A review of the toxicity of ingredients in e-cigarettes, including those ingredients having the FDA's "Generally Recognized as Safe (GRAS)" regulatory status for use in food.

INTRODUCTION: Some firms and marketers of electronic cigarettes (e-cigarettes; a type of electronic nicotine delivery system (ENDS)) and refill liquids (e-liquids) have made claims about the safety of ingredients used in their products based on the term "GRAS or Generally Recognized As Safe" (GRAS). However, GRAS is a provision within the definition of a food additive under section 201(s) (21 U.S.C. 321(s)) of the U.S. Federal Food Drug and Cosmetic Act (FD&C Act). Food additives and GRAS substances are by the FD&C Act definition intended for use in food, thus safety is based on oral consumption; the term GRAS cannot serve as an indicator of the toxicity of e-cigarette ingredients when aerosolized and inhaled (i.e., vaped). There is no legal or scientific support for labeling e-cigarette product ingredients as "GRAS". This review discusses our concerns with the GRAS provision being applied to e-cigarette products and provides examples of chemical compounds that have been used as food ingredients but have been shown to lead to adverse health effects when inhaled. The review provides scientific insight into the toxicological evaluation of e-liquid ingredients and their aerosols to help determine the potential respiratory risks associated with their use in e-cigarettes. IMPLICATIONS: The rise in prevalence of e-cigarette use and emerging evidence of adverse effects, particularly on lung health, warrant assessing all aspects of e-cigarette toxicity. One development is manufacturers' stated or implied claims of the safety of using e-cigarette products containing ingredients determined to be "Generally Recognized As Safe" (GRAS) for use in food. Such claims, typically placed on e-cigarette product labels and used in marketing, are unfounded, as pointed out by the United States Food and Drug Administration (FDA)1 and the Flavor and Extract Manufacturers Association (FEMA)2. Assessment of inhalation health risks of all ingredients used in e-liquids, including those claimed to be GRAS, is warranted.

Chemical and physiological interactions between e-liquid constituents: cause for concern?

Studies of Electronic Nicotine Delivery Systems (ENDS) toxicity have largely focused on individual components such as flavour additives, base e-liquid ingredients (propylene glycol, glycerol), device characteristics (eg, model, components, wattage), use behaviour, etc. However, vaping involves inhalation of chemical mixtures and interactions between compounds can occur that can lead to different toxicities than toxicity of the individual components. Methods based on the additive toxicity of individual chemical components to estimate the health risks of complex mixtures can result in the overestimation or underestimation of exposure risks, since interactions between components are under-investigated. In the case of ENDS, the potential of elevated toxicity resulting from chemical reactions and interactions is enhanced due to high operating temperatures and the metallic surface of the heating element. With the recent availability of a wide range of e-liquid constituents and popularity of do-it-yourself creation of e-liquid mixtures, the need to understand chemical and physiological impacts of chemical combinations in ENDS e-liquids and aerosols is immediate. There is a significant current knowledge gap concerning how specific combinations of ENDS chemical ingredients result in synergistic or antagonistic interactions. This commentary aims to review the current understanding of chemical reactions between e-liquid components, interactions between additives, chemical reactions that occur during vaping and aerosol properties and biomolecular interactions, all of which may impact physiological health.

Emerging ENDS products and challenges in tobacco control toxicity research.

Electronic nicotine delivery systems (ENDS) continue to rapidly evolve. Current products pose unique challenges and opportunities for researchers and regulators. This commentary aims to highlight research gaps, particularly in toxicity research, and provide guidance on priority research questions for the tobacco regulatory community. Disposable flavoured ENDS have become the most popular device class among youth and may contain higher nicotine levels than JUUL devices. They also exhibit enhanced harmful and potentially harmful constituents production, contain elevated levels of synthetic coolants and pose environmental concerns. Synthetic nicotine and flavour capsules are innovations that have recently enabled the circumvention of Food and Drug Administration oversight. Coil-less ENDS offer the promise of delivering fewer toxicants due to the absence of heating coils, but initial studies show that these products exhibit similar toxicological profiles compared with JUULs. Each of these topic areas requires further research to understand and mitigate their impact on human health, especially their risks to young users.

Urinary metabolites of furan in waterpipe tobacco smokers compared to non-smokers in home settings in the US.

