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OCR for page 499
Effects of Automotive
Emissions on Susceptibility
to Respiratory Infections
JAMES E. PENNINGTON
Brigham and Women's Hospital and Harvard Medical School
The Hypothesis / 500
Background / 501
Determinants of Susceptibility / 501 Occurrence of Respiratory
Infections / 501 Lung Defense Mechanisms / 502 Long-Term
Effects of Infection / 503
Epidemiologic Approach / 503
Documentation and Measurement of Respiratory Infection / 503
Other Epidemiologic Variables / 505
Experimental Approach / 506
Experimental Infections / 506 Studies of Lung Defense
Mechanisms / 507
Gaps in Knowledge and Research Recommendations / 508
Epidemiologic Study Design / 508 Experimental Studies / 510
Summary / 513
Summary of Research Recommendations / 514
Air Pollution, the Automobile) and Public Health. @) 1988 by the Health Effects
Institute. National Academy Press, Washington, D.C.
499
OCR for page 500
500
Effects of Automotive Emissions on Susceptibility to Respiratory Infections
The Hypothesis
Respiratory infection is the most common
type of infection occurring in the United
States. It is estimated that between 200
million and 600 million respiratory infec-
tions occur in this country each year, re-
sulting in a loss of more than 150 million
work days (Monto and Ullman 1974; Ga-
ribaldi 1985~. Costs associated with respi-
ratory infections are enormous, with $10
billion expended each year for the common
cold alone (Dixon 1985~. Mortality from
most types of respiratory infections is low,
with morbidity and economic factors the
major concerns. However, Or pneumonia,
which accounts for 1 to 2 percent of respi-
ratory infections in adults (Garibaldi 1985),
mortality also becomes an issue: pneumo-
nia is currently the sixth most frequent
cause of death in the United States (Gari-
baldi 1985~. Thus, any factor that favorably
or unfavorably influences the incidence or
severity of respiratory infections is of enor-
mous importance to our population.
The hypothesis considered in this chap-
ter is that exposure to automotive emis-
sions can result in greater susceptibility to
respiratory infections. This hypothesis is
worthy of careful study for a number of
reasons. First, if increased susceptibility to
respiratory infection can be documented
among populations heavily exposed to mo-
bile source emissions (for example, traffic
police, tollbooth attendants, mechanics),
then specific vaccination programs, respi-
ratory function monitoring, and occu-
pational counseling for these high-risk
individuals can be initiated. Second, if
emissions are clearly linked to risk of infec-
tion, then more extensive studies can be
undertaken to identify the most hazardous
components of automotive emissions;
and, if specific components are identified,
they could be taken into account in future
engine design. Finally, short-term and
long-term noninfectious sequelae have
been linked to respiratory infections. For
example, protracted bronchial hyperre-
activity sometimes follows an acute epi-
sode of influenza (Empey et al. 1976), and
childhood respiratory infections have
been linked to an increased risk of adult
lung disease (Kattan 1979~. Thus, preven-
tion of respiratory infections associated
with automotive emissions might reduce
subsequent noninfectious pulmonary dis-
eases.
In organizing a method for assessment of
the basic hypothesis, a natural starting
point is agreement about the constituents of
automotive emissions and about the con-
centration ranges relevant to human expo-
sures; some components (for example, ni-
trogen dioxide, acrolein) exist in low
amounts in automotive emissions but in
exceedingly high amounts elsewhere (for
example, blasting areas, siloes, cigarette
smoke). The emission components relevant
to this discussion and their upper limits of
exposure recommended by the National
Ambient Air Quality Standards (NAAQS)
of the U. S. Environmental Protection
Agency, are listed in table 1. Recently,
aldehydes have been added to this list in
anticipation of future use of methanol fuel.
In that case, acrolein, formaldehyde, and
acetaldehyde would increase in importance
as components of automotive emissions.
However, on the basis of studies of Los
Angeles smog, Tuazon and coworkers
(1981) estimated that formaldehyde levels
deriving from automotive emissions would
be considerably less than 1 ppm, and levels
of other aldehydes would be even lower.
What methods, then, are available for
analysis of the hypothesis that automotive
emissions increase susceptibility to respira-
tory infection? The approaches taken in-
clude epidemiologic studies, and experi-
mental studies using animal models.
Although chamber studies using nitrogen
dioxide (NO2), ozone (O3), and other rel
Table 1. Major Pollutants Related to
Automotive Emissions
Component
Air Quality Standard
(ppm)
' 0.05/year
Nitrogen dioxide
(NO2)
Ozone (03)
Carbon monoxide
(CO)
Total suspended
particulates (TSP)
' 0.12 (1-hr average)
9 ppm/8 hr
35 ppm/1 hr
260 ,ug/m3124 hr
OCR for page 501
James E. Pennington
501
Table 2. Ambient Concentrations of NO2
Setting
Concn.
(ppm)
Rural air
Urban air
Los Angeles freeway (usual)
Los Angeles freeway, highest
recorded (1962)
Cigarette smoke exiting
cigarette
Mine shafts immediately after
dynamite blast
Siloes with advanced
decomposition of ensilage
0.01
0.03-0.12
0.15-0.45
1.3
1.0-5.0
250
500
event gases on humans have been reported,
those studies have been directed toward
range finding for acute toxicity and effects
on bronchial hyperreactivity (Ferris 1978~.
Virtually no data on the relationship be-
tween pollutants and the risk of infection
have been published.
The discussion that follows reviews epi-
demiologic and experimental approaches to
this problem. Since data on NO2 are exten-
sive and the approaches taken in NO2
studies appear relevant to the question
raised here, the background information
presented below emphasizes findings with
NO2 exposures. Table 2 lists ambient con-
centrations of NO2 in various settings
which may be useful in the experimental
design of some of the studies discussed
below. After the background discussion,
gaps in our understanding are identified,
and suggestions for future studies that
might improve our ability to prove or
disprove the basic hypothesis are presented.
1'
Background
Determinants of Susceptibility
Frequency of infections as well as severity,
as measured by physician visits, hospital-
ization, absenteeism from work or school,
and so on, should be considered relevant
indicators of susceptibility. Health-impaired
populations (for example, the immunosup-
pressed or chronic lung disease patients) are
important to consider, as are infants and the
elderly, in whom developing or senescent
lungs may be factors in susceptibility. Also
to be considered is the specific type of infec-
tion, that is, viral versus bacterial, especially
as it relates to available vaccines. And certain
anatomic locations in the lung and conduct-
ing airways may be at greater risk of infec-
tion than others. For example, is ciliary dys-
function with associated bronchitis/sinusitis a
major determinant, or is the alveolar paren-
chymal region more prone to infection if
stressed by automotive emissions? Naturally,
if certain locations in the respiratory tract
appear to be more susceptible, then research
could be directed at analysis of the most
relevant local defense mechanisms.
