Environmental Tobacco Smoke and Coronary Heart Syndromes: Absence of an Association

Concerns about possible cardiovascular and especially coronary effects of environmental tobacco smoke (ETS) derive from the reported effects of active smoking. Despite similarities, however, ETS has composition and physical characteristics different from the mainstream smoke (MS) that active smokers inhale and appears more relatively chemically inert and less biologically active. ETS doses to nonsmokers are small and often below the sensitivity of detection technologies. They are several orders of magnitude less than MS doses in active smokers.
Numerous epidemiologic studies report that the active smoking of less than 10 cigarettes/day is not associated with measurable risk of coronary heart disease (CHD). Thus, even assuming that ETS and MS have equivalent biological activities, conceivable ETS doses to nonsmokers are far below apparent no-effect thresholds for active smoking.
Hence, it is no surprise that epidemiologic reports are inconclusive about a possible association of ETS exposure and CHD, some suggesting a slight elevation, others a reduction of risk. Often, the elevations reported are higher than the CHD risk values associated with active smoking. Such equivocations likely result from the presence of contrasting protective or aggravating confounders, of which more than 200 have been reported in the literature -- confounders that were not and could not be adequately controlled by any epidemiologic study. By scientific standards, the weight of evidence continues to falsify the hypothesis that ETS exposure might be a CHD risk factor.

INTRODUCTION

Several reviews have attempted to appraise the literature on environmental tobacco smoke (ETS) and coronary heart disease (CHD) (Glantz and Parmley, 1991; Taylor and Johnson, 1992; Steenland, 1992; Wells, 1994). In general these reviews have been selective and conjectural and have failed to account for the many pertinent considerations that a scientific evaluation requires. Although written by a long-time consultant to the tobacco industry, this present review strives for a comprehensive evaluation of available knowledge by avoiding assumptions and standing by the evidence.

In considering ETS as a possible CHD risk factor it will be useful to address what is known of the chemical, physical and biological comparability of ETS and the smoke that smokers inhale. Exposures and doses will then be compared in light of the no-observable adverse effect levels for active smoking and CHD, as reported in the literature. Finally, the epidemiologic studies of ETS exposure and possible CHD risk are evaluated against the background of numerous confounders, difficulties in establishing and measuring exposures, classification and other logical biases, statistical criteria of significance, and inferential conjectures from in vitro and in vivo experiments and clinical effects in humans.

ETS AND ACTIVE SMOKING

Mainstream smoke -- inhaled directly by smokers -- is concentrated and confined to the moist environment of mouth, throat, and lung. Its higher gas-phase concentrations favour larger respirable particles that condense and retain more water and volatiles. By contrast, ordinary ETS is over 100,000 times more diluted, with much lower humidity and extremely low concentrations of volatiles. Evaporation is faster from ETS particles which -- within fraction of seconds from their generation -- attain sizes 50 to 100 times smaller in mass and volume than their mainstream counterparts. As ETS ages, it undergoes oxidative and photochemical transformation, polymerization from loss of water and volatiles, reactions with other environmental components, differential absorption to environmental surfaces, and other changes (NAS,1986; USSG,1986; USEPA,1992c; Guerin et al., 1987; Baker and Proctor, 1990). The reducing capacity and free radicals of MS are lost within minutes (Schmeltz et al., 1977, Tanigawa et at.. 1994), and ETS is considerably less cytotoxic than inhaled MS (Sonnenfeld and Wilson,1987).

Of the several thousand components identified in mainstream smoke, only 100 or so have been detected in sidestream smoke under Field conditions, due to extreme dilutions. Because of even greater dilution, only about 20 ETS components have been identified directly under field conditions. In natural settings, most ETS components are below the sensitivity of current analytical capabilities (Guerin et al.,1987; Baker and Proctor.1990).

Compilers of ETS reports from the National Academy of Sciences (NAS, l986), the U.S. Surgeon General (USSG, 1986), and the Environmental Protection Agency (USEPA, 1992c) have been forced to infer the presence of ETS components by proxy, based on the composition of the sidestream smoke from which ETS primarily derives.

