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Published in final edited form as: Chem Res Toxicol. 2022 Jul 20;36(4):583–588. doi: 10.1021/acs.chemrestox.2c00145

Increased Levels of the Acrolein Metabolite 3-Hydroxypropyl Mercapturic Acid in the Urine of e-Cigarette Users

Menglan Chen 1, Steven G Carmella 1, Bruce R Lindgren 1, Xianghua Luo 1, Joshua Ikuemonisan 1, Brittany Niesen 1, Nicole M Thomson 1, Sharon E Murphy 1, Dorothy K Hatsukami 1, Stephen S Hecht 1,*
PMCID: PMC9852357  NIHMSID: NIHMS1846935  PMID: 35858275

Abstract

Carcinogen and toxicant uptake by e-cigarette users have not been fully evaluated. In the study reported here, we recruited 30 e-cigarette users, 63 non-smokers, and 33 cigarette smokers who gave monthly urine samples over a period of 4-6 months. Their product use status was confirmed by measurements of exhaled CO, urinary total nicotine equivalents (TNE), cyanoethyl mercapturic acid (CEMA), and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL). Urinary biomarkers of exposure to the carcinogens acrolein (3-hydroxypropyl mercapturic acid, 3-HPMA), benzene (S-phenyl mercapturic acid, SPMA), acrylonitrile (CEMA), and a combination of crotonaldehyde, methyl vinyl ketone, and methacrolein (3-hydroxy-1-methylpropyl mercapturic acid, HMPMA) were quantified at each visit. Data from subject visits with CEMA > 27 pmol/ml were excluded from the statistical analysis of the results because of possible unreported exposures to volatile combustion products such as secondhand cigarette smoke or marijuana smoke exposure; this left 22 e-cigarette users with 4 or more monthly visits, and all 63 non-smokers. Geometric mean levels of 3-HPMA (1249 vs 679.3 pmol/ml urine) were significantly higher (P=0.003) in e-cigarette users than non-smokers, while levels of SPMA, CEMA, and HMPMA did not differ between these two groups. All analytes were significantly higher in cigarette smokers than either e-cigarette users or non-smokers. The results of this unique multi-month longitudinal study demonstrate consistent significantly higher uptake of the carcinogen acrolein in e-cigarette users vs. non-smokers presenting a warning signal regarding e-cigarette use.

Graphical Abstract

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Introduction

The U.S. National Academies of Sciences, Engineering, and Medicine Consensus Study Report entitled “Public Health Consequences of E-Cigarettes” concluded that e-cigarette aerosol contains fewer toxicants and carcinogens, and lower levels of these substances, than does the smoke of tobacco cigarettes.1 They also concluded that e-cigarettes are likely to be far less harmful than tobacco cigarettes, but that there is presently insufficient data to evaluate their absolute health risk.1 Considering the growing popularity of e-cigarettes, particularly among younger people, it is essential that we explore their potential health effects.2–5 The study reported here focuses on exposure to certain volatile carcinogens in e-cigarette users compared to non-smokers, as determined by collecting urine samples at multiple monthly visits and quantifying their mercapturic acid metabolites as biomarkers.

Multiple studies have evaluated biomarkers of carcinogen and toxicant exposure in subjects who used e-cigarettes versus conventional cigarettes or non-users of any tobacco product, as recently reviewed.6–8 The vast majority of these studies have made biomarker measurements at a single time point, or more than one time point over a relatively short duration. While e-cigarette use consistently resulted in significantly lower exposure to carcinogens and toxicants than cigarette smoking, a few of these single time point studies demonstrated elevated levels of certain biomarkers of volatile toxicants or carcinogens such as acrolein and acrylonitrile in e-cigarette users versus non-tobacco users, as summarized in Table 1.

Table 1.

Examples of toxicant and carcinogen exposure in e-cigarette users versus non-users of any tobacco or nicotine-containing product as reported in the literature.

Study Time points Fluid analyzed Reported increased toxicant exposure in e-cigarette users vs. non-users
Lorkiewicz et al.19, 20 single urine acrylonitrile, xylene, N,N-dimethylformamide, glycidol
Rubinstein et al.21 single urine acrylonitrile, acrylamide, acrolein, crotonaldehyde, propylene oxide
Keith et al.22 single urine acrylonitrile, acrylamide, acrolein, xylene
Samburova et al.23 single breath aldehydes and methyl ethyl ketone
Fuller et al.24 single urine o-toluidine, 2-naphthylamine
Goniewicz et al.25 single urine acrylonitrile, lead, cadmium, pyrene
St. Helen et al.26 single urine acrylamide, benzene
Smith et al.27 single urine acrylonitrile, N,N-dimethylformamide
De Jesus et al.28 single urine acrylonitrile, acrolein
Prokopowicz et al.29 single urine None for various metals
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Another set of published reports compared biomarkers of exposure in cigarette smokers who switched to e-cigarettes, and generally showed decreases in exposure to volatile toxicants and carcinogens.9–16 While most of these investigations were also of relatively short duration, one followed subjects who switched for up to 2 years, with multiple measurements.17, 18 However, these studies did not include non-user comparison groups.

