! Springer-Verlag 199 5

Int Arch Occup Environ Health (1995) 67 :287–294
ORI(,11 \I . \R 11(1 1Peter N . Lee"Marriage to a smoker" may not be a valid marker of exposure in studie s
relating environmental tobacco smoke to risk of lung cancer in Japanes e
non-smoking women

Received: 24 September 1994/Accepted : 28 April 199 5

Abstract There is no direct evidence that workplac eenvironmental tobacco smoke (ETS) increases lun gcancer risk . Demands for regulation of workplac e
smoking are based on studies reporting increased ris kin non-smoking women whose husbands smoke . Al though denying smoking can artificially elevate ris kestimates, and although many studies reporting an in crease have been conducted in Asia, no previous stud yof smoking habit misclassification has been conducted
there . In this study 400 married Japanese women answered questions on smoking and ETS exposure an d
supplied urine for cotinine analysis . Of 106 wit ha cotinine/creatinine ratio (CCR) indicating curren t
smoking (> 100 ng/mg), 22 reported never smoking .
These misclassified smokers had a median CC R
(1408 ng/mg) similar to the 78 self-reported curren t
smokers (1483 ng/mg) . Of current smokers, 89 .7% ha da currently smoking husband, while this was true o f
51 .0% of non-smokers . Among 264 confirmed non smokers (with CCR < 100 ng/mg), CCR was non-significantly lower if the husband smoked (11 .51 vs
17.98 ng/mg) and was unrelated to various indices ofsmoking by the husband . Japanese epidemiologica lstudies using "marriage to a smoker" to index ET S
exposure may therefore have compared groups wit hsimilar ETS exposure, suggesting that associations re ported between lung cancer and this index in some o fthese studies may result from bias . While other biases ,including confounding, may also be important, bia s
resulting from smoking misclassification combine dwith husband/wife smoking concordance is shown t o
be of major concern . The high misclassification rates i nJapan, much higher than in Western populations ,undermine conclusions from epidemiological studie s
conducted there .

P. N. Le e
Independent Consultant in Statistics and Epidemiology ,17 Cedar Road, Sutton, Surrey, SM2 5DA, UK

Key words Bias(epidemiology) Cotinine–urin eLung neoplasms • Tobacco smoke pollutio n

Introductio n
In the early 1980s Hirayama [10–12] reported that ris kof lung cancer among self-reported lifelong non-smoking women was significantly, 1 .45, times higher if thehusband had ever smoked than if he had never smoked .
Since then, more than 30 studies, about half conductedin Asian populations, have investigated a possible relationship of lung cancer to environmental tobacc osmoke (ETS) exposure using "marriage to a smoker" a san index of ETS exposure [18, 31] . While only a few o f
the studies have reported a statistically significant rela tionship, most have reported relative risks in excess o f
1, though generally below 2 . This had led some reviewers [e .g . 22,31,33–35], though not all [e .g. 5, 18] ,to claim a causal link between risk of lung cancer an d
exposure to ETS, and there have been recent move sin some countries, e .g . by the US Occupational Safet yand Health Administration [32], to regulate workplacesmoking.
It is interesting to note that there is no direct evidence that ETS exposure in the workplace causes lun gcancer . LeVois and Layard [16] recently reviewed evidence from 14 epidemiological studies demonstratin g
no excess lung cancer rate in non-smokers workin gwith a smoker . Based on 12 of these studies (two re ported no association, but did not cite a relative risk) ,they estimated a summary relative risk of 1 .01, wit h
a 95% confidence interval of 0 .92–1 .11 . This finding i s
consistent with the conclusion that "marriage t oa smoker" is the only index of ETS exposure associate dwith lung cancer risk ; the overall evidence does no t
suggest any increase associated with childhood or social exposure either [17, 18] .
Why are the results of workplace and spousal studie sof ETS and lung cancer inconsistent? Some studie s32142781 6
BATC' US FS, r Phi Gy Mom,

