Glantz: OSHA Post-Post Hearing Comment


POST-POST HEARING COMMENT

Stanton Glantz, January 23, 1996
POST-POST HEARING COMMENT


Stanton A. Glantz, PhD
Professor of Medicine
University of California
San Francisco, CA 94143-1024 January 23, 1996

This comment responds to issues raised in several post hearing comments that OSHA requested I review. I have not reviewed the entire record submitted during the post-hearing comment period, but only the post hearing comments OSHA asked me to review.

Gio Gori (No. 410)

Gori's post-hearing comment is essentially a restatement of his written and oral testimony and contributes no new information to the record. He continues to restate his two views that scientists who find that ETS is dangerous are somehow "going along with the crowd" and are somehow lacking in scientific integrity and that it is impossible to conclude anything about small risks from epidemiology. He also continues to assert his view that no animal experiments are relevant to humans. If medical science adopted this view, most biomedical research would stop.

Gori's argument that epidemiologists cannot reach conclusions about small risks is based on a news article in Science [1] in which several leading epidemiologists provide a candid discussion of the problems of identifying small risks. Gori (p. 4) states that Prof. Dimitrios Trichopoulos "holds that relative risk or odds ratios values below 3 or 4 are not interpretable." Gori ignores the clarification of this view Trichopoulos published [2] in a letter in Science; Trichopoulos wrote:

"Taubes [1] writes that I have expressed the view that only a fourfold risk should be taken seriously. That is correct, but only when the finding stands in a biological vacuum or has little or no biological credibility. We all take seriously small relative risks when there is a credible hypothesis in the background. Nobody disputes that the prevalence of boys at birth is higher than that of girls (an excess of 3%), that men have a 30% higher death rate compared to women of the same age, or that fatality in a car accident is higher when the car is smaller. [emphasis added]"

The risks that Trichopoulos discusses are similar in magnitude (or smaller) than the risks associated with breathing ETS. Gori's representation of Trichopoulos' position to imply that it is impossible to reach conclusions about small risks from epidemiology is misleading and incorrect. It seems reasonable to assume that Gori was aware of this statement because he published a letter on the same article in the same issue of Science [3]. One wonders why Gori failed to provide an accurate representation of Trichopoulos' views.

It is also important to emphasize that the news article [1] is about the limits of drawing conclusions based on epidemiology alone. As the epidemiologists quoted in Taubes' news article stated in a letter to the editor [4], it is important to consider all the evidence, including epidemiology, biochemical, animal, and human experimental studies. (I made the same point in my opening comments in my testimony (Tr. 402-410).) Considering the weight of all the evidence leads to strong conclusions that passive smoking causes lung cancer, heart disease, and other problems.

Gori continues to insist, without presenting any empirical data to support his assertion, that there are threshold effects for lung cancer induced by ETS, and supports his assertion by citing a low quality and out-of-date study prepared by two economists at the Congressional Research Service [5]. In contrast, the most recent report on ETS by the Congressional Research Service, which was written by life scientists, explicitly recognized that there is no evidence for assuming a threshold effect [6, p. CRS-50]:

"It is important to point out that the threshold illustration is a hypothetical example and does not mean that any lung cancer which might result from ETS exposure would actually exhibit a threshold dose response relationship. While data from some studies have shown such a behavior as seen in the previous chapter, the statistical power of those studies is too weak to conclude that such a behavior exists. The use of a threshold model in these calculations is only to simulate the upper limit of a possible upward dose response behavior in order to bracket the range of consequences of possible dose response relationships. Finally, even if a threshold model were approximately correct, public health officials may still chose to use a model closer to the no-threshold approach in order to build in ensure [sic] that all populations are protected. [emphasis added]

"It is also worth noting that the second, and more recent, CRS report [6], which has been mischaracterized by the tobacco industry and its allies [7,8] as discrediting the EPA report on passive smoking and lung cancer [9], actually provides results consistent with the EPA. The second CRS report [6, p. CRS-2] says:

