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8 Conclusions and Recommendations In this report, the committee has examined three relationships in re- sponse to its charge (see Box 8-1 for specific questions): • The association between secondhand-smoke exposure and cardio- vascular disease, especially coronary heart disease and not stroke (Question 1). • The association between secondhand-smoke exposure and acute coronary events (Questions 2, 3, and 5). • The association between smoking bans and acute coronary events (Questions 4, 5, 6, 7, and 8). This chapter summarizes the committee’s review of information relevant to those relationships; presents its findings, conclusions, and recommenda- tions on the basis of the weight of evidence; and presents its responses to the specific questions that it was asked in its task. SuMMARy OF REPORT Exposure Assessment To determine the effect of changes in exposure to secondhand smoke it is necessary to quantify changes in epidemiologic studies. Airborne mea- sures and biomarkers of exposure to secondhand smoke are available; they are complementary and provide different information (see Chapter 2). Bio- markers (such as cotinine, the major proximate metabolite of nicotine) in- 0

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0 SECONDHAND SMOKE EXPOSURE BOX 8-1 Specific Questions to the Committee The Centers for Disease Control and Prevention requested that the IOM convene an expert committee to assess the state of the science on the relationship between secondhand smoke exposure and acute coro- nary events. Specifically, the committee was to review available scientific literature on secondhand smoke exposure (including short-term expo- sure) and acute coronary events, and produce a report characterizing the state of the science on the topic, with emphasis on the evidence for causality and knowledge gaps that future research should address. In conducting its work the committee was to address the following questions: 1. hat is the current scientific consensus on the relationship be- W tween exposure to secondhand smoke and cardiovascular dis- ease? What is the pathophysiology? What is the strength of the relationship? 2. s there sufficient evidence to support the plausibility of a causal I relation between secondhand smoke exposure and acute coronary events such as acute myocardial infarction and unstable angina? If yes, what is the pathophysiology? And what is the strength of the relationship? 3. s it biologically plausible that a relatively brief (e.g., under 1 hour) I secondhand smoke exposure incident could precipitate an acute tegrate all sources of exposure and inhalation rates, but cannot identify the place where secondhand-smoke exposure occurred and, because of a short half-life they reflect only recent exposures. Airborne measures of exposure can demonstrate the contribution of different sources or venues of exposure and can be used to measure changes in secondhand-smoke concentrations at individual venues, but they do not reflect the true dose. Airborne con- centration of nicotine is a specific tracer for secondhand smoke. Particulate matter (PM) can also be used as an indicator of secondhand-smoke expo- sure, but because there are other sources of PM it is a less specific tracer than nicotine. The concentration of cotinine in serum, saliva, or urine is a specific indicator of integrated exposure to secondhand smoke. Although in most of the smoking-ban studies the magnitude, frequency, and duration of exposures that occurred before a ban are not known, monitoring studies demonstrate that exposure to secondhand smoke is dramatically reduced in places that are covered by bans. Airborne nicotine

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0 CONCLUSIONS AND RECOMMENDATIONS coronary event? If yes, what is known or suspected about how this risk may vary based upon absence or presence (and extent) of preexisting coronary artery disease? 4. hat is the strength of the evidence for a causal relationship be- W tween indoor smoking bans and decreased risk of acute myocar- dial infarction? 5. hat is a reasonable latency period between a decrease in sec- W ondhand smoke exposure and a decrease in risk of an acute myo- cardial infarction for an individual? What is a reasonable latency period between a decrease in population secondhand smoke ex- posure and a measurable decrease in acute myocardial infarction rates for a population? 6. hat are the strengths and weaknesses of published population- W based studies on the risk of acute myocardial infarction following the institution of comprehensive indoor smoking bans? In light of published studies’ strengths and weaknesses, how much confi- dence is warranted in reported effect size estimates? 7. hat factors would be expected to influence the effect size? For W example, population age distribution, baseline level of secondhand smoke protection among nonsmokers, and level of secondhand smoke protection provided by the smoke-free law. 8. hat are the most critical research gaps that should be addressed W to improve our understanding of the impact of indoor air policies on acute coronary events? What studies should be performed to address these gaps? and PM concentrations in regulated venues such as workplaces, bars, and restaurants decreased by more than 80% in most studies; serum, salivary, or urinary cotinine concentrations decreased by 50% or more in most stud- ies, probably reflecting continuing exposures in unregulated venues (for example, in homes and cars). Pathophysiology The pathophysiology of the induction of cardiovascular disease by cigarette-smoking and secondhand-smoke exposure is complex and un- doubtedly involves multiple agents. Many chemicals in secondhand smoke have been shown to exert cardiovascular toxicity (see Table 3-1), and both acute and chronic effects of these chemicals have been identified. Experi- mental studies in humans, animals, and cell cultures have demonstrated ef- fects of secondhand smoke, its components (such as PM, acrolein, polycyclic

