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. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: Exp Clin Psychopharmacol. 2020 Jul 13;29(6):625–635. doi: 10.1037/pha0000417

Tobacco use behavior and toxicant exposure among current dual users of electronic cigarettes and tobacco cigarettes

Caroline O Cobb 1,2, Rebecca C Lester Scholtes 1,2, Alyssa K Rudy 1,2, Cosima Hoetger 1,2, Megan Scott 1, Makeda Austin 1, Alison Montpetit 3, Thokozeni Lipato 2,4, Amanda L Graham 5, Andrew J Barnes 2,6, Thomas Eissenberg 1,2
PMCID: PMC9307076  NIHMSID: NIHMS1731611  PMID: 32658532

Abstract

Electronic cigarette (e-cigarette) use continues to grow with most users reporting concurrent cigarette smoking, but few studies have focused on tobacco use and toxicant exposure among naturalistic dual-using populations. This controlled clinical laboratory study examined how dual versus exclusive use of e-cigarettes and cigarettes and no tobacco/nicotine affected behavioral, physiological, and subjective measures among current dual users. Twenty-two participants identifying as cigarette (≥10 cigarettes per day [CPD]) and e-cigarette (≥3 days/week) users of “cig-a-like” e-cigarettes completed four, 5-day outpatient conditions, which differed by own brand products used ad libitum: 1) cigarette and e-cigarette (dual), 2) cigarette only, 3) e-cigarette only, 4) no tobacco/nicotine. Primary outcomes included daily tobacco use, expired air carbon monoxide (CO), and urinary cotinine and NNAL. Linear mixed models with pairwise comparisons (Bonferroni-corrected) were performed (p<0.05). CPD did not differ significantly between dual and cigarette only use, but e-cigarette use and liquid consumed increased significantly during e-cigarette only relative to dual use. Relative to dual use, expired air CO did not differ during cigarette only and was significantly lower during e-cigarette only use. Urinary cotinine was significantly lower during e-cigarette only use relative to dual and cigarette only use while urinary NNAL did not differ between the nicotine-containing conditions. In summary, among current dual users, e-cigarettes in combination with cigarettes did not reduce CPD relative to exclusive cigarette use or toxicant exposure relative to exclusive use of either product. However, exclusive e-cigarette use did reduce CO and cotinine highlighting the benefits of cigarette cessation.

Keywords: electronic cigarette, smoking, nicotine, toxicant, dual use

Electronic cigarettes (or e-cigarettes), a tobacco class defined by the ability to heat a liquid containing nicotine to produce an inhalable aerosol, have been the subject of much debate in the public health community (Bareham, Ahmadi, Elie, & Jones, 2016; A. Breland et al., 2017; Malas et al., 2016). Of particular interest to many is the influence of e-cigarettes on measures of harm potential among current cigarette smokers via smoking reduction/cessation as well as dual use (concurrent use of e-cigarettes and tobacco cigarettes). As dual use with cigarette smoking is the most common form of e-cigarette use among adults (Borland et al., 2019; Patel et al., 2016; Rodu & Plurphanswat, 2018), information related to this tobacco use pattern has grown in recent years, including data from observational studies as well as relatively brief, small sample controlled studies (see Maglia, Caponnetto, Di Piazza, La Torre, & Polosa, 2018 for review).

Much of this previous work has focused on changes in cigarette smoking and toxicant exposure associated with dual use (Goniewicz et al., 2017; McRobbie et al., 2015; Meier et al., 2017; O’Connell, Graff, & D’Ruiz, 2016; Pulvers et al., 2016). In terms of the immediate effects (e.g., 5 days to 4 weeks) of e-cigarette initiation among exclusive cigarette smokers, several reports support the idea that dual use can result in significant reductions in cigarettes per day (CPD) and related toxicant exposures (Goniewicz et al., 2017; McRobbie et al., 2015; O’Connell et al., 2016). For example, when a group of 40 daily cigarette smokers were asked to quit smoking with a “cig-a-like” e-cigarette for four weeks, 17 (43%) reported dual use and 16 (40%) reported smoking abstinence (i.e., e-cigarette use only; McRobbie et al., 2015). Dual users had a significant decrease in expired air CO, urinary cotinine, and S-(3-hydroxypropyl)mercapturic acid (3-HPMA; toxicant found in e-cigarette aerosol and cigarette smoke) and e-cigarette only users had similar decreases in many of these same biomarkers with the exception of urinary cotinine (McRobbie et al., 2015). In another study in which investigators provided e-cigarettes with and without nicotine for one-week periods to 24 cigarette smokers, there were no significant changes in cigarette smoking behavior, expired air CO, or cotinine compared to baseline cigarette smoking (Meier et al., 2017).

In terms of studies examining the effects of dual use under more naturalistic conditions (i.e., where dual use behavior is not experimentally controlled or dual use behavior exists prior to experimental manipulation), the scope of evidence is much smaller. A cross-sectional study of long-term (at least 6-month) dual cigarette and e-cigarette users (N=36) versus participants engaging other product use patterns (N=145) indicated only exclusive users of e-cigarettes and nicotine replacement therapy had significantly lower concentrations of tobacco-related toxicants relative to cigarette only smoking (Shahab et al., 2017). Thus, dual use of combustible cigarettes and e-cigarettes in this sample did not appear to confer any appreciable reductions in toxicant exposure. In a within-subjects study of 60 current daily dual users (of any amount and any e-cigarette type) performed in Canada, investigators asked participants to complete four 7-day dual use, cigarette only use, e-cigarette only use, and no tobacco use conditions where compliance was monitored but not reinforced (Czoli, Fong, Goniewicz, & Hammond, 2019). Compared to dual use, cotinine remained stable during cigarette only use and decreased during e-cigarette only use; measures of expired air CO, 1-hydroxypyrene (1-HOP), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) were significantly lower during e-cigarette only use relative to dual use whereas during cigarette only use CO and 1-HOP concentrations significantly increased (Czoli et al., 2019). Taken together, these data suggest that the effects of dual use on measures of harmful constituents are still uncertain and may depend on whether participants are new or habitual dual users.

