By Dr. Christopher Proctor, Consultation Event Nicotine Panel Presenter is British American Tobacco’s Chief Scientific Officer, working at Group Research and Development in Southampton. A PhD chemist, Dr Proctor has represented BAT in public hearings on the World Health Organisation’s Framework Convention on Tobacco Control and has recently been invited as a scientific expert presenting at US FDA workshops. In 2003 Dr Proctor published: ‘Sometimes a cigarette is just a cigarette’.

The World Health Organisation estimates that over the course of the 21st Century tobacco use may cause the premature deaths of a billion people or more unless urgent action is taken.

Although use of all forms of tobacco and nicotine carries some health risks, cigarette smoking is both by far the most risky and also the dominant form of tobacco use in most countries. I can understand skepticism in some quarters as to why we, the manufacturers, can claim to have perhaps the most important role to play in delivering reduced harm. As first and foremost a scientist driven by this challenge, I believe we have turned an important corner. The opportunities at our fingertips and in the pipeline thanks to recent scientific and product development advances are truly of immense significance.

Increased risks for a range of fatal diseases (including lung cancer, chronic obstructive pulmonary disease and various cardiovascular diseases) are related with cigarette smoking in a dose response manner. These risks increase particularly with the duration of smoking but also with the numbers of cigarettes smoked each day. The increased relative risks reduce following cessation, and the rates of such reductions vary with both the disease (cardiovascular relative risks typically reducing quicker than cancer risks) and the individual’s history of smoking. Many smokers state a desire to quit smoking and cigarette smoking prevalence rates have been reducing, particularly in Western populations. In many countries former smokers now outnumber current smokers. However, cigarette smoking is very addictive and many who quit for a period of time return to smoking, even with medical interventions such as the use of nicotine replacement therapy.

In its 2007 Report, Harm Reduction in Nicotine Addiction – Helping People Who Can’t Quit, the Tobacco Advisory Group of the UK Royal College of Physicians reviewed research on nicotine addiction and the health risk profiles of cigarette smoking, oral tobacco use and medicinal nicotine. They noted that: “Extensive experience with nicotine replacement therapy in clinical trial and observational study settings demonstrates that medicinal nicotine is a very safe drug” and that: “On toxicological and epidemiological grounds, some of the Swedish smokeless products appear to be associated with the lowest potential for harm to health.” The Group also noted that: “Addiction to nicotine arises from a combination of genetic, environmental and pharmacological factors, but characteristics of the nicotine delivery system are also crucially important.” Hence, many interested researchers and authorities have focused their efforts on developing products that will provide smokers with the desired nicotine through a delivery system presenting dramatically reduced health risks as compared to cigarettes.

Nicotine and receptors

The pharmacological effects of nicotine have been characterised following decades of research effort. John Newport Langley, alongside other researchers, used nicotine in classic experiments performed at the beginning of the 20th Century to develop the concept of receptive substances and receptors. Studies using the marine ray Torpedo helped the initial characterisation of the muscle nicotinic acetylcholine receptors (nAChR), now a very well characterised ligand-gated ion channel. Neuronal nAChRs are typically made up of five subunits, are heterogeneous, and the configuration of the receptor sub-units will determine the action of nicotine on the receptor.

It is this heterogeneity of the neuronal nAChR receptors that leads to the biphasic nature of nicotine, which can result in both stimulation and relaxation. For example, the average plasma level of nicotine found in smokers is likely to be sufficient to desensitise some nAChR receptors that have a high affinity to nicotine (also making them unresponsive to the natural ligand acetylcholine), while a bolus of cigarette smoke may activate or desensitise other, less sensitive nAChR subtypes.

Large bodies of research have focused on the neurobiology of nicotine, understanding of nicotine addiction and development of better methods of cessation for smokers. The neurobiology of nicotine is complex and not fully elucidated. It is clear that nicotine preferentially stimulates dopamine release from neurons, particularly after temporary abstinence. However, for most of the day a regular smoker will have plasma levels that result in the desensitisation of nicotinic receptors, and nicotine inhaled by smokers would not during this time cause stimulation of some of the dopamine pathways. This suggests that the nicotine from smoking during this time is operating on other neurobiological pathways and/or smoking during these periods is reinforced by conditioned stimuli.

