S6 ch28 air_pollution

UNIT 6

ENVIRONMENTALTOXICOLOGY

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Copyright © 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com

tochemically transformed stationary and mobile emissions. Weknow most about the health effects of individual pollutants, andwe use this knowledge to drive controls where single pollutantsdominate the situation. However, much less is understood aboutthe realities of present-day patterns of diurnal and prolonged ex-posure and how mixtures of pollutants can affect human health.This chapter is intended to inform the reader as to the state of ourknowledge of air pollution, with the goal of providing the readerwith a fundamental knowledge and appreciation of the nature ofthe problem, its complexity, and the uncertainties in need of in-vestigation.

A Brief History of Air Pollution

For most of history, air pollution has been a problem of microen-vironments and domestic congestion. The smoky fires of early caveand hut dwellers choked the air inside their homes. When it waseventually vented outdoors, it combined with that of the neighborsto settle around the village in the damp cold night. With urbaniza-tion and the concomitant decrease in forest wood as a source offuel, the need for heat and energy led to the burning and ambientrelease of sulfurous, sooty smoke from cheap coal. City dwellershad to endure the bad air, while those with wealth had countryhomes to which they could escape from time to time. The poorquality of urban air is well documented historically. Seneca, theRoman philosopher, in A.D. 61 wrote: “As soon as I had gotten outof the heavy air of Rome, and from the stink of the chimneysthereof, which being stirred, poured forth whatever pestilential va-pors and soot they had enclosed in them, I felt an alteration to mydisposition” (emphasis added: Miller and Miller, 1993).

AIR POLLUTION IN PERSPECTIVE

A Brief History of Air Pollution

ASSESSING RISKS ASSOCIATED WITH AIRPOLLUTION

Animal-to-Human Extrapolation: Issues andMitigating Factors

Air Pollution: Sources and Personal ExposureIndoor versus Outdoor

EPIDEMIOLOGIC EVIDENCE OF HEALTH EFFECTS

Outdoor Air PollutionAcute and Episodic ExposuresLong-Term Exposures

Indoor Air PollutionSick-Building SyndromesBuilding-Related Illnesses

POLLUTANTS OF OUTDOOR AMBIENT AIR

Classic Reducing-Type Air Pollution

AIR POLLUTION IN PERSPECTIVE

The last fifty years have brought remarkable changes in the waywe view our environment. In the early 1950s, our industrial pros-perity was often depicted as an expanse of factories with smoke-stacks belching opaque black clouds into the surrounding air. Thegrowing environmental activism in the latter decades of the cen-tury—stemming from aesthetic and, more importantly, health con-cerns—forced regulatory legislation that has now made such scenesrare in most technologically advanced nations. Today, every urbancommunity is in search of “clean industries.” Yet ironically, we en-dure increasingly congested thoroughfares of automobiles com-muting to these industries as we fuel a photochemical cauldron ofoxidant air pollution—i.e., smog. Moreover, areas once considered“pristine” are today tarnished by the influx of polluted air massesthat drift and disperse across hundreds of miles. Clearly, air pol-lution remains a reality of our twenty-first-century lifestyle, andwhile great strides have been made to reduce emissions from bothstationary and mobile sources, unsatisfactory air quality nowplagues much broader geographic areas. As a result, millions ofpeople in the United States live in areas that are not in compliancewith current National Ambient Air Quality Standards (NAAQS)(Fig. 28-1).

Most peoples of the western world today face fewer episodesof extreme air pollution; instead, they experience prolonged peri-ods of relatively low-level exposure to complex mixtures of pho-

Sulfur DioxideSulfuric Acid and Related SulfatesParticulate MatterPhotochemical Air PollutionShort-Term Exposures to SmogChronic Exposures to Smog

OzoneNitrogen DioxideOther OxidantsAldehydesFormaldehydeAcroleinCarbon MonoxideHazardous Air PollutantsAccidental versus “Fence-Line” Exposures

WHAT IS AN ADVERSE HEALTH EFFECT?

CONCLUSIONS

CHAPTER 28

AIR POLLUTION*

Daniel L. Costa

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*This article has been reviewed by the National Health and Environmental EffectsResearch Laboratory, U.S. Environmental Protection Agency, and approved for pub-lication. Approval does not signify that the contents necessarily reflect the views andthe policies of the Agency.

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Efforts to regulate air pollution, on the other hand, evolvedmore slowly. Beginning in the thirteenth century, community-basedoutcries received some recognition by governing officials, oneexample being the banning of domestic burning of “sea coal” inLondon by Edward I. Enforcement, however, was not effective andpeople largely resigned themselves to polluted air as part of urbanlife. By the seventeenth century, England, in the middle of severaldecades some refer to as “the little ice age,” experienced furtherreductions in wood harvests, thus increasing reliance on sea coalfor domestic heating. Despite Percival Pott’s discovery that sootwas related to the occurrence of scrotal cancer in chimney sweeps,the health community offered only a simple recommendation: “Flythe city, shun its turbid air; breathe not the chaos of eternal smoke. . . ” (Brimblecombe, 1999)—advice hardly advanced from thatof Seneca 1600 years earlier. In the late eighteenth century, the in-dustrial revolution, which was powered by the burning of minedcoal, added a second dimension to urban air pollution. These emis-sions were more acidic and hung in the air longer than the fluffysoot of the cheaper sea coal burned in home heaters. Continuedsoiling of buildings and damage to nearby crops brought commu-nity boards to address sanitary reforms to cut the worse of the pol-lution peaks and episodes, but any gains were soon offset bygrowth. By the end of the nineteenth century and into the earlytwentieth century, power plants were being built to provide energyfor factories and eventually to light homes. Steel mills and otherindustries proliferated along riverbanks and lakeshores, oil re-

fineries rose in port cities and near oilfields, and smelters roastedand refined metals in areas near large mineral deposits.

By 1925, air pollution was common to all industrialized na-tions, but people became less tolerant of the nuisance of acidic-soot corrosion of all exposed surfaces and the general discomfortthat came with smoky air. Public surveys were initiated—as in SaltLake City in 1926, New York City in 1937, and Leicester, GreatBritain, in 1939—to bring political attention to the problem andpromote the implementation of controls (Miller and Miller, 1993).However, it was not until the great air pollution disasters in theMeuse Valley, Belgium, in 1930; Donora, Pennsylvania, in 1948;and the great London fog of 1952 that air pollution was indictedprimarily as a health issue. In the United States, California was al-ready leading the way with passage of the Air Pollution ControlAct of 1947 to regulate the discharge of opaque smokes. Visibil-ity problems in Pittsburgh during the 1940s had also prompted ef-forts to control smoke from local industries, but it was the initia-tive of President Truman that provided the federal impetus to dealwith air pollution. This early effort culminated in congressionalpassage of a series of acts starting with the Air Pollution ControlAct of 1955.

The prosperity and suburban sprawl of the late 1950s providedthe third and perhaps most chemically complex dimension of airpollution. The term smog, though originally coined to describe themixture of smoke and fog that hung over large cities such asLondon, was curiously adopted for the eye-irritating photochemi-cal reaction products of auto exhaust that blanketed cities such asLos Angeles. Early federal legislation addressing stationary sourceswas soon expanded to include automobile-derived pollutants (theClean Air Act of 1963, amended in 1967, and the Motor VehicleAir Pollution Control Act of 1965). The landmark Clean Air Act(CAA) of 1970 evolved from the early legislation, and despite be-ing only an amendment, it was revolutionary. It recognized theproblem of air pollution as a national issue and set forth a plan tocontrol it. The Act established the U.S. Environmental ProtectionAgency (USEPA) and charged it with the responsibility to protectthe public from the hazards of polluted outdoor air. Seven “crite-ria” air pollutants [ozone (O3), sulfur dioxide (SO2), particulatematter (PM), nitrogen dioxide (NO2), carbon monoxide (CO), lead(Pb), and total hydrocarbons—the last now dropped from the list,leaving six criteria pollutants] were specified as significant healthhazards in need of individual National Ambient Air Quality Stan-dards (NAAQS). These NAAQS were mandated for review every5 years as to the adequacy of the existent standard to protect hu-man health (Table 28-1). For each of the criteria pollutants, therewas to be developed a Criteria Document, which would provide adetailed summary of the available database on that pollutant andthen would be integrated into a staff paper for use by the EPA Ad-ministrator to set the NAAQS. With regard to the Primary NAAQS,only health criteria could be used, including a safety factor for themost susceptible groups. Secondary consideration was given toagricultural and structural welfare; economic impacts were not tobe involved in standard setting itself—only in the implementationprocedures. Other hazardous air pollutants (HAPs), of which therewere eight listed at the time, were to undergo health assessmentsto establish emission controls. The CAA of 1970 was by far themost far-reaching legislation to date.

The accidental release of 30 tons of methyl isocyanate va-por into the air of the shanty village of Bhopal, India, on De-cember 3, 1984, killed an estimated 3000 people within hours of

980 UNIT 6 ENVIRONMENTAL TOXICOLOGY

Figure 28-1. Number of people (millions) living in U.S. counties not incompliance with current 1998 NAAQS. (Adapted with permission fromNational Air Quality & Emission Trends Report, 1998.)

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the release, with another 200,000 injured and/or permanently im-paired. The tragedy shocked the world, and raised the issue ofHAPs in the United States to a new level of concern. While sucha disaster has never struck the United States, accidental indus-trial releases or spills of toxic chemicals are surprisingly com-mon, with 4375 cases recorded between 1980 and 1987, inflict-ing 11,341 injuries and 309 deaths (Waxman, 1994). The HAPs,which had been the stepsister of the criteria pollutants for morethan a decade after the passage of the CAA, have since garneredmore public and policy attention. There is concern not only foraccidental releases of fugitive or secondary chemicals—such asphosgene, benzene, butadiene, and dioxin, into the air of popu-lated industrial centers—but also for potential chronic health ef-fects, with cancer often being the focus of attention. The slowprogress of regulatory decisions on HAPs (only eight between1970 and 1990) led to a mandated acceleration of the process un-der the CAA amendment of 1990. Section 112(b) currently lists188 chemicals or classes of chemicals for which special standardsand risk assessments are required. The chemicals listed are thoseof greatest concern on the basis of toxicity (including cancer) andestimated release volumes. These emissions are mandated forcontrol to the maximal achievable control technology (MACT),and any residual health risk after MACT is to be considered ina separate quantitative risk assessment. The database for thisprocess utilizes existing knowledge or, if necessary, mandatesfurther research by the emitter. While many of these chemicalsare now better controlled than in the past, most residual risk es-timates are yet to be completed.

Emissions from motor vehicles are addressed primarily underthe CAA Title II, Emission Standards for Mobile Sources. The re-duction of emissions from mobile sources is complex and involvesboth fuel and engine/vehicle reengineering. Despite continued re-finements in combustion engineering through the use of comput-erized ignition and timing, fuel properties have drawn recent at-tention for improvement. For example, to reduce wintertime CO,several oxygenates (including ethers and alcohols) have be formu-lated into fuels both to reduce cold-start emissions and enhanceoverall combustion. Perhaps the most prominent of the ethers isMTBE (methyl tertiary butyl ether), which became a controversialadditive in the early 1990s, arising in part from odor and reportsof asthma-like reactions by some individuals during auto refueling

at service stations. Today, the controversy has taken an unexpectedtwist; MTBE has now been removed from fuel, not because healthconcerns associated with airborne exposure but rather due to leak-age from service-station storage tanks into groundwater. Ironically,this prescribed remedy for an air problem has evolved into a newproblem: groundwater contamination. This example illustrates thebroad complexity of pollution control, measures that transcend en-gineering. Meanwhile, the introduction of another fuel additive,methylcyclopentadienyl manganese tricarbonyl (MMT)—to boostoctane ratings of fuel and improve engine performance and com-bustion—is being carefully reviewed under Title II because of con-cerns regarding the potential introduction of manganese into theenvironment, reminiscent of use lead in fuels from the 1930s to1970s, when lead fuel additives were banned.

Internationally, the magnitude and control of air pollutionsources vary considerably, especially among developing nations,which often forgo concerns for health and welfare because of costand the desire to achieve prosperity. Fig. 28-2 illustrates the vari-ation among international megacities in regard to three major ur-ban pollutants: total suspended particulate (TSP) matter, sulfur ox-ides (SOx), and O3. The recent political upheaval in eastern Europehas revealed the consequences of decades of uncontrolled indus-trial air pollution. While vast improvements are now becoming ev-ident in this area, as industries are being modernized and emis-sions controlled, many Asian, African, and South American citieshave virtually unchecked air pollution. Some nations as well as theWorld Health Organization (WHO) have adopted air quality stan-dards as a rational basis for guiding control measures, but the lackof binding regulations and/or economic fortune has impeded sig-nificant controls and improvements (Lipfert, 1994). In addition tolocal socioeconomic and political concerns, emissions of air pol-lutants will, in all probability, spawn problems of “internationalpollution” as we enter the twenty-first century, when the impact oflong-range transport of polluted air masses from one country to an-other fully matures as a global issue (Reuther, 2000). This was thesubject of some controversy between Canada and the United Statesin the late 1980s and into the 1990s as a result of the air masstransport of acid sulfates from industrial centers of the midwest-ern United States to southern Ontario. However, reduction in SO2

emissions has somewhat relieved the tension over the last severalyears (Fig. 28-3).

CHAPTER 28 AIR POLLUTION 981

Table 28-1U.S. National (Primary) Ambient Air Quality Standards*

POLLUTANT UNIT AVERAGING TIME CONCENTRATION STATISTIC

Sulfur dioxide �g/m3 (ppm) Annual 80 (0.03) Annual mean24 h 365 (0.14) Maximum

Carbon monoxide �g/m3 (ppm) 8 h 10 (9) Maximum1 h 40 (35) Maximum

Ozone �g/m3 (ppm) 1 h 235 (0.12) Maximum8 h 157 (0.08) Maximum

Nitrogen dioxide �g/m3 (ppm) Annual 100 (0.053) Annual meanParticulates PM10 �g/m3 Annual and 24 h 150 and 50 Annual mean and

Annual and 24 h 65 and 15 maximumPM2.5

Lead �g/m3 3 months 1.5 Quarterly average

*For detailed information regarding policy and precise statistical and time-based computations to achieve attainment, contact EPA website: www.epa.gov/airs/criteria.html

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ASSESSING RISKS ASSOCIATEDWITH AIR POLLUTION

“Risk Assessment” has become a formalized process, originallydescribed in the landmark 1983 National Research CouncilReport, whereby evidence regarding toxicity, exposure, anddose-dependency are systematically organized to estimate thedegree of risk to a population. The health database for any airpollutant comprises data from animal toxicology, controlled hu-man studies, and epidemiology. But, because each of these re-search approaches has inherent strengths and limitations, an ap-propriate assessment of an air pollutant requires the carefulintegration and interpretation of data from all three methodolo-gies. Thus, one should be aware of the attributes of each (Table28-2).

Epidemiologic studies reveal associations between exposureto a pollutant or pollutants and the health effect or effects in thecommunity or population of interest. Because data are garnereddirectly under real exposure conditions and involve large num-bers of humans, the data are of direct utility to the regulatorycommunity assessing the impact of that pollution. Moreover, withproper design and analysis, studies can explore either acute orlong-term exposures and theoretically can examine trends in mor-tality and morbidity, accounting irreversible effects as well as re-sponses in population subsets (i.e., sensitive groups). Why, then,is this approach to the study of air pollution not the exclusivechoice of regulators in decision making? The problem here is thatit is often difficult to control independent and personal variablesin the human population because of genetic diversity among in-dividuals and lifestyle differences, their mobility over time, and

the lack of adequate exposure data—especially on a personal ba-sis. Also, it is difficult to segregate a single pollutant from copol-lutants and the influence of meteorologic confounders. Thus, atbest, only associations can be drawn between the broad-based ex-posure data and effects, with these effects typically of a gross na-ture—mortality, hospitalizations, etc. Rarely is a causal relation-ship discernible even in the presence of strong statisticalsignificance. However, recent advances in exposure estimationand study design and analysis (e.g., time series) have allowed epi-demiologists to examine relationships with greater confidenceand specificity. These models limit the impact of covariates andlonger time-based influences and thus allow epidemiologists totease out effects of short-term pollution not accessible formerly(Schwartz, 1991). Similarly, newer approaches that employ fieldstudies—sometimes called panel studies—incorporate time-se-ries design and regression analyses of more focused exposure data(ideally personal) and targeted clinical endpoints in the exposedpopulation under study. The endpoints often derive from empirichuman and animal studies. These novel approaches are clearlyevident in the most recent studies of particulate matter air pollu-tion (see below).

Studies that involve controlled human exposures have beenused extensively to evaluate the criteria air pollutants regulatedby the USEPA. Because most people are exposed to these pollu-tants in their daily lives, human volunteers can be ethically ex-posed to them (with the exception of Pb, which has cumulativeand irreversible effects). Exposures are conducted in a controlledenvironment, are generally of short or limited repeat durations,and all responses must be reversible. Clearly, data of this typeare very valuable in assessing potential human risk, since they


Figure 28-2. Comparison of ambient levels of 1-h maximum ozone, annual average of total suspended par-ticulate matter, and sulfur dioxide in selected cities from around the world to illustrate the variation in theselevels from country to country with respect to the United States. (Reproduced with permission from the Na-tional Air Quality and Emission Trends Report, 1992.)

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Figure 28-3. Reduction in ambient sulfate concentrations be-tween 1990–1991 and 1997–1998 in the rural U.S. Midwestfrom CASTNet monitoring data.

The acid sulfates are dispersed by prevailing winds toward theeastern United States and southeastern Canada, contributing tothe acid rain deposition (see Fig. 28-9). (Adapted with permis-sion from National Air Quality & Emission Trends Report, 1998.)

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are derived from the species of concern and are rooted in ourwell-established clinical knowledge and experience. Additionally,suspected “susceptible or sensitive” individuals representing po-tential high-risk groups can be studied to better understand thebreadth of response in the exposed public. However, clinical stud-ies have practical limitations. Ethical issues are involved in everyaspect of a clinical test; potentially irreversible effects and car-cinogenicity are also always of concern, along with the defini-tion of an acceptable level of hyperresponsiveness in a so-calledsensitive individual who may be subjected to testing. Likewisefor any test subject, there are obvious restrictions on the inva-siveness of biological procedures, though sophistication in med-ical technology has made accessible a large array of molecularbiomarkers from peripheral blood and nasal, bronchial, and alve-olar lavage fluids as well biopsied cells from airway segments(Devlin et al., 1991; Salvi et al., 1999). Finally, the cost, the lim-ited numbers of subjects that usually can be evaluated, and theinability to address chronic exposure issues are also constraintson human testing. Where partnership with animal toxicologystudies has been established, studies in laboratory animal speciescan sometimes open the door for at least limited direct humanexposure study. Analogously, in vitro studies in both human andanimal cell and tissue systems allow the elucidation of mecha-nisms of toxicity and identify basic biological responses thatserve the extrapolation of animal data to humans as well as sup-porting the feasibility and ethical limitations of human study evenwith toxic air pollutants (see below).

Animal toxicology is frequently used to predict or corrobo-rate suspected effects in humans. In the absence of human data,animal toxicology constitutes the essential first step of risk as-sessment: hazard identification. The importance of animal toxi-cology in elucidating pathogenic mechanisms should not be over-looked, however, as knowledge of the basic in vivo biologicalprocesses involved in toxic injury or disease is critical to extrapo-lating databases across species and to estimating uncertainties.Knowledge of the toxic mechanism(s) provides the underpinnings

to the “plausibility” of the findings when extrapolated to humansand, under carefully defined and highly controlled circumstances,may allow quantitative estimates of risk. Animal toxicology stud-ies have been used to investigate all of the criteria air pollutantsand many of the HAPs as well. The strength of this discipline isthat it can involve methods that are not practical in human studies,including a diversity of exposure concentrations and durations, andthe inclusion of a wide array of invasive biological procedures. Theminimization of uncontrolled variables (e.g., genetic and environ-mental) may be the greatest strength of the animal bioassay. Onthe other hand, the clear limitation of this approach lies in the ex-trapolation of the findings from animals to the day-to-day humanlife scenario. Ideally, a test animal is selected with knowledge thatit responds in a manner similar to that of the human (homology).Qualitative extrapolation of homologous effects is not unusual withmost toxic inhalants, but quantitative extrapolation is frequentlyclouded by uncertainties of the relative sensitivity of the animal orspecific target tissue compared with that of the human. Uncertain-ties about the target tissue dose also loom large, as it constitutesthe first obstacle to quantitative extrapolation (see below). With re-spect to the target tissue dose, however, most animal toxicologistsmake every effort to keep exposure concentrations at 5- to 10-foldthat of the anticipated human exposure until appropriate dosimet-ric data can be ascertained. The higher doses are typically neededto achieve a group response among a limited pool of animals(maybe 6 to 10) to represent a large population effect, where per-haps only a few of hundreds or thousands may be responsive; al-though it must be appreciated that mechanisms may differ at dif-ferent dose levels. Despite these limitations, animal studies haveprovided the largest database on a wide range of air toxicants andhave proven utility in predicting human adverse responses to chem-icals.

Health scientists must appreciate the strengths and weak-nesses of these approaches if an appropriate estimation of toxicrisk or potential hazard is to be reached. However, other scien-tific disciplines also are integral to the full assessment of the im-


Table 28-2Strengths and Weaknesses of Disciplinary Approaches for Obtaining Health Information

DISCIPLINE POPULATION STRENGTHS WEAKNESSES

Epidemiology Communities Natural exposure Difficult to quantify exposureMany covariates

Diseased groups No extrapolationIsolates susceptibility trait Minimal dose–response dataLong-term, low-level effects Association vs. causation

Field/Panel groups Good exposure data Usually short-termFewer covariates VolunteersFocus on host traits ExpensiveUtilizes clinical evaluations

Clinical studies Experimental Controlled exposures Artificial exposuresDiseased subjects Few covariates Acute effects only

Isolates susceptibility trait HazardsCause–effect Volunteers

Toxicology Animals Maximum control Human extrapolationDose-response data Realistic models of humanCause–effect disease?

In vitro systems Rapid data acquisition In vivo extrapolationMechanisms

SOURCE: Modified from Boubel et al., 1994: with permission.

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pact of air pollution on society. Chemical and engineeringmethodologies are used together to detect and control pollutantsin the atmosphere and develop empiric test systems to gather in-formation used to evaluate individual toxicity and/or physico-chemical interactions. Their use in determining local and personalexposure for panel and prospective epidemiologic studies is mostimportant. Other disciplines, such as meteorology and atmos-pheric chemistry, relate to the real world by yielding informationon the dispersion of pollutants from their sources and the condi-tions leading to the stagnation of air masses and the accumula-tion of pollutants. Recreating these environments to the extentpossible, using surrogate atmospheres, is critical to understand-ing toxic risks and creating models to estimate human risk. Last,data derived from studies in plants are now being appreciatedmore than ever. Not only are commercial and native vegetationaffected by pollution but plants themselves are being appreciatedas sensitive “sentinels,” warning us of the impact of pollution.When these elements are considered collectively, the economistcan inform regulators and the public at large of the cumulativeimpact and adversity of pollution on our standard of living(Maddison and Pierce, 1999).

