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235

377-313 0 - 82 - Ii


PART IV. INVOLUNTARY SMOKING
        AND LUNG CANCER

237


INVOLUNTARY SMOKING AND LUNG CANCER

Introduction

The social pressure to limit smoking in public places (6) reflects
concern for protecting nonsmokers from the annoyances of others'
cigarette smoke, as well as concern about the possible adverse health
effects of involuntary smoking, or secondhand exposure to others'
cigarette smoke.

A recent publication presented the scientific evidence linking
involuntary smoke exposure to adverse health effects (44). Children
of smoking parents had more bronchitis and pneumonia during the
first year of life (17); and acute respiratory disease accounted for a
higher number of restricted activity days (1.1 days) and bed disability
days (0.8 day) in children whose families smoked than in those whose
families did not (3). A reduction in exercise tolerance with exposure
to sidestream cigarette smoke has been demonstrated in patients
with angina pectoris (I), and a decrease in small airway function of
the lung equivalent to that observed in light smokers (1 to 10
cigarettes a day) has been reported in adults who never smoked
themselves nor lived with smokers, but who were exposed to
cigarette smoking in the workplace (49).

Only recently has attention focused on the possibility that lung
cancer may be caused by involuntary inhalation of tobacco smoke.
This concern is based upon: (1) the occurrence of similar chemical
constituents in sidestream smoke (smoke released from the cigarette
between active puffs) and mainstream smoke (smoke actively
inhaled); (2) the established dose-response relationship between
voluntary cigarette smoking and lung cancer, and the absence of
evidence establishing a threshold for effect; and (3) the recent
epidemiologic studies that examined lung cancer mortality in
nonsmoking spouses of cigarette smokers.

Smoke Constituents

The average person spends most of the time indoors where there
may be significant exposure to tobacco smoke generated by others
(32). For various reasons, the exposure of nonsmokers is more
difficult to quantitate than that of the smoker. The constituents of
the particulate and gas (vapor) phases of tobacco smoke have been
quantitatively analyzed in several studies (8, 22, 37, 38). As is shown
in Table 1, many of the chemical constituents of mainstream smoke
are also found in sidestream smoke. Some constituents occur in
markedly higher concentrations in sidestream than in mainstream
smoke (note SS to MS ratio); however, sidestream smoke is released
into the ambient air, resulting in dilution of constituents. The
resulting concentration of smoke is dependent upon the amount of

239


TABLE l.-Constituents of cigarette smoke.' Ratio of
       sidestream smoke (SS) to mainstream smoke
       (MS)

Carbon Dioxide
Carbon Monoxide
Methane
Acetylene
Propane Propene
Methylchloride
Methylfuran
Propio+dehyde
%Butan0ne
Acetone

A. GAS PHASE         MS   WMS                     MS   SSMS

                       8.1   Nitrogen Oxides (NOx)
                       25   Ammonia
                       3.1   Hydrogen cyanide
                       0.8   Acetonitrile
                       4.1   f'yridine
                       2.1   3-Picoline
                       3.4   SVinylpyridine
                       2.4   Dimethylnitrosamine
                       2.9   Nitmspyrmlidine

8. PARTICULATE
PHASE

MS SS/MS                      MS   WMS

"Tar"
Water
Toluene
Stigmasterol
Total Phytostemls
Phenol
Catechol
Napthalene
Methyln~phthalene
Pyrene
Benzo(4wene

1.7
2.4
5.6
0.8
0.8
2.6
0.7
16
28
3.6
3.4

Quinoline            1.7 Irg     11
Methylquinolines        0.7 pg     11
Aniline             360 w     30
%Naphthylamine         2%     39
4-Aminobipheny!          5 m3     31
Hydrazine            32%     3
N'-Nitrownornimtine    lo&x@ ng     5
NNKZ            mmng     10
N&tine           l-2.5 mg     27

