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OCR for page 465
Asthma and Automotive
E· ~
missions
PHILIP A. BROMBERG
University of North Carolina
Asthma: Definition, Demography, and Clinical Spectrum / 466
Definition / 466 Demography / 466 Clinical Spectrum / 467
Asthma: Pathogenesis / 468
Extrinsic and Intrinsic Asthma / 468 Early and Late Reactions to
Allergens / 469 Bronchial Hyperreactivity / 469
Controlled Exposure Studies / 470
Normal Subjects / 470 Asthmatic Subjects / 471 Need for Further
Research / 472
Asthma: Pathophysiology / 473
Assessment of Airways Size / 474 Distribution of Airflow Resistance
Along the Airways / 474 Mechanisms of Bronchoconstriction / 475
Ozone Exposure / 478
Respiratory Epithelium: Asthma and Ozone / 481
Permeability / 482 Mucous Production and Secretion / 483 Ion
Transport / 484 Mucociliary Clearance / 484
Experimental Models / 485
Human Studies / 485 Laboratory Animal Models / 485 Cells in
Culture / 487
Summary of Research Recommendations: Discussion / 487
Summary of Research Recommendations: Priorities / 489
Air Pollution, the Automobile, and Public Health. (it) 1988 by the Health Effects
Institute. National Academy Press, Washington, D.C.
465
OCR for page 466
466
Asthma and Automotive Emissions
Urban air pollution is characterized by in-
creased levels of ozone (03) and nitrogen
dioxide (NO2) resulting from photochem-
ical reactions of automotive emissions.
Lung damage caused by exposure to oxi-
dant gases is well recognized. For instance,
inhalation of 5(}100 parts per million
(ppm) NO2 causes acute pulmonary edema
in humans, and survivors may develop a
chronic progressive obstructive bronchio-
litis several weeks after~apparent recovery
from the acute edema. O3 is also capable of
producing acute pulmonary edema at a
concentration of less than 10 ppm.
Levels of NO2 and O3 in ambient air
generally do not exceed 1 ppm. Therefore,
the toxic effects of inhalation of high levels
of these gases may not be relevant for
low-level ambient exposures. Neverthe-
less, several population surveys have found
a relation between episodes of oxidant air
pollution and adverse respiratory health
effects including exacerbations of asthma.
More chronic effects of oxidant air pollu-
tion on respiratory function have also been
suggested (see Bresnitz and Rest, this
volume; U. S. Environmental Protection
Agency 1986~.
The notion that individuals with preex-
isting respiratory disease might be espe-
cially susceptible to effects of ambient air
pollution has been strengthened by the
relatively recent observation that, unlike
normal subjects, asthmatic individuals with
mild disease are highly susceptible to the
experimental inhalation of low concentra-
tions of sulfur dioxide (SO2) during exer-
cise. During brief exposures, asthmatic
subjects have developed acute, sometimes
symptomatic, increases in specific airflow
resistance (SRaW) attributed to bronchocon-
striction (Sheppard et al. 1981; Bethel et al.
1983~.
In this chapter, the clinical forms of
asthma and their pathogenesis are de-
scribed, and the results from controlled
exposure studies of the effects of inhalation
of pollutant gases relevant to automotive
emissions on normal and asthmatic subjects
are summarized. These findings are dis-
cussed with respect to the mechanisms of
asthma, and key questions about possible
interactions between asthma and automo
tive air pollution whose answers have so far
been elusive are formulated.
Asthma: Definition,
Demography, ant! Clinical
Spectrum
DeJitzition
Asthma is a common paroxysmal disorder
of the airways but is difficult to define
because of its complex pathogenesis, mul-
tiple etiologic factors, and clinical overlap
with other airway diseases. It is character-
ized by recurrent episodes of diffuse air-
ways obstruction associated with wheez-
ing, coughing, and breathlessness (dyspnea).
These episodes are largely reversible, espe-
cially with pharmacological therapy, but an-
atomic and physiological evidence of persist-
ent diffuse airways disease can be found on
careful investigation even during apparently
quiescent periods. One important indication
of persistent abnormality, even in asympto-
matic asthmatics, is nonspecific bronchial
hyperreactivity, that is, enhanced airways
response to bronchoconstrictive stimuli that
. .. . .
are nelt per speailc antigens operating
through immunologic mechanisms nor spe-
cific chemicals in the occupational environ-
ment (for example, toluene diisocyanate).
Demography
A 1970 U.S. Public Health Service survey
of national health suggested that the prev-
alence of asthma was about 3 percent
(Wilder 1973~. Regional population surveys
in Tecumseh, Michigan (Broder et al. 1962,
1974a, b), and Tucson, Arizona (Lebowitz
et al. 1975), suggest a prevalence of 4-8
percent. In the Public Health Service sur-
vey, three-fifths of the asthmatics had con-
sulted a physician for asthma during the
previous year, one-fifth had visited their
physician at least five times during the year,
and one-sixth felt the disease limited their
activity (Bonner 1984~.
Prevalence is highest among children
(males >> females) and a second peak
occurs in older adults (males > females).
This later peak may include patients with
OCR for page 467
Philip A. Bromberg
467
relatively irreversible airways obstruction.
In young to middle-aged adults, women
may be somewhat more at risk than men.
In young children, asthma (wheezing) as-
sociated with viral respiratory tract infec-
tions is a common problem. This associa-
tion (Busse 1985) and the demonstration of
IgE-type antibody, particularly to respira-
tory syncytial virus, in such patients (Wel-
liver et al. 1986) suggest that respiratory
tract infections can provoke an asthmatic
state in some children. Of the various
"types" of asthma, allergen-related (ex-
trinsic) asthma occurs more commonly in
somewhat older children and in young
adults than does intrinsic (no identifiable
allergen or specific antibody) asthma
(Bonner 1984~. Intrinsic asthma increases in
importance in older adults and is a form of
the disease that can manifest increasingly
irreversible airways obstruction even in the
face of chronic treatment with large doses
of corticosteroids.
