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Department of Epidemiology, University of California Los Angeles School of Public Health, and Jonsson Comprehensive Cancer Center, Los Angeles, California 90095-1772 [Z-F. Z., H. M.]; Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [M. R. S.]; Department of Medicine, University of California Los Angeles School of Medicine, Los Angeles, California 90095 [D. P. T.]; New York Eye and Ear Infirmary, New York, New York 10003 [G-P. Y., S. P. S.]; and Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [T. C. H.]
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The association between ETS and lung cancer and the similarities between the carcinogenic properties of passively and actively inhaled tobacco smoking suggest the possible role of environmental tobacco smoke or passive smoking on the development of squamous cell carcinoma of the head and neck. Although tobacco smoking and alcohol drinking have been identified as major risk factors for head and neck cancer, few clinical or epidemiological studies have been conducted to examine the possible effects of passive smoking on the risk of head and neck cancer. One of those studies was a case report involving a 69-year-old nonsmoking woman with squamous carcinoma of the left tonsil. Her illness was suspected to be related to her husband’s 40 years of smoking (5) . In another study of the possible role of passive smoking in the development of squamous cell head and neck cancer (SCHNC), a group of 59 non-smoking cases with squamous cell head and neck cancer were retrospectively studied at the Cleveland Clinic Foundation (6) . When compared with the individuals without ETS exposure, an elevated risk of head and neck cancer was noted for those exposed to ETS both in the home and in the workplace. The authors concluded that a cause and effect relationship between passive smoking and head and neck cancer cannot be clearly established on the basis of their study because of the small sample size, the limited data collection, and inadequate adjustment for potential confounding effects in their analysis.
The aim of the present analysis was to examine the association between ETS and head and neck cancers, controlling for other known risk factors for the disease, including cigarette smoking and alcohol drinking. We will also explore the possible interactions between ETS and mutagen sensitivity, and with other known risk factors for head and neck cancer. Mutagen sensitivity is considered a predisposition marker of cancer risk (7 , 8) . Defects in one or more steps of the DNA repair process may play a significant role in environmental carcinogenesis, and the extent of such defects may be partially responsible for susceptibility or resistance to environmental mutagens (9) . Mutagen sensitivity tests are indirect indicators of DNA repair competence. Bleomycin, a radiomimetic agent, was used as the test mutagen, an assay developed to evaluate the rates of induced chromosome breakage as a crude indicator of the response to a genotoxic agent (10 , 11) .
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Data Collection and Variables.
The study was approved by the Institutional Research Board on Human
Subjects of Memorial Sloan-Kettering Cancer Center. All cases and
controls were asked to sign an informed consent form if they agreed to
participate in the study, to complete a structured questionnaire, and
to donate a sample of blood. The questionnaire requested information on
the following variables: age, gender, race, year and place of birth,
religion, family income, and education; average number of tobacco
cigarettes smoked/day, years of smoking, age at initiation of smoking;
exposure to ETS (at home and at work); alcohol consumption, types and
frequency of alcohol consumption; occupational and environmental
exposures; family history of cancer; sexual history; medical history;
and oral hygienic history. In addition, all subjects were asked if they
had ever used marijuana. If they responded yes, subjects were asked the
average number of times they smoked per day and the number of years of
marijuana use. For ETS exposure, all subjects were asked:
(a) "Have you ever been regularly exposed to other
people’s cigarette smoke at home?" and (b) "Have you
ever been regularly exposed to other people’s cigarette smoke at
work?" There were three choices for each question: never,
occasionally, and regularly. In addition, a question regarding
partner’s or spouse’s smoking was asked: "Does your current
partner/spouse smoke? (yes/no)". A total of 155 cases (89.6%) and
166 controls (94.3%) had complete data on passive smoking at home and
at work. Individuals with missing data on passive smoking were excluded
from analysis. Those reported either occasional or regular exposure to
ETS at home or work were categorized as ever exposed to ETS, and those
who reported no exposure to ETS both at home and at work were defined
as never exposed to ETS. The degree of ETS exposure was defined
according to history of passive smoking both at home and at work.
"Never exposed to ETS" was defined as those individuals who were
exposed to ETS neither at home nor at work, "heavily exposed to
ETS" was defined as those individuals who were exposed to ETS both at
home and at work, and "moderately exposed to ETS" included those
who were either exposed to ETS at home or at work.
Mutagen Sensitivity Assay.
