BMC Cancer 2008, 8:157 http://www.biomedcentral.com/1471-2407/8/157 secondhand smoke was not associated with breast cancer risk, whether the exposure occurred in childhood or adult- hood. No increased risk of breast cancer was associated with heavy exposure to secondhand smoke at work. No large differences in breast cancer risk associated with sec- ondhand smoke were observed by menopausal status. Our findings for secondhand smoke are consistent with the 2002 International Agency for Research on Cancer Monograph on Tobacco Smoking and Tobacco Smoke, which stated that existing evidence was inconsistent and did not support a causal association between passive smoking and breast cancer [32]. In contrast, the more recent report published by the California Environmental Protection Agency concluded that the weight of the evi- dence was consistent with a causal association between secondhand smoke exposure and breast cancer diagnosed in women younger than age 50 who are mostly premeno- pausal [33]. Premenopausal women accounted for only 11 percent of the breast cancer cases included in the present study, thus, power to assess differences in risk by menopausal status was limited. Although a number of previous studies report no associa- tion between active smoking and breast cancer risk (reviewed in [3,4]), these tended to use less intensive exposure assessment and include all non-smokers in the reference group. Our study, which meets criteria for high quality exposure assessment as outlined in a recent meta- analysis [28], found no association when the reference group excluded women with secondhand smoke exposure in contrast to other past studies meeting these criteria [19,20,24-28]. Use of a more stringent reference group did not increase the smoking risk ratios in part because of the limited number of women who had no active or passive smoke exposure and the lack of an association between secondhand smoking and breast cancer in this sample. This association was not seen despite collection of exten- sive secondhand smoke exposure histories, including the number of smokers in the home, the amount smoked by each smoker, and the hours per day of exposure to others' smoke, both in childhood and adulthood, in addition to secondhand smoke exposures at the workplace. It is highly unlikely that any major sources of secondhand smoke were missed in this study. Some have suggested that there may be a critical period for exposure to active and/or secondhand smoking at early ages, prior to the birth of a first baby when cellular differ- entiation within the breast is completed [23,24]. In our study, women who reported smoking prior to age 18 or prior to their first live birth were not more likely to have breast cancer than those who did not actively smoke dur- ing these periods, even after restriction of the reference group to women who were not exposed to secondhand smoke in childhood. Our findings are consistent with a recent meta-analysis of 12 studies [6,11,14,19,23,24,34- 38] that calculated a pooled risk estimate of 1.07 (95% CI: 0.72, 1.00), concluding that active smoking prior to first live birth is not associated with breast cancer [38]. Results from the California Teacher's Study recently suggested that only long duration tobacco smoke exposure prior to the first live birth increased breast cancer risk [39]. We did not observe differences in breast cancer risk associated with 30 or more pack-years of active smoking among those with five or more years of pre-partum tobacco smoke exposure (OR = 1.78, 95% CI = 0.66–4.85) versus those with less than five years of exposure (OR = 0.94, 95% CI = 0.50–1.77). However, among nulliparous women in this study, 28 of 44 cases and 12 of 35 controls reported ever smoking 100 cigarettes in their lifetime (OR = 3.34, 95% CI = 1.31–8.48), and when the reference group was restricted to women with zero years of residen- tial secondhand smoke exposure before the age of 18, the risk of breast cancer associated with ever smoking 100 cig- arettes became even stronger (OR = 8.11, 95% CI = 1.22– 53.92), but was based on only 15 cases and 10 controls. Larger studies should attempt to replicate these small sub- group findings, since nulliparous women are unique in that their entire life of exposure is "prepartum" and may represent a susceptible subgroup to particular exposures related to increased breast cancer risk. The statistically significant increased risk of breast cancer we observed for ever smoking juxtaposed with the lack of a dose-response relationship observed for any measure of frequency or duration suggests that the former association may be due to confounding. In a recent cross-sectional analysis from the California Teacher's Study [40], active smoking was associated with increased alcohol consump- tion, nulliparity, and among parous women, and later age at first birth. These factors were systematically assessed as potential confounders in the present study, and none affected the smoking odds ratios by 10 percent or greater. However, the observed overall association between ever smoking and breast cancer could be confounded by unknown factors. Recall bias may also explain the statisti- cally significant increased risk of breast cancer observed with ever smoking, if the controls were less likely to remember past exposures than the cases. Alternatively, the association could simply be due to chance or could be due to differential nonparticipation among controls that were active smokers. While control non-participation rates were comparable to those from other breast cancer case- control studies [41,42] they were of a magnitude where differential participation would likely influence odds ratio estimates. That said, one case-control study with similar control non-participation rate still observed increased risk among long-term smokers compared to non-smokers [42]. Page 7 of 9 (page number not for citation purposes)