Occurrence of Respiratory Infections
In considering the contribution of emis
. . . ,# . . . .
s1ons to respiratory 1ntectlons, it IS worth-
while to review the types of infectious
agents that commonly cause respiratory
tract infection in the United States. In a
large prospective study over a 6-yr period,
approximately 14,600 cases of respiratory
infections were documented in 4,905 resi-
dents of Tecumseh, Michigan (Monto and
Ullman 1974~. Microbiological monitoring
was carried out using throat cultures for
Group A streptococcus, respiratory viral
agents, and mycoplasma. Cultures were
only obtained if available within 2 days
after onset of symptoms. Of the isolates, 82
percent were viral, 13.3 percent were Group
A streptococcal, and 4.7 percent were
"other," which included mycoplasma. Res-
piratory infections were far more frequent
during childhood (five to six per year in
newborns to 2-year-olds) and decreased
steadily with age. By adulthood, one to two
infections occurred per year. This study
and others (for example, Garibaldi 1985)
emphasize the predominance of upper res-
piratory sites for infection, with bronchitis
and pneumonia accounting for only 10
percent of the episodes.
Although upper respiratory viral infec-
tions are more common, the morbidity and
mortality associated with bronchitis and
pneumonia are far greater (Pennington
1983~. The major agents causing serious
lower respiratory infection are Mycoplasma
OCR for page 502
502
Effects of Automotive Emissions on Susceptibility to Respiratory Infections
pneumonias, Legionella species, influenza A
and B. parainfluenza type 1, respiratory
syncytial virus, and bacteria, especially
Streptococcus pneumonias ("pneumococcus")
and Hemophilus infuenzoe. In certain high-
risk individuals such as alcoholics, diabet-
ics, and the elderly, enteric gram-negative
bacilli also may cause pneumonia.
Thus, in selecting appropriate infectious
agents for surveillance studies of respira-
tory infection, a broad-based cultural and/or
serologic approach is necessary. In selecting
relevant infectious agents for use in animal
models of respiratory infection, a wider
range of infectious agents could be consid-
ered.
Lung Defense Mechanisms
Requisite to an analysis of effects of inhaled
pollutants on lung defenses against infec-
tion is a thorough understanding of the
respiratory defense system that is operative
under normal conditions. Numerous reviews
describe the lung's complex and remark-
ably effective defense against infection
(Green 1970; Kaltreider 1976~. Table 3
summarizes the basic components of this
system. Specific defects in this defense sys-
tem appear to predispose to specific types
of infections (Reynolds 1983; Pennington
Table 3. Host Defense Mechanisms in the
Human Respiratory Tract
Upper airways
Nasopharyngeal filtration
Mucosal adherence
Bacterial "interference"
Saliva (proteases, lysosome)
Secretory IgA
Epiglottis
Lower airways and alveoli
Cough reflex
Mucociliary clearance
Humoral factors
Immunoglobulins
Complement
Cells and cell products
Bronchus-associated lymphoid tissue
Lymphocytes
Alveolar macrophages
Polymorphonuclear leukocytes
Cytokines (interleukin-1, interleukin-2,
interferons)
1984~. For example, impaired mucociliary
clearance (which can occur with ciliary
dyskinesia, cystic fibrosis, bronchiectasis)
results in bacterial sinusitis and bronchitis,
generally caused by encapsulated bacteria
such as H. in1?uenzoe, and the pneumo-
coccus. Local deficiency in immunoglobulins
such as IgG2 and IgG4 are associated with
recurrent bacterial bronchitis and broncho-
pneumonia. Absent or impaired cough re-
flex from neurological disease results in
. . .
asplratlon pneumonias.
Cellular defenses are particularly impor-
tant in the lower respiratory tract. For
example, immunosuppressive drugs may
reduce alveolar macrophage and local lym-
phocyte function, resulting in opportunis-
tic pneumonias, such as Pneumocystis carinii,
and cryptococcal pneumonia (Pennington
1985~. Impaired polymorphonuclear leu-
kocyte recruitment to the lungs during
myelosuppression correlates with an in-
creased risk for aerobic gram-negative ba-
cillary pneumonia (Pennington 1985~. All
of these relationships have been well de-
scribed, and numerous other components
of the lung defense system are now being
investigated. For example, investigations
undertaken by Bukowski et al. (1984) on
the local importance of natural killer (NK)
cells in antiviral activity and by Ennis et al.
(1978) on the importance of other cytotoxic
lymphocyte populations in lung defenses
are being actively pursued. Likewise, the
role of various cell-derived immune mod-
ulators interleukin-1, interleukin-2, and
interferons in local pulmonary defenses is
a subject of great interest (Pinkston et al.
1983; Wewers et al. 1984; Robinson et al.
1985~.
The functional integration of this com-
plex system is not completely understood
and in some cases is controversial. For
example, some debate exists about the im-
portance of alveolar macrophages versus
neutrophils in bacterial defenses; alveolar
macrophages appear to be critical resident
phagocytes for the surveillance against low
numbers of bacteria arriving in the lung,
but recruitment of neutrophils into the lung
is necessary for larger bacterial challenges.
Furthermore, although secretory immuno-
globin A (IgA) is generally considered the
OCR for page 503
lames E. Pennington
503
primary humoral immunoglobulin in-
volved in local respiratory defenses, recent
information suggests that IgG is a more
potent humoral factor in the lower respira-
torv tract (Reynolds 19831. Finallv. the
, ~ , . . .
lymphocyte-directed cellular immune re-
sponse has been traditionally viewed as the
mainstay against facultative intracellular
pathogens such as mycobacteria but of little
importance against acute infection with
pyogenic organisms such as Pseudomonas
aeruginosa. Recent investigations, however,
suggest that this distinction may not be
clear-cut. It thus appears that for most
infections, a combination of mechanical,
secretory, and cellular defenses is needed
for optimal lung defense.
Long-Term EfJects of Infection
Although most respiratory infections are
not fatal, long-term adverse sequelae may
result from childhood respiratory infec-
tions (Burrows et al. 1977; Kattan 1979;
Pullan and Hey 1982~. Long-term effects of
infections may be particularly severe if in-
fection-related lung injury occurs during
infancy or early childhood- a critical pe-
riod in lung development. Sequelae may
take the form of asthma in children or
adolescents or chronic airway obstruction
in adults. However, a review of the rele-
vant studies by Samet et al. (1983) suggests
that evidence for these associations was
incomplete and that many such studies
suffer from recall bias. Nevertheless, the
potential importance of such associations
with childhood respiratory infections offers
considerable incentive to pursue this anal-
ys~s.
Epidemiologic Approach
The ideal method to test the hypothesis that
links automotive emission exposure and
increased susceptibility to respiratory infec-
tions would be to document the frequency
and/or severity of respiratory infections in
individuals with greater exposure to emis-
sions. Numerous epidemiologic studies
have suggested that exposure to NO2 or
other air pollutants increases the incidence
of respiratory illness, and, in some cases,
actual infection (discussed below). To date,
no firm link between mobile source emis-
sion exposures and respiratory infection has
been established because of methodological
difficulties including insufficient use of di-
agnostic tests; unreliable techniques for col-
lection of data (for example, recall, ques-
tionnaires); and inaccurate measurements
of ambient gas concentrations. Since expo-
sure to air pollutants may cause respiratory
irritation and increased bronchial hyper-
reactivity, the use of symptoms such as
cough, sputum production, sore throat,
and wheezing as indicators of infection is
much less accurate than viral or myco-
plasmal serologies, or sputum and throat
cultures. The use of questionnaires to
record respiratory symptoms as a marker
of infection is particularly problematic.
