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OCR for page 389
Epidemiologic Studies of
Effects of Oxidant
Exposure on Human
Populations
EDDY A. BRESNITZ
KATHLEEN M. REST
The Medical College of Pennsylvania
Role of Epidemiology in Air Pollution Research / 390
Prior and Ongoing Studies Designs, Findings,
and Problems / 390
Cross-Sectional Studies of Pulmonary Function and
Symptoms / 391 Prospective Cohort Studies / 399
Retrospective Studies / 400
Generic Issues / 400
Exposure Assessment / 400 Effects Assessment / 401
Specific Issues and Study Approaches / 404
Chronic Obstructive Pulmonary Disease / 404 Asthma/Bronchial
Hyperresponders / 405 Respiratory Infection / 407 Attributable
Risk / 408
Summary / 409
Summary of Research Recommendations / 409
Specific Research Issues / 409 Generic Issues / 411
Air Pollution, the Automobile, and Public Health. @) 1988 by the Health Effects
Institute. National Academy Press, Washington, D.C.
389
OCR for page 390
390
Epidemiologic Studies of Oxidant Exposure
Role of Epidemiology in
Air Pollution Research
Epidemiology is the primary research dis-
cipline that allows investigators to examine
the long-term effects of air pollution on
public health. Controlled human studies in
exposure chambers generate useful hypoth-
eses and allow maximum quantification of
dose/response relationships, but they can
only address acute effects and short-term
changes in functional parameters. The as-
sessment of long-term exposures and
chronic health effects in humans must nec-
essarily fall to the epidemiologist. In epide-
miologic investigations, causal relation-
ships between exposure and effect are
usually plausibly inferred by the strength of
the association, the consistency of data, the
specificity of results, the temporality of
observations, the demonstration of a bio-
logical gradient, and the plausibility and
coherence of results (Hill 1965~.
In air pollution research, animal, cham-
ber, and epidemiologic studies have served
to investigate a variety of health outcomes.
Mortality studies have often followed on
the heels of major air pollution episodes.
Morbidity studies have looked at respira-
tory as well as nonrespiratory end points.
The former include acute effects such as
asthma and infection, chronic effects such
as chronic obstructive pulmonary disease
(COPD), and long-term effects such as
lung cancer and accelerated decline in lung
function. Research on nonrespiratory ef-
fects has usually focused on nonoxidant
exposures (for example, on lead, organic
solvents, and carbon monoxide), and has
investigated neurotoxic effects, heart dis-
ease, and leukemia.
When epidemiology is used to study
these outcomes in air pollution research,
several technical and methodological issues
arise. These include selection of appropriate
study design and study population, assess-
ment of exposure, definition and assess-
ment of adverse health effects, control of
bias and confounding variables, and analy-
sis of data. Many studies done to date have
been flawed by their method of addressing
these difficult problems, leaving their re-
sults and conclusions open to question. Yet
the weight of the aggregate evidence sug-
gests that air pollutants do cause adverse
health effects at certain levels, and that
further epidemiologic studies are needed to
quantify dose/response and to assess the
consequences of long-term exposure to air
pollutants at low levels.
The use of epidemiology in air pollution
research is examined in this chapter. The
focus of the chapter is on photochemical
oxidants, mainly ozone (03) and nitrogen
dioxide (NO2), and their effects on the
respiratory system, exclusive of lung can-
cer. A review of selected studies illustrates
how investigators have addressed impor-
tant technical and methodological issues,
and suggests how such issues might be better
addressed in the future. Important scientific
and methodological knowledge gaps are then
identified, and several approaches for closing
these gaps are recommended.
Prior and Ongoing
Studies Designs, Findings,
and Problems
Researchers have made considerably more
progress in studying the acute effects of
exposure to short-term, high levels of O3
and NO2 than in studying the effects of
long-term, low-level oxidant exposure, or
repeated episodic oxidant exposure at peak
levels. The contribution of these exposure
patterns to such respiratory diseases as
COPD, asthma, and pulmonary infection
remains a research gap. The effect of oxi-
dants on the normal rate of decline in
pulmonary function with age is also an
unresolved question.
The studies required to fill these gaps are
difficult to accomplish because of several
factors: the generally low level of ambient
(outdoor) exposures in the United States;
the relative infrequency of some chronic
respiratory diseases; the multifactorial na-
ture of these chronic respiratory diseases;
the lack of sensitivity and specificity of
some of the tools used to detect physiolog-
ical dysfunction or disease; the poor char-
acterization of the actual composition of
pollutants over time; the difficulty in esti
OCR for page 391
Eddy A. Bresnitz and Kathleen M. Rest
391
mating biologically effective dose; and the
ethical problems inherent in conducting
controlled studies of long-term exposures.
Epidemiologic observational studies to date
have generally suffered from one or more
of these problems, precluding definitive,
quantitative conclusions about causal rela-
tionships between exposure to oxidants and
adverse health effects.
In table 1, the most commonly used
types of epidemiologic study design are
described. The cross-sectional study has
been the most frequently used observa-
tional design in epidemiologic studies of air
pollution. Studies with this design deter-
mine the prevalence of particular health
outcomes in a population at one or more
points in time and correlate them with
some concurrent measure of exposure. The
risk for disease development (incidence)
and the temporal sequence of exposure and
disease cannot always be determined in this
type of study. Although cross-sectional
studies have been useful for generating
hypotheses, comparing health outcomes in
communities exposed to high and low lev-
els of air pollution, and studying the acute
effects of short-term exposures, they have
not been very helpful in assessing dose/re-
sponse effects of long-term exposure.
A cross-sectional study may be repeated
in populations over time to assess trends in
the prevalence of specific outcomes of in-
terest. A study done this way is called a
secular trend or time-series analysis. In air
pollution research, the outcomes under
study may be correlated with serial mea-
surements of ambient air pollutants. Paral-
lel changes in the prevalence of symptoms
or mean pulmonary function and average air
pollutant levels would suggest an association
between the exposure and the outcomes.
A closer examination of several cross-sec-
tional studies that attempt to assess the rela-
tionship between exposure to oxidants and
respiratory morbidity illustrates the prob-
lems and limitations of this type of study.
Cross-Sectional Studies of
Pulmonary Function and Symptoms
Healthy Populations. Shy and coworkers
(1970a) compared the ventilatory function
of 987 second-grade children who lived in
Chattanooga, Tennessee, in four geo-
graphic areas that varied in their average
24-hr levels of ambient NO2 and particu-
lates (one high-NO2 area, one high-partic-
ulate area, and two control areas). Mea-
surements were taken from stationary air
pollutant monitoring sites during the 65-
day study period.
Assessment of mean weekly height-
adjusted forced expiratory volume in the
first 0.75 sec (FEVo 75) of the spirogram,
averaged over each month of the study for
children of the same sex, showed that the
FEVo 75 was statistically significantly lower
in the high-NO2 area compared to the two
control areas in both months of the study.
However, the differences were very small
and clinically not very significant.
This study has several methodological
problems. First, the investigators did not
adjust the results for parental smoking and
indoor sources of NO2 which may have
been associated both with decreased lung
function in the children (Speizer et al. 1980)
and levels of outdoor NO2. That is, paren-
tal smoking may have confounded this
association. Second, the levels of total sus-
pended particulates (TSP) and sulfates
(S04) were highest in the high-NO2 area.
