presented in Figure 4. When cancer death rates are examined by
birth cohort (Figure 51, no decline with age can be demonstrated. The
explanation for this seeming discordance in the data is the differ-
ences in pattern of cigarette smoking in different birth cohorts in the
U.S. population (Figure 6) (US DHHS 1982). Those birth cohorts that
currently represent the oldest age groups have lower smoking
prevalences than the birth cohorts in the younger ages (those born
between 1910 and 19301, and this decreased smoking prevalence
resulted in a decreased lung cancer mortality. The risk ratios
presented in Figure 3 are comparisons with the risk in the general
population, and therefore represent the combined effect of the
increased smoking prevalence among asbestos workers and the
increased risk due to the asbestos exposure. To the extent that the
age-related changes in smoking prevalence among older asbestos
workers presented in Table 9 represent a return toward or below the
smoking prevalence in the general population, a decline in the risk
ratio among older asbestos workers would be expected. Regardless of
the reason for the change in risk ratio among older workers (i.e.,
either differences in smoking behavior or decline in risk following
cessation of asbestos exposure), the magnitude of the decline is
modest, particularly when the rapidly increasing baseline risk of
lung cancer in the general population with increasing age used to
calculate these risk ratios is considered.

A somewhat different approach to this question was taken by
Seidman and colleagues (19791, who examined the mortality experi-
ence of a group of workers exposed to asbestos over a very limited
period of time during World War II and followed them for 35 years
after the onset of this exposure. These workers had an extremely
intense exposure to asbestos, but only very brief exposures with no
subsequent asbestos work-exposure history. If the risk of lung cancer
declines significantly following the cessation of exposure to asbestos,
then these workers would be expected to have a declining risk of
developing lung cancer with increasing duration from the onset of
asbestos exposure. Figure 7 shows the ratio of observed to expected
lung cancer deaths for the lo-year periods beginning 5, 15, and 25
years after the onset of exposure in workers who had worked less
than 9 months and those who had worked more than 9 months in
this plant. In both cases the risk is greater in workers for the lo-year
period beginning 25 years after onset of exposure than for the period
beginning 15 years after exposure. The small number of deaths
recorded in the study limits its interpretation; however, the data are
consistent with the conclusion that cessation of asbestos exposure
may not be associated with a decline in the relative risk of
developing lung cancer with increasing duration of time since last
exposure.

226


6.1

m
f 6
h
B 5
P
0 4

l-l   5.7
  I

5.0
r-l /I

I r

4.9
1

                                             3.9
i              3.4 3.5                     -
5
%   3-    - 2.6
;   2-
a"

l-I-r---.-.-II-.--..-      .1,-
    . . .
n

   "
        <to   lo-14 15-19 2&24 25-29 30-34 35-39 40-44 245

            Numbecofyearssubsequenttoonsetofe~wre

observed 0    7 29 59 105 112 65 40 69
-0.7
Expead     ----~--- 2.7 6.5 17.0 21.0 16.4 11.5 6.1 17.0

FIGURE 3.-Ratios of observed to expected deaths from
      lung cancer among 17,806 asbestos insulation
      workers observed prospectively, 1967 and 1976,
      in byear periods subsequent to beginning

employment in this trade

NOTE: The decline in ratios after the 30. to Syear period may be the result of B "survivor effect." because
deaths associated with cigarette smokmg 1e.g. myocardial infarction. lung cancer) tend to selectively change the
composition of the surviwng cohort in relatmn to smoking status wth time.
SOURCE: Selikoff. Hammond et al. (1980).

A similar result was reported by Blot and colleagues (1980) in a
case-control study of male lung cancer patients. They found a small
excess risk of developing lung cancer in workers who had been
employed in shipyards for only a few years during World War II, and
the relative risk in these workers was similar to that for workers
who had worked regularly in the shipyards.

In summary, the data suggest that elimination of further asbestos
exposure may prevent the further increase in relative risk that
would accompany an increase in cumulative exposure. However, the
relative risk of developing lung cancer persists even after prolonged
avoidance of additional asbestos exposure. In contrast, the cessation
of cigarette smoking appears to reduce the risk of developing lung
cancer in asbestos insulation workers compared with those workers
who continue to smoke, and the time course of this reduction in risk

227


TABLE 8.-Changes in the ratio of observed to expected
      deaths with time since first employment, four
       cohort studies

Years since             Quebec               New York-     Asbestos
initial      North Amerum   miners and    Factory    New Jersey     cement
exposure      insulators      millers 2      workers3     insulators '     workers '

< 10

! 1-15

16-20

21-25

26-30

31-35

36-40

4145

46250

Total number
of deaths

2.55    171

3.40   1291

3.48   159)

5.00  (1051

6.08  (1121

5.68   (65)

4.93   (40)

3.89   (691

(466,

                   0.00   (0)     0.77   (1)

                             1.25   (31

000   CO!     2.38   141     8.67  (26)     1.54   (6)

                             2.33   (71

1.94   (71     3.73  cx3)               3.33   (5)

                   6.63  (67)     3.08   (4)

4.19  (16~     1.37  6)

1.6i   151

128J        (33)        (93)        (26)

I Data from Sehkoff, Hammond et al. (19801.
`Data from Nicholson et al. (1979).
3 Data from Nicholson et al. 119791.
' Data from Selikoff et al (19791
a Data from Weill et al. 119791
NOTE Number of deaths gven III parentheses
SOURCE Walker c 19841

is similar to that found among smokers in the general population
who stop smoking.

