On January 26, 2006, the California Air Resources Board adopted a regulation adding secondhand smoke (environmental tobacco smoke) to the state’s list of “toxic air contaminants.” Other toxic air contaminants include diesel particulate exhaust, benzene, formaldehyde, and PAHs. The Board unanimously approved this regulation based on a report that assessed the exposures and health effects of secondhand smoke. This report, an update of the widely praised 1996 report CalEPA published (and that NCI republished in 1997 as Smoking and Health Monograph 10) was developed beginning in 2001 by the CalEPA Air Resources Board and Office of Environmental Health Hazard Assessment.
There were three review drafts of the report before it was finalized. The report was made available for “public comment” and the CalEPA had, by law, to respond to these public comments by a combination of modifying the report or explaining why they were not changing it. The Board acted on a recommendation of the state’s Scientific Review Panel on Toxic Air Contaminants (for members, see http://www.arb.ca.gov/srp/public.htm), which held four public hearings on the report and required many changes before unanimously approving it. While there are many new conclusions in the report, the one that has attracted the most attention is the one that secondhand smoke causes breast cancer in younger, primarily prememopausal women.
The International Agency of Research on Cancer (IARC) has identified 20 mammary carcinogens found in tobacco smoke including several polycyclic aromatic hydrocarbons and nitrosamines. Other studies have shown that human breast tissue is susceptible to the formation of DNA adducts following exposure to these carcinogens and that these tobacco smoke carcinogens can be measured in breast tissue. This provides a likely mechanism for tobacco smoke exposure to cause breast cancer.
Studies of the biology of breast cancer indicate that one would expect these carcinogens to induce breast cancer, based on several lines of basic science investigations.
Secondhand smoke exposure misclassification is common in epidemiologic studies. Cotinine is a metabolite of nicotine that is widely used to determine if people have been exposed to secondhand smoke. While the people who report no exposure to secondhand smoke at home or at work (yellow) have lower levels of cotinine than people who report exposure at home or work (red), there is a large overlap (orange). This overlap indicates that many people who report no exposure are actually being exposed to secondhand smoke. This so-called non-differential exposure bias will make it more difficult to detect an association between exposure and disease when one truly exists.
Let’s look at an example. Take this hypothetical study. Among 1000 people truly exposed, 10 are cases or 1%. Among the 1000 people who are truly not exposed, there are only 2 cases or 0.2%. The relative risk for this exposure is 1% divided by 0.2% or 5.
Now, suppose that 2 people who were actually exposed reported that they were not (i.e., the people in the orange area two slides earlier). As a result, we will list 8 people as exposed and 4 people as being unexposed. The result of this exposure missclassification will be to reduce the estimated relative risk from 5 to 2, a substantial underestimate of the true risk.
This is the summary figure from the Cal EPA report (Figure 7.4.4) that presents the findings from all of the studies considered in the review by menopausal status as well as by those studies that were deemed to be most informative (solid points) by virtue of the completeness of their exposure measurement and their ability to categorize women as never current and never passive smokers throughout their lifetime as the referent group. Of the 14 studies evaluating breast cancer risk in younger/premenopausal women, 13 found risk estimates greater 1. 7 were statistically significant individually, including all 6 of the most informative studies. The pooled risk estimate from meta-analysis is 1.68 with a 95% confidence interval ranging from 1.31 to 2.15. In contrast to younger women, the risk estimates for post-menopausal women are clustered around 1. For that reason, CalEPA considered the evidence linking breast cancer and breast cancer in older women “inconclusive.” Many previous investigators have combined all the studies on breast cancer, regardless of age, into a single analysis. Doing so leads to a less definitive picture than treating the pre- and post-menopausal studies separately because the effects of secondhand smoke – and the disease processes involved in breast cancer – are different in younger and older women. Even so, combining all the studies in a meta-analyses still yields a statistically significant increase in risk of 1.25.