Clinical Spectrum
The clinical severity of asthma (either the
background level of airways obstruction or
the intensity and the frequency of the epi-
sodes) varies greatly, not only among af-
fected individuals, but at different times in
the same individual. Some asthmatic chil-
dren seem to grow out of their disease. On
the other hand, relatively asymptomatic
asthma can flare so severely that it becomes
life-threatening or even fatal. This variabil-
ity is reflected in the intensity of therapy
and the number of physician contacts.
Some asthmatics use only an occasional
inhalation of a bronchodilator aerosol; oth-
ers use aerosols more frequently, either as
required or on a regular basis. Other asth-
matics use long-acting oral bronchodilators
supplemented with one or more inhaled
agents. Some affected individuals require
intermittent or chronic corticosteroid ther-
apy. Life-threatening, severe episodes re-
quire hospitalization and often involve a
period of assisted ventilation.
Nonspecific Bronchial Hyperreactivity.
Although patients with recently developed
asthma may have normal airway reactivity
between attacks, the presence of nonspe-
cific bronchial hyperreactivity is considered
an important, but not specific, feature of
asthma (Hargreave et al. 1981~. Various
stimuli have been used to elicit a broncho-
constrictive response. Quantitative inhala-
tion challenge with aerosolized histamine
and methacholine has gained widespread
acceptance and use as an investigative and
diagnostic tool. Individual reactivities to
histamine and methacholine challenge cor-
relate well with the presence of clinically
severe asthma as judged by degree of
symptoms, medication requirements, oc-
currence of spontaneous early morning in-
crease in airflow obstruction, presence of
more-or-less continuous airflow obstruc-
tion, and general instability of the airways
despite chronic use of multiple bronchodi-
lator medications. Such unstable patients
with exquisite nonspecific bronchial hyper-
reactivity are at risk for life-threatening
asthmatic crises. A sharp decrease in non-
specific bronchial hyperreactivity correlates
with clinical improvement (Hargreave et
al. 1985b; Woolcock et al. 1985~.
Inhalation of cold dry air is also com-
monly used as a bronchoconstrictive stim-
ulus, but its quantitation is more difficult,
its mode of action is less well understood
than that of specific drugs, and its effects
are subject to the development of decreased
response on repeated application (Har-
greave et al. 1985a).
Nonspecific bronchial hyperreactivity to
various challenges is an index of the intrin-
sic responsiveness of elements in the airway
wall (smooth muscle, submucosal blood ves-
sels and glands, afferent nerve endings and
efferent nerve ganglia, mast cells, and possi-
bly neuroendocrine cells), and presumably
reflects or mimics certain events in "naturally
occurring" asthma. Of course, multiple me-
diators are involved in asthma. Even with
respect to histamine or methacholine, the
naturally occurring release of these autacoids
probably causes changes in local concentra-
tions at receptor sites that are not precisely
mimicked by inhalation challenge.
Other Obstructive Airways Disease. Dif-
fuse airways disease associated with the
impairment of forced expiratory flow rates
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468
Asthma and Automotive Emissions
and increased airflow resistance is not lim-
ited to asthma. In addition to at least 6
million asthmatics, it has been estimated
that 7.5 million people in the United States
have chronic bronchitis and 2 million have
emphysema (U.S. Department of Health
and Human Services 1979~. Etiologies vary
among the obstructive airways diseases.
Cigarette smoking is a major risk factor for
chronic nonspecific bronchitis as well as for
emphysema. Chronic airways infection
with suppurative destruction of airway
walls characterizes diffuse bronchiectasis.
In some cases, a specific underlying reason,
such as dysmotile cilia syndromes, immu-
noglobin deficiencies, autoimmune dis-
eases, cystic fibrosis, or hereditary defi-
ciency of the c~-1-proteinase inhibitor can
be identified. In others, the etiology is
obscure and may be related to remote dif
~ . . . . . .
ruse ung 1nJury or Injection occurring In
childhood.
Chronic airways obstruction generally is
much less reversible in these diseases than
in asthma, but to varying degrees. Airways
obstruction associated with cystic fibrosis
frequently manifests considerable reversi-
bility in response to bronchodilators. Ob-
struction is partially reversible with ,l3 ad
. . . . .
renerg1c or muscarln1c agonists In some
patients with chronic bronchitis. Airways
hyperreactivity to bronchoconstrictor drugs
also occurs in some chronic bronchitics.
Unusual reactivity to bronchodilators or
bronchoconstrictors may be associated
with relatively rapid deterioration of pul-
monary function in chronic bronchitis
(Barter and Campbell 1976~.
An important unresolved question is
whether there are specific risk factors for
the development of irreversible obstructive
airways disease in some asthmatics. In view
of the extensive inflammation and epithelial
damage that appears to be characteristic of
asthma (see below), it is surprising that
most patients with asthma retain the feature
of substantial reversibility of airways ob-
struction for long periods.
Patients with chronic obstructive pulmo-
nary disease (COPD) and increased airways
reactivity may not be considered "asth-
matics," but they should not be neglected
in studies of the health effects of air pollu
tion. Such disease groups would include
patients with chronic nonspecific bronchitis
with reactive airways, cystic fibrosis, and
children with a history of bronchopulmo-
nary dysplasia or of respiratory infections
associated with wheezing.
Asthma: Pathogenesis
Extrinsic and Intrinsic Asthma
The variability of the clinical features
among different asthmatics and in a given
individual at different times or periods of
life has prompted efforts to classify the
disease in a meaningful fashion. One ap-
proach differentiates extrinsic asthma, in
which antigens (allergens) affect tissue
cells primarily mast cells sensitized by
specific IgE antibody (see Chemical Medi-
ators) from intrinsic asthma, which oc-
curs without an identifiable antigen or a
specific IgE antibody.
Thus, extrinsic asthma occurs com-
monly among allergic (atopic) individuals
who have (usually) multiple specific IgE-
class antibodies to airborne antigens associ-
ated with pollens, mold spores, animal fur,
or various insects (for example, mites
found in house dust, cockroaches). The
proclivity toward the development of IgE
antibodies against common inhaled anti-
gens (allergens) characterizes atopic indi-
viduals and is importantly influenced by
genetic factors. Asthma exacerbations are
provoked by inhaled antigen (for example,
laboratory workers handling certain an~-
mals or insects) and tend, in the case of
pollen and spore allergy, to be seasonal and
regional.