Mechanisms of Carcinogenesis in Cigarette-Smoking
Asbestos Workers

An increased risk of developing lung cancer has been observed
with all commercially used types of asbestos. Most studies indicate
that crocidolite exposure may produce a higher human lung cancer
risk than chrysotile (Weill et al. 1979; Enterline and Henderson
19731, but some studies have shown the opposite (McDonald et al.
1983a, b; Dement et al. 1982). All of the four major histologic types of
bronchogenic carcinoma develop in asbestos workers who smoke
(Churg 1985; Auerbach et al. 1984; Whitwell et al. 1974). Although
an increased risk of lung cancer with exposure to asbestos in
nonsmokers has been demonstrated in a number of epidemiologic
studies (Hammond et al. 1979; McDonald et al. 19801, it remains
unclear whether the asbestos fiber by itself acts as a complete
carcinogen for lung cancer in the respiratory tract of man. This is in
contrast to the role of asbestos as a carcinogen in mesothelioma,

228


FIGURE 4.-Age-specific mortality rates for cancer of the
      bronchus, trachea, and lung, white men and
       women, United States
SOURCE. McKa> of al / 19821

229


, ~~

30-

I
4&

1         1         1        1
5s       60-       70-       eo-

   Age

1885


1990


1875

FIGURE L-Age-specific mortality rates for cancer of the
      bronchus and lung, by birth cohort and age at
       death, men, United States, 1950-1975
SOURCE Data derived from McKay et al. 11982).

230


  70 -







  60----







  50 -







  40 -

E
0
a"


  30 -







  20 -







  10







   o-

l-1950

-1960

1900   1910   1920    1930   1940    1950 1960    1970   1980


                     Year

FIGURE 6.-Changes in the prevalence of cigarette
      smoking among successive birth cohorts of
       men, 1900-1978

SOTE Calculated from the resulLs of more than 13.ooO lnterwews conduct& dunng the last two quarters of
1978, prowded by the Natmnal Center for Health Statlstlcs. D~vwon of Health Interview Statlstia.
SOURCE US DHHS r19821.

where asbestos exposure alone is clearly able to produce the tumor
and where cigarette smoking does not alter the mesothelioma risk.
Laboratory investigations have been undertaken to evaluate the
mechanisms through which asbestos interacts with the combustion
products of cigarettes to induce neoplasms. In this regard, the
carcinogenic properties of polycyclic aromatic hydrocarbons (PAH),
documented chemical carcinogens in cigarette smoke, have been

231


TABLE 9.-Prevalence of smoking among asbestos
      insulation workers whose smoking history was
       known

Age

Current          Former
smokers          smokers

NWW
smoked
regularly

PW
and
tiger

25-29             64.8            19.3            13.0          2.5

30-34             61.0            19.3            13.5          6

35-39             60.9            22.2            11.6          4.9

40-44             61.3            25.0             9.2          45

4S-u             55.8            26.8             9.8          56

5M4             53.7            32.2             9.1          5.0

55-59             50.1            34.1             9.8          6.0

6&64             45.4            35.1            10.4          91

65-69             42.3            33.7            12.4         li.6

7&74             30.7            34 3            17.5          17 5

X-79             51.5            34.3             7.1          71

B&84             37.1            33 3            11.1          18.5

2%              30.0            35.0            25          10.0

Source Hammond et al t 19791

evaluated in combination with asbestos both in tissue cultures and in
grafts of respiratory tract epithelium (reviewed in Craighead and
Mossman 1982; Mossman, Light et al. 1983). This section summarizes
the results of these experimental studies.

Animal Studies of the Carcinogenic Interactions Between
Cigarette Smoke and Asbestos

When animals are administered asbestos in inhalation chambers
or by intratracheal instillation, differences among species and
strains appear to influence the occurrence of lesions. For example,
only benign lesions (papillomas and adenomas) are found in ham-
sters, guinea pigs, and rabbits after prolonged inhalation of asbestos
(Botham and Holt 1972a, b; Gardner 1942; Reeves et al. 19741,
whereas cats (Vorwald et al. 1951) and nonhuman primates (Wagner
1963; Webster 1970) develop fibrosis of the lung but not tumors.
Small numbers of neoplasms (squamous cell carcinoma., adenocarci-
noma, small and large cell carcinoma) have been reported in rats
(Davis et al. 1978; Reeves 1976; Reeves et al. 1974; Wagner et al.
1974), but benign neoplasms and fibrosarcomas (tumors rare in the
human lung) predominate. Mice also appear to develop both benign
and malignant tumors after inhalation of asbestos (Bozelka et al.
1983; Gardner 1942). Bozelka and colleagues (1983) found a large

232


Starting
p01llt
(Years)



    5


   15


   25









    5


   15


   25

Lung cancer

Worked c 9 months

Worked > 9 months

0    1    2    3    4    5    6    7    6    9   10   11   12

               Rabo of observed lo expected

FIGURE 7.-Observed compared with expected weighted
      average probabilities of lung cancer death in
      lo-year periods, starting at 5-, 15-, and 25-year
      points after beginning of work in an amosite
      asbestos factory, 1941-1945, for men who
        worked less than or more than 9 months
NOTE: Computed by assigmng wwghts of 55 and 45 percent to the prababllitles given in Sadman and colleagues
t19791 for men aged 40 to 49 and 60 to 59, respecuvely. at the start of the 1Gyear pen&
SOURCE- Sadman et al !19791.

number of lesions of questionable malignancy in the lungs of Balb/c
mice 12 to 18 months after a 75day exposure to chrysotile asbestos.

