Smoking Gun: Manipulating Definitions

A report just published in Nicotine & Tobacco Research (abstract here) draws an obvious conclusion: How surveys define cigarette smokers and smokeless tobacco users influences the prevalence rate of dual use (consumption of both products).

Robert Klesges and colleagues used information obtained from Air Force recruits to show that if dual users are defined as using both products daily (a narrow definition), prevalence of dual use will be low. However, if dual users are defined as using either product once in the past month (a broader definition), prevalence of dual use will be high.

It is not surprising that Dr. Klesges found that defining tobacco use influences survey results. In 2001, he co-authored a study (with first-author C. Keith Haddock, abstract here; hereafter called Haddock-2001) that perfectly demonstrates how definitions can be manipulated to produce desirable results. Haddock-2001 purported to show that smokeless tobacco use is a gateway to smoking among Air Force recruits; it has been widely cited in American prohibitionist attacks on smokeless tobacco. In fact, its results are based on manipulation of definitions.

Haddock-2001 studied 14,340 men (average age, about 20 years) who had never smoked when they reported to Air Force basic training in 1995 and 1996. After one year, Dr. Haddock followed up with 7,865 subjects, finding that 1,099 of them were smoking. That’s a 14% smoking initiation rate among 20-year old men after one year in the Air Force! At one year, Haddock-2001 also found that, compared with recruits who had never used tobacco before basic training, recruits who were current smokeless users were 2.33 (95% Confidence interval = 1.84 – 2.94) times more likely to be smoking.

First, how did 14% of first-year never-smoking Air Force recruits start smoking? It turns out that this number is grossly inflated. In 1999, Drs. Klesges and Haddock had published a study of these same recruits (abstract here; hereafter called Klesges-1999), in which they reported that only 8% of never smokers had started to smoke after one year in the Air Force.

The discrepancy between Haddock-2001 and Klesges-1999 is due to differences in the category definitions of smoking, summarized in this table.

Different Definitions of Smokers in Klesges-1999 and Haddock-2001
Category	Klesges-1999	Haddock-2001(%)
At Enrollment
Never Smoker	Never smoked a cigarette	Never Smoked regularly
Experimental Smoker	Smoked on one or two occasions, never regularly	Not mentioned
Ex-smoker	Smoked regularly, but quit	Smoked regularly, but quit
Current Smoker	Smoked regularly, at least one cigarette per day	Smoked regularly, at least one cigarette per day
At One Year
Current Smoker	Smoked even a puff in last 7 days	Smoked even a puff in last 7 days

At enrollment, Klesges-1999 identified a group of “experimental smokers,” 26% of whom became smokers at the one-year follow-up. But Haddock-2001 never mentioned experimental smokers, which means that they were in the “never-smoking” group at enrollment; that significantly accounts for the 14% initiation rate, instead of the 8% rate found in the Klesges-1999 report.

It is likely that many Haddock-2001 smokeless tobacco users were also experimental smokers. The only apparent reason to eliminate the experimental smoker category and effectively shift those subjects to the never-smoking category was to bolster the case for labeling smokeless tobacco use as a gateway to smoking.

Dr. Haddock also defined current smoking differently at enrollment than after one year of follow-up. Good practice in scientific investigation is to establish definitions and stick with them throughout a research project. As the table shows, Haddock-2001 defined a current smoker at enrollment as smoking at least one cigarette per day, but then defined a current smoker at one-year as someone who smoked even a puff in the last 7 days.

The manipulation of smoking definitions in Haddock-2001 casts considerable doubt on its claim that smokeless tobacco use is a gateway to smoking.

American Cancer Society Withholds Important Information About Tobacco Use and Risk

Last week, I discussed how the American Cancer Society (ACS) misinforms Americans about the risks of smokeless tobacco use (here). The ACS is also withholding important information that has profound implications for FDA regulation of smokeless tobacco.