A total of 91 patients and 131 controls provided a blood specimen for
the assessment of mutagen sensitivity. The mutagen sensitivity assay
used in this study has been described in detail previously
(12)
. A peripheral blood sample (10 ml or less) was
collected from cases and controls in a heparinized tube prior to
initiation of lymphocyte culture. The standard lymphocyte culture
procedure used RPMI 1640, supplemented with 15% FCS and
phytohemagglutinin, in a ratio of blood:medium of 1:9. At 67 h of
incubation, one set of cultures was treated with bleomycin (0.03
units/ml) for 5 h. Colcemid (0.04 mg/ml) was added in the last
hour to induce mitotic arrest prior to harvesting. A conventional cell
harvesting procedure followed. The cells were treated with hypotonic
KCl (0.975 M KCl) solution for 15–20 min, fixed, washed
with a freshly prepared mixture of methanol and acetic acid (3:1),
and air-dried on wet slides. The slides were stained with
Giemsa solution without banding. Fifty well-spread
metaphases were examined from coded slides. Chromatid aberrations
recorded were frank chromatid breaks or exchanges. Bleomycin tends to
induce few chromatid exchanges (which, if present, are considered as
two breaks). Chromatid gaps or attenuated regions were disregarded. The
frequency of breakage was expressed as breaks/cell. The reliability of
cytogenetic scoring has been evaluated previously by comparing four
separate blood samples from a respective donor with a minimum interval
between samples of 1 week (9)
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Statistical Analysis.
The effects of ETS on the risk of head and neck cancer were estimated
with ORs and their 95% CIs, derived from logistic regression analysis
(13)
. Dummy variables were used in logistic regression
analysis to estimate ORs for each category of exposure. Trend tests for
ordered variables were performed by assigning the score j to
the jth exposure level of a categorical variable (where
j = 1, 2, ... ) and treating the categorical
variable as an interval predictor in unconditional logistic regression.
We have selected several potential confounders or effect modifiers in
our analysis. In addition to active tobacco smoking and alcohol
drinking, we considered marijuana smoking as a possible confounder or a
effect modifier in our analysis because marijuana smoking was
associated with head and neck cancer (14)
. Three
models were used to assess ETS effects: (a) no covariates
(crude analysis); (b) statistical adjustment for pack-years
of cigarette smoking (continuous variable); (c) statistical
adjustment for pack-years of cigarette smoking plus age (continuous
variable), sex (male versus female), race (white
versus non-white), education (
high school, college
education, postgraduate education), history of marijuana use (yes
versus no), and heavy alcohol drinking (
100 drinks/month
versus <100 drinks/month;). Stratified analysis was used to
assess departures from additive or multiplicative effects between ETS
and other known risk factors for head and neck cancer, including
cigarette smoking, alcohol drinking, and mutagen sensitivity.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. No obvious differences for passive smoking were found in terms of age,
gender, and race. Education was strongly associated with ETS exposure;
high prevalence of the ETS exposures was found in people with lower
education (less than or equal to high school) in controls, but not in
cases. Cigarette smoking was generally independent of ETS exposure in
both cases and controls, although the prevalence of ETS exposure was
elevated with increased pack-years of smoking, cigarettes smoked/day,
and years of smoking in controls. Heavy alcohol drinking and mutagen
hypersensitivity were not related to ETS exposure in cases or controls.
Marijuana use was associated with passive smoking in cases but not in
controls.
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). Strong dose-response relationships were observed for the effects of
the degree of ETS exposure. The adjusted ORs were 2.1 for those who had
moderate ETS exposure and 3.6 for those who had heavy ETS exposure
(P for trend test = 0.025). When ETS exposure at home,
ETS exposure at work, and spouse smoking were analyzed separately and
after controlling for potential confounding effects, the ETS effect for
each variable was weaker in comparison to results of crude analysis.
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. The crude OR for the effect of lifetime ETS exposure was 2.2 (95%
CI, 0.6–8.4) for never-smokers and 3.1 (95% CI, 1.1–8.3) for
ever-smokers. Strong dose-response relationships were also observed for
the effects of the degree of ETS exposure among never-smokers and
ever-smokers. The crude ORs were 1.8 for those who had moderate ETS
exposure and 4.3 for those who had heavy ETS exposure (P for
trend test = 0.0082) among never-smokers. The crude ORs were 2.5
and 5.3 for moderate and heavy ETS exposure, respectively, among
ever-smokers (p for trend = 0.0016).