Overall, these biomarker results are potentially important in the evaluation of e-cigarette safety, but the measurements over a limited period of time in many studies and lack of parallel non-user control groups in others raise questions regarding the relationship of the reported results to e-cigarette use as opposed to other exposures. Based on these studies, exposure to volatile toxicants and carcinogens due to e-cigarette use per se is difficult to evaluate. Therefore, we have quantified urinary biomarkers of exposure to selected volatile toxicants and carcinogens in 30 e-cigarette users, 63 non-smokers, and 33 cigarette smokers, who gave monthly urine samples over a 4-6 month period.

Materials and Methods

The participants in this study were recruited through the Tobacco Research Programs, University of Minnesota. Inclusion criteria were age >18, in stable and good physical and mental health, excellent oral health, no current infection as determined by medical history and investigator assessment, and no current use of medicinal nicotine products or any tobacco products other than cigarettes. e-Cigarette users exclusively used e-cigarettes for at least 3 months and at least 4 days per week, and had exhaled CO < 6 ppm. Smokers smoked at least 5 cigarettes per day for a minimum of 4 days per week for the past year and had exhaled CO > 8 ppm. Average urinary total nicotine equivalents (TNE, the molar sum of nicotine, cotinine, 3’-hydroxycotinine and their glucuronides plus nicotine-1’-N-oxide) and 2-cyanoethyl mercapturic acid (CEMA) were quantified to confirm e-cigarette use (TNE > 3 nmol/ml; CEMA < 27 pmol/ml) or non-smoking, non-user status (TNE < 0.1 nmol/ml; CEMA < 27 pmol/ml), whereas cigarette smokers had TNE > 3 nmol/ml and CEMA > 27 pmol/ml. Non-smokers smoked less than 100 cigarettes in their lifetime and had exhaled CO < 6 ppm, and never used any other tobacco product or e-cigarettes. Additional validation was provided by measurement of urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL) which was below the limit of detection at most time points in the e-cigarette users. Neither e-cigarette users nor smokers intended to quit using these products in the next 6 months. Subjects had no current use of antibiotics or anti-inflammatory agents and did not use marijuana for at least 2 days before study visits. Body mass index of all subjects was ≤40 kg/m2 and they consumed less than 21 alcoholic drinks per week. The participants were not pregnant, nursing or planning on becoming pregnant while enrolled in the study.

Participants in this study visited the clinic monthly for 4-6 consecutive months. They came in the morning before eating breakfast or after at least a 4-h fast, and reported not ingesting alcohol, or using cigarettes or any other tobacco product or e-cigarettes immediately before the clinic visit. At each visit, participants provided a spot urine sample which was collected in a 100 mL sterile specimen cup, aliquoted, and immediately frozen at −20 °C.

TNE,30 3-hydroxypropyl mercapturic acid (3-HPMA),31 hydroxymethylpropyl mercapturic acid (HMPMA),32 S-phenyl mercapturic acid (SPMA),33 CEMA,34 and total NNAL35 were analyzed as described previously, except that in the total NNAL assay 0.5% aqueous HCOOH was used instead of HCl in all the SPE steps, and the final elution was with 5% (v/v) NH4OH in MeOH. The HMPMA analysis includes mercapturic acids of crotonaldehyde, methyl vinyl ketone, and methacrolein.32 Creatinine was quantified using a colorimetric microplate assay (CRE34-K01) purchased from Eagle Bioscience.

Statistical methods

All biomarkers were analyzed in the logarithmic scale due to skewed distributions and reported as geometric means with 95% confidence intervals (CI). The limit of detection (LOD) for each biomarker is reported in Table S2, Supporting Information. Biomarkers 3-HPMA and HMPMA had no values below the LOD and were evaluated over the 6 months and compared among the three groups using a linear mixed model (SAS PROC MIXED). Biomarkers CEMA and SPMA had frequent values below the LOD for some of the study groups and were analyzed by group and month using a left-censored mixed effects model36 (SAS PROC NLMIXED) where values below the LOD were treated as being left censored. These two mixed models can handle cases with missing time points, such that participants with less than 6 months of data were not excluded from the analysis. Using a Bonferroni adjustment for multiple comparisons, the overall group effect for each biomarker was significant at the 0.01 level and the three pairwise group comparisons within each biomarker were evaluated at the 0.017 level of significance. Since no intervention was planned for any of the study groups, no significant changes over time were expected or observed. All statistical analysis was performed using SAS version 9.4 (SAS Institute Inc., Cary NC).