In many atopic individuals, clinical man-
ifestations are limited to the skin or the
nasal mucosa (allergic rhinitis) and the con-
junctivae (allergic conjunctivitis). These
patients often have some symptoms com-
catible with asthma that are sufficiently
mild to go unrecognized. They also may
have a modest increase in nonspecific bron-
chial reactivity to histamine or metha-
choline. Indeed, Fish and Norman (1985)
have found substantial hyperreactivity to
inhaled pro s ta glandin (P G) F2~ in atopi c,
OCR for page 469
Philip A. Bromberg
469
nonasthmatic subjects. Atopic persons may
constitute a useful population for study of
the effects of exposure to air pollutants
since the nasal epithelium is a good model
for the large-airways epithelium. Basic im-
munologic mechanisms in the allergic
bronchial mucosa are also present in the
nasal mucosa, which is readily accessible to
experimental manipulation as well as to
environmental exposures.
Intrinsic asthma implies the absence of
atopy, that is, no evidence of specific IgE-
class antibodies against common airborne
antigens in the patient's environment.
These asthmatics have perennial rather than
seasonal symptoms. Exacerbations seem to
be triggered by poorly characterized respi-
ratory tract infections, which on the basis
of serologic evidence and in the absence of
a bacterial infecting agent, are assumed to
be viral. A subclass of these individuals has
nasal polyps and demonstrates an unusual
proclivity to precipitation of asthma
shortly after ingesting acetylsalicylic acid
(aspirin) or other nonsteroidal antiinflam-
matory agents all of which inhibit cyclo-
oxygenase activity and therefore affect cel-
lular arachidonate metabolism.
Asthma also can develop in workers
(probably nonatopic) exposed to chemicals
such as toluene diisocyanate, plicatic acid
(western red cedar wood dust), and others.
Exquisite airways sensitivity to inhalation
of the specific offending agent is often
present, although specific antibodies may
not be demonstrable. Some of these indi-
viduals develop chronic perennial asthma
despite prolonged avoidance of the sensitiz-
ing chemical. Such cases of asthma do not
fit clearly into either the extrinsic or the
. . .
Intrinsic category.
Early and Late Reactions
to Allergens
Recent descriptions of asthma pathophys-
iology emphasize the discovery that tissues
bearing IgE-sensitized mast cells, such as
skin, nasal mucosa, and airways, display a
complex series of responses to specific an-
tigen (Gleich 1982; Cockcroft 1983~. A
rapid, "early" response is dominated by
local microvascular dilatation, edema, and
in the airways, smooth-muscle contraction,
all of which are mediated by substances
released from sensitized mast cells as well as
other sensitized cells. This reaction re-
gresses spontaneously, or regression can be
induced with ,B adrenergic agonists.
Several hours later, a second local reac-
tion occurs, again associated with broncho-
spasm in the airway, but now with sub-
stantial cellular infiltration by eosinophils,
neutrophils, and basophils. These cells are
thought to be attracted by chemotactic
factors released by the activated mast cells.
For reasons that are not clear, this "late"
reaction is not reversed by ,~adrenergic
agonists but can be diminished or pre-
vented by pretreatment with corticoste-
roids.
Bronchial Hyperreactivity
Late reactions following antigen challenge
in asthmatic subjects are associated with
enhancement of nonspecific bronchial
hyperreactivity. Marked enhancement of
bronchial hyperreactivity may last for
weeks and is associated with the emergence
of more severe clinical manifestations of
asthma. The patient develops bronchocon-
striction on exposure to a wide variety of
stimuli. If no further exposure to the pro-
voking agent (antigen or chemical) occurs,
the bronchial hyperreactivity gradually re-
cedes to baseline levels along with the
clinical symptoms. The intensity of the late
response to antigen correlates with the sub-
sequent degree and duration of increased
nonspecific bronchial hyperreactivity (Car-
tier et al. 1982; Cockcroft 1983~.
Airways inflammation constitutes a cen-
tral feature of both the late reaction to
specific antigens and the genesis of nonspe-
cific bronchial hyperreactivity. The specific
features of the inflammatory process re-
quired for the development of hyper-
reactivity are far from understood. For
example, among patients with chronic
bronchitis, only a fraction appear to exhibit
nonspecific bronchial hyperreactivity al-
though all presumably have some degree of
airways inflammation.
The prolonged state of bronchial hyper-
reactivity provoked by a single exposure to
OCR for page 470
470
Asthma and Automotive Emissions
.. . . .
a speailc antigen or to certain occupatlon-
ally related chemicals suggests the possibil-
ity that the airways of so-called intrinsic
asthmatics may be sensitized to nonspecific
stimuli in a similar fashion by intermittent
exposure to some undefined specific
agent(s). *
The intensity of the bronchoobstructive
response of a sensitized individual exposed
to a particular antigen will therefore depend
not only on the specific IgE-mediated dis-
charge of mediators from local mast cells
(and possibly other cells), but also on the
degree of coexistent nonspecific bronchial
reactivity (Cockcroft et al. 1979~. A corol-
lary to this notion is that anv stimulus (for
example, 03) that increases nonspecific
bronchial reactivity should also enhance
reaction to inhaled antigen, even in the
absence of any change in immunologic
status. Furthermore, to the extent that air
pollutants can provoke bronchoconstric-
tion in a "nonspecific" manner, highly
bronchoreactive asthmatics should be more
. .
sensitive to suc 1 exposures.
Controlled Exposure Studies
While field studies and practical experience
indicate an association between air pollu-
tion and exacerbation of asthma, confirma-
tion of the association and its physiological
manifestations have been sought in con-
trolled studies. The following section as-
sesses the status of this research to date.
Normal Subjects
Ozone and Nitrogen Dioxide. Although
NO2 and O3 are both classified as oxidants,
and are relatively insoluble in aqueous me-
dia and thus able to penetrate into the lower
*Note, however, asthmatic children who are perenni-
ally exposed to the relevant antigen, and who receive
repetitive antigen injections in hyposensitization ther-
apy, tend to outgrow their asthma and show a de-
crease in IgE and IgG antibodies. In contrast, children
who are intermittently (seasonally) exposed to another
allergen, such as rye-grass pollen, continue to demon-
strate seasonal asthma associated with rises in IgG and
IgE antibodies (Hill et al. 1981).
airways, their mechanisms of action on the
airways may well be quite different.
