Abstract
This study assesses temporal trends of biomarkers among adult nicotine and nonnicotine e-cigarette users and cigarette smokers.
Urinary nicotine metabolites and tobacco-specific nitrosamines are biomarkers of exposure to tobacco-related toxicants implicated in nicotine addiction and cancer risk. High-nicotine vaping devices have recently become available.1,2 We assessed temporal trends of biomarkers among adult nicotine and nonnicotine e-cigarette users and cigarette smokers.
Methods
A nationally representative longitudinal study, the Population Assessment of Tobacco and Health (PATH), included US civilian, noninstitutionalized individuals; data from individuals in waves 1 to 5 (2013-2019) were analyzed. Weighted adult interview response rates ranged from 69.4% to 83.2%.3 Urine biospecimens from individuals during all waves were collected in person from a stratified probability sample of wave 1 adults; 28.9% of participants had biospecimen data. PATH data collection was approved by Westat’s institutional review board and participants provided written informed consent.
Based on self-reported current tobacco use (every day or some days), participants were classified into 3 mutually exclusive groups: cigarette smokers, nonnicotine vapers (NNVs), and nicotine vapers (NVs). Concurrent users of other tobacco products were excluded.4 Biomarkers included nicotine metabolites (total nicotine equivalents [TNEs] and cotinine) and a carcinogen metabolite (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]),5 which was collected during the first 4 waves. For current vapers, data on whether they were former smokers or daily vapers, device types, and the number of puffs taken within the past 3 days were also collected.
Multivariable regressions tested linear trends, pairwise group effects between vapers and smokers, and group × wave interactions. Biomarkers were normalized with creatinine and log transformed. Covariates included age, sex, race and ethnicity, and education. For vapers, additional covariates included device types and number of puffs. Geometric means (95% CIs) of creatinine-corrected biomarkers along with the ratio of means (95% CIs) for pairwise between-group comparisons were reported. Statistical significance was 2-tailed (P < .05) with analyses conducted using SAS version 9.4 (SAS Institute Inc).
Results
There were 17 830 participants with urine samples (median age, 43.3 [IQR, 31.6-55.3] years; 51.5% female; 68.0% non-Hispanic White individuals; 93.2% smokers; 0.8% NNVs; and 5.9% NVs). Nicotine vapers were more likely to vape daily vs NNVs and reported a higher number of recent puffs (Table 1).
Table 1. Sample Characteristics by Collapsing 5 Cross-sectional Waves of the PATH Study, 2013-2019.
| Smokersa | Nonnicotine vapersb,c | Nicotine vapersb,d | P valuef | ||||
|---|---|---|---|---|---|---|---|
| No. | Weighted % (95% CI)e | No. | Weighted % (95% CI)e | No. | Weighted % (95% CI)e | ||
| Overall | 16 393 | 93.2 (92.4-94.0) | 197 | 0.8 (0.7-1.0) | 1240 | 5.9 (5.3-6.7) | |
| Wave | |||||||
| 1 (2013-2014) | 4077 | 20.7 (20.1-21.3) | 52 | 18.2 (13.5-24.2) | 238 | 13.3 (11.5-15.3) | <.001 |
| 2 (2014-2015) | 3295 | 20.4 (19.8-21.0) | 40 | 20.5 (14.5-28.2) | 235 | 18.6 (16.4-21.1) | |
| 3 (2015-2016) | 3291 | 20.9 (20.3-21.5) | 38 | 24.3 (16.7-33.8) | 237 | 20.9 (18.2-23.9) | |