Results

Thirty e-cigarette users (12 male), 63 non-smokers (21 male) and 33 cigarette smokers (16 male) completed 4-6 monthly visits. Mean/median ages of e-cigarette users were 32.7/28.5 (range 18-62); non-smokers were 33.0/31.0 (18-67); and cigarette smokers were 46.8/49.0 (21-67). Further demographic information is summarized in Table S1 and biomarker data validating product use are presented in Table S2, Supporting Information. We excluded from the analysis time points at which e-cigarette users’ or non-users’ CEMA values were >27 pmol/ml, as this would signal potential exposure to combustion products, for example from secondhand cigarette smoke or marijuana smoke or waterpipe use which could confound the analysis. The 8 e-cigarette users who were not included were subjects 1, 3, 12, 16, 21, 23, 28, and 29 (Table S2). In addition, the two time points from subject 8 and one time point from subject 26 with CEMA>27 pmol/ml were not included in the analysis. After this rigorous exclusion rule, there were 22 e-cigarette users and 63 non-smokers who finished at least 4 monthly visits.

The results summarized in Table 2 demonstrate significantly elevated levels of 3-HPMA in e-cigarette users compared to non-smokers. No significant differences were found for SPMA, CEMA, and HMPMA between e-cigarette users and non-smokers. When the data were expressed per mg creatinine instead of per ml urine, the comparative results among the 3 groups were the same. For the 18 e-cigarette users of the 22 considered in this study who were ex-smokers, the average time since stopping smoking was 45.6 months (range 1 to 108 months) which is well beyond the lifetime of these biomarkers as measured in human urine.31 The results in Table 2 also confirm significantly higher levels of all biomarkers in cigarette smokers than in e-cigarette users or non-smokers, as previously documented in multiple studies.25, 28, 37 There were no significant effects of gender on the results expressed per ml of urine, and there was no relationship of any of the biomarkers to age of the subjects. Biomarker data at each time point are presented in Table S2, Supporting Information.

Table 2.

Levels of biomarkers in 22 e-cigarette users (E, 8 male), 63 non-smokers (N, 21 male), and 33 smokers (S, 16 male) in urine samples collected monthly for 4-6 months. Among the groups, the number of monthly visits completed were: e-cigarettes - 22 participants completed 6 visits; non-smokers - 55 completed 6, 3 completed 5, 5 completed 4; smokers - 29 completed 6 and 4 completed 4. Samples from all completed visits were used in the analysis.

Biomarker Group Geometric mean 95% CI Group p-value Pairwise
3-HPMA (acrolein) pmol/ml Non-smokers 679.3 554.2, 832.4
<0.001		 E vs S, p<0.001
E-cig users 1249 885.7, 1762 E vs N, p=0.003
Smokers 5576 4210, 7384 N vs S, p<0.001
SPMA (benzene) pmol/ml Non-smokers 0.12 0.09, 0.17
<0.001		 E vs S, p<0.001
E-cig users 0.17 0.10, 0.30 E vs N, p=0.250
Smokers 10.00 6.54, 15.29 N vs S, p<0.001
CEMA (acrylonitrile) pmol/ml Non-smokers 1.74 1.31, 2.32
<0.001		 E vs S, p<0.001
E-cig users 2.72 1.68, 4.41 E vs N, p=0.120
Smokers 531.9 358.4, 789.4 N vs S, p<0.001
HMPMA (crotonaldehyde; methyl vinyl ketone; methacrolein) pmol/ml Non-smokers 586.5 485.4, 708.8
<0.001		 E vs S, p<0.001
E-cig users 696.3 505.5, 959.1 E vs N, p=0.363
Smokers 4771 3673, 6197 N vs S, p<0.001
TNE nmol/ml Non-smokers a
E-cig users 34.3
Smokers 58.2
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a

there were only 2 TNE values above the LOD for non-smokers

Discussion

This is to our knowledge the first multi-month longitudinal study to quantify urinary toxicant and carcinogen biomarkers in e-cigarette users compared to non-smokers. We quantified mercapturic acids – 3-HPMA, SPMA, and CEMA - which are specific biomarkers of exposure to acrolein, benzene, and acrylonitrile respectively; and HMPMA which is a biomarker of exposure to crotonaldehyde, methyl vinyl ketone, and methacrolein. Our findings showing higher levels of 3-HPMA in the urine of e-cigarette users compared to non-smokers are consistent with our recent report of significantly higher acrolein-DNA adducts in buccal brushings of e-cigarette users versus non-users of any tobacco product.38 That study encompassed 3 monthly visits and 18 of the 20 subjects were the same ones who participated in the present study. Levels of DNA adducts of acrolein in buccal brushings did not significantly correlate (non-parametric, Spearman) with those of 3-HPMA in urine, possibly because DNA repair may influence adduct levels and 3-HPMA is relatively short-lived and also has endogenous sources. Our results for 3-HPMA are also consistent with the results of many studies that demonstrate the presence of acrolein in e-cigarette vapor.39–50