OBJECTIVES: Determine uptake of furan, a potential human carcinogen, in waterpipe tobacco (WPT) smokers in home settings. METHODS: We analysed data from a US convenience sample of 50 exclusive WPT smokers, mean age 25.3 years, and 25 non-smokers, mean age 25.5 years. For WPT smokers, data were collected at a home visit by research assistants during which participants smoked one WPT head of one brand for a mean of 33.1 min in their homes. Research assistants provided and prepared a WP for participants by weighing and loading 10 g of WPT in the WP head. At the completion of the smoking session, research assistants measured the remaining WPT. Cotinine and six furan metabolites were quantified in first morning urine samples provided on 2 consecutive days for non-smokers, and on the morning of a WPT smoking session and on the following morning for smokers. RESULTS: WPT smokers consumed a mean of 2.99 g WPT. In WPT smokers, urinary cotinine levels increased significantly 26.1 times the following morning; however, urinary metabolites of furan did not increase significantly. Compared to non-smokers, 2 furan metabolites, N-acetyl-S-[1-(5-acetylamino-5-carboxylpentyl)-1H-pyrrol-3-yl]-L-cysteine and N-acetyl-S-[1-(5-amino-5-carboxypentyl)-1H-pyrrol-3-yl]-L-cysteine sulfoxide, were significantly higher in WPT smokers in pre and in post WPT smoking levels. CONCLUSIONS: To enable a more rigorous assessment of furan exposure from WPT smoking, future research should determine furan concentrations in WPT smoke, quantify furan metabolites from users of various WPT brands; and extend the investigation to social settings where WPT smoking is habitually practiced.

College Student Beliefs and Behavior Regarding Sharing When Smoking Hookahs.

Objectives: We examined college students' beliefs and behavior regarding sharing when smoking a hookah, a practice that may involve substantial risk of disease transmission. Methods: We carried out a cross-sectional Web-based survey of undergraduate ever users of hookah (N = 970) at a US university in 2007. Results: Hookah sharing started at initiation of hookah use. The first-time participants smoked hookah, 96.9% shared it, and 97.5% were with friends either in a hookah lounge (59.5%) or at a friend's home (30%). Participants shared a hookah when they first smoked it because sharing was acceptable with friends, family, or trusted others, normative etiquette, not problematic/harmful, cheaper, or the only smoking option. Participants did not use a mouth tip when they first smoked a hookah because it is not necessary with friends/family, there was no tip available, they were unaware of tips, or did not want to use one. Conclusions: Overwhelmingly, hookah sharing started at smoking initiation. Efforts are needed to create an environment in which sharing hookah practices are less acceptable such as increasing awareness of potential health risks of sharing, particularly among youth, and providing disposable hoses, disposable mouth tips, and proper hookah device cleaning practices in private and public hookah venues settings.

Levels of Urine Cotinine from Hookah Smoking and Exposure to Hookah Tobacco Secondhand Smoke in Hookah Lounges and Homes.

BACKGROUND: Nicotine, an addictive drug, is present in all forms of tobacco products, including hookah tobacco, which is not yet regulated in the United States. OBJECTIVES: This study aimed to investigate the uptake of nicotine in hookah smokers and non-smokers exposed to secondhand smoke (SHS) at indoor hookah social events in natural settings where hookah tobacco was smoked exclusively. PATIENTS AND METHODS: We quantified cotinine, a metabolite of nicotine, in the urine of 105 hookah smokers and 103 non-smokers. Participants provided spot urine samples the morning of and the morning after attending an indoor hookah-only smoking social event at a hookah lounge or in a private home. RESULTS: Following a social event where exclusively hookah tobacco was smoked, urinary cotinine levels increased significantly 8.5 times (geometric mean (GM): 16.0 ng/mg to 136.1 ng/mg) among hookah smokers, and 2.5 times (GM: 0.4 ng/mg to 1.0 ng/mg) among non-smokers exposed exclusively to hookah tobacco SHS. Among hookah smokers, the highest increase in urinary cotinine levels post a hookah event was found in occasional hookah smokers in which GM levels increased significantly 31.2 times post smoking (from 2.0 ng/mg to 62.3 ng/mg). Reported reasons for preference to smoke hookah at home by hookah smokers who attended a hookah social event in a private home included recreational purposes, socializing with friends and family, 'Me' time and relaxing at home, more comfortable to smoke hookah at home, owning a hookah and hookah tobacco, eating and drinking while smoking hookah, and saving money by smoking at home and not going to hookah lounges. CONCLUSIONS: Hookah tobacco smoke is a source of substantial nicotine exposure. Our results call for protecting hookah smokers' and non-smokers' health by requiring accurate hookah tobacco labels, raising taxes on hookah tobacco, reducing the spread of hookah lounges, and encouraging voluntary bans on smoking hookah tobacco in private homes.

Acrolein Exposure in Hookah Smokers and Non-Smokers Exposed to Hookah Tobacco Secondhand Smoke: Implications for Regulating Hookah Tobacco Products.