I wrote to ACS president John Seffrin in September 2010, asking the organization “to fully and publicly disclose important information from its Cancer Prevention Study II (CPS-II) regarding the health risks associated with tobacco use. Notwithstanding the fact that this information has been in the possession of the ACS for years, it has not been made public. The tobacco regulatory and research community, as well as the American public, need access to this information in order to validate significant differences in the health risks associated with smokeless tobacco use compared with smoking in the U.S.”

I noted that the ACS has released highly selective bits of information about smoking and smokeless tobacco use:

“The ACS has provided the Centers for Disease Control and Prevention (CDC) with risk estimates for cigarette smokers, which are derived from a 6-year follow-up of CPS-II. For many years the CDC has used these risks to estimate that smoking kills 400,000 Americans every year. Although these estimates serve as the cornerstone for federal government actions regarding smoking, there is no way to validate them, because the ACS has never published the risks or released the CPS-II data on which they are based.

“In addition to smoker risk estimates, the ACS must release complete risk estimates for smokeless tobacco users and smokers who switched to smokeless tobacco. Previous ACS releases have been highly selective and incomplete, and none are directly comparable because the ACS used different follow-up intervals. As I noted, the ACS provided unpublished risk estimates derived from a 6-year follow-up of CPS-II for smokers. For smokeless tobacco users, ACS investigators have published risk estimates using an 18-year follow-up of CPS-II; for switchers, ACS and CDC investigators have together published risk estimates using a 20-year follow-up.”

I explained why this information was important for FDA regulation:

“There are compelling reasons why the ACS should release this information. Officials at the U.S. Food and Drug Administration (FDA), which now has regulatory authority over tobacco products, may not be aware that the health risks from smokeless tobacco use are vastly lower than those from smoking. Earlier this year, Lawrence Deyton, director of the FDA Center for Tobacco Products, Principal Deputy Commissioner Joshua Sharfstein and Commissioner Margaret Hamburg authored a commentary about tobacco regulation for the New England Journal of Medicine, in which smoking and tobacco use were used synonymously. These physicians wrote that ‘tobacco use causes more than 400,000 deaths in the United States annually…,’ and they described ‘tobacco products’ as ‘the leading cause of preventable death in the United States.’ If the ACS and the FDA are committed to reducing the morbidity and mortality from tobacco use, the first critical step must be to recognize that all forms of tobacco use are not equally risky. That critical issue was overlooked in the New England Journal of Medicine commentary.

“When FDA officials characterize all tobacco products as equally lethal, they are effectively denying smokers lifesaving information about safer cigarette substitutes. A 2004 study, in which ACS Vice President Emeritus Michael J. Thun participated, concluded that ‘…smokeless tobacco products pose a substantially lower risk to the user than do conventional cigarettes. This finding raises ethical questions concerning whether it is inappropriate and misleading for government officials or public health experts to characterize smokeless tobacco products as comparably dangerous with cigarette smoking.’ ”

I strongly urged the ACS to end its misinformation campaign by releasing ALL of its risk data:

“The public health is not well served when information that can save lives is buried and/or ignored. The selective and incomplete provision of risk information by the ACS is contrary to its public health mission and will only serve to hamper the FDA from undertaking an independent assessment of this issue in pursuit of its overarching mission: reducing the harm associated with tobacco use.

“I urge the ACS to release comparable risk estimates for male smokers, smokeless tobacco users and switchers in CPS-II for all three follow-up periods, 6-years, 18-years and 20-years. In addition, the ACS should release the CPS-II data, so that the risk estimates for all tobacco users can be validated by external scientists. I would be happy to meet with ACS officials to discuss this request.

“Dr. Deyton has confirmed that the FDA’s ‘objective is to use the best available science to develop and put into action effective public health strategies to reduce the enormous toll of illness and death caused by tobacco products.’ I strongly urge you to release these data and risk estimates, which constitute the best available science distinguishing the health risks related to smoking from those related to smokeless tobacco use. Because this matter has implications for future regulatory actions by the FDA, I have sent copies of this letter to relevant FDA officials.”

