The Mt. Sinai Catechism

There are mythologies in science as there in religion.  Back in the day, Dr. Irving Selikoff invented a catchy catechism about synergistic interaction between asbestos and smoking in producing lung cancer.  Selikoff’s study of insulators advanced lung cancer point estimates for asbestos alone, for smoking alone, and for asbestos and smoking together:  5-10-50, which became incorporated in innumerable textbooks, articles, expert witness reports, and court opinions.

E. Cuyler Hammond, Irving J. Selikoff,  and Herbert Seidman, “Asbestos Exposure, Cigarette Smoking and Death Rates,” 330 Ann. N.Y. Acad. Sci. 473, 487 (1979).  Selikoff tells us that each insulator, starting in 1961, answered “a detailed questionnaire,” and later, repeat questionnaires on their smoking histories.  Id. at 475.

“Of the 8220 men who answered the questionnaire, 891 (11%) said that they had never smoked regularly; 488 (6%) had a history of pipe or cigar smoking but never smoked cigarettes regularly and; 6841 (83%) were either current or ex-cigarette smokers. Some of the cigarette smokers also smoked pipes or cigars or had done so in the past.”

Id. at 481.

The 5 supposedly represented the relative risk of asbestos exposure alone in insulators who did not smoke; the 10 supposedly represented the relative risk of smoking alone in the non-insulator general population of smokers; and the 50 represented the relative risk of insulators who had smoked.  Selikoff claimed that his data supported a multiplicative model of synergistic interaction between smoking and asbestos exposure.

Like other mythologies, there was a good bit of exaggeration and fabrication in Selikoff’s story. First, the non-smoking relative risk was based upon the observed risk ratio among insulators who “never smoked regularly.”  Smoking data were collected by survey, and the actual questionnaires and definition have never been published or provided by Selikoff and his colleagues.  Even taken at face value, “never smoked regularly” is not the same as non-smoker.  Adding that the insulators union was widely engaged in personal injury litigation, and that the membership had a strong motive to downplay their smoking histories, this exposure information becomes suspect.

The non-asbestos smoking lung cancer point estimate (10) was equally dubious.  The ten-fold risk statistic represented an average smoking lung cancer risk in the first Cancer Prevention Survey (CPS-1).  The insulators who smoked were rarely average smokers, and the CPS-1 point estimate was superseded within a couple of years by the new, revised CPS-II overall smoking lung cancer point estimate that was greater than twenty.  The CPS-II results were published in the 1980s and early 1990s, but Selikoff and his protégés contained to testify to the 5-10-50. See, e.g., Shopland, “Smoking-Attributable Cancer Mortality in 1991: Is Lung Cancer Now the Leading Cause of Death Among Smokers in the United States?” 83 J. Nat’l Cancer Inst. 1142 (1991).

These problems and others led astute authors to note their dissent from the simplistic multiplicative model.  F. Douglas K. Liddell, “The Interaction of Asbestos and Smoking in Lung Cancer,” 45 Ann. Occup. Hyg. 341 (2001) (“Both cigarette smoke and inhaled asbestos fibres can cause lung cancer, but the assessment of how these agents act in combination is a matter of great difficulty.”)

Despite the serious problems with the multiplicative model, Selikoff’s wanton republication of the 5-10-50 data, and the popularity of these data with testifying expert witnesses and regulating agencies, cemented their use in litigation. Consider, for instance, how the orthodoxy infiltrated the ostensibly neutral Reference Manual on Scientific Evidence, which proclaimed the multiplicative synergy of smoking and asbestos in its second edition:

“Occupational asbestos exposure in nonsmokers increases the risk of lung cancer by a factor of about five, from about 11 per 100,000, for nonsmoking industrial workers not exposed to asbestos to about 58 per 100,000 for nonsmoking asbestos workers; a significant smoking history increases the rate of lung cancer by a factor of at least ten. See U.S. Surgeon Gen., U.S. Dep’t of Health & Human Servs., The Health Consequences of Smoking: Cancer and Chronic Lung Disease in the Workplace 216 (1985); see also Rodolfo Saracci, “The Interactions of Tobacco Smoking and Other Agents in Cancer Etiology,” 9 Epidemiologic Revs. 175, 176–80 (1987). Because the effects of smoking and asbestos are multiplicative for lung cancer, the population of smoking asbestos workers has a lung cancer incidence of 5 times 10, or 50 times the background rates, rather than the 15-fold increase predicted by adding the separate risks. See U.S. Surgeon Gen., U.S. Dep’t of Health & Human Servs., supra, at 216–17.”

Mary Sue Henifin, Howard M. Kipen, and Susan R. Poulter, “Reference Guide on Medical Testimony,” in Federal Judicial Center, Reference Manual on Scientific Evidence 439, 476 & n. 136 (2d ed. 2000).  Dr. Kipen was a protégé of Dr. Selikoff.  The reference to the multiplicative mantra was eliminated from the Third Edition of the Reference Manual.