Animal-to-Human Extrapolation: Issuesand Mitigating Factors

Extrapolation is the process of relating empiric study findings toreal-world scenarios. The utility and value of animal toxicology ismost dependent on this process. Thus, the selection of an animalspecies as a toxicologic model should involve more than consid-erations of cost and convenience. Whenever possible, effects thatare homologous between the study species and humans shouldguide selection of the test species. For example, if irritant responsesto an upper airway irritant (e.g., SO2 or formaldehyde) are of in-terest, the guinea pig, with its labile and reactive bronchoconstric-tive reflex, should be selected over the rat, which is not particu-larly responsive to sensory irritants. By contrast, certain strains ofrats exhibit a clear neutrophilic response to deep lung irritants, suchas O3, that resembles the human response. Other innate differencesin sensitivity among species may relate to differences in lung struc-ture, specific regionally based cell metabolism or polymorphisms,or overall defenses (e.g., antioxidants) (Paige and Plopper, 1999;Slade et al., 1985). When such nuances are unclear or unknown,the replication of responses in multiple species builds confidencein the finding as being the product of conserved mechanisms acrossspecies and therefore its relevance to the human. However, newtransgenic and knockout strains of mice (and in some cases rats),specially engineered to address hypotheses focused on geneticallylinked traits, have given toxicologists a new instrument for thestudy of air pollutants.

An essential part of extrapolating responses from species tospecies is an accurate assessment of the relative dosimetry of thepollutant along the respiratory tract. Significant advances in stud-ies of the distribution of gaseous and particulate pollutants havebeen made through the use of empiric and mathematical models,the latter of which incorporate parameters of respiratoºry anatomyand physiology, aerodynamics, and physical chemistry into pre-dictions of deposition and retention. Empiric models combinedwith theoretical models aid in relating animal toxicity data to hu-mans and help refine the study of injury mechanisms with betterestimates of the target dose. Figure 28-4A and B illustrates the ap-plication of such an approach to the reactive gas ozone and insol-

uble 0.6-�m spherical particles, respectively, as each is distributedalong the respiratory tract of humans and rats. Anatomic differ-ences between the species clearly affect the deposition of both gasesand particles, but the qualitative and to a large extent quantitativesimilarities in deposition profiles are noteworthy. This is not sur-prising if one argues teleologically that the lungs of each speciesevolved with similar functional demands (i.e., O2–CO2 exchange,blood acid/base balance), mechanical impediments, and environ-mental stresses. One needs only a cursory review of the compara-tive lung physiology literature to appreciate the allometric consis-tency of the mammalian respiratory tract to meet the challenge ofbreathing air. This design coherency has provided the fundamen-tal rationale for the use of animal models for the study of air pol-lutants.

Susceptible subpopulations that may show exaggerated re-sponsiveness to a pollutant deserve special mention. The exis-tence of hyperresponsive individuals and groups is well acceptedamong those who study air pollution toxicology, but little is ac-tually known about the host traits that make certain individualsresponsive. This appreciation for sensitive populations is specif-ically noted in the CAA, where their protection is mandated inthe promulgation of NAAQS. There are some definable sub-groups that are assumed to be susceptible, including children,the elderly, and those with a preexisting disease (e.g., asthma,cardiovascular disease, lung disease). However, the assumptionthat these groups are indeed susceptible is based more on per-ceptions than on real data. In some cases susceptibility may re-side in some innate responsiveness, while in other cases it mayrelate more to the loss of functional reserve or compensation,perhaps altering a response threshold. The reasons for paucityof data likely lie in the difficulty in ethically conducting studiesin humans who are potentially at higher risk and recruiting suchindividuals on a volunteer basis. However, inroads into this is-sue have been made in recent years, in part because of more pre-cise definitions of potential risk factors, allowing researchers todesign studies that examine host attributes that need not be atlife-threatening stages of impairment and the development ofmore appropriate animal models of disease or dysfunction.Hence, studies in both animals and human subjects are being de-vised specifically to investigate the roles of diet (e.g., antioxi-dant content), exercise (as it relates to dosimetry), and age, gen-der, and race. In addition, studies in human subjects with mildasthma or heart-lung disease have been conducted to address thedegree of sensitivity that these compromised groups exhibit.Analogously, animal models with imposed cardiopulmonary im-pairments are being used more and more to address the same ba-sic questions.

Recent advances in molecular biology have provided toolsto bioengineer mice (and occasionally rats) with virtually anytrait that is under the control of identifiable genes. Transgenicstrains can express desired traits derived from other animals oreven humans, or knockout models can be made devoid of spe-cific traits to isolate the impact of that trait on the animal’s re-sponsivity to a toxic challenge. These animal models add to theavailability of natural mutants that have been inbred historicallyto purify a desired genotype to achieve a specific phenotype, ide-ally one that is analogous to that of the human (Ho, 1994: Glasseret al., 1994). Natural mutant and bioengineered transgenic andknockout rodent models provide unparalleled potential to exam-ine specific genetic factors involved in response (i.e., suscepti-bility). Current technology can also target genes for specific


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expression in the lung (e.g., linked to surfactant protein C), andin some cases it can even provide a control gene with which aninvestigator can switch the gene of interest on or off using apharmacologic or chemical prechallenge. Such advances allowthe dissection of underlying mechanisms under very controlledscenarios and avoid the problems of having a gene be inappro-

priately active or inactive through all life stages (Gossen et al.,1996).

To date the emphasis of studies using these genetically mod-ified animal models have been on mechanisms associated withdisease pathogenesis (Recio, 1995; Suga et al., 2000). Among themost popular uses of knockout and transgenic mice has been in


Figure 28-4. Theoretical (normalized to the concentration in inspired air) uptake curves for the reactive gasozone in a resting/exercising human and a rat (A). Likewise, the percent deposition in the airways of a 0.6�m insoluble particle in the respiratory tracts of a resting/exercising human (B) and rat (C).

Here 8% inspired CO2 in the rat augments ventilation up to threefold. Airway generation refers to that airwaybranch numbered from the trachea (0). [Panel A is from Overton and Miller, 1987, and panels B and C are fromMartonen et al., 1992. Reproduced with permission.]

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the study of inflammatory cytokines and associated products inasthma, as the expression of many of these mediators are thoughtto be under the control of single genes (e.g., Kakuyama et al.,1999, Kuhn et al., 2000). Clearly these genetically modified miceare ideally suited for the study of mechanism of action where aspecific mediator-based hypothesis can be tested as it relates toan impaired function, pathology, or altered inflammatory pattern.When these models are derived to exhibit a desired pathology ordisease due to a genetic defect—for example involving lungstructure or growth (e.g., emphysema or fibrosis), such that byadulthood the animal exhibits the disease—the model may serveas a surrogate of the human condition (e.g., O’Donnell et al.,1999).

The use or genetically modified animal models in air pollu-tion research has lagged behind that of basic science and toxicol-ogy in general. The reasons for this are unclear and may relate tothe difficulties in incorporating such data into conventional risk-assessment paradigms. However, with recent interest in potentiallysusceptible groups, there has been a definitive upswing in the useof pharmacologically or naturally altered as well as bioengineeredanimals (Kodavanti et al., 1999) and an effort to more closely linkmechanistic profiles to basic human biology. Ozone has frequentlybeen the test pollutant in these new studies, since more is knownabout O3 and its effects in humans than about any other air pollu-tant. Frequently, these studies address aspects of inflammation andantioxidant capacity relative to challenge by ozone and other oxi-dants (Johnston et al., 1999; Kleeberger et al., 2000). But with thecurrent interest in particulate matter (PM) health effects, these andother models are being redirected; for example: strain differencesand acid coated PM (Ohtsuka et al., 2000); hypertransferrinemicmice and metal-rich PM (Ghio et al., 2000); and metallothionein-null mice and mercury vapor (Yoshida et al., 1999). The curiousare directed to the rapidly evolving literature in this area ofresearch.

Air Pollution: Sources and Personal Exposure

In terms of tons of anthropogenic material emitted annually in theUnited States (as of 1998), five major air pollutants account for 98percent of pollution (Fig. 28-5): CO (52 percent), SOx (14 per-cent), volatile organic compounds (VOCs; 14 percent), PM (4 per-cent), and NOx (14 percent). The remainder consists of Pb, whichis down �90 percent since 1983, when it was banned from gaso-line, and a myriad of other compounds considered under the cate-gory of hazardous air pollutants. On a national basis, since 1996,PM and SOx increased slightly and NOx remained the same, whileVOCs and CO decreased slightly. Obviously, for any specific lo-cality, this emission picture can vary widely. In the vicinity of asmelter, for example, SOx, metals, and/or PM dominate the pollu-tant profile; while a refinery air shed would be dominated by VOCs;and in suburban areas, where the automobile is the main source ofpollution, CO, VOCs, and NOx would prevail along with their pri-mary photochemical product, O3.

Classically, air pollution has been distinguished on the basisof the chemical redox nature of its primary components. Dick-ens’s eighteenth-century “London’s particular,” in which SO2 andsmoke from incomplete combustion of coal accumulated as achilled, acidic fog, was termed “reducing-type” air pollution. Thisacidic mix would react with surfaces, corroding metal and erod-ing masonry, as is characteristic of reductive chemistry. Histori-

cally, this reducing-type atmosphere has been associated withsmelting and related combustion-based industries (as along theMeuse River in 1930 and Donora, Pennsylvania, in 1948) as wellas large, coal-based urban centers such as London (1952) and NewYork (1962). In contrast, Los Angeles has always had a charac-teristically “oxidant-type” pollution consisting of NOx and manysecondary photochemical oxidants, such as O3, aldehydes, andelectron-hungry hydrocarbon radicals. In photochemical air pol-lution, atmospheric reaction products of automobile exhaust andsunlight are trapped by regional topography or meteorologic in-version. This condition is today referred to colloquially as “smog”or “haze.”

The classic types of air pollution were implicitly seasonal. Re-ducing air pollution occurred during winter periods of oil and coalcombustion and meteorologic inversions, while the oxidant at-mospheres occurred during the summertime, when sunlight is mostintense and can catalyze reactions among the constituents of autoexhaust. While some regions of the United States may still expe-rience a more reducing-type or oxidant-type atmosphere, today thedistinction between these smogs is largely academic. Most mod-ern industrial centers have undergone a considerable reduction insmoky, sulfurous emissions while experiencing a proliferation ofautomobiles that contribute tons of oxidant precursors into the air.Thus, major metropolitan areas, most notably those in the north-eastern United States, have atmospheres with both reducing andoxidant air pollutants. Sulfates may predominate over nitrates inthe air, in contrast to the southwestern United States, but no longeris the northeastern smog simply a sulfur-based problem. Nonethe-less, Los Angeles (though challenged by Houston for the number-one spot in 1999) remains the prototypical center of photochemi-cal air pollution in the United States. Outside the United States,however, many megacities remain plagued by the classic forms ofair pollution. For example, uncontrolled industrial emissions sur-rounding cities like Beijing and the northern sectors of Mexico Cityare dominated by oil, coal, and industrial emissions, whereas south-ern Mexico City, Santiago, and Tokyo have substantially (but notso exclusively) automobile-derived oxidant smogs. The lack of


Figure 28-5. Emission trend for volatile organic compounds (VOC),nitrogen oxides (NOx), sulfur dioxide (SO2), and particulate matter (PM�10 �m) from 1900 (or when records began) to 1998.

Note that since the passage of the Clean Air Act of 1970, most emissionshave decreased or, in the case of nitrogen oxides, have leveled off.(Reproduced with permission from National Air Pollutant Emission TrendsReport, 1998.)

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policies and controls are responsible for the fact that the levels ofair pollution in these cities greatly surpass those of any U.S. city.Clearly, air pollution remains a worldwide problem, where the es-timate of people exposed to ozone at potentially harmful levels ex-ceeds 480 million (Schwela, 1996).

Indoor versus Outdoor People in the United States (and in mostindustrialized nations) spend in excess of 80 percent of their timeindoors at work, at school, and at home or between these places inan automobile (Robinson and Nelson, 1995). Generally, the timespent indoors is disproportionately higher for adults, who have rel-atively less time to participate in outdoor activities, especially dur-ing the day, when outdoor pollutants are usually at their highestlevels. Children and outdoor workers, by contrast, are much morelikely to encounter outdoor air pollution at its worst; in fact, be-cause of the relatively high activity levels of these subgroups com-pared with inactive office workers, their lungs may incur a con-siderably larger dose of any given pollutant. Thus, while it isimportant to characterize and track pollution levels in outdoor air,the most appropriate measure for exposure should involve a para-digm that addresses the total personal exposure of the individualor group of concern, and taken one step further, also dose to thelungs. However, defining typical paradigms of personal exposurecan be exceedingly difficult, as personal monitoring is tedious, ex-pensive, and complex given the many potential pollutants one mayencounter and can involve a personal dynamic as individual as thatperson’s lifestyle. Frequently, groups of people are monitored inorder to develop models for the projection expected exposure val-ues.

The indoor environment has only recently been widely ap-preciated as a major contributor to total personal exposure. Theenergy crisis of the 1970s spurred efforts to increase home andbuilding insulation, reduce infiltration of outside air, and mini-mize energy consumption. At the same time, indoor sources ofair contaminants have been on the rise from household productsand furnishings, which—when combined with poorly ventilatedheating systems and overall reductions in air-exchange rates—give rise to potentially unhealthy indoor air environments. As peo-ple began to notice patterns of odors, microbiologic growth, andeven ill health, measures of indoor air became a significant partof environmental assessment. Personal exposure has, therefore,come to include the myriad of potential sources, both outdoorsand indoors.

It is clear now that indoor air can be even more complex thanoutdoor air. Indeed, outdoor air permeates the indoor environmentin spite of the reduced air exchange in most buildings. However,many variables determine how well components of the outdoor airinfiltrate. The current evidence suggests that the average insulatedhome has about one air change per hour, resulting in indoor con-centrations of pollutants that range from 30 to 80% of those out-doors. For nonreactive gases (e.g., CO), there could likely be nearlya 1:1 indoor/outdoor ratio in the absence of a “sink” for that gas;the ratio for fine particulate matter (�2.5 �m) could also be fairlyhigh (~0.4 to 0.7), since these particles can easily penetrate throughcracks and open spaces. In contrast, the indoor/outdoor ratio of O3

would likely be low (�0.3) because of its reactivity. Obviously,household differences in the use of window ventilation and air con-ditioning would be important variables. Where there are inde-pendent sources of contamination indoors, the ratio of an indoorpollutant to that outdoors can even exceed 1 (e.g., NO2). Unventedspace heaters and poorly vented fireplaces and wood stoves or fresh

paint and cleaning agents can be significant indoor sources. How-ever, attention now is being directed toward the many and variedinsidious sources of indoor contaminants: certain soils and con-struction masonry (radon), gas cooking appliances (NOx), side-stream tobacco smoke (PM, CO, and a host of carcinogenic pol-yaromatics), and carpets, furnishings, dry-cleaned clothes, andhousehold air fresheners (VOCs). Some of these chemicals caneven interact with one another as has been found to occur with O3

diffused indoors reacting with VOCs emitted from householdcleaners. The complexity of these multiple sources underscores theimportance of appreciating the total exposure scenario if we are tounderstand the nature of air pollution and its potential effects onhumans (Fig. 28-6).

EPIDEMIOLOGIC EVIDENCE OFHEALTH EFFECTS

Outdoor Air Pollution

Acute and Episodic Exposures A number of air pollution inci-dents have been documented where concentrations of contaminantshave risen to levels that are clearly hazardous to human health.When a single chemical has been accidentally released (e.g., methylisocyanate in Bhopal, India), establishing the relationship betweencause and ill effect is typically straightforward. However, most airpollution situations involve complex atmospheres, and establish-ing a specific cause other than the air pollution incident itself canbe difficult. Three acute episodes of community air pollution areconsidered classic (Meuse Valley, Donora, and London). In eachevent, community inhabitants were clearly affected adversely;hospitalizations were concomitant with or were followed closelywith an elevation in the mortality rate. Although no single con-taminant could be fully blamed in any of these, the air pollutionwas the “reducing-type,” in which acrid, coal-derived sulfurous gasand industrial particulate matter (including many metal sulfates)accumulated within a blanket of cool moist air. In each case, a me-teorologic inversion (cold air capped above by a blanket of warmair, with little or no vertical air mixing) prevailed for 3 or 5 days,during which time the concentration of pollutants rose well abovethe normal levels for these already heavily polluted areas. No ac-tual measurements of pollution were made in the Meuse Valley andDonora, but crude measurements of the London fog recorded dailyaverages of smoke and SO2. These were estimated at 4.5 mg/m3

and 1.34 ppm, respectively, on the worst day. Brief (on the orderof hours) peak concentrations probably reached even higher lev-els. During the Meuse Valley episode, 65 people died, while inDonora the number was 20. These deaths were considered “ex-cess” deaths when compared with normal mortality rates for thattime of year.

The famous “London smog” of 1952 is estimated to have re-sulted in 4000 excess deaths. Hospital admissions increased dra-matically, mainly among the elderly and those with preexisting car-diac and/or respiratory disease. Even otherwise healthy pedestrians,their visibility limited to as little as 3 ft, covered their noses andmouths in an attempt to minimize their exposure to the “choking”air. Those with preexisting health problems were particularly af-fected and made up the majority of deaths. It is ironic that 16 yearsearlier, 3200 deaths had been predicted for London should it ex-perience an episode like that of the Meuse Valley (Firkert, 1936).Although the London 1952 incident brought the issue of air pol-lution to the public consciousness, many additional episodes oc-


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curred later, with the 1956 and 1962 incidents being among themost notable. As recently as December 1991, London experienceda winter smog alert that exhibited black smoke at 148 �g/m3 andSO2 at 72 ppb (four times and twice the seasonal average, respec-tively). The difference here was that the polluted atmosphere wasfar more the result of air contamination by automobile emissionsthan domestic burning of coal (Anderson, 1999), in keeping withthe trends noted above. Mortality and hospital admissions wereagain affected, and again mostly among the elderly and car-diopulmonary-impaired (mortality: ↑14 percent cardiovascular and↑22 percent respiratory; ↑43 percent for respiratory admissions).London has not been alone among industrialized cities significantlyaffected by air pollution episodes in the more recent past. NewYork; Steubenville, Ohio; Pittsburgh, Pennsylvania; Athens,Greece, and entire regions like those of the Netherlands and theRuhr Valley of Germany have all had air pollution episodes of notebetween 1970 and 1990. Air pollution events continue to decreaseover time in the modern world, both in their frequency and inten-sity. What episodes do arise are dwarfed in their impact by the clas-sic smog episodes.

So much has the air improved in recent times that many havethought that the problem of sulfur-based industrial pollution wasessentially resolved. However, in the late 1980s, there were reve-lations regarding acidic pollution of lakes and defoliation of forests(Calvert et al., 1985) as well as new studies showing increasedemergency room visits among potentially susceptible populations—asthmatics (Bates and Sizto, 1987). A series of studies showedacute effects of ambient levels of pollution that occur during thesummer (summer haze) in areas of central and northeastern NorthAmerica. These peaks of pollution were typified by increases inO3 and sulfates, characteristic of the new generation of pollutionin most U.S. urban areas. The increase in sulfate consisted of bothacidic and atmospherically neutralized forms of sulfuric acid andphotochemically derived O3; such hazes cover large regions and

can be widely transported. In one southern Ontario–based study,there was a consistent association in the summer between hospitalvisits for acute respiratory problems, especially among asthmaticchildren, and daily levels of both O3 and sulfate. Interestingly, theapparent combined temporal or sequential patterns of O3 and sul-fate were associated with the health effects, but neither constituentalone. Similar results have been reported for the upstate New Yorkarea as well (Thurston et al., 1992), but acidity as [H�], which iscommon in summer haze, was thought to play a more dominantrole. However, studies of children at summer camps, where theyare active and outdoors most of the day, had reported decrementsin daily measured pulmonary function on days when both O3 andacidity levels were elevated but still below those that would be pre-dicted to have a measurable effect (Lippmann, 1989). Animal tox-icology and clinical studies in adolescent asthmatics have lent fur-ther support to the belief that H� can affect airway function,particularly in the presence of O3. Studies in the South and South-west similarly have found effects in young asthmatics, but theseappear to relate more specifically to O3, since sulfate is less promi-nent. This finding is in agreement with earlier data from the LosAngeles area showing a high degree of correlation between di-minished performance among high school athletes and increasedoxidant levels.

Of the many studies of air pollution over the last 10 to 15years, none has had more impact on today’s perspective of the risksassociated with pollution than a series of studies using a relativelynew analyses of contemporary or preexistent daily mortality andmorbidity trends and regional air monitoring data. These studiesshowed significant and consistent associations between health im-pacts of ambient PM at levels thought to be safe. Prior to this pe-riod, measurable effects of PM and SO2 were not easily detectedbelow the 24-h mean for smoke and SO2 levels of 250 �g/m3 and0.19 ppm, respectively. The new findings showed effects, evidencedby increases in mortality and morbidity rates at or below their con-


Ground -water flow

Figure 28-6. Illustration of contributors to the total personal exposure paradigm showing how these indoorand outdoor factors interact.

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temporaneous NAAQS [50 �g/m3, annual mean; 150 �g/m3 dailymaximum for PM of diameter �10 �m (PM10)]. The new studiesmade use of novel time-series analyses that are based on Poissonregression modeling to distinguish changes in daily death countsassociated with short-term changes in PM air pollution. The stud-ies initially found effects with TSP matter, which includes virtu-ally all particles to about 35 �m in mass median aerodynamic di-ameter (MMAD—a median particle size normalizing the particleto unit density and spherical shape for aerodynamic comparison).These studies were followed with stronger associations with par-ticles considered almost fully inhalable—PM10 (an MMAD atwhich PM is aerodynamically separated at an initial 50 percent ef-ficiency at 10 �m and increasingly at smaller sizes). Most recently,even stronger associations have been found with an analogous butfully and deeply respirable particle—PM2.5. As the PM getssmaller, it represents more anthropogenic sources of pollution. Thestatistical methodology applied in these studies had an advantageover conventional regression analyses in that it could detect short-term trends and minimized the effects of other pollutants and po-tential confounders with longer time constants (Schwartz, 1991;reviewed by Pope and Dockery, 1999).