The current study aimed to add to this sparse literature by comparing short-term (5-day) tobacco use behavior, toxicant exposure, and associated physiological and subjective effects of dual use relative to exclusive use of either product and tobacco/nicotine abstinence in a sample of current dual cigarette and e-cigarette users. Unique design features included the restriction to dual users of specific set of e-cigarette brands (to control for variability in design and nicotine delivery) as well as the use of condition compliance verification methods used in previous work (Blank & Eissenberg, 2010; A. B. Breland, Kleykamp, & Eissenberg, 2006; Gray, Breland, Weaver, & Eissenberg, 2008). Conditions were dual use of cigarettes and e-cigarettes, cigarette only use, e-cigarette only use, and no tobacco/nicotine use. Primary hypotheses related to tobacco use behavior and toxicant exposure were: 1) cigarette smoking behavior would not differ during dual and cigarette only use, 2) e-cigarette use behavior would be greater during e-cigarette only use relative to dual use; 3) dual use would result in greater urinary cotinine exposure relative to exclusive use conditions and no tobacco/nicotine use, and 4) expired air CO/urinary NNAL exposure during dual use would be similar to cigarette only use but higher than those observed during e-cigarette only and no tobacco/nicotine use.

Method

Participants

A total of 57 participants were recruited in 2015–2017 from the area surrounding Richmond, VA, USA and provided informed consent for this IRB-approved study (HM20002700). Of these individuals, 33 were enrolled following in-person screening. Among those enrolled, 18 completed all four conditions and 4 completed more than half of the study (2 were unable to complete the e-cigarette condition in its entirety as well as the no tobacco/nicotine use condition; 2 participants were unable to complete the no tobacco/nicotine condition in its entirety). These 22 participants comprise the final sample. Of the 11 enrolled that were not included in the final sample, these individuals either self-withdrew during the study or were removed via PI decision (e.g., failing to comply with study condition/compliance criteria).

Participants were enrolled if they were healthy (self-report), aged 18–60 years, provided an expired air carbon monoxide (CO) concentration of at least 10 ppm and a urine cotinine concentration of at least 3/6 (NicAlert test strip; Jant Pharmacal Corporation) at screening, reported smoking at least 10 cigarettes per day for at least 1 year, and reported use of an approved ‘cig-a-like’ e-cigarette (i.e., small cylinder or cigarette-shaped device with a non-refillable liquid chamber or cartridge; disposable or rechargeable; Malek et al., 2018) at least 3 times/week for at least 3 months. Importantly, the sample was restricted initially to dual users of blu-branded e-cigarettes which were popular at the time of study initiation (Herzog, 2013) and well-characterized in terms of nicotine delivery (Yan & D’Ruiz, 2015). This brand restriction was also used to control for variability in nicotine concentration, liquid flavor, and other device characteristics but later was widened to increase enrollment. All participant e-cigarette products were examined for similar design and product characteristics to blu-branded products (e.g., shape, size, containing nicotine, inability to add liquid manually). Exclusion criteria included self-reported current uncontrolled chronic medical/mental health conditions, use of medications that may interact with nicotine/tobacco abstinence, current pregnancy (confirmed by urinalysis) or breastfeeding, plans to quit smoking within the next 30 days, self-reported use of other tobacco/nicotine products (cigars/cigarillos/little cigars, hookah/pipe/smokeless tobacco/other nicotine-containing products; >5 days in the past month), marijuana use (>10 days in the past month), and alcohol use (>25 days of 3 or more alcoholic drinks per day in the past month).

Table 1 includes demographics and cigarette and e-cigarette use behavior of the final sample. On average the sample was 42 years old with an equal gender distribution. Race/ethnicity was distributed almost equally between White and Black individuals. Education level varied, but most had achieved at least a high school diploma/GED. Alcohol and cannabis use was less than 5 days per month on average. Over 30% of the sample smoked Newport cigarettes and 82% reported a menthol cigarette preference. Consistent with the original inclusion criteria, blu was the most common e-cigarette brand reported followed by Mark10 and Vuse. Most participants used a disposable e-cigarette type. Cigarette menthol preference matched identically to e-cigarette liquid flavor preference (menthol=menthol; tobacco=nonmenthol). E-cigarette liquid nicotine concentration varied by brand and ranged between 2.4% and 4.8% overall. On average, participants used an e-cigarette product containing approximately 3.1% nicotine or 31 mg/ml (of note brands differed in nicotine calculated by weight/volume as well as use of nicotine salts). On average, participants smoked 15 CPD for 18 years and had been using e-cigarettes less frequently (about 5 days/week) for less than 2 years. Age of initiation was consistently younger for cigarettes relative to e-cigarettes. Dependence scale scores (indexed by the FagerströmTest for Nicotine Dependence [FTND; Heatherton, Kozlowski, Frecker, & Fagerström, 1991, original and adapted for e-cigarettes) indicated significantly greater dependence for cigarettes relative to e-cigarettes (paired samples; t(21)=4.3, p<0.001).

Table 1.

