and higher codes representing those values indicative of obstructive
disease. Scores of 45 to 55 were considered consistent with a normal
profile when all five coded values were between 9 and 11, and
consistent with an undifferentiated profile when a mathematical
balance of codes under, equal to, and over 10 resulted in a score of 45
to 55. Scores under 45 were assumed to represent restrictive profiles
and scores over 55 to represent obstructive profiles. Forty-three
percent of the population had normal lung function profiles, and 26.5
percent had undifferentiated lung profiles. The remainder was
divided relatively evenly between the restrictive and obstructive
lung profiles, with 14.9 percent having a restrictive defect and 14.3
percent having an obstructive picture. In Table 13 are revealed the
results in smokers and nonsmokers, stratified by increasing asbestos
exposure category. The data seem to suggest that neither obstructive
nor restrictive lung disease occurs in nonsmoking asbestos workers
and that restrictive and obstructive lung disease occur with equal
frequency in asbestos miners who smoke. In addition, it appears that
there is, if anything, a negative dose-response relationship between
restrictive lung disease and increasing cumulative asbestos expo-
sure. These results are particularly remarkable in the face of data
from the same group of workers presented earlier in this section,
which show a relatively clear dose-response relationship between
cumulative asbestos exposure and decline in TLC and FEV, in both
smokers and nonsmokers. The authors have interpreted this data to
suggest that an association between smoking habit and the develop-
ment of asbestos-related fibrosis may exist and that asbestos workers
who smoke may develop either obstructive or restrictive lung
disease. The inconsistencies between the data on pattern pulmonary
function tests and the measures of individual test responses de-
scribed earlier may be explained by the effects of changes in lung
volumes on some of the measurements used to code the lung function
profile. FEVY,Q and MMEFzw~~~ are measurements that, when
reduced, are used in this coding scheme to define an individual as
being obstructed. Both of these are measurements of airflow
obstruction in the presence of normal lung volumes, but may also be
reduced in the presence of diminished lung volumes secondary to
restrictive lung disease. Indeed, examination of the pattern of
pulmonary function response in nonsmoking asbestos miners (Figure
10) reveals that with increasing cumulative asbestos exposure, the
decline in TLC in these workers was accompanied by a decline in
FEVW and MMEFz~-w+. This pattern, consistent with progressive
restrictive lung disease, would define the worker by the coding
scheme as having obstruction, or would counterbalance those scores
for a restrictive category, thereby placing the worker in the
undifferentiated category. A similar effect would occur in asbestos
miners who smoke. As can be seen in Figure 10, the decline in FEV,,

251


TABLE 12.-Coding of lung function profile

code

Volumes          Flow rates
(RI'. TLC)       (FEVw MMF)

(FEV, PVC)%
percent predicted

7          <70            > 130           >116

8          70-79           121-130          111-115

9          80-89           111-120          llo-106

10          90-110           90-110           95105

11          111-120           80439           90-94

12          121-130           7iL79           ass9

13          > 130            <70           <84

SOURCE Fornw-kiasey and Becklake (19751

FEVX~, and MMEFzs-75o is greater in smoking asbestos miners than
in nonsmoking miners. This pattern, which is consistent with a
combination of restriction and obstruction in these workers, would
result in a progressive increase in the coding scheme obstructive
score, and therefore may account for the absence of a dose-response
relationship between asbestos exposure and restrictive lung disease
in the asbestos workers who smoke. With increasing severity of
restrictive lung disease, more and more workers would be catego-
rized as having an obstructive or undifferentiated pattern and thus
would drop out of the restrictive category.

A similar approach was taken by Muldoon and Turner-Warwick
(1972), who categorized the lung function results in a consecutive
series of 75 subjects with a history of exposure to asbestos who were
referred to the Pneumoconiosis Medical Panel of London. The
researchers categorized workers as having obstructive, restrictive,
mixed, or normal lung function. They reported that the workers with
obstruction did not have heavier smoking histories than the subjects
with restrictive or normal lung function. However, examination of
the data presented in their report reveals that, although the
percentage of current smokers in the obstructive and restrictive
groups was somewhat similar, there were marked differences in the
frequency of former smokers. Indeed, all of the workers who had
obstructive disease had a history of cigarette smoking. There were 13
workers in the group; 8 were current cigarette smokers and 5 were
former cigarette smokers, of whom 3 had stopped smoking less than
1 year prior to the study. Of the entire group examined, there were
only four workers who had never smoked cigarettes, and all of these
workers fell into the restrictive category.

Murphy and colleagues (1972, 1978) also attempted to answer the
question whether an increased prevalence of obstructive lung disease
occurs in asbestos workers. They examined a group of 101 shipyard

252


TABLE 13.-Effects of chrysotile exposure on the health of
      1,015 current Quebec asbestos workers

Dust index 1            c 10    lo-99   10x199    2cc-399    4c&799    >a00

Prevalence percent2
Chronic bronchitis
Dyspnea
Function profile3
  prevalence percent
Restrictive
Obstructive
Percentage fall in function'
vc
FEV,
DLCO,, rest
DLCO,, exercise

Prevalence percent'
Chronic bronchitis
l&pIlea
Fun&on profile-3
  prevalence percent
Restrictive
Obstructive
Percentage fall In function'
vc
FEV,
DUO,, rest
DLCO,, exercise

10
0



3
0


0
0
0
0






23
4



8
12


0
0
0
0

Konsmokers

19       19       46       21       49
19       24       31       13       44

3       3
1       0

-10      -16
-9       -9
-11      -15
-8       -9


Smokers

22      30      29       46      45
15       18       21       30      32

14       16       10        4       13
12       13       12       23       12

-3       -7
-3       -8
-4      13
0       -2

1

-18      -19      -23
-13      -15      -22
-18      -12      -15
-18      -18      -20

