Volume 18: No. 4, April 2004

Tobacco Harm Reduction: The Need for Research to Inform Policy by Dorothy K. Hatsukami and Mitch Zeller

Dorothy Hatsukami, PhD, is currently Professor of Psychiatry and Adjunct Professor of Psychology and of Epidemiology at the University of Minnesota, and Director of the Tobacco Use Research Programs. She has conducted research in the areas of nicotine addiction and treatment of nicotine addiction, among a general population of adult smokers as well as adolescents. She has also conducted research in the area of smokeless tobacco. She is currently a Principal Investigator of one of the seven NIH funded Transdisciplinary Tobacco Use Research Centers (TTURC). The research focus of this TTURC is on methods and understanding mechanism associated with reducing tobacco toxin exposure. She is a co-recipient of the Ove Ferno award for her research on tobacco dependence. Because of her expertise, she has served on a number of national committees including the National Advisory Council for Substance Abuse and Mental Health Services Administration, National Advisory Council on Drug Abuse, the Interagency Committee for Smoking and Health, Drug Control Research, Data, and Evaluation Committee for the Office of National Drug Control Policy, the Institute of Medicine and was on the Scientific Board of Counselors for the Intramural Research Program of NIDA. She has served on many advisory panels for other United States federal, non-profit and international organizations. She is a past President of the Society on Research on Nicotine and Tobacco and a past President of the College on Problems of Drug Dependence.

Mitch Zeller, JD, attended Dartmouth College in Hanover, New Hampshire and is a graduate of the American University Washington College of Law in Washington, D.C. From 1993 until June 2000, Zeller served as associate commissioner and director of the Food and Drug Administration's (FDA) Office of Tobacco Programs where he built the first nationwide program to reduce youth access to tobacco. He served as the FDA's representative on tobacco issues in all dealings with the Congress, federal and state agencies, public health groups and foreign governments. Zeller also served as an official U.S. delegate to the World Health Organization (WHO) Working Group for the Framework Convention on Tobacco Control.

From June 2000 until August 2002, Zeller was executive vice president of the American Legacy Foundation, a public health foundation located in Washington, D.C., created by the November 1998 Master Settlement Agreement. In January 2002, Zeller created the foundation's first Office of Policy and Government Relations.

Zeller has published papers in several leading medical and public health journals including the New England Journal of Medicine, and the Journal of the American Medical Association. In addition, he has won many awards for his work on tobacco, including the Secretary's Award for Distinguished Service and the National Public Affairs Special Recognition Award from the American Heart Association. Zeller also had the honor of being selected to travel to Moscow on behalf of President Bill Clinton to accept the "World No Tobacco Day" medal from the President of WHO in recognition of the Clinton Administration's groundbreaking work on tobacco. He is Vice President for Policy and Strategic Communications at Pinney Associates.

The best advice for health concerned smokers has been and remains to quit. But what about smokers who, for whatever reason, are either unwilling or unable to quit completely? Tobacco harm reduction is the general term used to describe the scientific, policy, legal, and communications issues raised by products designed to continue tobacco use, albeit with products holding out the promise to reduce risk of tobacco-related disease.

Several types of “potential reduced exposure products” (PREPs) that contain tobacco have been on the market for several years (Stratton, Shetty, Wallace, & Bondurant, 2001). These PREPs include modified tobacco products that claim to reduce the levels of selected toxins. These claimed reductions are achieved by using different curing or fermentation processes, or adding chemicals, such as palladium, to the tobacco leaves (e.g., Advance and OMNI cigarettes, or Revel smokeless tobacco). Additionally, products bearing claims to significantly reduce nicotine levels have been developed by genetically engineering the tobacco plant (e.g., Quest). There are also products that are nicotine delivery devices that heat rather than burn tobacco, and which claim to reduce the levels of toxic combustion products (e.g., Eclipse, Accord). Finally, the use of oral non-combustible tobacco products in lieu of smoking has been proposed as a method of reducing health risks among cigarette smokers (e.g., Ariva, Exalt, Revel).

There are several significant public health concerns posed by tobacco-based products purporting to reduce harm. First, they are completely unregulated. Tobacco manufacturers are free to sell any products they desire and make any claims they wish. There is no independent scientific scrutiny of these reduced risk claims prior to their appearance in the marketplace. Second, consumer research demonstrates that these products constitute a significant threat to cessation efforts. Current smokers have a high degree of interest in these products, and falsely assume that these products dramatically reduce the risk of tobacco product use when compared to conventional cigarettes (Shiffman, Pillitteri, Burton, & Di Marino, 2004). The state of the harm reduction science is in its infancy and the tobacco companies do not know if products that reduce exposure to toxins actually reduce risk in any meaningful way. Most disturbing is the data indicating that one of the reasons smokers are interested in these products is because it will enable them to put off the need to quit smoking (Zeller, 2003).