Methodological problems must be taken
into account in the design of future epide-
miologic studies, even though some of the
problems may prove insurmountable. The
following discussion highlights important
considerations in the design and implemen-
tation of epidemiologic investigations that
explore the link between emissions and
infection (see also Bresnitz and Rest, this
volume).
Documentation and Measurement of
Respiratory Infection
Past Studies. Numerous epidemiologic
studies have attempted to demonstrate an
association between NO2 exposure and res-
piratory illness. In some cases direct evi-
dence of respiratory infection was sought,
but in most cases infection was simply
implied by association with cough, coryza
(head cold, inflammation of nasal mucous
membranes), or sore throat. In no studies
were serologic assays performed, nor, with
rare exception, were throat or sputum cul-
tures obtained.
Several of these studies illustrate this
diagnostic difficulty. In one questionnaire-
based study Speizer and Ferris (1973a,b)
compared respiratory symptoms of a group
of urban traffic police exposed to automo-
tive emissions with symptoms of a group
OCR for page 504
504
Effects of Automotive Emissions on Susceptibility to Respiratory Infections
of suburban police. No differences in
symptoms were noted, and the incidence of
respiratory infections could not be deter-
mined in either group. Similarly, a large-
scale study was undertaken in groups of
Chattanooga, Tennessee, schooich~uren
residing in geographic areas with high ver-
sus low levels of NO2 (Shy et al. 1970a,b).
Respiratory symptoms were monitored by
biweekly postcard survey, and positive re-
sponses were followed up by direct ques-
tioning. In addition, teams of parents using
spirometers measured gas volumes of sec-
ond-grade children in each locality. Initial
analysis of these data suggested that chil-
dren in the high-NO2 area experienced
more frequent respiratory symptoms, were
more prone (according to history) to "in-
fluenza" when exposed during an epi-
demic, and had lower FEVo75 values. A
subsequent study in this area by Pearlman
et al. (1971) also suggested that an increased
incidence of childhood bronchitis was asso-
ciated with increased NO2 exposure. Later
analysis of study design and of the method
used for NO2 measurements, however,
rendered the findings from these studies
less conclusive than originally thought
(Ferris 1978~.
Another relevant subject in investigating
the health effects of NO2 exposure deals
with the levels of NO2 inside homes with
gas cooking appliances (Melia et al. 1977,
1979; Keller et al. 1979; Speizer et al. 1980~.
In these studies, indoor exposure to NO2
was used as a method for isolated analysis
of an ambient pollutant gas. Results of
these studies conflict, again impaired by the
use of questionnaires as well as the use of
contemporary fuel exposures to assess past
events.
Practical suggestions for improving di-
agnostic methods in future studies are more
difficult to devise than might be imagined,
because such methods of documenting and
measuring respiratory infections generally
suffer from insensitivity, impracticality,
and expense.
Personal History and Physical Examina-
tion. A personal history taken during an
acute respiratory illness is useful but ex-
tremely time-consuming. Even with care
ful questioning, differentiation between
allergic and viral rhinitis or between asth-
matic and infectious cough may be im-
possible. The presence of fever, purulent
sputum, pleuritic chest pain, and sore
throat are informative but are absent in
many cases of respiratory infection (Glezen
and Denny 1973; Monto and Ullman
1974~. Of course, questionnaires, letters,
infrequent telephone surveys, and patient
recall are all even less accurate, although
much less expensive, than personal histo-
r~es.
As with history taking, individual phys-
ical examinations of patients with respira-
tory complaints are labor and cost inten-
sive. Also, symptoms of most bacterial
infections are evident on examination (ex-
udative pharyngitis, purulent sputum pro-
ctuct~on, or even septic appearance), but
viral or mycoplasmal infections may be
difficult to differentiate from hypersensitiv-
ity because of the similarity of symptoms
(for example, coryza, erythematous throat,
wheezing, tales).
Thus, taken together a physical exami-
nation and a personal history can provide
useful concurrent diagnostic information.
These data would clearly be superior to the
data collected using questionnaire surveys,
but the costs of these combined procedures
may preclude their use for large-scale stud-
~es.
~ .
Nonmicrobiological Laboratory Methods.
Hematologic or radiographic tests do not
provide conclusive evidence of respiratory
infection. An elevated white blood cell
count may suggest bacterial infection, and
infiltrative patterns on chest x rays may
suggest lung infection (among other possi-
bilities). However, these tests are expensive
and offer little diagnostic advantage over
more specific microbiological tests discussed
previously. If it is critical, however, that
pneumonia be differentiated from bronchitis,
then chest x rays would be necessary.
Microbiological Methods. Although widely
considered the methods of choice for diagno-
sis of respiratory infections (McIntosh 1985),
microbiological methods are surprisingly in-
sensitive. For example, in large prospective
OCR for page 505
James E. Pennington
505
studies of respiratory infections in pediatric
practices, routine use of throat swab cultures
for viral, mycoplasmal, and bacterial isola-
tion yielded etiologic agents in less than 30
percent of the cases (Henderson et al. 1979;
Murphy et al. 1981~. Similar results were
reported in the Tecumseh study, in which
throat cultures were collected from patients
with symptoms for 2 days or less (Monto
and Ullman 1974~. In several studies (re-
viewed.by Pennington 1983) of adults who
required hospitalization for community-ac-
quired pneumonia, specific etiologic agents
were found in only 60 to 70 percent of the
cases.
In attempts to define etiologies of respi-
ratory infection, several studies used throat
swab cultures to determine whether the
pathogen was a virus, mycoplasma, or
group A streptococcus (Glezen and Denny
1973; Monto and Ullman 1974; Henderson
et al. 1979; Murphy et al. 1981), because
respiratory infections caused by these
agents are extremely common and because
most infected patients cannot produce spu-
tum for culture. But the use of throat
cultures to isolate respiratory pathogens has
certain drawbacks: first, most viral patho-
gens are excreted for brief periods, early in
infection, and often in low titers; second,
viral, mycoplasmal, and chlamydial cul-
tures require specialized and expensive
methods, which are not available in most
diagnostic laboratories; and third, in large
population studies the logistics for obtain-
ing proper specimens early in the illness
may be difficult. Bacterial culture tech
Table 4. Serologic Diagnosis of Common
Respiratory Infections
Agent
Tests
Viral
Respiratory syncytial virus
Influenza A and B
Parainfluenza
Adenovirus (group)
Mycoplasma pneumonias
Legionella sp.
Chlamydia
CF, IF
CF, IF
HI, IF
CF, IF
CF
IFA, IF
IFA
NOTE: CF = complement fixation; HI = hemagglu-
tination inhibition; IF = immunofluorescence (direct
smear); IFA = indirect fluorescent antibody.
niques are widely available, but most res-
piratory infections are nonbacterial.