-10
-10
1-5
0

-13
-15
-3
-5

1

-14
-15
0
-7

SOTE For all measurements. prevalence percent has been age-standardized to the total working population BS
of October 31. 1966 This was to allow for the smaller of number of men for whom function profiles were analyzed
' Expressed in mllhon particles per cubic foot years '
1 Based on a total sample of 1.015 men I
"Basedon995men 2
SOURCE Becklake et al 119761

pipe coverers and compared them with 95 control subjects. The
prevalence of smoking in these two populations was approximately
the same. There were significant differences between the asbestos-
exposed workers and the control population in vital capacity and
FEV, in measurements taken both in 1966 and in 1972. However,
there was no difference between the two groups in FEV, as a percent
of FVC at either time point. In 1972, there was a significant
difference between the two groups in the reported symptom of
wheezing apart from colds. When this symptom was combined with
the prevalence of an abnormal FEV,/FVC%, using the criteria of
Ferris and Anderson (1962) for obstructive lung disease, the asbestos
workers had a significant higher prevalence of obstructive lung
disease in comparison with the control population. However, this

253


increased prevalence resulted from their reported symptoms and not
from differences in measured pulmonary function.

In summary, lung function has been examined in several popula-
tions of smoking and nonsmoking asbestos workers. In populations of
nonsmoking asbestos workers, a dose-related decline in TLC and a
decline in FEV, and in FEFZMSS consistent with the decline in TLC
can be identified, a pattern consistent with a primarily restrictive
lung function profile. In populations of cigarette-smoking asbestos
workers, the decline in TLC is somewhat less than in nonsmoking
asbestos workers and the decline in FEV, and FEFXJSS is somewhat
more. The percentage decline in FEV, compared with the percentage
decline in FVC is greater in smoking asbestos workers, but not in
nonsmoking asbestos workers. When smoking asbestos workers are
compared with control populations with similar smoking habits,
there is a significantly greater decline in FVC and TLC, but the ratio
of FEV, to FVC is similar in the asbestos-exposed and the non-
asbestos-exposed populations. The data are therefore consistent with
independent effects of asbestos and cigarette smoking on lung
function. This issue has been examined statistically by Samet and
colleagues (1979) and by Rossiter and Weill (1974); an additive effect
of smoking and asbestos exposure on the FVC was present, but there
was no statistically demonstrable synergism.

Regan and colleagues (1971) evaluated the relative power of 16
clinical-radiological-pulmonary function variables in evaluating as-
bestosis and chronic airway disease. A decreased diffusing capacity
for carbon monoxide (DLCO) and a decrease in the vital capacity had
the greatest power to measure the severity of either obstructive or
restrictive lung disease in workers with both smoking and asbestos
exposure, but had little ability to distinguish between the two
processes. The best indicator for distinguishing between restrictive
lung disease and obstructive airway disease was FEV, as a percent-
age of the vital capacity. This variable had a better ability to
distinguish between obstructive and restrictive disease than either
the clinical or the chest roentgenogram findings or other tests of
pulmonary function.

The absence of an effect of asbestos exposure on FEV,/FVC%
must be interpreted with caution. Although this test is the best
measure of the presence of airflow obstruction in the presence of
restrictive lung disease, it is not sensitive to changes in the small
airways. Because both cigarette smoking and asbestos exposure have
been shown to result in changes in the small airways of the lung, it is
important to examine the effects of these two exposures on tests of
small airway function.

254


Small Airways Function
Airways in the lung with diameters of 2 mm or less are considered
small airways and consist of bronchioles and respiratory bronchioles
(airways with both nonrespiratory epithelium and alveoli in their
walls). Considerable obstruction can be present in these airways
without significantly altering the airway resistance or lung mechan-
ics. In addition, abnormalities in the small airways are a prominent
part of the abnormality present in chronic obstructive lung disease
(COLD). The relationship of cigarette smoking to abnormalities in
tests of small airways function, and of pathologic abnormalities of
the small airways to functional changes, was reviewed in a previous
Report of the Surgeon General (US DHHS 1984). Changes in the
small airways of cigarette smokers may occur within the first few
years of smoking, are more prevalent in heavy smokers, and increase
in frequency with increasing duration of the smoking habit. Because
the small airways are also involved in people who develop cigarette-
induced COLD, tests of small airways function are usually abnormal
in people with chronic airflow obstruction on conventional spirome-
try; however, it is not yet clear whether the early and reversible
inflammatory changes in the small airways of smokers are the first
stage in the pathophysiologic process of developing COLD or are
merely a nonspecific irritant response to smoke that does not
predispose to the development of COLD.
The response of the lung to asbestos also involves the small
airways, and there has been considerable interest in functional
changes of the small airways of asbestos workers. Relevant questions
are these: Does asbestos cause changes in the small airways
independent of smoking? Do the morphologic changes in the small
airways caused by smoking differ from those caused by asbestos? Do
the changes in the small airways of asbestos workers progress to
airflow obstruction, as measured by standard spirometry, indepen-
dent of cigarette smoking?
Woolcock and colleagues (1969) demonstrated that a group of
bronchitic subjects with normal lung volumes and flow rates had
abnormal tests of small airways function. Cosio and colleagues (1978)
and Berend and colleagues (1979) were able to correlate abnormali-
ties of tests of small airways function with morphologic changes in
the small airways. The morphologic changes consisted of a respira-
tory bronchiolitis with goblet cell metaplasia, inflammation of the
bronchiolar wall, smooth muscle hypertrophy, peribronchiolar fibro-
sis, and pigmentation of the bronchiole. Tests of small airways
function (closing capacity and slope of the single breath nitrogen
washout) were abnormal, with lower degrees of pathologic change;
however, abnormalities on spirometric testing (FEV,/FVC and
FEF25-754r) were also correlated with more severe morphologic
changes in the small airways.


