The First 10 Years: Reflecting on Opportunities and Challenges of the Tobacco Products Scientific Advisory Committee of the United States Food and Drug Administration.

Introduction: Tobacco control policies have helped to reduce the health, social, and economic burden of commercial tobacco use worldwide. Little is known about the long-term impact of regulatory policies and functioning bodies that make recommendations to inform policies. The Tobacco Products Scientific Advisory Committee (TPSAC) of the U.S. Food and Drug Administration (FDA) was formed in 2009 to evaluate the safety, health, and dependence of tobacco products and provide related advice and recommendations to the FDA and the Secretary of Health and Human Services. This article describes the first 10 years of the TPSAC activities and reflects on the impact of their service on regulatory actions.Methods: We reviewed public documents from the 2010-2019 TPSAC meetings to examine the purposes, TPSAC decisions, public health participation in meetings, and concordance of the TPSAC recommendations with regulatory actions. Meeting agendas, transcripts, public testimony, and presentations were reviewed to obtain this information.Results: Since 2010, the TPSAC held 25 public meetings with 178 speakers who provided oral public testimony. Sixty-four percent of meetings were held from 2010 to 2012, when three congressionally mandated reports were due on the topics of menthol cigarettes, harmful and potentially harmful constituents in tobacco products, and dissolvable tobacco products. Forty-four percent of meetings focused on menthol cigarettes, 32% on modified risk tobacco products, 16% on harmful and potentially harmful constituents, 12% on dissolvable tobacco, and 4% on tobacco addiction/dependence. FDA regulatory actions were largely nonconcordant with voting decisions by TPSAC.Conclusions: The TPSAC has evaluated an enormous amount of science during the first 10 years, but their influence on regulatory policies has been limited. The TPSAC roles and functioning should be reevaluated to determine how TPSAC can better fulfill its mandate to inform the FDA's regulatory decision making, which could ultimately reduce the burden of tobacco use in the United States.

Sugar and Aldehyde Content in Flavored Electronic Cigarette Liquids.

Introduction: Sugars are major constituents and additives in traditional tobacco products, but little is known about their content or related toxins (formaldehyde, acetaldehyde, and acrolein) in electronic cigarette (e-cigarette) liquids. This study quantified levels of sugars and aldehydes in e-cigarette liquids across brands, flavors, and nicotine concentrations (n = 66). Methods: Unheated e-cigarette liquids were analyzed using liquid chromatography mass spectrometry and enzymatic test kits. Generalized linear models, Fisher's exact test, and Pearson's correlation coefficient assessed sugar, aldehyde, and nicotine concentration associations. Results: Glucose, fructose and sucrose levels exceeded the limits of quantification in 22%, 53% and 53% of the samples. Sucrose levels were significantly higher than glucose [χ2(1) = 85.9, p < .0001] and fructose [χ2(1) = 10.6, p = .001] levels. Formaldehyde, acetaldehyde, and acrolein levels exceeded the limits of quantification in 72%, 84%, and 75% of the samples. Acetaldehyde levels were significantly higher than formaldehyde [χ2(1) = 11.7, p = .0006] and acrolein [χ2(1) = 119.5, p < .0001] levels. Differences between nicotine-based and zero-nicotine labeled e-cigarette liquids were not statistically significant for sugars or aldehydes. We found significant correlations between formaldehyde and fructose (-0.22, p = .004) and sucrose (-0.25, p = .002) and acrolein and fructose (-0.26, p = .0006) and sucrose (-0.21, p = .0006). There were no significant correlations between acetaldehyde and any of the sugars or any of the aldehydes and glucose. Conclusions: Sugars and related aldehydes were identified in unheated e-cigarette liquids and their composition may influence experimentation in naïve users and their potential toxicity. Implications: The data can inform the regulation of specific flavor constituents in tobacco products as a strategy to protect young people from using e-cigarettes, while balancing FDA's interest in how these emerging products could potentially benefit adult smokers who are seeking to safely quit cigarette smoking. The data can also be used to educate consumers about ingredients in products that may contain nicotine and inform future FDA regulatory policies related to product standards and accurate and comprehensible labeling of e-cigarette liquids.

Warning Statements and Safety Practices Among Manufacturers and Distributors of Electronic Cigarette Liquids in the United States.