Demographics and tobacco use characteristics

Characteristic N=22
Age (years), M (SD) 41.9 (13.2)
Gender (Female), N (%) 11 (50.0)
Race, N (%)
  White/Caucasian 11 (50.0)
  Black/African American 10 (45.5)
  Middle Eastern 1 (4.5)
Hispanic/Latino, N (%) 1 (4.5)
Education (N=21), N (%)
  Did not graduate HS 2 (9.5)
  HS graduate/GED 7 (33.4)
  Some college 8 (38.1)
  College graduate or higher 4 (19.0)
Past 30-day alcohol use, (days; N=19), M (SD) 4.1 (6.4)
Past 30-day marijuana use (days; N=13), M (SD) 0.5 (1.5)
Cigarette brand, N (%)
  Newport 8 (36.4)
  Marlboro 5 (22.7)
  Maverick 3 (13.6)
  Pall Mall 2 (9.1)
  Other brands 4 (18.0)
Cigarette menthol preference, N (%)
  Menthol 18 (81.8)
  Non-menthol 4 (18.2)
Cigarettes smoked per day (cigarettes), M (SD) 15.2 (7.5)
Smoking history (months), M (SD) 216.0 (172.0)
Age of smoking initiation (years), M (SD) 18.7 (5.6)
FTND Summary Score – Cigarette, M (SD) 5.4 (2.0)
E-cigarette brand (nicotine concentration), N (%)
  blu (2.4–4.8%) 13 (59.1)
  Mark10 (2.4–3.5%) 4 (18.2)
  Vuse (4.8%) 3 (13.6)
  NJOY (4.5%) 1 (4.5)
  ‘E-cig’ (2.4%) 1 (4.5)
E-cigarette Type, N (%)
  Disposable 14 (63.6)
  Rechargeable 8 (36.4)
E-cigarette liquid flavor preference, N (%)
  Menthol 18 (81.8)
  Tobacco 4 (18.2)
E-cigarette use per week (days), M (SD) 4.5 (1.9)
E-cigarette history (months), M (SD) 21.5 (26.3)
Age of e-cigarette initiation (years), M (SD) 40.0 (12.6)
FTND Summary Score – E-cigarette, M (SD) (SD) 3.1 (2.7)
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Note: Nicotine concentration reported by brand varied by weight/volume as well as use of nicotine salts. An adapted version of the FTND, in which the words “smoke cigarettes” were substituted with “use e-cigarettes”, was used to assess nicotine dependence for e- cigarettes. E-cigarette = electronic cigarette.

Materials

Participants used their self-reported own brand cigarettes and e-cigarettes. These products were purchased locally by research staff following enrollment and provided to participants on Day 1 and Day 3 of conditions involving tobacco use. Baseline consumption for cigarettes and e-cigarettes was used as a reference, and participants were given 150% of this daily amount to allow for potential variability in day-to-day use patterns. Participants were asked to only use provided tobacco products during each condition.

Procedure

Following consent/eligibility screening, participants were assigned to the first of four 5-day conditions that differed by ad libitum product use: 1) cigarette and e-cigarette (dual use), 2) cigarette only, 3) e-cigarette only, and 4) no tobacco/nicotine. Condition order of the first three conditions was assigned using a balanced Latin square design (to control for order effects), but the last condition for all participants was no tobacco/nicotine. The reason for this study design feature was to ensure participants were not incentivized to reinitiate tobacco use following abstinence. Each condition lasted from Monday to Friday and participants visited the laboratory for 1 hour on Day 1 (Monday), Day 3 (Wednesday), and Day 5 (Friday) of each study week for provision/return of provided and used tobacco products, expired air CO measurement, exhaled breath condensate (EBC; to measure a biomarker of air-way associated oxidative stress) and urine collection, 30 minutes of heart rate (HR) and blood pressure (BP) monitoring, and subjective questionnaire administration. Participants were also asked to monitor their daily tobacco (cigarette/e-cigarette) consumption during each 5-day condition using product counts and tally cards which was documented via a telephone call (non-automated) on Day 2 and 4 and in-person on Day 1, 3, and 5. The timing of participant’s daily sessions varied between subjects but remained the same within subjects (to reduce variability in product use and toxicant exposure measures). On weekends (considered a washout period), participants were instructed to use their own brand of cigarettes and e-cigarettes with no monitoring or restrictions. Participants were provided travel compensation of up to $5 for each in-person visit and payment for study completion was $400 (prorated for completion of each condition).

Condition Compliance

Compliance with tobacco product use restrictions for all conditions was verified using self-report and physiological measures. For the dual and e-cigarette use only conditions, compliance could only be confirmed with self-report measures. For the e-cigarette condition, compliance was verified with self-report measures and lower concentrations of expired air CO on Day 3 and 5 relative to Day 1. For the no tobacco/nicotine condition compliance was verified with lower concentrations of CO on Day 3 and 5 relative to Day 1 and lower concentrations of semi-quantitative urine cotinine (NicAlert test strip; scale from 0–6) on Day 3 and 5 relative to Day 1. If participants were non-compliant based on self-report or physiological measures, they were allowed to repeat each condition once.

Following data collection, quantitative urine cotinine results were used to check compliance within the no tobacco/abstinence condition. Similar to the other compliance criteria, quantitative urine cotinine had to decrease relative to the previous measurement taken and/or concentrations had to be below <100 ng/ml (tobacco user cutoff based on semi-quantitative urine cotinine strip) to be considered compliant.

Measures

Tobacco product consumption.

Two measures were used to measure tobacco product consumption. (1) Physical product counts (smoked cigarette butts and used e-cigarette products such as cartridges and/or disposable e-cigarettes) were documented at each session. In addition, e-cigarette products were weighed before and after use to measure consumption of nicotine-containing liquid objectively. (2) Paper tally cards (pocket-sized to monitor cigarettes smoked and e-cigarette use episodes defined for participants as about 15 puffs/5 minutes of use; e-cigarette use episode definition similar to Foulds et al., 2015) were completed by participants during each condition. Rows of each tally card listed 24 individual hours of the day (e.g., 12 pm-1 pm). Tally cards were dispensed and/or retrieved at each session.

Physiological measures.