`Nonfiltereigarette

ZNNK - ~N-methyl-N-ni~mino)-1~5pyridgl~l-butanone(tobrcm c.pecificcarcinogenk nitmumim)
SOlIH~`E I: S lkrwrtment 01 Health. Educatmn. and Welfaretlll

smoke generated, the volume of ambient air, and the type and
amount of the ventilation of that space (2, 4, 24, 34, 44). In addition,
the chemical composition of smoke changes with the passage of time
(24~). Further complicating factors include the continuous low-dose
exposure of involuntary smokers contrasted with the intermittent
high-dose exposure of the active smoker. Thus, many factors
complicate the theoretical extrapolation of machine measurements
of smoke constituents to the biologic effects to be expected with
exposure of nonsmokers.

The actual absorption of smoke c0nstituent.s by nonsmokers in
smoke-filled spaces has not been completely characterized. A few
studies have examined the absorption of carbon monoxide by
measuring carboxyhemoglobin levels in exposed nonsmokers (44);
however, the absorption of most other constituents has not been
studied. Furthermore, the pattern of involuntary inhalation proba-
bly differs from that of voluntary inhalation of smoke by the smoker,
affecting the pattern and amount of deposition or absorption of

240


chemical constituents in nonsmokers compared to smokers. Differ-
ences in the carcinogenicity of sidestream and mainstream smoke
may also exist; sidestream smoke condensate is more tumorigenic
per unit weight in mouse skin assays than is mainstream smoke
condensate (50).

Some evidence exists that suggests, however, that involuntary
exposure to cigarette smoke does result in deposition or absorption of
constitutents. Involuntary inhalation of cigarette smoke has been
shown to produce tracheobronchial epithelial metaplasia and dyspla-
sia in animals (23). The applicability of these data to human
exposures is not clear, however, since the levels of smoke exposure
used in this animal study were substantially higher than those
normally encountered by humans in enclosed spaces where smoking
is allowed (38). In a smoke-filled, unventilated, unoccupied room, the
concentrations of several smoke constituents, including several
volatile gases, total particulate matter, and nicotine, remained
constant and were higher than when humans were present. Further,
several vapor phase constituents such as nitrogen oxide, acrolein,
and aldehydes were observed to decrease continuously over 3 hours
when humans were placed in the room, despite fresh sidestream
smoke being generated to keep the ambient carbon monoxide level
stable (24). The difference in absolute levels and the continuing
decrease in constituent concentrations despite the continuing addi-
tion of smoke to the environment suggest absorption by humans,
although the actual site(s) of deposition has not been determined.

Dose-Response Relationships

Examination of the dose-response relationship for voluntary
smokers suggests an increased risk with any level of regular
cigarette smoking (43). No threshold level of exposure for the
development of lung cancer has been established and, therefore, any
level of exposure is of concern. Figure 1 reflects the data that led to
the scientific consensus that there is no threshold level. This absence
of a clear threshold level of exposure raises the issue of whether the
levels of exposure reached through involuntary smoking may also
produce an increased risk of lung cancer.

Epidemiologic Studies

The use of epidemiologic techniques to search for an association
between involuntary smoke exposure and lung cancer has a number
of methodologic difficulties.

241


10          20          30          10

CURRENT NUMBER OF CIGARETTES SMOKED PER DAY

0       0 Bnttsh Physictans

)6----$(   Canadmn Veterans

.a . . . . . . . . . . . .   u s veterans

v----q   u s. men I" 25 states

FIGURE l.-Mortality ratios of deaths from lung cancer in
      men. Data from four large prospective studies