In contrast to the three epidemiologic studies used to defendthe 1987 PM10 NAAQS, there were more than thirty used for the1997 revision of the standard and promulgation of a new PM2.5

NAAQS [15 �g/m3, annual mean; 65 �g/m3 daily maximum forPM of diameter �2.5 �m (PM2.5)]. These newer studies haveshown a significant health impact of PM, linked to mass and notnecessarily sulfate or any other constituent. Although effects aremost apparent in individual groups already compromised by car-diopulmonary diseases, there is no one accepted mechanism to ac-count for these findings (Schwartz, 1994; Costa, 2000). That theassociation is not somehow linked to the composition of the PMhas drawn considerable attention from researchers who are tryingto establish a “biologically plausible” link to some attribute of PMother than mass alone. The linkage to mass and not compositionis somewhat counterintuitive to the toxicology community, espe-cially in light of the fact that all PM is not constitutively identical.Nevertheless, the collective data show that for day-to-day fluctua-tions in the mass concentration of 10 �g/m3 airborne PM, thereoccurs an increase of about 0.6 to 1 percent (excess) mortality. Inaddition to mortality, morbidity (in terms of hospital visits, inhaleruse by asthmatics, and school absenteeism) also is associated withambient PM levels; other factors such as temperature, humidity,O3, SO2, and other pollutants per se do not explain the observedeffects. At this point the consistency of the phenomenon from onegeographic site to another and over time is remarkable. Even re-visiting the mortality data from the 1952 London incident demon-strates that PM was likely the pollutant of most prominence in-terms of the adverse health consequences back almost 50 years(Schwartz and Marcus, 1990).

The direction and design of population studies today, fre-quently referred to as panel or cohort studies, are largely person-based, where groups of people are studied (e.g., nursing home res-idents, schoolchildren) in their immediate environment using non-or minimally invasive clinical tools (e.g., pulmonary or cardiacfunction, symptoms, blood screenings, etc.) to correlate effects withambient and/or personal environmental and air pollutant measures.These studies sacrifice the power of group numbers for more di-rect and individual data in an attempt to link biomarkers with ex-posure. These novel approaches have the promise of eventually of-fering clues as to causality, which is not possible with conventional

epidemiology, and recent studies are showing increasingly moresubtle changes in cardiopulmonary function with exposure to verymodest air pollution.

Long-Term Exposures Epidemiologic studies of the chronic ef-fects of air pollution are difficult to conduct because of the natureof the goal: outcomes associated with long-term exposures. Theusual approach of retrospective, cross-sectional studies is fre-quently confounded with unknown variables and inadequate his-torical exposure data. A good example of the problem of con-founding is cigarette smoking. Without extensive control of bothactive of passive smoking, the ability to discern the impact of airpollution or a disease outcome such as chronic bronchitis and em-physema would be greatly impaired because of the high back-ground of disease attributable to smoking and the imprecision ofmost indices of smoking exposure in this type of study. In contrast,prospective studies have the advantage of more precise control ofconfounding variables, such as the tracking of urinary cotinine asan index of tobacco smoke exposure, but they can be very expen-sive and require substantial time and dedication on both the partof the investigators as well as the population under study. De-pending on the study size and design, exposure aspects can alsobe problematic, but loss of subjects due to dropout is usually moretroublesome.

Despite these deficiencies, there have been several epidemi-ology studies of both types conducted with the aim of determin-ing long-term air pollution health effects. In general, these studieshave suggested a positive association between urban pollution andprogressive pulmonary impairment. On the one hand, cross-sectional studies in the Los Angeles Air Basin have found evidenceof accelerated “aging-like” loss of lung function in people livingfor extended periods in regions of high oxidant pollution as com-pared with areas where sea air circulates and lowers the overallpollutant concentrations (Detels et al., 1991). Similarly, chronic ex-posure to SO2 and PM in the Netherlands over a 12-year periodwas shown prospectively to gradually impair lung function (VanDe Lende et al., 1981). And even rural areas in western Pennsyl-vania, which are swept by reducing-type pollutants transportedfrom midwestern industrial centers, have been shown to have ahigher incidence of respiratory symptoms as determined from aquestionnaire-based design (Schenker et al., 1983). While the roleof any specific pollutant in these studies is difficult to dissect, themessage that air pollution contributes to deterioration of lung healthseems clear.

Among the most detailed prospective epidemiologic studiesof the chronic health effects of current levels of air pollution hasbeen the so-called Harvard Six Cities Study begun in the early1970s. The cities were chosen to represent a range of air quality(based on SO2 and PM). Initially, there was great dependence onroutine regional air-monitoring data, but over time air analyses ofmicroenvironments by the investigators themselves predominated.The initial design of these studies included the gathering of parentalquestionnaire data (including some 20,000 people) about theprevalence of respiratory problems in schoolchildren and has beencontinued over twenty years with tracking of similar data alongwith periodic assessments of pulmonary function. When comparedacross cities, [H�] (measured in four of the six cities) was corre-lated (Fig. 28-7A) better than was sulfate with the prevalence ofbronchitis in children age 10 to 12 (Speizer, 1989). However, asthe assessment program evolved, more detailed study revealed mor-tality associations with PM as noted above, and represented in Fig.


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28-7B through D, but the role of [H�] in this relationship withacute mortality was less convincing than that associated with thesulfate or fine (�2.5 �m) PM (sulfates co-associate with fine PMin the atmosphere) (Dockery et al., 1993). But more importantlywith regard to long-term health, this study showed very significanteffects of PM on the life spans of people living in Steubenville,Ohio — an area of industrial reducing-type pollution. Over a 15-year period, the average human life span was reduced by about2 years due to PM exposure. Another cohort-based mortality studyof the long-term effects from PM, especially that derived from com-bustion (PM2.5 and sulfate), was conducted using the data from 151cities (Pope et al., 1995). This study confirmed the impact of PMon mortality, showing a 15 to 17 percent increased risk over 7 years,about equivalent to the risk of smoking over that period. Hence,there is now growing concern for the potential chronic health im-pacts and heightened risk of premature death from lifelong air pol-lution exposure.

The role of air pollution in human lung cancer is also diffi-cult to assess because the vast majority of respiratory cancers re-sult from cigarette smoking. However, many compounds that oc-cur as urban air pollutants are known to have carcinogenic potency.Several of these compounds are among the 188 HAPs listed in theCAA Amendment of 1990. However, most of the HAPs and evenfewer (about 10 percent) of the more than 2800 compounds thathave been identified in the air have been assayed for carcinogenicpotency. Figure 28-8 gives estimates of the relative contributionsof various chemicals to the lung cancer rate that is not associatedwith cigarette smoking, which, for outdoor air, is estimated to beabout 2000 cases per year (Lewtas, 1993). This compares withabout 2000 cases per year for passive environmental tobacco smokeand about 100,000 cases per year for smokers. Volatile organiccompounds (VOCs) and nitrogen-containing and halogenated or-ganics account for most of the compounds that have been studiedwith animal and genetic bioassays. Most of these compounds are


Figure 28-7. Data from the Harvard Six Cities Studies indicating the superior relationship of PM10 and sul-fate to mortality rates (A–C) in contrast to acidity (D), which correlates better with the prevalence of bron-chitis in children. [Reproduced with permission from Speizer, 1989 (D) and Dockery et al., 1993 (A–C).]

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derived from combustion sources ranging from tobacco to powerplants to incinerators. Other potential carcinogens arise from mo-bile sources as products of incomplete combustion and their at-mospheric transformation products as well as fugitive or acciden-tal chemical releases. This contrasts with indoor air, where thesources are thought to derive largely from environmental tobaccosmoke and radon, with some contribution from the off-gassedorganics (e.g., adhesives, carpet polymers).

The cancer risk of any individual should be some function ofthe carcinogenic nature of the substance, the amount of materialdeposited, which is itself a function of the concentration in the am-bient air and the cumulative volume inhaled, and of course the in-nate susceptibility of the individual (including genotypic traits andenvironmental factors such as diet, etc.). A significant body of datasuggests that the majority of cancer risk from ambient air pollu-tion lies within the particulate fraction. Among the many potentchemicals are the polycyclic organic chemicals, along with a groupof less-volatile organics sometimes referred to as “semivolatiles”(including nitroaromatics). These persistent organics associate withthe particulate matrix and thus could have a prolonged residencetime at deposition sites within the respiratory tract. Genetic bioas-says have revealed the potent mutagenicity, and presumably car-cinogenicity, of various chemical fractions of ambient aerosols(Lewtas, 1993). Some of these compounds require metabolic trans-formation to activate their potency while others may be detoxifiedby their metabolism.

The cells lining the respiratory tract turn over relativelyquickly, since they continuously interface with the ambient envi-ronment. Conceptually, their DNA would thus be frequently vul-

nerable to carcinogenic or oxidant-induced replication errors that,when fixed as mutations, could be tumorigenic. Copollutants, suchas irritant gases that initiate inflammation, may promote carcino-genic activity by damaging cells and further enhancing theirturnover. For example, there is experimental evidence thatbenzo(a)pyrene inhaled by rats whose respiratory tracts have beenchronically irritated by SO2 inhalation may result in bronchogeniccarcinoma. Likewise, epidermoid carcinomas were produced inmice that inhaled ozonized gasoline, containing many reactive or-ganic products, if these mice had been previously infected with in-fluenza virus and had presumably developed inflammation. Manybelieve that the so-called rural-urban gradient of lung cancer, ap-parent even when corrected for cigarette smoking, is a product ofthese complex interactions. Thus, while the phenomenon of envi-ronmental lung cancer remains poorly understood, there is generalsentiment for the early opinion expressed by Kotin and Falk in1963: “Chemical, physical and biological data unite to form a con-stellation that strongly implicates the atmosphere as one dominantfactor in the pathogenesis of lung cancer.” At the time of this state-ment, however, the role of tobacco smoke was not widely appre-ciated.

Indoor Air Pollution

As outdoor air quality has improved over the last 20 to 30 years,there has been a growing awareness of the potential for indoor airpollution to elicit adverse health effects. The concerns about in-door air that at first brought skepticism have gained an element ofrespectability as various attributes of the indoor environment and


Figure 28-8. Relative contribution of individual airborne hazardous pollutants to lung cancer rates after re-moval of tobacco smoke cancer.

The total number of cancers from non-tobacco-smoke sources is estimated to be about 2000 per year. (Repro-duced with permission from Lewtas, 1993.) PIC � products of incomplete combustion.

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its effect on health and well-being are being investigated. However,the issue remains controversial because many of the health prob-lems associated with indoor air pollution generally involve non-specific symptomatology and appear to involve a wide range of po-tential toxicants and sources (Molhave et al., 1986). The responsesto indoor air pollution also appear to be affected by ambient com-fort factors such as temperature and humidity. Two broadly definedillnesses that are largely unique to the indoor environment are dis-cussed below (Brooks and Davis, 1992).

Sick-Building Syndromes This collection of ailments, definedby a set of persistent symptoms enduring at least 2 weeks(Table 28-3), occurs in at least 20 percent of those exposed and istypically of unknown specific etiology but is relieved sometime af-ter an affected individual leaves the offending building (Hayes etal., 1995). Frequently but not always, this syndrome occurs in new,poorly ventilated, or recently refurbished office buildings. The sus-pected causes include combustion products, household chemicals,biological materials and vapors, and emissions from furnishings;they are exacerbated by the effect of poor ventilation on comfortfactors. The perception of irritancy to the eyes, nose, and throatranks among the predominant symptoms that can become intoler-able with repeated exposures. Controlled clinical studies haveshown concentration- and duration-dependent worsening of sen-sory discomfort after exposure to a complex mixture of 22 VOCscommonly found in the indoor environment (Molhave et al., 1986).The many factors contributing to such responses are poorly un-derstood but include various host susceptibility factors such as per-sonal stress and fatigue, diet and alcohol use, and other factors.Current biomarkers of response used in the laboratory include sen-sory irritancy to the eyes in volunteer test subjects and sometimesin animals as well. Animal studies using standard measures of sen-sory irritation or other corporal endpoints have had limited successin assessing sick-building syndromes (SBS) and related syndromes.The biggest problem generally lies in the VOC concentrations re-quired to achieve responses in a limited pool of animals that relateto likely human exposures is too high to establish a plausible linkto the human condition.

Building-Related Illnesses This group of illnesses, in contrast tothe SBS, consists of well-documented conditions with defined di-agnostic criteria and generally recognizable causes. These illnessestypically call for a conventional treatment regimen, since simplyexiting the building where the illness was contracted does not read-

ily reverse the symptoms. Several of the bicontaminant-related ill-nesses (e.g., legionnaires’ disease, hypersensitivity pneumonitis,humidifier fever) fall into this group, as do allergies to animal dan-der, dust mites, and cockroaches. Some toxic inhalants might beclassified in this group, such as carbon monoxide. In many cases,however, when the concentrations of CO, NO2, and many VOCsresult in less discernible or definable conditions, the responses maybe mistaken for or considered to be SBS, thus complicating the as-sessment of the situation. It should be noted that many inhalants,such as NO2 and trichloroethylene (a VOC common to the indoorair arising from chlorinated water or dry-cleaned clothes), havebeen shown in animal toxicology studies to suppress immune de-fenses and allow opportunistic pathogens to proliferate in the lung.The involvement of immunologic suppression is a particularly con-troversial yet important attribute of indoor pollution because of itsinsidious nature and implications for all building-related illnesses.This is further complicated in that complex indoor environmentscomprising of chemicals and biologicals may also lead to in un-expected interactions that are virtually unstudied and thus are notappreciated in the assessment of indoor pollution.

POLLUTANTS OF OUTDOORAMBIENT AIR

Classic Reducing-Type Air Pollution

The acute air pollution episodes of this century have made it clearthat high concentrations of the reducing-type air pollution, char-acterized by SO2 and smoke, are capable of producing disastroushuman health effects. Empiric studies in human subjects and ani-mals have long stressed the irritancy of SO2 and its role in theseincidents, while the full potential for interactions among the copol-lutants in the smoky, sulfurous mix has not been fully replicatedin the laboratory. Nevertheless, the irritancy of most S-oxidationproducts in the atmosphere is well documented, and there are bothempiric and theoretical reasons to suspect that such products actto amplify the irritancy of fossil fuel emission atmospheres viachemical transformations and related interactions.

Sulfur Dioxide General toxicology Sulfur dioxide is a water-soluble irritant gas. As such, it is absorbed predominantly in theupper airways and, as an irritant, can stimulate bronchoconstric-tion and mucus secretion in a number of species, including hu-mans. As one of the earliest suspect air pollutants, it has been wellstudied over the years. Early studies with relatively high exposureconcentrations of SO2 showed airway cellular injury and subse-quent proliferation of mucus-secreting goblet cells. This attributeof SO2 has led to its use (�250 ppm) in the production of labora-tory animal models of bronchitis and airway injury (Kodavanti etal., 1999). At much lower concentrations (�1 ppm), such as mightbe encountered in the polluted ambient air of industrialized areas,long-term residents experience a higher incidence of bronchitis. Infact, prior to the breakup of the Soviet block, many easternEuropean cities were renowned for widespread public afflictionwith bronchitis; now, 20 years later, the prevalence of bronchitis isgreatly reduced (von Mutius et al., 1994). While other factors (diet,access to health care, other pollutants) may well have been involvedin this reversal, reductions in ambient smoke and SO2 are gener-ally thought to be most important.

The concentrations of SO2 likely to be encountered in theUnited States are lower still—on average, less than 0.1 ppm. Man-


Table 28-3Symptoms Commonly Associated with the Sick-BuildingSyndromes

Eyes, nose, and throat irritationHeadachesFatigueReduced attention spanIrritabilityNasal congestionDifficulty breathingNosebleedsDry skinNausea

SOURCE: Modified from Brooks and Davis, 1992, with permission.

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dated use of cleaner (low-S) fossil fuels, emission control devices,and the use of tall emission stacks have largely been responsiblefor the reductions. However, on occasional down-drafting ofsmokestack plumes or meteorological inversions near point-sourcesresult in low ppm levels of SO2 that may pose a hazard to someindividuals. A 2-min exposure to 0.4 to 1.0 ppm can elicit bron-choconstriction in exercising asthmatics within 5 to 10 min (Gonget al., 1995). However, it is the low-level, long-term effects, whicherode pulmonary defenses, that continue to worry some regulators.Studies have shown that SO2 is itself capable of impairingmacrophage-dependent bacterial killing in murine models. Ex-posed mice have a greater frequency and severity of infection,which has been suggested to be linked to diminished ability to gen-erate endogenous oxidants for bacterial killing. Analogously, ratsexposed for 70 to 170 h to 0.1, 1.0, and 20 ppm exhibited reducedclearance of inert particles, while dogs exposed to 1 ppm for a yearhad slowed tracheal mucocilliary transport. The fact that the low-concentration exposures showed marked effects when extendedover longer periods is consistent with the epidemiologic associa-tions between SO2 exposure and bronchitis. The evidence is notclear, however, as some studies show no overt pulmonary pathol-ogy. Guinea pigs and monkeys, for example, showed no effect onlung function or pathology after a year of continuous exposure toconcentrations of 0.1 to 5 ppm (Alarie et al., 1970, 1972).

The penetration of SO2 into the lungs is greater during mouthas opposed to nose breathing. An increase in the airflow rate fur-ther augments penetration of the gas into the deeper lung. As a re-sult, persons exercising would inhale more SO2 and, as noted withasthmatics, are likely to experience greater irritation. Once de-posited along the airway, SO2 dissolves into surface lining fluid assulfite or bisulfite and is readily distributed throughout the body.It is thought that the sulfite interacts with sensory receptors in theairways to initiate local and centrally mediated bronchoconstric-tion. Labeled 35SO2 studies indicate, however, that some residualS (presumably as protein reaction products) persists in the respi-ratory system for a week or more after exposure, and is slowly ex-creted in the urine (Yokoyama et al., 1971). In both rabbits and hu-man subjects, sulfite that reaches the plasma has been shown toform S-sulfonate products of reaction with the disulfide bonds inplasma proteins (Gunnison and Palmes, 1974). The toxicologic sig-nificance of S-sulfonate proteins is unknown, but they might serveas markers of exposure.Pulmonary Function Effects The basic pulmonary response toinhaled SO2 is mild bronchoconstriction, which is reflected as ameasurable increase in airflow resistance due to narrowing of theairways. Concentration-related increases in resistance have beenobserved in guinea pigs, dogs, and cats as well as humans. Expo-sure of isolated segments of the nose or airways of dogs and guineapigs appeared to alter resistance in a manner consistent withreceptor-mediated sensory stimulation. Airflow resistance increasedmore when the gas was introduced through a tracheal cannula thanvia the nose, since nasal scrubbing of the water-soluble gas wasbypassed. Isolated nasal exposures increased nasal airflow resist-ance through the nose largely as a result of mucosal swelling, butthe irritant effect appeared to signal to the more distal airways aswell. Direct exposure of the trachea had a more dramatic effect onairflow resistance, but exposure of the intact nose and lungs to-gether gave the most marked responses, consistent with the theorythat a neural network involving receptor stimulation is involved inbronchoconstriction (Frank and Speizer, 1965; Nadel et al., 1965).Intravenous injection of atropine (a parasympathetic receptor

blocker) or cooling of the cervical vagosympathetic nerves abol-ishes bronchoconstriction in the cat model; rewarming of the nervereestablishes the response. The rapidity of the response and its re-versal emphasize the parasympathetic tonal change in airwaysmooth muscle. Studies in human subjects have confirmed the pre-dominance of parasympathetic mediation, but histamine from in-flammatory cells may play a secondary role in the bronchocon-strictive responses of asthmatics (Sheppard et al., 1981).

Human subjects exposed to 1, 5, or 13 ppm SO2 for just 10min exhibit a rapid bronchoconstrictive response, with 1 to 3 ppmbeing a threshold for most if exercise is involved. Healthy indi-viduals at rest seem to have a clear response at about 5 ppm, thoughthere is considerable variation among individuals (Frank et al.,1962). Even 0.25 to 1 ppm for a few hours can induce bron-choconstriction in adult and adolescent subjects with clinically de-fined mild asthma (Sheppard et al., 1981; Koenig et al., 1981).Findings such as these (responses �0.5 ppm) have raised concernsabout potential adverse effects in this sensitive subpopulation whenit is exposed to peaks of SO2 that are known to occur near pointsources.Chronic Effects Few long-term studies have been conducted withSO2 at levels approaching those found in ambient air. Alarie andassociates (1970) exposed guinea pigs to 0.13, 1.01, or 5.72 ppmSO2 continuously for a year without adverse impact on lung me-chanics. Similarly, monkeys exhibited no alteration in pulmonaryfunction when exposed continuously for 78 weeks to 0.14, 0.64,and 1.28 ppm SO2 (Alarie et al., 1972). Even in the presence of0.1 mg/m3 sulfuric acid, dogs exposed 16 h a day for 18 monthsto 0.5 ppm SO2 showed no impairment in pulmonary function(Vaughan et al., 1969). Only higher levels of SO2 for protractedperiods of time [dogs to 5 ppm for 225 days (Lewis et al., 1969);rats to 350 ppm for 30 days (Reid, 1963)] have been shown to al-ter airway mucus secretion, goblet cell topography, or lung func-tion, but these results are of little relevance to typical SO2 levelsin ambient air.

Sulfuric Acid and Related Sulfates

The conversion of SO2 to sulfuric acid is favored in the environ-ment. During oil combustion or the smelting of metal, sulfuric acidcondenses downstream of the combustion processes with availablemetal ions and water vapor to form submicron sulfated fly ash. Sul-fur dioxide continues to oxidize to sulfate in dispersing smokestackplumes in the presence of free soluble or partially coordinated tran-sition metals such as iron, manganese, and vanadium within theash particles. When coal is burned, the acid may adsorb to the sur-face or solubilize in ultrafine (�0.1 �m) metal oxide particles dur-ing emission. These sulfates on the surface of coal ash may con-stitute as much as 9 percent of the emitted sulfur—the rest isemitted as SO2 gas. Photochemical environments in the lower tro-posphere can also promote acid sulfate formation via both metal-dependent and independent mechanisms, but studies have shownthat most of the oxidation of SO2 occurs within diluted plumesdrifting in the atmosphere. Stack emissions may undergo long-range transport to areas distant from the emission source, allowingconsiderable time for sunlight-driven chemical reactions to occur.Although the fine-particle sulfates may exist as fine sulfuric acid(the primary source of free H�), partially or fully neutralized forms(ammonium bisulfate and ammonium sulfate) predominate due tothe abundance of natural atmospheric ammonia. As fine PM sul-fates are transported long distances, they may contribute to regional


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summer haze and pose not only a health hazard to certain groups(e.g., asthmatics)–(Koenig et al., 1989), but may stress the generalenvironment as acid rain (Calvert et al., 1985) (Fig. 28-9).General Toxicology Sulfuric acid irritates respiratory tissues byvirtue of its ability to protonate (H�) receptor ligands and otherbiomolecules. This action can either directly damage membranesor activate sensory reflexes that initiate inflammation. Ammonia,which exists in free air at about 25 ppb and in much higherconcentrations in the mammalian nasopharynx/oropharynx, is ca-pable of neutralizing most of the irritant potential of acidic sul-fates. The efficiency of this process is dependent on temperature,relative humidity, and air mixing and thus is a likely source of vari-ability in biological responses. This is particularly true in animalstudies involving standard whole-body exposure-chamber opera-tion, in which excreta and bacteria may interact, giving rise tochamber ammonia concentrations up to 1100 ppb—more thanenough to fully neutralize sulfuric acid up to several mg/m3

(Higuchi and Davies, 1993). Similarly, endogenous ammonia suchas that which exists in the mouth has been shown to inhibit re-sponses up to 350 �g/m3 sulfuric acid in exercising asthmatics(Utell et al., 1989). For this reason, most human test subjects rinseorally with citrus juice before a sulfuric acid study, so as to mini-mize this phenomenon.