"Calculations based on data from the Fontham et al study [the largest, best study of passive smoking and lung cancer, published after the EPA report was completed in 1992] and assuming an average exposure for the entire population at risk (a no-threshold model) result in a range of 470 to 5500 annual lung cancer deaths in the U.S. from ETS with a mean value of 2780. This compares to a mean value of 3300 calculated by the EPA under the same assumption. Data from the Brownson et al study, on the other hand, produce no annual lung cancer deaths from ETS under the no-threshold assumption. If a threshold model is used to simulate the upper limit of a possible upward dose response behavior, the mean number of lung cancer deaths is 440 calculated from the Fontham et al data and 530 for the Brownson et al data. Over 70 percent of these deaths calculated in the no-threshold example and all those calculated in the threshold model occur to individuals who are exposed to both spousal and background ETS. The remaining deaths in the no-threshold model would result from exposure only to background ETS."

Given the uncertainties in computing these estimates, there is no practical difference between 2780 and 3300.

The second CRS report also recognizes that the EPA report has received wide support from the scientific community and that virtually all the criticism is coming from the tobacco industry [6, p. CRS-6]:

"The EPA report received widespread support from the public health community and from the larger scientific community. But it has been criticized by tobacco industry researchers and scientific consultants. A few independent statisticians and epidemiologists have also raised objections to EPA's statistical analysis of the ETS epidemiologic studies."

All the "independent" statisticians and epidemiologists that are critical of the EPA that I have seen have ended up having (often quiet) financial ties to the tobacco industry [10-14].

During the Hearing, the tobacco industry placed a report, Choices in Risk Assessment report [15], in the record by the tobacco industry; Choices discussion of ETS was almost entirely based on the first CRS study [5], which has been superseded by the second CRS study [6]. This fact is another reason that Choices does not represent the best available evidence; OSHA should discount this report in its deliberations.

It is also important to emphasize that even the second CRS study [6] took a very narrow view of the issue of ETS and lung cancer and simply looked at the studies published since the EPA report was issued. It would have been better to provide a review of all the data. The bottom line: despite the weakness of the approach in the second CRS report, it reaches essentially the same conclusions as the EPA and is certainly not a repudiation of the EPA.

The California Environmental Protection Agency has released a more complete and careful review of all the evidence on ETS and lung cancer, with special emphasis on studies published after the EPA report [16, p. 7]. This report concludes:

"In 1992, the U.S. Environmental Protection Agency (U.S. EPA) issued a report in which it concluded that ETS is a human lung carcinogen. Similar conclusions were reached in earlier reports by the U.S. Surgeon General (U.S. DHHS, 1986) and the National Academy of Sciences (NAS, 1986). The present document reviews the four U.S. studies that were published since 1991 and were not included in the U.S. EPA document. Results from the largest population-based study, conducted in several metropolitan areas of the U.S. (Fontham et al., 1994), were closest to the pooled estimate from the U.S. EPA report. Of the two other population-based studies, the association found in a Florida study (Stockwell et al., 1992) was stronger and that in a Missouri study (Brownson et al., 1992) was weaker than that indicated by the EPA's pooled estimate. Although the authors of the fourth study, a hospital-based case-control study (Kabat et et al., 1995), interpreted their findings to be unsupportive of an association between ETS exposure and risk of lung cancer, their results (analyzing men and women separately) were based on much smaller sample sizes than the three population-based case-control studies; nevertheless, the odds ratio we calculated from their results (for men and women combined) was in fact very similar to the U.S. EPA result. Despite the compelling biologic plausibility of an effect of ETS on lung cancer, detection has been problematic because a small excess in risk is difficult to establish in a single epidemiologic study. The three population-based studies published since the U.S. EPA report, by design, have successfully addressed many of the weaknesses (i.e., small sample size, possible selection bias, possible misclassification biases, inadequate adjustment for potential confounders) for which the previous studies on ETS and lung cancer have been criticized. The concordance in these study results gives further credibility to the finding of a causal association between spousal ETS exposure and risk of lung cancer described in the U.S. EPA report."