The changes in the small airways of asbestos workers have been
examined (Wright and Churg 1984; Churg and Wright 1984), and
differences in the pattern of injury from that produced by cigarette
smoking alone were identified. The researchers examined lung
sections from 15 patients who had been exposed to asbestos and had
abnormalities of the respiratory bronchioles, and compared these
individuals with 15 control subjects matched for age, sex, and
smoking status. Almost all of the subjects smoked (13 of 151, so it was
not possible to examine the differences between smoking and
nonsmoking asbestos workers or to rule out an interaction between
smoking and asbestos. However, two distinct patterns seem to
emerge. Churg and Wright found changes in the membranous
bronchioles of the cigarette-smoking controls similar to those found
by others (Casio et al. 1978; Berend et al. 1979), including inflamma-
tion, pigmentation, and periobronchiolar fibrosis. The changes in the
membranous bronchioles of the asbestos workers (almost all of whom
were smokers) were qualitatively identical to those in the non-
asbestos-exposed smokers; but quantitatively, the degree of fibrosis,
the amount of pigmentation, and the percentage of membranous
bronchioles involved was greater in the asbestos-exposed individuals.
In the asbestos-exposed group, 67 percent of the membranous
bronchioles showed marked fibrosis in comparison with 19 percent in
the control population of smokers. The clearest distinction and the
most diagnostically useful lesions occurred in the respiratory
bronchioles and alveolar ducts. Forty-eight percent of the respiratory
bronchioles and 35 percent of the alveolar ducts showed marked
fibrosis in the asbestos-exposed group in contrast to 4 percent of the
respiratory bronchioles and 0 percent of the alveolar ducts in the
control population. These data suggest that cigarette smoking
produces an inflammatory response with only modest amounts of
fibrosis in the membranous bronchioles, and that the addition of
asbestos exposure results in a marked increase in the fibrosis around
the membranous bronchioles and an extension of this fibrosis to the
respiratory bronchioles and alveolar ducts. Because there were so
few nonsmokers examined in this study, the questions whether
asbestos exposure alone causes an inflammatory response and
whether the fibrotic lesions characteristic of asbestos exposure are
influenced by smoking could not be addressed.

Given this description of the pathologic response of the small
airways to cigarette smoke and asbestos dust, examination of the
physiologic testing of the small airways in asbestos workers should
focus on several questions: Does asbestos exposure alter the function
of the small airways in people who have never smoked? Does this
alteration in small airways function result in reductions in the rate
of expiratory airflow (as occurs in cigarette smokers) independent of
the reductions in lung volume that occur secondary to asbestos

256


exposure? (The increased resistance in the small airways may be
compensated for by an increased elastic recoil of the lung available
to drive expiratory airflow.) Does asbestos exposure increase the
prevalence of abnormalities on tests of small airways function above
that expected from smoking alone?
A number of researchers have examined small airways function in
asbestos workers. Jodoin and colleagues (1971) examined 24 workers
with normal chest roentgenograms whose asbestos exposure ranged
from 6 months to 24 years. Two groups with comparable age and
smoking prevalence, but with differing exposure to asbestos dust,
were defined among those 24 workers. The more heavily exposed
group had a 30 percent increase in lung static recoil pressure and
had reduced rates of expiratory airflow for any given transpulmo-
nary pressure, suggesting increased resistance in the small airways.
This increased resistance did not result in obstruction on spirometric
testing, as both FEV,/FVC% and FEFz+xc~ actually increased in the
workers with heavier asbestos exposure. In five of the subjects with
heavier exposure, but with a normal FEV, and FEV,/FVC%, the
maximal expiratory flow was reduced throughout the entire range of
lung volume despite an increased driving pressure, suggesting that
the degree of small airway obstruction was greater than the degree
of increase in driving pressure. However, all five of the subjects were
cigarette smokers; therefore, the reduced airflow could not be
identified as due to the asbestos. The authors provided no separate
analysis of the data for the nonsmokers in the study.
Several other authors (Harless et al. 1978; Cohen et al. 1984;
Rodriguez-Roisin et al. 1980; Siracusa et al. 1983) have also
presented evidence suggesting that asbestos exposure results in
small airway dysfunction; however, the data on nonsmokers were
not presented in a manner to allow evaluation as a separate group,
or included ex-smokers with never smokers, making interpretation
difficult.
Begin and colleagues (1983) examined airways function in 17
lifetime nonsmoking asbestos workers with an average of 28 years of
exposure in the asbestos mines and mills of Quebec. Seven workers
met the diagnostic criteria for asbestosis and 10 did not; none of the
workers met the diagnostic criteria for chronic bronchitis, emphyse-
ma, or asthma. The lifetime nonsmokers without asbestosis had
relatively normal lung function, but there was a slightly lower
maximal expiratory flow at 25 percent of the vital capacity and a
significantly elevated isoflow volume, suggesting dysfunction in the
small airways. The seven workers with asbestosis had clear evidence
of smali airway obstruction with a threefold or fourfold increase in
upstream resistance at low lung volumes. These data were supported
by histologic evidence of peripheral airway obstruction and narrow-
ing on lung biopsies in three of these men. However, this obstruction


in the small airways was not severe enough to significantly reduce
the usual spirometric parameters of airflow obstruction, and none of
these men had a significant reduction in FEV,/FVC%. The authors
attributed this phenomenon to the higher pressures available to
drive airflow in these workers with restrictive lung disease.
Cohen and colleagues (1984) attempted to examine the relation-
ship of smoking and asbestos exposure in a cross-sectional study of a
group of asbestos litigants. Unfortunately, ex-smokers were included
with the group of nonsmokers. This results in an increasing
prevalence of ex-smokers with increasing age, and ex-smokers have
reduced lung function (US DHHS 1984); correspondingly, with
increasing duration of asbestos exposure, there would also be an
increasing prevalence of ex-smokers. This confounding of their
exposure data makes meaningful interpretation impossible.
In summary, the evidence suggests that asbestos exposure can
result in small airways dysfunction in nonsmoking workers, but this
small airways dysfunction does not result in obstruction on standard
spirometric testing. FEV,/FVC% remains normal in these non-
smoking asbestos workers even in the presence of substantial
increases in the airway resistance at low lung volumes and decreases
in TLC. This picture differs from that in small airway dysfunction in
cigarette smokers, where there is a decline in the FEV,/FVC%. This
difference may be accounted for by the differences in elastic recoil
pressure of the lung produced by these two injuries. Asbestos
exposure results in increased elastic recoil of the lung, which
provides an increased driving pressure that compensates for the
increased resistance in the small airways. Thus, the rate of expirato-
ry airflow is preserved. In contrast, the elastic recoil either remains
normal or frequently decreases (in emphysema) with cigarette-
induced lung injury, and therefore there is no compensatory increase
in driving pressure to maintain the rate of expiratory airflow in the
presence of an increased resistance in the small airways. In
combined exposure to cigarette smoke and asbestos, the largely
inflammatory response in the small airways due to smoking may
occur conjointly with the largely fibrotic response in the same
airways due to asbestos, and the resultant increase in the resistance
in the small airways may be large enough to reduce expiratory
airflow even in the presence of an increased elastic recoil.
In conclusion, asbestos exposure can result in reduced lung
volumes in both smoking and nonsmoking workers, and may result
in small airway dysfunction. However, the evidence does not suggest
that airflow obstruction, as measured by a reduced FEV,/FVC, is a
result of asbestos exposure in nonsmoking asbestos workers or that it
is worse than would be expected from the smoking habits of asbestos
workers who smoke.