| 4 (2016-2018) | 3067 | 20.0 (19.4-20.7) | 36 | 21.4 (15.7-28.5) | 232 | 19.9 (17.8-22.2) | |
| 5 (2018-2019) | 2663 | 18.0 (17.4-18.6) | 31 | 15.6 (10.3-22.7) | 298 | 27.3 (24.4-30.4) | |
| Demographics | |||||||
| Age, median (IQR), y | 16 393 | 43.7 (32.0-55.5) | 197 | 41.1 (24.1-56.7) | 1240 | 35.6 (27.0-49.9) | <.001 |
| Sex | |||||||
| Female | 8779 | 51.6 (49.0-54.1) | 114 | 59.8 (51.1-67.9) | 608 | 48.5 (42.1-54.8) | .24 |
| Male | 7607 | 48.4 (45.9-51.0) | 83 | 40.2 (32.1-48.9) | 632 | 51.5 (45.2-57.9) | |
| Race and ethnicityg | |||||||
| Hispanic | 2351 | 12.7 (11.3-14.2) | 42 | 18.5 (12.6-26.3) | 109 | 7.0 (5.0-9.7) | <.001 |
| Non-Hispanic | |||||||
| Black | 2353 | 14.7 (12.8-16.8) | 18 | 8.7 (5.1-14.5) | 79 | 10.1 (5.9-16.8) | |
| White | 10 280 | 67.5 (64.9-69.9) | 115 | 65.4 (55.7-74.0) | 947 | 76.7 (70.3-82.1) | |
| Otherh | 1208 | 5.2 (4.4-6.1) | 22 | 7.4 (4.4-12.2) | 100 | 6.2 (4.2-9.0) | |
| Education | |||||||
| Less than high school | 4937 | 28.2 (26.4-30.1) | 47 | 23.6 (16.0-33.3) | 202 | 16.3 (12.5-21.1) | <.001 |
| High school | 4048 | 28.1 (26.0-30.4) | 53 | 26.3 (19.0-35.2) | 236 | 20.5 (16.7-24.9) | |
| Some college | 5791 | 32.8 (30.6-35.1) | 83 | 42.9 (34.4-51.9) | 616 | 48.5 (42.8-54.1) | |
| College graduate | 1604 | 10.9 (9.5-12.5) | 14 | 7.2 (3.4-14.6) | 185 | 14.7 (11.6-18.4) | |
| Cigarette and e-cigarette use | |||||||
| Former smokersi | 76 | 38.2 (29.4-47.9) | 537 | 46.2 (41.8-50.8) | .09 | ||
| Daily e-cigarette vapers | 68 | 37.5 (29.2-46.7) | 1005 | 80.9 (76.6-84.6) | <.001 | ||
| e-Cigarette device type | |||||||
| Disposable | 23 | 10.8 (6.5-17.2) | 49 | 3.4 (2.3-5.1) | <.001 | ||
| Rechargeable with cartridge | 66 | 33.0 (25.9-40.8) | 327 | 28.8 (24.5-33.4) | |||
| Other rechargeable | 109 | 56.3 (48.0-64.2) | 862 | 67.8 (62.9-72.4) | |||
| No. of recent e-cigarette puffs, median (IQR)j | 197 | 2.6 (0-6.7) | 1240 | 14.8 (5.2-29.3) | <.001 | ||
Abbreviation: PATH, Population Assessment of Tobacco and Health.
Smoked 100 cigarettes or more during their lifetime and currently smoke cigarettes every day or some days without current use of other tobacco products (defined as traditional cigars, cigarillos, filtered cigars, pipe, hookahs, smokeless tobacco, snus, dissolvable tobacco, and e-cigarettes for smokers or cigarettes for vapers).
Current users of e-cigarettes every day or some days without current use of other tobacco products.
The e-cigarettes have a nicotine concentration of 0 mg or 0%.
The e-cigarettes have a nicotine concentration greater than 0 mg or 0%.
The percentages are for the column. The analyses applied urinary sample weight, 100 replicated weights, and the balanced repeated replication method using a Fay adjustment of 0.3 to account for the complex design.
Calculated using the Rao-Scott χ2 test for categorical variables and linear regression for continuous variables.
Derived from respondents’ answers to the PATH surveys and were assessed in this study as a covariate.
American Indian/Alaska Native, Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese, Other Asian, Native Hawaiian/Other Pacific Islander, Guamanian or Chamorro, and Samoan.
Reported smoking 100 cigarettes or more during their lifetime and not currently smoking.
Recent puffs taken from yesterday, today, and the day before yesterday.
