Health Effects of Atmospheric Acid Aerosols: A Model Problem in Inhalation Toxicology and Air Pollution Risk Assessment

FUNDAMENTAL

AND

APPLIED

TOXKOLOGY

18,

17-24 (1992)

SYMPOSIUM

OVERVIEW

Health Effects of Atmospheric Acid Aerosols: A Model Problem in Inhalation Toxicology and Air Pollution Risk Assessment RICHARDB.

SCHLESINGER* ANDJUDITHA.GRAHAM~

*New York University Medical Center, New York, New York 10016; and TUnited States Environmental Protection Agency, Research Triangle Park, North Carolina 27711 Received July 18, 1991; accepted July 19, 1991

aerosols but found that the emerging data base was not yet adequate for definitive, quantitative health risk determinations. Aside from the timeliness of this topic, there is also a broader issue of importance for those involved in inhalation toxicology and air pollutant risk assessment. From this perspective, atmospheric acids become a model of the complex mixture of air pollutants and how research programs can be developed and results used in the presence of major scientific uncertainty to achieve risk assessment. The purpose of this Symposium was to present what is known about the health effects of acid aerosols within a framework that also treats the topic generically from the perspective of a model problem in the development of a risk assessment. Attention was focused on the need to understand exposure assessment rather than merely health assessment; to develop and integrate programs using dosimetry, animal toxicology, clinical, field, and epidemiology studies; to understand the toxicologically active species within a complex mixture that is different in various regions of the country; and on the desirability of considering complex mixture problems from a broad perspective. Before proceeding to the discussions of the acid aerosol health evidence, it is useful to frame them with an overview of potential human exposures. The information presented was drawn from three recent reviews (EPA, 1989; Graham et al., 1990; Spengler et al., 1990). Acid aerosols contain strong acids such as sulfuric acid (H2S04), ammonium bisulfate (NH4HS04), and nitric acid (HNOs) and weak acids, such as organic acids (e.g., formic, acetic). They are in gaseous (HN03) and particulate form. The fine mode (~2.5 pm mass median aerodynamic diameter, MMAD) particles predominantly consist of the acidic sulfates. Coarse mode particles exist in acid fogs and can be as large as 100 grn MMAD. Fogs can be even more chemically complex since they scavenge other pollutants in the air, thereby concentrating them. The particle sizes have important implications for deposition within the respiratory tract. Size distribution studies of both sulfate and hydrogen ions indicate that most are
Health Effects of Atmospheric Acid Aerosols: A Model Problem in Inhalation Toxicology and Air Pollution Risk Assessment. SCHLESINGER, R.B., ANDGRAHAM, J. A. (1992). Fundum.Appl. Toxicol. 18, 17-24.

A symposium entitled, Health Effects of Atmospheric Acid Aerosols: A Model Problem in Inhalation Toxicology and Air Pollution Risk Assessment, washeld at the 30th Annual Meeting of the Society of Toxicology (SOT) in Dallas, Texas. The symposium was sponsored by the Inhalation Toxicology Specialty Section of SOT, and was organized to integrate evidence from various disciplines concerning health effects from acid aerosols in ambient air. 0 1992 society of Toxicology.

Introduction and Perspective(7. A. Graham, U.S. Environmental Protection Agency) Acid aerosols consist of a solid or liquid particle phase suspended in a gas phase, the mixture of which has acidity. Acid aerosols have been of interest for some time due to excess mortality of sensitive subpopulations from acute acid fog episodes in the Muese Valley, Belgium in 1930; Donora, Pennsylvania in 1948; and London, England in 1952. More recent information from animal toxicological and human clinical and epidemiological studies summarized by other Symposium speakers suggests acute and chronic effects and illustrates the reasons for the current heightened interest in the health effects of acid aerosols. Although the particulate phase of acid aerosols is regulated by the Environmental Protection Agency (EPA) under the National Ambient Air Quality Standard for Particulate Matter less than 10 pm, the EPA is considering whether a separate acid aerosol standard is needed and can be developed. To these ends, the EPA (1989) reviewed and evaluated the literature. The Clean Air Science Advisory Committee (an external expert advisory group to the EPA) reviewed this report and expressed significant concern about the potential health effects of acid 17

0272-0590/92

$3.00

Copyright 5 1992 by the Societyof Toxicology. All rights of reproduction in any form reserved.

