The Dissolvable Deficit: FDA and CDC Must Fill Data Void

The FDA Tobacco Products Scientific Advisory Committee (TPSAC) held a public hearing January 18-20 on dissolvable smokeless tobacco products. The information gleaned there will help inform a congressionally mandated report on the subject, due March 23.

The proceedings (agenda here) underscored the dearth of information on dissolvable tobacco use. Committee members repeatedly observed that there is no reliable data on who uses these products and in what context. Are dissolvables temporary or permanent substitutes for cigarettes? Do they promote tobacco initiation among teenagers?

These are legitimate questions for which we need definitive answers. One problem is that dissolvables from major manufacturers have only been in limited markets since 2009, when RJ Reynolds test-marketed Camel Orbs, Strips and Sticks in Indianapolis, Columbus and Portland, Oregon. Testing was discontinued early last year, but Reynolds later launched the products in Denver and Charlotte. In 2011, Altria introduced Skoal and Marlboro Sticks in Kansas. A smaller player, Star Tobacco, has sold Ariva dissolvable tobacco since 2001.

It is not surprising that we know next to nothing about dissolvable tobacco use; little is known about smokeless tobacco use generally, despite the fact that some 6 million U.S. adults consume these products. This information deficit can be blamed on the federal government, and specifically on the Centers for Disease Control and Prevention (CDC).

Each year, the CDC publishes detailed information on U.S. smoking prevalence, based on the annual National Health Interview Survey. What about smokeless tobacco? It turns out that the CDC has only produced detailed smokeless tobacco information twice in the last decade, in 2000 and in 2005, when the NHIS included a special supplement sponsored by the National Cancer Institute. There is a lot of information in these supplements, as I documented in 2009 publication (abstract here).

There has been growing discussion over the past decade about smokeless tobacco as a substitute for cigarettes. The U.S. House of Representatives in 2003 held a hearing titled “Can Tobacco Cure Smoking: A Review of Tobacco Harm Reduction” (my testimony here). It should have been a wakeup call for government officials to collect more information on smokeless tobacco use. Instead, there is evidence that NHIS staff decided to collect less.

In addition to smokeless tobacco information, the 2000 NHIS also collected information on the techniques used by smokers during their last attempt to quit. This data proved that tobacco harm reduction with smokeless tobacco was working. As I noted in a published study (abstract here):

“An estimated 359,000 men switched to smokeless tobacco in their most recent quit attempt. This method had the highest proportion of successes among those attempting it (73%), representing 261,000 successful quitters (switchers)… Switching to ST compares very favorably with pharmaceutical nicotine as a quit-smoking aid among American men, despite the fact that few smokers know that the switch provides almost all of the health benefits of complete tobacco abstinence. The results of this study show that tobacco harm reduction is a viable cessation option for American smokers.”

If the 2000 NHIS survey proved that tobacco harm reduction was viable, what did the 2005 NHIS survey show? Absolutely nothing. NHIS removed the switch-to-smokeless option from the 2005 survey, despite the huge explosion in awareness of and discussion about tobacco harm reduction.

Today, the TPSAC committee is preparing to make important decisions concerning tobacco harm reduction... lacking basic information about smokeless tobacco use and with no current data about transitions between cigarettes and smoke-free products.

This information deficit is unacceptable. The FDA Center for Tobacco Products, generously funded by fees from tobacco manufacturers, must act. At a minimum, it should fund annual use of the 2000 NHIS smokeless tobacco supplement – with appropriate revisions for e-cigarettes – in every annual survey, in order to collect unbiased information about use of smoke-free tobacco products.

Discussing Dissolvable Smokeless Tobacco

When Congress gave the FDA regulatory authority over tobacco in 2009, it directed the agency to evaluate dissolvable smokeless tobacco. This week the FDA Tobacco Product Scientific Advisory Committee is holding hearings, and this has prompted a media blitz by anti-tobacco extremists.

Thomas J. Glynn, the director of science and trends for the American Cancer Society, issued a strange statement (here): “At this point, we don't know the full range of what is in them.”

Dr. Glynn may not be aware that dissolvable tobacco has been analyzed extensively (discussed here), and we do know what is in them: tobacco, flavors, non-caloric sweeteners and a few food-grade additives.