28 8
[e .g . 24] have indicated that "marriage to a smoker "[24] . Furthermore, a stronger association between l u
may be associated, on average, with a greater increas e cancer and "marriage to a smoker" has not been cons iin actual ETS exposure that is "working wit h tently demonstrated in Japan [18] . Nevertheless, ta smoker" . However, even if this were true for al l second objective was to validate "marriag e
populations, it would hardly seem to explain the ob- a smoker" as an index of ETS exposure in lifel oserved complete lack of association of lung cancer ris k non-smoking Japanese women by comparing levels )with "working with a smoker" . An alternative explana- cotinine according to husband's smoking habits .
tion may be that relative risk estimates based on th eindex "marriage to a smoker" are particularly prone t obias . This paper describes the results of a study invesMaterials and method stigating one specific form of bias, that due to smoking
habit misclassification .
Organisatio n
Because smokers tend to marry smokers, rando m
misclassification of some smokers as non-smokers wil l In order to carry out the objectives it was necessary to recr■
cause an apparent increase in risk of lung cancer i n expertise from Japan . Dr. E . Yano of Teikyo University assisted
self-reported non-smokers married to smokers even i f the translation of the questionnaire, the design of the sampl ino true effect of ETS exposure exists [17] . Smokin g regime, and the training of the interview staff from the Tokyo-bas
habit misclassification bias is less likely to affect studie s market research company Emu Efu . Dr . Yano also organised t icollection of samples from the field .
of workplace ETS exposure, because there is not th esame tendency for smokers to work with smokers .
Earlier, I concluded that such misclassification bias ca nSamplin glargely explain the weak association between lung cancer and spousal smoking reported in European an d
The study involved 400 married female subjects, 200 from the den s
American women [19] . Since fewer Asian wome n ly populated city of Osaka and 200 from the more rural tow nsmoke, and since active smoking tends to be mor e Shizoka . The subjects were selected semi-randomly, with quot e
weakly associated with lung cancer in Asian than i n assigned by district within the target areas to provide a represen t
Western populations, I showed [17] that misclassifica- five mix by socio-economic conditions and by age (range 20 years). Most subjects were identified through door-to-door canvasl
tion rates needed to be much higher than in the Wes t ing during
the early evening when they could be expected to be !.
for this bias to be important in Asian studies . Theoret- home. The subjects were told the study was to identify life-st yically social pressure against smoking by women i n factors common to women in their area. Those who agreed
participate (response rate 33°/0) were questioned for on aver a
Japan and other Asian countries might increase mis20 min on their own and their husband's smoking habits, on th eclassification . However, although further studies relatto ETS from various sources, and on a variety of life-st y
ing lung cancer to "marriage to a smoker" have bee n exposureand dietary issues . The subjects then supplied approximately 50 ni
conducted in Japan [1, 13, 14, 26, 28], there are n o urine, which was immediately frozen and transported to Teiky lpublished reports of misclassification rates specific t o University, where all samples were stored at — 20°C . As incentivethat country. Results from the IARC multi-countr y to participate, the subjects were offered a token gift and informati c
cotinine study [24], which in any case concerned onl y concerning the sugar and protein content of their urine .
non-smokers, have not been reported separately fo r
Japan . The first objective of the study, therefore, was t oinvestigate the extent to which Japanese wome n Cotinine estimatio nsmokers misclassify themselves as non-smokers on inCotinine was measured in each urine sample by an enzyme linke ■terview, in an attempt to determine the likely magniimmunoassay (ELISA). The assay was performed according t
tude of bias from this source in lung cancer studie s a modified version [4] of the method of Bjercke et al . [3] . A
conducted in Japan using "marriage to a smoker" as a n samples were presented to the laboratory blind for an initial scre e
index of ETS exposure .
After the cotinine concentrations had been estimated, the samp lShortly after Hirayama [10] reported the finding s were re-run in triplicate against the appropriate calibration rang ;samples were randomly selected and cross-checked again 5
from his large Japanese prospective study, Garfinke l aFiftygas chromatographic (GC) method . Correlation between the tw'[9] reported a much weaker, statistically non-signifimethods was ELISA = I .07GC — 0.974 (R = 0.93). The limit dcant, association between lung cancer risk and "mardetection (LOD) represents the minimum response which can t> jriage to a smoker" based on a large US prospectiv e distinguished from a response of four replicates of the zero standar q
study . Hirayama [11] suggested husband's smokin g assayed on the same plate, by a one-tail students t test (P < 0 .05 1
and was found to be 5 .6 ng/ml using the ELISA procedure .
may correlate better with ETS exposure in Japan ,where homes are smaller [25] and women less frequently have jobs outside the home . This suggestion
Statistical analysis
can be questioned because of the possibility that Japanese men spend less time at home than their Unite dResults are expressed as cotinine/creatinine ratios, counting zero f aStates counterparts and because the IARC multi - subjects with a cotinine less than the LOD . Because of the zeros an t
country cotinine study did not support this hypothesis
the skewness of the distribution, medians rather than mean level a r

32142781 7
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usually presented . Standard statistical methods were used to test fo r
the significance of differences of proportions . For continuous variables, rank tests stratified for age as appropriate were used [8] .