Unfortunately, it is difficult to evaluate many of these animal
studies critically because satisfactory controls were not employed
and data on exposure regimens and concentrations of asbestos are
often not available. In addition, adequate pathologic documentation
of the lesions is often lacking. Benign adenomas could occur
spontaneously in many lesser species (Mitruka et al. 19761, and
luxuriant squamous metaplasia and bronchiolization of the respira-
tory mucosa may be misinterpreted as malignant lesions. These last
epithelial changes may occur as a response to injury induced by
asbestos (Davis et al. 1978; Mossman et al. 1980; Reeves et al. 1974;
Wagner 1963; Woodworth et al. 1983a, b).

233

157-964 0 - 86 - 9


Several investigators have administered chrysotile to rats and
hamsters in combination with either cigarette smoke or ben-
zo[a]pyrene (BaP), a major polycyclic aromatic hydrocarbon (PAH) in
cigarette smoke (Table 101 (Miller et al. 1965; Pylev and Shabad
1973; Shabad et al. 1974; Smith et al. 1968; Wehner et al. 1975). A
striking increase in neoplasms (both benign and malignant) of the
respiratory tract was observed. In contrast, a synergistic effect on
tumor development was not apparent in rats exposed to asbestos and
cigarette smoke by inhalation (Shabad et al. 1974; Wehner et al.
1975); however, the majority of the animals in these studies died
prematurely of pulmonary fibrosis.

The effects of asbestos on the carcinogenicity of PAH in the
respiratory tract have been evaluated using grafts of tracheal tissue
implanted into syngeneic animals. Two model systems have been
developed. In the first, the tracheas of rats are excised and formed
into tubular sacs by ligatures at the ends and then transplanted
subcutaneously (Topping and Nettesheim 1980; Topping et al. 1980).
When relatively large amounts of chrysotile are introduced into the
lumina of these grafts, inflammatory changes appear and fibrosarco-
mas develop in a substantial proportion of animals (Topping et al.
1980). On the other hand, epithelial tumors (carcinomas) appear
when low concentrations of the PAH dimethylbenz[a]anthracene are
introduced into the tracheal grafts before chrysotile (Topping and
Nettesheim 1980). The amounts of PAH used in these experiments
were insufficient to cause tumors; therefore, the asbestos acted as a
promoting agent.

In the second model system, organ cultures of hamster trachea are
exposed to crocidolite asbestos and implanted into syngeneic recipi-
ents after various periods of incubation in vitro (Craighead and
Mossman 1979; Mossman and Craighead 1979, 1981, 1982). Neo-
plasms failed to develop in these experiments. However, tumors, the
majority of which were carcinomas, were found when the PAH 3-
methylcholanthrene (3MC) was coated on the surface of the crocido-
lite fibers and precipitated onto the epithelial surfaces of the
tracheal organ cultures prior to transplantation. This tissue served
as the nidus for the development of squamous cell carcinomas in the
hamsters implanted with the cultures. In these experiments, asbes-
tos appeared to be a carrier of PAH, because 3MC also produced
tumors when absorbed to nonfibrous particulates such as kaolin,
hematite, and carbon (Mossman and Craighead 1979,1982).

Concepts of Carcinogenesis

The concepts of initiation and promotion were developed to
explain the complex, multistep process of chemical carcinogenesis.
"Initiation" is defined as the irreversible DNA damage of a cell
induced by a carcinogenic agent. In contrast, tumor "promotion" is a

234


TABLE lO.-Tumors occurring in rodents after exposure to asbestos in combination with components
      of cigarette smoke

Number of tumors/Number of animals

Chrysotile

Agent alone

Combination

Tumor types

Animal

Reference

Inhalation

5151

12151 (smoke)

9/51 (+smoke)

Adenoma, papilloma. carcinoma

Rat

Wehner et al.
  (1975)

O/46            ND'

O/16 (+smoke)
O/21 (+BaPY

ND

Rat

Shabad et al.
  (1974)

Intratracheal instillation

    ND

13137 (BaP)

18135 ( + BaP)

Adenoma, papilloma, carcinoma

Hamster

Smith et al
(1966)

o/17

lo/34 (BaP)

24/31 (+BaP)

Adenoma. papilloma. carcinoma

Hamster

Smith et al
(1966)

o/49




0110

O/19 (BaP)



4110 (BaP)

6111 (+Bap mixed)
6/21 (+BaP adsorbed)


  15/10" c+BaPj

  Adenoma, carcinoma,
reticulosarcoma, mesothelioma

  Papilloma, carcinoma

Bat




Hamster

Pylev and Shabad
   (19731


Miller et al.
   (1965)

' ND = no details provided
z BaP = benzcjalpyrene.
' Anunals developed multiple tumors.


sequential process whereby a second, but unrelated, generally
noncarcinogenic substance acts to enhance the effect of an initiator.
Initiated cells undergo proliferative changes and differentiation that
ultimately result in transformation to a malignant lesion. Much of
the information that has accumulated on classical tumor promoters
and their mechanisms of action was derived from studies with mice
in which the animal's skin was painted with PAH, followed by
repeated applications of phorbol esters (or related compounds)
(reviewed in Slaga et al. 1982). Nonetheless, the concepts of initiation
and promotion appear broadly relevant to carcinogenesis in the
mammary gland, liver, colon, urinary bladder, brain, and lung (Marx
1978). In this regard, a wide variety of chemical, physical, and
infectious agents interact with tissues to induce a constellation of
inflammatory and proliferative changes ultimately resulting in
malignancy.