Acrolein is considered “probably carcinogenic to humans, Group 2A” by the International Agency for Research on Cancer (IARC), which concluded that “there is consistent and coherent evidence that acrolein exhibits key characteristics of carcinogens.”51 Acrolein administered by inhalation significantly increased the incidence of malignant lymphoma in female mice and caused rare rhabdomyoma and squamous cell carcinoma of the nasal mucosa in female rats. These findings, together with a massive amount of biochemical and molecular biological data, strongly support the IARC classification.51 The clear evidence for increased uptake of acrolein in e-cigarette users, and increased levels of acrolein-DNA adducts in buccal brushings of e-cigarette users, compared to non-users of any tobacco or nicotine product, present a warning signal regarding the potential carcinogenicity of e-cigarette use.

Several previous studies have reported increased uptake of benzene and acrylonitrile based on measurements of SPMA and CEMA in the urine of e-cigarette users versus non-users (Table 1), but all of these studies used single time points and may not have fully considered other sources of exposure to combustion products such as marijuana smoking and exposure to secondhand cigarette smoke. These issues are clearly important in the evaluation of e-cigarette safety because benzene is a known human carcinogen according to evaluations by IARC and the U.S. Government52, 53 and acrylonitrile is considered “possibly carcinogenic to humans” by the IARC.54 Benzene is not commonly detected as a component of e-cigarette vapor, although some reports have appeared.46, 55 Similarly, acrylonitrile has been infrequently detected as a component of e-cigarette vapor.46 The possible increased exposure of e-cigarette users to benzene and acrylonitrile requires further study.

HMPMA had been considered as a specific urinary biomarker of crotonaldehyde exposure until our recent study demonstrating that the LC-MS response for HMPMA could actually be resolved into peaks corresponding to the isomeric mercapturic acids derived from crotonaldehyde, methyl vinyl ketone, and methacrolein.32 Published data summarized in Table 1 rarely showed an increase of this mixture in e-cigarette users, consistent with the present results, and the fact that these compounds have an additional carbon atom compared to the major e-cigarette ingredients propylene glycol and glycerol. Methyl vinyl ketone, methacrolein, and crotonaldehyde are all powerful irritants and toxicants56–58 and crotonaldehyde caused liver tumors in rats when administered in the drinking water.59

A clear strength of our study compared to previous reports is its longitudinal nature. Single time point studies could be misleading for the reasons noted above. Exposures could occur through inhalation of secondhand tobacco smoke, but our measurements of NNAL in e-cigarette users (Table S2, Supporting Information) provided scant evidence for that. Cooking fumes, industrial emissions, and endogenous processes are further sources of acrolein exposure51 which could confound single time point measurements but would be less likely to be elevated over a period of months.34

A limitation of this study is that we did not analyze the e-cigarettes used by our subjects for acrolein, or the other volatiles which are the sources of the mercapturic acids measured here. It would be informative to carry out studies specifically linking e-cigarette vapor constituents to their urinary biomarkers under normal conditions of use. However, a more practical and important need is to decrease the unregulated use of these products.

In summary, this is the first multi-month longitudinal study to demonstrate significantly increased levels of a urinary biomarker of acrolein in e-cigarette users compared to non-smokers. While e-cigarettes are likely less carcinogenic than tobacco cigarettes, our results indicate that e-cigarette users may have increased risk relative to non-users.

Supplementary Material

supporting info

Table S1. Demographic information for e-cigarette users, non-smokers, and cigarette smokers

Table S2. Levels of biomarkers in the urine of e-cigarette users at each time point.

Acknowledgements.

This study was supported by grant CA-203851 from the U.S. National Cancer Institute and the Food and Drug Administration Center for Tobacco Products. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the Food and Drug Administration. Mass spectrometry was carried out in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, University of Minnesota, supported in part by Cancer Center Support Grant CA-077598. Salary support for Peter W. Villalta, head of the Analytical Biochemistry Shared Resource, was provided by National Cancer Institute grant CA-211256.

Footnotes

Conflict of Interest

The authors declare no competing financial interest.