The ACS response was written by Chief Medical Officer Otis W. Brawley on December 1, 2010. He explained why the ACS would not share its data:

“[The ACS] have not found it productive to share the CPS-II data with researchers supported by the tobacco industry, because of their repeated misuse and misrepresentation of the data.”

I have conducted research on tobacco harm reduction for almost 20 years; published numerous studies in professional journals; written dozens of articles in the general media; and given hundreds of lectures. No one has ever accused me of misusing or misrepresenting any data.

The ACS continues to misinform Americans, and especially American smokers, about the vast difference in health risks related to smoking versus smokeless tobacco use. This is vitally important because the CPS-II survey is the only source for comparable information about the health risks from smoking and smokeless tobacco use.

FDA regulation of tobacco should not compromised by the withholding or selective release of critical data by the American Cancer Society.

More Misinformation About Smokeless Tobacco From the American Cancer Society

American Cancer Society (ACS) investigators have just published results of a study on alcohol consumption and the development of pancreas cancer in the Archives of Internal Medicine (abstract here). Led by Susan M. Gapstur, the study found that, compared with never alcohol drinkers, consumers of three or more drinks per day had an elevated risk of pancreas cancer mortality. The higher risk was statistically significant for never smokers (Relative risk, RR = 1.36, 95% Confidence Interval, CI = 1.13 – 1.62) and for ever smokers (RR = 1.16, CI = 1.06 – 1.27). They did not detect higher risks for beer or wine drinkers, but only for consumption of liquor.

The article discussed the public health implications of the research:

“Alcoholic beverage consumption—a modifiable lifestyle factor—is causally related to several cancers, including oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast. Findings from the prospective study presented herein strongly support the hypothesis that alcohol consumption, in particular heavy intake, also is an independent risk factor for pancreatic cancer, the fourth most common cause of cancer mortality in the United States. These results underscore the importance of adhering to the following guideline for cancer prevention by the American Cancer Society: ‘If you drink alcoholic beverages, limit consumption.’”

Thus, while the ACS acknowledges that alcohol is associated with considerable cancer risks, its advice to consumers emphasizes moderation. Historically, moderation has played no role in ACS messages to tobacco users: quit now and abstain completely and permanently.

The ACS web page on smokeless tobacco (available here) was revised on December 16, 2010; it is replete with misinformation, especially about cancer risks. Following are the cancers that the ACS claims, with no supporting data, are caused by smokeless tobacco use, followed by the actual scientific evidence derived from the most comprehensive study ever published (read about it here).

American Cancer Society Claim	Actual Scientific Evidence
Mouth, tongue and throat cancer	Not significantly elevated, RR = 1.07 (CI = 0.84-1.37)
Esophagus cancer	Not significantly elevated, RR = 1.13 (CI = 0.95-1.36)
Stomach cancer	Not significantly elevated, RR = 1.03 (CI = 0.88-1.20)
Pancreatic Cancer	Not significantly elevated, RR = 1.07 (CI = 0.71-1.60)

RR = Relative Risk.

Scientific evidence shows clearly that smokeless tobacco use only slightly elevates cancer risks, if at all. The reported elevations are so small that they are not statistically significant; in other words, they may have occurred purely by chance. It is also important to point out that small RRs (those under 2) should not be seen as reliable. The National Cancer Institute advises: “Relative risks or odds ratios less than 2 are viewed with caution,” because they “are sometimes difficult to interpret.”

Next week I will discuss ACS intransigence with respect to refusing to provide information in its possession about the health risks related to tobacco use.

The Price of Prohibition: Illicit Tobacco Trade

I recently discussed Tacit Incremental Prohibition – Tobacco Elimination, or TIP-TOE (here). A new report from the United States Government Accountability Office (GAO) provides important lessons about how prohibitive policies have created a thriving illicit tobacco industry (read the report here).