With regard to workplace exposures, the California Environmental Protection Agency concludes that [16, p. 25-26]:

"Studies in which the assessment of workplace exposure to ETS was complete (covering all jobs) with considerable ETS exposure of subjects in the studies are generally supportive of an association between workplace ETS exposure and risk of lung cancer (Wu et al., 1985; Wu-Williams et al., 1990; Fontham et al., 1994) suggested a trend of increasing risks with increasing duration of ETS exposure at the workplace. Compared to women who had no ETS exposure at the workplace, women who reported exposure for 1-15, 16-30, and 30 or more years showed adjusted odds ratios of 1.30, 1.40, and 1.86, respectively (p for trend = 0.001) (Table 7.7)

"In addition to the incomplete assessment of exposure to ETS at the workplace in some studies, respondents, particularly surrogate respondents, may be less able to provide information on the subjects' exposure to ETS at the workplace. In a study in which a test-retest design was used to examine the reliability of passive smoke histories reported in personal interviews, self-respondents more reliably reported residential exposure than exposure at work (Pron et al., 1988). This may be a particularly important problem in studies in which the proportion of surrogate respondents was high (Brownson et al, 1992; Stockwell et al., 1992).

"Despite some of the above mentioned difficulties in obtaining histories of lifetime ETS exposure at the workplace, there is reason to believe that this source of ETS exposure also increases the risk of lung cancer, as does ETS exposure from spouses. The workplace has been a major source of ETS exposure outside the home (Cummings et al., 1989 and 1990; Emmons et al, 1992; Siegel, 1993), although the relative importance of workplace ETS exposure may be declining in California as the result of increasing restrictions on smoking in the workplace. In the International Agency for Research on Cancer (IARC) 10-country collaborative study which correlated urinary cotinine levels to self-reported recent exposure to ETS at home (from spouses), in the workplace, and other social settings, Riboli et al (1990) found that exposure to ETS at the workplace was a significant predictor of cotinine levels, similar to ETS exposure from spouses."

It is worth noting that the tobacco industry's misrepresentation of the second CRS report [6] as contradicting the EPA report is not the first time that the tobacco industry has misrepresented scientific reports in an effort to discredit other scientific reports. (Indeed, the tobacco industry's efforts to "create controversy" where none existed has been a feature of its strategy for dealing with the evidence that passive smoking is dangerous since the earliest evidence that passive smoking caused lung cancer emerged in the early 1980s [17].) For example, in 1986, the US Surgeon General published "The Health Effects of Involuntary Smoking" [18] that concluded that ETS caused lung cancer, was bad for kids, and that simply separating smokers and nonsmokers would "reduce, but not eliminate" the risks of passive smoking. About 6 weeks later, the National Academy of Sciences produced its "Environmental Tobacco Smoke" report [19], which concluded the same things. Even so, the tobacco industry loudly claimed that the NAS report discredited the Surgeon General.

There is another point to keep in mind here: The EPA report, while very important, was not the first time that major scientific bodies concluded that ETS caused cancer. The Surgeon General [18] and NAS [19] reached this conclusion a decade ago. Viewed in this context, the controversies surrounding both CRS reports are another tempest in a teapot being stirred up by the tobacco industry based on hot air rather than scientific substance.

Most of Gori's criticisms of our experimental work on passive smoking and heart disease [20,21] are simply restatements of points he has made earlier and that were addressed in the original publications, my testimony at the hearing, and my post hearing comment. His primary new criticism is that our results are an artifact of increased catecholamine levels due to the stressful conditions in the experiments. As noted in my original testimony (Tr. 422-423, 701-704, 727-728), we have specifically excluded this possibility by showing that administration of beta blocker drugs, which block the effects of catecholamines, did not prevent the ETS effects [22]. Moreover, all our work includes control groups of animals housed under the same conditions eating the same diet; the only difference between the animals in the control and exposed groups is the presence of ETS. In our papers we documented that the exposure conditions were reasonable for this sort of toxicological study, particularly given the short term exposures.

