The National Academy of Sciences ‘Clearing the Smoke: assessing the Science Base for tobacco harm reduction’. Washington DC, National Academy Press, 2001

Abstract

In 2000 the Food and Drug Administration (FDA) commissioned the US National Academy of Sciences (NAS) to assess the scientific plausibility of THR. The NAS Expert Committee produced a detailed report on the feasibility of developing ‘potential reduced-exposure products’ (PREPs) that would form part of a comprehensive approach to reducing the harms caused by tobacco smoking in the United States.¹

In 2000 the adult smoking prevalence in the United States was 25%, having declined from 42% in 1965.¹ The FDA had approved nicotine replacement therapies (NRT) and the antidepressant bupropion for smoking cessation but they were only modestly effective, and some leading figures in the US public health community argued that harm reduction policies were needed to reduce tobacco-related harm among smokers unable or unwilling to quit.¹

The Committee's report assumed that: tobacco smoking was a major cause of human disease that was sustained by nicotine addiction; that the best ways to protect individual and public health from tobacco-related harms were to prevent non-smokers from starting to smoke cigarettes; to encourage people who smoked to stop; and to introduce regulations that prevented non-smokers from being exposed to environmental tobacco smoke.¹

The Committee defined a PREP as a product that: ‘lowers total tobacco-related mortality and morbidity’ even though its use ‘may involve continued exposure to tobacco-related toxicants’ (p. 2). E-cigarettes and heat-not-burn products had not yet been marketed in the United States, so the Committee only considered the following candidate PREPs: smoked tobacco with lower levels of nitrosamines; the long-term use of pharmaceutical nicotine and bupropion to prevent relapse to smoking; the use of oral tobacco products; and the use of non-combustible tobacco products that were then under development (chapter 4).

In answering question 4, the Committee was asked to consider whether any reduction in harms that PREP provided to users may be offset if (1) people used PREPs in ways that increased harm to themselves; (2) substantial numbers of non-smokers began to use PREPs; and (3) smokers used PREPs while continuing to smoke instead of quitting smoking or fully switching to using the PREP.

In chapter 3 the Committee provided a cautionary history of the failure of ‘low tar and low nicotine’ or ‘light’ cigarettes to reduce tobacco-related harm in the 1970s and 1980s. This showed that people who smoked ‘light’ cigarettes undermined any potential harm reduction benefits by changing how they smoked to maximize the amount of nicotine extracted from each cigarette. For example, they increased the number of cigarettes smoked and the number of puffs per cigarette, they inhaled the tobacco smoke more deeply and they blocked ventilation holes near the filter that were intended to dilute tobacco smoke (chapter 3). The committee believed that similar compensatory changes could potentially nullify any individual and public health benefits that new PREPs promised to deliver. Given the experience with light cigarettes, the Committee was also concerned that the marketing of PREPs could encourage people who smoked to continue to smoke rather than quitting.

In Section II of the report (chapters 9–16, pp. 243–582), the Committee provided detailed reviews of the ‘science base’ of tobacco harm reduction. This included research on nicotine pharmacology, tobacco smoke and its toxicology, exposure and biomarker assessment in humans and epidemiology of diseases related to tobacco use such as cancers, cardiovascular disease, neoplastic respiratory diseases, reproductive and developmental effects and other health effects.

The Committee concluded that THR was feasible because the epidemiological evidence showed that many of the adverse health effects of cigarette smoking were greatly reduced by substantial periods of abstinence. The risks of these diseases steadily declined as the years of abstinence increased, although they remained higher than the risks in people who had never smoked cigarettes. The Committee also concluded that it was possible to develop PREPs that delivered nicotine in ways that substantially reduced the amounts of carcinogens and toxicants found in tobacco smoke (chapter 8).

Nevertheless, the Committee concluded that, with one ‘narrow exception’, there was insufficient evidence that any of the PREPs that they examined reduced tobacco-related harm. The ‘narrow exception’ was the long-term use of nicotine gum and patches to assist smokers to remain abstinent after they quit smoking. The Committee argued that NRT posed fewer health risks than any PREPs that involved inhaling modified tobacco smoke or nicotine in vapor. It acknowledged that there was some uncertainty regarding the adverse health effects of very long-term NRT use.

The Committee concluded that low nitrosamine tobacco, oral tobacco products and tobacco products that did not involve combustion had not been investigated for long enough to conclude that they reduced the incidence of smoking-related cancers and heart and respiratory diseases. It argued that allowing the tobacco industry to promote these as THR products would entail a large-scale public health experiment, the results of which would not be known for 50 years in the case of cancers (chapter 8).

The Committee argued that research essential to answer the four critical questions listed above should be conducted under the supervision of a federal agency that would regulate PREPs in the same manner as pharmaceutical products and regulate tobacco cigarettes even more strictly than PREPs.

The Committee gave a high priority to research to develop: (1) biomarkers of exposure to tobacco toxicants and carcinogens and (2) biological measures that would predict future risks of PREP users developing tobacco-related diseases. The first type of research was necessary to identify promising PREPs. The second was required to assess whether PREPs that were approved for sale delivered the promised reductions in tobacco-related health harms. This approach was based on the evaluation of new pharmaceutical drugs to treat chronic illnesses in which clinical trials assessed short- to medium-term safety and efficacy and post-marketing surveillance assessed their longer-term safety and efficacy.