Introduction: Acrolein is a highly ciliatoxic agent, a toxic respiratory irritant, a cardiotoxicant, and a possible carcinogen present in tobacco smoke including hookah tobacco. Methods: 105 hookah smokers and 103 non-smokers attended exclusively hookah smoking social events at either a hookah lounge or private home, and provided urine samples the morning of and the morning after the event. Samples were analyzed for 3-hydroxypropylmercapturic acid (3-HPMA), a metabolite of acrolein. Results: Geometric mean (GM) urinary 3-HPMA levels in hookah smokers and non-smokers exposed to secondhand smoke (SHS) increased significantly, 1.41 times, 95% CI = 1.15 to 1.74 and 1.39 times, 95% CI = 1.16 to 1.67, respectively, following a hookah social event. The highest increase (1.68 times, 95% CI = 1.15 to 2.45; p = 0.007) in 3-HPMA post a hookah social event was among daily hookah smokers (GM, from 1991 pmol/mg to 3348 pmol/mg). Pre-to-post event change in urinary 3-HPMA was significantly positively correlated with pre-to-post event change in urinary cotinine among hookah smokers at either location of hookah event, (ρ = 0.359, p = 0.001), and among non-smokers in hookah lounges (ρ = 0.369, p = 0.012). Conclusions: Hookah tobacco smoke is a source of acrolein exposure. Findings support regulating hookah tobacco products including reducing humectants and sugar additives, which are precursors of acrolein under certain pyrolysis conditions. We suggest posting health warning signs for indoor smoking in hookah lounges, and encouraging voluntary bans of smoking hookah tobacco in private homes. Implications: Our study is the first to quantify the increase in acrolein exposure in hookah smokers and non-smokers exposed to exclusively hookah tobacco SHS at hookah social events in homes or hookah lounges. Our findings provide additional support for regulating hookah tobacco product content, protecting non-smokers' health by posting health warning signs for indoor smoking in hookah lounges, and encouraging home bans on hookah tobacco smoking to safeguard vulnerable residents.

Urinary NNAL in hookah smokers and non-smokers after attending a hookah social event in a hookah lounge or a private home.

Tobacco smoking and exposure to tobacco secondhand smoke (SHS) can cause lung cancer. We determined uptake of NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone), a tobacco specific potent pulmonary carcinogen, in hookah smokers and non-smokers exposed to hookah tobacco SHS. We analyzed data from a community-based convenience sample of 201 of adult (aged ≥18 years) exclusive hookah smokers (n = 99) and non-smokers (n = 102) residing in San Diego County, California. Participants spent an average of three consecutive hours indoors, in hookah lounges or private homes, where hookah tobacco was smoked exclusively. Total NNAL [the sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides], the major metabolites of NNK, were quantified in spot urine samples provided the morning of and the morning after attending a hookah event. Among hookah smokers urinary NNAL increased significantly (p<0.001) following a hookah social event; the geometric mean doubled, from 1.97 to 4.16 pg/mg. Among non-smokers the increase was not significant (p = 0.059). Post hookah event urinary NNAL levels were highest in daily hookah smokers, and significantly higher than in non-daily smokers or non-smokers (GM: 14.96 pg/mg vs. 3.13 pg/mg and 0.67 pg/mg, respectively). For both hookah smokers and non-smokers, pre-to-post event change in urinary NNAL was not significantly different between hookah lounges and homes. We suggest posting health warning signs inside hookah lounges, and encouraging voluntary bans of smoking hookah tobacco in private homes.

Hookah Smoking and Facilitators/Barriers to Lounge Use among Students at a US University.

OBJECTIVE: To examine hookah tobacco use, hookah lounge attendance, and facilitators and barriers to hookah lounge attendance. METHODS: A cross-sectional Web-based survey of a random sample of 1332 undergraduate students (Mean Age = 21.2 years) attending a United States university. RESULTS: The majority of respondents (72.8%) had ever smoked hookah tobacco, and 28% of those had ever smoked during adolescence. The majority of ever hookah smokers (81.5%) and a portion of never hookah smokers (20%) had ever been to a hookah lounge. The adjusted odds of ever visiting a hookah lounge were 2.1 times higher among participants who reported that the closest hookah lounge to the university was < 5 miles away than those who reported that the closest hookah lounge was ≥ 5 miles away. Facilitators of visiting hookah lounges included friends and close proximity of hookah lounges to campus; barriers included cost of smoking hookah, crowded lounges, and having to be 18 years old. CONCLUSION: Youth are vulnerable to experimenting with hookah tobacco smoking. Hookah lounges provide patrons the opportunity to smoke hookah tobacco with smoker and non-smoker friends in entertaining settings. Our findings suggest that zoning laws and anti-hookah smoking legislation may help curb hookah uptake by prohibiting hookah lounges from opening in close proximity to universities, reducing the density of hookah lounges in cities, and raising the admission age for hookah lounges to 21 years.