Chest Roentgenographic Changes

One of the hallmarks of interstitial fibrosis due to asbestos is an
abnormal chest roentgenogram, and despite the fact that biopsy-
proven disease may be present with a normal roentgenogram (Epler
et al. 1978), the x ray commonly reflects both the presence and the
extent of fibrosis. Occasionally, particularly in early asbestos-in-
duced lung disease, the chest roentgenogram may not be abnormal
and the only abnormalities may be a reduced diffusing capacity or
decreased lung volumes. The chest roentgenogram is less frequently
abnormal in cigarette-induced chronic obstructive lung disease, but
roentgenographic abnormalities can occur, particularly in advanced
disease or when extensive emphysema is present. The abnormalities
produced by these two processes are usually quite different on chest
roentgenogram once the disease process is sufficiently advanced, and
confusion about the roentgenographic diagnosis in severe disease is
unusual.

The radiographic changes associated with asbestos include small
irregular opacities, which commonly begin as a reticular pattern in
the lower lung fields and may progress to diffuse interstitial
densities throughout the entire lung with reduced lung volumes
(Selikoff and Lee 1978; Fraser and Pare 1979). The abnormalities
that have been reported with COLD include overinflation, promi-
nence of lung markings ("dirty lungs"), tubular shadows, and in the
presence of significant emphysema, oligemia, and bullae (Fraser and
Pare 19791.

Roentgenographic Changes in Non-Asbestos-Exposed
Populations

The literature establishing asbestos as a cause of interstitial
fibrosis is extensive, and no significant scientific debate remains over
the potential for occupational asbestos exposure to result in intersti-
tial fibrosis; substantial numbers of asbestos workers have developed
interstitial fibrosis as a direct consequence of their inhalation of
asbestos dust. A review of this evidence is beyond the scope of this
chapter and can be found elsewhere (Selikoff and Lee 1978). The
questions raised by the combination of cigarette smoking and
asbestos exposure do not include whether cigarette smoking is an
independent competing cause of the extensive fibrotic process found
in many workers following prolonged heavy exposure to asbestos.
Cigarette smoking has not been shown to independently cause this
kind of reaction in the lung. Therefore, this section focuses on three
questions concerning the relationship of cigarette smoking to the
roentgenographic changes caused by asbestos. In the absence of
asbestos exposure, are the chest roentgenograms of cigarette smok-
ers more likely to be interpreted as positive for interstitial fibrosis
than those of nonsmokers? Do cigarette-smoking asbestos workers

259


have a higher prevalence of chest roentgenograms interpreted as
positive for interstitial fibrosis than nonsmoking asbestos workers?
Do cigarette-smoking asbestos workers have more severe interstitial
fibrosis on chest roentgenograms than nonsmoking asbestos workers
for comparable asbestos exposures?

The determination of whether radiologic findings consistent with
interstitial fibrosis are present is part of the standard clinical
interpretation of the chest roentgenogram. However, the Interna-
tional Labour Office (ILO) (1980) developed a classification by which
the roentogenographic changes of pneumonconiosis can be measured
and reported in a standardized way. Small opacities are character-
ized as rounded or irregular, and the profusion of the opacities is also
described and quantitated on a numerical scale (from O/O to 3/4).
This classification was designed as a descriptive rather than a
clinical tool; as such, it is structured to be sensitive to the earliest
roentgenographic changes. This sensitivity allows the investigation
of early or mild disease, but also may reduce specificity. Using this
classification, other mild, but not pneumoconiotic, disease in the
general population may be interpreted as positive. Indeed, given the
variety of causes of interstitial fibrosis other than inhalation of
inorganic dust, the absence of any false positives by this classifica-
tion would be surprising, and therefore the questions are the
magnitude of this false positive rate and whether cigarette smoking
influences that rate.

The semiquantitative IL0 classification system can have substan-
tial variability of interpretation, particularly at the lower levels of
abnormality (Werner 1980). Table 14 shows the differences between
the highest and lowest categorizations of 32,695 chest roentgeno-
grams interpreted according to the IL0 classification by three
different readers as part of a study of asbestos-related disease. In
general, there was good agreement, but in a number of cases marked
differences of interpretations occurred, including the same radio-
graphs being interpreted by different readers as negative (O/O) and
as substantially positive (2/2). Werner discussed some of the
problems generated by these differences in interpretation and
offered some potential remedies, but the data pointed out that a
system designed to be sensitive to low levels of abnormality may be
expected to have a some variability of classification, particularly
around the threshold of abnormality.

Weiss (1967, 1969) published a pair of studies evaluating the
prevalence of a roentgenographic interpretation of interstitial
fibrosis in smokers and nonsmokers drawn from the general
population. The first study involved the examination of 70 mm chest
photofluorograms of 999 men and women who came consecutively to
the central survey unit of the Philadelphia Tuberculosis and Health
Association. The films were evaluated for increased bronchovascular

260


TABLE 14.-Analysis of x rays of asbestos workers, lowest readings by highest readings (IL0 U/C
       scale)

L0wee.t
reading


01.

o/o

O/l

l/O

l/l

l/2

211

212

213

312

313

314

01.