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0 SECONDHAND SMOKE EXPOSURE aromatic hydrocarbons [PAHs], and metals), or both on the cardiovascular system (see Figure 3-1 for summary). Those studies have yielded sufficient evidence to support an inference that acute exposure to secondhand smoke induces endothelial dysfunction, increases thrombosis, causes inflammation, and potentially affects plaque stability adversely. Those effects appear at concentrations expected to be experienced by people exposed to second- hand smoke. Data from animal studies also support a dose–response relationship between secondhand-smoke exposure and cardiovascular effects (see Chapter 3). The relationship is consistent with the understanding of the pathophysiology of coronary heart disease and the effects of secondhand smoke on humans, including chamber studies. The association comports with known associations between PM, a major constituent of secondhand smoke, and coronary heart disease. Overall, the pathophysiologic data indicate that it is biologically plau- sible for secondhand-smoke exposure to have cardiovascular effects, such as effects that lead to cardiovascular disease and acute myocardial infarction (MI). The exact mechanisms by which such effects occur, however, remain to be elucidated. Smoking-Ban Background Characteristics of smoking bans can heavily influence their conse - quences. Interpretation of the results of epidemiologic studies that in- volve smoking bans must account for information on the bans and their enforcement. Secondhand smoke should have been measured before and after imple- mentation of a ban, and locations with and without bans should have been compared. Studies that include self-reported assessments of exposure to secondhand smoke cannot necessarily be compared with each other unless the survey instruments (such as interviews) were similar. The comparability of the time and length of followup of the studies should be assessed. For example, the impact of a ban in one area may differ from the impact of a ban in another solely because the observation times were different and other activities may have occurred during the same periods. In comparing studies, it may be impossible to separate con- textual factors associated with ban legislation—such as public comment periods, information announcing the ban, and notices about the impend- ing changes—from the impact of the ban itself. The committee therefore included such contextual factors in drawing conclusions about the effects of a ban. Interpretation needs to consider the timeframes in the epidemiologic evidence, for example, the time from onset of a smoking ban to the mea-

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0 CONCLUSIONS AND RECOMMENDATIONS surement of incidence of a disease, the timing and nature of enforcement, and the time until changes in cardiovascular-event rates were observed in people who had various baseline risks. Interpretation should account for the extent to which studies assessed possible alternative causes of decreases in hospitalizations for coronary events, including changes in health-care availability and in the standard of practice in cardiac care, such as new diagnostic criteria for acute MI during the period of study. The latter is especially important in making before–after comparisons in the absence of a comparison geographic area in which no ban has been implemented. When designing and analyzing future studies, researchers should exam- ine the time between the implementation of a smoking ban and changes in rates of hospital admission or cardiac death. Future studies could evaluate whether decreases in admissions are transitory, sustained, or increasing, and ideally they would include information on individual subjects, includ- ing prior history of cardiac disease, to answer the questions posed to the committee. Epidemiologic Studies Cardiovascular disease is a major public-health concern. The results of dozens of epidemiologic studies of both case–control and cohort design car- ried out in multiple populations consistently indicate about a 25–30% in- crease in risk of coronary heart disease from exposure to secondhand smoke (see Chapter 4). Epidemiologic studies using serum cotinine concentration as a biomarker of overall exposure to secondhand smoke indicated that the relative risk (RR) of coronary heart disease associated with secondhand smoke is even greater than those estimates. The excess risk is unlikely to be explained by misclassification bias, uncontrolled-for confounding effects, or publication bias. Although few studies have addressed the risk of coronary heart disease posed by secondhand-smoke exposure in the workplace, there is no biologically plausible reason to suppose that the effect of secondhand- smoke exposure at work or in a public building differs from the effect of exposure in the home environment. Epidemiologic studies demonstrate a dose–response relationship between chronic secondhand-smoke exposure as assessed by self-reports of exposure (He et al., 1999) and as assessed by bio- markers (cotinine) and long-term risk of coronary heart disease (Whincup et al., 2004). Dose–response curves show a steep initial rise in risk when going from negligible to low exposure followed by a gradual increase with increasing exposure. The INTERHEART study, a large case–control study of cases of first acute MI, showed that exposure to secondhand smoke increased the risk of nonfatal acute MI in a graded manner (Teo et al., 2006). Eleven key epidemiologic studies evaluated the effects of eight smok-