At concentrations < 1 ppm, effects of
acute NO2 inhalation on the respiratory
system of normal subjects have not been
demonstrated. In contrast, acute (2-hr) ex-
posure of exercising adults to levels of O3
as low as 0.12 ppm causes a reduction of
mean vital capacity accompanied by cough
(McDonnell et al. 1983~. Similar findings,
which can be accounted for specifically by
the O3 content of the air, have resulted
from exposure of exercising adults to Los
Angeles air pollution under controlled con-
ditions (Avol et al. 1984), in active children
exposed to about 0.10 ppm O3 in a summer
camp (Lippman et al. 1983), and in children
exposed to 0.12 ppm O3 in an environmen-
tal chamber (McDonnell et al. 1985a).
Decreases in vital capacity do not appear
to be caused by changes in mechanical
properties of the lung (Beckett et al. 1985;
Hazucha et al. 1986), but are probably due
to neurally mediated involuntary inhibition
of inspiration. Bronchoconstriction is not a
prominent feature of the response of nor-
mal individuals to O3; nor does the degree
of bronchoconstriction correlate with the
vital capacity decrease (McDonnell et al.
1983~. In addition, inhaled atropine failed
to prevent O3-induced changes in vital
capacity (Beckett et al. 1985~. Unmyelin-
ated airway sensory nerves (C-fibers),
which contain and can release substance P
and other physiologically active neuropep-
tides, could mediate the inhibition of inspi
. . . . . .
ration, t ne subJectlve airway sensations,
and a more shallow, rapid pattern of
breathing. Since the stimulation of airway
C-fibers in dogs also causes reflex broncho-
constriction (Roberts et al. 1981; Coleridge
and Coleridge 1986) as well as reflex tra-
cheal gland secretion (Davis et al. 1982), the
relative weakness of the human broncho-
constriction response to inhaled O3 is sur-
prising. Substance P or other neuropeptides
may also provoke other features of the
acute airways response to 03, such as mu-
cous secretion (Coles et al. 1984) and in-
creased epithelial permeability and ion
transport (Al-Bazzaz et al. 1985~.
Among a group of normal subjects, there
is a substantial range of vital capacity re
OCR for page 471
Philip A. Bromberg
471
spouses to a given O3 exposure (McDon-
nell et al. 1983~. In a single individual,
however, the response to O3 exposure is
relatively reproducible (McDonnell et al.
1985b). Whether this between-subject vari-
ability is attributable to different tissue
doses of O3 in different individuals under
the same exposure conditions or to biolog-
ical factors affecting individual responsive-
ness remains to be determined.
A feature of repeated daily experimental
exposures to O3 is the initial enhancement
(Hackney et al. 1977; Farrell et al. 1979;
Bedi et al. 1985; Folinsbee and Horvath
1986) but eventual disappearance of the
vital capacity response and the associated
subjective sensations (Farrell et al. 1979;
Folinsbee et al. 1980; Horvath et al. 1981~.
Among the possible explanations for this
phenomenon (often termed "tolerance" or
"adaptation") is the depletion of neuropep-
tides from repeatedly stimulated C-fibers.
A more subtle feature of the response to
03, first described 20 years ago in guinea
pigs (Easton and Murphy 1967), and then
shown in dogs (Lee et al. 1977), sheep
(Abraham et al. 1980), and humans (Gol-
den et al. 1978), is a transient increase,
lasting hours to perhaps a day in humans,
in the bronchoconstrictive response to pa-
renteral (Easton and Murphy 1967; Gordon
and Amdur 1980; Gordon et al. 1984;
Murlas and Roum 1985a) as well as inhaled
histamine and cholinergic agonists (Lee et
al. 1977; Golden et al. 1978; Holtzman et al.
1979; DiMeo et al. 1981; Holtzman et al.
1983; Roum and Murlas 1984~. This re-
sponse also appears to undergo an adaptive
suppression on repeated O3 exposure (Di-
Meo et al. 1981~.
Mixtures of Ozone and Other Pollut-
ants. Synergy between O3 and other pol-
lutants in causing respiratory effects during
environmental chamber exposures has not
been proven. Hazucha and Bates (1975)
described synergism between SO2 and O3
in normal subjects, but other researchers
were not able to duplicate their results (Bell
et al. 1977; Bedi et al. 1979; Kleinman et al.
1981; Folinsbee et al. 1985~. Stacy and
coworkers (1983) noted increased mean
changes of respiratory parameters when
low concentrations of acid aerosols were
mixed with 0.4 ppm O3, but these differ-
ences were not statistically significant. Us-
ing a sequential rather than simultaneous
exposure protocol, Kulle and colleagues
(1982) found no effect of sulfuric acid
(H2SO4) aerosol (100 ,ug/m3) following an
exposure to 0.3 ppm O3.
Recommendation 1. The uptake pro-
file of pollutant gases in different regions of
the airways should be measured by sam-
pling and analyzing inspired air at different
airway levels. Variables to be explored
with such systems include concentration of
pollutants, ventilatory parameters, dura-
tion of exposure, and presence of disease
(for example, asthma, chronic bronchitis).
· Recommendation 2. These data
should be compared with the predictions of
currently available mathematical models.
~ Recommendation 3. The uptake pro-
files should be examined for their ability to
account for some of the variability in vital
capacity response to O3 exposure observed
among individuals.
Asthmatic Subjects
Ozone. Controlled studies have yet to
demonstrate that O3 dramatically affects
lung function in asthmatic subjects, atopic
nonasthmatic subjects, or patients with
COPD. The most pertinent publications
on asthmatics (Linn et al. 1978, 1980; Sil-
verman 1979; Koenig et al. 1985), persons
with smoking-related COPD (Linn et al.
1982, 1983; Solic et al. 1982; Hackney et al.
1983; Kehrl et al. 1983, 1985; Kulle et al.
1984), and atopic subjects (Holtzman et al.
1979) have been reviewed in the U.S. En-
vironmental Protection Agency's (1986)
most recent revision of the air quality cri-
teria document for O3 and other photo-
chemical oxidants.