All physiological measures were taken at Days 1, 3, and 5 of each condition. Expired air CO was assessed with a BreathCO monitor (Vitalograph, Lenexa, KS). Urine samples (stored initially following collection at −80C) were analyzed later for quantitative concentrations of cotinine and total NNAL concentration (sum of NNAL and its glucuronides) with liquid chromatography tandem mass spectrometry techniques using previously developed assays (Jacob et al., 2008; Naidong, Shou, Chen, & Jiang, 2001). HR was measured every 10 seconds and BP every 5 minutes for 30 minutes during each in-person session using a Criticare Systems VitalCare Monitor 506N3 (Criticare Systems Inc.; Waukesha, WI). EBC was collected by having participants exhale normally through their mouth into a collecting chamber covered by the cooling sleeve and insulating cover. After 7 to 15 minutes, the resulting condensate was then aliquoted for later analysis. Participants were instructed to abstain from eating, drinking, and using e-cigarette/cigarettes for 30 minutes prior to EBC collection to prevent substantial analysis artifacts. EBC was analyzed using an ELISA kit from Cayman Chemical which expressed 8-isoprostane concentration in pg/ml (dynamic range=0.8–500 pg/ml; lowest limit of detection [LLOD]=3.0 pg/ml).

Subjective measures.

Participants used a computer keyboard and mouse to respond to three subjective measures on Days 1, 3, and 5 of each condition. The Direct Effects of Nicotine Scale (DENS) was used consisting of 10 visual analog scale (VAS) items and was developed to describe the effects of nicotine (Evans, Blank, Sams, Weaver, & Eissenberg, 2006). An adapted version of the Minnesota Nicotine Withdrawal Scale (Hughes & Hatsukami, 1986) was used consisting of 13 VAS items. These 23 items were presented as a word or phrase centered above a horizontal line that ranges from 0 (“Not at all”) to 100 (“Extremely”). Participants used a computer mouse to place a vertical mark anywhere along the horizontal line. Lastly, the Positive and Negative Affect Schedule (PANAS) was administered to participants consisting of 24 Likert-scaled items characterized by words that describe different feelings and emotions. Items were summed to form two psychometric mood categories, positive and negative affect (Watson, Clark, & Tellegen, 1988).

Data Preparation

Among individuals who successfully completed all four conditions of the study (N=18/22), 11 were deemed compliant during the no tobacco/nicotine condition following examination of their urinary cotinine (following Day 1 cotinine must decrease relative to previous measurement taken and/or concentrations had to be below <100 ng/ml). Based on the discrepancy, we first examined whether demographics and cigarette smoking and e-cigarette use/dependence characteristics differed significantly between those who successfully abstained during the no tobacco/nicotine condition (N=11) versus those who did not (N=11; no significant differences detected). Thus, we decided to restrict our analyses to the nicotine-containing conditions (N=22) and include abstinence status (i.e., ability to abstain from tobacco/nicotine; yes versus no) as a covariate in all analyses. Data from the no tobacco/nicotine condition from participants deemed compliant were analyzed descriptively and included for comparison where relevant.

Self-reports (from the phone-based measures), tally cards, and product counts for cigarette smoking were reconciled to produce a single measure of CPD for four 24-hour periods completed during the dual use and cigarette only conditions (Day 1/2, Day 2/3, Day 3/4, and Day 4/5; 0.6% missing data). Self-reports (from the phone-based measures) and tally cards for e-cigarette use were reconciled to produce a single measure of e-cigarette use in terms of episodes of use (e-cigarette episodes) for the same four 24-hour periods for the dual use and e-cigarette only use conditions (6.3% missing data). E-cigarette liquid consumed per week was calculated using the weights of products dispensed and returned each week (total liquid weight consumed for dual use and e-cigarette only use conditions; 13.6% missing data). For HR and BP, the last 10 min of data collected during each in-person visit was averaged to produce a single value for that visit (3.5% missing data for HR and BP). For urinary cotinine, there were no values below the limit of quantitation (LOQ; 1.0 ng/ml). For urinary total NNAL, values below the LOQ (2.5 pg/ml) were replaced with 2.5 pg/ml (N=7/198 samples; 1% missing data). Very few subjective data was missing across all items (~1%).

For EBC 8-isoprostane, across all four conditions, 23 samples (8.7%) were missing/unable to be analyzed, 74 samples (28.0%) were above the LLOD (3.0 pg/ml), and 167 samples (63.3%) were below the LLOD (total N=264 total). Considering the lack of previous data for this outcome among dual users and availability of quantitative results above and below the LLOD, an exploratory descriptive strategy utilizing all available data was used to analyze this outcome.

Statistical Analysis

Linear mixed models were used to analyze all outcomes including the following factors: condition (2–3 levels dependent on outcome; dual use, cigarette only, or e-cigarette only) and time (number of levels dependent on outcome), abstinence status (yes/no), and participant (treated as a random factor). Interactions between abstinence and condition/time were examined for physiological measures of tobacco exposure (i.e., expired air CO, urinary cotinine, urinary NNAL) but no consistent evidence was found to suggest condition or time effects were moderated by whether or not participants were confirmed as having abstained during the abstinence condition (via urinary cotinine). Thus, our main models do not include an interaction between abstinence status and condition or time. To explore mean differences between conditions and across time for these outcomes, we used results from the estimated marginal means (EMM; controlling for abstinence status) and t-tests with a Bonferroni adjustment (p<0.05). Results for all outcomes during the no tobacco/nicotine condition and for EBC 8-isoprostane across all conditions were examined using descriptive statistics. All analyses were performed in IBM SPSS Version 25.

Results

Tobacco Product Consumption

Statistical analysis results for all outcomes are presented in Table 2. For CPD, there were significant main effects of condition and time but not their interaction. Examination of EMM indicated that there were no significant differences between dual and cigarette only use conditions (EMM±SEM on Day 1/2 dual=18.6±2.0 vs. cigarette only=19.3±2.0 CPD; Day 2/3 dual=13.7±2.0 vs. cigarette only=16.7±2.0 CPD; Day 3/4 dual=18.0±2.0 vs. cigarette only=19.6±2.0 CPD; Day 4/5 dual=15.8±2.0 vs. cigarette only=18.0±2.0 CPD), but within the dual condition, Day 2/3 CPD was significantly lower than Day 1/2 (see Figure 1A; p<0.05, Bonferroni-adjusted). For e-cigarette episodes there was a significant main effect of condition. When EMM were examined by condition and time, the number of e-cigarette episodes reported was significantly greater during the e-cigarette only condition relative to the dual condition for every 24-hour period (Day 1/2 dual=10.8±3.2 vs. e-cigarette only=17.9±3.3 episodes; Day 2/3 dual=9.5±3.2 vs. e-cigarette only=19.5±3.3 episodes; Day 3/4 dual=8.9±3.2 vs. e-cigarette only=18.5±3.3 episodes; Day 4/5 dual=10.0±3.3 vs. e-cigarette only=22.8±3.3 episodes; ps<0.05, Bonferroni-adjusted), but there were no significant differences relative to baseline for either condition. Results for the e-cigarette liquid weight consumed by condition were consistent with e-cigarette episodes per day. E-cigarette liquid weight differed significantly by condition; EMM e-cigarette liquid weight consumed during the e-cigarette only condition (1.1±0.1 g) was more than twice the amount consumed during the dual use condition (0.4±0.1 g; p<0.05, Bonferroni-adjusted).