Results

smokers and in residents of Shizoka . Numbers ofpeople living at home were also significantly higher o naverage in Shizoka than in Osaka .

Concordance between smoking habits of husban d
and wife

Exclusion s
One subject with an inadequately completed questionnaire and three who provided insufficient urine fo r
creatinine determination were excluded, leaving dat aon 396 women .

Self-reported smoking habit s
According to self-report, 78 (19 .7%) were curren t
smokers, 32 (8 .1%) ex-smokers and 286 (72 .2%) lifelong non-smokers . Ever smokers were significantl y(P < 0 .001) younger (mean age 36.7) than lifelong non smokers (mean age 42.7) .

Socio-demographic characteristic s
Table 1 shows the distribution of various socio-demographic characteristics by city and self-reported smoking habits . Annual income, the number of rooms in thehouse and the likelihood of working in the previou sweek were all significantly (P < 0 .05) higher in neve r
Table I Socio-demographi c
distribution of the sample (%) bycity and self-reported smoking
statusThere was a strong relationship between the smokin ghabits of husband and wife. The percentage of womenreporting having a husband who currently smoked wa s
89 .7% for current smokers, 59.4% for ex-smokers an d
51 .0% for lifelong non-smokers . Among lifelon g
non-smokers, age was not associated with husband' s
smoking .

Detection of misclassified smoker s
Table 2 shows the distribution of CCR by self-reported
smoking status . CCR and cotinine levels were abou t
100 times higher (P < 0.001) among current smoker sthan among non-smokers . Creatinine levels were slight ly but not significantly higher in smokers . No valu eclearly discriminates occasional smokers from subject s
heavily exposed to ETS, but it seems reasonable fromour results to follow the precedent set by IARC [24 ]and use a cut-off of 100 ng/mg CCR to distinguis hmisclassified current smokers . Using this cut-off poin ta total of 28 women who claimed on interview to be

Osaka

Shizoka

NeverEver
smoked smoked Total

Never
Eve r
smoked smoked Total

Subjects

136

60

196

150

50

20 0

Age (years)
22-34
35- 44
45 55

15
49
36

48
37
15

25
45
30

15
41
43

40
42
18

22
42
37

Annual income (inn yen)'-500
500-900
900 +

27
51
22

52
37
11

36
46
18

27
53
20

28
38
34

27
49
24

Worked in preceding week

53

58

55

62

74

65

People living in residence °
-3
4
5
6+

29
47
19
5

35
38
25
2

31
44
21
4

28
37
15
20

14
54
16
16

25
32
15
19

Rooms in house-3
4 or 5
6+

29
44
27

63
28
8

39
39
21

21
51
28

28
40
32

23
48
29

' Numbers of subjects reporting data on income were, respectively, 95, 54, 149, 130, 47 and 17 7
° One Osaka never smoker did not answer the question on people living in residence

32142781 8
BATC., US VW v Philip Mon'r
290
Table 2 CCR (ng/mg) by sclfreported smoking status

Self-reported smoking statu s

Number of subjects (% )CCR (ng/mg )062102550100 25050010002000Tota lMedian CCR (ng/mg)
Median cotinine (ng/ml )Median creatinine (ng/mll

Non-smoker Never smoker'

Ex-smoke r

84 (26 .4)
29 (9.1)
95 (29.9)64 (20.1)
18 (5.7)
3 (0.9)2 (0.6)6 (1.9)9 (2.8)8 (2.5)318 (100 .0)
17.4
14.3
0.91

6 (18 .8)
6 (18 .8)
9 (28 .1)
3 (9 .4)
2 (6.3)0 (0 .0)
1 (3 .1)
2 (6 .3)
1 (3 .1)
2 (6 .3)
32 (100.0)
13.6
16.5
1 .06

78 (27 .3 )
23 (8 .0 )86 (30 .1 )
61 (21 .3)
16 (5 .6)
3 11 .0)
1 (0 .3)
4 (1 .4 )
8 (2 .8)
6 (2 .1 )
286 (100.0)
17 . 414 . 00.91

