
Because these compounds are highly toxic and in some cases carcinogenic, further human clinical testing is unlikely. Consequently, in vitro toxicology testing with human cell culture systems may be an acceptable alternative. End points important to airway inflammation, for example cytokine and eicosanoid production, should be examined to establish doseresponse information. These end points can readily be investigated in laboratory animals. Unfortunately, animal models of asthma have limitations, with most previous investigations focusing on acute, reversible airway hyperreactivity instead of persistent chemically induced asthma. Although small rodents (mice in particular) have advantages for measurement of molecular end points (e.g., detection of mRNA for key cytokine by in situ hybridization), these species are often less responsive than humans and make tests of lung functions difficult. Larger laboratory species (e.g., guinea pigs), in contrast, have disadvantages in that molecular end points are harder to measure (requiring gene cloning to generate riboprobes for this species) but are useful in evaluation of airway bronchoconstriction and hyperreactivity. The effects of chronic inhalation exposure to the UATs and the induction of persistent hyperreactivity is worthy of future investigations. In addition, information is needed on the dose related to continuation of a persistent syndrome in animals that already have hyperreactivity. Animal data on the effects of complex mixtures, including exposure to two or more UATs, UATs with particulate matter, or UATs with criteria pollutants also could be investigated with animals.
Dose-response data would be helpful to evaluate a current assumption made in risk assessment that the effect of each substance is additive for a given organ system. This assumption is contradicted by studies with respiratory irritants that suggest synergy can occur, e.g., acid sulfates dioxide and metal aerosols (176). Currently, ambient air quality standards are based largely on data obtained when each criteria pollutant is tested independently. Indeed, concerns about exceedances are based on the expected adverse effects of the pollutant in highest concentration (often ozone) without concern about coexposure to other irritant pollution present in the typical oxidant urban plume. For example, urban concentrations of aldehydes and other volatile organic compounds follow diurnal patterns and have peaks above 50 pg/mi3 (171). These exposures can occur with subsequent high ozone exposures (>250 pg/Mi3), and recent epidemiological studies tentatively suggest that pollution interactions may potentate respiratory responses (177). (Note that formaldehyde, acetaldehyde, and acrolein exposures often occur together in concentrations that exceed the REL values presented in Table 17.) The number of persons living near emitting point sources is unknown but could be derived from census data and information on the location of point sources throughout the United States. Furthermore, the percentage of persons in these populations that have asthma can be estimated based on NHANES survey. It would be useful to estimate the extent of exposure to these identifiable asthmagens. Such data could be useful in assessments of health care costs (178).
Last, the current epidemiological information on the possible associations between UATs and asthma is inadequate. Recent studies with criteria pollutants suggest that animal and clinical exposure data can underestimate respiratory health effects. One epidemiological study of formaldehyde suggests that children exposed in homes with concentrations of >150 pg/mi3 had a higher frequency of asthma and bronchitis than children with residential exposure <50 pig/mi3 (179).
Decrements in PEF were also correlated with formaldehyde exposure. Clinical studies with formaldehyde, in contrast, require much higher concentrations to produce transient increases in airway resistance (171). This suggests that persistent respiratory effects can result from indoor formaldehyde exposures and that environmental exposures produce effects not observed in clinical studies with short-term exposures. Confirmation through additional investigation of the effects of environmental aldehyde and other UAT exposure on persistent pulmonary function is thus warranted.

Conclusions
In summary, asthma is a serious illness with a high prevalence among the general population. Over the last 15 years, the incidence and severity of asthma have continued to increase. In the past, exposure to air pollution has been associated with an increase in respiratory symptoms and hospital admissions for asthma. The role of UATs in this condition (with and relative to other known hazardous compounds in air pollution) has yet to be explored thoroughly. Nonetheless there is good reason to think that certain compounds may be etiological factors in asthma.
Several UATs are known comounds or are related to compounds that are occupational asthmagens. Environmental agents associated with asthma include ambient particulate matter and environmental tobacco smoke; both are complex mixtures containing many compounds that are UATs. Last, several UATs that have not been reported to produce asthma directly may be particularly hazardous to persons with asthma because they can exacerbate asthma through repetitive irritation of airway epithelium. Other UAT compounds have antigenic potential and can be inhaled. The latter includes respiratory carcinogens that can form antigenic determinants through alkylation reactions with cellular macromolecules. Further research is needed to clarify the issues surrounding the extent of human exposure and the potential role of UATs in asthma.