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AND GRAHAM

lar) region. Nitric acid, being very soluble, is expected to aerosols, followed by an integration of the evidence. Although deposit primarily in the nasopharyngeal region. the first three topics were treated independently in the SymSince standard validated methods for monitoring acid posium, it is interesting to note the relatively high degree of aerosols are not yet available, most information on ambient correlations between the human clinical and animal toxiair levels is derived from specific research studies rather than cological findings. The epidemiological studies are of interest large-scale monitoring projects. From such limited inforsince they indicate the potential for ambient exposures to mation, some patterns emerge. Air levels of acid aerosols are cause health effects. The final topic, risk assessment, draws very dynamic, varying by season, time of day, and geography. upon the available knowledge from all the experimental apThe levels are influenced strongly by atmospheric ammonia proaches to summarize the current state of knowledge. neutralization and meteorology. For example, as an air mass (This article has been reviewed by the Environmental Cricontaining acids is transported across areas with high am- teria and Assessment Office, EPA, and approved for publimonia content, HzS04 is neutralized toward ammonium cation. Approval does not signify that the contents necessarily reflect the views and policies of EPA.) sulfate which has less toxicological potency than HzS04. There can be considerable geographical variability (i.e., different sulfate mixtures) as a result of this neutralization and References as a result of the acid precursors. For example, regions such Environmental Protection Agency. ( 1989). An Acid Aerosols Issue Paper.’ Health Effects and Aerometrics. Office of Health and Environmental Asas the eastern United States have acidic sulfate aerosols due sessment, Environmental Criteria and Assessment Office, EPA Report to sulfur dioxide emissions sources; in Southern California, No. EPA-600/8-88-005F. HN03 levels are elevated due to nitrogen oxide sources. Graham, J. A., Grant, L. D., Folinsbee, L. J., Gardner, D. E., Schlesinger, Typically, acid aerosol levels are higher in the summer R. B., Overton, J. H., Lounsbury, S. W., McCurdy, T. R., Hasselblad, than in the winter and peak levels occur in the daytime. This V., McKee, D. J., Richmond, H. M., Poikowsky, B. V., and Marcus, A. H. (1990). Direct health effects of air pollutants associated with acidic has important implications for human exposures. During precursor emissions. NAPAP SOS/T 22. In Acidic Deposition, State of summer daytime periods, more people are likely to be outScience and Technology, pp. 22-43-22-58. National Acid Precipitation doors engaged in some level of physical exercise which will Assessment Program, Washington, DC. further increase the dose delivered to the respiratory tract. Spengler, J. D., Brauer, M., and Koutrakis, P. (1990). Acid air and health. This period coincides with peak ozone exposures which have Environ. Sci. Technol. 24, 946-956. additive and synergistic (depending on the nature of the Spengler, J. D., Keeler, G. J., Koutrakis, P., and Raizenne, M. (1989). Exposure to acid aerosols. Environ. Health Perspect. 79, 43-5 1. study) effects with acidic sulfates. Children are of special concern, not only because of their extensive summer outdoor activities, but also because of the potential impacts of chronic Animal Toxicologic Evidence for Health Eflects (R. B. Schlesinger,New York University Medical Center) exposures beginning at an early age. Toxicological studies using laboratory animals are essential Levels of acid aerosols are poorly characterized, except in a very few locations. The majority of measurements (pre- in developing an adequate data base for use in attempts to reliably estimate risk to humans from exposure to acidic dominately >6 hr averaging times) show levels of <5 &m3 HzS04 or equivalent H+. Events with higher level peaks are aerosols. Such studies are designed to identify the nature of observed in most studies. As examples, 12-hr peaks can range responses to exposure and the range of concentrations and from 5-36 &m3 H2S04 or H+ equivalent, 6-hr peaks from exposure durations over which such responses occur, as well 5-21 pg/m3, and I-hr peaks from 7 to 27 &m3. One-hour as to provide information concerning the underlying mechmaximums of 40-50 pg/m3 have been reported (Spengler et anisms of potential human toxicity and disease pathogenesis. al., 1989, 1990). The toxicologic data base for acid sulfates (primarily sulfuric Research issues for acid aerosols are quite challenging, as acid) is fairly robust, and it is possible to come to a number they are for any complex mixture. Health research on each of reasonable conclusions concerning potential health effects possible exposure scenario is not feasible. Rather, researchers from exposure. The most commonly measured indices of response are need to determine sets of studies that can be done to predict the effects of mixtures. Key questions would include: (1) pulmonary mechanics, usually assessed by monitoring rewhat are the likely causative factors-H+, the anion, indisistance and compliance. Most of these studies have been vidual acidic chemical species, and/or nonacidic co-occurring performed using the guinea pig, which is a likely model for pollutants; (2) what concentrations and durations of expo- a sensitive human subpopulation. However, except for this sures are critical; and (3) how can human clinical, animal animal model (Amdur et al., 1978), acute exposure to sulfuric toxicological, field, and epidemiological studies be applied acid at concentrations less than 1000 pg/m3 (measured as and subsequent data linked to achieve a fuller interpretation SO;‘) does not result in changes in standard indices of pulof health risk? monary mechanics. The discussions to follow center on animal toxicological, The use of pharmacologic agents capable of inducing human clinical, and epidemiological observations of acid smooth muscle contraction, a technique known as broncho-