Arab-American Hookah Smokers: Initiation, and Pros and Cons of Hookah Use.

OBJECTIVES: To examine initiation, pros and cons of hookah tobacco smoking among Arab Americans. METHODS: In this descriptive cross-sectional study, we recruited a community-based convenience sample of 458 adult Arab-American hookah smokers, mean age 28.4 years, who completed self-administered questionnaires. RESULTS: Irrespective of sex, most participants initiated hookah tobacco use by young adulthood in private homes or hookah lounges influenced by friends and family. Women initiated hookah use later than men. Ever dual smokers (hookah smokers who ever smoked a cigarette) initiated hookah use later than cigarettes; however, early hookah initiators < 18 years initiated hookah and cigarettes concurrently. Participants enjoyed the flavors of hookah tobacco, and complained about coughing, dizziness, and headaches. CONCLUSIONS: Early and late initiation of hookah tobacco use warrant prevention programs targeting the youth and older adults in communities, colleges, and middle and high schools that include health education campaigns, and encouragement of voluntary smokefree home rules. Tobacco control policies aimed to prevent initiation of hookah use should include regulation of hookah tobacco flavors, and should target the physical environments in neighborhoods, especially around schools and colleges, to reduce the proliferation of hookah lounges. Dual hookah tobacco and cigarette use warrant continuous monitoring.

Benzene uptake in Hookah smokers and non-smokers attending Hookah social events: regulatory implications.

BACKGROUND: Benzene is a human hematotoxicant and a leukemogen that causes lymphohematopoietic cancers, especially acute myelogenous leukemia. We investigated uptake of benzene in hookah smokers and non-smokers attending hookah social events in naturalistic settings where hookah tobacco was smoked exclusively. METHODS: We quantified S-phenylmercapturic acid (SPMA), a metabolite of benzene, in the urine of 105 hookah smokers and 103 non-smokers. Participants provided spot urine samples the morning of and the morning after attending an indoor hookah-only smoking social event at a hookah lounge or in a private home. RESULTS: Urinary SPMA levels in hookah smokers increased significantly following a hookah social event (P < 0.001). This increase was 4.2 times higher after hookah lounge events (P < 0.001) and 1.9 times higher after home events (P = 0.003). In non-smokers, urinary SPMA levels increased 2.6 times after hookah lounge events (P = 0.055); however, similar urinary SPMA levels were detected before and after home events, possibly indicating chronic exposure to benzene (P = 0.933). CONCLUSIONS: Our data provide the first evidence for uptake of benzene in hookah smokers and non-smokers exposed to hookah tobacco secondhand smoke at social events in private homes compared with their counterparts in hookah lounges. Hookah tobacco smoke is a source of benzene exposure, a risk factor for leukemia. IMPACT: Because there is no safe level of exposure to benzene, our results call for interventions to reduce or prevent hookah tobacco use, regulatory actions to limit hookah-related exposure to toxicants including benzene, initiate labeling of hookah-related products, and include hookah smoking in clean indoor air legislation.

Children's exposure to secondhand and thirdhand smoke carcinogens and toxicants in homes of hookah smokers.

INTRODUCTION: We examined homes of hookah-only smokers and nonsmokers for levels of indoor air nicotine (a marker of secondhand smoke) and indoor surface nicotine (a marker of thirdhand smoke), child uptake of nicotine, the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and the toxicant acrolein by analyzing their corresponding metabolites cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and NNAL-glucuronides (total NNAL) and 3-hydroxypropylmercapturic acid. METHODS: Data were collected at 3 home visits during a 7-day study period from a convenience sample of 24 households with a child 5 years or younger. Three child urine samples and 2 air and surface samples from the living room and the child bedroom were taken in homes of nonsmokers (n = 5) and hookah-only smokers (n = 19) comprised of daily hookah smokers (n = 8) and weekly/monthly hookah smokers (n = 11). RESULTS: Nicotine levels in indoor air and on surfaces in the child bedrooms in homes of daily hookah smokers were significantly higher than in homes of nonsmokers. Uptake of nicotine, NNK, and acrolein in children living in daily hookah smoker homes was significantly higher than in children living in nonsmoker homes. Uptake of nicotine and NNK in children living in weekly/monthly hookah smoker homes was significantly higher than in children living in nonsmoker homes. CONCLUSIONS: Our data provide the first evidence for uptake of nicotine, the tobacco-specific lung carcinogen NNK, and the ciliatoxic and cardiotoxic agent acrolein in children living in homes of hookah smokers. Our findings suggest that daily and occasional hookah use in homes present a serious, emerging threat to children's long-term health.