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0 SECONDHAND SMOKE EXPOSURE ing bans on the incidence of acute coronary events (see Table 8-1 and Chapter 6). The results of those studies show remarkable consistency: all showed decreases in the rate of acute MIs after the implementation of smoking bans (Barone-Adesi et al., 2006; Bartecchi et al., 2006; CDC, 2009; Cesaroni et al., 2008; Juster et al., 2007; Khuder et al., 2007; Lemstra et al., 2008; Pell et al., 2008; Sargent et al., 2004; Seo and Torabi, 2007; Vasselli et al., 2008). Two of the studies (Pell et al., 2008; Seo and Torabi, 2007) examined rates of hospitalization for acute coronary events after the implementation of smoking bans and provided direct evidence of the relationship of secondhand-smoke exposure to acute coronary events by presenting results in nonsmokers. The decreases in acute MIs in the 11 studies ranged from about 6 to 47%, depending on characteristics of the study, including the method of statistical analysis. The consistency in the direction of change gave the committee confidence that smoking bans result in a decrease in the rate of acute MI. The studies took advantage of bans as “natural experiments” to look at questions about the effects of bans, and indirectly of a decrease in secondhand-smoke exposure, on the incidence of acute cardiac events. As discussed in Assessing the Health Impact of Air Quality Regulations: Concepts and Methods for Accountability Research (HEI Accountability Working Group, 2003) in the context of air-pollution regulations, studies of interventions constitute a more definitive approach than other epidemio- logic studies to determining whether regulations result in health benefits. All the studies are relevant and informative with respect to the questions posed to the committee, and overall they support an association between smoking bans and a decrease in acute cardiovascular events. The studies have inherent limitations related to their nature, but they directly evaluated the effects of an intervention (a smoking ban, including any concomitant activities) on a health outcome of interest (acute coronary events). The committee could not determine the magnitude of effect with any reasonable degree of certainty on the basis of those studies. The variability in study design, implementation, and analysis was so large that the com- mittee concluded that it could not conduct a meta-analysis or combine the information from the studies to calculate a point estimate of the effect. In particular, the committee was unable to determine the overall portion of the effect attributable to decreased smoking by smokers as opposed to de- creased exposure of nonsmokers to secondhand smoke because of a lack of information on smoking status in nine of the studies (Barone-Adesi et al., 2006; Bartecchi et al., 2006; CDC, 2009; Cesaroni et al., 2008; Juster et al., 2007; Khuder et al., 2007; Lemstra et al., 2008; Sargent et al., 2004; Seo and Torabi, 2007; Vasselli et al., 2008). The results of the studies are consis- tent with the findings of the pathophysiologic studies discussed in Chapter 3 and the data on PM discussed in Chapters 3 and 7. At the population level,

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0 CONCLUSIONS AND RECOMMENDATIONS results of the key intervention studies reviewed by the committee are for the most part consistent with a decrease in risk as early as a month following reductions in secondhand-smoke exposure; however, given the variability in the studies and the lack of data on the precise timing of interventions, the smoking-ban studies do not provide adequate information on the time it takes to see decreases in acute MIs. Plausibility of Effect The committee considered both the biologic plausibility of a causal relationship between a decrease in secondhand-smoke exposure and a de- crease in the incidence of acute MI and the plausibility of the magnitude of the effect seen in the key epidemiologic studies after implementation of smoking bans. The experimental data reviewed in Chapter 3 demonstrate that several components of secondhand smoke, as well as secondhand smoke itself, exert substantial cardiovascular toxicity. The toxic effects include the in- duction of endothelial dysfunction, an increase in thrombosis, increased inflammation, and possible reductions in plaque stability. The data provide evidence that it is biologically plausible for secondhand smoke to be a potential causative trigger of acute coronary events. The risk of acute coro- nary events is likely to be increased if a person has preexisting heart disease. The association comports with findings on air-pollution components, such as diesel exhaust (Mills et al., 2007) and PM (Bhatnagar, 2006). As a “reality check” on the potential effects of changes in secondhand- smoke exposure, the committee estimated the decrease in risk of cardio- vascular disease and specifically heart failure that would be expected on the basis of the risk effects of changes in airborne PM concentrations after implementation of smoking bans seen in the PM literature. The PM in ciga- rette smoke is not identical with that in air pollution, and the committee did not attempt to estimate the risk attributable to secondhand-smoke exposure through the PM risk estimates but rather found this a useful exercise to see whether the decreases seen in the epidemiologic literature are reasonable, given data on other air pollutants that have some common characteristics. The committee’s estimates on the basis of the PM literature support the pos- sibility that changes in secondhand-smoke exposure after implementation of a smoking ban can have a substantial effect on hospital admissions for heart failure and cardiovascular disease. SuMMARy OF OvERALL WEIGHT OF EvIDENCE The committee examined three relationships—of secondhand-smoke exposure and cardiovascular disease, of secondhand-smoke exposure and