These other air pollutants may interact
with NO2 or confound the relationship
between lung function and the oxidant
levels. Finally, the technique used to mea-
sure NO2 was subsequently shown to be
invalid. Thus, technical as well as method-
ological problems affected the results of the
study.
In the second phase of the study, Shy and
coworkers (1970b) investigated the trend in
the incidence of acute respiratory illness
among all families in the study having a
child in the second grade. A total of 4,043
study subjects, comprising 871 families of
the children who had participated in the
ventilatory testing portion of the study,
agreed to participate in this phase.
Temporal variations of self-reported res-
piratory illness rates were similar in each
study area, and rates among smokers did
not differ from rates in nonsmokers. Abso-
lute illness rates over the entire study pe-
riod were consistently and significantly
OCR for page 392
392
Epidemiologic Studies of Oxidant Exposure
Table 1. Epidemiologic Research Designs
Study Type Description Advantages Disadvantages
Cross-sectional · Examines presence or
(also called absence of exposure and
prevalence effects at same point in
study) time.
· Sometimes repeated
observations will be made
over time and combined to
compare trends in the
population.
· Is essentially the first phase
of any cohort study.
Cohort · Individuals (exposed and
unexposed) are selected for
observation and followed
over time.
· Study proceeds from
suspected cause to effect
(i.e., subjects selected on
basis of exposure).
· Data may be collected
prospectively (i.e., outcome
and exposure data unknown
at beginning of study but
collected as study proceeds).
OR
· Data may be collected
retrospectively (i.e.,
exposures and outcome
have already occurred at
beginning of study and data
are historical in nature).
Case-control · Individuals with particular
diseases or conditions (cases)
are selected and compared
to individuals without the
disease or condition
(controls). They are
compared with respect to
the exposure of interest.
· Study proceeds from effect
to cause (i.e., subjects
selected on basis of disease).
· Exposure data are collected
retrospectively.
· Relatively easy and quick to · Does not permit cause/effect
perform. inferences.
· Especially suited for · Individuals who
studying subclinical health demonstrate an effect or
effects for which records do have a disease (prevalent
not exist, and for studying cases) may not be
representative of all
individuals who have same
effect/disease.
· Temporal relationship
between exposure and effect
may be difficult to ascertain.
effects that can be
quantitated (e.g.,
pulmonary function) and
that can vary over time.
· Also useful for studying
relatively frequent diseases
that have long duration.
· Generates useful etiologic
hypotheses for analytical
research.
· Excellent method for
studying effects of rare
exposures.
· Permits observation of
multiple effects.
· Quality control in data
collection is more
manageable.
· Yields incidence rates as
well as relative risk.
· Permits observation of
entire exposure to disease
state continuum.
· Excellent method for
studying rare diseases with
long latency periods.
· Relatively quick and
Inexpensive.
· Requires small number of
subjects.
· Existing records may be
available for use.
· Permits investigation of
multiple causal factors.
· Requires long follow-up
period.
· Very costly.
· Requires large number of
subjects.
· Problems with attrition and
loss to follow-up.
· Changes in exposure,
lifestyle factors during
course of study may make
findings irrelevant or
difficult to interpret.
· Exposure data may not
exist, may be inadequate, or
may be available only
through recall.
· Validation of exposure data
may be difficult or
impossible.
· Selection of proper control
group may be difficult.
· Control of extraneous
variables may be
incomplete.
· Incidence rates cannot be
ascertained.
higher in all family segments in the high-
NO2 areas compared to the two control
areas, especially during the interinfluenza
periods. The differences in illness rates be-
tween the high-particulate area versus the
two control areas were smaller and less
consistent. There was no consistent differ-
ence in the severity of illnesses among the
OCR for page 393
Eddy A. Bresnitz and Kathleen M. Rest
different areas, nor was there a dose/re-
sponse effect on the rates of illnesses ob-
served in the subjects whose children at-
tended the three schools in the high-NO2
area.
In addition to the study design weak-
nesses discussed earlier, the major problem
in this part of the study was the failure to
relate symptoms with incidence of true
infection. Self-reporting of disease was ac-
cepted as evidence of respiratory illness.
Although the investigators assessed the se-
verity of the illnesses through follow-up
telephone interviews, there was no sero-
epidemiologic evidence of infection. More-
over, the investigators were unable to dis-
criminate between the effects of short-term
peak levels and long-term averages in pol-
lutant exposures, nor did they adjust for
differences in indoor exposure to NO2.
Also, the absolute differences in rates were
small despite being statistically significant.
The authors concluded that exposure to
higher levels of ambient NOR and to par-
ticulates (to a lesser degree) increased the
incidence of acute respiratory illnesses. It is
not possible to conclude that infections
was the cause of these illnesses in this
secular trend analysis.
Cohen et al. (1972) studied 441 non-
smoking, middle-aged Seventh Day Ad-
ventists living in either a high- or a low-
oxidant pollution area in- California. Air
pollutant concentrations were measured at
four sampling stations in each area; only
total oxidants were measured. The mean
percent daily maximum hourly concentra-
tion of oxidants in the two areas varied, but
the annual mean value of oxidants was
identical in both areas. Of the study sub-
jects, 76 percent completed spirometry and
maximum expiratory flow-volume curves
and 97 percent completed a Medical Re-
search Council questionnaire assessing
symptoms. There were no differences in
age, socioeconomic status, occupation, eth-
nic background, and length of residence in
the two different areas. Maximum hourly
averages of exposure to pollutants other
than oxidants between the two groups
were also the same. There was no signifi-
cant difference from expected values in
either respiratory symptoms or pulmonary
393
function adjusted for age, gender, and
height in either group.
This cross-sectional study did well in
adjusting for some variables that may con-
found or bias any apparent association be-
tween the level of ambient oxidants and the
health outcome of interest. Unfortunately,
the differences in the pulmonary function
measurements were small and the likeli-
hood of detecting statistically significant
differences in outcomes was correspond-
ingly diminished. Moreover, the overall
prevalence of chronic bronchitis was less
than two percent. Limiting the study to
nonsmokers, however, strengthened the
conclusions about lack of an effect on pre-
viously healthy individuals. It did not ad-
dress the question of a possible increased
risk of morbidity secondary to low-level,
long-term exposures among individuals
with or without preexisting respiratory dis
ease.
Other, more recent cross-sectional stud-
ies have investigated the effects of short-
term, low levels of O3 exposure on differ-
ences in pulmonary function in children
(Lippmann et al. 1983) and exercising
adults (Selwyn et al. 1985~. These studies
found a significant correlation between one
or more measures of pulmonary function
derived from spirometry and some mea-
sure of maximum O3 concentration.
There was a significant negative correla-
tion between a single day's peak 1-fur O3
concentration and the peak expiratory flow
rate in 39 healthy children between the ages
of 7 and 13 (Lippmann et al. 1983~. The O3
level was less than 0.1 parts per million
(ppm) on most days (28 of 32) of the study.