Interestingly, there is considerable species variability in sen-sitivity to sulfuric acid, with guinea pigs being quite reactive toacid sulfates, in contrast to rats, which are highly resistant. Thereasons for this difference are not fully understood but relate to re-ceptor type and density in the airways and probably not on differ-ences in neutralization by ammonia in the airway. The sensitivityof healthy humans appears to fall somewhere in between, with asth-matic humans being perhaps best modeled by the guinea pig. Over-all, however, the collective data involving animals and humans areremarkably coherent, as reviewed in an article by Amdur (1989).

To illustrate this point, Table 28-4 compares the acute toxicity ofSO2 and sulfuric acid in animals and human subjects, using indicesdetailed below, airway resistance, and bronchial clearance. To al-low direct comparisons, the concentrations are presented as�mol/m3 of the two compounds.Pulmonary Function Effects Sulfuric acid produces an increasein flow resistance in guinea pigs due to reflex airway narrowing,or bronchoconstriction, which impedes the flow of air into and outof the lungs. This process can be thought of as a defensive meas-ure to limit the inhalation of air containing noxious gases. Themagnitude of the response is related to both acid concentration andparticle size (Amdur, 1958; Amdur et al., 1978). Early studies in-dicated that as particle size was reduced from 7 �m to the submi-cron range, the concentration of sulfuric acid necessary to inducea response and the time to the onset of the response fell signifi-cantly. With large particles, even the sensitive guinea pig was ableto withstand an exceedingly high (30 mg/m3) challenge with littlechange in pulmonary resistance, in contrast to the �1 mg/m3 chal-lenge needed with the 0.3 �m particles (Amdur et al., 1978).Human asthmatics exposed to 2 mg/m3 of acid fog (10 �m) for 1 h, a very high concentration for an asthmatic, experienced vari-able respiratory symptoms suggesting irritation, but no changes inspirometry were elicited (Hackney et al., 1989). The apparent rea-son for this PM size–based differential response is probably thescrubbing of large particles in the nose, while the small particlesare able to penetrate deep into the lung, reaching receptors thatstimulate bronchoconstriction and mucus secretion. The thickermucus blanket of the nose may blunt (by dilution or neutralizationby mucus buffers) much of the irritancy of the deposited acid, thuslimiting its effects to mucous cell stimulation and a minor increasein nasal flow resistance. In contrast, the less shielded distal airwaytissues, with their higher receptor density, would be expected to bemore sensitive to the acid, as reflected by their responsiveness to


Figure 28-9. Areas in 1988 where precipitation in the East fell below pH 5: acid rain.

The acidity of the air in the east is thought to result from air mass transport of fine sulfated particulate matterfrom the industrial centers of the Midwest. (Reproduced with permission from National Air Pollutant EmissionTrends Report, 1998.)

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the small particles reaching that area (Costa and Schlegele, 1998).This regional sensitivity and the longer residence time of a de-posited particle relative to SO2 gas probably were reflected in therelatively protracted recovery times observed in acid-exposedguinea pigs compared with animals exposed to SO2 alone. Alter-natively, the particles of ZnO used in this study provided solubleZn�2 when combined with acid.

Asthmatics appear to be somewhat more sensitive to the bron-choconstrictive effects of sulfuric acid than are healthy individu-als, but published studies have been inconsistent (Koenig et al.,1989; Utell et al., 1984). Asthma generally is characterized by hy-perresponsive airways, so their tendency to constrict at low acidconcentrations would be expected, just as asthmatic airways aresensitive to nonspecific airway smooth muscle agonists (e.g., car-bachol, histamine, exercise) (Hanley et al., 1992). The variabilitymay well relate to differences in the degree of impairment or un-derlying inflammation in the subjects, but this hypothesis remainsto be confirmed. Airway hyperreactivity has been observed as anacute response in guinea pigs 2 h after a 1-h exposure to 200 �g/m3

sulfuric acid and appears to be associated with pulmonary inflam-mation. Likewise in rabbits, increased airway reactivity was asso-ciated with arachidonate metabolites, products of epithelial cellsas well as inflammatory cells. The general correlation between air-way responsiveness and inflammation that appears to be importantin grading asthma severity and risk of negative clinical outcomesmay also be predictive of responses to environmental stimuli.Effects on Mucociliary Clearance and Macrophage Func-tion Sulfuric acid alters the clearance of particles from the lungand thus can interfere with a major defense mechanism. Effects onclearance of insoluble, radioactively labeled ferric oxide particleshave been observed after as little as a single 1-h exposure in don-keys, rabbits, and human subjects. The impact on mucus clearanceappears to vary directly with the acidity ([H�]) of the acid sulfate,with sulfuric acid having the greatest effect and ammonium sul-fate the smallest (Schlesinger, 1984). Curiously, there appears tobe a biphasic response to the acid that has been observed in all an-imal species studies to date as well as in human subjects. In gen-eral, brief, single exposures of �250 �g/m3 accelerate clearance,while high concentrations of �1000 �g/m3 clearly depress clear-ance. Over several days, there also appears to be a cumulative (con-centration times duration) dose-related depression of clearance.Longer-term exposure of rabbits to low-level acid ultimately slowsclearance in apparent concert with hyperplasia of airway mucose-

cretory cells (Gearhart and Schlesinger, 1989). Acidification of mu-cus by H� (i.e., a fall in pH), even if localized, is hypothesized tohave potential effects on mucus rheology and viscosity (Holma,1989) as well as on mucus secretion and ciliary function. Theseeffects are not unreasonable in light of the drop in macrophage in-tracellular pH reported in some acid studies (Qu et al., 1993).

Sulfate effects on bronchial clearance in both rabbits and hu-mans and airway resistance in guinea pigs and in asthmatics(though sensitivities in these subjects can be quite variable) appearcoherent relative to the irritant potency of sulfates: sulfuric acid �ammonium bisulfate � ammonium sulfate. Acidity appears to bethe primary driving factor on most respiratory effects attributableto the acid sulfates even at the level of pulmonary macrophages.Lavaged rabbit macrophage phagocytosis was affected more aftera single exposure to 500 �g/m3 sulfuric acid than after 2000 �g/m3

ammonium bisulfate (Schlesinger et al., 1990). However, there issome evidence at the level of cellular activation and arachidonatemetabolism suggesting that the anionic component of the aerosolalso plays some role. Although the consensus is that acidity is theactive toxicant and is the primary metric to associate with popula-tion health effects, it remains unclear whether the bioactive formof [H�] is more appropriately assayed as free ion concentration (aspH) or as total available ion concentration (titratible H�).Chronic Effects As might be expected, sulfuric acid inducesqualitatively similar effects along the airways as are found withSO2 at much higher concentrations. As a fine aerosol, sulfuric aciddeposits deeper along the respiratory tract, and its high specificacidity imparts greater injury effect on various cells (e.g., phago-cytes and epithelial cells). Thus, a primary concern with regard tochronic inhalation of acidic aerosols is its potential to cause bron-chitis, since this has been a problem in occupational settings inwhich employees are exposed to sulfuric acid mists (e.g., batteryplants). Early studies in the donkey that later were expanded in arabbit model have provided fundamental data on this issue. Theprofound depression of clearance found in donkeys exposed re-peatedly (100 �g/m3 1 h per day for 6 months) promoted the hy-pothesis that a similar response (i.e., chronic bronchitis) can occurin humans. This argument was strengthened by the similar bron-chitogenic responses of the two species when chronically exposedto cigarette smoke.

Many studies conducted with sulfuric acid in the rabbit are ingeneral agreement with the early findings in the donkey(Schlesinger et al., 1979; Schlesinger 1984). These studies have


Table 28-4Comparative Toxicity of SO2 and H2SO4 in Acute Studies

�mol

SO2 H2SO4 REFERENCE

Guinea pigs: 1 h;10% � airway resistance 6 1 Amdur, 1974

Donkeys: 30 min; 1-h altered Spiegelman et al., 1968bronchial clearance 8875 2 Schlesinger et al., 1978

Normal subjects: 7 min; Lippmann and Altshuler, 19761-h altered bronchial clearance 520 1 Leikauf et al., 1981

Normal subjects: 10 min;5% � tidal volume 29 1.25 Amdur, 1954

Adolescent asthmatics: 40 min;equal � airway resistance 20 1 Koenig et al., 1989

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expanded our knowledge of the biological response and itsexposure-based relationship. The initial stimulation of clearancewith subsequent depression has been shown to occur over 12months with as little as 2 h per day at 125 �g/m3 sulfuric acid(Schlesinger et al., 1992). Related studies also have demonstratedthat the airways of exposed animals become progressively moresensitive to challenge with acetylcholine, showed a progressive de-crease in diameter, and experienced an increase in the number ofsecretory cells, especially in the smaller airways (Gearhart andSchlesinger, 1989).

Unlike other irritants, such as O3 (see below), sulfuric aciddoes not appear to stimulate a classic neutrophilic inflammationafter exposure. Rather, eicosanoid homeostasis appears to be dis-turbed resulting in macrophage dysfunction and altered host de-fense, perhaps in part mediated by a decrease in intracellular pH.Long-term disease attributable to connective tissue disturbances in-duced by sulfuric acid seems to be of lesser concern than is theimpact on mucociliary function and the potential effect on venti-lation and arterial oxygenation (Alarie et al., 1972, 1975). There-fore, it seems reasonable to postulate that chronic daily exposureof humans to sulfuric acid at levels of about 100 �g/m3 may leadto impaired clearance and mild chronic bronchitis. As this is lessthan an order of magnitude above haze levels of sulfuric acid, thepossibility that chronic irritancy may elicit bronchitic-like diseasein susceptible individuals (perhaps over a lifetime or in childrenbecause of dose differences) appears to be reasonable.

Particulate Matter

Particulate matter in the atmosphere is a mélange of organic, in-organic, and biological materials whose compositional matrix canvary significantly depending on local point sources. The contribu-tion to any regional PM matrix from long-range transport ofemissions or transformation products can also be substantial, par-ticularly for fine (�2.5-�m) particles. There is now a large epi-demiologic database contending that PM elicits both short- andlong-term health effects at current ambient levels (near theNAAQS). According to the epidemiology, these effects appear tobe less affected by gross particle composition (e.g., inorganic ver-sus organic) and nominal size (e.g., TSP, PM10, PM2.5) than bybasic gravimetric measures of ambient exposure. Many have ar-gued that this relationship contradicts the basic tenets of conven-tional air pollution toxicology, which is rooted in the concept ofchemical-specific toxicity. A number of hypotheses that draw uponvarious physical and chemical attributes of PM have been offeredin search of a “biologically plausible” explanation for the reportedepidemiologic observations. Prominently included among these hy-potheses are PM-associated metals, organics, acidity, size distri-bution (focusing on the unique bioactivity of ultrafine PM), PMoxidant activity or reactivity, and potentially toxic or allergenic bi-ologicals. However, at present, there is simply not enough basicunderstanding of the respective roles of PM composition and sizeto defend one hypothesis overwhelmingly over another, nor is therereason to unseat the PM mass-based correlation with health out-comes. Although the animal and human toxicologic database isgrowing rapidly with regard to the issue of causation, much re-mains to learned before new regulatory indices can be adopted.

From research directed initially toward potential occupationalhazards, it is known that several metals and silicates that make upat least part of the inorganic phase of PM can be cytotoxic to lungcells, and that organic constituents theoretically can induce toxic-

ity either directly or via metabolism to genotoxic agents. Also, stud-ies focusing on very small, ultrafine (�0.1 �m) particles suggestthat though these particles are low in mass, they are high in num-ber and thus provide substantial particle surface to biological sur-face interaction. Less is known about the role of biologically de-rived materials such as endotoxin and bioallergen fragments thatmay elicit rudimentary inflammatory responses, but the involve-ment of these substances in agricultural and indoor exposures isvery real. Finally, in the early days of air pollution toxicology, therewas considerable interest in PM–copollutant interactions, but ourknowledge in this area beyond the data derived largely from onelaboratory (Amdur et al., 1986) is very limited.Metals There have been many standard acute and subchronic ro-dent inhalation studies with specific metal compounds, often ox-ides or sulfates. These relate most appropriately to occupationalexposures. The systemic toxicities of metal compounds are pre-sented in detail elsewhere in this text; the effects of many metalsdelivered by inhalation may differ from their impact when admin-istered systemically. Since virtually any metal can be found at someconcentration in ambient PM and many have toxic or prooxidantpotential, their role in PM toxicity has garnered considerable in-terest (Costa and Dreher, 1999). The most common are metals re-leased during oil and coal combustion (e.g., transition and heavymetals), metals derived from the earth’s crust as dust (e.g., iron,sodium, and magnesium), and metals used functionally in fuels,such the antiknock gasoline metal lead (much reduced since its banin 1983) or metals released from engine wear. Metals derived fromanthropogenic combustion sources tend to enrich the fine fraction(�2.5 �m) of PM, while coarse (2.5- to 10-�m) PM is made upof metal compounds of crustal origin (e.g., Fe2O3, SiO2).

Metal compounds can be separated physicochemically: thosethat are essentially water-insoluble (e.g., metal oxides andhydroxides such as those that might be released from high-temperature combustion sources or derived from the geocrustal ma-trix) and those that are soluble or mostly soluble in water (oftenchlorides or sulfates such as those that might form under acidicconditions in a smoke plume or leach from acid-hydrated silicateparticles in the atmosphere). Solubility appears to play a role inthe toxicity of many inhaled metals by enhancing metal bioavail-ability (e.g., nickel from nickel chloride versus nickel oxide), butinsolubility can also be a critical factor in determining toxicity byincreasing pulmonary residence time within the lung (e.g., insolu-ble cadmium oxide versus soluble cadmium chloride). Moreover,some metals, either in their soluble forms or when coordinated onthe surface of silicate or bioorganic materials, can promote elec-tron transfer to induce the formation of reactive oxidants (Ghio etal., 1992). Thus, caution is warranted in assessing inhaled metals,as both their chemical and physical attributes and not simply theirtotal mass govern their effects in the lung. It is likely that a num-ber of mechanisms are involved in the action of inhaled PM-asso-ciated metals.Gas-Particle Interactions The coexistence of pollutant gases andparticles in the atmosphere raises the concern that these phases mayinteract chemically or physiologically to yield unpredictable out-comes. Many studies have shown that these generic interactionsare feasible as mechanisms for altering the toxicity of either theparticle or the gas. The guinea pig bronchoconstriction model usedfor many years by Amdur and associates has clearly shown thatSO2 can interact with metal salts to potentiate particle irritancy.The mechanism(s) behind this interaction involve the solubility ofSO2 in a liquefied aerosol as well as the ability of the metal to cat-


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alyze the oxidation of the dissolved gas to sulfate. In the case ofsodium chloride aerosol, potentiation appeared to be governed pri-marily by the solubility of SO2 in that salt droplet and its enhancedrespiratory penetration, while metal salts such as manganese, iron,and vanadium functioned through the formation of the stronger ir-ritant sulfate (Amdur and Underhill, 1968). The degree of responseto the mixture was dictated by the aerosol itself, indicating that itwas indeed the proximate irritant. Studies in humans have beenless revealing about such interactions, perhaps in part as a resultof differences in study design and methodology.

Metal smelting or the combustion of coal can emit sulfuricacid that is physically associated with ultrafine metal oxide parti-cles. Analogous particles can be furnace-generated in the labora-tory and diluted in cool clean air to expose animals (Amdur et al.,1986). These ultrafine particles are distributed widely and deeplyin the lung and enhance the irritant potency beyond that predictedon the basis of the sulfuric acid concentration alone. Exposure ofguinea pigs to 30 to 60 �g/m3 sulfuric acid combined with ultra-fine zinc oxide produced dose-dependent decreases in DLCO, totallung capacity, and vital capacity and increases in cells, protein, anda variety of enzymes in lavage fluid that were not completely re-solved 96 h after exposure (Amdur, 1989). Other studies of com-bustion products of different coals emphasized again the role ofsurface associated acidic S-compounds. Illinois No. 6 coal, whichhas a layer of sulfuric acid sorbed on the surface of the ultrafineash, produced more effects in the guinea pig model than the morealkaline Montana lignite, which has sorbed neutralized sulfate, eventhough the absolute amount of sulfate was greater in the Montanalignite (Chen et al., 1990). While the exact physicochemical inter-action between SO2 and zinc oxide to bring about enhanced effectsis arguably a combination of surface and solubility mechanisms,similar studies using inert carbon black appear consistent with itsrole as carrier for reactive gases such as ozone and various alde-hydes to enhance delivery of toxic materials to the deep lung(Jakab, 1992). The result was enhanced infectivity when the testanimals were subsequently exposed to pathologic bacteria. Thus,the combination of the inert or chemically active particles with atoxic gas appears able to enhance the impact of the gas alone, ei-ther by altering dose distribution or the formation of a more toxicproduct.

Another potential interaction may result from the ability ofgaseous pollutants to influence the clearance of particles from thelung or alter the metabolism or cellular interactions with lung-deposited particles. The early studies by Laskin at New York Uni-versity in the 1960s, showing an intriguing interaction of SO2 andbenzo(a)pyrene to promote carcinogencity, were noted earlier;however, this result may well have been due to impaired clearanceas well as the promoting activity of inflammation. Similarly, ratsexposed to an urban 8-h daily profile of ozone for 6 weeks, fol-lowed by a 5-h exposure to asbestos, were found to retain threetimes as many fibers as did the controls 30 days later. In this case,the fibers were deposited in the distal airways and penetrated moredeeply into the intercellular areas, where they seemed inaccessibleto phagocytic removal (Pinkerton et al., 1989). These studies, to-gether with those focusing on irritancy and infectivity, raise theprospect that realistic exposure scenarios of gaseous and particu-late pollutants can interact through either chemical or physiologicmechanisms to enhance either immediate or associated long-termrisks of complex polluted atmospheres.Ultrafine Carbonaceous Matter Carbonaceous material oftenforms the core of fine PM. The organic materials, which can be of

a semivolatile or nonvolatile nature, are more often dispersed withinthe structure of PM, forming layers or sheaths. Estimates of thecarbonaceous content vary considerably but are nominally consid-ered to be about 30 to 60 percent of the total mass of fine PM. Thesources of organic carbon are varied and include the combustionproducts of natural smoke (e.g., forest fires) and engine exhaust aswell as stationary sources (fugitive fly ash). Elemental carbon isat the core of most diesel PM, though many complex organics canbe associated with its surface. It has been estimated that diesel con-tributes about 7 percent of the fine urban PM emissions, which,when expressed as an annual U.S. average, are about 2 �g/m3

(USEPA, 1993). Because of the higher use of diesel fuel in Europeand along U.S. freeways, the diesel content of ambient PM hasbeen estimated to be as high as 30 percent.

As an air pollutant, the carbonaceous core of PM has beenconsidered largely inert except in experimental “overload” condi-tions associated with long-term, high-exposure concentrations inrodent bioassays (addressed below). The potential of PM to act asa carrier of certain irritant gases was noted earlier. Recently, how-ever, carbon in the ultrafine mode (�0.1 �m) has been suggestedto be more toxic than the same substance in the larger fine-moderange (2.5 �m), perhaps due to differences in surface reactivity ortissue penetration (Oberdorster et al., 1994; Donaldson et al., 1998).Ultrafine PM possesses extremely high surface area while con-tributing almost negligible mass to PM2.5. This is relevant to thediesel issue, since diesel PM is made up of aggregated ultrafinecarbon with small amounts of various combustion-derived com-plex polycyclic and nitroaromatic compounds and only a trace ofmetals. However, whole diesel exhaust also contains significantamounts of NOx, CO, and SOx as well as formaldehyde, acrolein,and other aldehyde compounds, which are known to be irritants.Recent studies of diluted exhaust in humans reveals that the dieselexhaust mix is inflammogenic and to a degree cytotoxic to airwaycells (Salvi et al., 1999). Animal and in vitro cell studies with dieselparticles themselves, however, have not shown much acute toxic-ity. But further studies of the same isolated diesel PM reacted invitro with ozone before testing in a biological system indicate sig-nificant enhancement of the inherently low toxicity of diesel PM(Madden et al., 2000). This underscores the potential importanceof interactions among air pollutants as the critical factor in air pol-lution toxicity.Chronic Effects and Cancer Chronic exposure studies have beenconducted with a number of particles ranging from titanium diox-ide and carbon to diesel exhaust and coal fly ash aerosol. Of thesesubstances, diesel exhaust has been the most extensively studied(reviewed by Cohen and Nikula, 1999). The diesel particle is ofinterest because it can constitute a significant portion of an urbanparticulate load in some cities (especially in Europe). The primaryconcern with diesel has been the suspicion that it can induce lungcancer and thus is classified as a Class B carcinogen. However, de-spite evidence from over forty occupational studies (primarily rail-way yard, truck, and bus workers) implicating diesel exhaust as amild carcinogen, confounding elements undermine virtually everystudy. If one looks to empiric studies, potential carcinogenicity issuggested by several chronic exposure studies in animals and invitro data indicating mutagenicity in Salmonella bacteria and en-hanced sister chromatid exchange rates in Chinese hamster ovarycells. (These genotoxic effects have been linked to the nitroarenesassociated with the diesel PM.) However, animal studies have notresolved the question of carcinogenic health risk from diesel. Thein vivo chronic bioassay studies in rats show a pattern of tumori-


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genesis that appears to be an effect of the bulk loading of particu-late material in the lungs. At high concentrations of diesel PM (3.5and 7 mg/m3), normal mucociliary clearance in rats is graduallyoverwhelmed, resulting in a progressive buildup of particles in thelungs. By 12 months (and increasingly upon approaching 18 to 24months), clearance essentially ceases and there is evidence of on-going inflammation, oxidant generation, epithelial hyperplasia, andfibrogenic activity around agglomerates of particles and phagocyticcells in the distal areas of the lung. These patchy sites of injury areassociated with the eventual development of adenosarcomas andsquamous cell carcinomas in the rats involved in these studies. Atlower concentrations, where the particle buildup does not occur,tumors do not develop.