The report highlights New York City, where the cost of a pack of name-brand cigarettes is a prohibitive $13.00. Here is a breakout of where that money goes:

Cigarettes at $13 Per Pack: Where the Money Goes
Who	How Much ($)	Percent (%)
Manufacturers	4.91	38
Tobacco Farmers	0.06	< 1
States (Master Settlement)	0.56	4
Local Govt. (Sales Tax)	0.61	5
Local Govt. (Excise Tax)	1.50	12
State Govt. (Excise Tax)	4.35	33
Federal Govt	1.01	8

Manufacturers, who produce, package, ship and market the cigarettes, get 38% of the purchase price. Everyone else, including local, state and federal governments, get the lion’s share. New York taxes are so high, compared to those in other states, that they have spawned a major, lucrative illicit cigarette industry. GAO breaks out the key elements:

1. Smuggling genuine and counterfeit cigarettes from foreign countries to the U.S. For example, in January the Customs and Border Protection announced that more than 22,000 cartons of counterfeit Marlboros were intercepted at the Los Angeles/Long Beach seaport complex after being shipped from China (story here).

2. Unlicensed manufacturers, located in northern New York on land controlled by the St. Regis Mohawk tribe, can produce a carton of cigarettes that sells for $20 in New York. This region is also the source for the contraband cigarettes that comprise half of all consumption in Ontario and 40% in Quebec (article here). A recent article describes the impact of illicit cigarette sales throughout Canada (here).

3. Diverting cigarettes during distribution and retail to avoid local and state taxes. “According to federal and state law enforcement officials, there are many different types of diversion schemes at the wholesale and distribution level of the supply chain. [Alcohol, Tobacco and Firearms] officials stated that criminal organizations may purchase state excise tax-paid cigarettes from wholesalers in a state with low state excise taxes, like Virginia, and illegally transport those cigarettes for resale in a state with higher excise taxes, like New York, to capitalize on state excise tax differentials.” The GAO reports that just one carton (10 packs) of cigarettes travelling from Richmond, VA to New York City will avoid $55.50 in taxes.

We can only guess at the huge scale of economic activity related to contraband cigarettes. Every so often, authorities announce a large seizure, such as one on March 8 at the Ontario-Quebec border involving six million cigarettes (here).

Excessively high taxes are irrational and counter-productive. New York should follow Kentucky’s rational risk-based tobacco tax policy, enacted in 2005, which bases excise taxes for cigarettes and smokeless tobacco products on differential risks. It recognizes that “[t]he relative taxes on tobacco products…reflect the growing data from scientific studies suggesting that although smokeless tobacco poses some risks, those health risks are significantly less than the risks posed by [cigarettes]…Taxing tobacco products according to relative risk is a rational tax policy and may well serve the public health goal of reducing smoking-related mortality and morbidity and lowering health care costs associated with tobacco-related disease.”

Chemical Analysis of Camel Dissolvables Reveals Tobacco, Flavors and Sweeteners

In 2009, R.J. Reynolds test-marketed dissolvable tobacco products in Indianapolis. Chemists at Indiana University-Purdue University Indianapolis, led by Christina Rainey, have just published the results of an extensive chemical analysis of Camel Orbs, Sticks and Strips in the Journal of Agricultural and Food Chemistry (abstract here).

Using several extraction methods, Rainey et al. documented that Camel Orbs, Sticks and Strips contain tobacco, flavors and sweeteners:

1. Tobacco: Measuring the nicotine content of the products, the researchers findings were similar to those reported in Reynolds’ product literature: 1 mg. per Orb, 3.1 mg. per Stick and 0.6 mg. per Strip.

2. Flavors: Rainey et al. found menthol, ethyl citrate, cinnamaldehyde, coumarin, vanillin and carvone. Readers will immediately recognize menthol, cinnamon and vanilla flavors. Carvone is a flavor component of spearmint, caraway and dill, so it also has a long history of use in foods (more here). Ethyl citrate is a derivative of citric acid (lemons and limes); it is a food additive.

