The present study suggests an elevated risk of bladder cancer in lifelong nonsmokers who were exposed to ETS as compared with those who had no ETS exposure. The risk increased with increasing intensity of exposure to ETS, and reached statistically significant levels for high level of exposure to ETS. In the subgroup analysis, female lifelong nonsmokers showed higher relative risk for bladder cancer associated with ETS exposure than their male counterparts, and so did individuals possessing high CYP1A2 phenotype score and/or NAT2 slow acetylation status, both of them were risk factors for bladder cancer in the present study population (9
Previous epidemiological studies on ETS and bladder cancer risk reported inconsistent results. Several studies reported a null association between ETS and bladder cancer risk (21
) including a recent meta-analysis (13
), whereas a few others found a positive association (18
). The null findings of the previous studies could be due to the following reasons. It has been shown that the dose of carcinogenic arylamines in secondhand smokers was only 0.3–0.5% that of active smokers (14
). Given the low levels of potential tobacco bladder carcinogens present in ETS, one would expect a moderate association between ETS and bladder cancer. Furthermore, a relatively large error in measurement of ETS for a given individual over lifetime could mask the moderate effect of ETS on bladder cancer risk. In addition, most of those studies lacked statistical power because of relatively small sample sizes. The present study employed a more comprehensive approach to assess the ETS exposure for each individual, which could reduce the measurement error. The relatively large sample size (195 cases and 261 controls) of the present study allowed for the detection of a moderate effect of ETS on bladder cancer. More importantly, the determination of genetic susceptibility to bladder cancer would identify more vulnerable individuals to ETS and could clarify the association between ETS and bladder cancer.
The present study showed that female lifelong nonsmokers who were exposed to ETS, especially at the high level of ETS exposure, had higher relative risk for bladder cancer than their male counterparts. This result was consistent with our previous study showing that women experienced higher risk for bladder cancer than men although they smoked comparable amount of cigarettes (32
). We also showed a stronger ETS-bladder cancer risk association in female lifelong nonsmokers in Los Angeles than their male counterparts in our previous report (18
). In the same report we demonstrated that women with current ETS exposure were 9 times more likely than men to possess elevated hemoglobin adduct level of 4-ABP, a risk predictor for bladder cancer among lifelong nonsmokers.
The high risk of bladder cancer associated with ETS from parental smoking suggested that exposure to ETS that took place during childhood might be more harmful than exposure during adulthood. In our previous report based on the Los Angeles Bladder Cancer Study, women who ever lived with two or more smokers during childhood experienced a statistically significant 3-fold increased risk for bladder cancer whereas no risk increase was associated with ETS exposure in adulthood (18
Genetically determined factors can potentially modify the association of ETS exposure with risk of developing cancer. A few epidemiology studies have shown that polymorphisms of NAT2, CYP1A1, or glutathione S
-transferase M1 (GSTM1) could modify the association between ETS exposure and risk of lung cancer in lifelong nonsmokers (33
). Although the overall association between ETS exposure and bladder cancer risk was moderate, the present study demonstrated a stronger association in lifelong nonsmokers possessing either a high efficiency CYP1A2 phenotype or a NAT2 slow acetylation phenotype, both of which have been associated with an increased risk of bladder cancer (8
). Our findings of an association between ETS exposure and bladder cancer risk, which became stronger among individuals either efficient in activating or deficient in detoxifying the putative bladder carcinogens in tobacco smoke, have important public health implications.
The strengths of the present study included a population-based study design, comprehensive approach to assess ETS exposure over lifetime, a relatively large sample size, and the determination of two important genetic risk factors for bladder cancer. A relatively large sample size of female lifelong nonsmokers given the low smoking prevalence in Chinese women in Shanghai (6% in female controls of the present study) enabled us to examine the association between ETS exposure and risk of bladder cancer in men and women separately. Although the study data was collected more than 10 years ago, our findings are still relevant to current public health in China, since the prevalence of smoking in men (63%) and women (4%) in China over the past 15 years have been remarkable stable; the change in rate of smoking between 1996 and 2002 was under 1% (37
). A potential weakness of the study was the possible recall bias in measuring ETS, inherent in any retrospective studies, which could lead to a spurious association between ETS and bladder cancer risk. However, given the stronger ETS-bladder cancer association among the genetically more susceptible subpopulation as predicted by well recognized biochemical models of tobacco smoking (36
), it is unlikely that the observed ETS-bladder cancer risk association was the result of recall bias.
The findings of the present study have important public health implications for the US population. For example, the present study demonstrates that ETS exposure in childhood was more harmful than that in adulthood. It is estimated that 40% of children worldwide and 37% of children in the US are exposed to ETS at home (39
). Thus, strategies aim at reducing or eliminating ETS exposure among children could lead to a lower bladder cancer burden in the next generation. This study also showed that the risk effect of ETS on bladder cancer was primarily confined to individuals possessing an unfavorable phenotype of either CYP1A2 or NAT2. In the US, over 50% of Caucasians possess the NAT2 slow acetylation phenotype (41
). Therefore, cancer prevention efforts targeting more susceptible sub-population could be more cost-effective in reducing the population burden of bladder cancer.
In summary, the present study demonstrates a positive association between high level of ETS exposure and risk of bladder cancer. The study also shows a stronger ETS-bladder cancer association among individuals possessing the at-risk phenotypes of CYP1A2 and NAT2, which are recognized to participate in the metabolism of putative bladder carcinogens in tobacco smoke.