1 (1 .3)
1 (1 .3 )
2 (2.6)
1 (1 .3)
3 (3 .8 )
4 (5.1 )
9 (11 .5 )
9 (11 .5)
18 (23 .1 )
30 (38 .5 )
78 (100 .
1482 . 81681. 8
1 .0 5' CCR for the 22 never smokers above 100 ng/mg were 102, 106, 193, 416, 511, 683 . 848, 888, 1052, 1
1177, 1639, 1689 . 1737, 1773, 1803, 2069, 2504, 2865 . 2923, 3045 and 3946 ng/m g
6
Subjects with cotinine
5.6 ng/ml were assigned a zero CC R

non-smokers (22 lifelong non-smokers and 6 ex smokers) were considered smokers. Using a 50 ng/m g
cut-off, 46 were .

Table 3 CCR (ng/mg) by husband's smoking 'Current smoker

Lack of association of CCR with husband's smokin g
in lifelong non-smoking women
After excluding misclassified current smokers (wit ha CCR > 100 ng/mg) there were 264 confirmed lifelon g
non-smokers . CCR was non-significantly lower if thehusband smoked and was not significantly associate dwith any index of husband's smoking (Table 3) . Thi s
conclusion was unaffected by using means (rather tha nmedians) . Assuming nicotine-based indices are ad equate markers and our study population is relevant ,the findings suggest that the association between lun gcancer and husband's smoking reported in some [1, 10 ,13], though not all [14, 26, 28], Japanese studies wa s
not due to ETS exposure . Data relevant to one majo r
potential source of bias, smoking misclassification, arenow considered .
Higher misclassification rates than see n
in Western population s
The study provided no data on accuracy of statements
made about past smoking and it is possible therefore ,that an unknown proportion of self-reported lifelon g
non-smokers smoked in the past . It did, however, pro vide data on accuracy of statements made about cur rent smoking . Table 4 presents such data for thre e
cut-off points based on CCR . As reported elsewher e[17], misclassified smokers were found more frequentl y

No
Yes

127
137

17 98 6 •`11 .51 6`

1- 15
16-20
21 +

34
53
50

13 .8 6
10.40
15 .24

1-15
16-20
21 +

50
46
39

16 .40
10.66
14 .0 7

1-5
6-10
11+

49
52
28

10 .93
16 .38
5 .74

Cigarettes smoked daily 1-10
at home (holidays)
11-20
21 +

45
62
22

7 .83
11 .1 1
12 .79Cigarettes smoked daily(workdays)

Cigarettes smoked daily(holidays)

Cigarettes smoked daily
at home (workdays)' Among lifelong non-smokers excluding those with a CC R
ng/m g
6
Means were 19.26 and 16 .49 ng/mg . For cotinine, media n
14 .00 and 12 .50 ng/ml and means were 16.97 and 14.39 ng/r
95% confidence intervals 15 .64-22 .12 ng/mg and 7 .99
ng/mg for current smoker no and yes respectivel yin self-reported ex-smokers than in self-reportellong non-smokers. Whether' expressed as a prope lof current smokers or as a proportion of 1ifelo nsmokers, misclassification rates in this study we r
much higher than reported in the literature, w hcomes from Western populations. For exampl
estimate of 8 .8% for the percentage of non- s

32142781 9
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,

29 1

with CCR above 100 ng/mg compares with 1 .9% in the
IARC study [24], and with an estimate of 1 .9% (range
0 .0%—2 .7%) based on ten Western studies for the percentage with cotinine levels consistent with curren t
regular smoking [17] . The estimate of 26 .4% for thepercentage of current smokers who deny current smoking (using a 100 ng/mg cut-off) can be compared wit han estimate of 3 .2% based on data for nine Wester nstudies (range 0 .0%—0 .4%) [17] . Similarly, the estimat eof 20.8% for current smokers claiming to be lifelon g
non-smokers is very much higher than an estimate o f
2 .2% from the Western studies .