Rainey et al. claim that “coumarin is a harmful ingredient and causes liver damage in rodents…and has been banned as a flavor additive to food.” This statement is misleading, as it implies that coumarin is a dangerous chemical that has been added to the dissolvables.

It is true that coumarin is toxic to the liver of rats, but this is due to the fact that rats process this agent via an enzyme system that humans lack. Extrapolating rat liver damage to humans is specious.

It is true that the FDA prohibits adding coumarin to human food (here). Why was it found in Camel dissolvables? It is well known that coumarin is present in some varieties of cinnamon; Rainey et al. found coumarin only in an Orb flavored with cinnamon (more information about coumarin is available here). In 2008, scientists from Germany found coumarin in bakery products and breakfast cereals flavored with cinnamon (here). Should Orbs be considered as dangerous as cinnamon buns and breakfast cereal?

3. Sweeteners: Xylitol and/or sorbitol, non-caloric sweeteners used in many products, were found in all three Camel dissolvables.

4. Others: Rainey et al. note that Orbs contain palmitic and stearic acid, food-grade additives that probably aid in the physical properties of the product (e.g., shape and texture). Strips contain glycerin, a food additive that helps products retain moisture.

In summary, smokers who switch to Camel Dissolvables are consuming smoke-free tobacco products that are consistent with government standards for human foods.

Tacit Incremental Prohibition - Tobacco Elimination (TIP-TOE)

Outright prohibition of psychoactive substances has proven futile, time and again. The disastrous consequences of U.S. prohibition of alcohol (1920 to 1933) and marijuana (ongoing) are well documented (examples here and here). Zealous prohibitionists have now targeted nicotine, using a strategy I call Tacit Incremental Prohibition - Tobacco Elimination, or TIP-TOE. Their aim is to employ an escalating series of legislative and regulatory controls in order, over time, to remove all tobacco products from the marketplace.

TIP-TOE has been promoted by a cadre of individuals using the cover of reputable organizations, including the Mayo Clinic (here), the American Cancer Society (here), the American Heart Association (here), the federal Centers for Disease Control (here) and the National Cancer Institute (here). The principals believe that a world without nicotine is both desirable and achievable, yet they are not courageous enough to demand outright prohibition. Instead, they’ve implemented the subtle TIP-TOE strategy of chipping away at consumer rights and industry initiatives. Several elements of their campaign were in view in recent weeks.

On February 15, Senators Frank Lautenberg (D, NJ) and Dick Durbin (D, IL) urged Major League Baseball commissioner Bud Selig and players’ association director Michael Weiner to ban smokeless tobacco in their sport. At the obvious prodding of TIP-TOE advocates, the senators pressed for a “solution” to a “problem” that doesn’t exist, as I discussed in a previous blog entry (here).

Another TIP-TOE initiative is the move to ban flavored tobacco products, an issue I addressed over a year ago (here). A bill in the Washington legislature (HB 1246, here) would ban flavored smokeless tobacco products and all dissolvable products. A Utah bill (HB 170, here) would ban flavored smokeless tobacco products and electronic cigarettes.

These TIP-TOE bills are especially egregious. They would ban tobacco products that are almost risk-free, while assuring continued market dominance by vastly more hazardous cigarettes.

Using TIP-TOE tactics, tobacco prohibitionists are sprinting toward a public health disaster.

Unbalanced FDA Guidance on Substantial Equivalence

On January 5, the FDA issued “guidance” concerning an important provision of the Tobacco Act – the demonstration of substantial equivalence for tobacco products. This post will explain why the provision might result in a regulatory nightmare for tobacco harm reduction by threatening existing smokeless products and completely inhibiting new-product innovation. Intrepid readers might wish to read the entire 17-page document (here).

According to the Act, any tobacco product in the American market on February 15, 2007 – a seemingly arbitrary date – is not subject to FDA review. For any product that was changed or introduced between February 15, 2007, and March 22, 2011, manufacturers are required to submit a 905(j) report by March 22, assuring the FDA that the product is “substantially equivalent” to a predicate product that was on the market February 15, 2007.