SOURCE Rn)al College of Physictans of London t&Y51

242


Exposure

An individual's actual smoke exposure dose is difficult to quantify,
even for an acute exposure. For the longer exposure periods, as in
chronic disease epidemiologic studies, the exposure quantification
problems are magnified. Dosage is dependent upon the amount of
smoking by those around the nonsmoker, the spatial distance
between the nonsmoker and smoker, the duration and frequency of
exposure, and a number of other factors that complicate the
quantification of involuntary smoke exposure in either retrospective
or prospective studies. Several studies have used the smoking habits
of the spouse of the nonsmoker as a means of identifying two groups
(nonsmokers with smoking or nonsmoking spouses). This estimate of
exposure is subject to misclassification, as the nonsmoker may be a
former smoker. This may be true for either the nonsmoker being
followed or the nonsmoking spouse in the control group. In addition,
in societies with a high rate of divorce or multiple marriages, the
smoking habits of the current spouse may not approximate the
actual exposure. Further, there is a demonstrable correlation
between the smoking habits of spouses that decreases the proportion
of couples available for study who are discordant for smoking.

Long Latency Periods

Lung cancer follows exposures experienced over decades and,
therefore, it is necessary to observe nonsmokers over an extended
time in order to estimate their actual exposure.

Other Carcinogenic Exposures

Exposure to cigarette smoke may occur in conjunction with
exposure to other occupational or environmental carcinogens. Epide-
miologic studies should control for or investigate possible interac-
tions with other environmental exposures as far as possible, but
limitations clearly exist here as well. Accurately assessing lifetime
exposures and attempting to control for such exposures are difficult,
if not impossible.

Current Epidemiologic Evidence

To date, three epidemiologic studies have been published that
examine the lung cancer risk of involuntary smoking. Two of these
studies (19, 42) were conducted in the relatively traditional societies
)f Greece and Japan; the third analysis was conducted in the Unit,ed
states by Garfinkel (IZ), based on data originally collected by
Hammond (14).
Trichopoulos et al. used the case-control method of study over the
oeriod of September 1978 through June 1980. They identified 51

243


Caucasian female lung cancer patients and 163 adult female
orthopedic patients in Athens. All subjects were questioned on their
personal smoking habits, and husbands were classified as nonsmok-
ers (never smoked or quit more than 20 years prior), ex-smokers
(stopped smoking 5 to 20 years prior), and current smokers (current-
ly smoking or smoked within 5 years prior to interview). Single
women were classified with the group having nonsmoking husbands.
The cases and controls did not differ in age, duration of marriage,
occupation, education, or place of residence, although specific
matching on these characteristics was not performed. Involuntary
exposure of the wife was estimated from her husband's daily
consumption, from the date of marriage until their divorce, her
husband's death, or change in his smoking habits; multiple mar-
riages were also considered.

Excluding 11 voluntary smokers from the 51 female lung cancer
cases, and 14 smokers from the 163 controls, the remaining 40
nonsmoking lung cancer patients and 149 nonsmoking control
women were compared by their husband's current smoking status,
and estimated total cigarettes smoked by the husband by the time of
interview. The results are shown in Tables 2 and 3 respectively.
Compared with the control group, at interview the lung cancer cases
showed l.&fold greater probability of being married to an ex-smoker;
2.4-fold greater odds of being married to a light or moderate smoker
(20 or fewer cigarettes per day); and 3.4-fold greater odds of being
married to a heavy smoker (more than 20 cigarettes per day). The
trend observed in these findings was statistically significant, with a p
value less than 0.02. Exclusion of single women from this analysis
modified the relative risks only slightly. Table 3 shows a similar
trend of increasing relative risks in nonsmoking wives with increas-
ing (estimated) total number of cigarettes smoked by the husband
prior to the interview.

Some limitations and strengths of this study were recognized and
discussed by the authors. Among the limitations were: the number of
cases was small; 35 percent of the tumors lacked histologic confirma-
tion; controls were chosen from a different hospital than were the
cases; a single unblinded interviewer was used for both cases and
controls. On the other hand, the authors suggested that the
conservative social setting for this study may be less subject to errors
of misclassification resulting from the exposure of nonsmoking wives
of nonsmokers to the smoke of others outside the home. The number
-of cases of adenocarcinoma that were excluded from the analysis is
not given. Analysis including such cases would be of interest (16), as
many investigators have found cigarette smoking to be a cause of
adenocarcinoma of the lung as well 2s of other histologic types of
lung cancer (45). Additional control groups for comparison to the
cases might have enhanced the findings of this study.