Unfortunately, deficiencies in the exper-
imental design in some of these studies
preclude making a definitive statement
about the effects of O3 on pulmonary func-
tion in asthmatic subjects. Among these
deficiencies are incomplete characterization
OCR for page 472
472
Asthma and Automotive Emissions
of the nature of the obstructive airways proc-
ess, little information on nonspecific bron-
chial reactivity status and no testing of the
effect of exposure on bronchial reactivity,
absence of airflow resistance (RaW) measure-
ments to assess airways response, no control
of the use of medications by asthmatic sub-
jects, possible investigator avoidance of sub-
jects with severe asthma, and inadequate
levels of ventilation (exercise) during the ex-
posure (this was a critical variable in the
demonstration of exquisite responsiveness of
asthmatics to SO2 exposure). Furthermore,
no studies of asthmatic subjects appear to
have been performed using prolonged single
exposures or repeated daily exposures. Nor
has possible synergism between O3 and other
relevant pollutants been studied in concur-
rent or sequential exposure protocols.
Nitrogen Dioxide. Orehek and cowork-
ers (1976) were the first to claim that some
asthmatics develop increased airways reac-
tivity to inhaled bronchoconstrictor drug
challenge after exposure to only 0.1 ppm
NO2. An editorial by Dawson and
Schenker (1979) provides a succinct evalu-
ation of our understanding of the effects of
NO2 inhalation as of the late 1970s. Since
then, other groups have explored the effect
of low levels of NO2 (<0.5 ppm) on lung
function and bronchial reactivity in asth-
mat~cs.
Koenig and colleagues (1985) examined
atopic asthmatic adolescents exposed to
0.12 ppm NO2 by mouthpiece for 1 hr at
rest and found no changes in lung function
during or after the exposure. Other re-
searchers (Roger et al. 1985; Bauer et al.
1986) independently found evidence that
bronchoconstriction in asthmatics follow-
ing exercise was enhanced in the presence
of 0.3 ppm NO2. In contrast, Linn and
Hackney (1984) and Linn and others (1985)
observed no effect on SRaW of exposure to
4 ppm NO2 (I) for 75 min with light or
heavy exercise. The route of inhalation
(oronasal versus oral), the duration of ex-
posure, and the number as well as intensity
of exercise stints may be significant varia-
bles (Kulle 1982; Bauer et al. 1985~. Bylin
and colleagues (1985) found enhanced non-
specific bronchial reactivity to aerosolized
histamine in asthmatics exposed to 0.5 ppm
NO2 for 20 min. Kleinman and coworkers
(1983) found no acute effect on respiratory
mechanics after a 2-fur exposure, which
included intermittent light exercise, to 0.2
ppm NO2. The enhancement of nonspe-
cific bronchial reactivity to aerosolized
methacholine was, however, borderline in
terms of group means. Ahmed and col-
leagues (1982) reported increased airways
reactivity to aerosolized carbachol in rest-
ing normal subjects as well as in asthmatics
following a 1-fur exposure to 0.1 ppm
NO2, despite the absence of any effects on
baseline lung function. However, in a care-
ful study, Hazucha and coworkers (1983)
were unable to confirm the Orehek finding
of increased airways reactivity following a
0.1-ppm NO2 exposure. In addition.
--7
Roger and colleagues (1986) failed to dem-
onstrate enhanced methacholine reactivity
following exposure of exercising asthmat-
ics to NO2 levels as high as 0.6 ppm.
Finally, Ahmed and colleagues (1983) chal-
lenged ragweed-sensitive asthmatic sub-
jects with specific antigen immediately and
24 hr after a 1-fur exposure to 0.1 ppm. No
effect of the exposure on specific bronchial
reactivity was found, but the exposure con-
ditions were extremely mild. None of the
other studies cited above appear to have
examined specific bronchial reactivity.
Evidence suggests that the airways of
exercising and perhaps even resting asth-
matic subjects are affected by exposure to
<0.5 ppm NO2. However, when all the
reports are considered, a coherent picture
fails to emerge. Even within a particular
laboratory, there may be diff~culty in re-
producing an observation (D. Horstman,
personal communication). The reasons for
this inconsistency are presently obscure.
Some of the problems mentioned for O3
exposure studies may also apply to NO2.
Needfor Further Research
The preceding discussion suggests that, in
contrast to the experience with SO2, initial
controlled exposure studies have failed to
demonstrate that asthmatics exhibit un-
usual sensitivity to acute exposure to O3.
Although the situation is less clear with
respect to NO2, the effects claimed have
been modest in extent. However, a conclu
OCR for page 473
Philip A. Bromberg
473
sion that asthmatics do not constitute a
sensitive subgroup in terms of possible
adverse health effects of air pollution re-
lated to automotive emissions would be
premature and possibly incorrect. Reasons
for this posture have already been alluded
to and include:
1. Two types of field studies suggest
that asthmatics do exhibit special sensitivity
to ambient oxidant air pollution. In one,
"panels" of asthmatic and control subjects
have been selected and their health status
monitored in relation to ambient air com-
position over time; the best example is the
analysis of Whittemore and Korn (1980~. In
the other, the respiratory health of an entire
community is assessed in terms of emer-
gency room visits, hospital admissions, and
physician visits, and correlated with envi-
ronmental air quality. The best study of
that type is the survey of almost 6 million
individuals in southern Ontario who re-
ceive medical care from a national health
service with a computerized data base
(Bates and Sizto 1983; Bates 1985~.
2. The known bronchoconstrictive pow-
er of SO2 and H2SO4 aerosols in asthmatics
supports the possibility that experimental
exposure to certain combinations of pollu-
tants, including oxidants, could demon-
strate that asthmatics constitute an oxi-
dant-susceptible population. The work of
Bates and Sizto (1983), and of others, in
which environmental air composition is
analyzed should be invaluable in designing
the types of multiple pollutant exposures
that could be tested in controlled exposure
chambers.
~1 ' 1 1 · 1
.
6. Severe asthmatics and chronic oron-
chitics with reactive airways have under-
gone little or no systematic study.
4. As previously noted, the clinical se-
verity of asthma is related to the degree
of nonspecific bronchial hyperreactivity.