References

  • (1).National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division. Public Health Consequences of E-Cigarettes; National Academies Press, 2018. DOI: 10.17226/24952. [DOI] [Google Scholar]
  • (2).Jerzynski T; Stimson GV; Shapiro H; Krol G Estimation of the global number of e-cigarette users in 2020. Harm Reduct. J 2021, 18 (1), 109. DOI: 10.1186/s12954-021-00556-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (3).Park-Lee E; Ren CF; Sawdey MD; Gentzke AS; Cornelius M; Jamal A; Cullen KA E-cigarette use among middle and high school students - National Youth Tobacco Survey, United States, 2021. MMWR 2021, 70 (39), 1387–1389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (4).Cornelius ME; Wang TW; Jamal A; Loretan CG; Neff LJ Tobacco product use among adults - United States, 2019. MMWR 2020, 69 (46), 1736–1742. DOI: DOI 10.15585/mmwr.mm6946a4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (5).Bandi P; Cahn Z; Goding Sauer A; Douglas CE; Drope J; Jemal A; Fedewa SA Trends in e-cigarette use by age group and combustible cigarette smoking histories, U.S. adults, 2014-2018. Am. J. Prev. Med 2021, 60 (2), 151–158. DOI: 10.1016/j.amepre.2020.07.026. [DOI] [PubMed] [Google Scholar]
  • (6).Akiyama Y; Sherwood N Systematic review of biomarker findings from clinical studies of electronic cigarettes and heated tobacco products. Toxicol. Rep 2021, 8, 282–294. DOI: 10.1016/j.toxrep.2021.01.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (7).Bjurlin MA; Matulewicz RS; Roberts TR; Dearing BA; Schatz D; Sherman S; Gordon T; Shahawy OE Carcinogen biomarkers in the urine of electronic cigarette users and implications for the development of bladder cancer: A systematic review. Eur. Urol. Oncol 2021, 4 (5), 766–783. DOI: 10.1016/j.euo.2020.02.004. [DOI] [PubMed] [Google Scholar]
  • (8).Hiler M; Weidner AS; Hull LC; Kurti AN; Mishina EV Systemic biomarkers of exposure associated with ENDS use: A scoping review. Tob. Control 2021. DOI: 10.1136/tobaccocontrol-2021-056896. [DOI] [PubMed] [Google Scholar]
  • (9).Hatsukami DK; Meier E; Lindgren BR; Anderson A; Reisinger SA; Norton KJ; Strayer L; Jensen JA; Dick L; Murphy SE; Carmella SG; Tang MK; Chen M; Hecht SS; O’Connor R J; Shields PG A randomized clinical trial examining the effects of instructions for electronic cigarette use on smoking-related behaviors and biomarkers of exposure. Nicotine Tob. Res 2020, 22 (9), 1524–1532. DOI: 10.1093/ntr/ntz233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (10).Pulvers K; Emami AS; Nollen NL; Romero DR; Strong DR; Benowitz NL; Ahluwalia JS Tobacco consumption and toxicant exposure of cigarette smokers using electronic cigarettes. Nicotine Tob. Res 2018, 20 (2), 206–214. DOI: 10.1093/ntr/ntw333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (11).McRobbie H; Phillips A; Goniewicz ML; Smith KM; Knight-West O; Przulj D; Hajek P Effects of switching to electronic cigarettes with and without concurrent smoking on exposure to nicotine, carbon monoxide, and acrolein. Cancer Prev. Res 2015, 8 (9), 873–878. [DOI] [PubMed] [Google Scholar]
  • (12).Goniewicz ML; Gawron M; Smith DM; Peng M; Jacob P 3rd; Benowitz NL Exposure to nicotine and selected toxicants in cigarette smokers who switched to electronic cigarettes: a longitudinal within-subjects observational study. Nicotine Tob. Res 2017, 19 (2), 160–167. DOI: 10.1093/ntr/ntw160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (13).Round EK; Chen P; Taylor AK; Schmidt E Biomarkers of tobacco exposure decrease after smokers switch to an e-cigarette or nicotine gum. Nicotine Tob. Res 2019, 21 (9), 1239–1247. DOI: 10.1093/ntr/nty140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (14).O’Connell G; Graff DW; D’Ruiz CD Reductions in biomarkers of exposure (BoE) to harmful or potentially harmful constituents (HPHCs) following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers. Toxicol. Mech. Methods 2016, 26 (6), 443–454. DOI: 10.1080/15376516.2016.1196282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (15).D’Ruiz CD; Graff DW; Robinson E Reductions in biomarkers of exposure, impacts on smoking urge and assessment of product use and tolerability in adult smokers following partial or complete substitution of cigarettes with electronic cigarettes. BMC Public Health 2016, 16, 543. DOI: 10.1186/s12889-016-3236-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (16).Morris P; McDermott S; Chapman F; Verron T; Cahours