244


TABLE 2.-Smoking habits of husbands of nonsmoking
     women with lung cancer and of nonsmoking
       control women

Cigarettes per day lcurrent smokers1

Diagnostic
group

Nonsmokers     Exsmokers

l-10   1 l-20   21-30   31+   Total

Lung cancer        11           6        2 13     4 4     40
COntr&           71          22    Q  f-2    149

RRa              1.0          1.8         2.4          3.4
RRb              1.0          1.5         2.0         3.0

* Relatwe r-k-the ratio of the risk of lung cancer among women whose husbands belong to a particular
.mokmg category to that among women whose husbands are nonsmokers X1=6.45. p(Z-talI~ 0 02
bAnalys~s excluding single women arbrtrardy clasafied as nonsmokers X'llrnear trendi=4.6. px 0 03
SOURCE Tnchopoulos et al (42)

TABLE 3.-Distribution of nonsmoking women with lung
     cancer and of nonsmoking control women
     according to the estimated total number of
     cigarettes smoked by their husbands by the
       time of the interview

Total number of cigarettes (in thousands)

Diagnostic
group            0     l-99    lOS199   200-299   3oLx399   400+    Total

Lung cancer       8       4       6 9       6 7       40
controls         56      21   L-2   ,`2      149

RRa            1.0      1.3         2.5            3.0

`Relative risk-the ratio of the risk of lung cancer among women whose husbands belong to a particular
smokmg category to that among women whose husbands are nonsmokers X2-6 50, p(2-tail]< 0.02.
SOURCE: Trichopoulos et al. t1981l.

Hirayama (19) used a prospective design in 29 health districts in
Japan over 14 years, from 1966 to 1979, in which 91 to 99 percent of
the census population was interviewed. He analyzed interview data
from 265,118 adults aged 40 years and older, and found that 72.3
percent of the couples had data on the smoking habit of both spouses.
Among 91,540 married women, 245 deaths from lung cancer were
recorded, of which 174 were nonsmokers. He reported 2 statistically
significant excess rate of lung cancer among nonsmoking wives of
smokers 2s compared to nonsmoking wives of nonsmokers. Table 4
shows the standardized mortality rates for lung cancer in non-
smoking wives, adjusted for age and occupation. There is an
apparent dose-response relationship in each of the analyses present-
ed. Certain methodologic details (e.g., the definition of an ex-smoker

245


husband, the method of age and occupation standardization, and the
technique or extent of histologic confirmation) were not presented.
Hirayama also examined the effects of I voluntary smoking in
relationship to involuntary exposure and nonexposure. The stand-
ardized annual mortality rate for nonsmokers who were not involun-
tarily exposed was 8.7 per 100,000. For women who reported being
exposed to cigarette smoke only involuntarily, the standardized
annual mortality rate was 15.5 per 100,000. For women who
voluntarily smoked, the standardized annual mortality rate was 32.8
per 100,000. He concluded that the effect of involuntary smoking was
approximately one half to one third that of active or voluntary
smoking.

The age and, occupation standardized risk ratios in this population
failed to show ,any statistically significant effect of spousal smoking
on nonsmoking women's standardized risk ratios for deaths from
other causes, including emphysema (although the trend in relative
risk was in the same direction as for lung cancer mortality), cervical
cancer, stomach cancer, or ischemic heart disease (Table 5); no
significant role of spousal alcohol consumption was demonstrated for
any of the above diseases.

The public press has reported a possible error in Hirayama's
computation of the chi square test of statistical significance (33).
However, the scientist to whom this finding was attributed has
subsequently stated that he raised questions about the study but
denied reaching any conclusion (29u).

Harris and DuMouchel (18) recalculated the chi square using the
originally presented data of Hirayama by combining Tables 1 and 2.
The calculated chi square of 8.09 yielded a statistically significant
two-sided p value of 0.0004.