Nominally, then, ETS and mainstream smoke may share some components, but their chemical and physical differences are substantial. Moreover, the presence of most ETS components can only be postulated because they are beyond material detection. Also, the chemical and biologic reactivity of ETS is less than that for the MS that active smokers inhale, because of the loss of free radicals, other quenching, and absorption Losses during dilution and aging.

ESTIMATING ETS EXPOSURE

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Estimates of exposure to other ETS components are even more problematic because of the numerous sources external to ETS. For instance, plasma concentrations of volatile organics in nonsmokers appear to be as much as two-thirds of the corresponding levels in active smokers (Angerer et al., 1992; Brugnone et al, 1992; Perbellini et al., 1988) -- an indication of significant sources other than tobacco combustion (Ritcher et al., 1994; Ong et al., 1994).

By utilizing surrogate sidestream smoke values, conceivable ETS exposure has been compared with current federal standards of permissible occupational exposure to several smoke components. Considering an unventilated room of 100 m3 (3533 cubic feet), the number of cigarettes that would have to be burned before reaching official threshold limit values varies among 1170 for methylchlorided to 13,300 for benzene to 222,000 for benzo(a) pyrene to 1,000,000 for toluene (Gori and Mantel, 1991).

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For the average ETS-exposed individual, this estimate translates into an annual dose equivalent to far less than the mainstream RSP of one cigarette evenly dispersed over a 12-month period (Gori and Mantel, 1991).

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COULD MINUTE ETS EXPOSURES POSE A HEALTH RISK?

Because direct measurements of the biologic activities, exposures, and doses of ETS are so problematic, initial attempts have inferred ETS-linked health risks by arithmetic derivation from the apparent risk associated with active smoking. However, this approach has been controversial.

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Moreover, epidemiologic studies of active smoking give evidence of No-Observable-Adverse-Effect- levels (NOAELs), namely that at low daily consumption of cigarettes the epidemiologic risks associated with certain diseases become nonsignificant (Gori, 1976; Gori and Mantel, 1991). No- effect observations at comparatively high doses are also routinely reported in experimental animal exposure to whole smoke or its fractions. In a recent evaluation of smoking and health issues, the Congressional Research Service of the Library of Congress stated:

"The existence of an exposure treshold for disease onset below which many passive smokers fall in not implausible. Most organisms have the capacity to cleanse themselves of some level of contaminants. It is for this reason that public policy usually does not insist that every unit of air or water pollution be removed from the environment... In fact, strongly non-linear relationships in which health effects rise with the square of the exposure, and more, have been found with respect to active smoking (see Surgeon General's Report, 1989, p. 44). Were these relationships projected backwards to construct the lower (unknown) portion of the health effect/physical damage function, the observed relationship might lead researchers a priori to expect no empirical relationship. Thus, the issue raised by the potential break in the causative chain is whether researchers should expect to find a significant relationship between passive smoking and health effects." (Gravelle and Zimmermann, 1994, p. 45).

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ETS AND POSSIBLE CHD RISK FACTORS IN HUMANS

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Significantly, studies report that the aborted fetuses from smoking mothers have 40% less chromosomal abnormalities than fetuses from nonsmoking mothers (Kline et al., 1993), while other studies report that maternal smoking is associated with a much decreased risk of mongoloid retardation or Down syndrome (Kline et al., 1993; Cuckle et al., 1990).

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Studies of human lung cancer tissues found that serum cotinine levels and adduct levels were not correlated and could detect adducts only in 7 of 38 individual tumour samples (Shields et al., 1993) DNA adducts of aromatic hydrocarbons in lymphocytes were not found to correlate with smoking habits (van Schooten et al., 1992; Grzybowska et al., 1993). DNA adducts were at similar levels in sperm cells of smokers and nonsmokers, a finding of interest given the intense DNA replication in spermatogenesis (Gallagher et al., 1993). Equal similarities were reported for DNA adducts of cervix tissues (King et al., 1994).