Two months ago Dr. Glynn authored an “Expert Voices” blog post titled “Here Come the Dissolvables” (here), in which he included some reasonable comments about dissolvable tobacco and one demonstrably false statement. ACS describes the blog as providing “timely insight on cancer topics from experts.” I have previously discussed other statements from Dr. Glynn (here).

ACS, at last, acknowledged that smokeless tobacco use is less hazardous than smoking. Dr. Glynn: “Certainly, as with all smokeless tobacco products, [dissolvable tobacco] will be less lethal than smoked cigarettes…” He added that “smokers should certainly continue to be made aware of that.”

A few paragraphs later, Dr. Glynn repeated the smokeless-is-safer theme: “…there is little doubt that, if all smokers in the U.S. suddenly switched from smoked cigarettes to smokeless tobacco – and stayed switched – we would see far fewer cancers and less heart disease 20 years from now…” He again noted, “smokers should continue to be made aware of the reduced, but by no means empty, threat posed by smokeless tobacco…”

Unfortunately, Dr. Glynn didn’t acknowledge ACS’s refusal to educate smokers about vastly safer smokeless tobacco, or the organization’s refusal to release critical information about the relative safety of smokeless tobacco (here).

Dr. Glynn made a passing reference to my research when he said, “Some proponents of smokeless tobacco, including dissolvables, make the argument that smokeless tobacco is as much as 98% less harmful than smoked cigarettes.” Later he opined that the “‘98% less harmful’ figure is suspect,” though he provides no evidence to support his suspicion.

Glynn’s core position remained prohibitionist. “It would be irresponsible,” he wrote, “for the public health community to urge [smokers to switch to smokeless tobacco] because there is also no evidence that smokers won’t just end up using both forms of tobacco, rather than using only smokeless – or better yet, quitting altogether.”

It is disappointing that Dr. Glynn repeatedly disrespected smokeless users by using the term “spit tobacco”. I previously reported this inappropriate and unprofessional practice to the ACS president (here), and I had been told that it had been discontinued.

Dr. Glynn made a demonstrably false statement when he predicted that “…if all smokers in the U.S. suddenly switched from smoked cigarettes to smokeless tobacco – and stayed switched…we would also see an increased number of oral cancers…”

The risk for oral cancer among smokeless tobacco users is much lower than the risk among smokers. In fact, since 1990, no epidemiologic study has reported any significantly elevated risk among smokeless users.

It is almost certain that a large-scale permanent switch from cigarettes to smokeless tobacco would not only result in a significant reduction in the number of oral cancers, it would substantially reduce all smoking-related diseases.

E-Cigarettes Vary Widely

Investigators from the University of California Riverside have published a study underscoring the wide variation in performance of e-cigarette brands, including Liberty Stix (here), Crown Seven (here), Smoking Everywhere (here), and VapCigs (here).

Tests conducted by Monique Williams and Prue Talbot measured airflow rates required to produce an aerosol, and the number of puffs available per unit, among other things (abstract here).

They reported, “Significant variation was found among e-cigarette brands in the airflow rate required to produce aerosol,…in aerosol density, and in the manner in which e-cigarettes performed over time….Consumers and researchers should be aware that e-cigarettes vary in performance across brands and within models from the same brand, that some brands will require harder inhalation to use than [combustible] cigarettes, and that aerosol density varies between puffs which may affect nicotine delivery.”

This research followed work published last year (abstract here), in which Williams, Talbot and first author Anna Trtchounian used a smoking machine to compare the puffing characteristics and smoke/aerosol densities of Liberty Stix, Smoking Everywhere, Crown Seven and NJOY (here) with those of combustible cigarettes. They found that most e-cigarettes required a much higher vacuum for puffing than commercial cigarettes, and that the vacuum required for Liberty Stix was the lowest of all tested products. In addition, puff strength had to be increased as puff number increased. They also found considerable variation in the maximum number of puffs delivered by the products, which ranged from 177 (Smoking Everywhere) to 313 (NJOY). In the current study, Smoking Everywhere also delivered only 160 puffs, while VapCigs delivered 250 and Crown Seven delivered 400 (no results were presented for Liberty Stix).

There are numerous e-cigarette brands available in retail stores, shopping mall kiosks and online; starter-pack prices range from about $20 to $100. Smokers should be aware of the variability among and within brands, so they won’t reject this cigarette alternative on the basis of one e-cigarette experience. Smokers should talk with consumers who have made the switch; learn about e-cigarette options and observations on the Internet; and try several products, if necessary, to find one that is satisfying.