The magnitude of the relationship, how-
ever, may have been underestimated be-
cause of a selection bias; that is, children
who had positive histories of respiratory
illness and did not participate in spirometric
tests on four or more days were not in-
cluded in the analysis.
A study of spirometry performed in 24
healthy adult runners before and after a
3-mile run correlated changes in airflow
during 28 separate runs with backside mea-
surements of a time-weighted average of
maximum O3 concentrations over 15-min
periods (Selwyn et al. 1985~. Increasing O3
OCR for page 394
394
Epidemiologic Studies of Oxidant Exposure
concentrations were statistically signifi-
cantly correlated with greater pre/post run
differences in the volume of air expired
during the first second (FEY, ~ and the
forced midexpiratory flow (FEF2~75%)
Although these findings suggest a direct
relationship between increasing biological
dose and pulmonary function, this associa-
tion did not remain statistically significant
after adjustment for relative humidity.
The University of California at Los
Angeles (UCLA) population study (Deters
et al. 1979, 1981, 1982; Rokaw et al. 1980)
is a longitudinal investigation of COPD
that examines the relationship between
long-term exposure to photochemical oxi-
dants and the prevalence of pulmonary
function decrements and respiratory symp-
toms. The initial survey in this (or any)
longitudinal study can be analyzed as a
cross-sectional study.
One phase of the study (Deters et al.
1981) compared 3,192 white adult residents
of Lancaster, California, a low-pollution
area, to 2,369 residents of Glendora, Cali-
fornia, a high-oxidant area. The age, gen-
der, race, and income distributions were
similar in the two cities. Daily maximum
hourly concentrations of specific air pollu-
tants were measured at stationary air mon-
itoring stations. The air monitoring station
used to estimate exposure in Glendora was
three times further from the center of the
community than the one used in Lancaster.
Pulmonary function tests included spi-
rometry and the single-breath nitrogen
test. The National Heart, Lung, and Blood
Institute respiratory questionnaire was used
to assess the prevalence of symptoms. Test-
ing in the two areas was separated by a
three-year interval.
The results were reported by smoking
status and were age-adjusted to the 1970
U.S. population census. The prevalence of
cough, sputum production, and wheezing
was higher in the high-pollution area com-
pared to the low-pollution area among
never smokers and smokers alike, although
the differences were smaller among smok-
ers. Although many of the differences were
statistically significant, the absolute differ-
ences were small.
The mean percents predicted for the
forced vital capacity (FVC), the FEY,, and
the FEF25_7s% were minimally lower in
Glendora men, but there were no di~er-
ences between women in the two areas.
Differences in mean values were greater
between smoking strata in both areas. The
prevalence of study subjects whose FIVE
and FVC were less than 50 percent pre-
dicted was higher in Glendora residents, in
male and female smokers and nonsmokers.
Tests primarily associated with small air-
way function showed little or no differ-
ences between the study subjects in two
areas.
This study has several limitations. First,
the measurement of exposure most likely
underestimated the true exposure in the
high-oxidant area because of the distance of
the monitoring site from the community.
Second, pulmonary function testing and
. . . . . .
questionnaire admlnlstratlon were not per-
formed concurrently in the two areas be-
cause of financial constraints. Changes in
smoking habits could have affected per-
formance of pulmonary function tests and
thus the study's findings. However, the
investigators stratified and compared the
study populations on smoking habit.
Third, questionnaire responses were not
tested for reliability or validity. Fourth,
there was no adjustment for potential con-
founders such as occupation and indoor air
pollutants, or for effect modifiers such as
daily activity. Finally, all levels of pollut-
ants were elevated in the Glendora area.
Therefore, it is not possible to specify the
pollutants) that best explains the differ-
ences between the two groups, even if
those differences could be attributed solely
to air pollutants and not to unanalyzed
confounders. The authors' conclusion that
long-term exposure to high concentrations
of photochemical oxidants, NO2, and SO4
results in respiratory impairment is tem-
pered by these limitations.
Confounders and Elect Modifiers. The
previous discussion refers to several poten-
tial study confounders such as parental
smoking and levels of other pollutants. A
confounder is an extraneous variable that is
a risk factor for the disease or symptoms
being studied and is associated with the
exposure of interest, but is not a conse
OCR for page 395
Eddy A. Bresnitz and Kathleen M. Rest
395
quence of that exposure. The effect of a
confounding variable may be to mask the
underlying association or to explain par-
tially (or wholly) the apparent effects of the
exposure of interest. For example, the
prevalence of smokers in a given geo-
graphic area may vary with the degree of
air pollution in that area (for example,
more blue-collar workers in an industrial
area). In this case, smoking is a confounder;
it is a risk factor- for COPD, and it is
associated with the levels of air pollution.
There are two general classes of potential
confounders that must be considered in air
pollution research: environmental con-
founders such as other air pollutants, occu-
pational exposures, smoking, and meteoro-
logical variables; and personal confounders
such as allergies and respiratory infections.
The validity of any study is affected by the
appropriate control of confounders, either
in the design phase or the analysis phase of
the study.
The investigators in the Chattanooga
studies did not consider the effect of paren-
tal smoking and indoor sources of NO2 on
pulmonary function. This was a serious
. . . . .
Omission In view ot recent epic ence sug
. .
gest1ng an association between exposure to
sidestream smoke as well as to NO2 from
gas cooking and respiratory symptoms or
impaired pulmonary function (Keller et al.
1979a,b; Tager et al. 1979; Speizer et al.
1980; Comstock et al. 1981; Ware et al.
1984).
An effect modifier is a variable that does
not, by itself, cause the effect under study
but modifies the effect of the risk factor~s)
under study. Use of medications, socioeco-
nomic status, and activity levels may affect
either the extent of exposure or the expres-
sion of dysfunction. Failure to account for
these variables may lead to underestimation
of exposure or disease or both.
Although confounders, effect modifiers,
and other potential sources of bias must be
considered in all epidemiologic studies,
specific variables are not uniformly impor-
tant across all studies. For example, smok-
ing and socioeconomic status may be im-
portant confounders or effect modifiers in
prospective or retrospective cohort studies
of the relationship between oxidant expo
sure and COPD, but they may be essen-
tially immaterial in cross-sectional studies
that correlate oxidant air pollution data
with hospital admissions (Bates and Sizto
1983~.
Sensitive Populations. The impact of am-
bient oxidant exposure on respiratory mor-
bidity in sensitive populations is potentially
greater than the impact on healthy popula-
tions. High-risk groups include people with
one or more of the following: (1) specific
diseases such as asthma, COPD, bron-
chitis, allergies, and sensitive airways; (2)
specific exposures such as cigarette smoke
and toxic fumes; and (3) biological factors
such as age and.~-1-proteinase inhibitor de-
flclency.
Several cross-sectional studies of asth-
matics have evaluated the association of
oxidant exposure and the frequency and
severity of asthma attacks. Table 2 summa-
rizes those studies. Many of these studies
suffer from the same methodological prob-
lems encountered in some of the previously
cited studies on healthy populations. The
studies are especially difficult to compare in
view of the variability or lack of definition
for an attack of bronchospasm. (See also
Bromberg, this volume. ~ However, the
study by Holguin et al. (1985) deserves
special comment in view of its overall
excellence.