It is doubtful that the action of asbestos in increasing lung cancer
risk is as a tumor initiator (reviewed in Craighead and Mossman
1982; Mossman and Craighead 1981). Few epithelial tumors develop
in experimental animals when PAH are not used in conjunction with
asbestos. Moreover, chrysotile and crocidolite do not seem to damage
the DNA of hamster or human tracheobronchial epithelial cells
(Fornace 1982; Mossman, Eastman et al. 1983). In most (but not all)
studies using cell culture systems, asbestos is neither mutagenic nor
carcinogenic (Chamberlain and Tarmy 1977; Daniel 1983; Kaplan et
al. 1980; Reiss et al. 19821, but the malignant transformation of
hamster embryo fibroblastic cells by asbestos, glass fibers, and silica
particles has been reported recently (Hesterberg and Barrett 1984;
Oshimura et al. 19841. Under these circumstances, asbestos may not
act like a classical mutagen, but appears to cause alterations in
chromosomal structure (Barrett et al. 19831, perhaps consequent to
its cytotoxic effects.

In contrast, asbestos exhibits many of the properties of classical
tumor promoters when introduced into grafts of tracheal tissue
(Topping and Nettesheim 1980) and monolayer cultures of hamster
and human tracheobronchial tissues (reviewed in Craighead and
Mossman 1982; Mossman and Craighead 1981; Mossman, Light et al.
1983). Like the phorbol esters, asbestos appears to induce perturba-
tions of the plasma membranes of cells, such as the stimulation of
membrane-associated enzymes (Mossman et al. 1979) and the
generation of oxygen free radicals (Mossman and Landesman 1983).
In addition, both asbestos and fibrous glass induce the biosynthesis of
polyamines, important biochemical markers of cell division and
proliferative changes in the tracheobronchial mucociliary epitheli-
urn (Landesman and Mossman 1982; Marsh and Mossman 1984).
This is accompanied by the development of squamous metaplasia, a
putative premalignant change. These alterations in cell function and

236


structure are not observed in tissues exposed to nonfibrous mineral
analogs of asbestos and glass, an observation indicating that the
fibrous geometry of the material is important (Woodworth et al.
1983b).

Cigarette smoke contains ciliostatic and toxic chemicals that
impair mucociliary transport and the function of phagocytic cells
(Warr and Martin 1978). Thus, intrapulmonary deposit,ion and
clearance of asbestos might be affected, resulting in increased
retention of asbestos in the lungs. In addition, the development of
squamous metaplasia consequent to exposure to both PAH and
asbestos (Mossman et al. 1984) might contribute to the retention in
the respiratory tract of asbestos and the constituents of cigarette
smoke.

Studies using artificial membranes and cells in culture suggest
other possible mechanisms of synergism between PAH and asbestos.
PAH are not carcinogenic in their natural state and must be
metabolized by a mixed-function, microsomal enzyme system (aryl
hydrocarbon hydroxylase, AHH) to degradative products and electro-
philic forms interacting with DNA (Freudenthal and Jones 1976). In
this regard, the association (adduct formation) of modified metabo-
lites of PAH with the DNA of "target" cells is thought to be a critical
event in initiation of those cells. A number of studies suggest that
the addition of asbestos and PAH to tracheobronchial epithelial cells
(Mossman and Craighead 1982), microsomal preparations from lungs
(Kandaswami and O'Brien 1981), and phagocytes (McLemore et al.
1979) affects the normal metabolism of PAH as measured by an
increase (or decrease) in activity of AHH enzymes. Unfortunately,
these results are inconsistent, possibly a reflection of the different
experimental systems evaluated. Accordingly, this important area of
carcinogenesis needs further exploration.

PAH are ubiquitous in the environment and are associated with
airborne particulates (Natusch et al. 1974). Thus, the ability of
asbestos and other particles to act as "condensation nuclei" for
chemical carcinogens has been explored using tracheobronchial
epithelial cells (Mossman, Eastman et al. 1983: Eastman et al. 1983)
and artificial or isolated cell membranes (Lakowicz and Bevan 1979;
Lakowicz et al. 1978). Transfer of PAH to cell membranes by
asbestos appears to occur more rapidly than with use of nonfibrous
particulates (Lakowicz and Bevan 1979; Lakowicz et al. 1978).
Moreover, the normal uptake of BaP and the formation of BaP-DNA
adducts by tracheal epithelial cells are increased when BaP is
adsorbed to chrysotile and crocidolite asbestos (Mossman, Eastman
et al. 1983; Eastman et al. 1983).

The pulmonary alveolar macrophage (PAM) is a key cell in the
response of the host to asbestos. PAMs accumulate at sites of
deposition of asbestos in the tracheobronchial tree (Brody et al.