2

o/o



857

20449

O/l



94

3406

46

l/O



47

2162

149

29

l/l



56

2699

385

189

53

Highest reading


   l/2      2/l      212      213     312     313     3f4     TOtal



    15       2       6      2             2            1063

   693      153      283      47             18            29910

   152      39      85      12       1       2             871

   100      43      69      10       1       2             443

    55      39      101      32       6       7      1       294

    1       3      25      10             6      1       46

                  8       5             3              16

                  3       9       3       6      2       23

                         2             6              8

                                                    0

                                      1              1

                                                    0

TOtd      2      21306      3546      2387      3382      1016      219      580     129      11      53      4     32695

SOURCE: Werner (1980)


markings or diffuse pulmonary fibrosis; 3.1 percent of the subjects
had abnormal films, with a prevalence of 1.5 percent in nonsmokers
and 4.4 percent in cigarette smokers. Dose-response relationships
were present for the number of cigarettes smoked per day and for
the duration of smoking. A second study evaluated 2,825 adults,
again using 70 mm photofluorograms; this time interpretation was
by readers other than the author, and the purpose of the evaluation
was to examine the population for COLD rather than for interstitial
fibrosis. The prevalence of diffuse interstitial fibrosis was 0.6 percent
in nonsmokers and 2.1 percent in smokers.

Kilburn (1981) criticized these studies on the basis of their use of
`70 mm films and the failure to use the IL0 criteria for grading the
roentgenographs. Epstein and colleagues (1984) applied the IL0
criteria to 200 admission chest roentgenograms at an urban universi-
ty medical center. Small opacities with profusions of l/O or greater
were found in 22 (11 percent) of the subjects, none of whom had a
documentable dust exposure or any known medical disease that
caused interstitial lung disease. Of the 22, 12 (55 percent) were
current or former cigarette smokers. Murphy and colleagues (1978)
also used the IL0 criteria in examining 68 shipfitters and pipefitters
without known exposure to asbestos who were selected to serve as a
control group for a study of similar workers with known exposure to
asbestos. Of the control workers, 60 had chest roentgenograms
classified as O/l or less, 6 (8.8 percent) had readings of l/O to l/2, and
1 had a reading higher than l/2. A previous study of the same group
of workers (Murphy et al. 1972) had classified 14 percent of the
controls as having slight abnormalities (l/O to l/2) and 2 percent as
has having moderately advanced abnormalities (2/l to 213). None of
the control group were classified has having more advanced disease,
and the results were not presented by smoking status.

In summary, the data suggest that a small percentage of chest
roentgenograms of the general population may have changes that
can be interpreted as interstitial fibrosis, and that slightly larger
percentages of hospitalized patients and shipyard workers with no
known asbestos exposure may have chest roentgenograms read as
positive for interstitial fibrosis by the IL0 criteria. Both the
prevalence in these populations and the severity of the changes are
far lower than those found in populations with significant asbestos
exposures (Murphy et al. 19781, and they may reflect the sensitivity
of the chest roentgenogram and the IL0 classification to other causes
of lung injury. The "dirty lung" described in smokers (Fraser and
Pare 1979) may contribute to the smoking-related prevalence of
"diffuse interstitial fibrosis" described by Weiss (1969) in the general
population, but it is unlikely to be confused with the more advanced
forms of fibrosis found in severe asbestos-related lung injury.
However, the prevalence of changes in the general population,

262


particularly in the population of shipyard workers with no known
asbestos exposure, suggests that classifying a mildly positive chest
roentgenogram as asbestosis in the absence of a clear exposure
history should require other confirming evidence of asbestos-induced
lung injury. This caution may be particularly true for cigarette
smokers.

Interstitial Fibrosis in Asbestos-Exposed Populations

As was mentioned earlier, cigarette smoking is not a competing
cause of the diffuse severe interstitial fibrosis that occurs in some
workers secondary to their inhalation of asbestos dust. However,
modest peribronchiolar fibrosis (Cosio et al. 1978; Berend et al. 1979)
and occasional fibrosis of respiratory bronchioles (Wright and Churg
1984) do occur as a response of the small airways to cigarette
smoking, in addition to the periobronchiolar inflammation that is
the predominant early response to cigarette smoking. These bron-
chioles are also the site of the early response to asbestos dust
(Craighead et al. 1982J and therefore the threshold for radiologic
perception of an abnormality may be crossed more frequently, or
earlier, or at a lower dose of asbestos exposure in cigarette-smoking
asbestos workers than in nonsmoking workers. In addition, the
inflammatory response to cigarette smoke may enable or facilitate
the fibrotic response to asbestos dust. Therefore, the question of a
different exposure-response relationship between asbestos exposure
and roentgenographic changes for smoking and nonsmoking asbestos
workers should be considered.

Weiss (1984) recently reviewed the evidence relating cigarette
smoking and roentgenographic fibrosis in asbestos-exposed popula-
tions. In Table 15, drawn from this review, is shown the prevalence
of radiologic "asbestosis" in studies of asbestos-exposed populations.
In general, the prevalence was higher in smokers than in nonsmok-
ers; in several studies the difference was statistically significant. The
highest prevalence ratios for smokers compared with nonsmokers
are recorded in the populations with the lowest overall prevalence of
roentgenographic fibrosis, and it is the studies where a high
prevalence of disease is present that show similar rates of roentgeno-
graphic fibrosis among smokers and nonsmokers (if studies of
populations of less than 100 are ignored). This observation is in part
an obligatory result of the mathematics involved (a given difference
in prevalence between smokers and nonsmokers produces a smaller
prevalence ratio when there is a high prevalence than when there is
a low prevalence), but it is also the effect that would be expected if
the effect of smoking were a small independent risk of radiologic
fibrosis or if the effect was to increase the frequency with which

263


smoking asbestos workers cross the threshold for perception of
roentgenologic abnormality.