Third, in the absence of credible and validated science proving that reductions in exposure lead to reductions in risk, this new generation of tobacco products may be nothing than a more sophisticated version of the “light” cigarette. We now know that “light” cigarettes were mistakenly believed by smokers to be safer than regular cigarettes. Worse, we now know that “lights” contained design features that resulted in no meaningful reductions in tar or nicotine when smoked by consumers (National Cancer Institute, 2001).

What Do We Need to Know?
These public health concerns underscore the importance of developing a science base to inform policies and educate consumers about these products. Several investigatory steps are required to determine whether a product reduces exposure or disease risk and to assess the population impact resulting from the introduction and marketing of these products (Hatsukami, Hecht, Hennrikus, Joseph, & Pentel, 2003; Hatsukami, Henningfield, & Kotlyar, 2004; Stratton et al., 2001). Each of these steps is associated with a research challenge. The first step involves identifying toxins in the tobacco product itself and in the smoke. Once these toxins are identified, then cell culture (e.g., genotoxicity and cytoxicity) as well as pre-clinical animal tests are conducted. The major challenge in this first step, however, is the ability to identify all the potential harmful toxins in the products. With novel methods of processing tobacco or delivery of tobacco, and the potential for the consumer to combine different tobacco products, new and yet unidentified toxins may be present (Hatsukami et al., 2003).

If the product demonstrates a reduction and no increases in potential toxicity during this initial assessment, then the next step would involve human clinical trials. The goals of clinical trials are primarily to determine the extent of tobacco toxin exposure in these products, as well as potential health effects, and the addiction potential for the product. In addition, these trials will monitor any unintended consequences as a result of product use. These clinical trials are also important to observe potential patterns of use of these products, in order to ensure that these patterns do not contribute to greater toxin exposure. The main research challenge for this step includes the limited availability of valid and reliable biomarkers that predict disease risk. Studies are needed that establish specificity, sensitivity, reliability, dose-response relationship and predictive validity of biomarkers. These biomarkers are essential in order to circumvent the need to wait 20 years before the health effects of these products are observed.

Another important step in the assessment of these products is pre-market testing of consumer perception. Research challenges in this area include understanding how images, messages, and message placement affect perception of these products. An additional research challenge is to determine how valid information and messages can be communicated in a way that allows consumers to make informed and rational decisions about product use. Finally, pre-market research can serve as an early warning signal of potential unintended consequences if, for example, research were to establish that a product might reduce smokers’ interest in quitting.

Finally, post marketing surveillance is also a crucial step in the assessment of potential harm associated with product use. If a product results in increased initiation, relapse to smoking among ex-smokers, or smokers continuing to smoke, then even if the product is associated with less toxin uptake, increase in harm may occur. In addition, long-term prospective surveillance studies can help determine how the product will actually impact health status. The primary research challenge will be to develop rapid post-marketing surveillance methods so that timely decisions can be made regarding a product.

What Do We Know?
Unfortunately, we know very little about the reduced exposure products. Only a few studies have examined the effects of these products on various biomarkers for exposure or health status. However, even with the limited number of studies, several conclusions can be made. First, when examining exposure to toxins in potential reduced exposure products, the use of machine-determined yields of toxins (e.g., Federal Trade Commission (Giovino et al., 1996) is not sufficient. This conclusion is based on prior research with low nicotine yield cigarettes, where studies showed no difference in nicotine exposure across machine-determined varying nicotine and tar yields of cigarettes, and also no differences in mortality and morbidity rates (Harris, Thun, Mondul, & Calle, 2004; National Cancer Institute, 2001). Smokers were observed to compensate for the low nicotine yield in cigarettes by smoking harder and more frequently (National Cancer Institute, 2001). Recent research of PREPs also demonstrate that if cigarettes with purported claims of reduced toxins are smoked by humans, the extent of toxin reduction is less -- and in some instances substantially less -- than the FTC determined levels described by the tobacco manufacturers (Hughes, Hecht, Carmella, Murphy, & Callas, in press; Lemmonds & Hatsukami, 2003).