While e-cigarettes vary widely, they are capable of improving and extending the lives of cigarette smokers.

An Informative Study on Tobacco-Specific Nitrosamines

Last week, I noted that University of Minnesota researchers, arguing for additional reductions of tobacco-specific nitrosamines (TSNAs) in moist snuff products (here), complained that “No evidence has been found that Conwood [a Reynolds company] and USST [United States Smokeless Tobacco, an Altria company] took any meaningful steps to reduce the relatively high levels of NNN and NNK in their products.” (The lead author was Stephen Hecht.)

The Hecht allegations are another false alarm, as a new study in Food and Chemical Toxicology (abstract here) provides evidence that, “…since 1997, average TSNA levels have declined by approximately half in USST moist smokeless tobacco products.” The authors, including lead author Michael Fisher, are from Altria.

Fisher et al. provide valuable information about how agricultural and production practices influence TSNA development. They collected samples from thousands of bales of tobacco over the past 15 years, and discovered that “…there is a general relationship between average rainfall during the tobacco curing season and TSNA in cured tobacco.”

Moist snuff is primarily made from dark-leaf tobacco, grown in western Tennessee and western Kentucky, and barn-cured in late-summer and autumn with smoke from hardwood fires. Fisher et al. show that the most important factors in TSNA formation are humid and/or moist curing conditions. Excess nitrogen fertilizer is also a factor, although tobacco needs high concentrations of nitrogen in order to thrive. As Hecht et al. pointed out in their article, American moist snuff has marginally higher TSNA levels than Swedish snus, which is also made with dark-leaf tobacco that is air cured. This suggests that fire curing may also play a minor role in TSNA formation.

In the past manufacturing may have also played a small role in TSNA formation, when particular bacterial strains used some of the nitrogen (in the form of nitrate) to form nitrite. The nitrate-reducing bacteria may be present in harvested tobacco, and in fermentation facilities, but in 2005 USST initiated strict sanitation practices and other programs to inhibit these bacteria. This resulted in TSNA levels in finished products that were consistent with the levels found in the incoming leaf.

As I have noted previously, TSNA levels in moist snuff products from Altria and Reynolds are at historically low levels. This study documents that TSNA levels are mainly influenced by weather conditions during the curing process. Furthermore, it is important to emphasize that there is no evidence that current TSNA levels are associated with ANY significant cancer risks.

Low Nitrosamine Levels in Altria and Reynolds Moist Snuff Products, say Minnesota Researchers

I discussed a year ago the tempest-in-a-teapot issue of tobacco specific nitrosamines (TSNAs) in smokeless tobacco products (here). TSNAs are contaminants found only in tobacco, and they are present in vanishingly small concentrations – mainly in the single-digit parts-per-million range. “Regardless of current TSNA levels,” I wrote, “anti-tobacco extremists will call for reductions.”

Last month, the University of Minnesota’s Stephen Hecht, Irina Stepanov and Dorothy Hatsukami (a member of the FDA Tobacco Products Scientific Advisory Committee) published a letter in Tobacco Control (here), demanding TSNA reductions. This, despite the fact that their data showed that TSNA levels in moist snuff products from Altria and Reynolds were at historically low levels in 2010. I have commented on this group’s anti-smokeless-tobacco articles before (here and here).

Hecht et al. list the levels of NNN and NNK in several Altria and Reynolds brands:

NNN + NNK Levels in Moist Snuff and Snus, in Parts Per Million (ppm), Dry Weight
Brand	NNN+NNK (ppm)
Altria
Copenhagen	5.6
Copenhagen Long Cut	5.8
Copenhagen LC Wintergreen	4.6
Skoal Long Cut Straight	4.9
Skoal Long Cut Wintergreen	5.2
Skoal Bandits Wintergreen	5.2
Marlboro Snus Rich	0.7
Marlboro Snus Spearmint	0.9
Marlboro Snus Peppermint	0.8
Marlboro Snus Mild	0.8
Reynolds
Grizzly	11.1
Kodiak Wintergreen	5.1
Camel Snus Frost	1.5
Camel Snus Mellow	1.7

These NNN and NNK levels are lower, across the board, than those of moist snuff products from the 1980s and 1990s, which I documented in a review article in 2004 (here). Epidemiologic studies from the 1980s and 1990s show that oral cancer risks among moist snuff users were minimally elevated, if at all, when those higher level products were being used.