HEALTH

EFFECTS OF ATMOSPHERIC

provocation challenge testing, can assessthe state of airway responsiveness after exposure to a nonspecific stimulus. Hyperresponsivity is a characteristic of some lung diseases, the most notable of which is asthma. Repeated exposures to sulfuric acid induced a state of increased airway responsivity in healthy animals (Gearhart and Schlesinger, 1986); the exposure concentration was 250 &m3 but total exposure levels were within those found in ambient air when the product of exposure concentration (C) and exposure time (T) was considered. The development of hyperresponsive airways in healthy animals due to acid aerosols, at an exposure level below that producing any change in lung function without bronchoprovocation challenge, does have implications for the pathogenesis of airway disease. Changes in airway morphology are generally seen with acute exposure to sulfuric acid at levels well above 1000 pg/ m3. Effects include alveolitis, bronchial and bronchiolar epithelial desquamation, and pulmonary edema. The severity of response depends upon some combination of concentration and length of exposure, rather than on concentration alone. Repeated or chronic exposures at levels
ACID AEROSOLS

19

for a single 2-hr exposure. With multiple exposures, the time at this concentration is reduced to 1 hr daily. In terms of clearance from the alveolar region, a level of 50 clglm3 can accelerate particle clearance when exposures are for 4 hr/ day for 14 days. The relative potency of acid sulfates is likely related to their acidity, with H2S04 more potent than NH4HS04 which, in turn, is more potent than (NH&S04. Thus, the biologically active portion of acidic sulfates is likely the H+ rather than the SO;*. What remains uncertain, however, is the relationship between response and H+ content. Recent data suggest that H2S04 is disproportionately potent compared to NH4HS04 when the H+ content of each compound is taken into account and that the effects of inhalation exposure to equal concentrations (in terms of H+) of each chemical species may not be the same (Schlesinger et al., 1990). The relationship between H+ content, specific sulfate compound, and response has implications in terms of ambient monitoring, since it is critical to know whether analysis for total hydrogen ion content of ambient air is adequate to assess the potential hazard from inhaling acidic sulfates, or whether it is necessary to speciate the measurements into individual sulfate compounds. Although most of the toxicologic data concerning acid aerosols has been obtained from exposures using single compounds, it is important to examine responses resulting from inhalation of typical pollutant mixes. The occurrence and extent of interactions involving acid aerosols depend upon the endpoint being examined, as well as on the coinhalant. In most studies with 03, for example, the response was primarily due to the ozone. However, an exception involves changes in collagen synthesis, lung protein content, and tracheal mucus glycoprotein in which case O3 and H2S04 acted synergistically with continuous daily exposures for up to 7 days (Last, 1989). Fairly low levels of sulfuric acid, down to 11 pg/m3, were effective in this regard in conjunction with peak ambient levels of 03. Toxic effects due to acid itself may be more manifest with other, less potent, coinhalants. The most realistic exposures are to multicomponent mixtures, but all possible combinations of toxicants cannot be examined experimentally. The data base does, however, suggest that the acid sulfate components of such atmospheres may be a factor in observed responses (Kleinman et al., 1989). In summary, the current data base permits speculation that the potential exists for production of chronic lung disease due to long-term inhalation of acid aerosols. Although the exposure concentrations associated with persistent changes are above those currently found in ambient air, responses are likely due to a combination form of C X T and, therefore, information from toxicological studies may have relevance to effects experienced by the general population. The biological changes considered as pathologically significant in this regard are alterations in bronchial responsivity, retarded

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SCHLESINGER

mucociliary clearance, epithelial secretory cell hyperplasia and hypertrophy observed with exposures to acid sulfates, and changes in lavage biochemical indices observed with coexposure to ozone. Consistent effects have been found in more than one species of laboratory animal with some of these endpoints, and clinical studies (see below) have also found increased responsivity and altered mucus clearance following acid sulfate exposure.