Among NVs, the mean level of TNEs increased from 11.0 nmol/mg of creatinine (95% CI, 7.2-16.7 nmol/mg) in 2013-2014 to 21.8 nmol/mg of creatinine (95% CI, 15.2-31.4 nmol/mg) in 2018-2019 (P = .001), as did cotinine levels. Total nicotine equivalents and cotinine did not increase among smokers or NNVs, resulting in significant wave × tobacco group interactions (Table 2). Levels of NNAL were not significantly different across waves for smokers (mean, 197.4 pg/mg of creatinine [95% CI, 180.2-216.2 pg/mg] in 2013-2014 vs 218.3 pg/mg of creatinine [95% CI, 197.4-241.3 pg/mg] in 2016-2018), NVs (mean, 6.3 pg/mg of creatinine [95% CI, 4.9-8.3 pg/mg] vs 5.1 pg/mg of creatinine [95% CI, 3.9-6.6 pg/mg]), and NNVs (mean, 10.1 pg/mg of creatinine [95% CI, 4.9-20.9 pg/mg] vs 3.8 pg/mg of creatinine [95% CI, 1.9-7.5 pg/mg]).
Table 2. Trends by Biomarker of Exposure for Smokers, Nonnicotine Vapers (NNVs), and Nicotine Vapers (NVs), 2013-2019a.
| Wave 1 (Sep 2013 to Dec 2014) | Wave 2 (Oct 2014 to Oct 2015) | Wave 3 (Oct 2015 to Oct 2016) | Wave 4 (Oct 2016 to Jan 2018) | Wave 5 (Dec 2018 to Nov 2019) | P value for within-group linear trendb | |
|---|---|---|---|---|---|---|
| Total nicotine equivalents, mean (95% CI), nmol/mg of creatinine c | ||||||
| Smokers | 27.3 (24.1-30.9) | 29.6 (27.0-32.5) | 32.8 (29.4-36.7) | 29.5 (26.2-33.2) | 30.8 (26.5-35.7) | .34 |
| NNVs | 0.8 (0.2-3.1) | 0.2 (0-0.8) | 0.2 (0.1-0.6) | 0.2 (0.1-0.5) | 0.2 (0.1-0.6) | .29 |
| NVs | 11.0 (7.2-16.7) | 14.3 (9.5-21.7) | 18.9 (13.9-25.7) | 19.4 (14.4-26.2) | 21.8 (15.2-31.4) | .001 |
| Smokers vs NNVsd | 33.7 (9.0-126.5) | 168.9 (39.4-723.6) | 165.7 (52.4-524.2) | 173.0 (56.6-528.5) | 149.9 (47.4-474.0) | |
| P valuee | <.001 | <.001 | <.001 | <.001 | <.001 | |
| NVs vs NNVsd | 13.5 (3.7-50.0) | 81.9 (17.9-374.7) | 95.2 (29.3-309.9) | 113.9 (36.9-351.4) | 106.3 (33.5-337.3) | |
| P valuee | <.001 | <.001 | <.001 | <.001 | <.001 | |
| Smokers vs NVsd | 2.5 (1.6-3.8) | 2.1 (1.4-3.1) | 1.7 (1.3-2.4) | 1.5 (1.1-2.1) | 1.4 (0.9-2.1) | |
| P valuee | <.001 | .004 | .007 | .07 | .32 | |
| Cotinine, mean (95% CI), ng/mg of creatinine f | ||||||
| Smokers | 1750.1 (1551.6-1974.0) | 1888.6 (1729.7-2062.1) | 2109.3 (1882.3-2363.6) | 1868.0 (1659.7-2102.4) | 2002.0 (1724.8-2323.8) | .17 |
| NNVs | 49.9 (12.3-203.2) | 9.9 (2.3-42.5) | 11.2 (3.6-34.5) | 11.1 (3.5-34.6) | 12.2 (4.2-35.8) | .35 |
| NVs | 709.0 (454.0-1107.3) | 965.4 (627.7-1484.6) | 1186.8 (865.3-1627.8) | 1226.1 (890.7-1687.9) | 1416.6 (993.7-2019.4) | .002 |
| Smokers vs NNVsd | 35.1 (8.8-139.9) | 191.4 (44.8-818.1) | 188.4 (60.7-585.2) | 168.5 (53.5-529.7) | 164.3 (55.0-490.6) | |
| P valuee | <.001 | <.001 | <.001 | <.001 | <.001 | |
| NVs vs NNVsd | 14.2 (3.5-57.1) | 97.8 (21.4-446.3) | 106.0 (33.2-338.6) | 110.6 (34.8-351.5) | 116.2 (38.7-349.3) | |
| P valuee | .001 | <.001 | <.001 | <.001 | <.001 | |
| Smokers vs NVsd | 2.5 (1.6-3.9) | 2.0 (1.3-3.0) | 1.8 (1.3-2.5) | 1.5 (1.1-2.1) | 1.4 (1.0-2.1) | |
| P valuee | <.001 | .008 | .003 | .06 | .22 | |
| Tobacco-specific nitrosamine: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), mean (95% CI), pg/mg of creatinine g | ||||||
| Smokers | 197.4 (180.2-216.2) | 204.2 (188.2-221.5) | 235.4 (216.1-256.3) | 218.3 (197.4-241.3) | .07 | |
| NNVs | 10.1 (4.9-20.9) | 3.3 (1.3-8.5) | 3.9 (2.4-6.3) | 3.8 (1.9-7.5) | .16 | |
| NVs | 6.3 (4.9-8.3) | 5.9 (4.6-7.7) | 4.9 (4.0-5.9) | 5.1 (3.9-6.6) | .14 | |
