Toxicological Sciences 58, 416-417 (2000)
Copyright © 2000 by the Society of Toxicology
Letters to the Editor |
Letter
Division of Cardiology, University of California, San Francisco, CA 94143-0130
To the Editor:
Smith et al. (2000) recently published a paper countering the hypothesis that secondhand smoke activates platelets. They stated that this effect, which would at least partially explain the high sensitivity of nonsmokers to secondhand smoke in terms of heart disease risk, could not be correct based on dose-response considerations. Their arguments, based on dose-response curves, ignore the fact that secondhand smoke does not appear to have an effect on platelet activity in smokers (whose platelets are already highly activated). This indicates that the underlying process involves either a different process in nonsmokers (who are not chronically exposed to the toxins in cigarette smoke at high levels) or that the process saturates. Either situation would render their dose-response argument invalid. More important, they neglect to mention that secondhand smoke exposure does increase platelet activation in both humans (Sinzinger and Kefalides, 1982
; Burghuber et al., 1986) and experimental animals (Zhu et al., 1993). One wonders why they ignored these direct positive observations as they struggled to reach a negative conclusion regarding the evidence that secondhand smoke causes heart disease.
REFERENCES
Burghuber, O., Punzengruber, C., Sinzinger, H., Haber, P., and Silberbauer, K. (1986). Platelet sensitivity to prostacyclin in smokers and non-smokers. Chest 90, 34–38.
Sinzinger, H., and Kefalides, A. (1982). Passive smoking severely decreases platelet sensitivity to antiaggregatory prostaglandins. Lancet 2, 392–393.[Web of Science][Medline]
Smith, C. J., Fischer, T. H., and Sears, S. B. (2000). Environmental tobacco smoke, cardiovascular disease, and the nonlinear dose-response hypothesis. Toxicol. Sci. 54, 462–472.
Zhu, B. Q., Sun, Y. P., Sievers, R., Isenberg, W., Glantz, S. A., and Parmley, W. W. (1993). Passive smoking increases experimental atherosclerosis in cholesterol-fed rabbits. J. Am. Coll. Cardiol. 21, 225–232.[Abstract]
Research and Development Department Bowman Gray Technical Center R.J. Reynolds Tobacco Company Winston-Salem, NC 27102 University of North Carolina at Chapel Hill School of Medicine Department of Pathology (FOBRL) 350 South Old Fayetteville Road Chapel Hill, NC 27516
Reply
To the Editor:
Gantz and Parmley cite three studies as evidence that environmental tobacco smoke (ETS) increases platelet activation in both humans and animals. The doses of ETS used in the cited studies are excessively high and are not toxicologically relevant to real-world ETS levels. In contrast, an environmental room study conducted at three times the 95th percentile of U.S. workplace ETS levels did not measure an increased tendency toward thrombosis in nonsmokers after 7.33 h of exposure (Smith et al., 1996). In addition, a field study of nonsmokers living with smokers suggested that platelets were not activated in the ETS-exposed nonsmokers (Smith et al., 1998a).
The studies cited by Glantz and Parmley that used human subjects are Sinzinger and Kefalides (1982) and Burghuber et al. (1986). Both of these studies were conducted by the same research group, followed similar experimental protocols, and examined only nine nonsmokers in each of the two experiments. At least two lines of evidence suggest that these studies do not support the existence of a pathological platelet response to ETS leading to an increased risk of cardiovascular disease in nonsmokers.
First, in the Sinzinger and Kefalides (1982) and Burghuber et al. (1986) protocols, the ETS exposure was generated by smoking 30 high-tar cigarettes in an 18-m3 room. L. Wallace from the U.S. Environmental Protection Agency has estimated that 14 mg of respirable particulate matter (RSP) is generated per cigarette (Wallace, 1996), a value validated by our laboratories (Martin et al., 1997). Smoking 30 cigarettes would liberate 420 mg of RSP into the room, an exposure dose of approximately 23.3 mg/m3 of room air, not adjusting for particle settling or deposition.