Holguin and coworkers studied 42 med-
ically stable, nonsmoking, well-defined
asthmatics without other pulmonary dis-
eases in Houston during periods of high
photochemical oxidant levels in 1981. Sub-
jects maintained 12-hr logs, twice daily
recording symptoms, location, activity,
and use of medications. The maximum
value of self-administered peak flow deter-
minations was recorded for each 12-hr
shift. Quality control was maintained by pre-
study instruction of the participants and
weekly review of the daily diaries and cali-
bration of the peak-flow meters by trained
technicians.
Exposures for 03, NO2, pollen, temper-
ature, and relative humidity were deter-
mined by air monitoring stations located
less than 2.5 miles from all study subjects.
An hourly exposure estimate was calcu
OCR for page 396
396
Epidemiologic Studies of Oxidant Exposure
Table 2. Studies of Aggravation of Existing Asthma by Photochemical Oxidant Pollution
Av. Max.
Conc. Range
(ppm)
Pollutant
Study Description
Results and Comments Reference
0.13a Oxidants
0.01-0.37 O3
Not reported O3
0.0000.235 O3
( Table continued next page.)
Daily records of times of
onset and severity of asthma
attacks of 137 asthmatics
residing and working in
Pasadena, California,
between September 3 and
December 9, 1956; daily
maximum hourly average
oxidant levels (KI) from
LA-APCD.
Daily diaries for symptoms
and medication of 45
asthmatics (aged 7-72 yr)
residing in Los Angeles
from July 1974 to June
1975; daily average
concentration of 03, NO,
NO2, SO2, and CO by LA-
APCD within the subjects'
residential zone.
Daily log for symptoms,
medication, and hospital
visitation of 80 children
with asthma (aged 8-15 yr)
in the Chicago area during
197~75; air quality data on
SO2, CO, PM; partial data
for 03, pollen, and climate.
Daily symptom rates in 82
asthmatic and allergic
patients compared to 192
healthy telephone company
employees in New Haven,
Connecticut, from July to
September 1976; average
maximum hourly levels of
O3 and average daily values
for SO2, TSP, SO42-,
pollen, and weather were
monitored within 0.8 km of
where the subjects were
recruited.
Of the 3,435 attacks reported, Schoettlin
<5% were associated with and
smog, and most of these Landau
occurred in the same (1961)
individuals; time-lagged
correlations were lower
than concurrent
correlations; mean number
of patients having attacks on
days when oxidant levels
were >0.25 ppm was
significantly higher than
days when levels were
<0.25 ppm.
No significant relationship Kurata et al.
between pollutants and (1976)
asthma symptoms; increased
number of attacks at >0.28
ppm in a very small number
of subjects; other factors
such as animal dander and
other pollutants may be
important.
Bad weather and high levels
of SO2, CO, and PM
exerted a minor influence
on asthma, accounting for
only 5-15% of the total
variance; high levels of O3
increased both the
frequency and the severity
of asthmatic attacks; pollen
density during fall and
winter temperature
variations had no influence;
no exposure data given for
quantitative treatment.
Maximum oxidants were
associated with increased
daily prevalence rates for
cough, and eye and nose
. . . .
1rr1tat1on 1n leavy smo hers
and patients with
predisposing illnesses; pH of
particulate was also
associated with eye, nose,
and throat irritation,
whereas suspended sulfates
were not associated with
any symptoms.
Questionable exposure
Khan (1977)
Zagraniski et
al. (1979)
OCR for page 397
Eddy A. Bresnitz and Kathleen M. Rest
397
Table 2. Continued
Av. Max.
Conc. Range
(ppm)
0.03-0. 15 Oxidants
0.07-0.39 ~O3
Pollutant Study Description
Statistical analysis (repeated-
measures design) of CHESS
data on daily attack rates for
juvenile and adult
asthmatics residing in six
Los Angeles area
communities for 3=week
periods (May-December)
during 1972-75; daily
maximum hourly averages
for oxidants (KI) were
monitored by LA-APCDs,
24-hr averages for TSP,
RSP, SOx, NOX, SO2, and
NO2 were monitored by the
EPA, and meteorological
conditions were monitored
within 1 to 8 miles of
homes in each community.
Emergency room visits and
hospital admissions for
children with asthma
symptoms during periods of
high and low air pollution
in Los Angeles from August
1979 to January 1980; daily
maximum hourly
concentrations of 03, S02,
NO, NO2, HCs, and
COH; weekly maximum
hourly concentrations of
SO42- and TSP; biweekly
allergens and daily
meterological variables from
regional monitoring
stations.
Results and Comments Reference
assessment, use of
prevalence rather than
incidence data, and lack of
correction for dropout rates
limit the usefulness of this
study for developing
quantitative exposure/
response relationships.
Daily asthma attack rates
increased on days with high
oxidant and particulate
levels and on cool days;
presence of attack on the
preceding day, day of week,
and day of study were
highly significant predictors
of an attack. Questionable
exposure assessment
including lack of control for
medication use, pollen
counts, respiratory
infections, and other
pollutants and possible
reporting biases limit the
usefulness of this study for
developing quantitative
exposure/response
relationships.
Asthma positively correlated
with COH, HCs, NO2, and
allergens on same day and
negatively correlated with
O3 and SO2; asthma
positively correlated with
NO2 on days 2 and 3 after
exposure; correlations were
stronger on day 2 for most
variables; nonsignificant
correlations for SO42- and
TSP. No indication of
increased symptoms or
medication use during high-
pollution period; however,
peak flow decreased (no
differentiation of
pollutants). Factor analysis
suggested possible
synergism between NO,
NO2, RH, and wind speed;
03, S02, and temperature;
and allergens and wind
speed. Presence of
( Table continued next page.)
Whittemore
and Korn
(1980)
Richards et
al. (1981)
OCR for page 398
398
Epidemiologic Studies of Oxidant Exposure
Table 2. Continued
Av. Max.
Conc. Range
(ppm)
Pollutant Study Description
Results and Comments Reference
0.03-0.12 O3
0.02 - 0.16 O3
Admissions to 79 acute-care
hospitals in southern
Ontario for the months of
January, February, July, and
August in 1974, 1976-78.
Hourly average
concentrations of particulate
COH, 03, SO2, NO2, and
daily temperature from 15
air sampling stations within
the region.
Fifty-one asthmatics (aged 7-
55 yr) exposed to ambient
air from May to October
1981 in Houston, Texas;
attack status determined
each 12-hr period using log
forms; individual
environmental exposure
estimates for the 12-hr
period (1-hr max used for
health data analysis) from
regression model describing
relationship of fixed-site
monitors (within 2.5 miles)
. .
to microenvironment;
multiple logistic regression
model of Whittemore and
Korn (1980) used for 42
subjects along with data on
03, NO2, temperature,
humidity, pollen, and attack
status.
confounding variables, lack
of definitive diagnoses for
asthma, and questionable
exposure assessment limit
the quantitative
interpretation of this study.
Excess respiratory admissions
associated with S02, 03,
and temperature during July
and August with 2t and
48-hr lag; only temperature
was associated with excess
respiratory admissions and
total hospital admissions for
January and February. Lack
of sufficient exposure
analysis limits the
quantitative use of this
study.