Nicotine addiction and the delivery system

There are a variety of reasons why cigarette smoking is the dominant form of nicotine use and why nicotine replacement therapies and oral tobacco products have not been complete substitutes for cigarette smoking for many people who seek to quit smoking. Cigarette smoking is a two-step process whereby smokers draw a volume of smoke into their mouths followed by an inhalation step that draws smoke down the respiratory tract into the lungs. Nicotine in the smoke causes an irritating sensation due to interaction with peripheral nerves at the back of the throat, often described by smokers as “throat catch” or “hit”, and this provides the smoker with feedback on the amount of nicotine they are taking as they puff, allowing them to adjust their next puff. Nicotine in the smoke reaching the lungs is rapidly absorbed and transferred through the arterial blood stream to receptors in the brain (a process sometimes referred to as the “bolus effect”).

For example, the Community Epidemiology Work Group (CEWG) at the U.S. National Institute on Drug Abuse identifies and interprets emerging drug trends in the United States. The experts in the CEWG interpret these trends through a local and regional lens based on the concept that drug abuse shifts at the local level. These local shifts are due to the interactions of social networks, including interpersonal and market forces which are now increasingly impacted by global forces facilitated via the Internet (REF). Without this level of local and regional understanding, an effective approach is much harder to achieve.

Absorption of nicotine from the oral cavity to the bloodstream following the use of oral tobacco or nicotine replacement products (“NRT”) is much slower than the nicotine absorption that follows smoke inhalation. For NRT users, the absence of both a bolus effect and feedback from throat sensations results in far less opportunity to adjust the nicotine dose during use. Nicotine replacement therapy is typically intended to provide short-term craving relief, and delivers less total nicotine than either cigarettes or oral tobacco products.

Studies of smoking behaviour show very large differences in nicotine intake across a population, even among users of identical types of cigarettes. One of our studies involved collection of spent cigarette filters to estimate mouth level exposure to nicotine in thousands of smokers across eight different countries. Results indicated that regardless of the machine-measured nicotine yield for any particular cigarette, exposure levels varied several-fold between individuals. Smokers can adjust the amount of nicotine they take daily by changing the number of cigarettes they smoke each day and by changing the way in which they smoke each cigarette. Taking larger and more frequent puffs will increase exposure to nicotine and to other smoke toxicants. Smokers switching from cigarettes with higher machine-measured tar and nicotine yields to lower machine-measured yields often adjust their smoking behaviour such that they compensate, at least partially, by taking in larger amounts of smoke.

Smokers’ ability to alter their smoke and nicotine exposure by changing their smoking behaviour may provide benefits to smokers by allowing for a continual optimisation of preferred nicotine or smoke dose. It is far more difficult to adjust the amount or rate of the nicotine dose derived from NRT or oral tobacco products, which may act as a barrier to satisfactory substitution of such products for cigarettes.

There is also data indicating that factors associated with cigarette smoking, other than obtaining nicotine also provide value to smokers and can make cessation difficult. These include the rituals of opening the pack, lighting and inserting the cigarette into the mouth, the taste and smell of the smoke, the sight of smoke on exhalation and issuing from the lit end of the cigarette and the social aspects of smoking in the presence of other smokers.

Potential opportunities offered by e-cigarettes

Electronic cigarettes, or electronic nicotine delivery systems (“ENDS” - as perhaps more accurately described by the World Health Organisation) since they contain no tobacco and are not burnt, have become popular in the past few years. In the United States and several Western European countries there has been an appreciable adoption of e-cigarettes amongst cigarette smokers, often as partial or complete substitutes for cigarettes.