Table 4 Misclassification of current smoking statu s
Index

Cut-off
point '% (n/N )Percent of self-reported non-smoker s
who are above cut-poin t
and assumed to be current smoker s
Percent of self-reported life-longnon-smokers assumed t o
be current smoker s
Percent of self-reported ex-smokers
assumed to be current
smokers
Percent of current smokers 'who deny current smokin g

50 ng/mg
100 ng/mg
250 ng/mg
50 ng/mg
100 ng/mg
250 ng/mg
50 ng/mg
100 ng/mg
250 ng/mg
50 ng/mg
100 ng/mg
250 ng/mg
50 ng/mg
100 ng/mg
250 ng/mg

14.5 (46/318)
8 .8 (28/318)
7 .9 (25,/3181
13 .3 (38/286)
7 .7 (22/286)
6 .6 (19/286)
25 .0 (8/32 )18 .8 (6/32 )18 .8 (6/32)
37 .1 (46/124)
26 .4 (28/106 )24 .3 (25/103 )30 .6 (38/124 )20.8 (22/106 )18 .4 (19/103)

Percent of current smokers 'who deny current smoking andreport being lifelong never smokers' Based on CC Rb
For this calculation current smokers include self-reported curren t
smokers and also those who denied current smoking but had a CC R
above the cut-off point
Table 5 Variation in CCR(ng/mg) by amount smoke dand various indices of ETS
exposure

CCR and amount smoke d
As shown in Table 5, CCR rose markedly with amoun t
smoked by current smokers (trend P < 0.001) .

CCR and other indices of ETS exposur ein non-smoker s
Table 5 presents further results relating CCR to variou squestionnaire indices of ETS exposure among con firmed non-smokers (with a CCR < 100 ng/mg) . CC R
was not associated with the number of cigarettes smoke d
at home per day and was not increased in those wome n
who had worked in the previous week . Although ther e
was some tendency (trend P < 0.05) for CCR levels toincrease in relation to the number of cigarettes smoke dclose to the subject at work per day, the general patter nof the results in Tables 3 and 5 does not show an yconvincing evidence of a relationship of CCR to questionnaire indices of ETS exposure . Thus, CCR was n olower in women reporting no ETS exposure than i n
those reporting any ETS exposure (see Table 4) .

CCR and die t
CCR was not associated with recent consumption o ftomatoes or aubergines, two dietary sources of nicotin e(results not shown).

Discussion
In our study, a major finding was that, among
self-reported lifelong non-smokers with a CC R

Base

Index of exposure

Level

No . o f
subjects

Median CC R
(ng/mg)Self-reported
current smokers

Cigarettes per day

1-5
6-10
11-15
16+

11
20
21
26

25 9
101 8
143 3
264 7

Confirmed'
non-smokers

Cigarettes smokedat home per day

0
1-10•
11-20

134
115
19

17 .64
10 .04
14 .0 7

Cigarettes smokedclose to subject
at work per day'

0
1-10
11+

62
67
41

9 .86
16 .1 418 .1 3

Working inpreceding week

No
Yes

122
168

16.72
14.49

Any exposure`

No
Yes

55
235

17.5 614.7 4' Self-reported non-smokers with CCR < 100 ng/m g' Excluding women who did not report workin g` Women count as exposed if husband current smoker, any smoking by other household members, an ycigarettes smoked close by in previous 48 h, or any workplace exposure to ETS

321427820
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US Cell r Phil,5 Mon,