References Amdur, M. O., Dubriel, M., and Creasia, D. A. (1978). Respiratory response of guinea pigs to low levels of sulfuric acid. Environ. Res. 15, 4 18-423. Gearhart, J. M., and Schlesinger, R. B. (1986). Sulfuric acid-induced airway hyperresponsiveness. Fundam. Appl. Toxicol. 7, 68 l-689. Gearhart, J. M., and Schlesinger, R. B. (1989). Sulfuric acid-induced changes in the physiology and structure of the tracheobronchial airways. Environ. Health Perspect. 79, 127- 137. Kleinman, M. T., Phalen, R. F., Mat&, W. J., Mannix, R. C., McClure, T. R., and Cracker, T. T. (1989). Health effects of acid aerosols formed by atmosphere mixtures. Environ. Health Perspect. 79, 137-145. Last, J. A. (1989). Effects of inhaled acids on lung biochemistry. Environ. Health Perspect. 79, 115- 119. Schlesinger, R. B. (1989). Factors affecting the response of lung clearance systemsto acid aerosols: Role of exposure concentration, exposure time, and relative acidity. Environ. Health Perspect. 79, 12 1- 126. Schlesinger, R. B., Chen, L. C., Finkelstein, I., and Zelikoff, J. T. (1990). Comparative potency of inhaled acidic sulfates: Speciation and the role of hydrogen ion. Environ. Res. 52, 2 10-224.

Controlled Clinical Studies: Evidencefor Health Eflects (AI. J. Utell, University of RochesterMedical Center) Until recently, acid deposition has been widely considered to be a serious ecological problem, but not a threat to human health. A growing body of evidence from animal and human studies indicates that acidic aerosols may effect human health. Carefully controlled quantitative studies of exposed humans offer an important approach in linking acidic aerosol inhalation with respiratory effects. Human clinical studies create laboratory atmospheric conditions, which are considered relevant to ambient pollutant atmospheres, and document any health-related effects which result from breathing the atmospheres. Advantage is taken of the highly controlled environment to identify responses to individual pollutants and characterize exposure-response relations as well as to examine interactions among pollutants per se or with other environmental variables such as exercise, humidity, or temperature. Insofar as individuals with acute and chronic respiratory diseases can participate in exposure protocols, potentially susceptible populations can be studied. This approach too has limitations: for practical and ethical reasons, studies must be limited to small groups presumably representative of larger populations, to short durations of exposure, and to pollutant concentrations that are expected to produce only mild and transient responses. End point assessment invariably includes pulmonary function. Further-

AND GRAHAM

more, efforts to predict chronic health effects from acute outcomes in clinical studies are fraught with hazard. Controlled inhalation studies have identified asthmatics as the subpopulation most responsive to acid aerosols. Exposures have been performed in environmental chambers and by mouthpiece with response assessed primarily by alteration in respiratory mechanics. In a series of studies in asthmatics, several factors have been identified which modulate the intensity of the bronchoconstrictor response: (1) The more acidic sulfates, sulfuric acid and ammonium bisulfate aerosols, provoke the greatest changes in lung function (Utell et al., 1983); (2) the amount of titratable acidity in an aerosol may play a role in determining bronchoconstriction (Fine et al., 1987); (3) the mitigation of airway responses during inhalation of sulfuric acid aerosols with high respiratory ammonia concentrations (Utell et al., 1989); and (4) the enhancement of sulfuric acid aerosol deposition and bronchoconstrictor responses during exercise. More recently, investigators have observed decrements in lung function in adolescent asthmatics after exposure to only 68 pg/m3 H2S04 and possibly greater effects when the H2S04 aerosol was combined with 0.1 ppm SOZ (Koenig et al., 1989). Significant reductions in lung function were observed, however, only during the exercise exposure. Thus, as with inhalation of sulfur dioxide, exercise played an important role in potentiating airway responses in asthmatics at pollutant levels relevant to high ambient concentrations. In contrast to the findings in asthmatics, studies in normal volunteers have demonstrated alterations in lung function only at concentrations far in excess of ambient levels. To date, the limited studies in volunteers with chronic obstructive pulmonary disease, a term that denotes pulmonary emphysema and chronic bronchitis, have failed to identify increased airway responsiveness in this population with fixed obstructive disease. However, since chronic obstructive pulmonary disease affects some 10 million Americans and is the fifth leading cause of death in the United States, small acute changes in lung function induced by ambient acidic aerosols could lead to increased exacerbations of respiratory disease and hospitalizations with major costs to society. Thus, this group of individuals with severe lung disease warrants more intensive investigation. With acidic aerosol pollutants, it is likely that the most sensitive site of action in the human respiratory tract has not been identified because the methodology required was inadequate or too invasive. The adaptation of clinical investigative tools, such as bronchoalveolar lavage, nasal lavage, measurement of epithelial permeability, or mucociliary clearance with radiolabeled aerosols, permits new approaches to the study of mechanisms of pollutant-induced effects. Limited applications of these techniques have appeared and indicate that, for example, short-term exposure to oxidants increases respiratory epithelial permeability, produces an influx of neutrophils in lavage fluid, and results in less efficient