The demonstration of an increased prevalence of roentgenographic
changes interpreted as fibrosis in cigarette smokers does not
establish that the changes are produced by smoking. As has been
discussed earlier, cigarette smokers may have had a different
cumulative asbestos exposure than nonsmokers in some of the
populations studied. Liddell and colleagues (1982) examined the
prevalence of roentgenographic fibrosis in a group of 515 asbestos
miners born between 1891 and 1920 and found an increased
prevalence of roentgenographic fibrosis with increasing age and
cumulative asbestos exposure. Smokers and nonsmokers had similar
prevalences of changes, but the smokers had marginally lower
cumulative asbestos exposure. Harries and colleagues (1976) exam-
ined a younger population of shipyard workers with a lower
prevalence of roentgenographic fibrosis (Table 16). The prevalence of
changes was slightly higher in smokers than in nonsmokers, and
seemed to increase in smokers after 10 to 14 years of asbestos
exposure in comparison with after 20 to 24 years of asbestos
exposure for nonsmokers. Dosage measures were not available for
this study. Samet and colleagues (1979) examined a population of 383
asbestos workers with a prevalence of roentgenographic fibrosis (l/O
or greater) of 33.7 percent. They tested for interaction between
smoking and asbestos exposure and found a small additive effect for
roentgenographic changes, but no synergism between cigarette
smoking and asbestos exposure. Rossiter and Berry (1978) examined
the interaction of smoking and duration of asbestos exposure in a
population with a lower prevalence of roentgenographic fibrosis and
found a duration-response relationship for asbestos exposure only
among cigarette smokers. The number of workers at risk in the
nonsmoking category was small, however, making it difficult to
determine whether the absence of a dose-response relationship in
nonsmokers resulted from differences between smokers and non-
smokers or was simply a reflection of the low rate of disease in the
population.

In summary, cigarette smokers appear to have a higher prevalence
of radiologic abnormality compatible with interstitial fibrosis than
nonsmokers among populations of asbestos-exposed individuals with
low prevalence of roentgenographic fibrosis (and presumably low
levels of asbestos exposure). This difference is not apparent in
populations with higher prevalences of roentgenographic fibrosis
(and presumably higher asbestos exposures). One study (Harries et
al. 1976) suggested that cigarette smokers develop an abnormal chest
roentgenogram after a shorter duration of asbestos exposure than
nonsmokers. There is little evidence to suggest that smokers develop
more severe fibrosis (in contrast with a higher prevalence of fibrosis)

264


=;   TABLE 15.-Results of prevalence studies of the cigarette factor in asbestosis

I
:                                     Smokers                     Nonsmokers

0                                          Asbestosis                     Asbestosis                 95% confidence limits
I                                                                           PFf&llC~
EE    Study                      Number     Number     Percent     Number     Number     Percent      ratio '      Lower    UPF

I
z     Weiss (1971)

Langlands et al. (1971)

Harries et al. (1972)

Harries et al. (1976)

Weiss and The&s (197RI
Chrysotile
Chrysotile + amosite

Hedenberg et al. 11978)

Rossiter and Harnes (1979)

McMillan et al. (1960)

Selikoff et al. (19Ro)

Pea& (1982)

Liddell (1982)

  73        29

  91        35

1,635       49

17.788       181

39.73

38.46

3.00

1.02

25        6       24.00       1.66       0.81       3.76

33        9       27.27       1.41       0.56       2.53

em        20        2.48       1.21       0.72       2.03

5.552        11        0.20       5.10       2.9R       8.65

31        8       25.81         9        2       22.22
33        26       42.11        10        0        0.00

103        7        6.80        94        1        1.06

944        39        4.13        142        3        2.11

1,346        18        1.34       3n5        0        0.00

228       180       78.95        56        44       78.57

99        9        9.09        32        1        3 13

341        89       26.10       174        46       26.44

1.16
m

6.42

1.96

m

100

2.90

099

0.29       4.57
1.26'      56.31 z

1.07      38.34

O.fTl       6.30

1.092     102.232

0.43      2006

0.61       1.59

1 Smokers to nonsmokers

`Calculated by substitutmg 0 5 for 0 casea of pulmonary fibrow in the nonsmoker group
SOURCE Weiss (1984)


TABLE 16.-Prevalence (percentage) of suspected or
      definite pulmonary fibrosis among 23,340 male
      in-yard British dockyard workers during 1972
       and 1973, by smoking habit and duration of
       asbestos exposure

  Nonsmokers

         With
        fibrosis
Yumber    rpercent I

Smoking hablt

   Ex-smokers

         With
        fibrosis
NLldEr    lpercenti

   Smokers

        With
        fibrosle
Number   ipercelr

j' 5           3,516       0.1      2,746       04      7,300      06

5-9             784       02        581       03       1.666      0.5

lo-14            392       00       442       11        979      1.5

15-19           293       03        320       1.6        869      2.5

20-24            20R       10       330       1.7        66:      31

2w29            140       1.1        214       2.6        486      2.8

230            219       0.9        357       2.2        811      3.1


Total          5.552       02      4,990       0.8      12,798      1.1

than nonsmokers. These data are consistent either with a small
independent risk of interstitial fibrosis on chest roentgenogram
produced by smoking (as suggested by the studies in non-asbestos-
exposed populations) being added to the risk of fibrosis due to
asbestos exposure or with the combination of asbestos-induced and
smoking-induced changes in the small airways resulting in asbestos
workers who smoke crossing the threshold for perceptible abnormali-
ty earlier than nonsmokers. However, it is clear that if cigarette
smoking contributes to the development of interstitial fibrosis in
asbestos-exposed workers, the contribution is a minor one in
comparison with the effect of asbestos dust exposure.

Immunologic Response to Cigarette Smoke and Asbestos
Dust

There is an extensive literature on both animal models and
humans regarding alterations in the immune system following
exposure to either asbestos or cigarette smoke; however, clinical and
laboratory studies of combined exposure to asbestos and cigarette
smoke are more limited.