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0 SECONDHAND SMOKE EXPOSURE TABLE 8-1 Summary of Key Studies (Studies Listed by Smoking-Ban Region in Order of Publication) Publication (Region) Study Design and Duration Helena, Montana Sargent et al., 2004 Retrospective based on hospital records; (Helena, Montana) 6 months of ban, 11 months after ban compared with same months of 5 years before ban Italy Vasselli et al., 2008 (four Retrospective based on hospital discharge registry; study regions in Italy: Piedmont, period January 10–March 10, 2001–2005; compared 2 Friuli–Venezia–Giulia, months after ban with same 2 months of 4 years before Latium, Campania) ban Barone-Adesi et al., 2006 Retrospective based on records from regional hospital (Piedmont region, northern discharge registry; 5 months before ban studied, ending Italy) 6 months before implementation; 6 months after ban studied Cesaroni et al., 2008 Retrospective based on hospital discharge registry, death (Rome, Italy) registry; January 1, 2000–December 31, 2005; follow-up just under 12 months after ban Pueblo, Colorado CDC, 2009 Retrospective based on hospital admission data; duration 1.5 (Pueblo, Colorado) years before, 1.5 and 3 years after ban Bartecchi et al., 2006 Same as CDC (2009) but only after 1.5 years of followup (Pueblo, Colorada) Monroe County, Indiana Seo and Torabi, 2007 Retrospective based on records; study period August 1, (Monroe County, Indiana) 2001–May 31, 2005, that is, 22 months before and 22 months after ban’s enforcement Bowling Green, Ohio Khuder et al., 2007 Retrospective based on hospital discharge records in 1999– (Bowling Green, Ohio) 2005; assessment from October 2002 to 39 months after ban went into effect (March 2002)

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0 CONCLUSIONS AND RECOMMENDATIONS Ban Characteristics Decrease in Admission Rates Legislation enacted to require smoke-free 40% decrease in average monthly admissions workplaces, public places, including (from 40 to 24; decrease of 16 cases, 95% restaurants, bars; suspended after about 6 CI) months Smoking banned in restaurants, bars, other workplaces Ban on smoking in all indoor public places, 6.4% decrease from previous year including offices, retail shops, cafes, 13.1% decrease (estimated) from expected on bars, restaurants, discotheques in Italy; basis of linear regression (RR, 0.6; 95% provision for smoking rooms CI, 0.83–0.92) Ban on smoking in all indoor public places, 11% decrease in people under 60 years old including offices, retail shops, cafes, (RR, 0.89; 95% CI, 0.81–0.98) bars, restaurants, discotheques in Italy; provision for smoking rooms Ban on smoking in all indoor public places, 11% decrease in people 35–64 years old (RR, including offices, retail shops, cafes, 0.89; 95% CI, 0.85–0.93) bars, restaurants, discotheques in Italy; 8% decrease in people 65–74 years old (RR, provision for smoking rooms 0.92; 95% CI, 0.88–0.97) Ban prohibiting smoking in workplaces, all 41% decrease (RR, 0.59; 95% CI, 0.49–0.70) public buildings—including restaurants, bars, bowling alleys, other business establishments—in city limits Ban prohibiting smoking in workplaces, all 27% decrease (RR, 0.73; 95% CI, 0.63–0.85) public buildings—including restaurants, bars, bowling alleys, other business establishments—in city limits Ban in all restaurants, retail stores, 70% decrease (from 17 to 5; decrease of 12 workplaces; extended to previously cases, 95% CI, 2.81–21.19) exempt bars and clubs January 1, 2005 Ban in public places except bars, restaurants 39% decrease (95% CI, 33–45%) in 2002 with bars if bar is isolated with separate (includes 2 months without ordinance) for smoking area; bars and bowling alleys 9–21 months of followup could allow smoking at owners’ 47% decrease (95% CI, 41–55%) for 34–39 discretion months of followup Continued

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0 SECONDHAND SMOKE EXPOSURE TABLE 8-1 Continued Publication (Region) Study Design and Duration New york State Juster et al., 2007 Retrospective based on hospital discharge records; estimates (New York state) of admissions calculated statistically; data for January 1995–December 2004 (17 months after statewide ban) Saskatoon, Canada Lemstra et al., 2008 Retrospective based on hospital discharge records; compared (Saskatoon, Canada) first full year after ban (July 1, 2004–June 30, 2005) with previous 4 years (July 1, 2000–June 30, 2004) Scotland Pell et al., 2008 Prospective study of acute coronary syndrome; 10 months (Scotland) before (June 2005–March 2006) and follow-up 10 months after (June 2006–March 2007) ban

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 CONCLUSIONS AND RECOMMENDATIONS Ban Characteristics Decrease in Admission Rates New York’s Clean Indoor Air Act is 8% (estimated) fewer admissions in 2004 100% statewide ban on smoking in all than expected with prior existing local workplaces—including restaurants, bars, smoking bans gaming establishments—with limited 19% (estimated) fewer admissions in 2004 exceptions than expected if no prior smoking bans Statewide smoking restrictions (limiting had been in effect or prohibiting smoking in some public places, such as schools, hospitals, public buildings, retail stores) had been implemented in 1989 Previously, various levels of smoking bans implemented at city or county level in some parts of New York state, including ban in workplaces—including restaurants, bars—in New York City State law does not preempt passage of local laws Smoking ban implemented in city of 13% decrease (rate ratio, 0.87; 95% CI, Saskatoon prohibiting smoking in any 0.84–0.90) enclosed public space that is open to public or to which public is customarily admitted or invited; smoking also prohibited in outdoor seating areas of restaurants, licensed premises Previously, smoking had been prohibited in government buildings As of January 1, 2005, 100% smoke-free law in all public places, workplaces, including restaurants, bars, bingo halls, bowling alleys, casinos; local municipalities have right to enact smoke-free air regulations Smoking prohibited in all enclosed public 17% decrease (95% CI, 16–18%) after places, workplaces throughout Scotland, implementation of smoking ban including bars, pubs, restaurants, cafes; exceptions included residential accommodations, designated rooms in hotels, care homes, hospices, psychiatric units