Ozone inhalation reproducibly causes an
enhancement of bronchial reactivity and
therefore may increase clinical manifesta-
tions of an underlying asthmatic condition
under the appropriate circumstances.
5. Despite inconsistencies, there is sig-
nificant evidence suggesting increased sen-
sitivity of asthmatics to the effects of NO2
inhalation.
Additional support for the plausibility of
significant interactions between oxidant air
pollution and asthma may emerge from a
more detailed comparison ofthe pathophys-
iology of asthma and of the effects of
oxidants, primarily O3 which has been
studied more extensively than NO2, on the
airway tissues.
Before proceeding, however, it may be
useful to anticipate some questions and
issues relevant to the goals in this chapter.
In extrinsic asthma, inhaled antigen must
gain access to antibody-sensitized cells in
the airways, particularly the submucosal
mast cells. In order to reach underlying
mast cells or immunecompetent cells, anti-
gens must penetrate the epithelial barrier.
Acute O3 exposure increases respiratory
epithelial permeability and should enhance
the ability of inhaled antigens to reach
critical cells in the submucosa. Thus, acute
or repeated oxidant pollutant exposures of
sensitized individuals might modify the
subsequent early and/or late airways re-
sponses to specific challenge. In addition,
increased epithelial permeability would al-
low egress of submucosal albumin onto the
airways surface where it could alter the
viscoelastic properties of the surface liquid
and impair mucociliary clearance.
Some important effecter mechanisms in
asthma involve stimulation of sensory
nerves and neurally mediated reflexes; re-
lease of chemical mediators, including ara-
chidonate metabolites, from mast cells and
possibly other cells; recruitment of inflam-
matory cells to the airways; and damage to
airways epithelium. Ozone is known to
have all of these effects. In addition, some
extracellular defense mechanisms against
proteolytic enzymes, for example, c'-1-
proteinase inhibitor, are oxidant sensitive.
By causing such overlapping effects in the
same tissue, short-term oxidant exposure
could lead to some acute enhancement of
asthma mechanisms.
Asthma: Pathophysiology
The hallmark of acute asthma is widespread
decrease in the diameter of airway passages,
due, in part, to contraction of circularly
OCR for page 474
474
Asthma and Automotive Emissions
arrayed airways smooth muscle. There is
also edema of the submucosal tissues, and
airway lumens are often plugged by tena-
cious, albumin-rich secretions containing
mucins, intact and degenerating inflamma-
tory cells, and sheets of airways epithelium.
Eosinophils are prominent among the in-
flammatory cells (Hog" 1985~.
Assessment of Airways Size
Descriptions of the caliber or geometry of
the airways are, at best, incomplete. The
conducting airways are a complex branch-
ing structure that includes over 20 branch
points before a fully alveolated region of
lung parenchyma is reached. In addition,
the caliber of the airways is affected by lung
elastic recoil which is a function of lung
volume and is continually changing during
. .
resplratlon.
Several techniques are available that can
be used to estimate airway size. The simul-
taneous measurement of the pressure gra-
dient between the alveoli and the airway
orifice and of airflow either during sponta-
neous breathing or panting allows an em-
pirical measurement of RaW, which is de-
fined as the ratio between pressure gradient
and flow. This relation varies with lung
volume and depends on airflow rate. Nev-
ertheless, this ratio is commonly used as a
descriptor of overall airways geometry.
Another indirect approach to assessing
airways caliber is the forced expiratory
spirogram (volume expired versus time)
which is equivalent in informational con-
tent to the flow-expired volume relation.
Since the inspiration that precedes the
forced expiratory maneuver may tempo-
rarily dilate constricted airways or, in asth-
matics, provoke increased bronchocon-
striction, the size of the inspiration can
be reduced and partial forced expiratory
maneuvers performed in order to avoid
these confounding factors. The quantitative
changes observed with RaW and spirometric
measurements in patients with airways nar-
rowing may be poorly correlated. Thus,
careful attention to selection of measure-
ment techniques is necessary when probing
for relatively small effects on airways func-
t~on.
l he direct relation between lung volume
(and lung elastic recoil) and intrathoracic
airways caliber is well known. Recent re-
ports suggest that the dose/response rela-
tion of the airways to inhaled bronchocon-
strictors is quite sensitive to the lung
volume at which RaW measurements are
made (Martin et al. 1986~. This factor will
need to be considered in assessing bronchial
reactivity.
Distribution of Airflow Resistance
Along the Airways
The longitudinal distribution of the pres-
sure changes between the airway opening
and alveoli is complex. The larynx repre-
sents a significant problem in clinical stud-
ies whereas an endotracheal tube poses
problems in intubated experimental ani-
mals. During quiet breathing or panting, a
major pressure drop occurs in the larynx
and the large airways of normal individuals
or mild asthmatics. In normal adults, the
small airways contribute little to total air-
flow resistance but become a major com-
ponent of the elevated airflow resistance in
persons with diffuse airways disease. In
addition, changes in the small airways are
particularly important in the pathogenesis
of COPD. Significant pathological changes
in the very small airways have been de-
scribed in primates chronically exposed to
moderate levels of O3 (Tyler et al. 1985~.
The caliber of the upper airways and the
trachea can be measured with radiological
or acoustic reflection techniques. Using
tantalum dust as an experimental contrast
material, researchers have obtained good
visual resolution of the intrapulmonary
bronchi (Hahn et al. 1976; Smith et al.
1979; Shioya et al. 1987~. A variety of
approaches have been devised to fractionate
resistance between the "large" and "small"
airways. Some of these (for example, anal-
ysis of the frequency dependence of respi-
ratory impedance using random-noise
forced oscillation, analysis of the gas-den-
sity dependence of forced expiratory flow)
are noninvasive. A more direct, though
invasive, approach uses a wedged broncho-
scope to isolate smaller airways. This tech-
nique has been applied to the study of O3
OCR for page 475
Philip A. Bromberg
475
effects on peripheral lung airflow resistance
and histamine reactivity in dogs by Menkes
and his colleagues (Gertner et al. 1983a,b,c).
Little or no attempt has been made in '
studies of pollutant effects in asthmatic
subjects to fractionate airways resistance
changes or, more specifically, to examine
small airways function.