| Smokers vs NNVsd | 19.5 (9.6-39.8) | 62.4 (24.0-162.6) | 60.6 (37.6-97.7) | 57.5 (28.7-115.1) | ||
| P valuee | <.001 | <.001 | <.001 | <.001 | ||
| NVs vs NNVsd | 0.6 (0.3-1.4) | 1.8 (0.7-4.9) | 1.2 (0.7-2.1) | 1.3 (0.7-2.7) | ||
| P valuee | .33 | .13 | .50 | .24 | ||
| Smokers vs NVsd | 31.1 (23.8-40.7) | 34.4 (26.4-44.8) | 48.5 (38.6-61.0) | 43.0 (32.8-56.3) | ||
| P valuee | <.001 | <.001 | <.001 | <.001 | ||
Urine biospecimens were collected in person from a stratified probability sample of wave 1 adults who provided a sufficient urine sample and were selected from a diverse mix of 6 tobacco product use groups representing never, current, and recent former (within 12 months) users of tobacco products. Biomarker concentrations below the limit of detection were imputed using a standard substitution formula (limit of detection/√2).
Wave served as the predictor and age, sex, race and ethnicity, and education served as covariates; for NNVs and NVs, there was further adjustment for e-cigarette device types and number of recent puffs. For the wave × group interaction P values, a linear regression model omnibus interaction test adjusted for age, sex, race and ethnicity, and education.
P = .003 for wave × group interaction. Total nicotine equivalents is the molar sum of the imputed values of cotinine and trans-3′-hydroxycotinine in urine.
The data are expressed as the ratio of means (95% CI) for the pairwise between-group comparisons.
From multivariable regressions adjusted for age, sex, race and ethnicity, and education.
P = .005 for wave × group interaction.
P = .06 for wave × group interaction.
Smokers had higher levels of TNEs than NVs across waves, but the ratios between smokers and NVs decreased over time from 2.5 (95% CI, 1.6-3.8; P < .001) in 2013-2014 to 1.4 (95% CI, 0.9-2.1; P = .32) in 2018-2019, with significant differences in 2013-2016 but not in 2016-2019. Similar results were found for cotinine. Across waves, smokers had significantly higher NNAL levels than NVs (eg, ratio, 43.0 [95% CI, 32.8-56.3] in 2016-2018). Nicotine vapers had significantly higher TNEs and cotinine than NNVs, with ratio of means increasing over time (eg, for TNEs, 13.5 [95% CI, 3.7-50.0] in 2013-2014 and 106.3 [95% CI, 33.5-337.3] in 2018-2019), but levels of NNAL did not differ.
Discussion
This study found that levels of NNAL, a carcinogen metabolite, were consistently lower in NVs than in smokers. Although nicotine metabolites were also generally lower in NVs than in smokers, this difference decreased over time. Nonnicotine vapers had lower levels of nicotine metabolites than NVs, underscoring the importance of separating these groups in studies.
The proliferation of vaping products containing high concentrations of nicotine and nicotine salt formulations with increased palatability could explain the increase in nicotine exposure observed, which may pose higher risks of addiction. Regardless of how vaping products have evolved, NNAL carcinogen exposure remained low in exclusive NVs and NNVs.
Study limitations include that the biomarker analysis was not stratified by device types due to small sample sizes and the data were analyzed cross-sectionally to test for linear trends. Findings can inform federal regulatory actions on tobacco products to prioritize public health.
Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.
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