Increased probability of
asthma attack associated
with increased O3 and
decreased temperature (and
previous asthma attack);
definition of asthma was
specific for each individual;
good control of
confounders except for
pollen levels. Quality
control of questionnaires
was excellent; peak flow
changes were measured but
not reported; personal
. .
monitors consistent .y
indicated underestimates of
exposures determined by
fixed-site monitors.
Bates and
Sizto
(1983)
Holguin et
al. (1985)
a Represents average maximum hourly concentrations during low (minimum) and high (maximum) pollution
periods.
NOTE: CHESS = Community Health Environmental Surveillance System; COH = coefficients of haze; HC =
hydrocarbon; KI = potassium iodine method; LA-APCD = Los Angeles Air Pollution Control District; PM =
particulate matter; RH = relative humidity; RSP = respirable suspended Articulates; TSP = total suspended
Articulates.
SOURCE: Adapted from U.S. Environmental Protection Agency 1986.
OCR for page 399
Eddy A. Bresnitz and Kathleen M. Rest
399
lated for each subject for each hour of every
12-hr period, and the 12-hr exposure esti-
mate was defined as the maximum hourly
estimate during the period. Time spent
indoors was not included in the estimate.
O3 and NO2 were the only exposure vari-
ables that covaried significantly during the
daytime.
The study developed individual attack
definitions after all health and activity data
had been collected but before the analysis of
air monitoring data began. Attack defini-
tions included self-reported symptoms, a
decrease in expiratory peak flow, and an
increase in the use of asthma-specific med-
ication (Holguin et al. 1983~. A logistic
regression model (Whittemore and Korn
1980) was used to estimate the effect of the
measured variables on the risk of an attack.
The probability of an attack was signifi-
cantly associated with an attack on the
previous day, increasing O3 levels, and
decreasing temperature. NO2, pollen
count, and relative humidity had little effect
on the risk of an attack. The average am-
bient O3 level in the 12-hr periods during
which the study subjects experienced at-
tacks was less than 0.05 ppm in all in-
stances.
The strength of this study lies in its
excellent assessment of individual exposure
and its effects, its careful definition of an
asthmatic attack unique for each individual,
and the quality of its statistical analysis.
Nevertheless, that study and the other
cross-sectional studies discussed here only
suggest associations between increased levels
of ambient oxidants and decrements in
pulmonary function, higher prevalence of
respiratory symptoms, and more frequent
asthma attacks. They cannot and do not
indicate whether these effects are tempo-
rary, have any long-term clinical signifi-
cance, or lead to increased morbidity with
time. Longitudinal cohort studies are best
suited to assess these issues.
Prospective Cohort Studies
The prospective cohort method identifies
study subjects on the basis of individual
exposure and then follows them forward in
time to assess disease development in ex
posed and unexposed groups. The ability
to identify exposure prior to disease devel-
opment makes this design theoretically
more powerful than cross-sectional studies
in assessing causality in disease/exposure
relationships. The magnitude of the risk
factor is measured by obtaining the ratio of
the disease incidence rates in the exposed
and unexposed groups (the relative risk).
The cohort design is particularly good for
studying many outcome measures simulta-
neously. Prospective cohort studies allow
for better quality and control of data col-
lection.
The disadvantages of the cohort design
include potentially long follow-up periods
with the attendant problems of loss to
follow-up and migration out of the geo-
graphic area; expense of maintaining fol-
low-up; changing levels of exposure; and
the low incidence of certain diseases, such
as COPD, necessitating large groups of
study subjects.
The Six-Cities study (Ferris et al. 1979) is
an ongoing cohort study of the respiratory
health elects of air pollution on children
and adults. The cities in the study were
selected on the basis of their historical levels
of air pollution. They represent a range of
ambient SO2 and particulate exposure lev-
els above and below the current ambient air
quality standard. The main goal of the
study is to assess the health effects of long-
term exposure to these pollutants. The
investigators are collecting data on SO2,
N02, 03, TSP, and mass respirable parti-
cles by use of personal monitors (where
possible) as well as central site monitors.
The published reports to date have fo-
cused on the health effects of ambient SO2
and TSP. The Six-Cities study has sup-
ported earlier findings by Spengler and
coworkers (1979) that indoor sources of
NO2 contribute more to total NO2 expo-
sure than outdoor, ambient levels. Ferris
and coworkers have not yet published their
analyses of the respiratory health effects of
ambient oxidants. However, the study may
provide important information on the ef-
fects of oxidants on the rate of decline in
pulmonary function and on the prevalence
of symptoms in smokers and nonsmokers
if the cities vary in their level of oxidants.
OCR for page 404
404
Epidemiologic Studies of Oxidant Exposure
rect measure of community morbidity has
several limitations. Statistics such as num-
ber of visits to the emergency room, num-
ber of admissions, and length of stay can be
affected by illness behavior, the demo-
graphic characteristics of the population in
the catchment area, the availability of beds,
and changes in the definitions of disease or
coding practices (Bennett 1981~. Most of
these problems also apply to data based on
outpatient visits to physicians' offices. As a
result, comparison of illness rates based on
encounters with the health care system can
be problematic. The lack of a gold standard
for diagnosing many respiratory illnesses
makes the interpretation of studies that
utilize these measures all the more difficult.
Nevertheless, several investigators have
utilized hospital data to assess the effects of
air pollutants on respiratory morbidity
(Sterling et al. 1966, 1967; Bates and Sizto
1983~. Bates (1985) has argued that despite
limitations on hospital data, systematic di-
agnostic bias would be unlikely in studies
that involved large populations over long
periods of time and many different institu-
tions and physicians. With such caveats,
hospital data may be used efficiently and
appropriately, especially in cross-sectional
studies.
Specific Issues ant! Stucly
Approaches
A number of questions remain unanswered
in oxidant air pollution research. Still lack-
ing is quantitative information on the
threshold levels of effects, dose/response
relationships, effects on sensitive groups,
and the quantification of disease burden on
public health. In particular, the effect of
long-term oxidant exposure on human
health remains a significant and unan-
swered question. Does such exposure in-
crease the risk of or exacerbate existing
COPD, bronchial hyperresponsiveness (for
example, asthma), or pulmonary infection?
Several approaches may be useful in exam-
ining these questions. Each approach will
have its strengths and weaknesses; no one
study by itself will produce conclusive ev
idence of causality. Nevertheless, the con-
sistency of findings from studies done in
different populations, during different peri-
ods of time, and using different study de-
signs would allow valid causal inference.
Chronic Obstructive Pulmonary
Disease
Cohort Methods. The two ongoing co-
hort studies (Six-Cities and UCLA) are
collecting morbidity data based on pulmo-
nary symptoms and pulmonary function
test results. These and any future cohort
studies should look carefully at nonsmok-
ing young adults who are long-term resi-
dents (more than 1~20 years) of the spec-
ified geographic areas to assess the
relationship between accelerated decline in
lung function and exposure to oxidants.
Exposure should be assessed periodically
by using personal monitors and time-ac-
tivity logs in at least a sample of the study
population. Information on confounders
and effect modifiers should be elicited pe-
riodically; any differences in the prevalence
of these variables between the exposure
groups must be adjusted in the analysis.