HEALTH

EFFECTS OF ATMOSPHERIC

ACID AEROSOLS

21

Historically, it appears that the health effects observed in the great air pollution episodes in the Meuse Valley of Belgium in 1930, Donora, Pennsylvania in 1948, and London, England in 1952, may be attributable to acid aerosols. In these events a different chemical transformation was operReferences ative. In all three cases a cold stagnating fog settled on these Fine, J. N., Gordon, T., Thompson, J. E., and Sheppard, D. (1987). The regions. Sulfur oxide and particle concentrations built up role of titratable acidity in acid aerosol-induced bronchoconstriction. Am. over several days. Sulfur dioxide can be catalytically conRev. Respir. Dis. 135, 826-830. verted to sulfuric acid by many metals found in particulate Koenig, J. Q., Covert, D. S., and Pierson, W. E. (1989). Effects of inhalation pollution in the presence of liquid water drops, that is, fog. of acidic compounds on pulmonary function in allergic adolescent subjects. Environ. Health Perspect. 19, 173- 178. Thus, it is likely that sulfuric acid was an important conUtell, M. J., Mar&ho, J. A., Morrow, P. E., Gibb, F. R., and Speers, D. M. stituent of these fogs. (1989). Effects of inhaled acid aerosols on respiratory function: The role In London, the health effect was particularly dramatic in of endogenous ammonia. J. Aerosol Med. 2, I4 1- 147. that daily mortality increased by a factor of three in correUtell, M. J., Morrow, P. E., Speers, D. M., Darling, J., and Hyde, R. W. lation with the increase and decrease in sulfur dioxide and (1983). Airway responses to sulfate and sulfuric acid aerosols in asthmatics: particulates. Although aerosol acidity was not measured An exposure-response relationship. Am. Rev. Respir. Dis. 128,440-450. during this episode, it was thought at the time that sulfuric Epidemiologic Evidence for Health Eflects (0. W. Dockery, acid might be the most important constituent of the pollution mix. During a similar episode in December 1962, daily mean Harvard School of Public Health) sulfuric acid concentrations had a maximum of 347 hg/m3. Although acid aerosols have been thought to be one of In 1963, daily measurements of sulfuric acid were begun the most important forms of air pollution for many decades, in London. Recent reanalyses of these data by Thurston and the available epidemiologic evidence is limited. Standardized co-workers (1989) suggest that there is a correlation between techniques for measuring acid aerosols have not been estab- daily mortality in London and daily sulfuric acid concenlished nor have routine monitoring programs been under- trations even at the much lower concentrations observed taken. Thus exposure data is limited, and surrogate measures during the winters of 1963 to 1972. Maximum 24-hr values of acid aerosols must be used to interpret community-based are on the order of 20 to 30 pg/m3 sulfuric acid, and annual studies. mean concentrations are 3 to 4 pg/m3 sulfuric acid. These Acid aerosols are primarily sulfuric acid droplets, but there are concentrations which are comparable to values currently are other acid species including nitric and nitrous acid which being measured in the United States. can contribute to total aerosol acidity. Sulfuric acid is a subset In the United States there is the suggestion that city-specific of the sulfate ion particles. Sulfate particles are the primary age-adjusted mortality increases with annual mean sulfate. subset of particles in the respirable size range. They are also In fact the correlation of mortality with average air pollution responsible for the light scattering of summer haze events. was better with sulfate than particle concentrations. Lippman Respirable particles are a subset of the total suspended par- ( 1989) has hypothesized that a stronger association would ticles. While these measures are all correlated, they provide be found if aerosol acidity data were available. only indirect measures of acid aerosol exposure, and the furWhile death is a well-defined and serious health end point, ther the pollution measure is from the direct measurement in many cases these excess deaths may represent an advance of acid aerosols, the greater the probability for misclassifiof the date of death among patients who were already serication of exposure. ously infirm. Thus, some fraction of these deaths will repIn North America acid aerosols are observed primarily in resent little loss of life compared to that accruing from the the summer. Sulfur dioxide is converted to sulfuric acid by death of a young person, for example. Thus, measures of the photochemical reactions in the presence of nitrogen oxides effect of acid aerosols on measures of morbidity, that is, illand hydrocarbons. These same photochemical reactions also ness, must also be considered. produce ozone and nitric acid. Thus high ozone and particBates and Sizto (1987) have examined the correlation of ulate levels that are associated with summer haze are often air pollution with daily hospital admissions for respiratory associated with high acid aerosol concentrations. The avail- complaints in Southern Ontario. Overall, the correlations able acid aerosol measurements from communities across were low, but statistically significant associations were found the United States and Canada show the highest 24-hr max- during the summer with the previous days’ sulfate and ozone imum concentrations of approximately 40 pg/m3 equivalent concentrations. These measures are both high during sumsulfuric acid in West Virginia and southwest Pennsylvania mer haze episodes when acid aerosol concentrations would (Spengler et al., 1990). The lowest mean values, ~0.5 pg/m3 also be elevated. or less, are found in the West where sulfur dioxide concenSeveral studies have shown an association between citytrations are low. specific respiratory illness reporting and indirect measures viral inactivation by alveolar macrophages. As more sensitive clinical tools emerge, more specific markers of acid-induced effects are likely to be identified.