X; Stevenson M; Thompson J; Chaudhary N; O’Connell G Reductions in biomarkers of exposure to selected harmful and potentially harmful constituents following exclusive and partial switching from combustible cigarettes to myblu() electronic nicotine delivery systems (ENDS). Intern. Emerg. Med 2022, 17 (2), 397–410. DOI: 10.1007/s11739-021-02813-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (17).Cravo AS; Bush J; Sharma G; Savioz R; Martin C; Craige S; Walele T A randomised, parallel group study to evaluate the safety profile of an electronic vapour product over 12 weeks. Regul. Toxicol. Pharmacol 2016, 81 Suppl 1, S1–S14. DOI: 10.1016/j.yrtph.2016.10.003. [DOI] [PubMed] [Google Scholar]
  • (18).Walele T; Bush J; Koch A; Savioz R; Martin C; O’Connell G Evaluation of the safety profile of an electronic vapour product used for two years by smokers in a real-life setting. Regul. Toxicol. Pharmacol 2018, 92, 226–238. DOI: 10.1016/j.yrtph.2017.12.010. [DOI] [PubMed] [Google Scholar]
  • (19).Lorkiewicz P; Riggs DW; Keith RJ; Conklin DJ; Xie Z; Sutaria S; Lynch B; Srivastava S; Bhatnagar A Comparison of urinary biomarkers of exposure in humans using electronic cigarettes, combustible cigarettes, and smokeless tobacco. Nicotine Tob. Res 2019, 21 (9), 1228–1238. DOI: 10.1093/ntr/nty089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (20).Lorkiewicz P; Keith R; Lynch J; Jin L; Theis W; Krivokhizhina T; Riggs D; Bhatnagar A; Srivastava S; Conklin DJ Electronic cigarette solvents, JUUL E-liquids, and biomarkers of exposure: In vivo evidence for acrolein and glycidol in e-cig-derived aerosols. Chem. Res. Toxicol 2022, 35 (2), 283–292. DOI: 10.1021/acs.chemrestox.1c00328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (21).Rubinstein ML; Delucchi K; Benowitz NL; Ramo DE Adolescent exposure to toxic volatile organic chemicals from e-cigarettes. Pediatrics 2018, 141 (4), e20173557. DOI: 10.1542/peds.2017-3557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (22).Keith RJ; Fetterman JL; Orimoloye OA; Dardari Z; Lorkiewicz PK; Hamburg NM; DeFilippis AP; Blaha MJ; Bhatnagar A Characterization of volatile organic compound metabolites in cigarette smokers, electronic nicotine device users, dual users, and nonusers of tobacco. Nicotine Tob. Res 2020, 22 (2), 264–272. DOI: 10.1093/ntr/ntz021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (23).Samburova V; Bhattarai C; Strickland M; Darrow L; Angermann J; Son Y; Khlystov A Aldehydes in exhaled breath during e-cigarette vaping: Pilot study results. Toxics 2018, 6 (3). DOI: 10.3390/toxics6030046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (24).Fuller TW; Acharya AP; Meyyappan T; Yu M; Bhaskar G; Little SR; Tarin TV Comparison of bladder carcinogens in the urine of e-cigarette users versus non e-cigarette using controls. Sci. Rep 2018, 8 (1), 507. DOI: 10.1038/s41598-017-19030-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (25).Goniewicz ML; Smith DM; Edwards KC; Blount BC; Caldwell KL; Feng J; Wang L; Christensen C; Ambrose B; Borek N; van Bemmel D; Konkel K; Erives G; Stanton CA; Lambert E; Kimmel HL; Hatsukami D; Hecht SS; Niaura RS; Travers M; Lawrence C; Hyland AJ Comparison of nicotine and toxicant exposure in users of electronic cigarettes and combustible cigarettes. JAMA Netw. Open 2018, 1 (8), e185937. DOI: 10.1001/jamanetworkopen.2018.5937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (26).St Helen G; Liakoni E; Nardone N; Addo N; Jacob P 3rd; Benowitz NL Comparison of systemic exposure to toxic and/or carcinogenic volatile organic compounds (VOC) during vaping, smoking, and abstention. Cancer Prev. Res 2020, 13 (2), 153–162. DOI: 10.1158/1940-6207.CAPR-19-0356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (27).Smith DM; Shahab L; Blount BC; Gawron M; Kosminder L; Sobczak A; Xia B; Sosnoff CS; Goniewicz ML Differences in exposure to nicotine, tobacco-specific nitrosamines, and volatile organic compounds among electronic cigarette users, tobacco smokers, and dual users from three countries. Toxics 2020, 8 (4). DOI: 10.3390/toxics8040088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (28).De Jesus VR; Bhandari D; Zhang L; Reese C; Capella K; Tevis D; Zhu W; Del Valle-Pinero AY; Lagaud G; Chang JT; van Bemmel D; Kimmel HL; Sharma E; Goniewicz ML; Hyland A; Blount BC Urinary biomarkers of exposure to volatile organic compounds from the Population Assessment of Tobacco and Health Study Wave 1 (2013-2014). Int. J. Environ. Res. Public