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 SECONDHAND SMOKE EXPOSURE smoke exposure and acute coronary events is biologically plausible (see Chapter 3). Experimental studies in humans, animals, and cell cultures have demonstrated short-term effects of secondhand smoke as a complex mixture or its components individually (such as oxidants, PM, acrolein, PAHs, benzene, and metals) on the cardiovascular system. There is suf- ficient evidence from such studies to infer that acute exposure to second- hand smoke at concentrations relevant to population exposures induces endothelial dysfunction, increases inflammation, increases thrombosis, and potentially adversely affects plaque stability. Those effects occur at magnitudes relevant to the pathogenesis of acute coronary events. Fur- thermore, indirect evidence obtained from studies of ambient PM sup- ports the notion that exposure to PM present in secondhand smoke could trigger acute coronary events or induce arrhythmogenesis in a person with a vulnerable myocardium. Taking all that evidence together, the committee concludes that there is sufficient evidence of a causal relationship between a decrease in secondhand-smoke exposure and a decrease in the risk of acute MI. Given the variability among studies and their limitations, the committee did not provide a quantitative estimate of the magnitude of the effect. Smoking Bans and Acute Coronary Events Nine key studies looked at the overall effect of smoking bans on the incidence of acute coronary events in the overall populations—smokers and nonsmokers—studied (Barone-Adesi et al., 2006; Bartecchi et al., 2006; CDC, 2009; Cesaroni et al., 2008; Juster et al., 2007; Khuder et al., 2007; Lemstra et al., 2008; Sargent et al., 2004; Vasselli et al., 2008). Those studies consistently show a decrease in acute MIs after implementation of smoking bans. The combination of experimental data on secondhand-smoke effects discussed above and exposure data that indicate that secondhand-smoke concentrations decrease substantially after implementation of a smoking ban provides evidence that it is biologically plausible for smoking bans to decrease the rate of acute MIs. The committee concludes that there is an association between smoking bans and a reduction in acute coronary events and, given the temporality and biologic plausibility of the effect, that the evidence is consistent with a causal relationship. Although all the studies demonstrated a positive effect of bans in reducing acute MIs, differences among the studies, including the components of the bans and other inter- ventions that promote smoke-free environments that took place during the bans, limited the committee’s confidence in estimating the overall magni- tude of the effect. There is little information on how long it would take for such an effect to be seen inasmuch as the studies have not evaluated periods shorter than a month.

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 CONCLUSIONS AND RECOMMENDATIONS DATA GAPS AND RESEARCH RECOMMENDATIONS Studies of the effect of indoor smoking bans and secondhand-smoke exposure on acute coronary events should be designed to examine the time between an intervention and changes in the effect and to measure the magnitude of the effect. No time to effect can be postulated for individu- als on the basis of the available data, and evaluation of population-based effectiveness of a smoking ban depends on societal actions that implement and enforce the ban and on actions that include smoke reduction in homes, cars, and elsewhere. The decrease in secondhand-smoke exposure does not necessarily occur suddenly—it might decline gradually or by steps. In a likely scenario, once a ban is put into place and enforced, a sharp drop in secondhand-smoke exposure might be seen immediately and followed by a slower decrease in exposure as the population becomes more educated about the health consequences of secondhand smoke and exposure becomes less socially acceptable. Future studies that examine the time from initia- tion of a ban to observation of an effect and that include followup after initiation of enforcement, taking the social aspects into account, would provide better information on how long it takes to see an effect of a ban. Statistical models should clearly articulate a set of assumptions and include sensitivity analyses. Studies that examine whether decreases in hospital ad- missions for acute coronary events are transitory or sustained would also be informative. Many factors are likely to influence the effect of a smoking ban on the incidence and prevalence of acute coronary events in a population. They include age, sex, diet, background risk factors and environmental factors for cardiovascular disease, prevalence of smokers in the community, the underlying rate of heart disease in the community (for example, the rate in Italy versus the United States), and the social environment. Future studies should include direct observations on individuals—including their history of cardiac disease, exposure to other environmental agents, and other risk factors for cardiac events—to assess the impact of those factors on study results. Assessment of smoking status is also needed to distinguish between the effects of secondhand smoke in nonsmokers and the effects of a ban that decreases cigarette consumption or promotes smoking cessation in smokers. Few constituents of secondhand smoke have been adequately studied for cardiotoxicity. Future research should examine the cardiotoxicity of environmental chemicals, including those in secondhand smoke, to define cardiovascular toxicity end points and establish consistent definitions and measurement standards for cardiotoxicity of environmental contaminants. Specifically, information is lacking on the cardiotoxicity of highly reactive smoke constituents, such as acrolein and other oxidants; on techniques for