237


19811, a process associated with activation and release of lysosomal
enzymes (Davies et al. 1974) and the generation of oxygen free
radicals (McCord and Wong 1979). In addition, these cells possess the
enzymatic capability to convert PAH to active metabolites (Autrup
et al. 1978) and may facilitate the transfer of hydrocarbons to
tracheobronchial epithelial cells and other cell types (Shatos and
Mossman 1983). Thus, either damage to or activation of macrophages
by asbestos and the components of cigarette smoke could influence
the process of carcinogenesis.

Conclusions

Several mechanisms by which cigarette smoke and asbestos may
interact to increase carcinogenic risk are possible, but they remain
unproved in man. First, asbestos fibers could serve as carriers of the
carcinogens of cigarette smoke into the cell. Physical transport of
this type has been demonstrated experimentally, and there is
evidence to suggest that asbestos transfers PAH to cell membranes
with unusual efficiency in comparison with other particulates. While
this mechanism is an intriguing possibility, it presupposes the
interaction of smoke constituents with aerosols of asbestos fibers in
the atmosphere. Events of this nature remain hypothetical and
unproved. A second mechanism is based on experimental evidence
accumulated in both animals and cell culture systems. In this
schema, asbestos serves as a promoter in the respiratory epithelium
to alter the properties of the epithelial cells and to enhance
neoplastic transformation in cells initiated by the combustion
products of cigarettes. Biological evidence supporting this mecha-
nism of carcinogenesis is compelling in experimental models of
carcinogenesis, but not easily tested in man.

The possible role of macrophages in the metabolism of PAH
adsorbed to asbestos is an intriguing consideration. These cells are
biologically activated in the smoker and in the lungs of those exposed
to asbestos. They frequently accumulate in large numbers in the
airspaces of individuals exposed to these and other pollutants. One
can only speculate on whether or not the alveolar macrophage
contributes to the metabolism of chemical carcinogens under these
circumstances.

Although obvious information gaps exist, consideration of the
experimental results described here and the contemporary concepts
of neoplastic transformation suggest several mechanisms of interac-
tion between components of cigarette smoke and asbestos. On the
one hand, asbestos appears to resemble a classical tumor promoter
after initiation of tracheobronchial epithelial cells by the carcinogen-
ic chemicals found in cigarette smoke. Alternatively, asbestos
appears to act as a vehicle for the transfer of PAH across cell
membranes and affects the metabolism of these carcinogens, factors

238


favoring the process of initiation. Finally, asbestos and the toxic
constituents of cigarette smoke injure cells, a situation potentially
encouraging the retention of these inhalants in the respiratory tract.

Chronic Lung Disease

Cigarette smoke (US DHHS 1984) and asbestos exposure (Selikoff
and Lee 1978) are well-established causes of chronic lung injury. As
in the preceding discussion of lung cancer, the enormous body of
literature that established the pathogenicity of each of these agents
is not presented; rather, this section focuses on the effects of
combined exposure. In contrast to their effect on the risk of
developing lung cancer, asbestos and cigarette smoke produce
different patterns of injury in the lung. The pattern of lung injury
associated with cigarette smoking is characterized by inflammation,
excess mucus production, narrowing of the airway lumen, and
emphysema (US DHHS 1984). The result is a reduction in maximal
expiratory flow rates and increased static lung volumes. The pattern
of lung injury associated with asbestos is fibrosis of the small
airways extending into the alveolar structures with obliteration of
alveoli, leading to a reticular nodular pattern of interstitial fibrosis
on chest roentgenogram and decreased lung volumes, with relative
preservation of the forced expiratory volume in 1 second (FEV,) as a
percent of the forced vital capacity (FVC) (Selikoff and Lee 1978).

In spite of these relatively distinct patterns of lung injury,
interpretation of the pattern of injury in combined exposure is
difficult. Both agents may act separately, but simultaneously, to
injure the lung. The injury in an individual worker is the combina-
tion of the injuries due to cigarette smoke, asbestos and other
environmental agents, and all other injurious processes that have
occurred during that individual's lifetime. The presence of a lung
injury secondary to one agent or process does not prevent the lung
from being injured by a second agent. In evaluating impairment in
an asbestos-exposed smoker, it may be difficult to apportion the
impairment between the two agents because both cigarette smoking
and asbestos exposure may alter a given lung function test in the
same direction (e.g., both of them reduce the diffusing capacity
(DLCO)), or they may change a test in opposite directions (e.g., an
increase in total lung capacity (TLC) due to smoking may mask a
decline in TLC due to asbestos). When a given physiologic test is
influenced in opposite directions by cigarette smoking and asbestos,
the degree of injury to the lung may be underestimated by the
change in that test. For example, the relative preservation of TLC in
cigarette-smoking asbestos workers does not represent a relative
protection of the lung in combined exposure, but rather reflects the
emphysematous destruction of alveolar walls secondary to cigarette

239


smoking (.which increases TLC) being combined with the asbestos-
related fibrosis and obliteration of other alveolar units (which
reduces TLC).

Interstitial fibrosis of the lung is a well-described and well-
established sequel of heavy asbestos exposure. In an individual, the
fibrosis is attributed to asbestos when a pattern of lung injury on
chest roentgenograph or lung biopsy consistent with that found in
asbestos-exposed populations is found in conjunction with a history
of significant asbestos exposure or with levels of asbestos in lung
tissue consistent with significant asbestos exposure. Fibrosis due to
other causes such as exposure to coal dust, silica, or infection needs
to be considered in evaluating individual patients, and both diagno-
sis and attribution to a specific etiologic agent may be difficult in the
very early stages of the fibrotic process. However, by the time the
process has progressed to the degree that it causes significant
disability or death, the diagnosis is usually readily evident and the
substantial asbestos exposure generally necessary to cause this
degree of fibrosis is also easily identifiable.