While Hecht and colleagues assert that “smokeless tobacco is carcinogenic to humans, causing oral, pancreatic and esophageal cancer,” a comprehensive study of cancer risks among smokeless users (here) documented no significant risk for any of these cancers. There is virtually no evidence that current TSNA levels are associated with ANY significant cancer risks. Reducing current levels cannot lower an immeasurable cancer risk.

The article by Hecht et al. indicates that the authors are comfortable with TSNA levels in Marlboro and Camel snus, and that they view these products as acceptable cigarette substitutes. Perhaps Drs. Hecht, Stepanov and Hatsukami will now endorse them in this manner.

Allegations and Answers in Owensboro

A letter published in the Owensboro Messenger-Inquirer on December 12 challenged the veracity and ethics of the Switch and Quit Owensboro campaign (described here). The letter, authored by a former administrator of the Kentucky oral/dental health program, reflected the hostility towards tobacco harm reduction that is common among dental organizations (previously described here and here).

The Messenger-Inquirer published this response from me on December 19:

To the Editor,

Dr. Jim Cecil’s December 12 letter criticizing Switch and Quit Owensboro contained serious inaccuracies.

Dr. Cecil states that smokeless tobacco products “are known to cause” a number of diseases. In fact, research shows that the health risks from smokeless use are so minuscule that they are barely measurable, and they are a tiny fraction of the health risks associated with smoking. Dr. Cecil suggests that smokers only be told about “FDA-approved smoking cessation aids,” but those products succeed with only 7% of smokers. Smokeless tobacco works as a cigarette substitute because it satisfies nicotine cravings; it is also more affordable and more widely available than nicotine medicines.

Dr. Cecil incorrectly states that “there is no scientific evidence that smokeless tobacco can help a smoker quit!” Numerous scientific studies published in prestigious medical journals document that smokeless tobacco is an effective quit-smoking tool. These studies are summarized in two comprehensive reviews in Harm Reduction Journal (here and here).

Rather than being an industry ploy, as Dr. Cecil implies, Switch and Quit embodies a smoking cessation concept that has been endorsed by the esteemed British Royal College of Physicians (among others), which found “...that smokers smoke predominantly for nicotine, that nicotine itself is not especially hazardous, and that if nicotine could be provided in a form that is acceptable and effective as a cigarette substitute, millions of lives could be saved.” (available here)

Dr. Cecil believes it is “unconscionable” and “unethical” to inform smokers about vastly safer smoke-free tobacco products. Consider this fact: If all American smokers instead used smokeless tobacco, over 430,000 lives would be saved each year. The Switch and Quit campaign is consistent with the highest medical and ethical standards.

Brad Rodu
Professor of Medicine
Endowed Chair, Tobacco Harm Reduction Research
University of Louisville

Karolinska Institute Study: Heart of Failure

I have described in detail (here, here, and here) studies from Stockholm’s Karolinska Institute (KI) that have driven smokeless tobacco regulation worldwide. These studies contain important and troubling discrepancies that KI researchers have refused to address. Rather, they continue to defy international scientific principles of data sharing, which stipulate that scientific results are open to challenge by other scientists to determine their accuracy and integrity.

Some of the same KI researchers, led by Gabriel Arefalk, recently authored another study, alleging that snus use causes heart failure (here). The article was published in the European Journal of Cardiovascular Prevention and Rehabilitation.

As in the past, KI focused on snus users in the Swedish Construction workers cohort. This time, construction workers who were snus users didn’t have a significantly higher risk for heart failure than nonusers. But the researchers also analyzed the Uppsala Longitudinal Study of Adult Men (ULSAM), reporting that snus use “was associated with a more than doubled risk for subsequent heart failure” in this group.

It appears that the ULSAM analysis was tailor-made to produce the desired result, and it is evident that the KI researchers employed highly unorthodox methods. I attempted to draw attention to these serious problems by submitting a letter to the journal editor. My submission was rejected, “on grounds that this commentary is a re-review of the analyses of the paper.” Ignoring my systematic description of the study’s deficiencies, the editor suggested that I “obtain data and write another scientific paper for the journal.” This is particularly ironic, since I have tried for three years to obtain data from KI.

Following is my letter to the European Journal of Cardiovascular Prevention and Rehabilitation.