CalEPA identified 14 studies that examined the effect of ETS exposure in women who were never smokers and developed breast cancer prior to menopause or age 50. The summary risk for all 14 studies found an almost 60% increase in breast cancer risk in women exposed to ETS (this is any exposure as identified in the studies vs no exposure – though many studies did not actually identify all exposures and therefore report risks biased to the null). For the 5 studies that did the best job of assessing exposure throughout the women’s lifetime the resulting risk of breast cancer was more than doubled.
Here’s another example of how selecting a truly unexposed referent group can impact the findings. In the Morabia, et al study that looked at active smoking and breast cancer risk, when passive smoking nonsmokers are included in the reference group, the relationship between active smoking and disease is weak. When the referent group has the passive smoking nonsmokers removed so that only never active / never passive smokers are considered, the risk estimates for active smoking increase and a strong dose response is observed.
Realizing the importance of utilizing an appropriate control group of never active/never passive smokers, the most informative studies that allow for these comparisons all have risk estimates above 1 both for exposure to active and to passive smoking with the majority of the individual studies reaching statistical significance. The right exposure assessment makes the difference! This comparison also indicates that the risks for active smoking are larger than passive smoking, but the difference is not great. This relatively small difference in risk between active and passive smokers helps understand why many of the older studies of active smoking did not report an increased risk of active smoking. These studies compared smokers to all nonsmokers, including passive smokers. By doing so, they had a contaminated comparison group and the risk estimate was biased towards the null. The oft heard statement question, “Since active smoking does not cause breast cancer, how can passive smoking?” is based on an incorrect predicate: Active smoking does increase the risk of breast cancer.
Some say that passive smoking can’t cause breast cancer if active smoking doesn’t. The CalEPA report has a detailed appendix on active smoking and breast cancer (Appendix A of Chapter 7 in Part B); meta analyses do show a significant risk estimate. The data were summarized in the previous slide. IARC and the US Surgeon General reviewed the data on SHS and did not concluded breast cancer was caused by SHS. While these reports were published in 2004, the research on which they were based essentially ended in 2001. (Indeed, the 1997 CalEPA report on secondhand smoke, which was largely based on the same sets of studies as IARC and the Surgeon General reached the same conclusion that they did.) The 2005 CalEPA report is based on a much larger collection of studies than the IARC and Surgeon General reports were. These agencies also did not consider the exposure misclassification or the effects of age/menopausal status like the Cal EPA has. (See Section 220.127.116.11.1 of Part B of the CalEPA report for the details of this comparison.) Epidemiologists are trained to believe cohort studies over case-control studies in general and the cohort studies generally show no association. However, the cohort studies fail to ascertain lifetime exposure that allows for a clean control group of never active / never passive smokers so their results are not unexpected. (Chapter 1 of Part B of the CalEPA report addresses these issues in detail and Section 18.104.22.168.1 applies them specifically to breast cancer.) The 1 case control study that did find a significant association was among Japanese women who’s spouses smoked. Japanese women were rarely exposed to SHS outside the home because of their culture, so there is little misclassification.
The evidence that SHS causes breast cancer today is stronger and more consistent than the evidence that SHS caused lung cancer back in the 1986 Surgeon General’s Report. The epi data are comparable; however, there is a wealth of toxicological and molecular epi data to support the population-based epi studies. Are people who refuse the accept the CalEPA conclusions applying a double standard to lung and breast cancer?
In some ways history is repeating itself. In 1981 Hirayama published the first study linking secondhand smoke with lung cancer in nonsmoking women married to men who smoked. Shortly thereafter, ACS published a study showing an elevated point estimate of risk, but it did not reach statistical significance. This difference in results probably reflected the fact that in Japan few women were exposed to secondhand smoke from sources other than their spouses, making marriage to a smoker a good surrogate marker for secondhand smoke exposure. In contrast, in the United States women had many other sources of exposure. Exposure missclassification was a problem. The American Cancer Society was slow to accept the evidence that passive smoking caused lung cancer.