Chronic Lung Disease Death Rates

Cigarette-induced chronic lung injury does not produce the
extensive fibrosis commonly found in individuals dying of asbestos-
induced interstitial fibrosis, and therefore does not interfere in the
diagnosis, or attribution to asbestos, of the severe fibrotic lung
disease in these individuals. However, cigarette smoking can cause
significant lung destruction and disability, and therefore it may
contribute to the mortality and degree of disability in individuals
with asbestos-induced interstitial fibrosis, independent of any effect
of cigarette smoking on the degree or extent of fibrosis. In addition,
because death and disability occur only after extensive lung injury,
the independent (i.e., additive) lung injuries due to smoking and
asbestos might sum to produce a level of disability that could exert a
synergistic effect on death rates.

Frank (1979) presented data on the death rates in smoking and
nonsmoking asbestos insulation workers (Table 11). The population
was drawn from the 17,800 asbestos insulation workers studied by
Hammond and colleagues (1979) and included those workers with
more than 20 years of exposure whose smoking habits were known.
The age-standardized death rates from chronic lung disease (includ-
ing asbestosis) were increased by either cigarette smoking or
asbestos exposure, and the rate in cigarette-smoking asbestos
workers was well above the sum of the rates for non-asbestos-exposed-
smokers and nonsmoking asbestos workers, This "synergism" was-
also present when only asbestosis deaths were considered, with them
death rate almost three times higher in cigarette-smoking asbestos
workers than in nonsmoking asbestos workers. This study revealed a


greater than additive effect for cigarette smoking and asbestos
exposure on death rates from chronic lung disease and asbestosis.
This may reflect a "synergistic" effect on death rates of the
"addition" of the two separate injuries, rather than an effect of
cigarette smoking on the degree of fibrosis produced by a given dose
of asbestos. In addition, these data reflect the fact that a death
certification of asbestosis does not rule out the possibility of a second
disease process existing in the lungs of that individual.

Pulmonary Function Testing

The most frequently used measures of lung function are lung
volumes and measures of maximal expiratory airflow, either as the
volume expired during a given time (e.g., forced expiratory volume in
1 second, FEV,) or as the rate of expiratory airflow at a given lung
volume or between two lung volumes (e.g., forced expiratory flow
from 25 to 75 percent of the forced vital capacity, FEFzMw).
Classically, diseases are divided by their pattern of abnormality on
lung function testing into obstructive (processes that predominately
limit expiratory airflow) and restrictive (processes that predominate-
ly decrease lung volumes and specifically decrease the total lung
capacity). Both of these processes may occur in a single individual,
resulting in a mixed pattern (both reduced lung volumes and
reduction in volume-adjusted expiratory flow rates).

Obstructive lung disease is marked by reductions in the rate of
expiratory airflow; normal or, more typically, increased TLC; and
substantial increases in residual volume (RV) and functional residu-
al capacity (FRC) (Figure 8). Restrictive diseases are marked by a
reduction in TLC. The flow rates in restrictive disease are usually
normal or even increased once an adjustment for the decreased lung
volume has been made. FEV, is obviously limited by the total
volume that can be expired, as well as by the amount of obstruction
to expiratory airflow. For this reason, FEV, is commonly divided by
the forced vital capacity (FVC), and expressed as the percentage of
the FVC that can be expired in 1 second (FEV,/FVC%). This
adjustment of FEV, for reductions in FVC aids in separating the
decline in FEV, that is due to a restrictive process (i.e., reduced TLC)
from that which represents increased resistance to, and decreased
driving pressure for, expiratory airflow.
The pattern of lung function change in cigarette smokers has been

well described (US DHHS 1984), and consists of a reduced FEV, and
FEV,/FVC%, an increased RV and FRC, and an increased TLC
(particularly in those individuals with emphysema). In addition,
FEFwwG, DLCO, and flows at specific lung volumes are also usually
reduced.

The pattern of change with the development of interstitial fibrosis
due to asbestos is also clear. Figure 9 shows the changes in lung

241


TABLE Il.-Age-standardized death rates for combinations of cigarette smoking, no smoking, asbestos
     exposure, and no asbestos exposure; selected causes of death

Gl-CUp

All
CfdB?S

All
cancer

Noninfectious
pulmonary diseases
(total includes
  aS!J.?ShiS)

Asbestosis

All
other
causes

Death rates per lOO,C%U man-years
I. No adeatos work and no smoking                980.9           208.2              28.6               -'           743.9
II. No asbestos work, but smoking                 1580.7           353.1             103.8               -1          1123.8
III. Asbestos work and no smoking                 1430.9           563.9              77.1               77.1           789.9
IV. Asbestas work and smoking                  2659.0           1317.0             286.5              225.5          1005.5

Mortality ratice
No asbestos work and no smoking (I + I)              1.00            1.00             1.00                            1.00
No asbestos work, but smoking (II + I)               1.61            1.70              3.60                            1.51
Asbestca work and no smoking (III + I)               1.46            2.71              2.68                            1.06
Asbestos work and smoking (IV i I)                 2.71            6.33              9.95                            1.42