The phenomenon of overwhelming mucociliary clearance ofinert particles deposited in the rodent lung has been termed“overload” and is a common finding at the highest exposureconcentrations of chronic bioassays involving PM exposures.While this phenomenon could not occur in humans exposed to PMin the ambient environment, it is a subject worthy of considerationin a discussion of PM health effects, as it relates to the interpreta-tion of toxicologic data. Several, poorly soluble particles have in-duced lung tumors in chronic rat bioassays only under the cir-cumstance of overload; tumors have not developed under similarconditions in mice and hamsters. Among these particles are tita-nium dioxide, carbon black, toner dust, talc, and diesel PM; thepotential for tumors is especially marked when the particles are inthe ultrafine mode. In the rat, the time course and pattern of accu-mulation, chronic inflammation, epithelial hyperplasia, and tu-morigenesis are essentially the same for all of the particles. In con-trast, the degree of active inflammation in the mouse and hamsterunder similar overload conditions appears much less and thus isthought to be an important distinction among the species that re-lates to their sensitivities. Classic in vivo genotoxicity seemslargely absent. Not surprisingly, the interpretation of cancer dataunder these conditions remains controversial. The closest analogyin humans would be coal miners who do not appear to have an enhanced risk of lung cancer except when smoking is not involved.

The issue, then, is whether rat bioassay cancer data under con-ditions of overload are relevant to risk assessment. A recent reviewby an expert panel (ILSI, 2000) concluded that rats, while appar-ently unique in this response, may represent a sensitive subgroup,and that tumorigenesis data from the rat bioassay under conditionsof overload cannot be summarily dismissed as not relevant to theconsideration of cancer risk in humans. However, the data shouldbe interpreted and weighed in the context of lower concentrationsand the tumor incidence and pathology found therein.

Photochemical Air Pollution

Photochemical air pollution arises from a series of complex reac-tions in the troposphere close to the earth’s surface and comprisesa mixture of ozone, nitric oxides, aldehydes, peroxyacetyl nitrates,and a myriad of reactive hydrocarbon radicals. If SO2 is present,sulfuric acid PM may also be formed; likewise, the complex chem-istry can generate organic PM, nitric acid vapor, and condensate.From the point of view of the toxicology of photochemical air pol-lutants, the gaseous hydrocarbon component is no longer listed col-lectively as a Criteria pollutant, although individual compoundsmay fall into the category of HAPs (most often associated withcancer). In general, the concentrations of the hydrocarbon precur-sors in ambient air generally do not reach levels high enough to

produce acute toxicity. Their importance stems largely from theirroles in the chain of photochemical reactions that leads to the for-mation of oxidant smog or haze.

The oxidant of most toxicologic importance in the so-calledphotochemical “soup” is O3. It is important to appreciate that at-mospheric O3 is not summarily undesirable. About 10 km abovethe earth’s surface there is sufficient short-wave ultraviolet (UV)light to directly split molecular O2 to atomic O•, which can thenrecombine with O2 to form O3. This O3 accumulates to severalhundred ppm within a thin strip of the stratosphere and absorbs in-coming short-wavelength UV radiation. The O3 forms and de-composes and reforms to establish a “permanent” barrier to UVradiation, which lately has become a issue of concern, as this bar-rier is threatened by various anthropogenic emissions (Cl2 gas andcertain fluorocarbons) that enhance O3 degradation. The conse-quence is excess infiltration of UV light to the earth’s surface andthe potential for excess skin cancer risk and immune suppression.

The issue is different in the troposphere, where accumulationof O3 serves no known purpose and poses a threat to the respira-tory tract. Near the earth’s surface, NO2 from combustion processesefficiently absorbs longer-wavelength UV light, from which a freeO atom is cleaved, initiating the following simplified series ofreactions:

NO2 � hv (UV light) � O• � NO• (1)O• � O2 � O3 (2)

O3 � NO• � NO2 (3)

This process is inherently cyclic, with NO2 regenerated by thereaction of the NO• and O3. In the absence of unsaturated hydro-carbons, this series of reactions would approach a steady state withno excess or buildup of O3. The hydrocarbons, especially olefinsand substituted aromatics, are attacked by the free atomic O•, re-sulting in oxidized compounds and free radicals that react withNO• to produce more NO2. Thus, the balance of the reactionsshown in Eqs. (28-1) to (28-3) is upset, leading to buildup of O3.This reaction is particularly favored when the sun’s intensity isgreatest at midday, utilizing the NO2 provided by morning traffic.Aldehydes are also major by-products of these reactions. Formalde-hyde and acrolein account for about 50 percent and 5 percent, re-spectively, of the total aldehyde in urban atmospheres. Peroxyacetylnitrate (CH3COONO2), often referred to as PAN, and its homologsalso arise in urban air, most likely from the reaction of the perox-yacyl radicals with NO2.

Short-Term Exposures to Smog

In the 1950s and 1960s, the complexity of photochemical air pol-lution challenged toxicologists to ascertain its potential to affect hu-man health adversely. The toxicity of O3 was shown to be very higheven at low ppm concentrations. Concerns that the complex at-mosphere was even more hazardous, a number of studies were un-dertaken with actual (outdoor-derived) or synthetic (photolyzed lab-oratory-prepared atmospheres) smog in an attempt to assess thepotency of a more realistic pollution mix. When human subjectswere exposed to actual photochemical air pollution (Los Angelesambient air pumped into a laboratory exposure chamber), they ex-perienced changes in lung function similar to those described incontrolled clinical studies of O3 alone (i.e., reduction in spiromet-ric lung volumes; see below), thus supporting the view that this isthe pollutant of primary concern. Acute animal studies using syn-


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thetic atmospheres (usually irradiated auto exhaust) provided evi-dence indicating deep lung damage, primarily within the small air-way and proximal alveolar epithelium. In some of these studies,early evidence of edema appeared in the interstitium, particularlyin older animals. Additionally, mice similarly exposed were foundto be more susceptible to bacterial challenge and lung pneumonias.With time, after the termination of an acute exposure, end-airwaylesions recovered and the susceptibility to infection waned, althoughsome pathology in the distal lung persisted for more than 24 h.

While O3 appeared to be the prime toxicant in many of thesestudies, there was some evidence that other copollutants were in-volved. When guinea pigs were exposed to irradiated auto exhaust,airway resistance increased quickly, in contrast to the pattern of O3

alone, where less effect is seen on resistance than on breathing rate.This indicated that a more soluble irritant(s) probably was active,presumably reactive aldehydes. Thus, the array of effects of a com-plex atmosphere may be more diverse than would be predicted ifit were assumed that O3 alone was responsible.

Chronic Exposures to Smog

Studies in animals and human populations have attempted to linkdegenerative lung disease with chronic exposure to photochemicalair pollution. Cross-sectional and prospective field studies havesuggested an accelerated loss of lung function in people living inareas of high pollution. However, as with many studies of this type,there are problems with confounding factors (meteorology, impre-cise exposure assessment, and population variables). Recently,studies have been conducted in children living in Mexico City,which has oxidant and PM levels far in excess of any city in theUnited States. These studies have focused on the nasal epitheliumas an exposure surrogate for pulmonary tissues, using biopsy andlavage methodologies to assess damage. Dramatic effects werefound in exposed children, consisting of severe epithelial damageand metaplasia as well as permanent remodeling of the nasal ep-ithelium. When children migrate into Mexico City from cleaner,nonurban regions were evaluated, even more severe damage wasobserved, suggesting that the remodeling in the permanent resi-dents imparted some degree of incomplete adaptation. Since thechildren were of middle-class origin, these observations were notlikely confounded by poor diet (Calderon-Garcidueñas et al.,1992). These dramatic nasal effects have raised concerns for themore fragile, deep lung tissues, where substantial deposition of ox-idant air pollutants is thought to occur.

An extensive, now classic synthetic smog study in animalswas undertaken at the Cincinnati EPA laboratory in the mid-1960sin an attempt to address the potential for long-term lung disease.Beagle dogs were exposed on a daily basis (16 h) for 68 months,followed by a clean-air recovery period of about 3 years (Lewis etal., 1974). A series of physiologic measurements were made on thedogs after the exposure, and after their 3-year recovery. They werethen moved to the College of Veterinary Medicine at the Univer-sity of California at Davis. The lungs of the dogs then underwentextensive morphologic examination to correlate with the physiol-ogy. Seven groups of 12 dogs each were studied. These were ex-posed to nonirradiated auto exhaust (group 1), irradiated auto ex-haust (group 2), SO2 plus sulfuric acid (group 3), the two types ofexhaust plus the sulfur mixture (groups 4 and 5), and a high anda low level of NOx (groups 6 and 7). The irradiated exhaust con-tained oxidant (measured as O3) at about 0.2 ppm and NO2 at about0.9 ppm. The raw exhaust contained minimal concentrations of

these materials and about 1.5 ppm NO. Both forms of exhaust alsocontained about 100 ppm CO. The controls did not show time-re-lated lung function changes, but all the exposure groups had ab-normalities, most of which persisted or worsened over the 3-yearrecovery period in clean air. Enlargement of airspaces and loss ofinteralveolar septa in proximal acinar regions were most severe indogs that were exposed to NOx and SOx with irradiated exhaust(Hyde et al., 1978). These studies described a morphologic lesionthat was degenerative and progressive in nature, not unlike that ofchronic obstructive pulmonary disease (COPD)—a condition mostoften associated with lifelong tobacco smoking.

More recently, “sentinel” studies have been attemptedwhereby the animals live in the same highly polluted air to whichpeople are exposed. This approach has had a troubled past, butnewer studies appear to have better control for the problems of in-fection, inappropriate animal care (e.g., heat), and variable expo-sure atmospheres. One such study, conducted in rats exposed for6 months to the air of São Paulo, Brazil, found considerable air-way damage, lung function alterations, and altered mucus rheol-ogy (Saldiva et al., 1992). The concentrations of O3 and PM in SãoPaulo frequently exceed daily maximum values (in the summermonths of February and March) of 0.3 ppm and 75 �g/m3 , re-spectively. This collage of effects is not unlike a composite of in-jury one might suspect from a mixed atmosphere of oxidants andacid PM on the basis of controlled animal studies in the labora-tory. However, the essential conclusion from most sentinel studiesis that “pollution is unhealthy,” since individual and mixed pollu-tant effects and interactions cannot be easily addressed.

Ozone General toxicology Ozone is the primary oxidant ofconcern in photochemical smog because of its inherent bioreac-tivity and concentration. Depending on the meteorologic conditionsof a given year, 60 to 80 million Americans live in areas not in ab-solute compliance with the 1-h NAAQS of 0.12 ppm. (Formal com-pliance limits use one exceedence per year averaged over 3 years.)Los Angeles frequently attains and occasionally exceeds 1-h lev-els of 0.2 to 0.3 ppm. Unlike SO2 and the reducing-type pollutionprofile discussed above, current mitigation strategies for O3 havebeen largely unsuccessful despite significant reductions in indi-vidual automobile emissions. These reductions have been offset bypopulation growth, which brings with it additional vehicles. Withthe spread of suburbia and the downwind transport of air massesfrom populated areas to more rural environments, the geographicdistribution of those exposed has spread, as has the temporal pro-file of potential exposure. In other words, O3 exposures are nolonger stereotyped as brief 1- to 2-h peaks. Instead, there are pro-longed periods of exposure of 6 h or more at or near the NAAQSlevel and may occur either downtown or in the formerly cleanersuburban or rural areas downwind. This recently noted shift hasgiven rise to concerns that cumulative damage from such prolongedexposures may be more significant than brief pulse-like exposures,and that many more people are at risk than was previously thought.With the recent revision of the O3 NAAQS in 1997 to includean 8-h maximum average of 0.08 ppm, even more cities andsuburban areas find themselves in violation of the standard. TheAmerican Lung Association estimates that 132 million Americanslive in O3-noncompliant areas (State of the Air, 2000). Perhaps ofgreater significance is that of those who might be consideredsusceptible due to preexistent cardiopulmonary problems, 80 to 90percent live in these areas that fail to comply with the present O3

NAAQS.


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Ozone has been the subject of considerable toxicologic inter-est because it induces a variety of effects in humans and experi-mental animals at concentrations that occur in many urban areas(Lippmann, 1989). These effects include morphologic, functional,immunologic, and biochemical alterations. Because of its low watersolubility, a substantial portion of inhaled ozone penetrates deepinto the lung, but its reactivity is such that about 17 percent and40 percent is scrubbed by the nasopharynx of resting rats and hu-mans, respectively (Hatch et al., 1994; Gerrity et al., 1988). Thereason for the higher degree of scrubbing in humans is unclear, butthe finding is reproducible. Moreover, mouth scrubbing does notdiffer from nasal scrubbing. However, regardless of species, the re-gion of the lung that is predicted to have the greatest O3 deposi-tion (dose per surface area) is the acinar region, from the terminalbronchioles to the alveolar ducts, sometimes referred to as the prox-imal alveolar ductal region (Overton and Miller, 1988). BecauseO3 penetration increases with increased tidal volume and flow rate,exercise increases the dose to the target area. Using 18O3 (a non-radioactive isotope of oxygen), Hatch and coworkers have shownthat the dose to the distal lung and the degree of damage to thelung as determined by extravasated protein into the alveolar space(as collected by bronchoalveolar lavage) in exercising human sub-jects exposed to 0.4 ppm for 2 h with intermittent periods of 15min of exercise (threefold normal ventilation on average) are sim-ilar to those in resting rats exposed for the same length of time to2.0 ppm. Thus, it is important to consider the role of exercise in astudy of O3 or any inhalant before making cross-study compar-isons, especially if that comparison is across species. With so manyyears invested in the study of O3, it is surprising that only now isthe nature of species differences with regard to exercise-associateddosimetry being appreciated.

Animal studies indicate that the acute morphologic responseto O3 involves epithelial cell injury along the entire respiratorytract, resulting in cell loss and replacement. The pattern of injuryparallels the dosimetry profile, with the majority of damage oc-curring in the centriacinar region. However, along the airways, cil-iated cells appear to be most sensitive to O3, while Clara cells andmucus-secreting cells are the least sensitive. Studies in the rat noseindicate that O3 also is an effective mucus secretagogue. In the dis-tal lung, the type 1 epithelium is very sensitive to O3, in contrastto type 2 cells, which serves as the stem cell for the replacementof type 1 cells. Ultrastructural damage can be observed in rats af-ter a few hours at 0.2 ppm, but sloughing of cells generally re-quires concentrations above 0.8 ppm. Recovery occurs within a fewdays, and there appears to be no residual pathology. Hence, fromanimal studies, it would appear that a single exposure to O3 at arelatively low concentration is not likely to cause permanent dam-age. On a gross level, when a bronchoscope is used to peer intothe human bronchus after O3 exposure, the airways appear “sun-burned” and, as with mild skin sunburn, recovery is typical. Whatis uncertain is the impact of repeated “sunburning”of the airwaysand lung.

The mechanisms by which O3 causes cellular injury have beenstudied using cellular as well as cell-free systems. As a powerfuloxidant, O3 seeks to extract electrons from other molecules. Thesurface fluid lining the respiratory tract and cell membranes thatunderlie the lining fluid contain a significant quantity of polyun-saturated fatty acids (PUFA), either free or as part of the lipopro-tein structures of the cell. The double bonds within these fatty acidshave a labile, unpaired electron which is easily attacked by O3 toform ozonides that progress through a less stable zwitterion or tri-

oxolane (depending on the presence of water); these ultimately re-combine or decompose to lipohydroperoxides, aldehydes, and hy-drogen peroxide. These pathways are thought to initiate propaga-tion of lipid radicals and autooxidation of cell membranes andmacromolecules (Fig. 28-10).

Evidence of free radical–related damage in vivo includes de-tection of breath pentane and ethane and tissue measurements ofdiene conjugates. Damage to the air-blood interface disrupts its bar-rier function and promotes inflammation. Inflammatory cytokines(e.g., interleukins 6, 8 and others) are released from epithelial cellsand macrophages that mediate early responses and initiate repair.This inflammatory process is generally transient, but it may alsointeract with neurogenic irritant responses to affect lung functionacutely. This latter response may have implications for those withpreexistent inflammation or disease.Pulmonary Function Effects Exercising human subjects ex-posed to 0.12 to 0.4 ppm O3 experience reversible concentration-related decrements in forced exhaled volumes [forced vital capac-ity (FVC) and forced expiratory volume in 1 s (FEV1)] after a 2 to 3 h of exposure (McDonnell et al., 1983). With the recent con-cern that prolonged periods of exposure (6 to 8 h) may lead to cu-mulative effects, similar protocols with lower exercise levels wereextended up to 6.6 h. In these studies, exposures to 0.12, 0.10, and0.08 ppm induced progressive lung function impairment during thecourse of the exposure (Horstman et al., 1989). The pattern ofresponse was linearly cumulative as a function of exposure timesuch that changes not detectable at 1 or 2 h reached significanceby 4 to 6 h. Decrements in FEV1 after 6.6 h at 0.12 ppm averaged13.6 percent and were comparable to that observed after a 2-h ex-posure to 0.22 ppm with much heavier exercise. Interestingly, thehuman lung dysfunction resulting from O3 does not appear to bevagally mediated, but the response can be abrogated by analgesicssuch as ibuprofen and opiates, which function to reduce pain andinflammation (see below). Thus pain reflexes involving C-fiber net-works are thought to be important in the reductions in forced ex-piratory volumes. On the other hand, animal studies suggest thatcardiac as well as lung function effects of O3 have a significantparasympathetic component. Other lung function indices, such asnonspecific airway reactivity to various pharmacologic agents, in-dicate hyperreactivity after acute 2- to 6-h exposures to O3 to sub-NAAQS levels of 0.08, 0.10, and 0.12 ppm (by 56, 86, and 121percent, respectively, to methacholine). It is widely thought that


Figure 28-10. Major reactions pathways of O3 with lipids in lung liningfluid and cell membranes. (Adapted with permission from the Air Qual-ity Criteria Document for Ozone and Photochemical Oxidants. 600/P-93/004cF, NCEA. Research Triangle Park, NC: U.S. EPA, 1996.)

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hyperreactive airways may predispose responses to other pollutantssuch as sulfuric acid or aeroallergens, but such evidence is limited.

When compared with field studies, chamber exposures mayunderestimate responses for a given exposure to O3. For a givenconcentration of O3, greater decrements in pulmonary functionhave been reported in children playing outdoors at summer campsthan were observed in controlled exposure studies involving exer-cise (Lippmann, 1989). The reasons for this difference are uncer-tain but might relate more to cumulative exposure in the childrenat camp, as they were outside all day, or to the fact that the ambi-ent exposures probably involve other haze copollutants, such asH�. The responses to the ambient exposures also have slightly al-tered temporal patterns, whereby responses to O3 are influencedby previous exposures (Kinney et al., 1988). Animal studies areconsistent with the fact that both duration and concentration areimportant in assessing the response to O3 exposure (Costa et al.,1989). Pulmonary function decrements increased with C � T (con-centration times time) in rats exposed for 2, 4, or 8 h to ozone at0.2, 0.4, and 0.8 ppm. Rats exposed for 7 h to 0.5 ppm with 8%CO2 added to increase the respiratory rate produced functionaldecrements similar to those observed in human chamber studies of6.6 h at 0.12 ppm when ventilation-adjusted C � T products werefactored in. This would imply that rats and humans respond withabout the same sensitivity and opens the door to the study of var-ious scenarios of exposure to predict human responses under var-ied conditions. It should be cautioned, however, that it is unknownwhether CO2-stimulated breathing in the rat might alter responsethresholds beyond mere incrementing of the dose. On the otherhand, in related studies without stimulated breathing, lavage fluidprotein content (an index of permeability) 24-h postexposure wasalso nearly linearly cumulative, with exaggerated responses at thehigher concentrations suggestive of an exponential pattern (High-fill et al., 1992) common to other biological functions.Inflammation of the Lung and Host Defense The mechanismby which O3 produces decrements in pulmonary function is notfully understood. In contrast to sulfuric acid and SO2, functionalresponses to O3 do not correlate with responsiveness to bron-choconstrictor challenge and are not ostensibly enhanced in asth-matics, as appears to be the general case with the sulfated acids.Because the contribution of vagal mechanisms in the acute humanlung functional response to O3 appears to be minimal, attention hasturned to the role of lung inflammation. Koren and colleagues(1989) found an eightfold increase in polymorphonuclear leuko-cytes (PMNs) in lavage fluid recovered from human subjects 18-h after a 2-h exposure to 0.40 ppm with intermittent exercise.There was also evidence of increased epithelial permeability (atwofold increase in serum proteins and albumin). The inflamma-tory markers did not correlate well with functional impairmentamong the individuals tested. Arachidonate metabolism products,including the prostaglandins PGE2 and PGF2a and the leukotrienethromboxane B2, have also been seen to increase in human bron-choalveolar lavage fluid after 0.4 ppm ozone for 2-h (Seltzer et al.,1986). Pretreatment with the anti-inflammatory agents in-domethacin and ibuprofen (cyclooxygenase inhibitors) decreasedthe pulmonary function deficit and PGE2, but other indicators ofcell injury and vascular leak in lavage fluid (PMNs, extravasatedprotein, and lactate dehydrogenase) were not attenuated after ex-posure to a similar ozone challenge. Because PGE2 can have ei-ther pro- or anti-inflammatory functions under certain conditionsas well as bronchodilatory action on constricted airways, it remainsto be seen whether there is any causal relationship between arachi-

donate metabolites and functional responses. Sensitivity to O3 ap-pears to have a genetic component as well. Studies in inbred stainsof mice have shown that O3-induced pulmonary neutrophilia andpermeability are governed by a single gene linked to the Toll4 lo-cus that has been associated with endotoxin sensitivity (Kleebergeret al., 2000). Advances in genetic mapping and molecular biologyhave yielded significant information on the nature of O3 suscepti-bility in mice and may one day explain differences seen among hu-mans.

The potential for O3 to influence allergic sensitization or chal-lenge-responses has received limited investigation in either humansor animals. In general, animal studies have shown the ability of O3

to enhance the sensitization process under certain conditions (Os-ebold et al.,1980), but evidence of this in humans is lacking. Con-trolled studies of heightened antigen responsiveness in allergic sub-jects have only been suggestive, with enhancement of allergicrhinitis after 0.5 ppm for 4 h providing the only credible data todate. However, diary studies of asthmatic nurses report worsenedallergy symptoms, as well as durations thereof, at concentrationsof O3 near the NAAQS (Schwartz, 1992).