Introduction: Prior to the US Food and Drug Administration's (FDA) regulation of electronic cigarettes and warning statements related to nicotine addiction, there was no critical examination of manufacturer/distributor voluntary practices that could potentially inform FDA actions aimed to protect consumers. This study examined the content of warning statements and safety characteristics of electronic cigarette liquid bottles using a national sample. Methods: Research staff randomly selected four electronic cigarette liquid manufacturers/distributors from four US geographic regions. Staff documented the characteristics of product packaging and content of warning statements on 147 electronic cigarette liquids (0-30 mg/ml of nicotine) purchased online from 16 manufacturers/distributors in April of 2016. Results: Data showed that 97.9% of the electronic cigarette liquid bottles included a warning statement, most of which focused on nicotine exposure rather than health. Only 22.4% of bottles used a warning statement that indicated the product "contained nicotine." Of bottles that advertised a nicotine-based concentration of 12 mg/ml, 26% had a warning statements stated that the product "contains nicotine." None of the statements that indicated that the product "contained nicotine" stated that nicotine was "addictive." All bottles had a safety cap and 12% were in plastic shrink-wrap. Fifty-six percent of the websites had a minimum age requirement barrier that prevented under-aged persons from entering. Conclusions: Most manufacturers/distributors printed a warning statement on electronic cigarette liquid bottles, but avoided warning consumers about the presence and the addictiveness of nicotine. Studies are needed to examine manufacturer/distributor modifications to product packaging and how packaging affects consumer behaviors. Implications: These data can inform future FDA requirements related to the packaging and advertising of e-cigarette liquids; regulation related to the content of warning statements, including exposure warning statements, which are not currently mandated; and requirements on websites or language on packaging to help manufacturers adhere to the minimum age of purchase regulation. The data can also be used to help FDA develop additional guidance on the framing of statements on packaging that helps consumers make informed decisions about purchasing the product or protecting young people from use or unintentional exposure to the product.

Why We Must Continue to Investigate Menthol's Role in the African American Smoking Paradox.

BACKGROUND: The disproportionate burden of tobacco use among African Americans is largely unexplained. The unexplained disparities, referred to as the African American smoking paradox, includes several phenomena. Despite their social disadvantage, African American youth have lower smoking prevalence rates, initiate smoking at older ages, and during adulthood, smoking rates are comparable to whites. Smoking frequency and intensity among African American youth and adults are lower compared to whites and American Indian and Alaska Natives, but tobacco-caused morbidity and mortality rates are disproportionately higher. Disease prediction models have not explained disease causal pathways in African Americans. It has been hypothesized that menthol cigarette smoking, which is disproportionately high among African Americans, may help to explain several components of the African American smoking paradox. PURPOSE: This article provides an overview of the potential role that menthol plays in the African American smoking paradox. We also discuss the research needed to better understand this unresolved puzzle. METHODS: We examined prior synthesis reports and reviewed the literature in PubMed on the menthol compound and menthol cigarette smoking in African Americans. RESULTS: The pharmacological and physiological effects of menthol and their interaction with biological and genetic factors may indirectly contribute to the disproportionate burden of cigarette use and diseases among African Americans. CONCLUSIONS: Future studies that examine taste sensitivity, the menthol compound, and their effects on smoking and chronic disease would provide valuable information on how to reduce the tobacco burden among African Americans. IMPLICATIONS: Our study highlights four counterintuitive observations related to the smoking risk profiles and chronic disease outcomes among African Americans. The extant literature provides strong evidence of their existence and shows that long-standing paradoxes have been largely unaffected by changes in the social environment. African Americans smoke menthols disproportionately, and menthol's role in the African American smoking paradox has not been thoroughly explored. We propose discrete hypotheses that will help to explain the phenomena and encourage researchers to empirically test menthol's role in smoking initiation, transitions to regular smoking and chronic disease outcomes in African Americans.

Nicotine Metabolism in Young Adult Daily Menthol and Nonmenthol Smokers.

