Systematic Reviews
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Meta-Anal. Apr 26, 2016; 4(2): 10-43
Published online Apr 26, 2016. doi: 10.13105/wjma.v4.i2.10
Environmental tobacco smoke exposure and lung cancer: A systematic review
Peter N Lee, John S Fry, Barbara A Forey, Jan S Hamling, Alison J Thornton
Peter N Lee, John S Fry, Barbara A Forey, Jan S Hamling, P.N. Lee Statistics and Computing Ltd., Sutton, Surrey SM2 5DA, United Kingdom
Alison J Thornton, Independent Consultant in Statistics, Okehampton EX20 1SG, United Kingdom
Author contributions: Lee PN, Fry JS and Forey BA planned the study; Hamling JS and Thornton AJ carried out the literature searches, assisted by Lee PN and Forey BA; Fry JS, Forey BA, Hamling JS and Thornton AJ carried out the data entry which was independently checked by one of these or Lee PN; Lee PN and Forey BA discussed any difficulties in interpreting published data or in the appropriate methods for derivation of RRs; Forey BA and Hamling JS conducted the main statistical analyses, and Fry JS the bias analyses along lines discussed and agreed with Lee PN; Lee PN drafted the paper, with the assistance of Thornton AJ, which was critically reviewed by the other authors.
Conflict-of-interest statement: Lee PN, Director of P.N. Lee Statistics and Computing Ltd., is an independent consultant in statistics and an advisor in the fields of epidemiology and toxicology to a number of tobacco, pharmaceutical and chemical companies including the sponsors of this study. Fry JS, Forey BA and Hamling JS are employees of, and Thornton AJ a consultant to, P.N. Lee Statistics and Computing Ltd.
Data sharing statement: Supplementary Files provide: (1) further information on the methods; (2) fuller description and results of the confounder/misclassification analyses; (3) description of reasons for rejection of some papers; and (4) fuller results of the main meta-analyses. Copies of the database files are available on request from the corresponding author at
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Peter N Lee, MA, Director, P.N. Lee Statistics and Computing Ltd., 17 Cedar Road, Sutton, Surrey SM2 5DA, United Kingdom.
Telephone: +44-20-86428265 Fax: +44-20-86422135
Received: November 24, 2015
Peer-review started: November 25, 2015
First decision: December 28, 2015
Revised: January 19, 2016
Accepted: March 9, 2016
Article in press: March 14, 2016
Published online: April 26, 2016

AIM: To review evidence relating passive smoking to lung cancer risk in never smokers, considering various major sources of bias.

METHODS: Epidemiological prospective or case-control studies were identified which provide estimates of relative risk (RR) and 95%CI for never smokers for one or more of seven different indices of exposure to environmental tobacco smoke (ETS): The spouse; household; workplace; childhood; travel; social and other; and total. A wide range of study details were entered into a database, and the RRs for each study, including descriptions of the comparisons made, were entered into a linked database. RRs were derived where necessary. Results were entered, where available, for all lung cancer, and for squamous cell cancer and adenocarcinoma. “Most adjusted” results were entered based on results available, adjusted for the greatest number of potential confounding variables. “Least adjusted” results were also entered, with a preference for results adjusted at least for age for prospective studies. A pre-planned series of fixed-effects and random-effects meta-analyses were conducted. Overall analyses and analyses by continent were run for each exposure index, with results for spousal smoking given by sex, and results for childhood exposure given by source of ETS exposure. For spousal exposure, more extensive analyses provide results by various aspects of study design and definition of the RR. For smoking by the husband (or nearest equivalent), additional analyses were carried out both for overall risk, and for risk per 10 cigarettes per day smoked by the husband. These adjusted for uncontrolled confounding by four factors (fruit, vegetable and dietary fat consumption, and education), and corrected for misclassification of smoking status of the wife. For the confounding adjustment, estimates for never smoking women were derived from publications on the relationship of the four factors to both lung cancer risk and at home ETS exposure, and on the correlations between the factors. The bias due to misclassification was calculated on the basis that the proportion of ever smokers denying smoking is 10% in Asian studies and 2.5% elsewhere, and that those who deny smoking have the same risk as those who admit it. This approach, justified in previous work, balances higher true denial rates and lower risk in deniers compared to non-deniers.

