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.

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.

Systemic biomarkers of inflammation, oxidative stress and tissue injury and repair among waterpipe, cigarette and dual tobacco smokers.

BACKGROUND: Waterpipe tobacco (WPT) smoking is associated with deleterious effects on cardio-pulmonary systems which may have adverse repercussions in pathophysiology and progression of chronic lung and cardiovascular diseases. We compared the biomarkers of systemic inflammation, lipid mediators, injury/repair and oxidative stress between groups of non-smokers (NS), exclusive WPT smokers (WPS), exclusive cigarette smokers (CS) and dual WPS and CS (DS). METHODS: Two cohorts were recruited. Cohort I consisted of WPS (n=12), CS (n=26), DS (n=10) and NS (n=25). Cohort II consisted of WPS (n=33) and NS (n=24). Plasma and urine samples were collected and analysed for various systemic biomarkers. RESULTS: Compared with NS, plasma levels of inflammatory mediators (interleukin (IL)-6, IL-8, IL1ß and tumor necrosis factor-α) were significantly higher in WPS and CS, and were further augmented in DS. Endothelial biomarkers (intracellular adhesion molecule-1, prostaglandin E-2 and metalloproteinase-9) were significantly higher in CS. Most notably, pro-resolving lipid mediator (resolvin E1) and biomarkers of immunity, tissue injury, and repair were significantly lower in WPS and CS. Urinary levels of 8-isoprostane were significantly higher in all smoking groups in cohort I, while 8-isoprostane, myeloperoxidase, receptor for advanced glycation end products (RAGE), En-RAGE and matrix metalloproteinase-9 were significantly higher in all smoking groups in cohort II. CONCLUSIONS: Biomarkers of inflammation, oxidative stress, immunity, tissue injury and repair were elevated in WPS and CS groups. Furthermore, concurrent use of WPT and cigarettes is more harmful than cigarette or WPT smoking alone. These data may help inform the public and policy-makers about the dangers of WPT smoking and dual use of tobacco products.

Effect of electric heating and ice added to the bowl on mainstream waterpipe semivolatile furan and other toxicant yields.

OBJECTIVES: We examined mainstream total particulate matter, nicotine, cotinine, menthol, pyrene, carbon monoxide (CO) and semivolatile furan yields from a commercial waterpipe with two methods for heating the tobacco, quick-light charcoal (charcoal) and electric head (electric) and two water bowl preparations: with (ice) and without ice (water). METHODS: Emissions from a single brand of popular waterpipe tobacco (10 g) were generated using machine smoking according to a two-stage puffing regimen developed from human puffing topography. Tobacco and charcoal consumption were calculated for each machine smoking session as mass lost, expressed as a fraction of presmoking mass. RESULTS: The heating method had the greatest effect on toxicant yields. Electric heating resulted in increases in the fraction of tobacco consumed (2.4 times more, p<0.0001), mainstream nicotine (1.4 times higher, p=0.002) and semivolatile furan yields (1.4 times higher, p<0.03), and a decrease in mainstream CO and pyrene yields (8.2 and 2.1 times lower, respectively, p<0.001) as compared with charcoal. Adding ice to the bowl resulted in higher furan yields for electric heating. Menthol yields were not different across the four conditions and averaged 0.16±0.03 mg/session. 2-Furaldehyde and 5-(hydroxymethyl)-2-furaldehyde yields were up to 230 and 3900 times higher, respectively, than those reported for cigarettes. CONCLUSION: Waterpipe components used to heat the tobacco and water bowl preparation can significantly affect mainstream toxicant yields. Mainstream waterpipe tobacco smoke is a significant source of inhalation exposure to semivolatile furans with human carcinogenic and mutagenic potential. These data highlight the need for acute and chronic inhalation toxicity data for semivolatile furans and provide support for the establishment of limits governing sugar additives in waterpipe tobacco and educational campaigns linking waterpipe tobacco smoking behaviours with their associated harm.

Waterpipe device cleaning practices and disposal of waste associated with waterpipe tobacco smoking in homes in the USA.

OBJECTIVES: To quantify postsmoking waterpipe tobacco (WPT) waste and describe postsmoking waterpipe (WP) device cleaning practices and disposal of associated waste in home settings. METHODS: We analysed data from a US convenience sample of 50 exclusive WPT smokers, mean age 25.3 years. Data were collected at a home visit during which participants smoked one WPT head and completed a self-administered questionnaire on WP cleaning practices and disposal of waste associated with WPT use. Research assistants provided and prepared a WP for participants by weighing and loading 10 g of WPT in the WP head and placing 470 mL of water in the WP bowl. At the completion of the smoking session, research assistants measured the remaining WPT and water. Descriptive analyses were performed. RESULTS: Of the 10 g of fresh WPT used for each smoking session, 70.1% (mean=7.01 g) was discarded postsmoking as waste; for each 470 mL of water used in the WP bowl, 94.3% (mean=443 mL) was discarded. WP device cleaning practices ranged from never cleaning the device to cleaning it after each smoking session. Respondents reported discarding smoked WPT residue in the trash (81.6%) or the kitchen sink (14.3%) and discarding postsmoking charcoal in the trash (57.6%), the kitchen sink (27.3%) or backyard soil (9.1%). Respondents reported discarding smoked WP water in the kitchen sink (76.5%), bathroom sink (14.7%), toilet (2.9%) and backyard soil (5.9%). CONCLUSIONS: Interventions and regulations are needed to inform proper WP device cleaning practices and disposal of waste associated with WPT use. TRIAL REGISTRATION NUMBER: NCT03253653.

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.