Information from questionnaires will re-
quire reliability and validity testing. To
assess the future clinical significance in any
statistically increased rates of decline in
high-exposure groups, prolonged follow-
up of these cohorts will be necessary.
Retrospective Methods. A case-control study
comparing individuals with a specific res-
piratory illness (for example, chronic bron-
chitis) to healthy controls for estimated
measures of exposure collected retrospec-
tively might yield dose/response and thresh-
old response information on the effects of
oxidants on the disease under study.
One of the data bases mentioned earlier
could be useful in assessing the role of
oxidants (or other air pollutants) in the
etiology of COPD, using a case-control
study of nonsmokers with COPD. For
example, most states now have large data
bases consisting of all patients enrolled in
Medicaid. Individual information such as
age, gender, race, county, diagnoses, drugs
dispensed, procedures, and place of visit are
OCR for page 405
Eddy A. Bresnitz and Kathleen M. Rest
405
recorded in these data bases. Use of these
data would allow comparisons of patients
who have a recorded diagnosis of COPD,
chronic bronchitis, or emphysema to con-
trols without these diagnoses for county of
residence.
Air pollution monitoring data in each
county should provide a qualitative esti-
mate of exposure. Personal contact with
the medical providers for selected cases and
controls would be necessary to estimate the
prevalence of smoking in each group and
the length of residence in each area. If the
COPD group lived in higher air pollution
areas than the control group, the study
would suggest air pollution as a risk factor
for the development of COPD. Arkansas
and Ohio are two states worthy of study,
given the high mortality rates for chronic
bronchitis in certain portions of each state
(National Research Council 1985~.
Recommendadon 9. Investigators should
do case-control studies using existing health
service data bases to assess the relationship
between specific diseases and long-term
residence in high-pollution areas.
Cross-Sectional Methods. Cross-sectional
studies and secular trend analyses using the
Medicaid data bases could also assess the
prevalence of chronic respiratory disease and,
perhaps, the frequency of various acute res-
piratory diseases in counties with different
average levels of air pollutants. A rough
estimate of a dose/response relationship may
be evident in this type of analysis, which
would also give information on other effects
of air pollution exposure. The diagnoses re-
corded by the physician in the office or
hospital would be used as the outcome vari-
able of interest.
Cross-sectional studies can also be used
to study the effects of point-source emis-
sions on respiratory health. New roads and
traffic patterns as well as industrialization of
previously rural areas may produce new
_
areas of high air pollution. If possible,
pulmonary function measurements and
morbidity surveys should be performed
before and after the development of a new
point source of oxidant pollutants. Changes
in the mean levels and predicted rates of
decline in pulmonary function or in the prev-
alence of morbidity outcomes would impli-
cate the point source as a causal factor.
A new point source may develop in
Spring Hills, Tennessee, where the con-
struction of a model automobile manufac-
turing plant is planned. General Motors
expects to employ approximately 6, 000
workers at the new plant. Construction and
operation of the plant is expected to in-
crease and change traffic patterns in the
community. The study outlined in the pre-
ceding paragraph could identify changes in
pulmonary function or morbidity out-
comes in relation to specific areas of high
traffic volume or congestion.
To strengthen the study, a nearby com-
munity that is unaffected by changing traf-
fic patterns can serve as an unexposed con-
trol group. The two areas can then be
compared on various measures of respira-
tory morbidity in the community (hospi
. . . . ~
ta Batons, VlSltS to emergency rooms, anc
so on) and personal morbidity (symptoms,
pulmonary function).
Such a study would be quasi experimen-
tal in that both communities would have a
similar initial exposure to air pollutants,
but a different level of exposure after the
construction of the plant.
Recommendation 10. New point-
source emissions should be identified and
their effects on air pollution and respiratory
morbidity should be studied longitudi-
nally.
Asthma/Bronchial Hyperresponders
Future epidemiologic studies of air pollu-
tion should include those groups at high
risk for developing adverse effects. Study-
ing high-risk groups will enhance our abil-
ity to detect increases in the risk of exacer-
bating preexisting diseases in populations
exposed to low ambient levels of pollutants.
Cohort Methods. The cohort design
would be appropriate for assessing the ef-
fects of oxidant exposure on the morbidity
of sensitive and normal individuals as de-
termined by methacholine challenge. The
National Heart, Lung, and Blood Institute
OCR for page 406
406
Epidemiologic Studies of Oxidant Exposure
recently funded a large multicenter ran-
domized clinical trial in smokers to assess
whether smoking cessation will effectively
modify the course of COPD at a stage
when mild dysfunction has already oc-
curred (Gunby 1984~. A subsample of
smokers with hyperreactive airways will
also be followed over a period of five years.
This study is being organized in eight cities
across the United States and may be a good
source of hyperreactive patients who are
exposed to different ambient levels of air
pollutants.
Retrospective Methods. Alternatively, a
case-control design can be used to compare
the past oxidant exposure of bronchial hy-
perresponders and nonresponders. Assum-
ing development of a valid questionnaire
for past exposures, higher exposure levels
in sensitive individuals would suggest that
. . . . . .
OX1C .ants elt per increase sensitivity or exac-
erbate the sensitive state. If oxidants have
one or both of these effects, exposure to
oxidants may contribute to the increased
prevalence of chronic bronchitis in hy-
perresponders and to the accelerated de-
cline in lung function in asthmatics noted
above.
Cross-Sectional Methods. The study de-
sign used by Holguin and coworkers (1985)
to study asthmatics should be applied to
other sensitive groups, such as people with
COPD, who may be at increased risk for
the exacerbation of symptoms. The design
could be strengthened by including healthy
people in the study group and by using
personal monitors to better assess actual
exposures to NO2. Studies should focus on
smokers as well as nonsmokers with sensi-
tive airways as determined by metha-
choline challenge testing.
Recommendation 11. A variety of de-
sign methods should be used to study non-
smoking and smoking individuals with
bronchial hyperresponsiveness to assess
whether long-term residence in high-oxi-
dant environments causes accelerated rates
of decline in pulmonary function, more
frequent encounters with the health care
system, and increased severity of pulmo-
nary symptoms.
Healthy Cohort Effect. Investigators must
be cautious in comparing morbidity rates in
groups of high-risk individuals living in dif-
ferent air pollution environments. Standard-
ized morbidity rates may be equal in popu-
lations with extremes in their exposure to
oxidants, yet the high-oxidant environment
may still be a risk factor for exacerbation of
disease that is not evident because of a selec-
tion bias. This bias is analogous to the
"healthy worker effect" seen in occupational
epidemiologic studies where disease rates in
occupational cohorts appear artificially low
because of the "healthiness" of working pop-
ulations (Monson 1980; Sterling and
Weinkam 1986~. This may be termed the
"healthy cohort" effect in epidemiologic air
pollution studies.
For example, asthmatics who are highly
susceptible to oxidants and other pollutants
may migrate out of a high-air-pollution
environment, leaving behind those asth-
matics the "healthy cohort" who may
tolerate high exposures. Comparison of the
remaining asthmatics (or a representative
sample) with a panel of asthmatics in a
low-exposure environment may show sim-
ilar asthma attack rates that suggest no
increased risk in high-pollution areas.