Excess in death rates
V. Smoking only (II-I)                        599.8           144.9              75.0               -1           379.9
VI. Asbestos work only (111-I)                    450.0           355.7              48.3               77.1            46.0
VII. Synergism (IV-I-V-W                     626.3           608.2             i34.4              148.4          -114.3

Percent excess in death rates
Smoking only (1cOV i I)                       61             70              260                             51
Asbestos work only (lOWI i I)                   46            171              -68                              6
Synergism WIOVII i I)                        64            292              467                            -15

NOTFK Rate per 100,ooO man-years standardized for age on the distribution of the man-yearn of all the asbestos msulation workers 2 20 years after onset of asbestos work. Rates for the asbestos
work-expoeure groups are based on cause of death coded according to the best available evidence.
' Death rates not available for the no asbestos work-exposure group.
SOURCE: Frank (1979).


Total lung

FlJ~tlO~al

esldual capacity

volume

COLD

Total lung

capacity

Functional

rasldual capackty

Resrdual

volume

I
   Normal

Total lung

Aestncttve
lung dfsease

FIGURE &-Lung volumes in normal individuals and in
     patients with chronic obstructive lung disease
      and restrictive lung disease

volumes and Figure 10 shows the changes in the forced expiratory
flow rates for the Quebec asbestos workers at several levels of
increasing cumulative exposure to asbestos dust (Becklake et al.
1972). The lung function tests were performed on 1,027 men aged 21
to 65 who represented an age-stratified random sample of the 6,180
men employed in the Quebec asbestos mines and mills on October 31,
1966. An additional 184 men between the ages of 61 and 65 were also
studied to increase the number of workers in the highest exposure
categories. The data in the figures represent the averages of the test
values for smokers and nonsmokers after they had been standard-
ized for age, height, and weight. Smokers were defined as those who
had ever smoked at least one cigarette per day for 1 year; therefore,
this category includes former smokers.

The pattern in nonsmoking asbestos workers is that of restriction;
there is a steadily declining TLC with increasing dust exposure.

243


t&l:                             *
                           
2 R       1            d
     -            : ,.,:,, :. .::: No
"6  ::     1               :.:.:
     -                      ..:.:.:.:,:.:
  ,-             -6
                              :.,. 1.
                  c
6  2    1               : :.:.: :. :j,..: 1. ..:
               -+

  0
  -  z    I               ,. ,. 0
  "                                          "

FIGURE 9.-Standardized mean values for subdivisions of
      lung volume (TLC[SS], IC, FRC, and RV) in
       nonsmokers and smokers, divided by dust
        index

FEV, also declines with increasing exposure, but this decline can be
accounted for by the decline in FVC, as FEV,/FVC% does not
decline with increasing exposure in nonsmokers and is above 80
percent in all but the lowest exposure category. FEFzs-75% is also
preserved in all but the two highest exposure categories. The FEFs

244


FIGURE lO.-Standardized mean values for flow rates
       (MMF, FEVTA, FEV,, and FVC) in
       nonsmokers and smokers, divided by dust
         index

NOTE in,= number of mdividuals m each subgroup
SOURCE Becklake et al 11972~

w measurement would also be expected to decline with a fall in
FVC, independent of any change in the degree of obstruction to
airflow. Thus, in this group of nonsmoking asbestos workers, the
pattern of asbestos-induced lung disease is a reduction in lung
volumes with preservation of FEV,/FVC%.


The changes in lung function in the smoking asbestos workers in
this study can be contrasted with those of nonsmoking asbestos
workers with comparable cumulative exposure histories (Figures 9
and 10). The static lung volumes (Figure 9) are larger for smokers
than nonsmokers at each level of cumulative asbestos exposure.
FEFz+x~, and FEV, are lower, as is FEV,/FEV%. There is a
progressive decline in FEV,/FVC% with increasing cumulative
asbestos exposure in the smokers but not in the nonsmokers. This
decline is probably attributable to the increase in cumulative
cigarette smoking exposure (and related injury) that occurs with
increasing cumulative asbestos exposure (Rossiter and Weill 19741,
because of the correlation between these cumulative measures. The
picture that evolves from this study of the effect of combined
cigarette smoke and asbestos exposure is one of an obstructive
process superimposed upon a restrictive process, In addition, in the
population of workers with relatively heavy asbestos exposure, TLC
is reduced in both smokers and nonsmokers, suggesting that the
restrictive pulmonary process exerts a greater effect than those
changes that tend to increase TLC (e.g., emphysema). The relative
preservation of TLC that occurs in cigarette-smoking asbestos
workers in comparison with nonsmoking workers should not be
interpreted as a protective effect of smoking, because it almost
certainly represents more extensive lung damage (i.e., the combina-
tion of emphysematous and fibrotic processes) in the lungs of the
cigarette smokers. It is also important to note that the data from this
study show a relatively clear dose-response relationship between
cumulative asbestos exposure and degree of restrictive impairment.

The pattern of lung function response in smoking and nonsmoking
workers found in this study is consistent with the premise that
asbestos exposure causes a relatively pure restrictive lung disease
and cigarette smoking causes a relatively pure obstructive process.
In combined exposure, the lung functional changes represent the
combination of the effects of these two independent processes. A
number of other studies have examined the lung function in smoking
and nonsmoking asbestos workers, and the data from these studies
can be used to explore this relationship further.