Gori also misunderstands or misstates the presentation of results on the effects of ETS on infarct size [21]; the results are nondimensional (i.e., infarct mass as a percentage of muscle mass at risk). Moreover, new experiments are beginning to indicate the mechanisms by which ETS increases the risk of myocardial infarction. We [23,24] have shown that it is possible to block the effects of ETS on infarct size with L-arginine. The effects of ETS appear to act at a cellular level rather than through changes in hemodynamics. This result suggests that ETS interferes with endothelial function in ways that aggravate the effects of myocardial infarction. As little as one hour a day of ETS exposure (at home or at work) produces significant changes in endothelium-dependent arterial dilation in healthy young humans [25]. Moreover, the effects of passive smoking on endothelium-dependent arterial dilation are similar to the effects of active smoking. This result provides additional biological evidence to support the large (compared to the dose) effects of ETS on the cardiovascular system. These results also indicate that even short-term exposures to ETS produce demonstrable adverse effects on the cardiovascular system. ETS exposure also interferes with normal endothelial responses to acetylcholine [26]. These results point to some of the specific biological mechanisms at a cellular and molecular level through which ETS adversely affects the cardiovascular system.

Gori raises essentially the same criticisms of the work of Penn et. et al. [27,28], which are no more valid than his criticisms of our work and which have been answered by Penn in response to tobacco industry-generated letters to the editor [29]. Indeed, the fact that two different investigators, using different animals and experimental models, reached the same conclusions strengthens the confidence OSHA can have in all the results of these experimental studies. None of the issues Gori raises refute the fundamental result that ETS induces heart disease-like changes in experimental animals exposed to ETS.

Gori's effort to distance himself from his identification of nicotine as an addictive drug (p. 15-18 of his post-hearing comment) has no relevance to the OSHA rule making, but it is amusing. Given the widespread acceptance of nicotine as an addictive drug by authorities including the US Surgeon General [30], the Food and Drug Administration [31,32], and tobacco industry [33], one would have thought that Gori would have been proud to have been one of the early scientists to identify nicotine as an addictive drug. His semantic games and citation of the 1964 Surgeon General's report [34], while ignoring the 1988 report [30] to wiggle out of this position -- which is obviously damaging to his tobacco industry clients -- calls into question the credibility of his entire presentation.

Joseph Wu (No. 422)

Wu did not appear at the hearing, so it was not possible to question him regarding his views.

Like several other submissions by the tobacco industry, Wu recites a long list of technical details about the mechanisms by which different events occur in the cardiovascular system. While this is interesting, it is beside the point. None of this material demonstrates that ETS does not affect the cardiovascular system or provides alternative, plausible explanations for the experimental findings that ETS affects lipid depositions, development of atherosclerotic plaque, size of myocardial infarct, exercise tolerance, platelet activity, ATP production, or any of the other changes that have been demonstrated to occur under controlled conditions during ETS exposure. (For citations, see our review papers [35,36], the American Heart Association position statement on passive smoking and heart disease [37], my testimony or Ford's testimony.)

Wu's statement that my interpretation of the evidence on passive smoking and heart disease is "based on unsound and selective interpretations of existing data that are lacking in scientific validity" (p. 2) is typical of the kind of hyperbole that the tobacco industry loves. While this sounds like a damning statement, Wu does not point to a single experimental or epidemiological paper on ETS that we ignored. Wu's numerous statements that our conclusions are not based on data are also incorrect; our papers [35,36] and my testimony was well supported with citations to the peer reviewed literature. It is also important to emphasize that these publications passed rigorous independent scientific peer review in leading journals (Circulation [35] and JAMA [36]), which apply high standards of proof. If Wu's assertions were true, these journals simply would have not allowed us to publish papers with unsupported statements. It is also worth noting that the review paper we published in JAMA [36] was essentially the same material as presented to OSHA in my testimony. The fact that this material passed the rigors of independent peer review by one of the leading medical journals in the world increases the level of confidence OSHA can have in the findings.