Second, even when examining results from human exposure studies, mean reductions are not informative to the consumer because significant individual variation in toxin uptake is experienced, with some smokers demonstrating an increase in exposure (Lemmonds & Hatsukami, 2003). Third, not all toxins are reduced and exposure to some toxins may, in fact, increase. For example, Eclipse demonstrated a reduction in several toxins, yet exposure to carbon monoxide increased (Breland, Buchhalter, Evans, & Eissenberg, 2002; Lee, Malson, & Pickworth, 2004). Although this finding is not unexpected, the issue becomes whether this product should have any claim indicating reductions in toxins and, if so, then how best to convey this information to consumers so the informed decisions can be based on valid information. Fourth, even if studies demonstrate that modified products or nicotine delivery devices can significantly reduce toxin levels, we do not know if these exposure reductions mean that harm has been reduced in any meaningful way. The uncertainty surrounding the relationship between exposure and harm reduction is a central policy issue and concern.

Fifth, if a reduction in toxins is achievable, it perhaps should be considered a standard for all tobacco products that are sold in that class, but without marketing claims. For example, a popular smokeless tobacco sold in Sweden has about half the amount of tobacco specific nitrosamines compared to products in the United States and result in about 50% less uptake of one of the major tobacco-specific carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. These significantly reduced levels of carcinogens found in Swedish smokeless tobacco products or snuff may account for the lack of association observed between snuff use and oral cancer, compared to an increased incidence of oral cancer in smokeless tobacco users relative to non-users observed in the United States (Hatsukami, Lemmonds, & Tomar, 2004).

A Word About Smokeless Tobacco
Although an active debate has evolved around the issue of substituting smokeless tobacco for cigarettes as a method to reduce harm from cigarette smoking, little research has been conducted to inform the debate. The arguments for using smokeless tobacco in lieu of cigarette smoking are: 1) smokeless tobacco use has less associated harms compared to cigarette smoking because of the lack of combustion products; and 2) the greater use of smokeless and the consequent reduction in cigarette smoking among males in Sweden are considered to be one of the major factors associated with reduction of tobacco-related mortality and morbidity in that country. The primary arguments against this proposition are: 1) smokeless is not harmless, and in some countries, are associated with a number of health problems including oral cancer, other oral pathologies, increased risk factors for cardiovascular disease, fetal toxicity and pancreatic cancer; 2) smokeless tobacco is addictive and can lead to persistent use and difficulty quitting its use; and 3) smokeless may facilitate the uptake and use of cigarettes (Hatsukami, Lemmonds et al., 2004).

More importantly, the population effect associated with marketing smokeless as a substitute for cigarettes is unknown. It is possible that in the competitive marketing environment seen in the United States, an increase in tobacco consumption without a significant decrease in mortality and morbidity will be observed. To date, only one small, open single arm pilot study has been conducted examining the effects of smokeless as a means to quit using cigarettes. In this study, of the 63 smokers who were enrolled in the study, 25% achieved cessation at one year and 13 out of 16 abstainers continued to use smokeless tobacco (Tilashalski, Rodu, & Cole, 1998). These rates are similar to those observed with medicinal nicotine, which is by far a safer product than smokeless. Unless a study is conducted comparing the use of smokeless tobacco with other pharmacological products, or as a substitute for smoking, it is difficult to assess if using smokeless tobacco as a method of cessation should be encouraged.

What Do We Need to Assure Public Health?
In order to circumvent a public health disaster with the introduction of products that claim reduced toxin exposure and reduced risk, assessment of these products by a regulatory agency, such as the Food and Drug Administration, is necessary. Regulation will require that companies that market these products demonstrate a proven reduction in toxins, an absence of unintended population level health effects, and a strong potential for a reduction in health risks. Furthermore, regulation of these tobacco products would also provide some assurance that the information that is provided to the consumer is valid and does not lead to misinterpretation.

References
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Giovino, G., Tomar, S., Reddy, M., Peddicord, J., Zhu, R. P., Escobedo, L., et al. (1996). Attitudes, knowledge, and beliefs about low-yield cigarettes among adolescent and adults. In The FTC Cigarette Test Method for Determining Tar, Nicotine, and Carbon Monoxide Yields of US Cigarettes. Report of the NCI Ad Hoc Committee (Vol. NIH Publication No. 96-4028, pp. 39-57). Maryland: National Institutes of Health.

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Hatsukami, D., Henningfield, J., & Kotlyar, M. (2004). Harm reduction approaches to reducing tobacco-related mortality. Annual Reviews of Public Health, 25, 1-19.

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Hughes, J. R., Hecht, S. S., Carmella, S. G., Murphy, S. E., & Callas, P. (in press). Smoking behaviour and toxin exposure during six weeks use of a potential reduced exposure product. Tobacco Control.

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Zeller, M. (2003). Today's tobacco-based products: unregulated nicotine delivery devices and a huge threat to cessation efforts. National Conference on Tobacco or Health. Boston, MA.