Back in April of this year, some other Selikoff protégés were busy trying to rehabilitate the 5-10-50 mantra, with a new study. Science Daily earnestly reported news of the new study as though it were ground breaking.  See “Asbestos Exposure, Asbestosis, and Smoking Combined Greatly Increase Lung Cancer Risk” (Apr. 12, 2013)  (reporting on the in-press version of Steve Markowitz, Stephen Levin, Albert Miller, and Alfredo Morabia, “Asbestos, Asbestosis, Smoking and Lung Cancer: New Findings from the North American Insulator Cohort,” Am. J. Respir. & Critical Care Med. (2013)).  Interestingly, only Stephen Levin, who died over a year ago, is listed as affiliated with the Mt. Sinai School of Medicine.  Although some of the other authors had previous affiliations with Mt. Sinai, they are now listed at the Center for the Biology of Natural Systems, Queens College – CUNY.

Science Daily quotes lead author Markowitz as saying that “[t]he interactions between asbestos exposure, asbestosis and smoking, and their influence on lung cancer risk are incompletely understood.”  It seems unlikely that this new article will shed much light on the problem.   The authors claim to apply and extend Selikoff’s approach from previous publications.  This new publication thus incorporates the serious problems that had afflicted Selikoff’s papers, especially his use of CPS-I to provide a point estimate for smoking alone (the alleged 10 in the 5-10-50 theory).  Here is the abstract of the paper:

“Rationale

Asbestos, smoking, and asbestosis increase lung cancer risk in incompletely elucidated ways. Smoking cessation among asbestos-exposed cohorts has been little studied.

Objectives

To measure the contributions of asbestos exposure, asbestosis, smoking and their interactions to lung cancer risk in an asbestos-exposed cohort, and to describe their reduction in lung cancer risk when they stop smoking.

Methods

We examined lung cancer mortality obtained through the National Death Index for 1981-2008 for 2,377 male North American insulators for whom chest x-ray, spirometric, occupational and smoking data were collected in 1981- 1983 and for 54,243 non-asbestos exposed blue collar male workers from Cancer Prevention Study II for whom occupational and smoking data were collected in 1982.

Measurements and Main Results

Lung cancer caused 339 (19%) insulator deaths. Lung cancer mortality was increased by asbestos exposure among non-smokers [rate ratio = 3.6 (95% CI: 1.7-7.6)], by asbestosis among non-smokers [rate ratio = 7.40 (95% CI, 4.0-13.7], and by smoking without asbestos exposure [rate ratio = 10.3 (95% CI, 8.8-12.2)]. The joint effect of smoking and asbestos alone was additive [rate ratio = 14.4 (95% CI, 10.7-19.4)] and with asbestosis, supra-additive [rate ratio = 36.8 (95% CI, 30.1-46.0)]. Insulator lung cancer mortality halved within 10 years of smoking cessation and converged with that of never-smokers 30 years following smoking cessation.

Conclusions

Asbestos increases lung cancer mortality among non-smokers. Asbestosis further increases the lung cancer risk and, considered jointly with smoking, has a supra-additive effect. Insulators benefit greatly by quitting smoking.”

The big news that Steven Markowitz did not trumpet in the press releases was that in the absence of asbestosis, there was no multiplicative interaction.  The asbestos-alone (point estimate) is still suspect.  The paper characterizes this point estimate as applying to non-smokers without asbestosis, but given this group’s history of equivocating between “never smoked regularly” and “non-smoker,” and the difficulty in obtaining accurate smoking histories from men enmeshed in litigation over respiratory claims, the asbestos-alone point estimate remains doubtful.  Curiously, the smoking histories were collected in 1981-83, but there is no mention of any attempt to verify the histories against smoking histories provided by the study participants in earlier versions of Selikoff’s studies on the insulators.

Similarly, the smoking-alone point estimate is incredible.  The authors purport to draw the smoking-alone risk ratio from CPS-II; yet the risk ratio presented (10.3) is less than half that reported in multiple publications of the CPS-II study.  Markowitz and colleagues cite to two papers for the 10.3 point estimate; neither appears to support this number.  Steven Stellman & Lawrence, “Smoking habits and tar levels in a new American Cancer Society prospective study of 1.2 million men and women,” 76 J. Nat’l Cancer Inst. 1057 (1986); Michael Thun, Eugenia Calle, Carmen Rodriguez, and Phyllis Wingo, “Epidemiological research at the American Cancer Society. 9 Cancer Epidemiol. Biomarkers & Prevention 861 (2000).  I would welcome contradiction from anyone who can find the point estimate in the cited papers.

Consider one of the most recent publications, which drew upon CPS-II data, in the New England Journal of Medicine.  For men who were current smokers, compared with men who never smoked, the relative risk of lung cancer mortality was 24.97. Michael Thun, Brian Carter, Diane Feskanich, Neal D. Freedman, Ross Prentice, Alan D. Lopez, Patricia Hartge, and Susan M. Gapstur, “50-Year Trends in Smoking-Related Mortality in the United States,” 368 New Engl. J. Med. 351 (2013).

The Markowitz, Levin, Miller paper is still “in press.”  There is still time for the editors to take a closer look.  There is also time for the editors to insist upon a disclosure of the authors’ conflicts of interest. See, e.g., Wannall v. Honeywell Internat’l, Inc., Civ. Action No. 10-351 (BAH), 2013 U.S. Dist. LEXIS 68523 (D.D.C. May 14, 2013) (discussing Markowitz’s participation as an expert witness).

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