Exposure to O3 before a challenge with aerosols of infectiousagents produces a higher incidence of infection than is seen in con-trol animals (Coffin and Blommer, 1967). Studies have demon-strated that this effect in a mouse model using an aerosol of Strep-tococcus (group C) bacteria is a direct result of altered phagocytosisby macrophages in the O3-exposed animals (Gilmour et al., 1993),allowing the bacteria to develop a thickened capsule that reducestheir attractiveness to phagocytes and enhances their virulence. Thishost resistance model has shown responsiveness to an exposure aslow as 0.08 ppm for 3 h. The susceptibility of mice and hamstersto Klebsiella pneumoniae aerosol is also increased by prior expo-sure to O3. In the rat, altered microbe-killing ability may relate tomembrane damage in macrophages, thus impairing the productionof bactericidal superoxide anions. However, the rat appears to havea more vigorous PMN response to bacteria than do mice, whichseems to compensate for macrophage impairments and lends therat less sensitive to bacterial proliferation.Chronic Effects Morphometric studies of the acinar region ofrats exposed for 12 h per day for 6 weeks to 0.12 or 0.25 ppmozone showed hyperplasia and hypertrophy of type I alveolar cellsand major alterations in ciliated and Clara cells in small airways(Barry et al., 1988). When quantitative estimates of type I cell hy-pertrophy (thickness) from this study and those of another that em-ployed a low-level, urban ambient profile of O3 through 12 weekswere combined, hypertrophy appeared linearly cumulative to theO3 C � T(Chang et al., 1991, 1992). This finding suggested thatover a season, the impact of O3 in the distal lung may be cumula-tive and perhaps more importantly may be without threshold. Thebiological significance of this change is unclear—it may be partof a compensatory response to “thicken” that part of the distal air-way most affected by the oxidant. Although most of the morpho-logic changes induced by O3 clearly regress over time when theanimals are returned to clean air, there is evidence of interstitialremodeling below the epithelium in this centriacinar region, whichmay have long-term implications. Examination of autopsied lungspecimens from young smokers shows many analogous tissue le-sions that come to be described as the “smoldering” precursors ofemphysema.

Studies involving episodic exposures of rats and monkeys us-ing a pattern of alternating months of O3 (0.25 ppm) for 18 monthsindicate that there may be carry-over effects, notably thickening


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of interstitial fibrous matrix (Tyler et al., 1988, 1991). These in-terstitial changes were quantitatively similar regardless of thetwofold difference in the cumulative exposure dose (i.e., C � T).This would imply that a pattern of exposure resembling seasonalO3 patterns might result in more serious lesions than predicted bydose alone—indeed more than would have occurred had the ex-posure been continuous. Hence, the concept of “more dose . . .more effect” may not hold in chronic scenarios, as it appears todo in acute exposures. The number of episodes experienced maywell be more significant to long-term outcomes than total dose—a phenomenon not unlike that of repeated sunburning and deteri-oration of the skin.

Studies of lung function in animals exposed chronically to O3

have been conducted but have yielded mixed results. Generally, thedysfunction is reflective of stiffened or fibrotic lungs, particularlyat higher concentrations. There have been two prominent chronicO3 studies—the EPA 18-month chronic study of a realistic urbanexposure profile (Chang et al, 1992; Costa et al., 1995) and theNational toxicology Program (NTP) — Health Effects Institute(HEI Report, 1994/1995) study of 0.125 to 1 ppm for 20 months(6 h/day; 5days/week). From an environmental relevance perspec-tive, the C � T doses for these studies were similar, but the urbanprofile study produced evidence for centriacinar interstitial fibro-sis suggesting a possible influence of the exposure pattern. Therewas no general biochemical evidence for fibrosis, however (Lastet al., 1994), as observed in monkey and rat studies at higher con-centrations. If one attempts to compare these results with theCincinnati beagle study, one finds that the synthetic smog atmos-phere showed degenerative and not fibrotic lung lesions. However,it should be noted that the mixture used in the beagle study wasboth more complex and involved considerably higher concentra-tions than most current-day rat and nonhuman primate studies.

One aspect of O3 that is important in any assessment of po-tential long-term toxicity is ability of O3 to induce tolerance to it-self. Classic O3 tolerance takes the form of protection against alethal dose in animals that received a very low initial challenge 7days before. The term tolerance is sometimes used to describe“adaptation” or acclimatization over time to near ambient levels ofO3. The process begins during and immediately after the initial ex-posure and progresses to completion in at most 2 to 4 days. Thisadaptive phenomenon has been reported a number of times for hu-mans with regard to lung function tests and recently has been cor-related with inflammatory endpoints (Devlin et al., 1993). Lavagelactate dehydrogenase (LDH; a marker of cell injury) and elastase(enzymatically active against lung matrix), interestingly, did notappear to adapt in humans. An analogous pattern of adaptation offunctional and biochemical endpoints (including LDH and elas-tase) in rodents also takes place with repeated exposures up to aweek. But to date, the linkages between acute, adaptive, and long-term process remain unclear, since over longer periods of exposureboth morphologic and functional effects do appear to develop. Inthe short run, however, O3 adaptation appears in part to be relatedto the induction of an endogenous acute-phase response (McKinneyet al., 1997) as well as lung antioxidants (Wiester et al., 2000) suchas ascorbic acid. The significance of this finding in humans is un-certain because ascorbic acid is not endogenously synthesized inhumans as it is in the rat. Self-administration of ascorbate has beenshown to reduce the lung function decrement to O3 in humans(Mudway et al., 1999), but the potential role of a regimen of self-administered antioxidants (including ascorbate) to protect fromozone is not confirmed.

Ozone Interactions with Copollutants An approach simplifyingthe complexity of synthetic smog studies yet addressing the issueof pollutant interactions involves the exposure of animals or hu-mans to binary or tertiary mixtures of pollutants known to occurtogether in ambient air. Such studies have had a number of per-mutations, but most have attempted to address the interactions ofO3 and nitrogen dioxide or O3 and sulfuric acid. Depending onstudy design, there has been evidence supporting either augmen-tation or antagonism of lung function impairments, lung pathol-ogy, or other indices of injury. This apparent conflict only empha-sizes the need to carefully consider the myriad of factors than mightaffect studies involving multiple determinants.

When O3 and NO2 (1 ppm and 14 ppm, respectively) wereadministered to rats from a premixed retention chamber, the re-sulting damage evident in bronchoalveolar lavage exceeded that ofeither toxicant alone, regardless of the temporal sequence of ex-posure (Gelzleichter et al., 1992). Fibrogenic potential also was in-creased (Last et al., 1994). Theoretically, the two oxidants formedan intermediate nitrogen radical that was more toxic than eithergas alone. At much more realistic concentrations (0.3 ppm O3 and3.0 ppm NO2), where this reaction would not be favored, the im-pact of these irritants on rabbits was only additive (Schlesinger etal., 1991). This contrast in response serves to illustrate that thetenet of dose-dependency that holds for any single-toxicant re-sponse is of equal or more importance when two or more pollu-tants coexist and have the potential to interact.

Studies of O3 mixed with acid aerosols also have shown po-tentiative or antagonistic responses that were time-dependent dur-ing the period of exposure. On the one hand, as noted above, fieldstudies of children in camps and asthma admissions in the North-east and in Canada, have found an apparent interdependence ofacid and O3 underlying responses to summer haze. Yet, over an ex-tended period, there was evidence of enhanced or antagonized se-cretory cell responses with combined O3 (0.1 ppm) and sulfuricacid (125 �g/m3) at different points in the 1-year exposure of rab-bits (Schlesinger et al., 1992). As the number of interacting vari-ables increases, so does the difficulty in interpretation. Studies ofcomplex atmospheres involving acid-coated carbon combined withO3 at relevant levels show variable strength of evidence of inter-action on lung function and macrophage receptor activities (Klein-man et al., 1999). The difficulty with any multicomponent study isthe statistical separation of the interacting variables and responsesfrom the individual or combined components. However, it is thecomplex mixture to which people are exposed that we wish to eval-uate for its toxicologic potential. Creative approaches to under-standing mixture responses are a likely part of the new agenda thattoxicologists will need to address in the next decade (Mauderly,1999).

Nitrogen Dioxide General Toxicology Nitrogen dioxide, likeO3, is a deep lung irritant that can produce pulmonary edema if itis inhaled at high concentrations. It is a much less potent irritantand oxidant than O3, but NO2 can pose clear toxicologic problems.Potential life-threatening exposure is a real-world problem forfarmers, as sufficient amounts of NO2 can be liberated from silage.Typically, shortness of breath ensues rapidly with exposures near-ing 75 to 100 ppm NO2, with delayed edema and symptoms ofpulmonary damage, collectively characterized as silo-filler’s dis-ease. Nitrogen dioxide is also an important indoor pollutant, espe-cially in homes with unventilated gas stoves or kerosene heaters(Spengler and Sexton, 1983). Under such circumstances, very


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young children and their mothers who spend considerable time in-doors may be especially at risk. Sidestream tobacco smoke can alsobe a source of indoor NO2. In the outdoor environment, the levelsof NO2 needed to produce clear effects are in general far abovethose that occur in ambient air. However, more recently, protocolsthat simulate an urban (rush hour) or household (cooking) patternof two daily peaks superimposed on a low continuous backgroundconcentration have produced effects in experimental animals whencontinuous exposure to NO2 did not, suggesting an important de-pendency on exposure profile.

Although the distal lung lesions produced by acute NO2 aresimilar among species, there are considerable differences in speciessensitivity. Where a direct comparison is possible, guinea pigs,hamsters, and monkeys are more sensitive than are rats, althoughcomparative dosimetry information might explain some of this dif-ference. As in the case of O3, theoretical dosimetry studies indi-cate that NO2 is deposited along the length of the respiratory tree,with its preferential site of deposition being the distal airways. Notsurprisingly, the pattern of damage to the respiratory tract reflectsthis profile: damage is most apparent in the terminal bronchioles,just a bit more proximal in the airway than is seen with O3. At highconcentrations, the alveolar ducts and alveoli are also affected, withtype I cells again showing their sensitivity to oxidant challenge. Inthe airways of these animals there is also damage to epithelial cellsin the bronchioles, notably with loss of ciliated cells, as well as aloss of secretory granules in Clara cells. The pattern of injury ofNO2 is quite similar to that of O3, but its potency is about an orderof magnitude lower.Pulmonary Function Effects Exposure of normal human sub-jects to concentrations of �4 ppm NO2 for up to 3 h produces noconsistent effects on spirometry. However, a study has shownslightly enhanced airway reactivity with 1.5 to 2.0 ppm. Interest-ingly, ascorbic acid pretreatment of human subjects appeared toprotect them from this hyperreactivity (Mohsenin, 1987). Whetherasthmatics have a particular sensitivity to NO2 is a controversialissue. A number of factors appear to be involved (e.g., exercise, in-herent sensitivity of the asthmatic subject, exposure method). Somestudies have reported effects in some individuals at 0.2 ppm, whichis an ambient level in a household with an unvented gas stove. Recent meta-analyses, which have incorporated the findings of many studies to achieve a weight-of-evidence perspective,appear to support an effect of NO2 on asthmatics. As for an appropriate animal model, only very high concentrations (10 ppmNO2) invoke an irritancy response in guinea pigs (tachypnea); theselevels are well above those a person probably would encounter ineveryday life. Recently, NO2 has been found to be associated withmortality in some time-series studies of air pollution attempting totease out specific pollutant effects (focusing mainly on PM) (Goldet al., 2000). These studies have found correlates with cardiovas-cular deaths, which has raised new questions of the mechanismsby which pollutants might affect health in susceptible subgroups.Inflammation of the Lung and Host Defense Unlike O3, NO2

does not induce significant neutrophilic inflammation in humansat exposure concentrations approximating those in the ambient out-door environment. There is some evidence for bronchial inflam-mation after 4 to 6 h at 2.0 ppm, which approximates the likelyhighest transient peak indoor levels of this oxidant. Exposures at2.0 to 5.0 ppm have been shown to affect T lymphocytes, particu-larly CD8� cells and natural killer cells that function in host de-fenses against viruses. Though these concentrations may be high,epidemiologic studies variably show effects of NO2 on respiratory

infection rates in children, especially in indoor environments. An-imal models, by contrast, have for years shown associations be-tween NO2 and bacterial infection (Gardner, 1984). Susceptibilityto infection appears to be governed more by the peak exposureconcentration than by exposure duration. The effects are ascribedto suppression of macrophage function and clearance from the lung.Altered function in the form of killing and/or motility was appar-ent in macrophages from rabbits exposed to 0.3 ppm for 3 days(Schlesinger, 1987) and from humans exposed to 0.10 ppm for 6.6h (Devlin et al., 1991).

Toxicologic studies of the interaction of NO2 with viruses aresuggestive of enhanced infectivity. Squirrel monkeys infected withnonlethal levels of A/PR-8 influenza virus and then exposed con-tinuously to 5 or 10 ppm NO2 suffered high mortality rates; 6/6monkeys exposed to 10 ppm died within 3 days, while only 1/3exposed to 5 ppm died (Henry et al., 1970). Other experiments sug-gest that the exposure of squirrel monkeys for 5 months to 5 ppmNO2 depresses the formation of protective antibodies against theA/PR-8 influenza virus. Controlled human studies, however, havebeen inconclusive, generally because of low subject numbers. Onestudy showed decreased virus inactivation by alveolar macrophagesrecovered from 4 of 9 subjects cultured in vitro and exposed to 3.5 h to 0.6 ppm NO2. These same macrophages also produced in-terleukin-1, which is a known cytokine modulator of immune cellfunction (Frampton et al., 1989). Thus, the issue of enhanced vi-ral infection associated with NO2 exposure remains of concern, es-pecially during seasonal use of unvented gas-heating indoors, butfull confirmation of this risk is absent at this time.Chronic Effects Concern about the chronic effects of NO2 stemfrom observations that 30-ppm exposures for 30 days produceemphysema in hamsters. Whether this has a bearing on humanexposures at 100-fold lower exposure concentrations is question-able. An 18-month study in rats exposed to an urban pattern of ni-trogen dioxide in which a background of 0.5 ppm for 23 h per daypeaked at 1.5 ppm for 4 h each day showed little ultrastructuraldamage to the distal lung (Chang et al., 1988). Other studies uti-lizing peak-base patterns of exposure have found some effect atnear-environmental levels of NO2 using other biological endpoints.Mice exposed for a year to a base level of 0.2 ppm NO2 with a1-h spike of 0.8 ppm twice a day 5 days per week (Miller et al.,1987) yielded effects that differed between base-only and peak-only exposure groups. The base level produced no effects, whilethe peak-only group experienced slight functional impairment andaugmented susceptibility to bacterial infection. Early studies(Ehrlich and Henry, 1968) showed that clearance of bacteria fromthe lungs is suppressed with 0.5 ppm NO2 through 12 months ofexposure. Interestingly, recent studies with a similar double diur-nal peak design for NO2, with NO used as a negative control,showed more pronounced effects of NO on alveolar septal remod-eling than did NO2 (Mercer et al., 1995). Apparently, NO as an in-tercellular signal can alter collagen metabolism; the potential forNO2 to act in this manner is not known. These and similar studiesutilizing peak-plus-baseline versus base-only or peak-only expo-sures indicate that, for NO2 or its reduction product NO, the ex-posure profile may be an important determinant of response.

Other Oxidants While a number of reactive oxidants have beenidentified in photochemical smog, most are short-lived because oftheir reaction with available volatile organic compounds (VOCs),nitrogen oxides, and other reducing equivalents that have the ef-fect of scrubbing them from the air before they can be breathed.


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One reactive, irritating constituent of the oxidant atmosphere is per-oxyacetyl nitrate (PAN), which is thought to be responsible formuch of the eye-stinging activity of smog. It is more soluble andreactive than ozone and hence rapidly decomposes in mucous mem-branes before it can get to tissues deep into the lungs. The corneahas many irritant receptors and responds readily, while the PANabsorbed into the thicker mucous fluids of the proximal nose andmouth presumably never reaches its target. A few studies with highlevels of PAN have shown that it can cause lung damage and havemutagenic activity in bacteria, but it is not likely that this is rele-vant to ambient levels of PAN.

Aldehydes Various aldehydes in polluted air are formed as reac-tion products of the photooxidation of hydrocarbons. The two alde-hydes of major interest are formaldehyde (HCHO) and acrolein(H2CPCHCHO). These materials contribute to the odor as well aseye and sensory irritations of photochemical smog. Formaldehydeaccounts for about 50 percent of the estimated total aldehydes inpolluted air, while acrolein, the more irritating of the two, may ac-count for about 5 percent of the total. Acetaldehyde (C3HCHO) andmany other longer-chain aldehydes make up the remainder, but theyare not as irritating because of their low concentration and lessersolubility in airway fluids. Formaldehyde and particularly acroleinare found in mainstream tobacco smoke (about 90 and 8 ppm, re-spectively, per drag ) and are likely to be found in sidestream smokeas well. Formaldehyde is also an important indoor air pollutant andcan often achieve higher concentrations indoors than outdoors ifdue to outgassing by new upholstery or other furnishings.

Empiric studies have shown that formaldehyde and acroleinare competitive agonists for similar irritant receptors in the air-ways. Thus, irritation may be related not to “total aldehyde” con-centration but to specific ratios of acrolein and formaldehyde. Theirrelative difference in solubility, with formaldehyde being some-what more water-soluble and thus having more nasopharyngeal up-take, may distort this relationship under certain exposure condi-tions (e.g., exercise). On the other hand, acrolein is very reactiveand may interact easily with many tissue macromolecules.

Formaldehyde Formaldehyde is a primary sensory irritant.Because it is very soluble in water, it is absorbed in mucousmembranes in the nose, upper respiratory tract, and eyes. The dose–response curve for formaldehyde is steep: 0.5 to 1 ppm yieldsa detectable odor; 2 to 3 ppm produces mild irritation; and 4 to 5ppm is intolerable to most people. Formaldehyde is thought to actvia sensory nerve fibers that signal through the trigeminal nerve toreflexively induce bronchconstriction through the vagus nerve. Inguinea pigs, a 1-h exposure to about 0.3 ppm of formaldehyde in-duces an increase in airflow resistance accompanied by a lesser de-crease in compliance (Amdur, 1960). Respiratory frequency andminute volume also decreased, but these changes do not becomestatistically significant until �10 ppm. The no observed effectlevel (NOEL) using these lung function criteria is about 0.05 ppm.The general pattern of the irritant response and its rapid recoveryis similar to that produced by higher concentrations of SO2. Andalso like SO2, the introduction of formaldehyde through a trachealcannula to bypass nasal scrubbing greatly augments the irritant re-sponse, indicating that deep lung irritant receptors can also be ac-tivated by this vapor.

Formaldehyde, like SO2, can interact with water-soluble saltsduring inhalation and produce irritancy beyond that expected forthe gas alone. When it was inhaled simultaneously with submicron

sodium chloride aerosol, irritancy was augmented in proportion tothe aerosol concentration, but this potentiation cannot be accountedfor by a simple “carrier” effect of the aerosol (Amdur, 1960). More-over, reversal of bronchoconstriction was slower than had beenobserved with SO2. Thus it appeared that the aerosol itself consti-tuted a new irritant species, the product of a chemical transforma-tion of formaldehyde—perhaps methylene hydroxide (Underhill,2000). In addition to interactions with water-soluble particles,formaldehyde has been shown to interact with carbon-based parti-cles (Jakab, 1992) to augment bacterial infectivity in a murinemodel. In this case, the potentiation appears to correlate with thesurface carrying capacity of the inhaled particle.

Two aspects of formaldehyde toxicology have brought it fromrelative obscurity to the forefront of attention in recent years. Oneis its presence in indoor atmospheres as an off-gassed product ofconstruction materials such as plywood or improperly installedurea-formaldehyde foam insulation. This aspect is discussed atlength in a review article (Spengler and Sexton, 1983). Complaintsof formaldehyde irritation in industry have been reported at 50 ppb(Horvath et al., 1988). In studies relating household formaldehydeto chronic effects, children were found to have significantly lowerpeak expiratory flow rates (about 22 percent in homes with 60 ppb)than did unexposed children. Asthmatic children were affected be-low 50 ppb. Thus, this irritant vapor has the potential to cause res-piratory effects at commonly experienced exposure levels(Krzyzanowski et al., 1990), and this may relate to evidence thatformaldehyde is a weak allergen.

Nasal cancer has been induced empirically with formaldehydevapor in rodents. In a 2-year study, rats were exposed to 2, 6, or14 ppm formaldehyde 6 h per day, 5 days per week. The occur-rence of nasal squamous cell carcinomas was zero in the controland 2-ppm groups, 1 percent in the 6-ppm group, and 44 percentin the 14-ppm group. An exposure-related induction of squamousmetaplasia occurred in the respiratory epithelium of the anteriornasal passages in all exposed groups. Rats exposed 6 h per day for5 days to 14 ppm had a greater than 20-fold increase in cell pro-liferation in the nasal epithelium. Mice were much less sensitive;only one carcinoma was seen at 14 ppm. The detection of DNAadducts in the two species paralleled the difference in the incidenceof tumors as well as regional dosimetry. With this collection ofdata, formaldehyde has been designated as a probable human car-cinogen by the IARC. The implications of these findings have beenreviewed by Starr and Gibson (1985), but recent epidemiologystudies have generally failed to find an increased incidence of nasalcancer in exposed workers.

Acrolein Because acrolein is an unsaturated aldehyde, it is moreirritating than formaldehyde. Concentrations below 1 ppm causeirritation of the eyes and the mucous membranes of the respiratorytract. Exposure of guinea pigs to 0.6 ppm reversibly increasedpulmonary flow resistance and tidal volume and decreased respi-ratory frequency (Murphy et al., 1963). With irritants of this type,flow resistance is increased by concentrations below those thatcause a decrease in frequency. This suggests that increases in flowresistance would be produced by far lower concentrations ofacrolein than were tested. The mechanism of increased resistanceappears to be mediated through a cholinergic reflex. Atropine(muscarinic blocker) and aminophylline, isoproterenol, and epi-nephrine (sympathetic agonists) partially or completely reversedthe changes, while the antihistamines pyrilamine and tripelen-namine had no effect.


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Exposures of rats to 0.4, 1.4, or 4.0 ppm for 6 h per day 5days per week for 13 weeks resulted in apparently paradoxical ef-fects on lung function (Costa et al., 1986). The lowest concentra-tion resulted in hyperinflation of the lung with an apparentreduction in small-airway flow resistance, while the highest con-centration resulted in airway injury and peribronchial inflamma-tion and fibrosis. The intermediate concentration was functionallynot different from the control, but airway pathology was evident.It appears that the high-concentration response reflected the cu-mulative irritant injury and remodeling as a result of the repeatedacrolein, while the low-concentration group had little overt dam-age and appeared to have slightly stiffened airways, perhaps a re-sult of the protein cross-linking action of acrolein. The pathologyin these animals contrasts with that found in formaldehyde stud-ies of similar duration in that there was much more upper airwayinvolvement. Ambient exposure to acrolein probably would beabout fivefold to tenfold lower than the low concentration used inthe subchronic study discussed above. Thus, as a class the alde-hydes can be very irritating and may constitute a significant frac-tion of the discomfort and sensation experienced during an oxi-dant episode, especially in mixed atmospheres containingparticles.