To the Editor:
Study of Snus Use and Heart Failure: Problems Requiring Resolution

The article by Arefalk et al. (1) reported that snus use was “a significant predictor of heart failure” among 70 year-old men in the Uppsala Longitudinal Study of Adult Men (ULSAM) (hazard ratio, HR = 2.09, 95% confidence interval, CI = 1.00 – 4.39). However, there are numerous problems that raise questions about the validity of the findings.

Among the 78 snus users at baseline, 62 (79%) were current smokers; in the referent group of 998 snus non-users, only 175 (18%) were current smokers. The large difference in smoking makes it extremely unlikely that the results were fully adjusted for current smoking, which is an important confounding factor (2). This problem was compounded by the authors’ highly unorthodox adjustment procedure.

The authors apparently did not utilize conventional categories of current, former and never smoking, even though it was clearly possible to do so according to the ULSAM questionnaire (3). Instead, they stated that “[s]moking was adjusted for by using a current smoking dose variable [none, < 10 or > 10 cigarettes per day] as well as a pack-year variable [never, < 33 and > 33 pack-years].” But this created a major problem: the 504 former smokers were combined with the 335 never smokers in the current smoking dose variable, and they were combined with the 237 current smokers in the pack-years of smoking variable (Table 1, Column labeled Total Sample). Thus, in the authors’ adjusted models former smokers were simultaneously pooled both with never smokers and with current smokers, two groups that ought to be mutually exclusive.

Although Arefalk et al. failed to define or categorize current and former smokers in the ULSAM cohort, the latter group appeared in the discussion: “…we performed a secondary analysis…further subdividing former smokers into those who quit smoking less than vs. more than 10 years before baseline.” Mentioning former smokers in the last third of the discussion without ever defining them is incomprehensible. In addition, the authors’ 10-year cut-point for smoking cessation was different from the 5-year cut-point in the questionnaire (3). The authors need to provide a complete explanation of the analysis that they employed.

Arefalk et al. reported that there were 78 snus users, which is consistent with the number on the ULSAM website (questionnaire item Z480, “Do you use snus?”; yes, n=79)(3). They also described 237 current smokers (167 moderate and 70 heavy), which was consistent with responses to the question asked during a euglycemic hyperinsulinemic clamp investigation, “Do you smoke?” (Z085; yes, n=245), but not with responses to the questionnaire item “Do you smoke?”(Z158; yes, n=173) (3). It would be helpful to understand the differences in these responses.

Arefalk et al. also estimated the risk of heart failure among snus users in the Swedish Construction Workers Cohort (CWC), and they evaluated the effect of dose among the 75 current snus users with heart failure (Table 4). They concluded that “[n]o clear dose-response relationship was observed…” In contrast, Arefalk et al. reported that “the limited sample size did not permit the study of dose-response relations” in the ULSAM cohort. This important information, which was available for the 14 snus users with heart failure (3), may be very informative even if it was inadequate for a formal analysis. For example, perhaps all 14 cases of heart failure were among users of very low doses. Arefalk et al. should not withhold this information.

There were numerous formatting errors in the tables. For example, in Table 1 the variables Diabetes prevalence, ECG-left ventricular hypertrophy, Body mass index, Office systolic blood pressure and Antihypertensive medication use were listed under Pack-years of smoking, and the variables Myocardial infarction before baseline and Myocardial infarction during follow-up were listed under Alcohol use. There were similar errors in Table 4.

Arefalk et al. concluded that they “observed an increased risk for subsequent heart failure” among male snus users in the ULSAM, but the conclusion is neither legitimate nor persuasive until the authors resolve the fundamental questions about the analysis.

References

1. Arefalk G, Hergens M-P, Ingelsson E, Ärnlöv J, Michaëlsson K, Lind L, Ye W, Nyrén O, Lambe M and Sundström J. Smokeless tobacco (snus) and risk of heart failure: results from two Swedish cohorts. European Journal of Cardiovascular Prevention and Rehabilitation 2011, DOI: 10.1177/1741826711420003 (here).

2. Dunlay SM, Weston SA, Jacobsen SJ, and Roger VL. Risk factors for heart failure: a population-based case-control study. American Journal of Medicine 2009; 122: 1023-1028 (here).

3. ULSAM-70 Questionnaire and Response Statistics (here).

Brad Rodu
Professor of Medicine
Endowed Chair, Tobacco Harm Reduction Research
University of Louisville