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shows the combined effects of ETS exposure (ever versus
never) and each of four potential effect modifiers: tobacco cigarette
smoking, alcohol use, marijuana use, and mutagen sensitivity. For these
analyses, we used >1.0 breaks/cell as the cutoff value to define
mutagen hypersensitivity. We categorized subjects as heavy alcohol
drinkers if they had 100 or more drinks/per month and tobacco cigarette
smoking into never smokers/ever smokers. The effects of ETS and mutagen
hypersensitivity were more than multiplicative; the adjusted OR for the
joint category of ETS exposure and mutagen sensitivity was greater than
the product of the two component effects for those two factors,
i.e., 17.5 > 2.6 x 2.0 = 5.2. The effects
of ETS and alcohol consumption appeared more than additive but less
than multiplicative, i.e., 4.9 (alcohol only) + 2.5 (ETS
only) minus 1 = 6.4 < 10.2 (both exposures) < 4.9 x 2.5 = 12.25. The effects of ETS and marijuana use appeared more
than additive but less than multiplicative, i.e., 3.5
(marijuana only) + 2.6 (ETS only) - 1 = 5.1 < 7.1
(both exposures) < 3.5 x 2.6 = 9.1. In each case,
however, the power for testing each null hypothesis (effects are
additive or multiplicative) and for comparing the fits of additive
versus multiplicative models was low.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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This study has several possible limitations. One limitation is potential selection bias, which might have resulted in an overestimate or underestimate of the ETS effect (bias away from or toward null). Using controls from the blood bank may result in potential selection bias because blood donors might be more health oriented. To assess the potential selection bias, we have compared selected demographic and potential risk factors between blood donor controls and non-cancer controls from the Surgical Day Hospital during the same study period at Memorial Sloan-Kettering Cancer Center. Generally, the two groups of controls were similar in terms of those selected factors; contrary to expectation, however, blood donor controls had a slightly higher proportion of cigarette smokers and a markedly higher proportion of alcohol drinkers than the other control group, potentially producing an underestimation of the association between cigarette smoking, alcohol drinking, and head and neck cancer and may lead to incomplete control of these potential confounders. Because we did not collect information on passive smoking in non-cancer controls from the Surgical day Hospital, we did not know whether the prevalence of passive smoking in blood donors would also be higher than non-cancer hospital controls so that the selection bias could not be clearly ruled out. On the other hand, because the majority of blood donors were relatives or friends of cancer patients hospitalized at Memorial Sloan-Kettering Cancer Center, they might have a slightly higher chance of exposure to ETS. We believe that the selection of blood donors as controls would probably underestimate the association between ETS and head and neck cancer under study.
When we evaluated the interaction between passive smoking and mutagen
sensitivity (Table 4)
, a possible selection bias might exist because
those with blood samples for mutagen assay may be different from
individuals without blood samples. A total of 26.1% of controls and
46.8% of cases refused to provide a blood sample for the bleomycin
sensitivity test in this study. We have compared the differences
between those with and without blood samples on selected variables.
This attempt is crucial to show whether there is selection bias because
of missing samples that may threaten the validity of the interaction
between passive smoking and mutagen sensitivity. The proportion of
passive smoking was comparable in those with and without blood
specimens for both cases and controls. No obvious difference was found
between those with and without blood samples in terms of age, gender,
education, and alcohol drinking in both cases and controls. Significant
differences were found for cigarette smoking and race in cases; cases
with blood specimens had a higher proportion of smokers and non-white
than cases without blood specimens. Those differences indicate that the
subjects with blood samples might not be a representative group for
smoking habits and non-whites from the original study population, which
might lead to a stronger confounder effects on the association between
passive smoking and head and neck cancer.
The second limitation is differential misclassification of ETS, which may bias the estimated effect under study (15 , 16) . The degree of overreporting may be greater for cases than controls because cases might want to rationalize their disease. Thus, the estimates of ETS effects could be positively biased. Self-reported ETS in the recent past has been validated in several studies and believed to be apparently valid (17, 18, 19) . The confirmation that dose-response relationships exist between urinary cotinine concentrations and self-reported passive smoking partially validates questionnaire measures of the degree of environmental smoke exposure (19) . The results of the analysis of self-reported recent exposure to ETS from any source in relation to urinary concentrations of cotinine indicated that duration of exposure and number of cigarettes to which the subject reported being exposed were strongly related to urinary cotinine (17) . However, questionnaire-based information on long-term exposure to ETS is difficult to integrate over time and almost impossible to validate. Nevertheless, the validity of self-reported exposure to ETS in the recent past supports the validity of self-reported of long-term exposure to ETS (20) . Thus, we believe that differential misclassification of past exposure to ETS is probably not sufficient to explain the positive findings in this study. The possible differential misclassification of using mutagen sensitivity assays in case-control study was discussed by Caporaso (21) . Cultured cells obtained from patients with cancer or control subjects in a hospital setting can differ for abnormal nutrition, secondary metabolic alterations of neoplastic disease, and effect of treatment, hospitalization, inactivity, or stress, which will allow bias because of differential misclassification. However, a recent paper by Cloos et al. (22) reported a high heritability estimate of the susceptibility to bleomycin-induced chromatid breaks, which indicates that a clear genetic basis for mutagen sensitivity-related cancer susceptibility may exist in the general population. If the mutagen sensitivity is highly inherited, the differential misclassification bias for this assay might be minimal.
The third limitation is the small sample size. We only have 10 cases and 27 controls who had no ETS exposure. If we further stratified by cigarette smoking or mutation sensitivity, the number becomes much smaller. The relatively small sample size may lead to the low power of the study and a poor precision of the measurement, which would limit our ability to estimate the ETS effect effectively and precisely.