The tobacco industry exploited the fact that the ACS study did not report an increase in lung cancer risk and used this fact to attack the Hirayama study, such as in this full page newspaper ad. (Note reference to ACS in the second column). It took five years for the ACS to change its position, and in the meantime people died unnecessarily and tobacco companies raked in more profits. The tobacco industry is already exploiting ACS’s refusal to accept the CalEPA conclusion on breast cancer. A consistent message is needed from the public health community. Let’s hope this scenario doesn’t continue to play itself again today.
Why is this important? Everyone knows SHS is bad for you in lots of different ways, so why press the breast cancer finding? The reason is that hospitality workers are the least protected occupational class from SHS. Young women are the people who typically work in bars and restaurants. Great public health gains can be made by protecting these women from this exposure. With a relative risk of 1.7, this translates to an attributable fraction of 30%. In other words, about 1/3 of premenopausal breast cancer cases could be prevented in SHS exposure were eliminated. That’s not too bad for a disease with few modifiable risk factors!
The ACS and CDC have justified their reluctance to accept the CalEPA findings on the grounds that they need to be “conservative” and provide the public with accurate information. That is everyone’s goal, including CalEPA. Indeed, the entire public and peer review process (which took 4 years to complete) is designed by law to produce the best current science. The Scientific Review Panel is specifically charged with certifying that the report represents the best current science. At the same time, it is important that there are two kinds of errors, what statisticians call “false positive” and “false negative” errors. A false positive (Type I) error is when you say that secondhand smoke increases the risk of breast cancer in younger women when, in fact, it does not. The ACS and CDC seem most worried about this kind of error. The tobacco industry’s aggressive attacks on science has conditioned them (and many others) to worry about such errors. At the same time, there is another kind of error, false negatives (Type II), when you do not say that passive smoking causes breast cancer when, in fact, it does. The consequences of this error mean that more young women will die of breast cancer. Given the very strong evidence reviewed in the CalEPA report, we can be confident that neither kind of error is being made. The conclusion that secondhand smoke causes breast cancer in younger, primarily premonopausal women is almost certainly a true positive statement.
It’s OK to be skeptical. But if these data pique your interest, please read the report and look at the evidence. You can also read the ACS’s (and tobacco industry’s) criticisms (in Part C of the report) and how the CalEPA responded to them. (The CalEPA was required by law to respond in writing to all such “public comments” by explaining how the report was changed or why it was not. The ACS criticisms were carefully considered by both the agency and the independent Scientific Review Panel on Toxic Air Contaminants, which has legal responsibility for providing independent peer review of such documents. Both the Panel and the California Air Resources Board unanimously endorsed the report. Lives depend on the public health community getting the answer to this right.
The ACS made its position clear during the public comment period on the drafts of the report and the CalEPA carefully considered its views in revising the report. (CDC and NCI seem to be following ACS's lead.) Unfortunately, ACS is repeating its historical behavior of being slow to respond to new scientific information. While this may be appropriate when confronted with new claims of "miracle cures for cancer“, it is not appropriate for ACS to ignore the findings of one of the leading scientific governmental agencies in the world. Scientists should take the time to read and disgest the report (Chapter 7 of Part B, including the appendix on active smoking) as well as the ACS (Michael Thun) comments and the agency responses. After absorbing this information, make your views known. Advocates should keep in mind that CalEPA has historically led the nation on issues of the environment and public health. Most of the nation's air pollution laws are modeled on the CalEPA Air Resources Board's initiatives. For example, the same CalEPA process that identified secondhand smoke as a toxic air contaminant was used to identify diesel exhaust (and develop subsequent regulations), something that the federal government has yet to do. The 1997 CalEPA report was the first governmental agency to conclude that secondhand smoke caused heart disease. Like breast cancer today, that conclusion was controversial at the time; it is now widely accepted. Use the data in the policymaking process. Would this finding help get more young women involved in pushing for smoke-free worksites? Would it create media opportunities to keep the dangers of SHS in the public eye? Would hospitality owners be more receptive to adopting smoke-free places if they knew they were putting their employees, friends, and family at risk for early onset breast cancer? I bet it would but nobody has tried before. Its OK to be skeptical. Before taking a stand on breast cancer and SHS, read the report. Lives depend on the public health community getting the answer to this right.