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of aerosol acidity. An early study of respiratory illness absences among RCA workers at various plants showed an association with annual mean sulfate concentrations. More recent evidence has suggested that the frequency of bronchitis is correlated with summer mean aerosol acidity concentrations for children participating in the Harvard Six Cities study. The city-specific rate of bronchitis reporting increases linearly from about 31 to 10% as the summer mean aerosol acidity increased from 0.5 to 2 pg/m3 of equivalent sulfuric acid (Speizer, 1989). The correlation is stronger than that shown with any of the pollutants for which ambient air quality standards have been established. Thus, there is a bcdy of evidence showing associations of mortality and morbidity with direct and indirect measures of aerosol acidity. Daily mortality has been associated with aerosol acidity. Daily respiratory admissions were correlated with summer haze events, that is, conditions in which high acid aerosol concentrations have been observed. City-specific chronic respiratory illnesses have been correlated with annual mean sulfates. Moreover, city-specific chronic respiratory symptoms have been correlated with direct measures of acidity. There are weaknesses in each of these epidemiologic investigations and individually none provides compelling evidence for an association between acid aerosols and impaired respiratory health. Taken together, however, they present a suggestive, consistent body of information. Epidemiologic studies are underway which should clarify the role of aerosol acidity in producing acute and chronic health effects.