Many e-cigarettes are designed so as to appeal to cigarette smokers. These look like cigarettes, with filter-like ends that make their insertion in the mouth familiar to the smoker and with light-emitting diodes at the other end simulating the glow of a lit cigarette when a puff is taken. They produce an inhalable aerosol that is typically visible on exhalation and the pharmacokinetics of the nicotine uptake is closer to that provided by cigarette smoke than the pharmacokinetics of nicotine uptake from NRT or oral tobacco products. E-cigarette aerosol is generated by an electric heating element which is activated manually or when the user draws air through the device. The heating element vaporises a liquid formulation that typically contains nicotine, an excipient such as glycerol and sometimes added flavourings; the resulting vapour then condenses to form an aerosol.

The chemical content of the e-cigarette aerosol is substantially different than cigarette smoke and contains fewer toxicants at much lower levels than does cigarette smoke. Thus, most public health authorities agree that e-cigarettes are likely to pose dramatically lower risks of tobacco-related disease than do cigarettes. However, in addition to the vapourised components of the e-cigarette liquid formulation, certain impurities and other degradation/reaction products (some of which are toxic) may also be transferred to the inhaled vapour.

The characteristics of the e-cigarette aerosol depend mainly on the power of heating coil, the physical characteristics of the formulation (such as viscosity and wettability) and its specific heat capacity. Many of the techniques developed to characterise cigarette smoke aerosols can be applied to e-cigarette aerosols. Both aerosols are sub-micron (200 – 500 nm) in diameter and have high particle concentrations on generation of up to 109 particles per cm3. Both aerosols are dynamic and change in size and composition within the lung through coagulation, hygroscopic growth (water uptake by the soluble fraction of the aerosol) and evaporation.

The processes for particle deposition in the body are reasonably well understood, and the rate of penetration into and absorption by the lung for the e-cigarette aerosol is comparable to tobacco smoke. Particles with diameters less than 2,500nm (2.5μm) can penetrate into the deep lung where there is a huge surface area available for systemic uptake. For particles of 50-1,000nm, deposition efficiency is low, with slow sedimentation of particles. For particles under 50nm, deposition efficiency increases in the deep lung through increased Brownian Motion although mass deliveries can be small. The exhaled e-cigarette aerosol will contain residual excipient with a very high percentage of water absorbed from the 100% humidity of the airways. The high water content is expected to disperse rapidly in the air.

E-cigarettes are a rapidly evolving product category, and it is likely that they can be improved to act as more complete substitutes for cigarette smoking both in their manner of delivering nicotine as well as provision of sensory and other experiences that smokers miss following cessation. The scientific understanding of e-cigarettes in terms of health risks and likely modes of use needs to improve in order to characterise their effects and potential to provide a complete substitute for cigarettes.

The development of public policies and regulatory oversight

Cigarette smoking, mediated to a large extent by nicotine addiction, is the largest preventable cause of premature mortality in many countries. One obvious public health reaction to this fact has been introduction of public health education and regulatory measures to prevent people from starting smoking and getting smokers to quit. These efforts have been relatively successful and smoking rates in some countries are considerably lower than they were a decade ago. However, there remain a considerable number of smokers globally, and alternative nicotine-providing products have to date only had modest commercial success in most places. E-cigarettes have the potential to be a transformative technology that accelerates the move from cigarette smoking to less risky forms of nicotine use.

Setting public policies to deal with tobacco harm reduction is not simple. The US Food and Drug Administration (“FDA”) approaches tobacco regulation with a population health standard that considers not only whether novel nicotine or tobacco products offer individuals reduced health risks as compared to cigarettes but also the population-wide effects of the introduction of such products. For example, products such as e-cigarettes offer reduced health risks for individual users, but such gains might be offset if the availability of e-cigarettes results in more individuals becoming attracted to nicotine use and potentially migrating to cigarettes. Thus, the FDA is determined to set regulations on the basis of sound science that incorporates such population-wide concerns. In contrast, the Tobacco Free Initiative of the World Health Organisation has recommended prohibiting e-cigarettes as a preferred regulatory option, and some countries have enacted such measures. More pragmatic public policy and regulatory approaches may emerge from regions such as the European Union where e-cigarette use is already popular. EU and FDA policies are likely to seek to maximise the public health opportunity that comes with e-cigarettes while minimising the potential risks. The direction of travel is clear. We are investing heavily in the supporting science and must make this journey together.