ETS, thrombus formation. Hypotheses have proposed that increased blood-clotting capacity may explain the association of heavy smoking and cardiovascular events. However the Framingham study reports an absence of cardiovascular risks for smokers of 1-10 cigarettes/day, consonant with an immaterial change in mean fibrogen (about 1%) in smokers of less than one pack of cigarettes/day (Kannel et al., 1987). It has been suggested that two eicosanoids, prostacyclin and tromboxane A2 are altered in smoking, but studies indicate no change in smokers of less that 10- 15 cigarettes/day (Wennalm et al., 1991). The large Koupio prospective study in Finland found a correlation of plasma fibrinogen levels with several psychosocial and socioeconomic variables, but not with smoking (Kubisz et al., 1994). Vicari et al., (1988) measured several thrombotic factors and found no differences due to active smoking. Haire et al. (1988) found no change in fibrinolytic activity after active smoking. Yamashita et al (1988) found no effect of smoking on platelet aggregation. Handley and Teather (1974) and Barbashet al. (1993, 1994) give an indication that smoking may protect against thromboembolic compilations after myocardial infarction and surgery. Similar results were reported by Pollack and Evans (1978). The Arteriosclerosis Risk in Communities Study of 15,800 men and women in the United States found that smoking was positively associated with levels of Antithrombin III, a major anticoagulant factor (Conlan et al.,1994). Some studies that suggest differently have been flawed or misinterpreted.

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ETS, cholesterol, lipidemias, and hypertension.

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The Cardiovascular Health Study Collaborative Research Group reports that in a cohort of 5201 men and women over 65 years of age, cigarette smoking was a negative predictor of blood pressure, confirming a number of prior reports (Tell et al., 1994).

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The massive WHO-MONICA study actually "showed a strong negative association between regular smoking and high cholesterol in the male populations and a strong negative association between regular smoking and high blood pressure in female populations" (MONICA, 1994). Well known is the so-called "French paradox," whereby the French population shows 55% less CHDs than the rest of the population surveyed in the MONICA project, despite experiencing high levels of cigarette smoking, hypertension, and total cholesterol (Renaud and de Longeril, 1993). The Helsinki Ageing Study reports a sight inverse association of active smoking and aortic valve degeneration in the elderly (Lindroos et al., 1994). In China, coronary mortality is some 10 times less frequent than in Germany, although the prevalence of smoking is 70% in China versus 37% in Germany. Total cholesterol, however, is much higher in German than in Chinese subjects (Stehle et al., 1991).

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These considerations tell that the active smoking of less than 10 cigarettes/day or ETS exposures are unlikely to adversely influence lipidemic Coronary Heart Disease risk factors. As such, they support the notion of No-Observable-Adverse-Effect-Levels for active smoking and cardiovascular diseases. In fact, the National Cholesterol Education Program only lists smoking over 10 cigarettes/day as possible CHD risk factor (NCEP, 1988)

CONCLUSIONS

Plausible ETS doses are thousands of times less than Main Stream doses that appear to have adverse CHD effects in active smokers. Such determination precludes the inference that ETS is a CHD risk, unless we are prepared to forgo all we have learned since Paracelsus about pharmacodynamic and kinetic discontinuities at low doses. By far the majority of experimental reports in man or animals either do not contradict or support this conclusion and together indicate that epidemiologic studies have been chasing an absent CHD effect -- a conclusion sustained by the generally equivocal or null reports from epidemiologic studies of ETS. The instability of data fro most epidemiologic studies, the heterogeneity in study design, data collection, and evaluation methods, precludes a metaanalysis numerical summation that is scientifically justifiable. The evidence favouring the ETS-CHD association remains conjectural, while the evidence against the association is suitably documented. According to the scientific method, the only justifiable conclusion is that the available data continue to falsify the hypothesis that ETS is a CHD risk factor.