AND GRAHAM

ment), (3) exposure assessment, and (4) risk characterization, which is built upon a combination of (2) and (3) above. In this summary, I first consider exposure assessment which provides a perspective for the overall issue. I then briefly summarize the information available for hazard assessment from the study of laboratory animals and people. The information available today is not sufficient to conduct a rigorous exposure-dose-response assessment and risk characterization for acidic aerosols. As reviewed in this symposium, the present state of our knowledge on ambient concentrations of aerosols is rudimentary when compared to the criteria pollutants such as ozone, particulate material, and many of the individual hazardous pollutants, such as butadiene or formaldehyde. This lack of exposure data is related to the recent development of interest in acid aerosols. In addition, a major stumbling block has been the lack of easy-to-use and universally accepted techniques for making measurements of acid aerosols. It is probably not surprising that there is still uncertainty as to the appropriate exposure metric; however, increasing acceptance is being gained for use of H2S04 or the hydrogen ion equivalent exposure term expressed as pg/m3. An additional related issue is the appropriate averaging time for exposure measurements, i.e., 1 hr, 6 hr, etc. Ideally, one should use an averaging time that makes sense from a biological response viewpoint; i.e., if responses are linked most tightly to exposures of a few hours duration, a very shortterm averaging time would be appropriate. However, if critical biological responses were linked most closely to an integrated exposure time-concentration over a period of days References or weeks, then a corresponding averaging time for field measurements of exposure would be most appropriate. Bates, D. V., and Sizto, R. (1987). Air pollution and hospital admissions in Southern Ontario: The acid summer haze effect. Environ. Res. 43, 3 17Based on the meager data available, ambient concentra331. tions of acid aerosols in the United States appear to be below Lippmann, M. ( 1989). Background on health effectsof acid aerosols. Environ. 5 &m3 for averaging times greater than 6 hr, with occasional Health Perspect. 79, 3-6. peak excursions of slightly less than 20 pg/m3 for averaging Speizer, F. E. (1989). Studies ofacid aerosols in six cities and in a new multitimes of less than 6 hr. The maximum recorded/hr meacity investigation; Design issues. Environ. Health Perspect. 79,61-67. surement was on the order of 50 &m3. These values indicate Spengler, J. D., Brauer, M., and Koutrakis, P. (1990). Acid air and health. the range of exposure of greatest interest for risk assessment Environ. Sci. Technol. 24, 946-956. purposes, A critical factor in assessing the health risks of Thurston, G. D., Ito, K., Lippmann, M., and Hayes, C. (1989). Reexamination of London, England, mortality in relation to exposure to acidic exposure to these low concentrations of acidic aerosols is the aerosols during 1963-1972 winters. Environ. Health Perspect. 79,73-82. extent to which copollutants such as ozone are almost always present. In fact, it is quite possible that ambient concentraIntegration of the Evidence: Risk Assessment for Ambient tions of acidic aerosols are only of concern when other polAcid Aerosols (R. 0. McClellan, Chemical Industry lutants are present. It is a formidable challenge to the toxiInstitute of Toxicology) cologist to assessthe risks of such combined exposures. The human health risks of exposure to ambient concenThe hazard assessment for acidic aerosols is very much trations of acidic aerosols can be best considered within the dependent upon the integration of evidence acquired from laboratory animal experimentation, controlled human studframework of the risk assessment/risk management paradigm advanced by the National Academy of Sciences/National ies, and epidemiological investigations. The need for this Research Council. Specifically, the NAS/NRC paradigm ad- integrated approach relates to the paucity of human data vocates an integrated approach that includes (1) hazard and the appropriateness of drawing on the complementary identification, (2) dose-response assessment (which is more strengths of these several approaches. The laboratory animal appropriately related as an exposure-dose-response assess- studies indicate alterations in mucociliary clearance, bron-

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OF

ATMOSPHERIC

ACID

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AEROSOLS

LINKING EXPOSURES AND RESPONSE Concentration H, SO, equivalent - pghn3

!

Resoonses

- Clinical - No response in normal subjects - Epid - Deaths in respiratory impaired individuals

200 Likely “killer” fog concentrations 100

Maximum Typical Typical

short-term short-term ambient

peaks peaks

- Animal

- Increased

* Animal

- Altered

* Clinical

- Reduced

- Animal

- Altered

airway

resistance

tracheobronchial pulmonary alveolar

with hospital

- Epid - Correlation

with frequency

chial responsivity, epithelial cell hyperplasia, and hypertrophy induced by acid aerosols. These effects are related to both exposure concentration and duration. Of the several acidic aerosols studied, H2S04 is the most potent acidic sulfur-containing compound. The data currently available suggest the effects are due to deposition of hydrogen ion. The controlled human studies have focused on evaluating changes in pulmonary function. Short-term exposure of healthy human subjects to several hundred &m3 of H2S04 is without measurable effect. Short-term exposure of asthmatics to 50- 100 &m3 while exercising results in reductions in pulmonary function, suggesting that such individuals may represent a sensitive subpopulation to be considered for standard-setting purposes. In asthmatics, short-term exposure to 100 pg/m3 resulted in altered mucociliary function. For standard-setting purposes, it is presently unclear whether such changes represent a physiological adaptation or should be considered as an adverse effect. The epidemiological data base for acidic aerosols is meager. This is related to past difficulties in adequately characterizing acidic aerosol exposures and the absence of populations for study in situations in which there is an adequate gradient of exposure. The success of any epidemiological investigation is dependent upon having a gradient in exposures against which one can “test” for a corresponding gradient in health outcome. The data available for acidic aerosols indicate that at very high concentrations there is a correlation between high concentrations of SO2 and particulate material and acute respiratory deaths. The relevance of these observations is open to question as regards assessing risks of current ambient acidic aerosol exposures. Other studies suggest an association between high levels of sulfate and ozone and daily hospital