Table 2.

Statistical analysis results for all measures

Condition (C) Time (T) CXT Abstinen Status
F P F P F P F P
Tobacco product consumption
  Cigarettes per daya 4.3 0.040 4.0 0.009 0.3 0.818 <0.1 0.981
  E-cigarette episodes per dayb 40.5 <0.001 0.6 0.629 0.6 0.622 <0.1 0.830
  E-cigarette weight (total)c 23.3 <0.001 - - - - 0.1 0.920
Physiological measures
  Expired air COd 63.7 <0.001 19.9 <0.001 10.1 <0.001 18.3 <0.001
  Urinary cotinined 9.1 <0.001 0.7 0.509 2.0 0.101 0.2 0.698
  Urinary NNALe 1.1 0.342 1.0 0.353 1.0 0.417 1.1 0.301
  Heart ratef 4.8 0.009 0.4 0.685 1.0 0.416 0.1 0.739
  Systolic BPf 1.4 0.245 0.2 0.834 1.1 0.356 0.5 0.509
  Diastolic BPf 3.0 0.053 3.4 0.036 0.6 0.652 0.1 0.737
Subjective Measures MNWSd
  E-cigarette urge 1.0 0.384 1.1 0.334 0.7 0.596 0.1 0.803
  Cigarette urge 2.0 0.136 1.0 0.370 5.1 0.001 0.3 0.570
  Irritability 0.9 0.403 0.4 0.669 1.4 0.238 2.9 0.102
  Anxious <0.1 0.958 0.8 0.446 1.2 0.328 <0.1 0.831
  Difficulty concentrating 0.3 0.728 0.5 0.590 1.1 0.366 0.4 0.521
  Restlessness 1.1 0.328 0.3 0.730 0.9 0.463 0.1 0.789
  Hunger 0.3 0.717 0.2 0.855 1.3 0.276 0.1 0.759
  Impatient 1.4 0.254 1.2 0.310 2.0 0.097 <0.1 0.987
  E-cigarette craving 4.3 0.015 0.6 0.545 0.7 0.624 <0.1 0.880
  Cigarette craving 1.8 0.168 1.2 0.298 6.0 <0.001 0.2 0.664
  Drowsiness 0.1 0.874 0.1 0.924 0.8 0.552 1.8 0.200
  Depression/feeling blue 0.7 0.488 0.4 0.691 1.8 0.131 0.8 0.391
  Desire for sweets 1.3 0.288 1.7 0.185 0.9 0.482 0.2 0.701
Direct Effects of Nicotined
  Nauseous 0.6 0.558 0.5 0.583 0.5 0.702 1.5 0.242
  Dizzy 0.5 0.595 0.7 0.502 0.3 0.846 1.8 0.201
  Lightheaded 0.1 0.869 1.1 0.333 0.6 0.683 1.1 0.315
  Nervous 0.7 0.488 1.8 0.168 0.8 0.517 0.4 0.560
  Sweaty 0.9 0.408 0.7 0.490 2.5 0.043 5.5 0.029
  Headache 1.3 0.278 1.3 0.268 1.0 0.412 2.4 0.139
  Excessive salivation 2.6 0.081 1.0 0.353 1.3 0.279 0.5 0.501
  Heart pounding 3.5 0.032 0.1 0.946 0.5 0.743 0.2 0.627
  Confused 1.8 0.177 0.5 0.601 0.4 0.813 1.7 0.202
  Weak 0.9 0.407 0. 8 0.467 0. 7 0.566 1.4 0.252
PANAS
  Positive Affectd 0.9 0.389 0.1 0.928 0.9 0.494 2.2 0.153
  Negative Affectd 0.1 0.890 0.9 0.405 1.1 0.337 1.35 0.258
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Note:

a

dfC = (1,146), dfT = (3,146), dfcxt = (3,146), dfAS = (1,20);

b

dfc = (1,138), dfT = (3,136), dfcxt = (3,136), dfAS = (1,20);

c

dfc = (1,14), dfAS = (1,17);

d

dfc = (2,166), dfT = (2,166), dfcxT = (4,166), dfAS = (1,20);

e

dfc = (2,164), dfT = (2,164), dfcxt = (4,164), dfAS = (1,20);

f

dfc = (2,161), dfT = (2,161), dfcxt = (4,161), dfas = (1,20).

Figure 1:

Figure 1:

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Estimated marginal means (+/− SEM) for cigarettes per day (CPD; Panel A) and e-cigarette episodes per day (Panel B) during the dual use, cigarette only, and e-cigarette only conditions (N=22) controlling for abstinence status. E-cigarette episodes defined by 15 puffs or 5 minutes of use. Filled symbols indicate a significant difference relative to Day 1/2 within that condition. Asterisks (*) indicate a significant difference relative to the dual use condition (all p<0.05, Bonferroni-adjusted).