--r
Mechanisms of Bronchoconstriction
Fundamental mechanisms intrinsic to
smooth muscle that regulate its contraction
and relaxation have been reviewed by
Kamm and Stull (1985), Rasmussen (1986),
and Russell (1986~. However, it is not
known whether asthma is associated with
changes in these mechanisms. It is, for
example, conceivable that the hypertro-
phied smooth muscle in the airways of
severe asthmatics might show differences in
composition of one or more of the mole-
cules in the contractile or regulatory appa-
ratus, or in properties of membrane cal-
cium channels, or in the quantity or type of
membrane receptors. Such abnormalities,
and others, could produce an abnormal
contractile response to normal stimuli.
More attention has been focused on ab-
normalities of mechanisms exogenous to
the muscle cells that might stimulate exces-
sive contraction and/or impair relaxation of
normally functioning smooth muscle.
These mechanisms fall into two broad
classes: neural and chemical.
Neural Mechanisms. The airway wall el-
ements, including smooth muscle, are in-
nervated by several different kinds of
nerves (for review, see Nadel and Barnes
1984~. Best known are the postganglionic
parasympathetic fibers. These fibers are
cholinergic and depolarize the muscle
membrane by reaction of acetylcholine re-
leased from the nerve endings with specific
muscarinic muscle membrane receptors.
Normal individuals exhibit parasympathet-
ically mediated airways smooth-muscle
tone which can be blocked by atropine or
ipratropium bromide, resulting in a signif-
icant decrease in airways resistance. The
preganglionic fibers in the airway wall are
also cholinergic, but their synapse with the
postgangi~onic nerve cell bodies is nicotinic
(rather than muscarinic) and can be blocked
by agents such as hexamethonium. The
ganglion cells are subject to other neural
and chemical influences that also influence
their excitability. Detailed study of the
anatomy and physiology of these impor
. . . . . . . .
tent tissue gang. pa Is Just beginning.
There appears to be little sympathetic
innervation of the airways despite the
abundance of adrenergic receptors on vari-
ous cellular elements in the airway walls.
On smooth muscle, these receptors are
normally of the beta type, and their activa-
tion causes muscle relaxation. Under some
circumstances, however, a-adrenergic con-
strictive responses have been demonstrated
which can be blocked by appropriate inhib-
itors. An abnormality of adrenergic recep-
tor function, in particular ,~adrenergic
blockade, was proposed 20 years ago by
Szentivanyi (1968) as an important mecha-
nism underlying asthma. Asthmatic pa-
tients often exhibit extraordinary sensitiv-
ity to orally or even topically (ocularly)
administered ,~adrenergic blockers which
can precipitate a serious exacerbation of the
asthmatic state. On the other hand, non-
asthmatic individuals fail to develop bron-
chial hyperreactivity or asthma when
treated chronically with ,~adrenergic
blocking agents.
Less well understood is the nonadrener-
gic, noncholinergic inhibitory system (see
Barnes 1984) whose neurotransmitter~s)
remained) to be firmly identified. Vasoac-
tive intestinal peptide (VIP) is an attractive
candidate for this role. Airway smooth
muscle preparations from appropriate spe-
cies including humans, when electrically
stimulated, develop a transient relaxation
followed by constriction. Constriction can
be blocked by atropine pretreatment; this
unveils a relatively prolonged relaxation
that cannot be prevented by ,~adrenergic
blockade. The neural nature of this re-
sponse is shown by its blockade by the
neuronal sodium ion channel blocker, te-
trodotoxin. It is possible that the postgan-
glionic cholinergic fibers are also VIP-
ergic, with the polypeptide transmitter
modulating the effect of the "classical"-
that is, acetylcholine transmitter. Re
OCR for page 488
488
Asthma and Automotive Emissions
sponges. It therefore seems necessary to
continue phenomenological or "descrip-
tive" studies in the expectation that clear-
cut findings that can be correlated with data
from ongoing field studies will emerge.
Asthmatic subjects and persons with other
diseases associated with bronchial hyper-
reactivity should be tested using NO2 as
well as O3.
With regard to field studies, it may be
useful to digress and present several sug-
gestions despite the fact that this general
area is addressed by Bresnitz and Rest (this
volume). In studies of large populations
(for example, Bates and Sizto 1983) careful
attention to the air quality measurements is
required. In addition to quantifying ambi-
ent gaseous and inorganic particulate pol-
lutants, as well as temperature and relative
humidity across a substantial area, it Is
necessary to ensure that all pollutant spe-
cies are examined and that the measure-
ments are frequent enough to assess the
pattern of fluctuation of each component
of interest. Indeed, these air quality mea-
surements may point the way to develop-
ing controlled exposure protocols. In addi-
tion, if asthma is the health effect of
concern, it is desirable to quantify common
airborne particulate antigens. The possible
presence of confounders, such as epidemics
of respiratory infections, must also be con-
sidered.
If not prohibited by considerations of
privacy and ethics, one should identify
individuals within the study population
whose respiratory health status "drives"
any overall population correlations ob-
served between asthma and air quality.
Such individuals could be invited to join a
panel of asthmatics for a prospective study.
They could also be clinically characterized
in depth to define the features of a puta-
tively sensitive subpopulation. Finally,
they might serve as subjects for controlled
exposures.
In studies of panels of asthmatics, air
quality monitoring might include personal
monitors and home monitors in an effort to
obtain the most precise exposure data.
Again, common airborne allergens should
be measured and evidence of respiratory
tract infection sought. The respiratory sta
tus of panel members should be character-
ized in detail.
In addition to descriptive studies, studies
aimed at enhancing our understanding of
the mechanisms underlying the multiple
airways effects of oxidant pollutants, espe-
cially 03, should be considered. Such in-
vestigations should clarify the relation of
automotive air pollution to relevant patho-
physiological mechanisms in asthma and
related diseases. Even if no relation to
asthma were to emerge, a better under-
standing of this issue is essential to a ratio-
nal health policy.