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< 100 ng/mg, "marriage to a smoker" was not asso- a never smoking husband, forming 1 .4% of the 8 1
ciated with an increased CCR . Indeed, those non - self-reported lifelong non-smokers married to a hussmokers with husbands who smoked tended to hav e band who had never smoked . Further assuming ther erather lower values than those whose husbands did no t are no true effects of spouse smoking on lung cancer
smoke . The failure to find an association is unlikely t o risk and that current smoking increases risk by a facto rof 5, one can then readily calculate that one woul dbe due to inadequate chemical methods, since the techniques used [3, 4] should be sensitive enough for th e actually observe that spouse smoking increases risk b y
purposes of this study . In an earlier Japanese stud y a factor of 1 .33 . This passive smoking bias of 1 .3 3[21] an increased CCR was reported in relation t o would only be decreased slightly, to 1 .29, by increasin gnumber of smokers in the home, but the mean CC R the cut-point to 250 ngjmg . Reducing it to 50 ng/m gvalue cited in non-smokers, 680 ng/mg, was imwould increase the bias but only marginally as the risk
plausibly high compared with the literature, suggestin g in women with a CCR of 50–100 ng/mg would be low .
weaknesses in their chemical methods and/or failure t o Increasing the assumed current smoking risk to 1 0
exclude, as in this study, women who clearly are would increase the bias to 1 .70, while reducing it t osmokers from the analysis . Since many husbands ma y 3 would decrease it to 1 .17 . Using (as some lung cance r
spend relatively little time with their wives and man y studies do) spouse current smoking rather than spous e
women work and are exposed to ETS outside th e ever smoking as the index of ETS exposure (and usin ghome, the lack of association between CCR and "marour main assumptions) would give a bias of 1 .45 .
riage to a smoker" is perhaps not entirely surprising . If
However, it is necessary to consider the validity ofthis is not a phenomenon of recent history–whic h the assumption that misclassification of smoking habit sseems unlikely, but cannot be formally tested–the n is independent of the smoking habits of the spouse . I n
Japanese epidemiological studies relating marriage t o the study, only 5 .1% of the 78 self-reported curren ta smoker to risk of lung cancer have compared group s smokers reported having a never smoking husband . O n
with approximately equivalent exposure to ETS . If so, the independence assumption, it can be calculated tha tthen presumably the increased relative risks reported i n only 1 .13 of the 22 misclassified current smokers shoul dsome of these studies must he due to factors other tha n have reported having a never smoking husband . In fact
ETS exposure .
seven did so . This significant (P < 0.01) discrepancy,
One possible explanation of the reported increase d not previously reported in Western studies [17], ma y
relative risks is misclassification of current smokin g have arisen for one or both of two reasons. One reaso n
status . This study clearly demonstrated, as has often is that the independence assumption is false and tha t
been predicted but never properly tested previously, women are much more likely to deny smoking if mara very much higher misclassification rate of smokers a s ried to a lifelong non-smoker . The second reason is tha t
non-smokers among Japanese women than has bee n data on her husband's smoking given by a woman who
reported in Western women . Probably this is becaus e has already denied her own smoking may be incorrect .
smoking by women is not considered socially accept - The study cannot distinguish the two possibilities, sinc eable in Japan . This study also showed, as reported i n cotinine data are not available for the husband, but it i snumerous populations [17], a strong concordance bepossible to estimate the bias making varying assumptween husbands' and wives' smoking habits. The ques- tions about the accuracy of statements made by th etion arises as to the extent of bias to the relationshi p women about their husband's smoking habits. If it i s
between lung cancer and spouse smoking that is likel y assumed that all seven of the misclassified curren t
to result from this high rate of misclassification o f smokers who reported having a never smoking husactive smoking status.
band actually denied their husband's smoking as wel lIn this study 22 women claimed to be lifelong non - as their own, the bias estimate rises from 1 .33, a ssmokers but had a CCR above 100 ng/mg . These mis- calculated above using the independence assumption ,classified women can be considered to have the lun g to 1 .43 . If it is assumed that three of these seven wome ncancer risk of typical current smokers, since their medenied their husband's smoking, the bias estimate fall s
dian CCR was 1408 ngjmg, very similar to that of th e to 1 .13 . If it is assumed that all seven of these women
78 self-reported current smokers, 1483 ng/mg . Firs t reported their husband's smoking accurately the bia s
bias estimations follow precedent [17, 22, 34, 35] in as - estimate becomes slightly negative, 0 .96, though eve nsuming that misclassification of current smoking i s then the 95% confidence limits, 0 .78–1 .19, still do no t
independent of the smoking habits of the spouse. Sinc e rule out the possibility that a meaningful bias exists .
74, i .e . 94 .9%, of the 78 self-reported current smoker s
A number of other issues make any estimation o fwere married to a husband who had ever smoked, thi s bias uncertain . These include sampling variation, theassumption implies that 94 .9%, i .e . 20 .87, of the 2 2 possibility that disease status is associated with th e
misclassified women would have been, thus formin g tendency to deny smoking, and non-representativenes s
10.2% of the 205 self-reported lifelong non-smoker s of the sample . The low response ratio in this study ,married to an ever smoking husband. Similarly, 1 .13 o f actually not untypical of Japanese interview studies ,the misclassified women would have been married toclearly leads to the possibility of selection bias, bu t