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 SECONDHAND SMOKE EXPOSURE quantitating those reactive components; and on the toxicity of low con- centrations of benzo[a]pyrene, of PAHs other than benzo[a]pyrene, and of mixtures of tobacco-smoke toxicants. Many questions remain with respect to the pathogenesis of cardio- vascular disease and acute coronary events and how secondhand-smoke constituents perturb the pathophysiologic mechanisms and result in disease and death. For example, a better understanding of the factors that promote plaque rupture and how they are influenced by tobacco smoke and PM would provide insight into the mechanisms underlying the cardiovascular effects of secondhand smoke and might lead to better methods of detecting preclinical disease and preventing events. The committee found only sparse data on the prevalence and incidence of cardiovascular disease and acute coronary events at the national level in general compared with other health end points for which there are cen- tral data registries and surveillance of all events, such as the Surveillance, Epidemiology, and End Results (SEER) Program for cancer. Although there are national databases that include acute MI patients—such as the National Registry of Myocardial Infarction (Morrow et al., 2001; Rogers et al., 1994), the Health Care Financing Administration database, and the Cooperative Cardiovascular Project (Ellerbeck et al., 1995)—and the Centers for Disease Control and Prevention’s annual National Hospital Discharge Survey and National Health Interview Survey provide some information on cardio- vascular end points, these are not comprehensive or inclusive with respect to hospital participation, patient inclusion, or data capture. A national database that captures all cardiovascular end points would facilitate future epidemiologic studies by allowing the tracking of trends and identification of high-risk populations at a more granular level. A large prospective cohort study could be very helpful in more accu- rately estimating the magnitude of the risk of cardiovascular disease and acute coronary events posed by secondhand-smoke exposure. It could be a new study specifically designed to assess effects of secondhand smoke or, as was done with the INTERHEART study, take advantage of existing studies—such as the Framingham Heart Study, the Multi-Ethnic Study of Atherosclerosis, the American Cancer Society’s Cancer Prevention Study-3, the European Prospective Investigation into Cancer and Nutrition study, and the Jackson Heart Study—provided that they have adequate informa- tion on individual smoking status and secondhand-smoke exposure (or the ability to measure it, for example, in adequate blood samples). If properly designed, such a study could identify subpopulations at highest risk for acute coronary events from secondhand-smoke exposure in relation to such characteristics as age and sex, and concomitant risk factors, such as obesity.

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 CONCLUSIONS AND RECOMMENDATIONS COMMITTEE RESPONSES TO SPECIFIC QuESTIONS The committee was tasked with responding to eight specific questions. The questions and the committee’s responses are presented below. 1. What is the current scientific consensus on the relationship between exposure to secondhand smoke and cardiovascular disease? What is the pathophysiology? What is the strength of the relationship? On the basis of the available studies of chronic exposure to secondhand smoke and cardiovascular disease, the committee concludes that there is scientific consensus that there is a causal relationship between secondhand- smoke exposure and cardiovascular disease. The results of a number of meta-analyses of the epidemiologic studies showed increases of 25–30% in the risk of cardiovascular disease caused by various exposures. The studies include some that use serum cotinine concentration as a biomarker of ex- posure and show a dose–response relationship. The pathophysiologic data are consistent with that relationship, as are the data from studies of air pol- lution and PM. The data in support of the relationship are consistent, but the committee could not calculate a point estimate of the magnitude of the effect (that is, the effect size) given the variable strength of the relationship, differences among studies, poor assessment of secondhand-smoke exposure, and variation in concomitant underlying risk factors. 2. Is there sufficient evidence to support the plausibility of a causal relation between secondhand smoke exposure and acute coronary events such as acute myocardial infarction and unstable angina? If yes, what is the pathophysiology? And what is the strength of the relationship? The evidence reviewed by the committee is consistent with a causal re- lationship between secondhand-smoke exposure and acute coronary events, such as acute MI. It is unknown whether acute exposure, chronic exposure, or a combination of the two underlies the occurrence of acute coronary events, inasmuch as the duration or pattern of exposure in individuals is not known. The evidence includes the results of two key studies that have information on individual smoking status and that showed decreases in risks of acute coronary events in nonsmokers after implementation of a smoking ban. Those studies are supported by information from other smoking-ban studies (although these do not have information on individual smoking status, other exposure-assessment studies have demonstrated that secondhand-smoke exposure decreases after implementation of a smok- ing ban) and by the large body of literature on PM, especially PM2.5, a