Some of these mechanistic studies can be
performed in human subjects (for example,
mucociliary clearance, airways surface liq-
uid composition and volume, analysis of
bronchial washes or of bronchoalveolar
ravage samples for mediators and macro-
molecules). The nasal mucosa can serve as a
model for the airways. However, to the
extent that invasive procedures are required
(bronchoscopy), there will be obvious lim-
itations, especially in asthmatic subjects.
Sensitive and specific analytical techniques
for certain cellular secretory products will
be needed, and their development may have
to await further progress in lung biology.
Some investigations may be better suited
by animal models, or by cultured cells,
human as well as animal. For example, the
bioelectric properties of respiratory epithe-
lium are being explored in considerable
detail using cultured cells as well as in vivo
techniques. Macromolecular secretion can
also be studied in cultured epithelial cell
layers. Alveolar macrophages are particu-
larly abundant in bronchoalveolar ravage
liquid and can be cultured and exposed to
air pollutants.
Excised perfused lungs allow for control
of the composition of the perfusate as well
as of the inspired gas or airways fluid. The
neural elements are disrupted, however,
and the bronchial circulation is absent. In
situ isolated lobe preparations are therefore
preferable to study permeability effects of
O3 exposure for various probe molecules
including specific antigens. Intact animal
models of
used for a
effects.
antigen-induced asthma can be
variety of studies of pollutant
OCR for page 489
Philip A. Bromberg
489
Summary of Research Recommendations:
Priorities
Descriptive Studies
HIGH PRIORITY
Recommendation 9 Exposure chamber atmospheres that mimic the acid sulfate
content and particle size distribution in ambient pollution should be
created. First, it will be necessary to analyze in greater detail the
composition of ambient atmospheres associated with increased
symptomatology in patients with asthma and other respiratory
diseases.
Recommendation 10 Asthmatic subjects should be exposed to such chamber atmo
spheres, with monitoring of airways caliber. The study of atmo
spheres containing more than one pollutant will greatly complicate
the design of such experiments and will require some choices to be
made of concentrations of the pollutants, time course of the
concentration of each pollutant, and particle size range of a
particulate pollutant (for example, acid sulfate aerosol).
Recommendation 11 Response of airways of extrinsic asthmatics to pollutants, espe
ciallv NOB. should be assessed in the Presence versus the absence of
, ,, ~
chronic low-level exposure to specific allergens.
Recommendation 16 The effect in allergic rhinitis patients or in extrinsic asthmatics of
experimental pollutant exposures on postexposure nasal or bron
chial reactivity ("early" and "late" phases) to specific antigen
challenge should be ascertained.
MEDIUM PRIORITY
Recommendation 7 Exercising asthmatics should be exposed to relevant O3 and NO2
levels for periods up to 8 hr. with monitoring of airways cali
ber.
Recommendation 13 The effect of experimental pollutant exposures on airways func
tion should be measured in patients with COPD (for example,
nonspecific chronic bronchitis, cystic fibrosis), in whom increased
bronchial reactivity is present.
Recommendation 15 The effect of oxidant pollutant exposures of asthmatics on
bronchial reactivity to stimuli such as SO2, cold dry air, noniso
tonic aerosolized solutions, and certain mast cell-derived mediators
should be explored.
LOW PRIORITY
Recommendation 8 Asthmatics should be exposed experimentally for 8 hr to O3 or
NO2 for two or three consecutive days, with monitoring of
airways caliber.
OCR for page 490
490
Asthma and Automotive Emissions
Recommendation 12 The effect of experimental pollutant exposures on nonspecific
airways reactivity in asthmatic subjects selected to display a range
of baseline reactivities should be measured.
Recommendation 14 Pollutant effects on airways should be measured in extrinsic
asthmatics in whom a transient state of marked bronchial hyper
reactivity has been induced by a single antigen inhalation challenge.
Individual subject responses could then be assessed over time at
several levels of baseline bronchial reactivity.
Mechanistic Studies
H I G H P R I O R I T Y
Recommendation 1 The uptake profile of pollutant gases in different regions of the
airways should be measured by sampling and analyzing inspired air
at different airway levels. Variables to be explored with such
systems include concentration of pollutants, ventilatory parame
ters, duration of exposure, and presence of disease (for example,
asthma, chronic bronchitis).
Recommendation 2 These data should be compared with the predictions of currently
available mathematical models.
Recommendation 3 The uptake profiles should be examined for their ability to
account for some of the variability in vital capacity response to O3
exposure observed among individuals.
Recommendation 4 Specific neuropeptides should be assayed in airways surface
liquid after O3 exposure, and the phenomenon of"tolerance" to the
O3 effect on vital capacity should be explored along these lines.
Highly sensitive neuropeptide assays will be required, and rapid
inhibition of peptidase activity may also be necessary to prevent
hydrolysis of peptides in the sample.
Recommendation 6 Animals prepared so as to render their airway C-fiber systems
nonfunctional should be used to examine the role of this sensory
system in O3 effects on epithelial permeability, mucous secretion,
epithelial ion transport, bronchial reactivity, and airways inflam
mation.
MEDIUM PRIORITY
Recommendation 5 O3 responsiveness in human subjects should be compared to the
responses to known stimulants of the airway C-fibers, such as
. .
capsalcln.
Recommendation 17 The effects of exposure to 037 or O3 plus other air pollution
components, on respiratory epithelial cell function should be
probed in greater detail. These functions include mucociliary
clearance, permeability to molecules including albumin and anti
OCR for page 491
Philip A. Bromberg
491
gens, secretion of mucins and of other specific macromolecules,
airway surface liquid composition and volume control, and release
of mediator substances.
Recommendation 18 Direct measurements of pollutant uptake (that is, covalent chem
ical reaction) by cells or tissues can be attempted using "labeled"
gases such as ~ O3. Cultured pulmonary endothelial cells, alveolar
macrophages, and epithelial cells could be used. Such studies would
be particularly useful if they could be correlated to specific pollut
ant effects on the system under study.
Recommendation 19 Although not a good representative of the conducting airways,
the pulmonary alveolar macrophage, as obtained by bronchoalveo
lar ravage following in viva pollutant exposure, may exhibit
functional changes that could be correlated with in vitro dose/re
sponse studies of cultured alveolar macrophages. Such data would
provide some information on parenchymal tissue dosimetry.
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Representative terms from entire chapter:
bronchial reactivity