266


Humoral Immunity

Two independent studies (Kagan et al. 1977; Huuskonen et al.
1978) reported elevated polyclonal immunoglobulin (Ig) levels in
populations of workers with asbestosis. Lange (1980) also correlated
serum Ig levels with asbestosis. This study differentiated groups by
sex and age, characteristics that can also affect the immune system.
Cigarette smoking did not significantly correlate with serum Ig
levels, whereas individuals with roentgenographically demonstrated
asbestosis had increased levels of IgA and IgG. Asbestos workers,
including those with interstitial fibrosis, were also evaluated for
symptoms of chronic bronchitis. Male workers exhibiting symptoms
for longer than 5 years had lower IgG and IgA values than asbestos
workers without chronic bronchitis or with symptoms of bronchitis
present for less than 5 years. Elevated IgA or IgM levels were found
in a subgroup of male asbestos workers who were heavy smokers, as
assessed by the duration of smoking multiplied by the average
number of cigarettes smoked per day. The authors concluded that
the asbestotic process and not the presence of chronic bronchitis was
responsible for the high serum IgA and IgG levels (variable results
have been reported regarding the level of serum IgA with chronic
bronchitis) (Falk et al. 1970; Medici and Buergi 1971; Varpela et al.
1977). The immunoglobulin level alterations were found in workers
with demonstrable lung disease. Therefore, it is unclear whether this
alteration is involved in the pathogenesis of the disease or is an
epiphenomenon, because the measurements were made when dis-
ease was already present.

Cellular Immunity

Wagner and colleagues (1979) evaluated factors affecting the
peripheral blood leukocytes and T lymphocytes in 138 asbestos-
exposed men. T lymphocyte subsets were identified by the ability of
lymphocytes to rosette with erythrocytes, after incubation either for
1 l/2 hours (T helper cells) or overnight (T suppressor cells). Age,
length of asbestos exposure, smoking history, evidence of roentgeno-
graphic fibrosis or pleural changes, and spirometric abnormalities
were assessed. The smoking history in these asbestos-exposed
workers was the factor that correlated best with lymphocyte
changes. The group with roentgenographic changes of asbestosis and
a history of smoking had an increased percentage in E-rosettes after
1 l/2 hours. This suggests an increase in the number of the T helper
cells. Among workers with parenchymal chest roentgenographic
changes, those who smoked had an increased number of the T helper
cells compared with those who did not smoke. The number of T
suppressor cells was not affected by the smoking history or by
roentgenographic change.

267


Age and smoking as individual factors affecting lymphocyte
percentage or number have also been assessed. There is some
controversy about the effects on T lymphocytes. Silverman and
colleagues (1975) showed no correlation between percentage of T
lymphocytes and smoking or aging. Friedman and colleagues (1973)
and Alexopoulos and Babitis (1976) did not demonstrate the effect of
age on the percentage of T lymphocytes, but the absolute number of
lymphocytes declined with age. Teasdale and colleagues (1976) and
Smith and colleagues (1974) demonstrated a decline in the percent-
age and total number of T lymphocytes with age. Friedman and
colleagues (1973) showed that the total number of leukocytes,
including lymphocytes, increased in smokers until age 50, and then
declined.
The effect of asbestos exposure on lymphocytes was studied by
Kang and colleagues (1974) and by Kagan and colleagues (1977). The
findings of both groups of investigators were similar. Kang and
colleagues reported decreased erythrocyte-binding lymphocytes. Ka-
gan and colleagues showed a decrease in percentage and in absolute
number of T lymphocytes in a group of workers with asbestos
exposure. Smoking as a contributing factor was not reported in these
two studies.
More recently, these findings were substantiated by Miller and
colleagues (1983) with the use of monoclonal antibody markers to
differentiate T lymphocyte subsets. Smoking, length of asbestos
exposure, and chest x-ray findings were evaluated. A decrease in
percentage of T lymphocytes (OKRsub3)+) and in the suppressor subset
of T lymphocytes (OKmb a~+), with an increase in the ratio of helper
T Cells to suppressor cells (OKmub 4i-/OKTcSub a~+), was found in the
group of 40 asbestos-exposed individuals compared with nonexposed
inGviduals. Those with short asbestos exposure (less than 5 years)
u~re similar to controls, and those with more than 5 years of
exposure had the abnormalities. When assessing radiographic
changes, those without chest roentgenographic changes had lympho-
cyte parameters similar to nonexposed individuals, those with
pleural plaques had increased circulating helper cells (OKTcsub 41+),
and those with interstitial changes had decreased percentages of T
lymphocytes (OKnsub 31-j and suppressor cells (OKn,,,b s)+) and an
increased ratio of helper to suppressor cells (OKmb 4)+/0Kkb a,+).
Smoking habit did not influence these results. Miller and colleagues
(1983) theorized several possibilities to explain the findings. The
asbestos exposure may initially stimulate the immune system,
accounting for the increase in the helper cells in subjects with
pleural plaques. There may be an isolated toxic effect to suppressor
cells affecting the percentage of this subset, and thus the total
percentage of T lymphocytes. Lymphocytes may be distributed in
organs (i.e., the lung) once fibers are inhaled, and thus the peripheral


blood lymphocyte parameters are altered. Although the differences
are most striking in subjects with roentgenographic changes, the
lymphocyte alterations may not be related to the pathogenesis of
these changes, but may be a secondary change due to chronic disease.

In other studies (Ginns et al. 1982; Miller et al. 1982), smoking was
also found to cause T lymphocyte subset changes. These changes
were found in heavy smokers (50 to 120 pack-years) and not in light
to moderate smokers (10 to 49 pack-years). Heavy smokers had
increased total T lymphocytes (GR.riiub 3'- ), a decreased percentage of
T helper cells (GKTtSUb 4)+), an increased total number of T suppressor
cells tORnsUb st-), and a decreased ratio of helper to suppressor cells.