Health 2020, 17 (15). DOI: 10.3390/ijerph17155408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (29).Prokopowicz A; Sobczak A; Szdzuj J; Grygoyc K; Kosmider L Metal concentration assessment in the urine of cigarette smokers who switched to electronic cigarettes: A pilot study. Int. J. Environ. Res. Public Health 2020, 17 (6). DOI: 10.3390/ijerph17061877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (30).Murphy SE; Park S-SL; Thompson EF; Wilkens LR; Patel Y; Stram DO; Le Marchand L Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups. Carcinogenesis 2014, 35, 2526–2533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (31).Carmella SG; Chen M; Han S; Briggs A; Jensen J; Hatsukami DK; Hecht SS Effects of smoking cessation on eight urinary tobacco carcinogen and toxicant biomarkers. Chem. Res. Toxicol 2009, 22 (4), 734–741. DOI: 10.1021/tx800479s. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (32).Chen M; Carmella SG; Li Y; Zhao Y; Hecht SS Resolution and quantitation of mercapturic acids derived from crotonaldehyde, methacrolein, and methyl vinyl ketone in the urine of smokers and nonsmokers. Chem. Res. Toxicol 2020, 33 (2), 669–677. DOI: 10.1021/acs.chemrestox.9b00491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (33).Tevis DS; Willmore A; Bhandari D; Bowman B; Biren C; Kenwood BM; Jacob P; Liu J; Bello K; Hecht SS; Carmella SG; Chen M; Gaudreau E; Bienvenu JF; Blount BC; De Jesus VR Large differences in urinary benzene metabolite S-phenylmercapturic acid quantitation: A comparison of five LC-MS-MS methods. J. Anal. Toxicol 2021, 45 (7), 657–665. DOI: 10.1093/jat/bkaa137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (34).Luo X; Carmella SG; Chen M; Jensen JA; Wilkens LR; Le Marchand L; Hatsukami DK; Murphy SE; Hecht SS Urinary cyanoethyl mercapturic acid, a biomarker of the smoke toxicant acrylonitrile, clearly distinguishes smokers from nonsmokers. Nicotine Tob. Res 2020, 22 (10), 1744–1747. DOI: 10.1093/ntr/ntaa080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (35).Carmella SG; Ming X; Olvera N; Brookmeyer C; Yoder A; Hecht SS High throughput liquid and gas chromatography-tandem mass spectrometry assays for tobacco-specific nitrosamine and polycyclic aromatic hydrocarbon metabolites associated with lung cancer in smokers. Chem. Res. Toxicol 2013, 26 (8), 1209–1217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (36).Liao W; Luo X; Le CT; Chu H; Epstein LH; Yu J; Ahluwalia JS; Thomas JL Analysis of cigarette purchase task instrument data with a left-censored mixed effects model. Exp. Clin. Psychopharmacol 2013, 21 (2), 124–132. DOI: 10.1037/a0031610 From NLM. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (37).Hecht SS; Carmella SG; Kotandeniya D; Pillsbury ME; Chen M; Ransom BW; Vogel RI; Thompson E; Murphy SE; Hatsukami DK Evaluation of toxicant and carcinogen metabolites in the urine of e-cigarette users versus cigarette smokers. Nicotine Tob. Res 2015, 17 (6), 704–709. DOI: 10.1093/ntr/ntu218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (38).Cheng G; Guo J; Carmella SG; Lindgren B; Ikuemonisan J; Niesen B; Jensen J; Hatsukami DK; Balbo S; Hecht SS Increased acrolein-DNA adducts in buccal brushings of e-cigarette users. Carcinogenesis 2022, 43 (5), 437–444. DOI: 10.1093/carcin/bgac026 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (39).Uchiyama S; Senoo Y; Hayashida H; Inaba Y; Nakagome H; Kunugita N Determination of chemical compounds generated from second-generation e-cigarettes using a sorbent cartridge followed by a two-step elution method. Anal. Sci 2016, 32 (5), 549–555. DOI: 10.2116/analsci.32.549. [DOI] [PubMed] [Google Scholar]
  • (40).Ogunwale MA; Li M; Ramakrishnam Raju MV; Chen Y; Nantz MH; Conklin DJ; Fu XA Aldehyde detection in electronic cigarette aerosols. ACS Omega 2017, 2 (3), 1207–1214. DOI: 10.1021/acsomega.6b00489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (41).Farsalinos KE; Kistler KA; Pennington A; Spyrou A; Kouretas D; Gillman G Aldehyde levels in e-cigarette aerosol: Findings from a replication study and from use of a new-generation device. Food Chem. Toxicol 2018, 111, 64–70. DOI: 10.1016/j.fct.2017.11.002. [DOI] [PubMed] [Google Scholar]
  • (42).Farsalinos KE; Voudris V Do flavouring compounds contribute to aldehyde emissions in e-cigarettes? Food Chem. Toxicol 2018, 115, 212–217. DOI: 10.1016/j.fct.2018.02.059. [DOI] [PubMed] [Google Scholar]