Clearly, the selection of relatively healthy
asthmatics is a form of selection bias that
may obscure the risk of exposure to envi-
ronmental pollutants.
The magnitude of the healthy cohort
effect is substantial and affects all age
groups. For example, an analysis of data
from the Household Interview Survey of
the National Center for Health Statistics
showed that employed individuals had
lower standardized morbidity rates of
chronic respiratory ailments compared to
unemployed people (Sterling and Weinkam
1985~. Unemployed males were four times
as likely to have chronic respiratory ail-
ments as employed males. Although the
magnitude of the healthy person effect is
unlikely to be so large in morbidity studies
on air pollutants, the size of the effect
should be estimated in all air pollution
OCR for page 407
Eddy A. Bresnitz and Kathleen M. Rest
\
407
studies. This may be done by asking the
study subjects whether they have ever
moved for health reasons.
· Recommendation 12. All epidemio-
logic studies should analyze the outcome
measure of interest by stratifying groups on
their length of residence in the study areas.
Respiratory Infection
Pennington (this volume) indicated that
there is little experimental evidence of a
relationship between automotive emissions
and the risk of respiratory infections. To
date, there have been no epidemiologic
studies assessing the incidence or severity
of infection in populations exposed to high
oxidant levels. Several studies have looked
at the prevalence of symptoms that may
Indicate either Injection or a direct Irritant
effect of oxidants (Shy et al. 1970a,b; Pearl-
man et al. 1971; Speizer et al. 1980; Com-
stock et al. 1981~. Investigators have not
used either sputum cultures or serology to
assess the presence of true infection.
A recent review examined the relation-
ship between respiratory illness in child-
hood and chronic airflow obstruction in
adulthood (Samet et al. 1983~. The authors
decided that results from different studies
on this question conflicted and that the data
to date were inconclusive. However, the
studies cited in the review support the
conclusion that a history compatible with
lower respiratory infection is associated
with impaired pulmonary function in chil-
dren. This association may be causal or
noncausal and may be mediated by a host
factor such as atopy (allergy that is proba-
bly hereditary) or an environmental factor
such as parental smoking or oxidant expo
sure.
Epidemiologic investigation of the rela-
tionship between the risk of respiratory
infection and exposure to oxidants would
be difficult to conduct. Selection of the
organisms to study would be the first of
several difficult decisions. Even limiting the
study to viral organisms would not neces-
sarily narrow the spectrum of tests needed
to assess true infection. Antibody levels for
Table 3. Sample Size Requirements for a
Cohort Study in a Low-Oxidant Area
Relative Frequency Total
Risk of Disease Sample Size
2
0.5
0.4
0.2
0.1
0.05
0.5
0.4
0.2
0.1
0.05
0.2
0.1
0.05
0.01
104
176
534
1,254
2,690
18
40
148
362
794
40
112
254
1,404
NOTE: c' = 0.05 (1-tail), ,l3 = 0.20.
several viral antigens would be needed to
ensure complete assessment for the most
likely pathogens.
Cohort Methods. After deciding on the
organisms) to evaluate, investigators could
study cohorts of high-risk populations (for
example, chronic bronchitics) residing in
high- versus low-level oxidant areas. Serial
measurements of antibody titers could be
compared to assess whether the high-oxi-
dant group had higher conversion rates
(fourfold rise) than the low-oxidant group.
Such a study would presuppose that the
right organists) has been identified a pri-
ori, that the populations have had the same
likelihood of exposure to these organisms,
that they are susceptible to infection with
these organisms, and that the prevalence of
exposure is high enough to ensure a suffi-
cient incidence of clinical disease with a
fourfold rise in antibody titers in both
groups. Culture of organisms would not
necessarily increase the ability to detect
differences in infection rate between the
two groups (Tager and Speizer 1975~.
It is easy to calculate the sample size of
previously uninfected subjects required to
detect a significant clinical difference be-
tween the high- and low-oxidant groups.
Table 3 shows how the required sample
OCR for page 408
408
Epidemiologic Studies of Oxidant Exposure
size varies depending on the frequency of
infection in the low-oxidant group and the
relative risk that the investigator would like
to detect with a reasonable degree of cer-
tainty (,8 = 0. 20) (see also Schlesselman
1974).
For example, 267 subjects would be re-
quired in each area (534 total) to detect a 50
percent Increase In Injection rate In the
high-oxidant group, assuming that 20 per-
cent of the low-oxidant group developed
disease on exposure to the organism of
interest. Note that the sample size require-
ments are minimum estimates and do not
account for loss to follow-up, failure to
develop clinical disease on exposure to or-
ganism, and the likelihood of being ex-
posed to the organism. All these factors
would increase the sample size needed to
do the study. However, if infection with
any one of several identified organisms was
the outcome measure of interest, the sam-
ple size required to detect a difference
in the incidence of infection between the
high- and low-oxidant group would de-
crease.
Retrospective Methods. A case-control
study of the relationship between respira-
tory infection and oxidant exposure would
also be difficult to do. However, if one
could specify the organisms of interest in
advance and, on a prospective basis, iden-
tify cases as they are presented to the hos-
pital (or to a physician), one could then
compare them to controls selected on the
basis of diagnoses not conceivably related
to oxidant exposure. Clearly, the investi-
gator would require a reliable and valid
Instrument tor assessing past exposure to
oxidants and the presence of potential con-
founders. The Medicaid data base described
previously may be an excellent resource for
doing this type of study.
~ Recommendation 13. Seroepidemio-
logic surveys should be done in cohorts
that have different exposures to oxidants.
More than one organism should be se-
lected as a suspected respiratory pathogen
to maximize the likelihood of detecting
differences in infection rate among the co-
horts.
Attributable Risk
Air pollution research efforts have focused
primarily on acute effects in attempts to
address issues of threshold effects, dose/re-
sponse relationships, and disease incidence
and prevalence in sensitive groups. Investi-
gators have paid little attention to assessing
the potential impact of improved air quality
standards on reductions in health risks.
Since most of the diseases associated with
exposure to oxidants (and other pollutants)
have multifactorial origins, it would be use-
ful to know how reducing average pollutant
levels might proportionally reduce morbid-
ity. The attributable risk of exposure to oxi-
dants is the proportion of disease in the
population that can be theoretically pre-
vented by eliminating exposure to oxidants.
Morganstern and Bursic (1982) outlined
a mathematical method for estimating the
potential impact of a public health policy
on the health status of a target population.
Investigators applying this method to am-
bient oxidants would have to assume that
(1) the distribution of oxidant levels in the
population is known; (2) oxidants are true
determinants of the diseased) in question
(as measured by the relative risks); (3) a
reduction in ambient oxidant levels would
reduce the risk of diseases in previously
exposed persons compared to the risk of
diseases in previously unexposed persons;
(4) there are no significant secular trends in
the risk of diseases) because of changes
unrelated to the reduction in ambient oxi-
dant levels; and (5) there are no significant
changes in other risk factors that would
interact with oxidants to synergistically in-
crease the risk of diseases. Because of the
latter assumption, such models must be
applied cautiously to air pollution research.