Physiological Measures

For expired air CO, there was a significant main effect of condition, time, and interaction of condition by time as well as abstinence status. When EMM were examined by condition and time (see Figure 2A), CO was significantly lower within the e-cigarette only condition at Day 3 (4.2±1.5 ppm) and Day 5 (4.1±1.5 ppm) relative to Day 1 (16.6±1.5 ppm; p<0.05, Bonferroni-adjusted). Between conditions, CO on Day 3 and 5 during the e-cigarette only condition was significantly lower relative to the dual use (Day 3=15.9 ±1.5 ppm; Day 5=16.5±1.5 ppm) and cigarette only conditions (Day 3=18.1±1.5 ppm; Day 5=17.6±1.5 ppm; ps<0.05, Bonferroni-adjusted). Across condition and time, abstainers had about 8.2 ppm lower EMM CO; however no evidence was found that condition or time effects on CO varied across abstinence status. As expected when examined descriptively, the no nicotine/tobacco condition (abstinence) condition resulted in the lowest concentration of CO on Day 3 (M=2.8±0.9; N=11) and 5 (M=1.9±0.5; N=11) similar to those observed during the e-cigarette only use condition. There was a significant main effect of condition for urinary cotinine. When EMM were examined by condition and time (see Figure 2B), cotinine concentrations were significantly lower on Day 3 (580.0±162.5 ng/ml) relative to Day 1 (894.9±162.5 ng/ml) within the e-cigarette only condition (p<0.05, Bonferroni-adjusted). Between conditions, cotinine during the e-cigarette only use condition on Day 3 and 5 was significantly lower relative to the dual use (Day 3=1021.5±162.5 ng/ml; Day 5=953.0±162.5 ng/ml) and cigarette only use conditions (Day 3=926.1±162.5 ng/ml; Day 5=1059.2±162.5 ng/ml; ps<0.05, Bonferroni-adjusted). As expected when examined descriptively, the no nicotine/tobacco condition (abstinence) condition resulted in the lowest concentrations of cotinine among those meeting compliance criteria on Day 3 (M=337.2±149.2 ng/ml; N=11) and 5 (M=106.5±46.1 ng/ml; N=11). For urinary total NNAL, there were no significant main effects or an interaction. Examination of EMM indicated no significant differences between conditions when total NNAL concentrations were collapsed across conditions or days. When examined by condition and time (see Figure 2C), descriptively NNAL concentrations were the lowest on Day 5 during e-cigarette only (94.2±28.2 pg/ml) and no tobacco/nicotine use (23.8±13.0 pg/ml; N=11) relative to dual (116.0±27.2 pg/ml) and cigarette only use (135.4±27.2 pg/ml).

Figure 2:

Figure 2:

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Estimated marginal means (+/− SEM) for expired air CO (Panel A), urinary cotinine (Panel B), urinary total NNAL (Panel C) during the dual use, cigarette only, and e-cigarette only conditions (N=22) controlling for abstinence status. Means (+/− SEM) during no tobacco/nicotine use (abstinence; in grey) are included for descriptive purposes only (N=11). Filled symbols indicate a significant difference relative to Day 1. Asterisks (*) indicate a significant difference relative to the dual use condition. Number signs (#) indicate a significant difference relative to the cigarette only condition (all p<0.05, Bonferroni-adjusted).

For HR, there was a significant main effect of condition. When EMM were examined collapsed across time, HR was significantly lower in the e-cigarette only condition (75.6±2.8 bpm) relative to the dual use (78.8±2.8 bpm) and cigarette only (79.4±2.8 bpm) conditions (p<0.05, Bonferroni-corrected). Diastolic BP had a significant main effect of time; EMM comparisons revealed no significant differences between time points collapsed across conditions (Time 1=74.4±1.9 mm hg, Time 2=76.7±1.9 mm hg; Time 3=74.6±1.9 mm hg). For EBC 8-isoprostane, across all four conditions, 74 samples were above the LLOD and were observed among 18/22 participants (with sample frequency for each participant ranging from 1–10). By condition their frequency was relatively similar (between 14–21 samples observed for each condition), but by time EBC 8-isoprostane samples that were above the LLOD were more frequent at Day 3 (33 samples) and Day 5 (33 samples) relative to Day 1 (8 samples). Descriptively, by condition and time, mean/median EBC 8-isoprostane concentrations were the highest during dual and e-cigarette only use conditions on Day 3 and/or 5. Descriptive statistics and scatterplots of EBC 8-isoprostane data above and below the LLOD are provided in Supplementary Figure 1 and Supplementary Tables 1 and 2.

Subjective Measures

Three MNWS items had either a significant main effect of condition or interaction of condition and time and one item had a significant effect of abstinence status. For the items related to cigarette smoking abstinence (“Urges to use a regular cigarette” and “CRAVING a regular cigarette”), examination of EMM revealed a similar pattern with significant increases relative to Day 1 (i.e., stronger urges/craving) occurring in the e-cigarette only condition (e.g., Urges to use a regular cigarette; e-cigarette only Day 1=42.9±7.4 vs. Day 3=63.6±7.4 and Day 5=61.5±7.5; ps<0.05, Bonferroni-corrected) as well as significantly greater values occurring during the e-cigarette only condition relative to the dual use condition on Days 3 and/or 5 (ps<0.05, Bonferroni-corrected). For “CRAVING an e-cigarette” item, EMM were significantly decreased on Day 3 during the e-cigarette only condition (41.9±6.2) relative to the cigarette only condition (27.1±6.2; p<0.05, Bonferroni-corrected); no other significant EMM differences were observed. Two DENS items had a significant main effect of condition or abstinence status and/or an interaction of condition and time. For “Sweaty”, during the dual use condition, Day 5 EMM (23.1±5.0) was significantly higher than Day 1 (10.4±5.0) as well as significantly higher than that observed during the cigarette only and e-cigarette only conditions (ps<0.05, Bonferroni-corrected). Individuals who were able to abstain during no tobacco/nicotine use had an EMM “Sweaty” score that was −18.0 points lower than those who were not compliant. For “Heart pounding”, during the dual use condition, Day 5 EMM (14.1±3.7) was significantly higher than the e-cigarette only condition (4.8±3.8; ps<0.05, Bonferroni-corrected). For other subjective measures, there were no significant main effects or interactions.

