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Chapter 2
Assessment of Health Effects
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2
ASSESSMENT OF HEALTH EFFECTS
I NTRODUCTION
Epidemiologic studies usually seek to determine the
relation between exposure and particular health effects.
Epidemiologists use two types of measures to assess health
effects: clinical data derived from medical diagnoses,
often presented as rates of mortality or morbidity in
established clinical diagnostic categories, such as
chronic bronchitis and lung cancer; and data that reflect
biologic changes that are not detected clinically. Data
of the second type, sometimes called subclinical or early
marker data, are obtained by measuring physiologic, bio-
chemical, or morphologic features or by analyzing symptoms
reported on questionnaires. We do not address the problem
of determining exactly what constitutes an adverse health
effect in an epidemiologic study, a topic recently
analyzed by a Committee of the American Thoracic Society,
with reference to the Clean Air Act.t Although
annoyance or esthetic effects (such as odors or impaired
visibility) undoubtedly affect human welfare, they are
not discussed in this chapter, because they are not
typical end points for epidemiologic study.
Biologic models of diseases and of the relationship of
exposure to pathologic response, whether implicit or
explicit, underlie the selection of outcome measures in
epidemiologic studies. The more accurately the available
models can describe, for instance, the temporal relation-
ship of exposure to response or the reasons for variation
in susceptibility, the easier it is to choose health
effects data that are valid and precise.
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This chapter reviews briefly some of the most important
adverse health effects that might be associated with air
pollution. It then discusses the various kinds of health
effects data needed for future epidemiologic studies.
After considering problems of data quality and availabil-
ity and opportunities for improvement, it discusses how
the use of these data is constrained by the incompleteness
of knowledge of disease biology and by limitations in the
instruments used to measure specific effects. Finally,
it addresses the potential use in epidemiologic studies
of biologic markers of respiratory health effects.
HEALTH EFE ECTS OF CONCERN
This chapter focuses on respiratory effects, because
clinical and epidemiologic studies and animal experiments
have shown that the major effects of air pollutants are
on the respiratory system. Health effects are divided
into four categories: acute respiratory effects, chronic
respiratory effects, excluding cancer; lung cancer; and
effects on other organ systems.
Acute effects have a sudden onset and are relatively
short-lived, lasting from a few minutes to a few days.
Examples are an asthmatic attack and an exacerbation of
symptoms of chronic obstructive pulmonary disease (COPD)
Chronic effects persist over an extended time, generally
years. Examples are a permanent respiratory loss from a
decreased rate of lung growth in children and the syndrome
COPD itself. These definitions of "acute. and "chronic n
are somewhat arbitrary and do not provide information
about the time course of antecedent exposures. For
example, acute effects might be attributable to short-term
fluctuations in pollutant concentrations or to cumulative
exposures over an extended period. Similarly, although
chronic effects are normally associated with long
exposures, they can occur after single or small numbers
of exposures.
Some acute effects are discrete, and others are
exacerbations of chronic conditions. In most instances,
the relationship of acute events to the progression of
chronic disease is not well understood. In this report,
"exacerbations generally refers to an increase in fre-
quency or severity of symptoms, without any presumption
of faster progression of an underlying disease.
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Attempts to relate acute and chronic health conditions
to air pollution have to overcome both shared and unique
types of methodologic problems. Investigators of acute
effects usually suspect and examine exposures that have
occurred in the previous hours or days. However, many
factors that can influence the risk of illness increase
and decrease with pollution (for example, temperature and
photochemical oxidants), making it hard to separate the
effect of air pollution itself. Chronic effects are
usually related to exposure that persists over many
years; even with current sophisticated diagnostic tech-
niques, it is virtually impossible to pinpoint the onset
of disease and extremely difficult to identify persons
with early stages of disease.
The Committee has tried to answer two questions for each
of the health effects discussed here:
.
How is the adverse health effect defined and
categorized? The way in which a disease process is
conceptualized or modeled and the existence of gaps in
knowledge of its pathophysiology and natural history have
important implications for the design and conduct of
epidemiologic studies.