Although serologic tests to detect most
nonbacterial respiratory pathogens are
available (table 4), these tests are expensive,
require acute and convalescent specimens
(except for direct immunofluorescent prep-
arations), and may remain negative in in-
fants with infection. Furthermore, anti-
genic heterogeneity for rhinovirus, the
most common cause of respiratory infec
. . . . . . .
tons, precludes serologic evaluation. in
short, serologic diagnosis is expensive,
time-consuming, and incomplete.
Severity o/Respiratory Infections. In ad-
dition to documenting the incidence of
respiratory injections, a measurement of
the severity of infection may be useful.
Clinicians tend to measure severity in sub-
jective as well as objective terms. For data
collection, objective parameters are prefer-
able. Measures such as duration of symp-
toms and fever, time lost from work or
school, time bedridden, whether sputum
was produced, are all useful to gauge sever-
ity. Questions such as how sore is your
throat, how bad is your cough, are partic-
ularly unreliable. In addition, some mea-
sure of the overall effect of the respiratory
infection may be useful in determining
severity. Were physician visits needed,
how much did the entire illness cost, were
symptoms residual (for example, wheezing
and coughing for weeks to months), can all
be useful questions.
Other Epidemiologic Variables
Age. The highest risk of respiratory in-
fection occurs during the first year of life
and decreases steadily until adulthood
(Monto and Ullman 1974~. On the other
hand, risks of pneumonia and mortality
from respiratory infection increase with
advancing age (Pennington 1983~. Such
variables may be useful in targeting groups
for epidemiologic study.
Season. Most studies indicate that the
peak incidence of respiratory infections oc-
curs during winter months (Glezen and
Denny 1973~.
OCR for page 506
506
Effects of Automotive Emissions on Susceptibility to Respiratory Infections
Socioeconomic Status and Family Setting.
The Tecumseh study (Monto and Ullman
1974) showed that the incidence of respira-
tory infections increased with education
but decreased with family income. Supe-
rior reporting by well-educated subjects
may partially account for this finding. In
addition, larger families and rural life may
increase the risk of infection (Glezen and
Denny 1973~. Additional factors, such as
crowded family quarters, parental smok-
ing, and use of day-care centers, must be
considered in evaluation of epidemiologic
data.
Underlying Diseases. Increases in inci-
dence and/or severity of respiratory infec-
tions have been well described for certain
high-risk individuals (Pennington 1983~.
These groups include individuals with
chronic bronchitis, cystic fibrosis, alcohol-
ism, malnutrition, or immunosuppressed
states arising, for example, from organ
transplants and cancer chemotherapy. Re-
cent data suggest that bacterial pneumonia
is more frequent in patients with acquired
immune deficiency syndrome (AIDS)
(Polsky et al. 1986~. If limited resources
dictate studies of only selected, high-risk
populations, these may be the best groups
to study.
Experimental Approach
Experimental Infections
A link between respiratory mucosal dam-
age from inhalation of O3 and increased
susceptibility to localized infections was
postulated by Miller and Ehrlich (1958~.
They reasoned that mucous membranes,
known to be important in antiinfective
defenses, might be damaged by O3 during
high-altitude flight. To prove their hypoth-
esis, they exposed mice in inhalation cham-
bers to 4 ppm O3 for 3 hr and then moni-
tored survival rates after exposures to
aerosolized Klebsiella pneumonias. Mortality
was significantly higher among the O3-
exnosed mice than among nonexnosed but
Ehrlich, as well as by others, examining the
many variables that pertain to the effects of
pollutant exposure and susceptibility to ex-
perimental infection as measured by sur-
vival rates.
Later work using this model dealt with
NO2 rather than O3 (Purvis and Ehrlich
1963; Ehrlich 1966; Ehrlich and Henry
1968~. Ehrlich and coworkers concluded
that acute exposures (for example, 1 to 2
hr) to NO2 at levels below 3.5 ppm do not
affect survival from Klebsiella challenge. In
contrast, they found that chronic NO2 ex-
posure (' 3 months) of 0.5 ppm increased
mortality from Klebsiella challenge (Ehrlich
1966; Ehrlich and Henry 1968~. Recent
attempts to duplicate these results have
been unsuccessful. McGrath and Oyervides
(1983, 1985) found that mice exposed for 3
or 8 months to 0.5 ppm NO2 were not
significantly different from controls in their
resistance to aerosol challenge with Klebsi-
ella. In a subsequent study, they exposed
mice to 0.5, 1.0, and 1.5 ppm NO2 for 3
months, and again no decrease in resistance
to aerosolized Klebsiella challenges was
found. Acute exposures (3 days) to 5 ppm
NO2, however, did decrease survival rates
(McGrath and Oyervides 1985~. These au-
thors speculated that the older NO2 moni-
toring devices previously used by Ehrlich
and coworkers may have provided impre-
cise data during their chronic exposure
studies.
Inhalation studies using squirrel mon-
keys exposed to NO2 indicate that NO2
exposures in the 5- to 10-ppm range ad-
versely affect lung resistance to Klebsiella
(Henry et al. 1969) and influenza virus
inocula (Henry et al. 1970~. However, in
subsequent studies Fenters et al. (1973)
found that the antiviral defenses of mon-
keys exposed to 1 ppm NO2 for more than
a year were not significantly impaired.
Yet another system of analysis uses quan-
titative bacteriological monitoring of lung
tissues in animals exposed to inhaled gases.
This methodology provides an in vivo
evaluation of microbicidal function in res-
piratory tissues. In one typical study by
, ~Goldstein et al. (1973), mice were chal
infected control groups. This work was the lenged with aerosolized Staphylococcus au
first in a series of studies by Miller and reus and were then exposed to various
OCR for page 507
James E. Pennington
507
concentrations of NO2 (0 to 14.8 ppm) for
thr periods. Their lungs were removed
and quantities of remaining viable bacteria
were determined. Animals exposed to NO2
levels of 1.9 ppm killed pulmonary bacteria
as well as control groups, but bactericidal
capacity was reduced in groups exposed to
-3.8 ppm NO2
The method of analysis survival rates
or assays of intrapulmonary microbicidal
capacity most indicative of the clinical
setting is speculative. In either model sys-
tem, exposure to rather high levels of NO2
or O3 is required before significant impair-
ment of lung resistance to infection can be
demonstrated. Thus, it might be concluded
that NO2 only impairs lung defenses at
levels at or above 1.0 ppm, and that auto-
motive emissions probably do not impair
resistance to infection. An equally valid
possibility, however, is that these methods
of evaluation are not sensitive enough to
detect impairment of lung defenses that
might occur during exposures to NO2 in
lower concentrations.
Several methodological concerns can be
identified when reviewing past studies of
animal models of experimental infection.