321427821
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29 3seems unlikely to undermine the conclusions for two
reasons . In the first place, it seems likely that wome nwilling to be interviewed are more likely to tell the trut h
about their smoking than women who are unwilling to
be interviewed, so that the misclassification rate i sunderestimated. In the second place, even if the reverse
were true in an extreme form, so that all the women no t
interviewed were truthful about their smoking, the mis classification rate of the total population, thoug h
3 times lower than that observed in the respondents,
would still be very high .
The age of our sample (range 20–55 years) is markedly lower than that typical of subjects in epidemiologi cal studies of lung cancer . For this reason, and als obecause estimates of smoking habit misclassificatio nvary markedly from study to study depending on th e
circumstances under which the questions are aske d[17], one should not assume that the actual rates o f
misclassification observed would apply to all the Japanese studies. However, since the rates reported here
are much higher than those seen in comparable West ern studies [17], it seems reasonable to believe thata Japanese woman smoker is substantially more likel y
to deny her smoking than is a Western woman smoke rquestioned in similar circumstances .
In the EPA report [31], corrections for bias due t osmoking misclassification were applied to individua lstudy estimates of lung cancer risk associated wit hsmoking by the husband . These corrections were base don an estimate of the smoking misclassification rat ederived from Western studies . Because smoking b y
women in Japan is much less common than in the West ,corrections to Japanese study estimates were muc hlower than those to estimates for Western studies, an dwere in fact quite minor . Although there are difficultie s
in estimating the bias precisely, it is clear the EPA' scorrections are invalid, as they arc based on the totall yfalse assumption that Japanese misclassification rate s
are the same as in the West, when in fact they are muc hhigher .
The analyses presented mainly use CCR to inde x
ETS exposure and 100 ng/mg to indicate smoking .
Conclusions were unaffected by using alternative indices such as uncorrected continine, or continine corrected by Thompson's method [29], or alternative cut-off
points .
Sources of bias other than smoking habit misclassification may affect epidemiological studies of lung cancer and ETS exposure . Confounding by life-style ris kfactors may be another potential serious source of bias.
A number of studies in other countries have show n[15, 20, 27] that ETS-exposed non-smokers have diet swith a low intake of /3-carotene, one of the dietar y
factors associated with reduced risk of lung cancer [6] ,while "marriage to a smoker" has been associated [7 ]with increased exposure to occupational hazards, higher alcohol consumption and lower education . Mor egenerally, a recent large British study [30] confirmed

that, for a whole range of unhealthy life-style character istics, smokers tend to have higher prevalences tha nlifelong non-smokers, and that lifelong non-smoker sliving with a smoker (and ex-smokers) tend to hav eintermediate prevalences, sufficient to cause moderat e
confounding effects . The results relating to the life-styl echaracteristics measured in the Japanese study hav e
not been reported in detail in this paper, as the sampl esize proved to be too small to pick up any very clea reffects. However, the general pattern of findings was
similar to that in the British study . Among lifelon g
non-smokers (with a CCR < 100 ng/mg), marriage toa smoker was associated inter alia with reduced consumption of dark green vegetables and dietary source sof vitamin A and /3-carotene, including carrots an dvitamin supplements, lack of exercise, and reduced con sumption of green tea . All these factors have been
linked to an increased risk of lung cancer [2. 6, 23] .
The overall conclusion from the study is that th efindings strongly question the reliability of epidemiological studies in Japanese women using "marriage to a smoker" as a marker of ETS exposure. The
lack of association of cotinine levels with "marriage t oa smoker" suggests the marker is invalid in Japan, an dthe large proportion of smokers denying smoking give sa substantial potential for bias . While more studie s(including some in which cotinine is determined fo r
both the husband and wife) are needed to clarify th eimportance of misclassification and confounding a ssources of bias, the evidence reported here urges caution when interpreting studies of spousal smoking an dlung cancer in Japan . The findings of this study help to
explain why the epidemiological evidence indicates a n
association with spousal but not with workplace ET S
exposure, and suggests that demands for regulation o fworkplace ETS exposure based on studies using "marriage to a smoker" as an index of ETS exposure ma y
have little scientific basis.
Acknowledgements I gratefully acknowledge financial support fro mseveral companies of the tobacco industry .
I am extremely grateful to Dr . Eiji Yano of Tcikyo University fo r
assistance provided in Japan, and to Emu Efu Co . Ltd . for help insample collection and analysis . I also thank Dr. John Fry fo r
assistance in statistical analysis, Dr . Francis Roe for numerous
helpful comments, and Mrs. Pauline Wassell and Mrs . Diane Morri s
for typing the various drafts .

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