· What evidence links the health effect to air
pollution and suggests that the link is a plausible
concern for the future? The purpose is not to determine
whether existing evidence is conclusive, but rather to
determine whether it is sufficient to warrant further
study.
ACUTE RESPIRATORY EFFECTS
Asthma and Airway HyperreactivitY
Asthma is characterized by intermittent obstruction of
airflow that reverts either spontaneously or with treat-
ment. Physiologically, it is manifested by general
narrowing of the air passages due to increased tone of
the bronchial smooth muscle and by plugging of the
airways with thick, excessive mucus. Clinical symptoms
are paroxysms of shortness of breath, coughing, and
wheezing. Asthma is usually an episodic disease, with
acute attacks being interspersed with relatively
symptom-free periods. Many asthmatics have abnormalities
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of pulmonary function even while symptom-free; a few,
considered chronic asthmatics, are essentially always
symptomatic. No standard definition of asthma for
epidemiologic purposes has been established.
Approximately half of patients with asthma have atopic
(allergic) asthma, which depends on an antibody response
to a specific, identifiable antigen. Once sensitivity
(the formation of antibodies) has developed, even minute
amounts of the antigenic material induce symptoms. Many
different inhalants have been identified as primary
sensitizers in asthma, including large complex proteins,
such as ragweed and animal dander, and low-molecular-
weight synthetic chemicals, such as toluene
diisocyanate.i 3 ~ Asthma that does not appear to be due
to allergy to specific substances can arise from a
complex set of genetic and environmental factors.
Whatever its origin, asthma is often exacerbated by a
variety of nonspecific stimuli, including respiratory
infection, exercise, cold air, and emotional stress.
Asthmatics vary greatly in their responses to these
factors, as well as in their responses to conventional
forms of therapy. This heterogeneity must be considered
by epidemiologists.
_ _ _ , _ ,,
The precision of studies will advance
as groups with particular response characteristics are
identified. For instance, there is evidence that some
asthmatics develop prolonged responses due to inflammatory
cells in the airways.8 2
There is reason to believe that
clarification of distinct categories will result from
current breakthroughs in the understanding of biochemical
mediators of airway response, such as the arachidonic
acid metabolites.5 2
Air pollution can increase the risk of an attack in
persons with established asthma, but it is not known
whether air pollution itself is a cause of asthma. Little
research has focused on the latter question. Some con-
temporary studies have reported increased asthmatic attack
rates with greater pollution, but others have found no
such correlation. Whittemore and Korn used novel statis-
tical methods for asthma epidemiology to analyze diaries
kept by a panel of 443 asthmatics in the Los Angeles area
during 1972-1975.~7 3 The most significant predictor of
attacks was the presence of an attack on the previous
day. However, on the average, panelists also tended to
have increased numbers of attacks on days with high
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oxidant and particulate pollution, on cool days, and
during the first 2 months of the study.