  • (43).Urena JF; Ebersol LA; Silakov A; Elias RJ; Lambert JD Impact of atomizer age and flavor on in vitro toxicity of aerosols from a third-generation electronic cigarette against human oral cells. Chem. Res. Toxicol 2020, 33 (10), 2527–2537. DOI: 10.1021/acs.chemrestox.0c00028. [DOI] [PubMed] [Google Scholar]
  • (44).Gillman IG; Pennington ASC; Humphries KE; Oldham MJ Determining the impact of flavored e-liquids on aldehyde production during vaping. Regul. Toxicol. Pharmacol 2020, 112, 104588. DOI: 10.1016/j.yrtph.2020.104588. [DOI] [PubMed] [Google Scholar]
  • (45).Zelinkova Z; Wenzl T Influence of battery power setting on carbonyl emissions from electronic cigarettes. Tob. Induc. Dis 2020, 18, 77. DOI: 10.18332/tid/126406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (46).Uchiyama S; Noguchi M; Sato A; Ishitsuka M; Inaba Y; Kunugita N Determination of thermal decomposition products generated from e-cigarettes. Chem. Res. Toxicol 2020, 33 (2), 576–583. DOI: 10.1021/acs.chemrestox.9b00410. [DOI] [PubMed] [Google Scholar]
  • (47).Belushkin M; Tafin Djoko D; Esposito M; Korneliou A; Jeannet C; Lazzerini M; Jaccard G Selected harmful and potentially harmful constituents levels in commercial e-cigarettes. Chem. Res. Toxicol 2020, 33 (2), 657–668. DOI: 10.1021/acs.chemrestox.9b00470. [DOI] [PubMed] [Google Scholar]
  • (48).Li Y; Burns AE; Tran LN; Abellar KA; Poindexter M; Li X; Madl AK; Pinkerton KE; Nguyen TB Impact of e-liquid composition, coil temperature, and puff topography on the aerosol chemistry of electronic cigarettes. Chem. Res. Toxicol 2021, 34 (6), 1640–1654. DOI: 10.1021/acs.chemrestox.1c00070. [DOI] [PubMed] [Google Scholar]
  • (49).Zhou Y; Irshad H; Dye WW; Wu G; Tellez CS; Belinsky SA Voltage and e-liquid composition affect nicotine deposition within the oral cavity and carbonyl formation. Tob. Control 2021, 30 (5), 485–491. DOI: 10.1136/tobaccocontrol-2020-055619. [DOI] [PubMed] [Google Scholar]
  • (50).Farsalinos KE; Gillman G Carbonyl emissions in e-cigarette aerosol: A systematic review and methodological considerations. Front. Physiol 2017, 8, 1119. DOI: 10.3389/fphys.2017.01119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (51).International Agency for Research on Cancer. Acrolein, Crotonaldehyde, and Arecoline; IARC, 2021. [PubMed] [Google Scholar]
  • (52).International Agency for Research on Cancer. Benzene. In IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, v. 100F: Chemical Agents and Related Occupations, IARC, 2012; pp 249–285. [PMC free article] [PubMed] [Google Scholar]
  • (53).NTP (National Toxicology Program). Report on Carcinogens, Fifteenth Edition; U.S. Department of Health and Human Services, Public Health Service, 2021. DOI: 10.22427/NTP-OTHER-1003. [DOI] [Google Scholar]
  • (54).International Agency for Research on Cancer. Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide (Part 1). In IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 71, Vol. 71; IARC, 1999; pp 43–108. [PMC free article] [PubMed] [Google Scholar]
  • (55).Pankow JF; Kim K; McWhirter KJ; Luo W; Escobedo JO; Strongin RM; Duell AK; Peyton DH Benzene formation in electronic cigarettes. PLoS One 2017, 12 (3), e0173055. DOI: 10.1371/journal.pone.0173055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (56).International Agency for Research on Cancer. Dry Cleaning, Some Chlorinated Solvents and Other Industrial Chemicals. In IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 63, Vol. 63; IARC, 1995; pp 373–391. [PMC free article] [PubMed] [Google Scholar]
  • (57).Larsen ST; Nielsen GD Effects of methacrolein on the respiratory tract in mice. Toxicol. Lett 2000, 114 (1-3), 197–202. [DOI] [PubMed] [Google Scholar]
  • (58).Morgan DL; Price HC; O’Connor RW; Seely JC; Ward SM; Wilson RE; Cunningham MC Upper respiratory tract toxicity of inhaled methylvinyl ketone in F344 rats and B6C3F1 mice. Toxicol. Sci 2000, 58 (1), 182–194. DOI: 10.1093/toxsci/58.1.182. [DOI] [PubMed] [Google Scholar]
  • (59).Chung FL; Tanaka T; Hecht SS Induction of liver tumors in F344 rats by crotonaldehyde. Cancer Res. 1986, 46, 1285–1289. [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supporting info

Table S1. Demographic information for e-cigarette users, non-smokers, and cigarette smokers

Table S2. Levels of biomarkers in the urine of e-cigarette users at each time point.

NIHMS1846935-supplement-supporting_info.docx (187.5KB, docx)

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