function

in asthmatics

clearance

- Epid - Correlation

FIGURE

clearance

admissions of bronchitis

1

admissions for respiratory complaints. Perhaps the epidemiological evidence of greatest concern is the correlation between frequency of bronchitis in children and mean acidic aerosol exposures of 0.5 to 2 pg/m3. The data from these three complementary approaches is summarized in Fig. 1. The available data indicate that health responses are observed with all three approaches with exposure concentrations below 100 pg/m3. There is a clear need to extend these studies to better assess the extent to which current exposures to ambient acidic aerosols are of environmental health concern. Looking to the future, the use of the three approaches discussed above, because they are complementary, should be considered and are summarized in Table 1. Each approach has inherent weaknesses and strengths: the ultimate strength comes through integration of the information provided by each. The integration of information from these several approaches and the study of cells and tissue culture discussed below will be greatly facilitated by using an (exposure) + (dose to critical biological units) + (health response) paradigm. In addition to the approaches shown in Table 1, investigations with cell and tissue culture systems may offer some advantage in characterizing the relative role of different acidic agents. To provide data relevant to assessing human health risks, the exposure concentrations and times must be matched to ambient exposure observations. Information on the mechanisms of action of high concentrations of acidic agents may be easy to acquire, but irrelevant to assessing human health risks. Additional studies involving controlled exposures of both laboratory animals and human subjects are needed. To be

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AND GRAHAM

TABLE 1 Characteristics of Complementary

Define exposure materials Flexibility in selecting exposure levels Typical duration of exposure Response endpoints evaluated Relevance of information to people Linkage to specific agent

Approaches

Laboratory animal studies

Controlled human exposure studies

Epidemiological studies

Yes High Short- to long-term Highly flexible Via extrapolation Yes

Yes Limited Short-term Limited Direct Yes

No None Short- to long-term Diseases of interest Direct Uncertain

most useful, these studies must include multiple exposure concentrations and durations ultimately to allow elucidation of interrelationships between exposure concentration, exposure duration, and response. A useful strategy may be to use data from cell/tissue studies to select acidic agents for study in short-term controlled exposure animal investigations and then to use these data to select a few agents for use in controlled human exposure studies. The results of these studies in aggregate can be used to guide the design of studies evaluating the role of coexposure to other key pollutants, such as ozone, in laboratory animals and human subjects. The National Toxicology Program currently has underway a study evaluating the effects of 2 years of exposure to multiple concentrations of ozone in rats and mice. This study goes beyond the traditional 2-year cancer bioassay and includes supplemental evaluations of functional, biochemical, and histopathological parameters supported by the Health Effects Institute. Dependent upon the outcome of this research with ozone alone, it may be appropriate to plan similar studies that include exposure to ozone and an acidic agent. In summary, exposures to acidic aerosols are only now beginning to be characterized. Past efforts have been hampered by uncertainty as to the appropriate exposure metric

and easy-to-use measurement equipment and methods. Current exposure data indicate widespread exposure of people at concentrations of less than 5 pg/m3 sulfuric acid equivalent with copollutants such as ozone almost always present in quantities that raise concern for combined exposure effects. The data base from laboratory animal, controlled human exposure, and epidemiological studies is meager. These data suggest the absence of a problem of overwhelming public health concern; however, the integrated data suggest the potential for human health effects at ambient exposure concentrations. Better definition of the acidic aerosol health effects issue requires better knowledge of the interrelationship between exposure concentration and exposure duration for specific acidic agents and copollutants such as ozone and a range of health outcomes from acute functional changes to possible chronic respiratory diseases. Progress is likely to be enhanced by a research strategy that utilizes cell and tissue culture systems, controlled animal exposure studies, controlled human exposure studies, and epidemiological investigations and that also considers the effective dose to critical biological units as a means of integrating information within an exposure ---t dose + response paradigm.