Wu presents a discussion of the effects of lactate on vascular relaxation (p. 3-4). While interesting, it does not say anything one way or the other about the effects of ETS. To the best of my knowledge, no one has yet pointed to lactate as a mechanism for ETS-induced cardiovascular effects. He also provides theoretical arguments as to why ETS should not affect endothelial function (p. 8-9). In contrast to Wu's theoretical arguments, there is direct evidence that ETS impairs normal endothelial function in humans. For example, Adams et et al. [38] recently demonstrated that passive smoking is associated with dose-related impairment of endothelium- dependent dilation in healthy teenagers and young adults, suggesting early arterial damage, which helps explain the observed increase in risk of heart disease in passive smokers. The effects of passive and active smoking were similar in magnitude, providing additional evidence against the practice, advocated by the tobacco industry, of using "cigarette equivalents" to assess the effects of ETS. In contrast to Wu's discussion of side issues, these data provide direct evidence of an effect of ETS on humans.

Likewise, Wu presents a general discussion about why ETS should not cause atherosclerosis, but he fails to explain why our group [20,22,39] and Penn's group [27-29] found these effects. He raises questions about diet and stress (as the other tobacco industry witnesses did). These questions ignore the fact that all the experiments in question included control groups in which the animals were fed the same diet and housed under the same conditions. The only differences between the ETS-exposed animals and the control animals was the presence of ETS. It is hard to see how anything but ETS could be explaining the differences associated with ETS exposure. Wu proposes no plausible explanations.

Wu presents a lengthy discussion of mechanisms of platelet aggregation (p. 14-16) which fails to explain why so many investigators have observed an increase in platelet aggregation in humans and animals with exposure to ETS (see [35] and [36] for references). The only logical explanation is that ETS exposure affects platelet activity. While Wu argued that there might be differences between in vitro and in vivo measurements of platelet activity, he does not provide any positive empirical evidence that this difference can explain the observed effects of ETS on platelet activity. Again, it is important to emphasize that the experimental work in this area included control groups, so any errors or biases that might be associated with the measurement method would be present in all the data. It is hard to believe that there would be differential errors in measuring blood samples taken from people or animals who happened to be breathing ETS compared to the similar people in the control groups. The only plausible explanation for the observed differences associated with ETS exposure in these experiments is the ETS exposure itself.

Wu's comment is another example of the tobacco industry's penchant for grasping at straws for any possible explanation for observed connections between passive smoking (and, for that matter, active smoking) and disease. The simplest and most plausible explanation for the body of evidence on passive smoking and heart disease is that passive smoking causes heart disease.

Peter Lee (No. 356)

Peter Lee is another of the tobacco industry witnesses who did not appear at the Hearing, thereby depriving OSHA and the public of the opportunity to question him regarding his views.

I believe that his comments are mislabelled: Mr. Lee does not have a PhD.

Lee presents a lengthy argument for a threshold effect of ETS on lung cancer risk (p. 5-8). As with the other tobacco witnesses, Lee presents no affirmative evidence to support this assertion. Indeed, as noted above, the second (and most recent) CRS report [6] has explicitly recognized the fact that any analysis based on thresholds is speculative. Even assuming a threshold, however, there would be hundreds of deaths from ETS-induced lung cancer. It is important to emphasize that none of the major national scientific consensus reports [9,18,19] recognizes any evidence that there is a threshold effect for ETS-caused lung cancer. OSHA should not base its risk assessment on the assumption that there is a threshold effect for ETS-induced lung cancer (or, for that matter, heart disease or anything else).

The refusal of tobacco industry consultants to accept the evidence that ETS causes any disease whatsoever is well-illustrated by Lee's meta-analysis of ETS and lung cancer (p. 8). Despite the fact that he reports a statistically significant increase in the risk of lung cancer when analyzing all the studies (RR=1.13, 95% CI 1.05-1.22), he refuses to conclude that ETS causes lung cancer because he fails to find a statistically significant elevation in risk when he limits himself to only the US studies (RR = 1.11, 95% CI = 0.99-1.24). There are two points worthy of comment. First, the fact that the confidence interval is wider when it is computed based on less data is a standard statistical result. Indeed, Lee could obtain a non-significant result by simply limiting his selection of studies for inclusion in order to make the effective sample size small enough. Second, 0.99 is pretty close to 1.00; while it is strictly true that the confidence interval includes 1.00, most investigators would hardly find Lee's US result "negative." At the very least it would be considered as "strongly suggestive" of an association. Lee tries to wiggle out of this conclusion (on p. 9) by repeating the tobacco industry's line that only large relative risks should be considered real (he says somewhere between 1.5 and 3.0). This line of argument was addressed and rebutted above (in response to Gori's comments). As I have stated several times, OSHA should use all the relevant evidence in its deliberations; by this standard, Lee's result supports OSHA's determination that ETS increases the risk of lung cancer.