First, in most cases, healthy animals were
used for the exposure studies. If impaired
hosts are involved, such as immunosup-
pressed animals, lung-injured animals, or
even neonatal or senescent animal hosts,
adverse effects of pollutant gas exposure on
lung defenses may occur at much lower
concentrations. Second, in most animal
studies, rather unusual respiratory patho-
gens were used (for example, Klebsiella, S.
aureus, Streptococcus pyogenes). More clini-
cally relevant choices of bacterial pathogens
might include S. pneumonias or H. inJqu-
enzue. And, although some work using
respiratory viruses has been reported
(Henry et al. 1970; Fenters et al. 1973), far
more emphasis on the use of viruses, My-
coplasma, and Legionella sp. in animal
models might produce more definitive con-
clusions regarding the effects of inhaled
gases on lung defenses. Furthermore, the
combined or synergistic effects of viral plus
bacterial infections, as described by Astry
and lakab (1983), may be a more relevant
method for analysis of emission effects on
lung infection. Finally, it is quite possible
that acutely overwhelming lungs with bac-
terial challenges simply does not simulate
the pathogenesis of most human lung in-
fections, and that a more detailed analysis
of various components of the lung defense
apparatus would be necessary to detect
adverse effects of realistically low gas con-
centrations.
Studies of Lung Defense Mechanisms
Careful analysis of past studies describing
the importance of specific lung defense
components in resistance against specific
types of infection is critically important to
test the hypothesis that automotive emis-
sions impair lung defenses. For example,
careful epidemiologic studies such as those
discussed above may demonstrate that in-
dividuals working or living in urban areas
with high levels of ambient NO2 have an
increased risk for viral respiratory infection
but not bacterial infections. In that case,
investigative priorities could be placed on
analyses of the effects of emission compo-
nents on antiviral defense mechanisms such
as NK cells, cytotoxic lymphocytes, and
local and systemic interferon responses. In
other words, the first clue regarding subtle
but important effects of emissions on spe-
cific components of lung defenses may be
suggested indirectly rather than by directly
analyzing the specific component.
In the meantime, the effects of NO2 and
O3 on alveolar macrophages and certain
other components of lung defenses have
been analyzed by Kavet and Brain (1975)
and Green et al. (1977~. In general, these
researchers first exposed animals to gas
inhalants, and then collected bronchoalveo-
lar cells and fluids by ravage. In a few
instances, they exposed lung cells or tra-
cheal tissues in vitro to gases. In consider-
ation of future research recommendations,
a review of these past findings is likely to be
helpful. '
Using histologic methods, Freeman et al.
(1968) found that 2-ppm NO2 exposures
resulted in decreased ciliary integrity of the
tracheal epithelium. Schiff (1977), on the
other hand, found no morphologic damage
to cilia in hamster tracheal explants after
OCR for page 508
508
Effects of Automotive Emissions on Susceptibility to Respiratory Infections
daily in vitro exposures to 2 ppm NO2 for
up to 3 weeks, although decreased ciliary
beat frequency as well as increased suscep-
tibility of tissues to influenza A viral inoc-
ulations were observed.
Effects of gas exposures on alveolar mac-
rophages have also been studied. For exam-
ple, Vassallo and coworkers (1973) found
that alveolar macrophages obtained from
rabbits exposed to 10 ppm NO2 demon-
strated reduced phagocytosis of bacteria,
and Gardner et al. (1969) found that higher
NO2 levels resulted in reduced numbers of
pulmonary macrophages. Others have
shown that O3 exposure reduces alveolar
macrophage hydrolases and other antibac-
terial metabolic functions (Hurst et al.
1970; Gardner et al. 1971; Hurst and Coffin
1971~. In another series of studies, Valand
et al. (1970) and Acton and Myrvik (1972)
acutely exposed rabbits to 25 ppm NO2,
and then evaluated alveolar macrophages
for antiviral defenses. In healthy rabbits,
the alveolar macrophages obtained after
parainfluenzal challenges produced inter-
feron; however, NO2 exposures sup-
pressed this normal response. Williams et
al. (1972) found that NO2 exposures sup-
pressed uptake of virus by macrophages.
Voisin and coworkers (1977) observed that
after 30-min in vitro exposures to 0.1 ppm
NO2 alveolar macrophages showed re-
duced bactericidal capacity as well as re-
duced cellular adenosine-triphosphate. The
relationship between in vitro NO2 concen-
trations and the in viva situation, however,
remains speculative. Finally, in more recent
work, Greene and Schneider (1978) ex-
posed baboons to 2 ppm NO2 for 8 hr/day,
5 days/week for 6 months and then ob-
tained alveolar macrophages by ravage.
They found that the capacity for alveolar
macrophage response to a lymphokine (mi-
gration inhibition factor) generated from
autologous lymphocytes was decreased
among NO2-exposed animals. In sum-
mary, the recurrent finding resembles that
in the infectivity studies: exposure to levels
of NO2 or O3 above 2 ppm is necessary for
adverse effects to be observed.
Effects of inhaled gas exposure on sys-
temic humoral antibody response have also
been studied. Holt et al. (1979) exposed
mice to 10 ppm NO2 daily for 30 weeks. At
various intervals during the 30-week expo-
sure period, they monitored serum anti-
body response to a T-cell independent an-
tigen (polyvinyl pyrrolidone) and a T-cell
dependent antigen (red blood cells), finding
that antibody response to red blood cells,
but not to polyvinyl pyrrolidone, was
blunted after prolonged NO2 exposure. In
contrast, Fenters et al. (1973) found slight
increases in serum antibody response to
influenza virus in squirrel monkeys ex-
posed to 1 ppm NO2/day for over 1 year.
Fujimaki and Shimizu (1981) found that
exposure to 5 ppm NO2 for 12 hr did not
decrease antibody responses to red blood
cells in mice, but exposures to 20 ppm and
40 ppm did reduce antibody-forming capa-
bility. Thus, it appears that animals ex-
posed to NO2 levels far above those ex-
pected to result from automotive emissions
have a reduced capacity for primary anti-
body response to certain antigens. Studies
of the effects of gas exposure on local
antibody production by pulmonary tissues
have not been reported.
Gaps in Knowledge and Research
Recommendations
Epidemiologic Study Design
Diagnostic Specificity. The epidemio-
logic information currently available is not
suff~cient either to prove or disprove the
hypothesis that exposure to automotive
emissions increases susceptibility to respi-
ratory infection. The most direct method
to prove this hypothesis would be to dem-
onstrate clearly that individuals exposed to
higher levels of automotive emissions
experience more frequent and/or more se-
vere respiratory infections than individuals
exposed to lower levels. Reliance on symp-
toms (cough, sore throat, "colds going to
chest," sputum production) rather than
on specific diagnostic methods as indica-
tors of respiratory infection should be
avoided.
Diff~culties encountered in such studies
OCR for page 509
James E. Pennington
509
may include lack of availability of certain
serologic tests in local laboratories, poor
patient compliance in collection of paired
(acute and convalescent) serologic speci-
mens, high costs of such a meticulous
diagnostic approach, and a high incidence
of false-negative cultures reported for
community-acquired respiratory infections.