In 2009 the US Congress gave the FDA responsibility for regulating tobacco and tobacco and nicotine products that their manufacturers claimed would reduce tobacco-related harm.² Critics argue, however, that the FDA has required applicants to meet unattainably high standards of evidence to convince regulators that new nicotine and tobacco products reduce tobacco-related harm and do not adversely affect public health.^{3, 4}

In 2018 the FDA commissioned the National Academy of Sciences, Engineering and Medicine (NASEM) to evaluate the public health impacts of e-cigarettes. The Committee concluded that e-cigarettes were less harmful than combustible cigarettes because they delivered lower levels of the toxins and carcinogens found in tobacco smoke. It cautioned that there was limited research on their effectiveness for smoking cessation, and their long-term adverse health effects on smokers were unknown.⁵ The report was published when e-cigarette uptake among adolescents was increasing, and many in the public health community were understandably concerned that adolescents who used e-cigarettes would make the transition to combustible smoking, and that young people who may never have smoked cigarettes would be exposed to the unknown adverse health effects of long-term e-cigarette use.⁵

By 2021, the prevalence of cigarette smoking among adults in the United States had declined to 11.5%,⁶ less than half that in 2001 (25%). The term ‘PREP’ was no longer used, and THR was a contentious concept because the tobacco industry was using it to market oral nicotine products, e-cigarettes and heat-not-burn tobacco products as safer alternatives to smoking.^7-9 Critics pointed to the tobacco industry's insincerity in promoting the use of THR products in high-income countries while continuing to sell combustible cigarettes in low- and middle-income countries.^{7, 8} They also criticized the marketing of THR products to youth and young adults who did not smoke cigarettes, and industry efforts to promote dual use by encouraging smokers to only use e-cigarettes when cigarette smoking was not allowed.⁷

Some leading tobacco control researchers are more positive regarding the potential for e-cigarettes and oral nicotine products to reduce population prevalence of cigarette smoking and tobacco-related harm.¹⁰ They advocate for regulatory policies that maximize access to THR products by cigarette smokers who wish to quit or switch while minimizing uptake among youth, especially among those who had not smoked cigarettes.¹⁰ The effectiveness of e-cigarettes as aids for smoking cessation have been supported in meta-analyses of controlled clinical trials comparing e-cigarettes with NRT.¹¹ Debate continues regarding whether the association between e-cigarette use and cigarette smoking in adolescents and young adults indicates that e-cigarettes are a gateway to smoking or that the association is the result of a shared susceptibility to developing nicotine dependence.¹²

Civil debate has been a casualty of the polarized opinions within the tobacco control community concerning the effectiveness, safety and public health impacts of e-cigarettes.^{13, 14} The perceived polarization has been heightened by the high visibility of people who express strongly pro and con views in the medical literature.¹⁵ For example, leading figures in tobacco control such as Chapman,¹⁶ McKee¹⁷ and Hendlin et al.⁸ and the World Health Organization¹⁸ have advocated for severe restrictions on the sale and use of e-cigarettes. Some opponents of e-cigarettes claim that article 5.3 of the Framework Convention on Tobacco Control precludes discussion of THR because the tobacco industry supports the concept.⁸ Members of the tobacco control community who support research on THR (e.g.¹⁰) risk being depicted as witting or unwitting allies of the tobacco industry.⁸

Substantial proportions of people who smoked cigarettes in many high-income countries now use e-cigarettes.^{2, 19} This development has occurred in the absence of the data collection and monitoring advocated by the NAS to identify biomarkers of exposure to tobacco toxicants and carcinogens and predictors of tobacco-related diseases. This is evident in the small numbers of studies of biomarkers of exposure to tobacco-specific nitrosamines^{20, 21} and indicators of future urinary cancer risk in people who use e-cigarettes.²²

The controversy regarding the public health impact of e-cigarettes has overshadowed the much stronger evidence for the safety and effectiveness of snus, a low-nitrosamine smokeless tobacco (LNST).²³ Unlike e-cigarettes, snus users do not inhale nicotine vapor because snus delivers nicotine via the oral mucosa. Snus is made from tobacco, but it has been treated to greatly reduce the levels of tobacco-specific carcinogens, a leading cause of tobacco-related cancers.

Early critics of ‘Clearing the Smoke’ argued that the Committee's caution regarding the THR use of low nitrosamine oral tobacco was inconsistent with its support for the long-term use of NRT.²⁴ Kozlowski and colleagues²⁵ provided compelling calculations which show that the population impact of oral nicotine products would be far less than that of tobacco smoking, even if these oral products were used by a larger proportion of the population than those who smoked cigarettes. An epidemiological modeling study that compared the effects on smokers switching to snus use and quitting smoking on healthy life expectancy showed minimal differences between the two.²⁶

In the past two decades, much stronger epidemiological evidence has shown that the uptake of snus by people who were smokers has reduced the prevalence of tobacco smoking to 5.3% among adults in 2022 in Sweden,²⁷ where the male smoking prevalence is now among the lowest in the European Union.²⁸ Snus use has also substantially reduced deaths from tobacco-related cancers in Swedish men^29-31 and has done so without increasing the prevalence of cigarette smoking among young people.²⁷ Sweden's experience with snus has been replicated in Norway since it permitted the sale of snus.³²

Tobacco companies have recently marketed a new oral nicotine product, nicotine pouches, that may or may not be derived from tobacco.³³ Critics of e-cigarettes have chosen to treat the advent of nicotine pouches as if they were a wholly new tobacco product whose health risks were entirely unknown.³⁴ Despite the absence of respiratory risks from oral nicotine products, including nicotine pouches, and the positive Swedish and Norwegian public health outcomes from snus, some opponents of e-cigarettes oppose the non-medical use of all oral tobacco and nicotine products, including nicotine pouches (e.g.³⁴). Their hostility seems to derive from the fact that these products maintain nicotine addiction; they ignore the strong evidence that their use very substantially reduces the incidence of tobacco-related cancers and cardiovascular diseases.^{35, 36}

The author was solely responsible for conceptualising, researching and writing this article.

None to declare.