RESULTS: One hundred and two studies were identified for inclusion, published in 1981 onwards, 45 in Asia, 31 in North America, 21 in Europe, and five elsewhere. Eighty-five were of case-control design and 17 were prospective. Significant (P < 0.05) associations were noted, with random-effects of (RR = 1.22, 95%CI: 1.14-1.31, n = 93) for smoking by the husband (RR = 1.14, 95%CI: 1.01-1.29, n = 45) for smoking by the wife (RR = 1.22, 95%CI: 1.15-1.30, n = 47) for workplace exposure (RR = 1.15, 95%CI: 1.02-1.29, n = 41) for childhood exposure, and (RR = 1.31, 95%CI: 1.19-1.45, n = 48) for total exposure. No significant association was seen for ETS exposure in travel (RR = 1.34, 95%CI: 0.94-1.93, n = 8) or in social situations (RR = 1.01, 95%CI: 0.82-1.24, n = 15). A significant negative association (RR = 0.78, 95%CI: 0.64-0.94, n = 8) was seen for ETS exposure in childhood, specifically from the parents. Significant associations were also seen for spousal smoking for both squamous cell carcinoma (RR = 1.44, 95%CI: 1.15-1.80, n = 24) and adenocarcinoma (RR = 1.33, 95%CI: 1.17-1.51, n = 30). Results generally showed marked heterogeneity between studies. For smoking by either the husband or wife, where 119 RR estimates gave an overall estimate of (RR = 1.21, 95%CI: 1.14-1.29), the heterogeneity was highly significant (P < 0.001), with evidence that the largest RRs were seen in studies published in 1981-89, in small studies (1-49 cases), and for estimates unadjusted by age. For smoking by the husband, the additional analyses showed that adjustment for the four factors reduced the overall (RR = 1.22, 95%CI: 1.14-1.31) based on 93 estimates to (RR = 1.14, 95%CI: 1.06-1.22), implying bias due to uncontrolled confounding of 7%. Further correction for misclassification reduced the estimate to a marginally non-significant (RR = 1.08, 95%CI: 0.999-1.16). In the fully adjusted and corrected analyses, there was evidence of an increase in Asia (RR = 1.18, 95%CI: 1.07-1.30, n = 44), but not in other regions (RR = 0.96, 95%CI: 0.86-1.07, n = 49). Studies published in the 1980’s, studies providing dose-response data, and studies only providing results unadjusted for age showed elevated RRs, but later published studies, studies not providing dose-response data, and studies adjusting for age did not. The pattern of results for RRs per 10 cigs/d was similar, with no significant association in the adjusted and corrected results (RR = 1.03, 95%CI: 0.994-1.07).

CONCLUSION: Most, if not all, of the ETS/lung cancer association can be explained by confounding adjustment and misclassification correction. Any causal relationship is not convincingly demonstrated.

Keywords: Passive smoking, Lung neoplasms, Dose-response, Meta-analysis, Review, Confounding factors (epidemiology), Misclassification

Core tip: We present an up-to-date meta-analysis of the evidence relating non-smoker lung cancer to environmental tobacco smoke (ETS) exposure. We demonstrate a clear risk increase for spousal, at-home, workplace and total exposure, but not childhood exposure. For husband smoking, the relative risk (RR) is estimated as (RR = 1.22, 95%CI: 1.14-1.31). However, adjustment for confounding by education and dietary variables, and correction for misclassified wife’s smoking reduces it to (RR = 1.08, 95%CI: 0.999-1.16). Given the other data limitations and biases we discuss, one cannot reliably conclude that any true ETS effect on lung cancer risk exists. Our results suggest caution in drawing inferences from weak epidemiological associations where known biases exist.