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0 SECONDHAND SMOKE EXPOSURE constituent of secondhand smoke. The evidence is not yet comprehensive enough to determine a detailed mode of action for the relationship between secondhand-smoke exposure and a variety of intervening and preexisting conditions in predisposing to cardiac events. However, experimental stud- ies have shown effects that are consistent with pathogenic factors in acute coronary events. Although the committee has confidence in the evidence of an association between chronic secondhand-smoke exposure and acute coronary events, the evidence on the magnitude of the association is less convincing, so the committee did not estimate that magnitude (that is, the effect size). 3. Is it biologically plausible that a relatively brief (e.g., under  hour) secondhand smoke exposure incident could precipitate an acute coronary event? If yes, what is known or suspected about how this risk may vary based upon absence or presence (and extent) of preexisting coronary artery disease? There is no direct evidence that a relatively brief exposure to second- hand smoke can precipitate an acute coronary event; few published studies have addressed that question. The circumstantial evidence of such a rela- tionship, however, is compelling. The strongest evidence comes from air- pollution research, especially research on PM. Although the source of the PM can affect its toxicity, particle size in secondhand smoke is comparable with that in air pollution, and research has demonstrated a similarity be- tween cardiovascular effects of PM and of secondhand smoke. Some stud- ies have demonstrated rapid effects of brief secondhand-smoke exposure (for example, on platelet aggregation and endothelial function), but more research is necessary to delineate how secondhand smoke produces car- diovascular effects and the role of underlying preexisting coronary arterial disease in determining susceptibility to the effects. Given the data on PM, especially those from time-series studies, which indicate that a relatively brief exposure can precipitate an acute coronary event, and the fact that PM is a major component of secondhand smoke, the committee concludes that it is biologically plausible for a relatively brief exposure to secondhand smoke to precipitate an acute coronary event. With respect to how the risk might vary in the presence or absence of preexisting coronary arterial disease, it is generally assumed that acute coronary events are more likely to occur in people who have some level of preexisting disease, although that underlying disease is often subclinical. There are not enough data on the presence of pre-existing coronary arterial disease in the populations studied to assess the extent to which the absence or presence of such preexisting disease affects the cardiovascular risk posed by secondhand-smoke exposure.

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 CONCLUSIONS AND RECOMMENDATIONS 4. What is the strength of the evidence for a causal relationship be- tween indoor smoking bans and decreased risk of acute myocardial infarction? The key intervention studies that have evaluated the effects of indoor smoking bans consistently have shown a decreased risk of heart attack. Research has also indicated that secondhand-smoke exposure is causally related to heart attacks, that smoking bans decrease secondhand-smoke exposure, and that a relationship between secondhand-smoke exposure and acute coronary events is biologically plausible. All the relevant studies have shown an association in a direction consistent with a causal relation- ship (although the committee was unable to estimate the magnitude of the association), and the committee therefore concludes that the evidence is sufficient to infer a causal relationship. 5. What is a reasonable latency period between a decrease in second- hand smoke exposure and a decrease in risk of an acute myocardial infarction for an individual? What is a reasonable latency period between a decrease in population secondhand smoke exposure and a measurable decrease in acute myocardial infarction rates for a population? No direct information is available on the time between a decrease in secondhand-smoke exposure and a decrease in the risk of a heart attack in an individual. Data on PM, however, have shown effects on the heart within 24 hours, and this supports a period of less than 24 hours. At the population level, results of the key intervention studies reviewed by the committee are for the most part consistent with a decrease in risk as early as a month following reductions in secondhand-smoke exposure; however, given the variability in the studies and the lack of data on the precise timing of interventions, the smoking-ban studies do not provide adequate informa- tion on the time it takes to see decreases in heart attacks. 6. What are the strengths and weaknesses of published population- based studies on the risk of acute myocardial infarction following the institution of comprehensive indoor smoking bans? In light of published studies’ strengths and weaknesses, how much confidence is warranted in reported effect size estimates? Some of the weaknesses of the published population-based studies of the risk of MI after implementation of smoking bans are

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 SECONDHAND SMOKE EXPOSURE • Limitations associated with an open study population and, in some cases, with the use of a small sample. • Concurrent interventions that reduce the observed effect of a smok- ing ban. • Lack of exposure-assessment criteria and measurements. • Lack of information collected on the time between the cessation of exposure to secondhand smoke and changes in disease rates. • Differences between control and intervention groups. • Nonexperimental design of studies (by necessity). • Lack of assessment of the sensitivity of results to the assumptions made in the statistical analysis. The different studies had different strengths and weaknesses in relation to the assessment of the effects of smoking bans. For example, the Scottish study had such strengths as prospective design and serum cotinine measure- ments. The Saskatoon study had the advantage of comprehensive hospital records, and the Monroe County study excluded smokers. The population- based studies of the risk of heart attack after the institution of comprehen- sive smoking bans were consistent in showing an association between the smoking bans and a decrease in the risk of acute coronary events, and this strengthened the committee’s confidence in the existence of the association. However, because of the weaknesses discussed above and the variability among the studies, the committee has little confidence in the magnitude of the effects and, therefore, thought it inappropriate to attempt to estimate an effect size from such disparate designs and measures. 7. What factors would be expected to influence the effect size? For example, population age distribution, baseline level of secondhand smoke protection among nonsmokers, and level of secondhand smoke protection provided by the smoke-free law. A number of factors that vary among the key studies can influence effect size. Although some of the studies found different effects in differ- ent age groups, these were not consistently identified. One major factor is the size of the difference in secondhand-smoke exposure before and after implementation of a ban, which would vary and depends on: the magnitude of exposure before the ban, which is influenced by the baseline level of smoking and preexisting smoking bans or restrictions; and the magnitude of exposure after implementation of the ban, which is influenced by the extent of the ban, enforcement of and compliance with the ban, changes in social norms of smoking behaviors, and remaining exposure in areas not covered by the ban (for example, in private vehicles and homes). The baseline rate of acute coronary events or cardiovascular disease could influence the effect