In contrast, Goldstein and co-workers found that
visits to the emergency room for asthma in New York City
were more common in autumn and on Sundays and Mondays,
but were not correlated with concentrations of outdoor
sulfur dioxide, SO2, or particles. They suggested that
indoor exposures trigger the attacks.55 s 6
Bronchial hyperreactivity is an abnormal degree of
airway narrowing in response to a stimulus that causes
little or no change in normal airways. It is always
present in asthma, and followup studies of workers who
develop asthmatic reactions to chemicals in the workplace
have demonstrated persistent bronchial hyperreactivity
even after the overt symptoms of asthma ceased.2 3 When
apparently normal persons inhale a nonspecific broncho-
constrictor, such as methacholine, some are hyperreactive
without meeting the clinical criteria for asthma.53
Airway reactivity seems to have a unimodal distribu-
tion; within a population, there appears to be a continuum
from the most reactive to the least reactive persons,
rather than a group of hyperresponders and a separate
group of normal responders.26 The health implications
of airway hyperreactivity without asthma are not known,
and the relationship of this state to development of other
diseases, such as COPO, or to severity of respiratory
infection needs further exploration. 6 9
In controlled-exposure studies, somewhat surprisingly,
volunteers with asthma or with COPD (subjects who,
according to current disease models, would be expected to
have increased airway reactivity) did not seem to be more
susceptible than healthy volunteers to the effects of
ozone, 03, at low concentrations.99 use However,
SCk at as low as 0.4 ppm and nitrogen dioxide, N02,
at as low as 0.3 ppm have induced symptoms or increased
airway resistance in some asthmatics undergoing heavy
exercise.~4 t°° Persons without respiratory disease
generally do not show effects below 1 ppm.~.s
Good animal models of chronic human asthma do not
exist, although acute episodes of bronchoconstriction can
be induced in animals by inhalation of ambient air
pollutants.59
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Respiratory Infections and Related Effects
Upper respiratory infections include colds, influenza,
and sore throats; almost all upper respiratory infections
are caused by viruses. Lower respiratory infections
include pneumonia and acute bronchitis, which are often
caused by bacteria. Early studies clearly demonstrated a
link between high concentrations of reducing pollutants--
e.g., SO2 and total suspended particles (TSP)--and
respiratory infection in children.3 6
Several recent studies have shown that current concen-
trations of specific pollutants might also be associated
with increases in respiratory infections and symptoms in
exposed populations. For example, Bates and Sizto studied
hospital admissions for nine respiratory and six nonrespi-
ratory conditions at 79 hospitals in southern Ontario
during January, February, July, and August in 1974, 1976,
and 1978. t3 Admission data were compared with pollutant
concentrations at 15 air sampling stations in the area.
The strongest correlation was between concentrations of
sulfates and total respiratory admissions, and the
significant correlation with sulfates remained when
asthma admissions were excluded from analysis.
Evidence of a relationship between acute respiratory
infection and exposure to NO2 from gas cooking stoves
is suggestive, but inconsistent and inconclusive. An
early report from the Harvard Air Pollution Health Study
indicated an increased risk of respiratory infection
before the age of 2 associated with exposure to gas
cooking in the home. A later analysis, based on a larger
sample, showed this risk to be still present, but no
longer statistically significant. 7 2 In another series
of studies, Melia and co-workers found a higher prevalence
of respiratory infection in children aged 5-10 living in
homes with gas stoves than in homes with electric stoves.
This effect persisted after adjustment for parental
smoking.
Results of animal studies suggest that low, and
sometimes brief, exposures to pollutants increase
susceptibility to infection. The animal infectivity
model appears to be extremely sensitive for demonstrating
pollution effects. Numerous reports have shown that low
concentrations of NO2 and O3 lower resistance of
animals to bacterial infection.38 .8 7 7 ~ ~ ~ Such
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lowering has been seen in mice exposed to NO2 at 0.5
ppm for 6 months (6 hours/day) 3 8 and to O3 at 0.08
ppm for 3 hours. Exercised mice were more sus-
ceptible than nonexercised mice.77 These effects were
seen at concentrations that humans might encounter, par-
ticularly during peaks of exposure. Thus, the findings
could be relevant to epidemiologic studies that show more
respiratory infections in areas of greater air pollution,
although such infections in humans are most often viral,
rather than bacterial. Animal models for studying the
effect of air pollutants on susceptibility to viral
agents have not yet been developed.
Transient Changes in Pulmonary Function
Pollution can cause transient changes in pulmonary
function in humans both in the laboratory and under
natural conditions. Changes measured in children at a
summer camp include reduction in the maximal volume of
air expired in 1 second (FEV1), the peak expiratory
flow rate (PEFR), and the forced vital capacity (FVC).
Decrements of a few percent were found on days when O3
concentrations were higher, particularly above 100 ppb,
and an exposure-response relationship between O3 and
degree of transient change in pulmonary function tests
was reported.~°t t02
Transient effects of short-term exposures have also
been demonstrated in clinical studies with healthy
volunteers. O3 has shown effects at concentrations
likely to be attained in polluted air.