Lee's comments on one- versus two-tailed tests are silly (p. 9), particularly when he states "I do not believe one can ever be certain any agent might not protect against a disease." Does he really think exposure to ETS could protect people from developing cancer or heart disease? He has certainly never advanced any empirical evidence to support this assertion. The implicit assertion that "a little ETS can be good for you" is another of the silly propositions that the tobacco industry and its consultants have advanced in an effort to avoid accepting the obvious conclusion that ETS causes disease.

Lee's discussion of misclassification (p. 19-26) avoids the key point that misclassification of smokers as nonsmokers (and vice versa) can only be important if active smoking causes disease in smokers. As discussed in my post-hearing comment, tobacco industry witnesses have assiduously avoided admitting that smoking causes disease in smokers. This failure to deal forthrightly with the effects of active smoking makes it hard to take seriously the other arguments that the tobacco industry's witnesses make seriously. (It would have been interesting to cross examine Lee on this point at the Hearing, but he decided not to attend.) Unless and until Lee -- and the other tobacco industry witnesses who are claiming that misclassification explains the observed link between passive smoking and disease -- unequivocally states that active smoking causes lung cancer and heart disease, OSHA should simply ignore their arguments on misclassification errors.

With regard to confounders, Lee noted (p. 27) that I asked LeVois whether he had considered the list of 33 confounders in the paper by Thornton, Lee, and Fry [40]. During the hearing LeVois admitted to having not controlled for these 33 confounding variables in his study (Tr. 5886-5890), yet Lee is not critical of LeVois' study, and indeed, backpedals on the importance of his 33 potential confounders in his post-post-hearing comment (p. 27-38). Lee's inconsistent application of his standards to papers that agree and disagree with the tobacco industry's position (including the dramatic shift in his position regarding the proper interpretation of the Thornton et al. [40] paper from his pre-hearing submission to his post-post-hearing comment) is one more reason that OSHA should not take any of Lee's written comments seriously.

Lee's distinction between active smoking and passive smoking in terms of effects on the heart (p. 58-59) is silly; no one is saying that the effects of ETS and active smoking are so different that they should be considered as totally independent risk factors. Indeed, a great deal of evidence (reviewed in [35] and [36], together with more recent studies [38,41]) demonstrates that in terms of the cardiovascular system nonsmokers exhibit large responses to small doses of ETS, often approaching that of habitual smokers. The evidence indicates a steep dose-response curve at low doses, with decreasing marginal effects as dose increase. Thus, one would not expect to see a large cardiovascular effect of ETS on active smokers.

Lee's unwillingness to accept the scientific evidence that ETS is dangerous is further illustrated when he presents his own meta-analysis of the available data, including the tobacco industry's analysis of the ACS CPS and NMFS data sets (p. 59). (As discussed in detail in my post-hearing comment, OSHA should not use the tobacco industry's analysis of these two data sets.) All Lee's estimates of the risk of heart disease associated with ETS are significantly above one. Lee even admits that our analysis is correct and that the elevated risks are unlikely due to chance. Nevertheless, he chooses to dismiss the finding that passive smoking causes heart disease. This frank refusal to accept the results of his own analysis is another reason that OSHA should not take Lee's comments seriously.

Lee devotes considerable energy (p. 60-63) to justifying the use of the ACS CPS data sets to analyze the effects of ETS on heart disease and urges the ACS to conduct such an analysis. As noted in my post-hearing comment, ACS did conduct such a (preliminary) analysis, which confirmed that ETS exposure is associated with an increase in heart disease.

In contrast to the exacting standards Lee demand