How high is an ETS exposure of 23.3 mg/m3? The 95th percentile of U.S. workplaces in terms of ETS RSP exposure has been estimated using solanasol at 53.7 µg/m3 of air (Jenkins et al., 1996). Therefore, the exposure dose used in the cited studies was approximately 435 times higher than the ETS level found in the top 5% of current U.S. workplaces. The rabbit study cited by Glantz and Parmley, Zhu et al. (1993), also used high ETS exposures of 32.8 mg/m3 for the "high-dose" group and 0.13 mg/m3 for the "low-dose" group, and thus does not model real-world exposure levels.
Second, Sinzinger and Kefalides (1982) and Burghuber et al. (1986) do not provide evidence that real-world ETS levels can cause a pathological response, because even the inordinately high ETS exposures used only resulted in a degree of platelet priming within the normal nonpathological range. Employing the same procedures used in the two cited ETS studies, Burghuber et al. (1981) reported that the exertion from jogging and playing squash primes platelets to a degree similar to high-dose ETS exposure. This latter result is biologically plausible, as there is a sizable body of evidence demonstrating that platelets are responsive to the normal acute and chronic changes in stress levels that are experienced in daily life via activation of the sympatho-adrenergic system and priming by catecholamines.
The extraordinarily high levels of ETS used in the Sinzinger and Kefalides (1982) and Burghuber et al. (1986) studies can be plausibly hypothesized to have induced catecholamine release associated with a normal physiological stress response to exposure to the irritation, odor strength, and confinement associated with the protocol. Conclusions drawn from platelet activation studies should carefully consider the normal range of platelet responses from routine sympatho-adrenergic activation.
Glantz and Parmley also make a circular argument based on the results of the three cited studies that dose-response relationships between active cigarette smoking and platelet aggregation are not relevant to ETS because processes are "different" or "saturated." Regarding the relevance of active smoking/ETS comparisons vis-à-vis platelet activation, many studies have demonstrated that active smokers experience platelet priming following the smoking of a single cigarette. A number of studies have also reported platelet activation in active smokers by using integrated measurements of the stable metabolites of thromboxane and prostacyclin in the urine (Smith et al., 1998b). This provides evidence that platelet responses are not "saturated" in active smokers.
Given the extremely low doses of ETS found in real-world environments as compared with active smoke exposures (100- to 300-fold less), neither active smokers nor ETS-exposed nonsmokers would be expected to experience platelet activation as a result of ETS exposure. We are not aware of human or animal evidence suggesting a pathological platelet or other cardiovascular response to real-world levels of ETS that falls outside the normal inter-individual variation inherent in the physiological functioning of the sympatho-adrenergic system. The results of field experiments currently submitted for publication will further address these issues.
REFERENCES
Burghuber, O., Sinzinger, H., Silberbauer, K., Wolf, C., and Huber, P. (1981). Decreased prostacyclin sensitivity of human platelets after jogging and squash. Prostaglandins Med. 6, 127–130.[Web of Science][Medline]
Jenkins, A., Palausky, A., Counts, R., Bayne, C., Dindal, A., and Guerin, M. (1996). Exposure to environmental tobacco smoke in sixteen cities in the United States as determined by personal breathing zone air sampling. J. Expo. Anal. Environ. Epidemiol. 6, 473–502.[Web of Science][Medline]
Martin, P., Heavner, D. L., Nelson, P. R., Maiolo, K. C, Risner, C. H., Simmons, P. S., Morgan, W. T., and Ogden, M. W. (1997). Environmental tobacco smoke (ETS): a market cigarette study. Environ. Int. 23, 75–90.
Smith, C. J., Bombick, D. W., McKarns, S. C., Morton, M. J., Morgan, W. T., and Doolittle, D. J. (1996). Environmental room human physiology study using fresh diluted sidestream cigarette smoke. Proceedings of the 1996 CORESTA Congress, Yokohama, Japan, November 6: pp. 18–36.
Smith, C. J., Morgan, W. T., Doolittle, D. J., Fischer, T. H., Ruppert, T., and Scherer, G. (1998a). Urinary prostacyclin in nonsmokers living with smokers. Inhal. Toxicol. 10, 431–441.
Smith, C. J., Steichen, T. J., and Fischer, T. H. (1998b). Platelet aggregation in cigarette smokers. Inhal. Toxicol. 10, 765–793.
Wallace, L. (1996). Indoor particles: a review. J. Air Waste Manage. Assoc. 46, 98–126.
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