These problems may require that larger
rather than smaller populations be studied.
They may also dictate that more specific
target groups be identified for prospective
study.
High-Risk Populations. An attempt has
been made to analyze special respiratory
risks to children during NO2 exposures
(reviewed above), but a much broader view
of high-risk populations should be taken.
For example, the difficulty in finding con-
sistent data in the childhood studies re-
ported to date may be related to the fact
that school-aged children are not among
the groups more sensitive to low-level
NO2 exposures. The elderly or infants
may, in fact, be far more susceptible to
inhaled air pollutants. Likewise, patients
whose immune systems are compromised
because of drug therapy or AIDS may be
especially vulnerable to low levels of NO2,
03, carbon monoxide (CO), or aldehyde.
It is noteworthy that the lung is the most
frequent target organ for infectious compli-
cations among immunocompromised pa-
tients, regardless of underlying disease
(Pennington 1985~. Further susceptibility
to respiratory infections for such patients
residing in congested urban areas with high
traffic density would be meaningful to doc-
ument. Other high-risk groups deserving
study would include patients with chronic
lung diseases (for example, cystic fibrosis,
chronic bronchitis, emphysema) or even
other chronic medical ailments. Even if an
epidemiologic survey in a general popula-
tic~n is not economically feasible using the
diagnostic methods described above, an
analysis in these high-risk populations
would be worthwhile.
Difficulties that might be encountered in
this type of study include rapid patient
attrition due to underlying illness, multiple
concurrent illnesses, and alterations in med
. . . · r
Cations colnclc sing Wlt n 1ntectlous epi-
sodes.
· Recommendation 1.
Epidemiologic
survey in high-risk populations exposed to
varying levels of automotive emissions
should be conducted.
These surveys should adhere to the fol-
lowing minimum set of requirements:
a. Use of population with defined expo-
sure. Prospective and accurate ambient air
analysis should document elevated levels of
relevant emission components in the
environment for study.
b. Use of defined group. Cost consider-
ations argue for selection of specific study
groups of persons at high risk for respira-
tory infection, in particular the elderly,
infants, patients with chronic lung diseases,
and immunocompromised patients. One
problem to be expected with groups suf-
fering from chronic lung disease is the high
rate of chronic symptoms not associated
with, but potentially confused with, acute
. , .
ntectlon.
c. Use of adequate history. Retrospective
questionnaires should not be used. Rather,
prospective and frequent telephone sur-
veys, followed up by visits to the clinic for
symptomatic patients, are recommended.
d. Use of diagnostic tests for infection.
At a minimum, throat swabs for respira-
tory viral cultures and bacterial cultures
should be collected within 2 days of onset
of illness. In addition, acute and convales-
cent sera should be evaluated for Myco-
plasma pneumonias and Legionella sp. anti-
body titers. If sputum is produced, it
should be cultured. These methods can be
expected to yield specific diagnoses in 20 to
30 percent of cases. Although considerably
more expensive, viral serologies could also
be done (see table 4), increasing diagnoses
by at least another 20 to 30 percent.
e. Measures of severity. Factors dis-
cussed above dealing with severity of infec-
tion and overall impact of illness (that is,
duration of symptoms and fever, absentee-
ism from work or school, time bedridden,
sputum production, need for physician vis
OCR for page 510
510
Effects of Automotive Emissions on Susceptibility to Respiratory Infections
its, cost of illness, residual symptoms)
should be routinely recorded.
Experimental Studies
Animal Versus Human Studies. Before
discussing areas where specific experimen-
tal studies could provide more useful infor-
mation regarding effects of inhaled gases on
lung defenses, it is important to point out
the lack of relevant data derived from hu-
man studies. In recent years a methodology
has been developed to collect cells and
fluids from the human lower respiratory
tract safely and rapidly with the flexible
fiberoptic bronchoscope (Hunninghake et
al. 1979~. Much valuable information is now
available regarding normal bronchoalveolar
cell populations and the fluid-phase constitu-
ents of lower respiratory secretions (Hun-
ninghake et al. 1979~. Further analyses using
specimens obtained bronchoscopically from
patients with lung diseases such as sarcoid,
idiopathic interstitial pneumonitis or asthma
have identified cell population alterations that
correlate with specific diseases and with the
status of disease activity (Weinberger et al.
1978; Hunninghake et al. 1979; Pinkston et
al. 1983; Rankin et al. 1984~.
To date, bronchoscopic analysis has not
been used in humans to evaluate the effects
of inhaled gases on various components of
the lung defense system. Ethical consider-
ations have, perhaps, slowed acceptance of
this approach because the risks attendant
with inhalation chamber exposures to NO2
or O3 in humans are unknown. But, nu-
merous chamber studies have been per-
fon~ed to develop guidelines for air quality
recommendations (reviewed by Ferris
1978~. Those using low-level, short-term
exposures appear to be safe and may be
considered favorably by human studies
committees. On the other hand, it could be
argued that until the basic hypothesis has
been disproved, it may not be wise to
expose humans even to low levels of in-
haled pollutants. After all, a basic premise
of such investigations is that low-level ex-
posure induces subtle but important defects
in local defenses, and that such defects will
be detected only by careful analytical meth-
odology.
Yet another method of human study
might use experimental viral infections in
association with inhalant exposures. The
use of healthy subjects for experimental
viral infections such as influenza and respi-
ratory syncytial virus is an accepted prac-
tice (see, for example, Bell et al. 1957;
Johnson et al. 1961; Feery et al. 1979),
particularly to evaluate vaccine efficacy.
Combining chamber exposures with ex-
perimental viral infections may be a useful
method to evaluate the effects of emissions
on respiratory pathogenicity of these
agents. For example, the effect of inhalants
on severity and duration of infection, and
on minimum size of infective inoculum,
could be determined. Again, ethical consid-
erations must be addressed in designing
such studies. Furthermore, the dose range
maintained for inhaled gas exposures
should be low enough to address the issue
of relevance to automotive emissions.
In summary, studies should be designed
for human subjects as well as animal mod-
els. Although dose-response studies can be
carried out over much broader ranges of
pollutant concentration in animals, the
more direct clinical relevance of human
data argues for strong consideration of at
least some analyses being carried out in
human subjects. Ideally, subjects exposed
to high levels of automotive emissions
could be compared with subjects from rural
or other areas of low-level exposure, but, if
this is not possible, chamber exposure
methods could be used.
Infectivity Models. Despite the large
body of information regarding susceptibil-
ity to infection in animals exposed acutely
or chronically to inhaled NO2 or O3, ques-
tions regarding lung defenses during exper-
imental infection remain unanswered. For
example, little or no information exists
about defenses against several extremely
common respiratory pathogens, including
mycoplasma, respiratory syncytial virus,
Legionella s p., S. pneumonias, and H. inf u-
enzoe. Experimental models of infection
with each of these pathogens have been
reviewed by Pennington (1986) and could
be used for analyses similar to those for
Klebsiella and influenza virus.
OCR for page 511
James E. Pennington
511
Recommendation 2. Perform experi-
mental studies in animals using common
respiratory pathogens.