De Shazo and colleagues (1983) also examined lymphocyte subsets
in 31 current and former asbestos-cement workers compared with 52
healthy controls after adjustments had been made for possible
confounding effects of age, race, and smoking. The asbestos workers
had significantly decreased percentages and numbers of B and T
lymphocytes in the peripheral blood. Analysis of T lymphocyte
subpopulations revealed that total T cell numbers (OKn,,t, 31-j and
helper-inducer T cell numbers (OKTtsub aI* ) were decreased by similar
proportions. These decreases were negatively correlated with time
since the end of exposure to asbestos. In both workers and controls,
lymphocyte proliferative response to phytohemagglutinin was corre-
lated positively with the number of (OKnBUb 4,-j cells and negatively
with age. No relationship was detected between any of the immuno-
logic aberrations noted in the workers and the radiographic category
of pneumoconiosis, estimates of cumulative asbestos exposure, or
abnormalities of pulmonary function.

Lymphocyte function was assessed by Campbell and colleagues
(1980) by the mitogen lymphocyte transformation response of
peripheral blood lymphocytes. Allowing for the decline in response
seen with increasing age, there was an increase in response to
phytohemagglutinin (PHA) and pokeweed mitogen (PWM) in asbes-
tos workers who smoked compared with ex-smokers and nonsmok-
ers These findings were in agreement with those reported by
Haslam and colleagues (1978).

Sister Chromatid Exchange Frequency

An in vitro cytogenetic assay, sister chromatid exchange (SCE)
frequency, has been utilized to demonstrate chromosomal breakage
in different mammalian cell lines following exposure to asbestos. In
a study reported by Rom and colleagues (1983), 25 asbestos insulators
had a small increase in frequency of SCE in peripheral blood
lymphocytes compared with controls. The SCE rate increased
slightly with increasing years of exposure to asbestos, when age and
smoking were controlled. Smokers had similar rates of occurrence of
SCE among both controls and asbestos workers. In nonsmokers,

269


those with asbestos exposure had a significantly increased SCE rate
compared with controls. Butler (1980) and Crossen and Morgan
(1980) did not detect a difference in SCE frequency.

Public Health Implications

The data are unequivocal that cige.rette smoking and asbestos
exposure have produced substantial death and disability. The
residual public health questions generated by these data focus on
how to reduce the future risk of illness and death. As asbestos
exposures are reduced, clinically disabling interstitial fibrosis should
become a rare phenomenon in workers currently beginning their
work careers. As asbestos exposures are reduced, it will become
increasingly difficult to identify an increase in lung cancer death
rates among asbestos workers that is greater than those of the
general population. While the risk of developing mesothelioma is not
associated with smoking, the risk of developing mesothelioma should
be reduced by the lower exposure levels that currently exist, but
persists even at very low levels of exposure. A reduction in the
current U.S. standard (2f/cc) is being considered; once adequate
asbestos dust controls are applied and enforced, future gains in
reducing asbestos exposure are likely to come from reducing the
exposure of workers employed in jobs other than asbestos mining
and manufacturing. These jobs include construction workers who
may be exposed during the demolition or remodeling of existing
structures constructed with asbestos materials, and maintenance
workers who may be similarly exposed to existing asbestos-contain-
ing materials. Current concerns are the risk involved in removing
asbestos from existing buildings in order to reduce environmental
contamination and the need to educate the workers involved in these
tasks to prevent their exposure as they remove these materials.

Unfortunately, little can be done to reduce the current asbestos
burden in workers exposed prior to the introduction of environmen-
tal controls. For these workers, it is clear that the single most
important intervention that would alter their future disease risk is
the cessation of cigarette smoking. The elimination of cigarette
smoking in this population would not only substantially reduce the
number of future lung cancer deaths but also moderate the
contribution of cigarette-induced COLD to the restrictive ventilatory
limitation that may develop in these workers. The issues of liability
and responsibility for the disease that is occurring in these workers
will continue to be argued for an extended period of time, but these
arguments should not confuse or impede the efforts to alter the
future disease risk in these workers. The goal is not, and should not
be, to eliminate only that disease burden attributable to future
asbestos exposure, but rather to reduce as much as possible, by any

270


means possible, the enormous risk of death and disability that
currently exists for these workers. Smoking cessation is therefore an
intrinsic and essential part of any effort to reduce asbestos-related
disease and disability.

Summary and Conclusions

1. Asbestos exposure can increase the risk of developing lung
cancer in both cigarette smokers and nonsmokers. The risk in
cigarette-smoking asbestos workers is greater than the sum of
the risks of the independent exposures, and is approximated by
multiplying the risks of the separate exposures.

2. The risk of developing lung cancer in asbestos workers
increases with increasing number of cigarettes smoked per day
and increasing cumulative asbestos exposure.

3. The risk of developing lung cancer declines in asbestos workers
who stop smoking when compared with asbestos workers who
continue to smoke. Cessation of asbestos exposure may result
in a lower risk of developing lung cancer than continued
exposure, but the risk of developing !ung cancer appears to
remain significantly elevated even 25 years after cessation of
exposure.

4. Cigarette smoking and asbestos exposure appear to have an
independent and additive effect on lung function decline.
Nonsmoking asbestos workers have decreased total lung capac-
ities (restrictive disease). Cigarette-smoking asbestos workers
develop both restrictive lung disease and chronic obstructive
lung disease (as defined by an abnormal FEV,/FVC), but the
evidence does not suggest that cigarette-smoking asbestos
workers have a lower FEV,/FVC than would be expected from
their smoking habits alone.

5. Both cigarette smoking and asbestos exposure result in an
increased resistance to airflow in the small airways. In the
absence of cigarette smoking, this increased resistance in the
small airways does not appear to result in obstruction on
standard spirometry as measured by FEV,/FVC.

6. Asbestos exposure is the predominant cause of interstitial
fibrosis in populations with substantial asbestos exposure.
Cigarette smokers do have a slightly higher prevalence of chest
radiographs interpreted as interstitial fibrosis than nonsmok-
ers, but neither the frequency of these changes nor the severity
of the changes approach levels found in populations with
substantial asbestos exposure.

7. The promotion of smoking cessation should be an intrinsic part
of efforts to control asbestos-related death and disability.

271


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