When there are several, noninteracting
causes of adverse health effects, the simple
addition of the attributable risks associated
with each causal factor will yield the total
benefit in risk reduction that is theoretically
achievable. However, in the case of inter-
acting or synergistic pollutants, attributable
risks must be viewed more carefully. When
synergism exists, no single etiologic factor
can be said to "cause" a percentage of the
disease that is numerically equivalent to the
OCR for page 409
Eddy A. Bresnitz and Kathleen M. Rest
409
attributable risk. For example, it is true that
smoking cessation could prevent x percent
of disease in a target population, but it may
also be true that the elimination of other
occupational or environmental toxins could
prevent y percent of the disease in the same
population. The addition of x percent and y
percent can yield a number much greater
than 100 percent in the case of synergistic
, , _
risk factors (Ashford 1985; Sterling 1985~.
With these caveats, studies that assess
attributable risk of oxidant exposure would
be highly useful to policy makers and reg-
ulators, as well as of great interest to the
general public, the automotive industry,
and public health professionals. Mathemat-
ical modeling using data collected from
previous studies could provide some esti-
mate of the amount of morbidity that could
be detected in populations with different
diseases and potential exposures. In addi-
tion, mathematical modeling could help esti-
mate the expected decree of interaction be-
tween air pollutants and other risk factors.
Recommendation 14. The potential
attributable risk for disease caused by ex-
posure to oxidants and other air pollutants
should be determined and expressed in a
meaningful way.
measures of acute respiratory morbidity.
Review of selected air pollution studies
shows that higher oxidant exposures are
associated with a higher prevalence of res
piratory symptoms, more frequent asthma
attacks, greater decreases from expected
pulmonary function, and more frequent
utilization of health care services. The long
term and chronic effects of low-level expo
sure to oxidants is essentially unknown.
The major gaps in oxidant air pollution
research include information on threshold
levels of effects and dose/response relation
ships, long-term effects on sensitive
groups, and the quantification of disease
burden on public health.
Investigators must address several meth
odological issues when conducting epide
miologic research in this area. They involve
developing more specific tools for assessing
personal exposure and adverse health ef
fects; improving assessment and control of
confounders and effect modifiers; identify
ing sensitive populations for more detailed
study; and assessing potential biases in pop
ulation selection.
Several approaches for addressing these
methodological issues and for answering
important research questions have been ad
dressed in this paper. Cross-sectional, case
control, and cohort studies can be used to
examine the relationship between oxidant
exposure and increased risk for or exacer
Summary bation of existing COPD, asthma, or pul
Epidemiologic studies in air pollution re-
search are necessary to assess the effects of
long-term oxidant exposure on human
health. Most studies done to date have
utilized the cross-sectional design, which is
best suited for correlating current levels of
exposure with the prevalence of various
monary injections. leach approach has its
strengths and weaknesses and will be ap-
propriate in different situations. The con-
sistency and reproducibility of findings
from different epidemiologic studies are
necessary to allow causal inference between
oxidant exposure and adverse health ef-
fects.
Summary of Research Recommendations
Specific Research Issues
HIGH PRIORITY
Studies that will provide data on the long-term, chronic health
effects of exposure to low levels of photochemical oxidants are of
highest priority.
OCR for page 410
410
Epidemiologic Studies of Oxidant Exposure
Recommendation 1 A cohort study of the effects of long-term exposure to oxidants
on respiratory morbidity in children, normal adults, and sensitive
populations should be done if the Six-Cities study and the UCLA
population studies cannot assess these issues.
Recommendation 6 Longitudinal cohort studies should assess small airway function
in nonsmokers. If residents of high-oxidant environments have
decreases in small airway function compared to residents of low
oxidant environments, the cohorts should be followed for a
sufficient amount of time to assess the development of COPD.
Recommendation7 Small panels of individuals with sensitive airways should be
studied carefully to assess whether oxidants are risk factors for
various outcome measures of respiratory morbidity.
Recommendation 11 A variety of design methods should be used to study nonsmok
ing and smoking individuals with bronchial hyperresponsiveness to
assess whether long-term residence in high-oxidant environments
causes accelerated rates of decline in pulmonary function, more
frequent encounters with the health care system, and increased
severity of pulmonary symptoms.
MODERATE PRIORITY
Existing data bases may be an untapped resource of information
on health effects. New environments may also provide an oppor
tunity to explore exposure/effect relationships.
Recommendation 8 Extant data bases should be explored for their use in studying the
effects of air pollution on health.
Recommendation 10 New point-source emissions should be identified and their effects
on air pollution levels and respiratory morbidity should be studied
longitudinally.
LOW PRIORITY
Causal hypotheses are strengthened if a variety of study designs,
methods, and data sources are used and yield similar results.
Recommendlation2 Future epidemiologic studies of air pollution should include
the use of retrospective methods to investigate the relationship
between oxidant exposure and respiratory morbidity if accu
~ 1
rate methods of assessing past cumulative exposure can be devel-
oped.
Recommendation 9 Investigators should do case-control studies using existing health
service data bases to assess the relationship between specific diseases
and long-term residence in high-pollution areas.
Recommendation 13 Seroepidemiologic surveys should be done in cohorts that have
different exposures to oxidants. More than one organism should be
OCR for page 411
Eddy A. Bresnitz and Kathleen M. Rest
411
selected as a suspected respiratory pathogen to maximize the
likelihood of detecting differences in infection rate among the
cohorts.
Recommendation 14 The potential attributable risk for disease caused by exposure to
oxidants and other air pollutants should be determined and ex
pressed in a meaningful way.
Generic Issues
Methodological innovation will greatly enhance the ability of
epidemiologic studies to investigate dose/response relationships,
long-term effects of low-level exposure, and attributable risk. Such
methodological research deserves the highest priority.
Recommendation 3 Future epidemiologic studies should use personal monitors and a
greater number of better-placed area monitors to improve the
assessment of true exposure in at least a sample of the individuals
under study.
Recommendation 4 Valid and reliable questionnaires that help assess personal expo
sure to air pollutants should be developed and used in future
epidemiologic studies.
Recommendations Valid and reliable questionnaires or diaries that assess health
effects should be developed further to facilitate epidemiologic
studies in air pollution. Ongoing cohort studies (Six-Cities,
UCLA) could be used to develop and test such data collection
instruments.
.
Recommendation 12 All epidemiologic studies should analyze the outcome measure of
interest by stratifying groups on their length of residence in the
study areas.
Acknowledgment
The authors wish to thank the following
individuals for their careful reviews and
thoughtful comments: Nicholas Ashford,
Ph.D., I. D.; Peter Gann, M.D.; Murray
Oilman, M.D.; Tee Guidotti, M.D.; Sandy
Norman, Ph.D.; and Brian Strom, M.D.
The authors also appreciate the unflagging
clerical support of Karen Menna and
Frances Seeds.
Correspondence should be addressed to Eddy A.
Bresnitz, Division of Occupational and Environmen-
tal Health, Department of Community and Preven-
tive Medicine, The Medical College of Pennsylvania,
3300 Henry Avenue, Philadelphia, PA 19129.
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Representative terms from entire chapter:
pulmonary function