In a subsequent, more detailed tabular presentation, Hirayama
(21a) confirmed the statistically significant excess in lung cancer
death rates in wives of smokers when adjusted for husband's age,
occupation and smoking habits. In this subsequent analysis, Hiraya-
ma restricted his analysis to data from one prefecture for a possible
dose-response relationship of involuntary smoking and lung cancer
mortality. The exposure of nonsmoking wives was calculated by
multiplying the hours of the day the husband was at home by the
number of cigarettes smoked per hour, assuming that the number of
cigarettes smoked per hour remained constant over waking hours.
There was a clear dose-response observed (Tabie 6) for each of three
categories for length of hours and for number of cigarettes smoked
per day. The risk of death from lung cancer in nonsmoking women
increased with either the time of exposure or increasing daily
number of cigarettes. In that set of analyses, the relative mortality
risk (as. measured by the standardized mortality ratio) observed

246


TABLE 4.-Standardized mortality for lung cancer in
      women by age, occupation, and smoking habit
       of the husband (patient herself a nonsmoker)

Husband's smoking habit              Nonsmoker

Ex-smoker
or l-19iday

> 20:day

Population of wves
No of deaths from lung cancer
Occupation-standardized
mortality/1OO,CKKl

Population of wwes
No. of deaths from lung cancer
Occupation-standardi~d
mortalityilWXKl

14,020        30.676        20.584
11          40          36

5 64         9 34         13.14

7,875         13.508        4,877
21           46          20

15 79         24 44         29 60

Standardized risk ratio far all ages          1.00          1.61          2.08

Population of wives
No. of deaths from lung cancer
.Age-standardized
mortality/100,O(Xl

10,406        20.044        9,391
17          52          24

9.54

17.02

16.40

Population of wives
No of deaths from lung cancer
Age-standardized
mortal~ty/1OO.OCG

11,489        24.140        16.070
15          34          32

9.13         10.46         17 78

Standardized risk ratlo for all occupations      1.00         1 43          1.90

among nonsmoking wives of smoking husbands was markedly lower
than that observed for women who actively smoked (Figure 2).
The observed differences between wives of smokers and wives of
nonsmokers were evident for each of the four socioeconomic status
classes.

Hirayama's article has stimulated much discussion, which has
been published as Letters to the Editor of the British Medical
Journal (5, 13, 25a, 27, 27a, 30, 36, 40, 42~). In three replies to the
same journal (20, 21,21a), the reader is referred to the specific issues
raised and responded to in these letters.

247


TABLE 5.-Age-occupation standardized risk ratio for
     selected causes of death in women by smoking
     habit of the husband (patient herself a
       nonsmoker)

Cause of
death

-

   Husband's smoking habit

Nonsmoker  Ex-smoker,   2 20/dsy    p value
      or I-19/day              *

Lung cancer (n = 1741
Emphysema, asthma in-66)
Cancer of cervix cn = 2501
Stomach cancer ln=716)
Ischaemic heart disease ln =406)

YkJlineartrendl
W"RCE H,rnyama G ,.Y,

1.00       1.61       2.08      0.0001
1.00       1.29       1.49      0.474
1.00       1.15       i.14      0.249
1.00       1.02       0.99      0.720
1.00       0.97       1.03      0.393

TABLE 6.430~ often wives with smoking husbands inhale
     cigarette smoke passively in Japan (calculation
     based on a study in Aichi Prefecture, Japan)

-

Length of contact in a day

                    15 h              4h             15.0 h

  No. cigarettes     FIX-   No cigarettes   FW   No. cigarettes   FR-   No. cigarettes
   smoked by    quency ta which they quency to which they quency to which they
  husband/day      1%l   were exposed'   (961   were exposed'   (%I   were exposed'

1-19 (average 101    11.8     (0.88      14.2     (2.55)     6.8      (8.821
20-29 (average 251    19.8     (2.21 I     25.4      (5.881     8.6     (22.06)
30-60 (average 451     5.6     (3.971      5.2     (10.59)     2.6     (39.71)

`Length alcontact multlplwd by number smoked in an hour(numbersmoked in an hourequalsaverage number
ofclyarcttessmoked I" a day divided by total hours awake)
SOURCE HirayamatPll

Nonetheless, the applicability of such results to the U.S. popula-
tion remains to be established.