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Toxic Air Contaminants ProgramToxic Air Contaminants Program
Tobacco smoke contains multiple fat-
soluble compounds known to induce
mammary tumors in rodents. (PAH’s,
heterocyclic amines, aromatic amines,
These carcinogens can be activated into
electrophilic intermediates by enzymes
active in the human breast epithelial
Genes coding for activation/detoxification
enzymes (e.g. NAT2, NAT1, CYP1a1, COMT,
BRCA1 And BRCA2) have been reported to
modify the relationship of tobacco smoke to
breast cancer risk (although results are
Electrophilic metabolites of tobacco compounds
bind to DNA and form DNA adducts that can be
detected in human breast epithelial Morabia A.,
Environmental and Molecular Mutagenesis 39:89-95 2002
Genomic alterations observed in vitro
after exposure of human breast
epithelial cells to tobacco carcinogens
resemble those in familial breast cancer.
p53 damage in some breast tumors of
smokers, but not nonsmokers
Morabia A., Environmental and Molecular Mutagenesis 39:89-95 2002
SHS and Breast Cancer in
14 studies evaluated breast cancer risk in
younger/premenopausal women strata.
13/14 found elevated risks (1.1-7.1), and 7
were statistically significant.
Pooled risk estimate from meta-analysis =
1.68 (95% CI 1.31-2.15).
Pooled risk estimate for studies with lifetime
exposure information from all sources = 2.2
(95% CI 1.69-2.87)
Some evidence of dose-response.
Utilizing Unexposed Referent Raises
(within study comparison, Morabia et al. 1996)
Smokers vs non-
with no ETS
Smokers vs non-
Active 1-9 cpd 2.2 (1.0; 4.4) 1.2 (0.8; 2.0)
10-19 cpd 2.7 (1.4; 5.4) 1.7 (1.1; 2.5)
≥ 20 cpd 4.6 (2.2; 9.7) 1.9 (1.2; 2.9)
Ever passive 3.2 (1.7; 5.9)
(Similar within study comparison results in Johnson et
Lash and Aschengrau, 1999, and Kropp and Chang
Comparison of breast cancer risk from active
and passive smoke exposure in studies
CalEPA considered most informative
If active smoking does not cause breast cancer, how can
Active smoking does cause breast cancer
IARC says no effect
2004 report based on meeting in 2001
Considered essentially the same studies as CalEPA 1997
(which did not say SHS caused breast cancer)
Only considered 4 studies published between 2000 and
Surgeon General says no effect
2004 report essentially completed in 2001
Considered 5 studies published after 2000
CalEPA considered 23 studies between 2000 and 2005
Cohort studies negative
Evidence for breast cancer in
younger women stronger than
lung cancer in 1986
Lung cancer 1986
11/13 elevated risk
1/3 cohort studies
No molecular epi
Breast cancer 2006
13/14 elevated risk
1/3 cohort studies
Passive smoking and lung
First study, Hirayama 1981
Cohort study in Japan
Nonsmoking women married to men who
• Few women smoked
• Few women worked outside the home
Significant elevation in risk
ACS CPS study, Garfinkle
Cohort study in USA
Nonsignificant elevation in risk
Many women smoked and worked outside the
Implications for Workplace
Exposure of Waitresses
Highest occupational exposure to
These women tend to get exposed
at the most vulnerable times
1.7 relative risk
30% of breast cancer in younger
What if you are wrong?
Type I (false positive)
Women unnecessarily alarmed about
passive smoking and breast cancer
Tobacco industry attacks
Type II (false negative)
Young women die of breast cancer
Tobacco industry quotes ACS
Where to read
the full CalEPA report
Passive smoking and breast cancer starts
on page 7-76 of Part B
Active smoking and breast cancer in
Discussion on exposure missclassification
and criteria for causality in Chapter 1 of
What Can You Do?
For scientists: Read the report and
make your views known
For advocates: Use the data. CalEPA
has a reputation for being first, ahead
of the ACS and CDC, and being right.
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