Carbon Monoxide Carbon monoxide is classed toxicologicallyas a chemical asphyxiant because its toxic action stems from itsformation of carboxyhemoglobin, preventing oxygenation of theblood for systemic transport. The fundamental toxicology of COand the physiologic factors that determine the level of carboxyhe-moglobin attained in the blood at various atmospheric concentra-tions of carbon monoxide are detailed in Chap. 11.

The normal concentration of carboxyhemoglobin (COHb) inthe blood of nonsmokers is about 0.5 percent. This is attributed toendogenous production of CO from heme catabolism. Uptake ofexogenous CO increases blood COHb as a function of the con-centration in air as well as the length of exposure and the ventila-tion rate of the individual. Uptake is said to be ventilation-limited,implying that virtually all the CO inspired in a breath is absorbedand bound to the available hemoglobin. Thus, continuous exposureof human subjects to 30 ppm CO leads to an equilibrium valueof 5 percent COHb. The Haldane equation is used to compute theCOHb equilibrium under a given exposure situation. The equilib-rium values generally are reached after 8 h or more of exposure.The time required to reach equilibrium can be shortened by phys-ical activity.

Analysis of data from air-monitoring programs in Californiaindicates that 8 h average values can range from 10 to 40 ppm CO.Depending on the location in a community, CO concentrations canvary widely. Concentrations predicted inside the passenger com-partments of motor vehicles in downtown traffic were almost 3times those for central urban areas and 5 times those expected inresidential areas. Occupants of vehicles traveling on expresswayshad CO exposures somewhere between those in central urban ar-eas and those in downtown traffic. Concentrations above 87 ppmhave been measured in underground garages, tunnels, and build-ings over highways.

No overt human health effects have been demonstrated forCOHb levels below 2 percent, and levels above 40 percent can befatal due to asphyxia. At COHb levels of 2.5 percent resulting fromabout 90-min exposure to about 50 ppm CO, there is an impair-ment of time-interval discrimination; at approximately 5 percentCOHb, there is an impairment of other psychomotor faculties. At

5 percent COHb in nonsmokers (the median COHb value for smok-ers is about 5 percent), however, maximal exercise duration andmaximal oxygen consumption are reduced (Aronow, 1981). Car-diovascular changes also may be produced by exposures sufficientto yield COHb in excess of 5 percent. These include increased car-diac output, arteriovenous oxygen difference, and coronary bloodflow in patients without coronary disease. Decreased coronary si-nus blood PO2 occurs in patients with coronary heart disease, andthis would impair oxidative metabolism of the myocardium. In theearly 1990s, a series of studies in subjects with cardiovascular dis-ease were conducted in several laboratories under the sponsorshipof the Health Effects Institute (HEI) to determine the potential forangina pectoris when they exercised moderately with COHb lev-els in the range of 2 to 6 percent (Allred et al., 1989). The resultsof these studies indicate that premature angina can occur underthese conditions but that the potential for the induction of ventric-ular arrhythmias remains uncertain. Thus, the reduction in ambi-ent CO brought about by newer controls should reduce the risk ofmyocardial infarct in predisposed persons.

The recent introduction of fuel oxygenates like MTBE and re-lated ether compounds into gasoline was an attempt to enhancefuel combustion and reduce CO emissions. The ensuing problemswith MTBE have been discussed earlier, but the goal of achievinglower CO was only partially successful. This finding reinforces theneed to carefully consider whether resolution of one problem hasthe potential for generating others.

Hazardous Air Pollutants Hazardous air pollutants (so-calledair toxics or HAPs) represent an inclusive classification for air pol-lutants that are of anthropogenic origin, are of measurable quan-tity, and are not covered in the Criteria Pollutant list. Some of theregulatory aspects of the HAPs were discussed above. The inclu-sive nature of this group of pollutants complicates a discussion oftheir toxicology because the group includes various classes of or-ganic chemicals (by structure, e.g., acrolein, benzene), minerals(e.g., asbestos), polycyclic hydrocarbon particulate material [e.g.,benzo(a)pyrene], and various metals and metal compounds (e.g.,mercury, beryllium compounds) and pesticides (e.g., carbaryl,parathion).

Most toxic air pollutants are of concern because of their po-tential carcinogenicity, as shown in chronic bioassays, mutagenic-ity tests in bacterial systems, structure-activity relationships, or—in a few special cases (e.g., benzene, asbestos)—their known car-cinogenicity in humans. These cancers need not be, and generallyare not, pulmonary. Noncancer issues frequently relate to directlung toxicants that, upon accidental release or as fugitive emissionsover time, might induce lung damage or lead to chronic lung dis-ease. The assessment of noncancer risk by air toxics to any organsystem is based on the computation of long-term risk reference ex-posure concentrations (RfCs) to which individuals may be exposedover a lifetime without adverse, irreversible injury. This approachto hazardous air pollutant assessment is discussed in detail byJarabek and Segal (1994). A short-term RfC method for brief oraccidental exposures is currently being developed.

Accidental versus “Fence-Line” Exposures The relationshipbetween the effects associated with an accidental release of a largequantity of a volatile chemical into the air from a point sourcesuch as a chemical plant and the effects associated with a chroniclow-level exposure over many years or a lifetime is not clear. Withregard to cancer, which defaults to a linearized model of dose and


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effect (through some alternative models can be used if there issome data), the issue is fairly straightforward. Any exposure mustbe minimized if not eliminated if cancer risk is to be kept as closeto zero as possible. With noncancer risks, the roles of nonspe-cific or specific host defenses, thresholds of response, and repairand recovery after exposure complicate the assessment of risk. Inlarge part the issue here relates to C � T. Can we better relatedisease or injury to cumulative dose or peak concentration forprotracted exposures? Is there an exposure peak beyond which acumulative approach fails (i.e., the effect is concentration-driven),or is concentration always the dominant determinant? Many ofthese questions have yet to be answered, not to mention theirspecificity with regard to individual compounds and tissues affected.

Methyl isocyanate provides a contrast between the effects ofa large accidental release versus those produced by a small releaseof fugitive vapor such that it is detectable in ambient air, but atvery low levels. The reactive nature of methyl isocyanate with aque-ous environments is of such magnitude that upon inspiration, al-most immediate mucous tissue corrosion can be perceived. The va-por undergoes hydrolysis within the mucous lining of the airwaysto generate hydrocyanic acid, which destroys the airway epithe-lium and causes acute bronchoconstriction and edema. The dam-age is almost immediately life-threatening at concentrations above50 ppm; at 10 ppm, it is damaging in minutes. These concentra-tions are in the range of the dense vapor cloud that for several hoursenshrouded the village of Bhopal bordering the Union Carbide pes-ticide plant. Studies in guinea pigs showed the immediate irritancyof this isocyanate, which in just a few minutes also resulted in sig-nificant pathology (Alarie et al., 1987). Rats exposed to 10 or 30ppm for 2 h also showed severe airway and parenchymal damage,which did not resolve in surviving rats; transient effects were seenat 3 ppm. Even 6 months after exposure, the airway and lung dam-age remained, having evolved into patchy, mostly peribronchial fi-brosis with associated functional impairments (Stevens et al.,1987). There was also cardiac involvement secondary to the dam-age to the pulmonary parenchyma and arterial bed. As a result,there was pulmonary hypertension and right-sided heart hypertro-phy. This same spectrum of health effects appeared in the surviv-ing exposed residents of Bhopal and is in large part associated withtheir above-average death rate.

In the United States, methyl isocyanate has been measured inKatawba Valley, Texas, as a result of small but virtually continualfugitive releases of the vapor into the community air (“fence-line”)from an adjoining region with several chemical plants. While theselevels of methyl isocyanate are not sufficient to cause the damageseen in Bhopal, there is concern that low-level exposure over manyyears may have more diffuse, chronic effects. Residents complainof odors and a higher frequency of respiratory disorders, but clearevidence of injury or disease is lacking.

Phosgene is best known for its use as a war gas, but it is alsoone of the most common intermediate reactants used in the chem-ical industry, particularly in pesticide formulation. It is also a con-stituent of photochemical smog. Because of its direct pulmonaryreactivity, it lends itself to use as a model pulmonary toxicant forstudies addressing C � T relationships. These studies suggest thatthere may be a threshold below which compensatory and other bod-ily defenses (e.g., antioxidants) may be able to cope with long-term low-level exposure (tolerance). For phosgene this appears tobe at or below the current threshold limit value of 0.1 ppm for 8 h. At higher concentrations, however, concentration appears to

be the primary determinant of injury or disease regardless of du-ration. Thus, even though there is some adaptation with time, therecontinues to be a concentration-driven response that exceeds thatpredicted by C � T. This relationship appears to be different fromthat of ozone at ambient levels, which can be approximated acutelyby the C � T paradigm.

WHAT IS AN ADVERSE HEALTHEFFECT?

Any attempt to establish criteria to define an “adverse effect” ofair pollution is likely to be questioned. Some effects would passuncontested, e.g., death, life-threatening dysfunction or disease, ir-reversible impairment, and pain. Other effects that may reflect mi-nor and temporary dysfunctions or discomfort could be argued bysome as not warranting significant or costly concern, especially ifeffects are minor or transient. The goal of air-quality managementis clearly to avoid or, at worse, limit negative impacts of air pol-lution on public health. However, one must appreciate the distinc-tion between risk to the individual and to a population. Clearly,risk to an individual can be beyond an acceptable limit and can putthat person’s health in jeopardy, but this response may be lost in apopulation index. On the other hand, risk to a population is thesummation of individual risks such that there is a shift in the nor-mal distribution putting unspecified individuals at risk. These twoforms of risk are clearly related, but most often in practice, thepopulation risk is considered most appropriate and most reason-ably quantifiable. This population-based risk is that used in theCAA of 1970.

In 1985, the American Thoracic Society issued a positionpaper that attempted to define an adverse effect related to air pol-lution. This has recently been revised because of the many ad-vances in clinical medicine and empiric health sciences (ATS,2000). This statement considers seven broad areas: biomarkers,quality of life, physiologic impacts, symptoms, clinical outcomes,mortality, and population health versus individual risk. The sum-mary conclusion states that caution should be exercised in eval-uating the many new biomarkers of effect (especially cell andmolecular markers), as there is need for validation that smallchanges in these markers represent a progression along a courseto disease or permanent impairment. Admittedly, in the clinicalenvironment many of these markers may appear as salient fea-tures of a disease or injury, but the health implications of minorchanges in these biomarkers remains uncertain. Significant alter-ations of standard clinical measures of health due to pollution areclearly adverse. However, a shift from the 1985 ATS statement isthat transient pulmonary function deficits (where a 10 percent ormore drop in FVC was defined as adverse) may not necessarilybe adverse. On the other hand, any irreversible reduction in pul-monary function would be adverse either for an individual oracross a population. Any population for which a significant mor-tality risk can be detected must be considered adverse. Of course,a common thread through all of these subject areas is the influ-ential role of susceptibility, which can take the form of hyper-re-sponsiveness or loss of reserve. What was a minor reversible ef-fect may now be a dysfunction that cannot be reversed orcompensated (Fig. 28-11). Obvious examples would be car-diopulmonary compromised individuals who function with littleor no reserve. In the end, however, the ATS statement realizes thelimits of definitions and the importance of value judgment in thefinal assessment. Implied in this position is that a loss of quality


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of life due to air pollution as well as enduring its associated ef-fects may also be designated as adverse.

CONCLUSIONS

In writing this textbook chapter on air pollution toxicology, theauthor’s goal has been to relate empiric studies in animals to phe-nomena known to occur in humans through epidemiologic or con-trolled clinical study. The breadth and complexity of the problemof air pollution—from the development of credible databases tosupporting regulatory action and decision making—has been thetheme throughout. The classic and still most important air pollu-tants provide a foundation for understanding and appreciating thenuances of the issues and strategies for air pollution control andprotection of public health. The key role of the toxicologist is todevelop sensitive methods to assay responses to low pollutantconcentrations, apply these methods to relevant exposure scenar-ios and test species, and develop paradigms to relate empiric tox-icologic data to real life through an understanding of mechanism.Last, the toxicologist must continually integrate laboratory datawith those of epidemiology and clinical study to ensure their max-imum utility.

ACKNOWLEDGMENT

The author would like to thank Mr. James R. Lehmann and Dr. JamesSamet of the USEPA for their constructive comments on the chapter.


REFERENCES

AlarieY, Ferguson JS, Stock MF, et al: Sensory and pulmonary irritationof methyl isocyanate in mice and pulmonary irritation and possiblecyanide-like effects of methyl isocyanate in guinea pigs. EnvironHealth Perspect 72:159–168, 1987.

Alarie YC, Krumm AA, Busey WM, et al: Long-term exposure to sulfurdioxide, sulfuric acid mist, fly ash, and their mixtures: Results of stud-ies in monkeys and guinea pigs. Arch Environ Health 30:254–262,1975.

Alarie YC, Ulrich CE, Busey WM, et al: Long-term continuous exposureof guinea pigs to sulfur dioxide. Arch Environ Health 21:769–777,1970.

Alarie YC, Ulrich CE, Busey WM, et al: Long-term continuous exposureto sulfur dioxide in cynomolgus monkeys. Arch Environ Health24:115–128, 1972.

Allred EN, Bleeker ER, Chaitman BR, et al: Short-term effects of carbonmonoxide exposure on individuals with coronary heart disease. N EnglJ Med 321:1426–1432, 1989.

Altshuler B: Regional deposition of aerosols, in Aharonson FF et al (eds):Air Pollution and the Lung. New York: Wiley, 1976.

Amdur MO, Underhill DW: The effect of various aerosols on the responseof guinea pigs to sulfur dioxide. Arch Environ Health 16:460–468,1968.

Amdur MO: 1974 Cummings memorial lecture: The long road fromDonora. Am Ind Hyg Assoc J 35:589–597, 1974.

Amdur MO: Sulfuric acid: The animals tried to tell us: 1989 Herbert E.Stokinger Lecture. Appl Ind Hyg Assoc J 4:189–197, 1989.

Amdur MO: The respiratory response of guinea pigs to sulfuric acid mist.AMA Arch Ind Health 18:407–414, 1958.

Amdur MO: The response of guinea pigs to inhalation of formaldehydeand formic acid alone and with a sodium chloride aerosol. Int J AirPollut 3:201–220, 1960.

Amdur MO: Toxicological studies of air pollutants. US Public Health Re-ports 69:724–726, 1954.

Amdur MO, Dubriel M, Creasia DA: Respiratory response of guinea pigsto low levels of sulfuric acid. Environ Res 15:418–423, 1978.

Amdur MO, Sarofim AF, Neville M, et al: Coal combustion aerosols andSO2: An interdisciplinary analysis. Environ Sci Tech 20:139–145,1986.

American Thoracic Society: What constitutes an adverse health effect ofair pollution? Am J Respir Crit Care Med 161:665–673, 2000.

Anderson HR: Health effects of air pollution episodes, in: Holgate ST,Samet JM, Koren H, Maynard RL (eds): Air Pollution and Health.London, Academic Press, 1999; pp 461–484.

Aronow WS: Aggravation of angina pectoris by two percent carboxyhe-moglobin. Am Heart J 101:154–157, 1981.

Barry BE, Mercer RR, Miller FJ, Crapo JD: Effects of inhalation of 0.25ppm ozone on the terminal bronchioles of juvenile and adult rats. ExpLung Res 14:225–245, 1988.

Bates DV, Sizto R: Air pollution and hospital admissions in southern On-tario: The acid summer haze effect. Environ Res 65:172– 194, 1987.

Boubel RW, Fox DL, Turner DB et al: Fundamentals of Air Pollution 3ded. New York: Academic Press, 1994, p 107.

Brimblecombe P: Air pollution and health history, in: Holgate ST, SametJM, Koren H, Maynard RL (eds.): Air Pollution and Health. London:Academic Press, 1999, p 10.

Brooks BO, Davis WF: Understanding Indoor Air Quality. Boca Raton,FL: CRC Press, 1992.

Calderon-Garcidueñas L, Osorno-Velazquez A, Bravo-Alvarez H et al:Histopathological changes of the nasal mucosa in southwest metro-politan Mexico City inhabitants. Am J Pathol 140:225–232, 1992.

Calvert JG, Lazrus A, Kok GL, et al: Chemical mechanisms of acid gen-eration in the troposphere. Nature 317:27–35, 1985.

Figure 28-11. Schematic illustration of the elements of a dose responseto an air pollutant(s) by a susceptible versus a healthy individual.

The hypothetical susceptible individual has both a loss of reserve and aninability to maintain homeostasis. The leftward shift in the slope of thedose-response curve also suggests an increase in responsiveness. These re-sponse elements of the susceptible individual may contribute to apparentsensitivity to challenge and the likelihood of progressing from subtle to se-vere effects.

2996R_ch28_977-1012 6/8/01 3:32 PM Page 1008

Copy

right

ed M

ater

ial


Chang L, Huang Y, Stockstill BL, et al: Epithelial injury and interstitial fi-brosis in the proximal alveolar regions of rats chronically exposed toa simulated pattern of urban ambient ozone. Toxicol Appl Pharmacol115:241–252, 1992.

Chang L, Miller FJ, Ultman J, et al: Alveolar epithelial cell injuries by sub-acute exposure to low concentrations of ozone correlate with cumu-lative exposure. Toxicol Appl Pharmacol 109:219–234, 1991.

Chang LY, Mercer RR, Stockstill BL, et al: Effects of low levels of NO2

on terminal bronchiolar cells and its relative toxicity compared to O3.Toxicol Appl Pharmacol 96:451–464, 1988.

Chen LC, Lam HF, Kim EJ, et al: Pulmonary effects of ultrafine coal flyash inhaled by guinea pigs. J Toxicol Environ Health 29:169–184,1990.

Coffin DL, Blommer EJ: Acute toxicity of irradiated auto exhaust: Its in-dication by enhancement of mortality from streptococcal pneumonia.Arch Environ Health 15:36–38, 1967.

Costa DL. Particulate matter and cardiopulmonary health: A toxicologicperspective. Inhal Toxicol 12(suppl 3):35–44, 2000.

Costa DL, Dreher KL: Bioavailable transition metals in particulate mat-ter mediate cardiopulmonary injury in healthy and compromised an-imal models. Environ Health Perspect 105(suppl. 5):1053–1060,1997.

Costa DL, Hatch GE, Highfill J, et al: Pulmonary function studies in therat addressing concentration vs. time relationships for ozone, inSchneider T, Lee SD, Wolters GJR, Grant LD (eds): AtmosphericOzone Research and Its Policy Implications. Amsterdam: Elsevier,1989, pp 733–743.

Costa DL, Kutzman RS, Lehmann JR, et al: Altered lung function and struc-ture in the rat after subchronic exposure to acrolein. Am Rev RespirDis 133:286–291, 1986.

Costa DL, Schlegele E: Irritant air pollutants, in Swift DL, Foster WM(eds): Air Pollutants and the Respiratory Tract. New York: MarcelDekker, 1998, pp 119–145.

Costa DL, Tepper JS, Stevens MA, et al: Restrictive lung disease in ratschronically exposed to an urban profile of ozone. Am J Respir CritCare Med 151:1512–1518, 1995.

Detels R, Tashkin DP, Sayre JW, et al: The UCLA population studies ofCORD: X. A cohort study of changes in respiratory function associ-ated with chronic exposure to SOx, NOx, and hydrocarbons. Am J Pub-lic Health 81:350–359, 1991.

Devlin RB, Folinsbee LJ, Biscardi F, et al: Attenuation of cellular and bio-chemical changes in the lungs of humans exposed to ozone for fiveconsecutive days. Am Rev Respir Dis 147:A71, 1993.

Devlin RB, McDonnell WF, Mann R, et al: Exposure of humans to ambi-ent levels of ozone for 6.6 hours causes cellular and biochemicalchanges in the lung. Am J Respir Cell Mol Biol 4:72–81, 1991.

Dockery DW, Pope CA: Acute respiratory effects of particulate air pollu-tion. Rev Public Health 15:107–132, 1994.

Dockery DW, Pope CA, Xu X, et al: An association between air pollutionand mortality in six U.S. cities. N Engl J Med 329(24):1753–1759,1993.

Donaldson K, Li XY, MacNee W: Ultrafine (nanometre) particle mediatedlung injury, J Aerosol Sci 29:553–560, 1998.

Ehrlich R, Henry MC: Chronic toxicity of nitrogen dioxide: I. Effect onresistance to bacterial pneumonia. Arch Environ Health 17:860–865,1968.

Environmental Progress and Challenges: EPA’s Update. U.S. EPA, Officeof Policy Planning and Evaluation (PM-219), EPA-230-07-88-033.Washington, DC: EPA. 1988, p 29.

Firkert M: Fog along the Meuse Valley. Trans Faraday Soc 32:1192–1197,1936.

Frampton MW, Smeglin AM, Roberts NJJ, et al: Nitrogen dioxide expo-sure in vivo and human macrophage inactivation of influenza virus invitro. Environ Res 48:179–192, 1989.

Frank NR, Amdur MO, Worchester J, Whittenberger JL: Effects of acutecontrolled exposure to SO2 on respiratory mechanics in healthy maleadults. J Appl Physiol 17:252–258, 1962.

Frank NR, Speizer FE: SO2 effects on the respiratory system in dogs:Changes in mechanical behavior at different levels of the respiratorysystem during acute exposure to the gas. Arch Environ Health 11:624–634, 1965.

Gardner DE: Oxidant induced enhanced sensitivity to infection in animalmodels and their extrapolation to man. J Toxicol Environ Health13:423–439, 1984.

Gearhart JM, Schlesinger RB: Sulfuric acid-induced changes in the phys-iology and structure of the tracheobronchial airways. Environ HealthPerspect 79:127–136, 1989.

Gelzleichter TR, Witschi H, Last JA: Synergistic interaction of nitrogendioxide and ozone on rat lungs: Acute responses. Toxicol Appl Phar-macol 116:1–9, 1992.

Gerrity TR, Weaver RA, Bernsten J, et al: Extrathoracic and intrathoracicremoval of ozone in tidal breathing humans. J Appl Physiol 65:393–400, 1988.

Ghio AJ, Carter JD, Richards JH, et al.: Diminished injury in hypertran-ferrinemic mice after exposure to a metal-rich particle. Am J PhysiolLung Cell Mol Physiol 278(5):L1051–L1061, 2000.

Ghio AJ, Kennedy TP, Whorton AR, et al: Role of surface complexed ironin oxidant generation and lung inflammation induced by silicates. AmJ Physiol Lung Cell Mol Physiol 263(7):L511–L518, 1992.