Discussion

Consistent with several of the study hypotheses, dual use of cigarettes and e-cigarettes in this study did not reduce cigarettes smoked or expired air CO exposure significantly compared to cigarette only use. While e-cigarette use indexed by self-report and liquid weight consumed did increase significantly during the e-cigarette only condition relative to dual use, urinary cotinine levels dropped significantly during e-cigarette only use relative to baseline and were significantly lower than that observed during dual and cigarette only use. Relatedly, HR was decreased significantly during e-cigarette only use relative to dual and cigarette only use. For urinary total NNAL, tobacco product consumption patterns did not result in significant changes over 5 days of use (excluding effects noted for the tobacco/abstinence condition).

The similarity of CPD between dual use and cigarette only use is consistent with previous research that examined short-term changes in cigarette consumption during dual use. When cigarette smokers without a recent history of dual use were provided a blu-branded e-cigarette starter kit for two weeks, there was no significant difference in CPD between the end of the two-week dual use condition and baseline (Meier et al., 2017). Further, when daily dual users (92% of whom used tank systems) completed two 7-day periods of dual use and cigarette only use, CPD was significantly higher during dual use (Czoli et al., 2019). However, results from another study in which cigarette smokers were provided with an eGo-style e-cigarette for four weeks indicated a significant decrease in CPD over time (average decrease of −7.1 CPD; Pulvers et al., 2016). Taken together, results from the current study and from similar designs suggest that dual use of cigarettes and e-cigarettes may not result in immediate reductions in CPD. More research is needed to understand the time course and variability in changes to CPD among dual users who use different types of e-cigarettes.

Greater e-cigarette consumption during the e-cigarette only use condition (EMM across days=19.7 episodes) relative to dual use (EMM across days=9.8 episodes) is consistent with a previous study which recruited daily dual users using similar methods (M=17.4 vs 11.1 episodes per day; Czoli et al., 2019). Importantly, in the current study, all participants had used a cig-a-like e-cigarette, but in the study by Czoli et al. (2019), most participants used tank-like systems. Conversely, in a quitting study with adult smokers who were encouraged to use a cig-a-like e-cigarette as a cessation aid for four weeks, there was no significant difference in the number of e-cigarette episodes between e-cigarette only users and dual users (McRobbie et al., 2015). This body of work supports the idea that e-cigarettes may serve as partial substitute for own brand cigarettes under some conditions.

In terms of toxicant exposure, we observed significantly lower levels of expired air CO and urinary cotinine for the e-cigarette only condition relative to dual use (consistent with Czoli et al., 2019). In contrast to our study hypothesis and the aforementioned study (Czoli et al., 2019), no significant changes in urinary total NNAL were observed across conditions (although concentrations during the no tobacco/nicotine condition decreased over time). These findings also contradict evidence from observational studies which support the idea that e-cigarette use (even short-term) can reduce exposure significantly to certain toxicants traditionally found in cigarette smoke (Goniewicz et al., 2017; Pulvers et al., 2016). One potential explanation for the lack of significant effects for the e-cigarette only condition may be due a statistical floor effect. Baseline NNAL concentrations in this study were lower than those performed previously by this research team using the same design among smokers (Blank & Eissenberg, 2010). It is also possible that individuals may not have complied during the e-cigarette only use condition. Analytical chemistry studies have indicated e-cigarette liquids and associated aerosol contain relatively low levels of tobacco-specific-nitrosamines including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; i.e., NNAL’s precursor) compared to cigarette smoke (Goniewicz et al., 2014; Farsalinos, Gillman, Oulas, & Voudris, 2015). We noted increases in urinary total NNAL from 6 participants from Day 1 to Day 5 during the e-cigarette only condition which suggests strategic cigarette smoking may have occurred. As described in the Methods section above, participants in this study had significant challenges in completing the e-cigarette only and tobacco/nicotine abstinence conditions. These findings suggest future work should consider other measures to confirm and incentivize compliance during e-cigarette only use.

Although current study findings for airway-associated oxidative stress measured in EBC did not indicate any short-term differences between study conditions, this study is the first to report 8-isoprostane in EBC among dual and e-cigarette only users. Results from a previous study (using a similar analysis method) suggests that 8-isoprostane in EBC is detectable and is significantly higher in healthy cigarette smokers (24.3±2.6 pg/ml) relative to healthy non-smokers (10.8±0.8 pg/ml), indicating that cigarette use is related to higher oxidative stress (Montuschi et al., 2000). Interestingly, even among those results that were above the LLOD in the current study, average and median values were well below 20 pg/ml. It is possible the relatively younger age of the current sample and potentially less lifetime exposure to cigarette smoke may have resulted in lower levels of EBC-8-isoprostane here. Of note, another report of EBC 8-isoprostane among smokers at several time points over the course of 1 week indicated only 37% of samples had detectable levels (Van Hoydonck et al., 2004). Oxidative stress plays an important role in airway inflammation and the development of tobacco-associated disease such as chronic obstructive pulmonary disease (Lim & Thomas, 2013). Understanding how patterns of tobacco use such as dual use influence markers of oxidative stress and subsequent damage (such as 8-isoprostane) as well as toxicants such as total NNAL and CO is important to understanding their overall harm potential. Based on the current results, different assays or biomarkers may be better suited to assess airway-associated oxidative stress among dual cigarette and e-cigarette users.

Findings for subjective measures indicated that during e-cigarette only use, cravings for cigarettes were not suppressed to the same extent as during dual use despite increased e-cigarette use. These effects may be influenced by the inability of cig-a-like e-cigarettes used by participants to provide sufficient nicotine delivery (also indexed by urinary cotinine concentrations). Despite being marketed as nicotine delivery devices, only a subset of e-cigarettes can deliver nicotine at concentrations that approach those of combustible cigarettes (Ramôa et al., 2016; Vansickel, Cobb, Weaver, & Eissenberg, 2010; Wagener et al., 2017). Nicotine delivery to the user and subsequent potential for effective cigarette craving suppression may depend on various factors, including liquid nicotine concentration. While our study used e-cigarettes containing liquid at 2.4–4.8% nicotine, cig-a-like devices likely have relatively low power (due to low battery voltage and/or high heater resistance) which is associated with poorer nicotine yield/delivery (Harvanko, St. Helen, Nardone, Addo, & Benowitz, 2019; Talih et al., 2015; Talih et al., 2017; Wagener et al., 2017).