For example, O3
at 0.3 ppm produced symptoms of irritation of the
respiratory tract and decreases in pulmonary function
during 2-hour exposures of normal volunteers. Avol
et al. detected effects of O3 at 0.16 ppm with heavy
exercise,. and McDonnell et al. detected effects at 0.2
Pam. 2
m e acute response to O3 varies greatly among
individuals. Horvath and co-workers reported that FEV
decreased by 2-48% in 24 normal subjects exposed to O3
at 0.42 ppm for 2 hours while they performed intermittent
moderate exercise. 7 4 McDonnell and associates reported
similar ranges. 12 McDonnell and co-workers showed that
this intersubject variability is apparently intrinsic,
inasmuch as it persisted over periods of months.
43
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The basis for this variation among normal subjects is
unknown, but it shows that some "normal" persons can be
especially sensitive to O3 and that this sensitivity is
detectable in repeated measurements. This finding has
implications for the design of epidemiologic studies of
air pollution, in which accurate definition of the
population at risk is important.
Summary
Various components and patterns of current air pol-
lution cause acute respiratory symptoms, including
asthmatic attacks and increases in respiratory infection,
especially among children. Transient decreases in pul-
monary function have been seen in sensitive or exercising
people exposed to O3 and SO2 at low concentrations.
Further study is needed to understand the basis of
individual variation in response and to determine whether
these acute effects have a long-term impact on lung
function. Whether airway hyperreactivity is related to
accelerated decrease in lung function or to impairment in
lung growth has not been determined. The resolution of
these questions will have a direct impact on possibilities
for and design of epidemiologic studies of air pollution
and acute health effects.
CHRONIC ~SPI=TORY EFFECTS
Three chronic effects of air pollution of great concern
are the set of disorders called chronic obstructive pul-
monary disease (COPD), diminished growth of lung function
in children, and accelerated decrease in pulmonary
function with age.
Chronic Obstructive Pulmonary Disease
The general use of the convenient, but imprecise, term
chronic obstructive pulmonary disease and the widespread
application of a single test of lung function, FEV1,
combine to give a false impression of simplicity to the
study of this disease. The syndrome of COPD has several
main components:
44
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· Chronic mucus hypersecretion (used synonymously
with "chronic bronchitisn), with hypertrophy of bronchial
mucous glands and changes in small airways.ls 6 Its
leading symptom is a chronic productive cough. Chronic
bronchitis is usually ascertained in epidemiologic studies
when a productive cough (one that produces sputum or
phlegm) is present for at least 3 consecutive months per
year for at least 2 years, provided that it is not
attributable to other lung or heart disease .6 ~ Only in
some people does chronic bronchitis lead to clinically
important COPD, manifested by recurrent pulmonary
infection, chronic airflow limitation, or both.
· Alveolar destruction, or emphysema. The chief
symptom is breathlessness without a cough. The essential
pathophysiologic element in emphysema--breakdown of
alveolar walls--is apparently caused by proteolytic
enzymes released by macrophages or polymorphonuclear
leukocytes.~9 At present, this irreversible change in
lung structure can be diagnosed with certainty only at
autopsy. 157
Small-airway disease. This condition is seen
most often as a component of COPD, but it also occurs in
other diseases or as a result of the inhalation of
irritants. It is thought to reflect the presence of
inflammation in the respiratory bronchioles. 2 6 Its
importance as perhaps the earliest lesion in smoking-
induced COPD has been recognized only recently. 7 2
Considerable obstruction may be present in airways
smaller than 2 mm in diameter before changes in FEV
are detected.29 Thus, small-airway disease plays a
major role in a current disease model that might be
applicable to air pollution studies.
Some persons with COPD also have airway hyperreactivity
and bronchospasm; many of these are long-term asthmatics
who have developed a degree of fixed airway obstruction.
These components can exist alone or in any combination
Widespread use of the term COPD came about because it is
difficult for clinicians to separate the roles of the
separate components in individual patients or in popula-
tions. Some persons have evidence of considerable
irreversible damage to lung tissue before breathlessness,
the cardinal symptom of COPD, appears.
45
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Representative terms from entire chapter:
epidemiologic studies