A general morbidity study was conducted of civilian naval
dockyard workers in Great Britain, and lung function tests were
performed on 612 male registered asbestos workers (Harries and
Lumley 1977). The measurements were standardized to a height of
1.7 meters and to a constant age within each of five age ranges.
Smoking habits were classified as smoker, nonsmoker, or ex-smoker.
TLC showed no relationship to age, smoking status, or duration of
asbestos exposure. There was a tendency for smokers to have a lower
FEV, than nonsmokers, and the difference increased with age. FEV,
and duration of asbestos exposure were related only for those aged

246


50 to 59. The differences in FVC between smokers and nonsmokers
were less than the differences in FEV1, demonstrating a relative
preservation of FEV,/FVC in nonsmokers, and a relationship
between duration of exposure and FVC was again present only in the
50- to 59-year-old age group. The absence of a relationship between
TLC and duration of exposure may be due to the somewhat lower
intensity of asbestos exposure in this population in comparison with
the Quebec miners.

In a companion study of the same naval dockyards, Rossiter and
Harries (1979) examined the lung function in 1,200 men aged 50 to
59. The sample included all men in the register of asbestos workers,
1 in 3 of those currently in occupations where intermittent exposure
to asbestos might occur, and 1 in 30 of the remainder. Lung function
measurements were standardized to age 55 and a height of 1.7
meters. Smoking was characterized as nonsmoker, ex-smoker, or
current smoker, and lung function was analyzed by duration of
exposure to asbestos. FEV, was lower in the smokers than in the
nonsmokers, and the workers in the registered asbestos-exposure
group had lower values than workers in other occupational groups.
This was particularly true of the group of asbestos laggers who had
been employed prior to 1957. The differences in FVC among the
different smoking habits were less than the differences for FEV,.
The FEV,/FVC ratio was markedly influenced by smoking. Even
among those workers employed before 1957, the FEV,/FVC ratio
was preserved in nonsmokers but declined among cigarette smokers.

Weill and colleagues (1975) adopted a somewhat different ap-
proach by developing predictive equations specific for the smoking
status of the worker, as well as age and height, for the individual
function tests. FEF2675~ was lower and declined more rapidly in
smokers than in nonsmokers (Figure 11) in the population used to
develop the predictive equations. The researchers applied these
smoking-specific regression equations to 859 workers who were
employed in two asbestos manufacturing plants in New Orleans on
November 3, 1969. Dust exposure measurements were derived from
midget impinger samples taken between 1952 and 1969 and from
estimates of exposures derived from interviews with employees who
had worked prior to this time period. Figures 12 and 13 reveal a
decline in TLC with increasing cumulative asbestos exposure; as
would be expected, this decline is accompanied by declines in the
vital capacity, FEVI, and FEFzx,~. However, there is no decline in
FEV,/FVC with increasing duration of exposure. The decline in TLC
and vital capacity at the lower exposure levels occurred entirely in
the group with x-ray changes, but for the two highest exposure
categories, the decline in TLC and vital capacity occurred even in the
group with no roentgenographic changes. Again, this study suggests
that the effect of asbestos dust exposure in a manufacturing plant is

247


Nonsmokers
(n=57)

35                45                55

Age, years

FIGURE Il.-Relationship between FEVB-75% and age for
      the smokers, ex-smokers, and nonsmokers in
      the standard group (height taken as 175 cm
       [5 feet 9 inches])
SOURCE Weill et al G 19751

largely that of a restrictive process producing a decline in TLC, with
the decline in FEV, and maximal midexpiratory flow between 25
and 75 percent of FVC (MMF 25-75~) being a reflection of the decline in
lung volumes rather than an indication of the presence of airflow
obstruction.

Several analyses have focused on the pattern of pulmonary
function response rather than on isolated test values (Fornier-
Massey and Becklake 1975, Becklake et al. 1976; Muldoon and
Turner-Warwick 1972; Murphy et al. 1972, 1978). These authors
were attempting to determine whether asbestos exposure results in
chronic obstructive lung disease, either in the absence of cigarette
smoking or in excess of the level to be expected solely from smoking.
The stratified sample of 1,027 Quebec asbestos miners and millers
described earlier in this section was also analyzed by the pattern of
pulmonary function response (Fornier-Massey and Becklake 1975;

248


Total lung capaccty

Percent standardlzed

All sublects

No x-ray

Any x-ray
change

V~tal capacity                                   .     .   . . .

                100

Percent standardmd

All subjects

No x-ray        Any x-ray
change        change

Functmal residual CapaCitY

                100

Percent standardnzed

All subjects

No x-ray
change

Any x-ray
change

FIGURE 12.-Relationship between lung volumes and dust
         exposure
SOURCE We111 et al t 19751

Becklake et al. 1976). These workers were categorized as having a
normal, undifferentiated, obstructive, or restrictive pulmonary func-
tion picture on the basis of a combined score of the percentage
deviations from the predicted value of five pulmonary function tests


FEV,

Percent standardzed

All subjects

No x-ray        Any x-ray
change         change

FEV,lVC             105

Percent standardzed

change

Any x-ray
change

Percent standardmed

All sublects

No x-ray
change

Any x-ray
change

FIGURE 13.-Relationship between expiratory flow and
       dust exposure
SOURCE We,ll et a, 119751.

(Table 12). The deviation of the percentage predicted value was
scored from 7 through 13 for each value, with lower numbers
representing those measurements indicative of restrictive disease

250