Altered-Host Studies.
~1 ~1
The influence of
altered-host status on lung susceptibility to
infection after exposure to components of
automotive emissions is poorly under-
stood. Ethical considerations preclude
bronchoscopic analyses in high-risk pa-
tients exposed to pollutant gases, but nu-
merous animal models of immunosuppres-
sion (Pennington 1985), chronic lung
damage (Snider et al. 1986), or extremes of
age (Sherman et al. 1977; Esposito and
Pennington 1983) exist from which valu-
able information may be obtained.
~ ~ ,
Recommendation 3. Animal models
should be used to determine whether al-
tered-host status or extremes of age influ-
ence the lung's susceptibility to infection
after exposure to automotive emission
components. Survival or lung clearance
during experimental infections could be
evaluated as well as the additive influences
of gas exposure plus underlying host defect
on lung defense components (for example,
alveolar macrophages, inflammatory reac-
tion in airways after infection, bacterial
adherence to respiratory mucosa).
Antiviral Defense Mechanisms. fudging
from current epidemiologic data, the most
likely source for increased infection in in-
dividuals exposed to high levels of automo-
tive emissions is viral. As discussed above,
this conclusion is by no means proven, but
sore throat, coryza, and cough without
sputum are the symptoms most frequently
noted in such studies. As such, high prior-
ity must be placed on analysis of the effects
of inhaled emission components on antivi-
ral defenses in the respiratory tract. Some
early data suggested that NO2 exposure
suppresses interferon production by alveo-
lar macrophages (Valand et al. 1970; Acton
and Myrvik 1972) and decreases lung resis-
tance to influenza (Henry et al. 1970) or
parainfluenza (Williams et al. 1972~. The
NO2 levels used in those studies, however,
were high (5 to 25 ppm). Using the more
sophisticated methodologies now available
for analysis of antiviral activities (Sissons
and Oldstone 1985), it may be possible to
detect adverse effects on lung defenses at
levels of gas exposure relevant to ambient
concentrations. Such studies may be ideal
for human subjects because low levels of
gas (for example, NO2) could be used in
chamber exposures, followed by collection
of large numbers of cells by bronchoscopic
ravage. This approach may be especially
useful because obtaining enough of the
appropriate cell population (for example,
NK cells, K cells, cytotoxic T cells) may be
impossible in small animals but feasible in
humans (Pinkston et al. 1983; Robinson et
al. 1984~.
Naturally, animal studies of antiviral de-
fense mechanisms also could be carried out
in experimentally exposed groups, allow-
ing more convenient dose-response studies.
If mice are used, pooling of lung specimens
would probably be necessary to obtain
enough cells for well-controlled, replicate
assays. If larger animals such as guinea pigs
and rabbits are used, difficulties in obtain-
ing appropriate reagents for analysis (for
example, monoclonal antibodies for NK
cells) may be encountered.
Especially important in these studies
would be the analysis of numbers and
function of pulmonary NK cells (Stein-
Streilein et al. 1983; Bukowski et al. 1984),
cytotoxic T lymphocytes (Ennis et al.
1978), antibody-dependent cellular cyto-
toxicity (using alveolar macrophages and K
cells) (Hunninghake and Fauci 1977; Kohl
et al. 1977), and interferon cat, ,l3, and fly
production by lung cell populations (Rob-
inson et al. 1985~. Since available data show
no viral antibody responses in animals ex-
posed to relevant levels of NO2, it is less
likely that studies of antibody response will
be helpful. Analysis of pulmonary secretory
antibody levels may be useful, however.
Recommendation 4. Components of
respiratory antiviral defense mechanisms
should be analyzed with respect to impair-
ment from exposure to automotive emis-
sion products.
Immunologic Modulators (Cytokines). A
rapid expansion has occurred recently in
OCR for page 512
512
Effects of Automotive Emissions on Susceptibility to Respiratory Infections
our understanding of how various immu-
nologic cell populations communicate and
modulate cellular responses to infectious
(and other antigenic) agents. Researchers
have shown that interleukin-1 (Wewers et
al. 1984), interleukin-2 (Pinkston et al.
1983), and various interferons (Robinson et
al. 1985), are produced by pulmonary cells
and may be affected by various disease
states, including infection (Lamontagne et
al. 1985) and sarcoidosis (Pinkston et al.
1983; Wewers et al. 1984; Robinson et al.
1985), or by immunosuppressive drugs
(Salomon et al. 1985~. Little is known
regarding the effects of automotive emis-
sion exposure on these important cyto-
kines.
Recommendation 5. Animal and/or hu-
man lung cell populations should be eval-
uated for the effect of inhaled gases on the
production of interleukin-1 by alveolar
macrophages, interleukin-2 by T lympho-
cytes, and the production of various in-
terferons by alveolar macrophages and
lymphocytes. Availability of enough bron-
choalveolar lymphocytes may be a limiting
factor, and, for that reason, human speci-
mens may be especially valuable.
Alveolar Macrophage Functions. Infor-
mation on alveolar macrophage functions
with regard to the viral defense mecha-
nisms and cytokines discussed above has
increased considerably in recent Years
(Hunninghake et al. 1979, 1985~. For ex-
ample, expression of the type 2 histocom-
patibility antigen determinant on the mac-
rophage surface is now known to be critical
for alveolar macrophage processing of an-
tigenic and infectious challenges (Mason et
al. 1982~. In fact, the role of alveolar mac-
rophages in accessory cell functions is be-
coming increasingly clear (Toews et al.
1984~. Also, the capacity of interferon By
treatment to activate alveolar macrophages
for microbicidal activity has been closely
associated with their defense function
(Schaffner 1985~. Furthermore, the capacity
for respiratory burst (for example, super-
oxide anion production) is known to be
directly related to alveolar macrophage mi-
crobicidal capacity (Hoidal et al. 1979; Pen
nington 1985~. Other metabolic activities,
such as the production of chemotactic leu-
kotrienes (leukotriene B4) (Martin et al.
1984), as well as complement components
(Pennington et al. 1979), and a low-molec-
ular-weight neutrophil-activating factor
(Pennington et al. 1985), have been identi-
fied for alveolar macrophages. Finally, the
intrinsic motility of alveolar macrophages
(Pennington and Harris 1981), plus their
capacity to produce neutrophil chemotactic
factors (Merrill et al. 1980), clearly relate to
lung defense activities. It is safe to say that
virtually no information is available regard-
ing the effects of automotive emission com-
ponents on these important alveolar mac-
roph.age products and functions, so the
possibility exists that one or more of them
may be significantly impaired by low and
relevant levels of air pollutants.
Recommendation 6. The effects of au-
tomotive emission components on alveolar
macrophage function should be determined.
Mucosal Binding. Several studies already
mentioned in the Background section have
described morphologic and functional de-
fects in mucociliary apparatus of airway
mucosa in intact animals or explanted tis-
sues exposed to NO2. These defects might
adversely affect mucociliary clearance of
potential infectious agents, but another
mechanism altered mucosal binding
properties might also predispose to infec-
tion. Increased mucosal binding aff~nity for
pathogenic bacteria occurs under a number
of stress conditions including surgery
(Woods et al. 1981a), necessity for intensive
care unit management (Woods et al.