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 CONCLUSIONS AND RECOMMENDATIONS size, as would the prevalence of other risk factors for acute coronary events, such as obesity, diabetes, and age. 8. What are the most critical research gaps that should be addressed to improve our understanding of the impact of indoor air policies on acute coronary events? What studies should be performed to address these gaps? The committee identified the following gaps and research needs as those most critical for improving understanding of the effect of indoor-air policies on acute coronary events: • The committee found a relative paucity of data on environmen- tal cardiotoxicity of secondhand smoke compared with other disease end points related to secondhand smoke, such as carci- nogenicity and reproductive toxicity. Research should develop standard definitions of cardiotoxic end points in pathophysi- ologic studies (for example, specific results on standard assays) and a classification system for cardiotoxic agents (similar to the International Agency for Research on Cancer classification of carcinogens). Established cardiotoxicity assays for environmen- tal exposures and consistent definitions of adverse outcomes of such tests would improve investigations of the cardiotoxicity of secondhand smoke and its components and identify potential end points for the investigation of the effects of indoor-air policies on acute coronary events. • The committee found a lack of a system for surveillance of the prevalence of cardiovascular disease and of the incidence of acute coronary events in the United States. Surveillance of incidence and prevalence trends would allow secular trends to be taken into ac- count better and to be compared among different populations to establish the effects of indoor-air policies. Although some national databases and surveys include cardiovascular end points, a national database that tracks hospital admission rates and deaths from acute coronary events, similar to the SEER database for cancer, would improve epidemiologic studies. • The committee found a lack of understanding of a mechanism that leads to plaque rupture and from that to an acute coronary event and of how secondhand smoke affects that process. Additional research is necessary to develop reliable biomarkers of early effects on plaque vulnerability to rupture and to improve the design of pathophysiologic studies of secondhand smoke that examine effects of exposure on plaque stability.

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 SECONDHAND SMOKE EXPOSURE • All 11 key studies reviewed by the committee have strengths and limitations due to their study design, and none was designed to test the hypothesis that secondhand-smoke exposure causes cardiovas- cular disease or acute coronary events. Because of those limitations and the consequent variability in results, the committee did not have enough information to estimate the magnitude of the decrease in cardiovascular risk due to smoking bans or to a decrease in secondhand-smoke exposure. A large, well-designed study could permit estimation of the magnitude of the effect. An ideal study would be prospective; would have individual-level data on smoking status; would account for potential confounders, including other risk factors for cardiovascular events (such as obesity and age), would have biomarkers of mainstream and secondhand-smoke exposures (such as blood cotinine concentrations); and would have enough cases to allow separate analyses of smokers and nonsmok- ers or, ideally, stratification of cases by cotinine concentrations to examine the dose–response relationship. Such a study could be spe- cifically designed for secondhand smoke or potentially could take advantage of existing cohort studies that might have data available or attainable for investigating secondhand-smoke exposure and its cardiovascular effects, such as was done with the INTERHEART study. Existing studies that could be explored to determine their utility and applicability to questions related to secondhand smoke include the Multi-Ethnic Study of Atherosclerosis (MESA) study, the American Cancer Society’s CPS-3, the European Prospective Investigation of Cancer (EPIC), the Framingham Heart Study, and the Jackson Heart Study. Researchers should clearly articulate the assumptions used in their statistical models and include analysis of the sensitivity of results to model choice and assumptions. REFERENCES Barone-Adesi, F., L. Vizzini, F. Merletti, and L. Richiardi. 2006. Short-term effects of Italian smoking regulation on rates of hospital admission for acute myocardial infarction. Eu- ropean Heart Journal 27(20):2468-2472. Bartecchi, C., R. N. Alsever, C. Nevin-Woods, W. M. Thomas, R. O. Estacio, B. B. Bartelson, and M. J. Krantz. 2006. Reduction in the incidence of acute myocardial infarction associ- ated with a citywide smoking ordinance. Circulation 114(14):1490-1496. Bhatnagar, A. 2006. Environmental cardiology: Studying mechanistic links between pollution and heart disease. Circulation Research 99(7):692-705. CDC (Centers for Disease Control and Prevention). 2009. Reduced hospitalizations for acute myocardial infarction after implementation of a smoke-free ordinance—city of Pueblo, Colorado, 2002–2006. MMWR—Morbidity & Mortality Weekly Report 57(51):1373-1377.

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