What information does the FDA require in 905(j) reports? Under normal circumstances, a federal agency would interpret legislation by formulating proposed regulations, submitting them for public comment, and eventually publishing final regulations. However, because the FDA is under pressure to get this equivalence provision into place, the agency issued a guidance document which says, “In the future, FDA intends to initiate a rulemaking that would establish requirements and standards for substantial equivalence.” For now, the guidance only “provides recommendations on the form and content of section 905(j) reports.”

According to the FDA, “guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.” (emphasis in original)

The FDA “suggests” that manufacturers submit a vast amount of information in 905(j) reports, including side-by-side comparisons of each new product with its predicate with respect to:

1. Ingredients and their levels

2. Design features and other materials; description of the heating source and composition (these mostly apply to cigarettes)

3. Harmful and potentially harmful constituents. The Tobacco Products Scientific Advisory Committee has started to develop this list of over 100 agents (see this document).

In addition to these basic requirements, manufacturers may need to submit “additional data.” The FDA guidance elements for additional information relating to consumer perception, clinical, abuse liability and toxicology data are so sweeping that I include them verbatim:

4. “Consumer Perception Studies - data comparing consumer perceptions with respect to the new tobacco product and the predicate that could affect initiation, cessation, frequency of use, patterns of use, smoking behavior, and perceptions of harm or addictiveness.”

5. “Clinical data - data comparing the biomarkers of exposure and biomarkers of potential harm and human toxicity of the new tobacco product as compared to the predicate tobacco product …Your report should include a summary of all studies conducted. In addition, your pivotal studies should be submitted and include: final approved study protocols, statistical analysis plans, any modifications to the study(ies), raw data, analysis platforms, and full reports.”

6. “Abuse liability data - data comparing the abuse liability of the new tobacco product to the predicate tobacco product ... Abuse liability can be assessed by a battery of studies, such as animal models of conditioned place preference, drug discrimination and self-administration, and human behavioral pharmacology studies that assess self-administration and subjective effects of the new tobacco product.”

7. “Toxicology data - data comparing the toxicity of the new tobacco product to the predicate tobacco product ... Comparisons between the new tobacco product and the predicate tobacco product can be assessed by a battery of studies, including nonclinical studies such as in vitro and in vivo mutagenicity and clastogenicity studies, general toxicology studies that include hematological, clinical chemistry, and histopathological endpoints, toxicology studies designed to specifically address cardiac, respiratory, and reproductive/developmental toxicity and studies to assess the carcinogenic potential.”

If you have read this far, you may suspect that the agency is pursuing an anti-tobacco agenda. Even if the FDA’s “guidance” is not binding or “legally enforceable,” the agency’s “current thinking” on this issue is clear: Require tobacco manufacturers to spend millions of dollars to keep their existing tobacco products on the market, and prevent the introduction of new products. If the FDA upgrades its guidance to binding regulations, it could strangle the tobacco industry. It would not be surprising if most U.S. cigarette and smokeless products have been altered in some manner since February 15, 2007; any such changes would subject their manufacturers to the onerous new data-production regulations.

Will consumers be any safer for all the corporate and government expense? Will such sweeping regulations dissuade companies from attempting to introduce new and safer smokeless tobacco products?

Last week, R.J. Reynolds and Altria made separate announcements about test markets of dissolvable tobacco products (here). Reynolds announced it will resume test markets in Denver and Charlotte of Camel Orbs, Strips and Sticks, products that had been tested in Columbus, Indianapolis and Portland, Oregon, in 2009-2010. In March, Altria will introduce in Kansas Marlboro and Skoal Smokeless Tobacco Sticks, which are 2.5-inch-long wooden sticks coated with finely milled tobacco.

These are exciting developments, demonstrating that cigarette manufacturers are committed to offering smokers vastly safer smoke-free options. It would be a public health tragedy if the FDA used equivalence criteria to deny smokers these products, thus assuring the continued market dominance of deadly cigarettes.