1981b), and malnutrition (Niederman et al.
1984~. Increased adherence of gram-nega-
tive bacilli to airway mucosa predisposes to
subsequent respiratory infections in certain
individuals (Johanson et al. 1972~. The
impact of emission exposures on binding
affinity of airway mucosa for potential
pathogenic infectious agents is unknown.
The adherence properties of airway cells
obtained from animals or humans experi-
mentally exposed to relevant levels of au-
tomotive emission components should be
studied. Such assays could be performed by
OCR for page 513
James E. Pennington
513
using radiolabeled, gram-negative bacilli
and quantitating their binding affinity for
buccal or tracheobronchial cells removed
by scraping and placed into tissue cultures
(Niederman et al. 1984; Woods et al. 1981a,
b), or tracheal explant cultures (Ramphal
and Pyle 1983~. These assays are relatively
insensitive due to high background radio-
activity, and it may be impossible to detect
very subtle alterations in mucosal binding
properties.
~ Recommendation 7. Mucosal cell bind-
ing affinity for respiratory pathogens
should be studied after exposure to relevant
concentrations of emission components.
Summary
The basic hypothesis under consideration is
that exposure to automotive emissions re-
sults in increased susceptibility to respira-
tory infections. The rationale for exploring
this hypothesis is that if it is true, then
special programs for vaccination, clinical
monitoring, and occupational counseling
of high-risk groups should be undertaken.
Current data are insufficient to test this
hypothesis, but numerous studies suggest
that it may be true. For operational pur-
poses, the components of automotive emis-
sions of interest include nitrogen oxides
(especially NO2), CO, 03, and particu-
lates. In addition, interest in aldehydes has
increased in expectation that methanol fuel
sources may be used in the near future.
Two basic research approaches have been
used in past studies to explore this hypoth-
esis. One approach has involved epidemi-
ologic surveys of populations exposed to
varying levels of known components of
automotive emissions. Frequency and se-
verity of respiratory symptoms, as well as
performance on spirometry testing, were
monitored and compared but results are
conflicting. Outdated methods for moni-
toring ambient gas levels, as well as lack of
serologic or cultural tests for diagnosing
infection, are justified criticisms of these
.
studies. Future epidemiologic studies
should take these problems into account.
Also, future studies may wish to identify
and focus attention on high-risk popula-
tions such as chronic lung disease patients,
the immunosuppressed, and the elderly.
The second approach has been to expose
animals to inhaled gases, commonly NO2 or
03, and then to study the effects of exposure
on lung defenses against infection. Numer-
ous studies have demonstrated decreased sur-
vival from experimental bacterial or viral
infection and decreased capacity to kill bac-
teria in the lungs of animals exposed to
pollutant gases. Levels of NO2 ' 0.5 ppm
(often much higher), however, were re-
quired to demonstrate these adverse effects.
Infectivity studies with animal models may
not be sufficiently sensitive to identify more
subtle defects in lung defense which might
result from lower levels of gas exposures.
To address this possibility, individual
components of the lung defense system
have been evaluated in specimens obtained
from exposed animals. To date, most stud-
ies have focused on alveolar macrophages,
although some studies have examined mor-
phologic effects of gases on mucociliary
tissues and effects on systemic antibody
responses. As in the infection models, im-
paired defenses have been identified only
after high (that is, - 2.0 ppm) and often
prolonged NO2 exposure. It is fair to point
out, however, that newer assays have been
developed (for example, NK cell function,
interleukin-1 and -2 production, cell migra-
tion) that may be better suited to detect
subtle, yet potentially important, defects in
lungs exposed to low-level emission com-
ponents. Furthermore, it is now safe and
ethical to obtain human lung specimens
using the flexible fiberoptic bronchoscope.
Thus, future chamber studies with human
subjects could be followed by an evaluation
of bronchoscopic specimens. In planning
such studies, it should be kept in mind that
adverse effects on one component of lung
defense might be compensated for by aug-
mented activity of other defense systems.
The complexity of this type of analysis
cannot be overstated.
OCR for page 514
514
Ejects of Automotive Emissions on Susceptibility to Respiratory Infections
Summary of Research Recommendations
HIGH PRIORITY
On the basis of current information, the following studies are
most likely to yield useful data and, given limited funding re-
sources, most highly recommended.
Recommendation 1 Epidemiologic survey in high-risk populations exposed to vary
ing levels of automotive emissions or components. The design of
such surveys should include populations with defined exposure,
specific study groups, adequate histories, diagnostic tests for infec
tion, and measures of severity.
Recommendation 4 Evaluation of components of respiratory antiviral defense mech
anisms. This analysis could be done in humans or animals exposed
to emission components under controlled conditions. Studies most
likely to yield useful new information would be numbers and
function of pulmonary NK cells and cytotoxic lymphocytes;
interferon production by alveolar macrophages and lymphocytes;
and antibody-dependent cellular cytotoxic activity of Fc receptor
bearing lung cells (that is, alveolar macrophages and K lympho
cytes).
MODERATE PRIORITY
Studies that include recent developments in methodology may
allow detection of more subtle defects, particularly at relevant
emission exposure levels.
Recommendation 5 Assays of immunologic modulator production by alveolar mac
rophages (interleukin-1, interferon) and pulmonary lymphocytes
(interleukin-2, interferon). As before, chamber studies with human
subjects or animal models could be used.
-
Recommendation3 Altered-host infection models. The influence of altered-host
status on lung susceptibility to emission components is important.
Animals at extremes of age, immunosuppressed, or with experi
mentally induced chronic lung damage, should be studied to
evaluate the effects of low-level exposures on lung defenses against
infection.
Recommendation 6 Specialized alveolar macrophage functions, such as chemotaxis,
production of complement and chemotactic factors, accessory cell
function, and capacity for respiratory burst. Chamber studies with
human subjects or animal models could be used.
LOW PRIORITY
These studies are similar to studies already performed which
have shown negative results at low emission levels (infection
model), or utilize relatively insensitive methodologies. However, if
OCR for page 515
James E. Pennington
515
funding is available, the indicated modifications of study may
provide new information.
Recommendation 7 Mucosal binding affinity. Human or animal respiratory cell
binding affinity for respiratory pathogens should be studied after
exposure to relevant concentrations of emission components.
Recommendation 2 Infection models using common human pathogens. Studies
using viral agents, mycoplasma7 Legionella sp., S. pneumoniae, and
H. in.f uenzoe for experimental infections in exposed animals might
over more relevant information than the numerous past studies
using Klebsiella and S. aureus.
References
Acton, J. D., and Myrvik, Q. N. 1972. Nitrogen
dioxide effects on alveolar macrophage, Arch. Envi-
ron. Health 24:4~52.
Astry, C. L., and Jakab, G. J. 1983. The effects of
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Representative terms from entire chapter:
automotive emissions
