Sara Crile Allen and James Frederick Allen Lung Cancer
Generally speaking, my research aims to identify the primary determinants and consequences of smoking behavior using human models of drug dependence. Dependent measures typically include toxicant exposure (carbon monoxide, nicotine, carcinogens), genetic substrates (nicotinic receptor polymorphisms), topography of use (puffing behavior, frequency of consumption), cardiovascular response (heart rate, blood pressure), and subjective ratings (product acceptability, withdrawal suppression). Currently I am involved in three areas of research:
1) Cigarette smokers’ use of alternative tobacco products such as cigars, smokeless tobacco, and waterpipes
2) Evaluation of novel tobacco products marketed as a means to reduce smoking-related harms
3) Genetic polymorphisms that influence nicotine metabolism and regulation
Alternative Tobacco Products
Traditionally, tobacco prevention and intervention efforts have centered on cigarette smoking. Trends in tobacco use over the past decade, however, have revealed a simultaneous decline in cigarette use and rise in alternative tobacco product (ATP) use (Nasim, Khader, Blank, Cobb, & Eissenberg, 2012). Products such as cigars, waterpipes, and smokeless tobacco have become increasingly popular, and are also often used in combination with cigarettes (Nasim, Blank, Cobb, & Eissenberg, 2012). One reason for this trend is that ATPs are perceived to be less harmful than cigarettes, despite evidence to the contrary (Blank, Cobb, Kilgalen, Austin, Weaver, Shihadeh, & Eissenberg, 2011; Blank, Nasim, Hart, & Eissenberg, 2011). This area of my work is dedicated to understanding the factors that promote and maintain ATP use, as well as to comparing the harm potential between ATPs and cigarettes using biomarkers such as carbon monoxide and tobacco-specific nitrosamines.
Potential Reduced Exposure Products
Potential reduced exposure products, or PREPs, are those marketed as a means to reduce the harms associated with cigarette use. Currently available products include oral, tobacco-based (e.g., snus, lozenges) and inhaled, non-tobacco based (e.g., electronic “cigarettes”). My work in this area has included evaluation of short- and long-term models of PREP use to understand products’ delivery of toxicants, ability to suppress nicotine/tobacco withdrawal symptomology, and acceptability among users (e.g., Blank, Sams, Weaver, & Eissenberg, 2008). For example, a recent study compared these outcomes among two PREPs, relative to smokers’ own brand of cigarette (positive control) and a period of nicotine/tobacco abstinence (negative control) (Blank & Eissenberg, 2010). The below figure shows that both oral products significantly reduced smokers’ exposure to expired air carbon monoxide, but not to urinary NNAL-T (a tobacco-specific carcinogen). Additionally, use of these products resulted in significantly lower levels of nicotine than use of cigarettes, as indicated by urinary cotinine (a nicotine metabolite). Such laboratory models can be used to predict the ability of PREPs to facilitate smokers’ quit attempts or to reduce the harms associated with continued nicotine/tobacco use.
Genetic Substrates of Smoking Initiation and Progression
Genetic polymorphisms involved with the metabolism (e.g., CYP2A6 enzyme activity) and regulation (e.g., nicotinic acetylcholine receptor subunits) of nicotine have been associated with cancer risk directly, as well as indirectly through their effects on smoking behavior This latter finding, however, is based largely on cross-sectional data and the use of broad and subjective smoking-related phenotypes (e.g., cigarettes smoked per day). A more accurate predictor of smokers’ exposure to carcinogens is the quantitative and objective measure of smoking topography: puff number, volume, duration, and inter-puff-interval per cigarette. Indeed, as smokers’ increase the number of puffs per cigarette, or the size (e.g., volume or duration) of individual puffs, their level of smoke toxicants increases (Blank, Disharoon, & Eissenberg, 2009). Thus, genetic polymorphisms that affect nicotine self-administration as measured via smoking topography will consequently affect cancer risk.
A single nucleotide polymorphism in the CHRNA5 subunit gene, rs16969968, is reliably associated with smoking status (smoker versus non-smoker), number of cigarettes smoked per day, and level of nicotine dependence. Our work (MacQueen, Heckman, Blank, Janse Van Rensburg, Park, Drobes, & Evans, in press) sought to investigate the association of this polymorphism with smokers’ topography across cigarettes that differed by nicotine yield: 0.6 mg and <0.05 mg (placebo). Genotype at rs16969968 predicted nicotine titration, with homozygotes for the major allele (G:G) displaying significantly reduced puff volume in response to nicotine, while minor allele carriers (A:G or AA) produced equivalent puff volumes for placebo and nicotine cigarettes (see below figure). Ongoing work is focused on the use of smoking topography measurement as an endophenotype for exploring the relationship between genetic variation, smoking, and subsequent health consequences.