Of note, many of the brands/products used by participants in this study are no longer marketed (i.e., Mark10) or may have had dramatic design changes (i.e., Vuse) since the study was performed. Others like blu appear to still exist in a similar form (i.e., blu disposable) but are offered in combination with other blu devices/products. Critically, a new class of e-cigarettes often defined by the termed ‘pod mods’ including JUUL have dramatically overtaken the e-cigarette market (Huang et al., 2019). Pod mods and associated liquid cartridges or pods are typically small but not cigarette-like in shape and contain nicotine salt-based liquid at high concentrations (e.g., 5% or higher) which may provide more effective nicotine delivery than cig-a-like e-cigarettes (Maloney, Eversole, Crabtree, Soule, Eissenberg, & Breland, 2020; Vansickel et al., 2010). Importantly, data are needed to understand the effects of e-cigarette use among users of differing devices including cig-a-likes (which continue to marketed today). Future research using rigorous designs such as the current study should aim to assess dual use behaviors and toxicant exposures associated with e-cigarettes with higher nicotine delivery capabilities.

Limitations to this study includes the targeting of predominate cigarette smokers who also used e-cigarettes which does not capture the full range of dual use patterns observed (e.g., dual daily users, predominant vaper; Borland et al., 2019). Findings would likely differ with inclusion of other dual use subgroups, but critically, predominant smoker dual users are the most common across several country-level surveys of tobacco users (Borland et al., 2019). Better understanding of the reasons why our sample initiated e-cigarette use could have provided some insight to results obtained. Our restriction to dual users of cig-a-like brands reduces generalizability, but allowed us to make more specific recommendations regarding the implications of dual use. It is also possible that variability in the cig-a-like brands used by participants influenced our ability to detect effects. Vuse products have utilized nicotine salts since 2013 (https://vusevapor.com/faqs/product/), and e-cigarette products varied in nicotine concentration and likely other device characteristics (wattage, coil resistance) which are known to influence nicotine delivery (Malek et al., 2018). The lack of significant between condition differences for some outcomes also may have been influenced by the relatively short 5-day product use assessment period and potential condition order confounds. Importantly, expired air CO and cotinine have elimination half-lives that are short enough to estimate intake over the course of 5 days, and while total NNAL’s elimination half-life is closer to 10 days (Goniewicz et al., 2009), the distribution half-life is 3–4 days (Hecht et al., 1999). Rapid declines of urinary total NNAL concentrations have been observed in two previous studies using this model among smokers (Blank & Eissenberg, 2010; A. B. Breland et al., 2006; e.g., 59% decrease relative to baseline on day 5) and in a pharmacokinetic study of smokers on a clinical research ward (50% of baseline levels within four days; Goniewicz et al., 2009). Urinary total NNAL levels particularly may have been affected for conditions following the e-cigarette only use condition resulting in lower levels on Day 1 of the subsequent condition, but this effect should have been reduced by the use of a balanced Latin square condition order assignment. The use of 5-day tobacco use conditions also has limitations in terms of real-world relevance to ad libitum use patterns, but our approach did provide a more compact study design and ability to compare short-term behaviors and biomarkers among current dual users.

Conclusions

Under these current study conditions, dual use of cigarettes and e-cigarettes did not result in immediate reductions in CPD, but e-cigarettes partially substituted for own brand cigarettes when they were the only product available. Expired air CO and urinary cotinine only were reduced during exclusive e-cigarette and no tobacco/nicotine use relative to cigarette only and dual use. These findings emphasize others (Czoli et al., 2019; McRobbie et al., 2015) that highlight the benefits of complete cigarette cessation among dual users.

Supplementary Material

Supplemental Material

Public Significance Statement:

Relative to dual use of “cig-a-like” e-cigarettes and tobacco cigarettes, exclusive use of cigarettes did not result in appreciable reductions in tobacco use behavior or associated toxicant exposure, however exclusive e-cigarette use was associated with reduced carbon monoxide and nicotine exposure.

Disclosures and Acknowledgements

This research has been presented, in part, at the NIH Tobacco Centers for Regulatory Science, Fall Meeting (Washington, DC; 2015), Annual Poster Symposium for Undergraduate Research and Creativity at Virginia Commonwealth University (Richmond, VA; 2016), the Society for Research on Nicotine and Tobacco (Chicago, IL; 2016) and Virginia Commonwealth University (Richmond, VA; 2017).

This research was supported by an Internal Grant from Virginia Commonwealth University’s School of Nursing and award number R21CA184634 from the National Cancer Institute of the National Institutes of Health and the Center for Tobacco Products of the U.S. Food and Drug Administration. COC and TE are also supported by grant number U54DA036105 from the National Institute on Drug Abuse of the National Institutes of Health and the Center for Tobacco Products of the U.S. Food and Drug Administration. Funding sources had no other role other than financial support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Food and Drug Administration.

All authors contributed to the writing of this manuscript and have approved the final version.

Thomas Eissenberg is a paid consultant in litigation against the tobacco industry and is named on a patent application for a device that measures the puffing behavior of electronic cigarette users. All other authors have no conflicts of interest to report.

We would like to acknowledge the contributions of the participants of this study as well as the staff of the Roswell Park Nicotine and Tobacco Product Assessment Resource (NicoTAR) and VCU Bioanalytical Core Laboratory for their assistance in analyzing urinary biomarkers. We also would like to thank Drs. David Abrams and Dorothy Hatsukami for their guidance during study development.

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