Gilmour MI, Park P, Doerfler D, Selgrade MK: Ozone-enhanced pulmonaryinfection with Streptococcus zooepidemicus in mice: The role of alve-olar macrophage function and capsular virulence factors. Am RevRespir Dis 147:753–760, 1993.

Glasser SW, Korfhagen TR, Wert S, et al: Transgenic models for study ofpulmonary development and disease. Am J Physiol Lung Cell MolPhysiol 267(11):L489–L497, 1994.

Gold DR, Litonjua A, Schwartz J et al: Ambient pollution and heart ratevariability. Circulation 101(11):1267–1273, 2000.

Gong Jr H, Lachenbruch PA, Haber P, et al.: Comparative short term healthresponses to sulfur dioxide exposure and other common stressors in apanel of asthmatics. Toxicol Ind Health 11:467–487, 1995.

Gunnison AF, Palmes ED: S-Sulfonates in human plasma following in-halation of sulfur dioxide. Am Ind Hyg Assoc J 35:288–291, 1974.

Hackney JD, Linn WS, Avol EL: Acid fog: Effects on respiratory functionand symptoms in healthy asthmatic volunteers. Environ Health Per-spect 79:159–162, 1989.

Hanley QS, Koenig JQ, Larson TV, et al: Response of young asthmatic patients to inhaled sulfuric acid. Am Rev Respir Dis 145:326–331,1992.

Hatch GE, Boykin E, Graham JA, et al: Inhalable particles and pulmonaryhost defense: In vivo and in vitro effects of ambient air and combus-tion particles. Environ Res 36:67–80, 1985.

Hatch GE, Slade R, Harris LP, et al: Ozone dose and effect in humans andrats: A comparison using oxygen-18 labeling and bronchoalveolarlavage. Am J Respir Crit Care Med 150:676–683, 1994.

Hayes SM, Gobbell RV, Ganick NR (eds): Indoor Air Quality: Solutionsand Strategies. New York: McGraw-Hill, 1995.

Hazucha M, Madden M, Pape G, et al: Effect of cycloxygenase inhibitionon ozone induced respiratory inflammation and lung function changes.Environ J Appl Physiol Occup Health. 73(1–2):17–27, 1996.

Health Effects Report: Consequences of Prolonged Inhalation of Ozone onF344 Rats: Collaborative Studies. Studies I-XIII, Report #65. Boston:Health Effects Institute, 1994–1995.

Henry MC, Findlay J, Spengler J, Ehrlich R: Chronic toxicity of NO2 insquirrel monkeys: III. Effect on resistance to bacterial and viral in-fection. Am Ind Hyg Assoc J 20:566–570, 1970.

Highfill JH, Hatch GE, Slade R, et al: Concentration time models for theeffects of ozone on bronchoalveolar lavage fluid protein in rats andguinea pigs. Inhal Toxicol 4:1–16, 1992.

Higuchi MA, Davies DW: An ammonia abatement system for whole-bodyanimal inhalation exposures to acid aerosols. Inhal Toxicol 5:323–333,1993.

Ho YS: Transgenic models for the study of lung biology and disease. AmJ Physiol Lung Cell Mol Physiol 266(10):L319–L353, 1994.


2996R_ch28_977-1012 4/26/01 8:37 AM Page 1009

Copy

right

ed M

ater

ial


Holma B: Effects of inhaled acids on airway mucus and its consequencesfor health. Environ Health Perspect 79:109–114, 1989.

Horstman DH, Folinsbee LJ, Ives PJ, et al: Ozone concentration and pul-monary response relationships for 6.6 hours with five hours of mod-erate exercise to 0.08, 0.10, and 0.12 ppm. Am Rev Respir Dis142:1158–1162, 1989.

Horvath E, Anderson H, Pierce W, et al: Effects of formaldehyde on mu-cous membranes and lungs: A study of an industrial population. JAMA259:701–707, 1988.

Hyde D, Orthoefer J, Dungworth D, et al: Morphometric and morphologicpulmonary lesions in beagle dogs chronically exposed to high ambi-ent levels of air pollutants. Lab Invest 38(4):455–469, 1978.

ILSI Report: The relevance of the rat lung response to particle overload forhuman risk assessment: A workshop consensus report. ILSI SponsoredWorkshop, March, 1998, in S.S. Olin (ed): Inhal Toxicol 12:101–117,2000.

Jakab GJ: Relationship between carbon black particulate-bound formalde-hyde, pulmonary antibacterial defenses and alveolar macrophagephagocytosis. Inhal Toxicol 4:325–342, 1992.

Jarabek AM, Segal SA: Noncancer toxicity of inhaled toxic air pollutants:Available approaches for risk assessment and risk management, inPatrick DR (ed): Toxic Air Pollution Handbook. New York: Van Nos-trand Reinhold, 1994, pp 100–132.

Johnston CJ, Finkelstein JN, Oberdorster G, et al.: Clara cell secretory pro-tein-deficient mice differ from wild-type mice in inflammatorychemokine expression to oxygen and ozone, but not to endotoxin. ExpLung Res 25(1):7–21, 1999.

Kakuyama M, Ahluwalia A, Rodrigo J, et al: Cholingergic contraction isaltered in nNOS kockouts: Cooperative modulation of neural bron-choconstriction by NOS and COX. Am J Respir Crit Care Med160:2072–2078, 1999.

Kinney PJ, Ware JH, Spengler JD: A critical evaluation of acute epidemi-ology results. Arch Environ Health 43:168–173, 1988.

Kistner A, Gossen M, Zimmermann F, Jerecic J, et al: Doxycycline medi-ated quantitative and tissue specific control of gene expression in trans-genic mice. Pro. Natl Acad Sci USA 93:10933–10938, 1996.

Kleeberger SR, Reddy S, Zhang LY, et al: Genetic susceptibility to ozone-induced lung hyperpermeability. Role of toll-like receptor 4. Am JRespir Cell Mol Biol 22(5):620–627, 2000.

Kleinman MT, Bailey RM, Whynot JD et al: Controlled exposure to a mix-ture of SO2, NO2, and particulate air pollutants: Effects on human pul-monary function and respiratory symptoms. Arch Environ Health40:197–201, 1985.

Kleinman MT, Mautz WJ, Bjarnason S: Adaptive and non-adaptive re-sponses in rats exposed to ozone, alone and in mixtures, with acidicaerosols. Inhal Toxicol 11(3):249–264, 1999.

Kodavanti UP, Costa DL, Bromberg P: Rodent models of cardiopulmonarydisease: Their potential applicability in studies of air pollutant sus-ceptibility. Environ Health Perspect 106 (suppl 1):111–130, 1998.

Kodavanti UP, Mebane R, Ledbetter A, et al: Variable pulmonary responsesfrom exposure to concentrated ambient air particles in a rat model ofbronchitis. Toxicol Sci. 54(2):441–451, 2000.

Koenig JQ, Covert DS, Pierson WE: Effects of inhalation of acidic com-pounds on pulmonary function in allergic adolescent subjects. Envi-ron Health Perspect 79:127–137, 173–178, 1989.

Koenig JQ, Pierson WE, Horike M, Frank R: Effects of SO2 plus NaClaerosol combined with moderate exercise on pulmonary function inasthmatic adolescents. Environ Res 25:340–348, 1981.

Koren HS, Devlin RB, Graham DE, et al: Ozone-induced inflammation inthe lower airways of human subjects. Am Rev Respir Dis 139:407–415, 1989.

Kotin P, Falk HF: Atmospheric factors in pathogenesis of lung cancer. Can-cer Res 7:475–514, 1963.

Krzyzanowski M, Quackenboss JJ, Lebowitz MD: Chronic respiratory ef-fects of indoor formaldehyde exposure. Environ Res 52:117–125,1990.

Kuhn III C, Homer RJ, Zhu Z, et al: Airway hyperresponsiveness and air

obstruction in transgenic mice: Morphologic correlates in mice over-expressing IL-11 and IL-6 in the lung. Am J Respir Cell Mol Biol22:289–295, 2000.

Last JA, Gelzleichter TR, Harkema J, Hawk S: Consequences of ProlongedInhalation of Ozone on Fischer-344/N Rats: Collaborative Studies.Part I: Content and Cross-Linking of Lung Collagen: Res. Report No.65. Cambridge, MA: Health Effects Institute, April 1994.

Leikauf G. Yeates DB, Wales KA, et al: Effects of sulfuric acid aerosol onrespiratory mechanics and mucociliary particle clearance in healthynonsmoking adults. Am Ind Hyg Assoc J 42:273–282, 1981.

Lewis TR, Campbell KI, Vaughan TR Jr: Effects on canine pulmonary func-tion: Via induced NO2 impairment, particulate interaction, and subse-quent SOx. Arch Environ Health 18:596–601, 1969.

Lewis TR, Moorman WJ, Yang YY, Stara JF: Long-term exposure to autoexhaust and other pollutant mixtures. Arch Environ Health 21:102–106, 1974.

Lewtas J: Airborne carcinogens. Pharmacol Toxicol 72(Suppl 1):S55–S63,1993.

Lipfert FW: Air Pollution and Community Health: A Critical Review andData Sourcebook. New York: Van Nostrand Reinhold, 1994, pp 10–57.

Lippmann M: Health effects of ozone: A critical review. J Air Pollut Con-trol Assoc 39:67–96, 1989.

Madden MC, Richards J, Daily LA, et al: Effect of ozone on diesel exhaustparticle toxicity in the rat lung. Toxicol Appl Pharmacol. 168:140–148, 2000.

Maddison D, Pierce D: Costing the health effects of poor air quality, inHolgate ST, Samet JM, Koren H, Maynard RL (eds): Air Pollutionand Health. London: Academic Press, 1999, pp 917–930.

Martonen TB, Zhang Z, Yang Y: Interspecies modeling of inhaled particledeposition patterns. J Aerosol Sci 23(4):389–406, 1992.

Mauderly JL: Toxicological approaches to complex mixtures. EnvironHealth Perspect 101(suppl 4):155–165, 1993.

McDonnell WF, Horstman DH, Hazucha MJ, et al: Pulmonary effects ofozone exposure during exercise: Dose-response characteristics. J ApplPhysiol 5:1345–1352, 1983.

McKinney WJ, Jaskot RH, Richards JH, et al: Cytokine mediation of ozone-induced pulmonary adaptation. Am J Respir Cell Mol Biol 18:696–705, 1998.

Mercer RR, Costa DL, Crapo JD: Effects of prolonged exposure to lowdoses of nitric oxide on the alveolar septa of the adult rat lung. LabInvest 73(1):1–9, 1995.

Miller FJ, Graham JA, Raub JA, et al: Evaluating the toxicity of urban pat-terns of oxidant gases: II. Effects in mice from chronic exposure tonitrogen dioxide. J Toxicol Environ Health 21:99–112, 1987.

Miller FW, Miller RM: Environmental Hazards: Air Pollution—A Refer-ence Handbook. Contemporary World Issues. Santa Barbara, CA:ABC-CLIO, 1993, pp 1–18.

Mohsenin V: Effect of vitamin C on NO2-induced airway hyperrespon-siveness in normal subjects. Am Rev Respir Dis 136:1408–1411,1987.

Molhave LB, Bach B, Pederson O: Human reactions to low concentrationsof volatile organic compounds. Environ Int 12:165–167, 1986.

Motor vehicle-related air toxics study U.S.EPA. EPA 420-R-93-005. AnnArbor, MI: Office of Mobile Sources, 1993.

Mudway IS, Krishna MT, Frew AJ et al: Compromised concentrations ofascorbate in fluid lining the respiratory tract in human subjects afterexposure to ozone. Occup Environ Med 56(7):473–481, 1999.

Murphy SD, Klingshirn DA, Ulrich CE: Respiratory response of guineapigs during acrolein inhalation and its modification by drugs. J Phar-macol Exp Ther 141:79–83, 1963.

Nadel JA, Salem H, Tamplin B, Tokiwa Y: Mechanism of bronchocon-striction during inhalation of sulfur dioxide. J Appl Physiol 20:164–167, 1965.

National Air Pollutant Emission Trends, 1988. EPA-230-07-88-033. Re-search Triangle Park, NC: U.S. EPA, Office of Air Quality Planningand Standards, 1988.


2996R_ch28_977-1012 4/26/01 8:37 AM Page 1010

Copy

right

ed M

ater

ial


National Air Pollutant Emission Trend Reports, 1998. EPA 454/R-00-002.Research Triangle Park, NC: U.S. EPA: Office of Air Quality Plan-ning and Standards, March 2000, p 21.

National Air Pollutant Emission Trend Reports, 1998. EPA 454/R-00-002.Research Triangle Park, NC: U.S. EPA: Office of Air Quality Plan-ning and Standards, March 2000, p 21.

National Air Quality and Emissions Trends Report, 1992. EPA 454 R-93-031. Research Triangle Park, NC: U.S. EPA: Office of Air QualityPlanning and Standards, October 1993.

National Air Quality & Emission Trends Report. EPA 454/R-00-003. Re-search Triangle Park, NC: U.S. EPA Office of Air Quality Planningand Standards, March 2000, pp 2, 5.

National Research Council (NRC) and Committee on the InstitutionalMeans for Assessment of Risks to Public Health: Risk Assessment inthe Federal Government: Managing the Means. Washington, DC: Na-tional Academy Press, 1983.

Oberdorster G, Ferin J, Lehnert BE: correlation between particle size, invivo particle persistence, and lung injury. Environ Health Perspect102(suppl. 5):173–179, 1994.

O’Donnell MD, O’Conner CM, FitzGerald MX, et al: Ultrastructure of lungelastin and collagen in mouse models of spontaneous emphysema. Ma-trix Biol 18(4):357–360.

Ohtsuka Y, Clarke RW, Mitzner W, et al: Interstrain variation in murinesusceptibility to inhaled acid-coated particles. Am J Physiol Lung CellMol Physiol 278(3): L469-L476, 2000.

Osebold JW, Gershwin LJ, Zee YC: Studies on the enhancement of aller-gic lung sensitization by inhalation of ozone and sulfuric acid aerosol.J Environ Pathol Toxicol 3:221–234, 1980.

Overton JH, Miller FJ: Modeling ozone absorption in the respiratory tract.80th Annual Meeting of the Air Pollution Control Association, paperno. 87–99.4, 1987.

Paige RC, Plopper CG: Acute and chronic effects of ozone in animal mod-els, in Holgate ST, Samet JM, Koren H, Maynard RL (eds): Air Pol-lution and Health, London: Academic Press, 1999, pp 531–557.

Pinkerton KE, Brody AR, Miller FJ, Crapo JD: Exposure to low levels ofozone results in enhanced pulmonary retention of inhaled asbestosfibers. Am Rev Respir Dis 140(4):1075–1081, 1989.

Pope CA, Dockery DW: Epidemiology of particle effects, in Holgate ST,Samet JM, Koren HS, Maynard RL (eds): Air Pollution and Health.San Diego, CA: Academic Press, 1999, pp. 673–706.

Qu QS, Chen LC, Gordon T, et al: Alteration of pulmonary macrophagepH regulation by sulfuric acid aerosol exposures. Toxicol Appl Phar-macol 121(1):138–143, 1993.

Recio L: Transgeneic animal models and their application in mechanisti-cally based toxicology research. CIIT Activities 15(10):1–7, 1995.

Reid L: An experimental study of hypersecretion of mucus in the bronchialtree. Br J Exp Pathol 44:437–440, 1963.

Reuther CG: FOCUS—Winds of change: Reducing transboundary air pol-lutants. Environ Health Perspect 108(4):A170-A175, 2000.

Robinson J, Nelson WC: National Human Activity Pattern Survey DataBase. Research Triangle, Park, NC: U.S. Environmental ProtectionAgency, 1998.

Saldiva PHN, King M, Delmonte VLC, et al: Respiratory alterations dueto urban air pollution: An experimental study in rats. Environ Res57:19–33, 1992.

Salvi S, Blomberg A, Rudell B, et al: Acute inflammatory responses in theairways and peripheral blood after short-term exposure to diesel ex-haust in healthy human volunteers. Am J Respir Crit Care Med159:702–709, 1999.

Schenker MB, Samet JM, Speizer FE, et al: Health effects of air pollutiondue to coal combustion in the Chestnut Ridge region of Pennsylvania:Results of cross-sectional analysis in adults. Arch Environ Health38:325–330, 1983.

Schlesinger RB: Comparative irritant potency of inhaled sulfate aerosol:Effects on bronchial mucociliary clearance. Environ Res 34:268–279,1984.

Schlesinger RB: Intermittent inhalation of nitrogen dioxide: Effects on

rabbit alveolar macrophages. J Toxicol Environ Health 21:127–139,1987.

Schlesinger RB, Chen LC, Finkelstein I, Zelikoff JT: Comparative potencyof inhaled acidic sulfates: Speciation and the role of hydrogen ion.Environ Res 52:210–224, 1990.

Schlesinger RB, Gorczynski JE, Dennison J, et al: Long-term intermittentexposure to sulfuric acid aerosol, ozone, and their combination: Al-terations in tracheobronchial mucociliary clearance and epithelial se-cretory cells. Exp Lung Res 18:505–534, 1992.

Schlesinger RB, Halpern M, Albert RE, Lippmann M: Effects of chronicinhalation of sulfuric acid mist upon mucociliary clearance from thelungs of donkeys. J Environ Pathol Toxicol 2:1351–1367, 1979.

Schlesinger RB, Lippmann M, Albert RE: Effects of short-term expo-sures to sulfuric acid and ammonium sulfate aerosols upon bronchialairway function in the donkey. Am Ind Hyg Assoc J 39:275–286,1978.

Schlesinger RB, Weidman PA, Zelikoff JT: Effects of repeated exposuresto ozone and nitrogen dioxide on respiratory tract prostanoids. InhalToxicol 3:27–36, 1991.

Schwartz J: Air pollution and daily mortality: A review and meta analysis.Environ Res 64:36–52, 1994.

Schwartz J: Air pollution and the duration of acute respiratory symptoms.Arch Environ Health 47(2):116–22, 1992.

Schwartz J. Particulate air pollution and daily mortality in Detroit. Envi-ron Res 56:204–213, 1991.

Schwartz J, Marcus A: Mortality and air pollution in London. Am J Epi-demiol 131:185–194, 1990.

Schwela D: Exposure to environmental chemicals relevant for respiratoryhypersensitivity: Global aspects. Toxicol Lett 86:131–142, 1996.

Seltzer J, Bigby BG, Stulbarg M, et al: O3-induced change in bronchial re-activity to methacholine and airway inflammation in humans. J ApplPhysiol 60:1321–1326, 1986.

Sheppard DA, Saisho A, Nadel JA, Boushey HA: Exercise increases sul-fur dioxide induced bronchoconstriction in asthmatic subjects. Am RevRespir Dis 123:486–491, 1981.

Slade R, Stead AG, Graham JA, Hatch GE: Comparison of lung antioxi-dant levels in humans and laboratory animals. Am Rev Respir Dis131:742–746, 1985.

Speigelman JR, Hanson GD, Lazurus A, et al: Effect of acute sulfur diox-ide exposure on bronchial clearance in the donkey. Arch EnvironHealth 17:321, 1968.

Speizer FE: Studies of acid aerosols in six cities and in a new multi-cityinvestigation: Design issues. Environ Health Perspect 79:61–68, 1989.

Spengler JD, Sexton K: Indoor air pollution: A public health perspective.Science 221:9–17, 1983.

Starr TB, Gibson JE: The mechanistic toxicology of formaldehyde and itsimplications for quantitative risk assessment. Annu Rev PharmacolToxicol 25:745–767, 1985.

State of the Air: 2000. American Lung Assoc. www.ala.org, 2000.Stevens MA, Fitzgerald S, Menache MG, et al: Functional evidence of per-

sistent airway obstruction in rats following a two-hour inhalation ex-posure to methyl isocyanate. Environ Health Perspect 72:89–94, 1987.

Suga T, Kurabayashi M, Sando Y, et al.: Disruption of the klotho genecauses pulmonary emphysema in mice. Am J Respir Cell Mol Biol22:26–33, 2000.

Thurston GD, Ito K, Kinney PL, Lippmann M: A multi-year study of airpollution and respiratory hospital admissions in three New York statemetropolitan areas: Results for 1988 and 1989 summers. J Expos AnalEnviron Epidemiol 2:429–450, 1992.

Tyler WS, Tyler NK, Hinds D, et al: Influence of exposure regimen on ef-fects of experimental ozone studies: Effects of daily and episodic andseasonal cycles of exposure and post-exposure. Presented at the 84thannual meeting of the Air and Waste Management Assoc., Vancouver,BC, Canada. Paper No. 91–141.5, 1991.

Tyler WS, Tyler NK, Last JA, et al: Comparison of daily and seasonal ex-posures of young monkeys to ozone. toxicology 50:131–144, 1988.

Underhill DW. Aerosol synergism and hydrate formation A possible con-


2996R_ch28_977-1012 4/26/01 8:37 AM Page 1011

Copy

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ial


nection. Inhal Toxicol 12(suppl 1):189–198, 2000.Utell MJ, Mariglio JA, Morrow PE, et al: Effects of inhaled acid aerosols

on respiratory function: The role of endogenous ammonia. J AerosolMed 2:141–147, 1989.

Utell MJ, Morrow PE, Hyde RW: Airway reactivity to sulfate and sulfuricacid aerosols in normal and asthmatic subjects. J Air Pollut ControlAssoc 34:931–935, 1984.

Van De Lende R, Kok TJ, Reig RP, et al: Decreases in VC and FEV1 withtime: Indicators for effects of smoking and air pollution. Bull EurPhysiopathol Respir 17:775–792, 1981.

Vaughan TR Jr, Jennelle LF, Lewis TR: Long-term exposure to low levelsof air pollutants: Effects on pulmonary function in the beagle. ArchEnviron Health 19:45–50, 1969.

von Mutius E, Martinez FD, Fritzsch C et al.: Prevalence of asthma and

atopy in two areas of West and East Germany. Am J Respir Crit CareMed 149(2 Pt 1):358–364, 1994.

Waxman HA: Title III of the 1990 Clean Air Act Amendments, in PatrickDR (ed): Toxic Air Pollution Handbook. New York: Van NostrandReinhold, 1994, pp 25–32.

Wiester MJ, Winsett DW, Richards JE, et al.: Ozone adaptation in mice andits association with ascorbic acid in the lung. Inhal Toxicol. 12:577–590, 2000.

Yokoyama E, Toder RE, Frank NR: Distribution of 35SO2 in the blood andits excretion in dogs exposed to 35SO2. Arch Environ Health 22:389–395, 1971.

Yoshida M, Satoh M, Shimada A, et al: Pulmonary toxicity caused by acuteexposure to mercury vapor is enhanced in metallothionein-null mice.Life Sci 64(20):1861–1867, 1999.


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