Garfinkel (12) published an analysis of data from the American
Cancer Society's prospective study conducted from 1960 through
1972. He reported results on 176,739 nonsmoking women who were
then married (a) to men who never smoked, (b) to men who currently
smoked less than 20 cigarettes per day, or (c) to men who currently
smoked 20 or more cigarettes per day. In an analysis that did not
attempt to control for possible confounding variables, the observed to
expected lung cancer mortality ratio (expected numbers were
derived from the lung cancer rates of women married to nonsmokers
by s-year age groups) was 1.27 for women married to smokers of less
than 20 cigarettes per day and 1.10 for women married to smokers of
20 or more cigarettes per day. These increases in mortality ratios
over those of wives of nonsmokers were reported to be not statistical-

248


o

FIGURE 2.-Active and passive smoking and standardised
      mortality rates for lung cancer: relative risks
      (RR) with 95 percent confidence intervals-
      prospective study, 19661979, Japan
`Includrh o.xa~,nal smoktv~ and rx smokers
SOURC'E Hway;,ma~L',u~

TABLE 7.-Observed versus expected* lung cancer deaths
      among nonsmoking women with cigarette-
      smoking husbands, ACS study, 1966-1972**

                                       Husband       Husband
                            Husband      smoked 20    smoked 120
  Parameter                     did not      cigarettes     cigarettes
                             smoke       per day      per day
-

Observed deaths                   65          39          49
Expected deaths                   65.00         311.67         44.67
Mortality ratio                     1.00          1.27          1 10

ly significant (p value not specified) (Table `7), and no dose-response
effect was evident.

The same three groups of nonsmoking women were compared in
another analysis. In an attempt to eliminate possible confounding

249


TABLE K-Matched group study: Adjusted lung cancer
      deaths among women -with nonsmoking
     husbands matched* with women with smoking
       husbands

         GTWp

Nonsmoking husband
Husband smoked 20 cigarettes/day

Number of
adjusted
lung cancer
deaths

  25.6
  35.0

Ratio          p"

1.00
1.37          NS

Nonsmokmg husband                  34.5          1.00
Husband smoked 120 cigarettes/day         35.8         1.04          NS

variables, pairs of women were matched on multiple factors. The
number of deaths in each matched diad was "adjusted" as described
in a prior publication (15). The results of this analysis are shown in
Table 8. Neither group of nonsmoking wives of smokers showed a
statistically significant difference (p > 0.05); there is no dose-response
pattern apparent. The actual size and composition of the matched
study population, however, were not shown. The author concluded
that any effect passive smoking had on lung cancer mortality would
be small.

The author presented the limitations of this analysis. The study
was not designed to examine the question of effects of passive
smoking and, therefore, there were difficulties with the accurate
assessment of exposure. The appropriateness of this analysis of the
ACS data has been questioned (16) for this reason. The difficulties
include the measurement of involuntary exposure t.o smoke from
persons other than the husband, and an inability to adjust for
changes in husband's smoking subsequent to actual interview or for
exposure(s) from previous husbands. A study should be specifically
designed to measure exposure, as neither the Japanese (19) nor the
ACS study met that criterion. Additionally, among 564 cases of lung
cancer in nonsmoking women, the husband's smoking status was
available for-only 153 (27 percent).

Thus, each of the three epidemiologic studies published to date
shows an increased risk of lung cancer with involuntary smoke
exposure (Table 9). The results.were statistically significant in two of
the three studies, which also found a dose-response effect. The
evidence currently available suggests that involuntary smoke expo-
sure may increase the risk of lung cancer in nonsmokers, but

250