Confounding by active cigarette smoking and alcohol consumption on the association between ETS and head and neck cancer was apparent. Although we attempted to adjust for active cigarette smoking and alcohol drinking in our analyses, residual confounding might still exist because ETS may be closely related to active cigarette smoking and alcohol consumption.
The observed association between exposures to ETS and head and neck cancer is relatively weak, similar to the observed association between ETS exposure and lung cancer. In comparison with the ETS effect in lung cancer, the OR of ETS for head and neck cancer is slightly higher. It may be caused by the small sample size of this study. On the other hand, considering the upper aerodigestive tracts as a first entrance for the ETS exposure, the degree of exposure might be higher than that in lung. In addition, the mechanism of the ETS carcinogenic action may be different in upper aerodigestive tract cancers from that in lung cancer.
Our results are supported by compelling biological evidence. This evidence includes the higher concentration of carcinogens in SS than MS, the strong causal link between active smoking and both lung and head and neck cancers, and the convincing evidence of the association between ETS exposure and lung cancer (1) .
Although non-cigarette smokers are major potential victims of the health consequences of ETS, active smokers might also have a greater opportunity to be exposed to SS, in addition to MS. Therefore, if ETS is associated with certain cancers in nonsmokers, it would be reasonable to assume that ETS would have a similar or even stronger impact on the risk of tobacco-related cancers in smokers when active cigarette smoking and other potential confounding effects are controlled for. The hypothesis is supported by the following: (a) cigarette smokers are exposed not only to MS but also to SS from their own cigarettes; (b) smokers tend to socialize with other smokers, thereby increasing their exposure to other smokers’ SS; (c) smokers are more likely than nonsmokers to have a smoking spouse or partner, thus further increasing their exposure to ETS (23) . Because most published studies of ETS and lung cancer are limited to nonsmoking women, we may not know the full impact of ETS on the risk of lung cancer. The effects of ETS need to be further studied in nonsmoking men, as well as in active smokers. In the present study, we found slightly different effects of ETS on the risk of head and neck cancer between smokers and nonsmokers. In never-smokers with 26 cases and 59 controls, the crude OR was 2.2 for ETS exposure. The dose-response relationship was apparent with ORs of 1.8 for intermediate ETS exposure and 4.3 for heavy ETS exposure (P for trend = 0.0082). Interestingly, the adjusted ORs for ETS exposure in the whole study population, including both active smokers and never-active smokers, were very similar to those in the subanalysis with never-active smokers: 2.4 for ETS exposure, 2.1 for moderate ETS exposure, and 3.6 for heavy ETS exposure, respectively (P for trend = 0.0249). These observations are consistent with our assumption.
Possible interaction effects were suggested between ETS and mutagen sensitivity and other risk factors for head and neck cancer. The interplay between carcinogens and intrinsic host susceptibility is an important factor in environmental carcinogenesis. Mutagen hypersensitivity, an indirect marker for DNA repair, interacts with tobacco smoking in head and neck cancer risk (24, 25, 26, 27) . Synergy between mutagen hypersensitivity and ETS was suggested in this study because the effects were much more than multiplicative, which suggests that the development of the upper aerodigestive cancers may be affected by gene-environment interaction. Because of the low power for testing these interactions, however, the present findings will need to be replicated in future large studies.
In summary, we found that ETS is associated with a dose-dependent increased risk of head and neck cancer. This association is supported by other evidence that provides a biologically plausible basis for the hypothesis that ETS is a risk factor for human head and neck cancer. Our results need to be examined with caution because of potential residual confounding effects of active tobacco smoking and small sample size. Further large-scale epidemiological studies are needed to replicate our results, to examine the relationships between ETS and increased risk of cancer, and to assess potential interactions between ETS and other risk factors.
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Footnotes |
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1 Supported in part by Grant ES-06718 from the
National Institute of Environmental Health Services; Grants CA-51845,
and CA16042–24 from the National Cancer Institute; Grant DA/CA11386
from the National Institute on Drug Abuse, NIH, Department of
Health and Human Services; by a seed grant by UCLA Jonsson Cancer
Center Foundation; and by the Weisman Fund. 
2 To whom requests for reprints should be
addressed, at Department of Epidemiology, University of California Los
Angeles School of Public Health, 71-225 CHS, Box 951772, Los Angeles,
California 90095-1772. Phone: (310) 825-8418; Fax: (310) 206-6039;
E-mail: zfzhang{at}ucla.edu
3 The abbreviations used are: ETS, environmental
tobacco smoke; SS, sidestream smoke; MS, mainstream smoke; OR, odds
ratio; CI, confidence interval.
Received 9/ 8/99; revised 7/ 7/00; accepted 7/21/00.
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