INTRODUCTION: Menthol cigarette smoking may increase the risk for tobacco smoke exposure and inhibit nicotine metabolism in the liver. Nicotine metabolism is primarily mediated by the enzyme CYP2A6 and the nicotine metabolite ratio (NMR = trans 3' hydroxycotinine/cotinine) is a phenotypic proxy for CYP2A6 activity. No studies have examined differences in this biomarker among young adult daily menthol and nonmenthol smokers. This study compares biomarkers of tobacco smoke exposure among young adult daily menthol and nonmenthol smokers. METHODS: Saliva cotinine and carbon monoxide were measured in a multiethnic sample of daily smokers aged 18-35 (n = 186). Nicotine, cotinine, the cotinine/cigarette per day ratio, trans 3' hydroxycotinine, the NMR, and expired carbon monoxide were compared. RESULTS: The geometric means for nicotine, cotinine, and the cotinine/cigarette per day ratio did not significantly differ between menthol and nonmenthol smokers. The NMR was significantly lower among menthol compared with nonmenthol smokers after adjusting for race/ethnicity, gender, body mass index, and cigarette smoked per day (0.19 vs. 0.24, P = .03). White menthol smokers had significantly higher cotinine/cigarettes per day ratio than white nonmenthol smokers in the adjusted model. White menthol smokers had a lower NMR in the unadjusted model (0.24 vs. 0.31, P = .05) and the differences remained marginally significant in the adjusted model (0.28 vs. 0.34, P = .06). We did not observe these differences in Native Hawaiians and Filipinos. CONCLUSIONS: Young adult daily menthol smokers have slower rates of nicotine metabolism than nonmenthol smokers. Studies are needed to determine the utility of this biomarker for smoking cessation treatment assignments.

Biomarkers of tobacco smoke exposure in racial/ethnic groups at high risk for lung cancer.

OBJECTIVES: We examined biomarkers of tobacco smoke exposure among Native Hawaiians, Filipinos, and Whites, groups that have different lung cancer risk. METHODS: We collected survey data and height, weight, saliva, and carbon monoxide (CO) levels from a sample of daily smokers aged 18-35 (n = 179). Mean measures of nicotine, cotinine, cotinine/cigarettes per day ratio, trans 3' hydroxycotinine, the nicotine metabolite ratio (NMR), and expired CO were compared among racial/ethnic groups. RESULTS: The geometric means for cotinine, the cotinine/cigarettes per day ratio, and CO did not significantly differ among racial/ethnic groups in the adjusted models. After adjusting for gender, body mass index, menthol smoking, Hispanic ethnicity, and number of cigarettes smoked per day, the NMR was significantly higher among Whites than among Native Hawaiians and Filipinos (NMR = 0.33, 0.20, 0.19, P ≤ .001). The NMR increased with increasing White parental ancestry. The NMR was not significantly correlated with social-environmental stressors. CONCLUSIONS: Racial/ethnic groups with higher rates of lung cancer had slower nicotine metabolism than Whites. The complex relationship between lung cancer risk and nicotine metabolism among racial/ethnic groups needs further clarification.

Menthol cigarette smoking and obesity in young adult daily smokers in Hawaii.

This study investigates 1) the relationship between menthol cigarette smoking and obesity and 2) the association of body mass index with the nicotine metabolite ratio among menthol and non-menthol daily smokers aged 18-35 (n = 175). A brief survey on smoking and measures of height and weight, carbon monoxide, and saliva samples were collected from participants from May to December 2013 in Honolulu, Hawaii. Multiple regression was used to estimate differences in body mass index among menthol and non-menthol smokers and the association of menthol smoking with obesity. We calculated the log of the nicotine metabolite ratio to examine differences in the nicotine metabolite ratio among normal, overweight, and obese smokers. Sixty-eight percent of smokers used menthol cigarettes. Results showed that 62% of normal, 54% of overweight, and 91% of obese smokers used menthol cigarettes (p = .000). The mean body mass index was significantly higher among menthol compared with non-menthol smokers (29.4 versus 24.5, p = .000). After controlling for gender, marital status, educational attainment, employment status, and race/ethnicity, menthol smokers were more than 3 times as likely as non-menthol smokers to be obese (p = .04). The nicotine metabolite ratio was significantly lower for overweight menthol smokers compared with non-menthol smokers (.16 versus .26, p = .02) in the unadjusted model, but was not significant after adjusting for the covariates. Consistent with prior studies, our data show that menthol smokers are more likely to be obese compared with non-menthol smokers. Future studies are needed to determine how flavored tobacco products influence obesity among smokers.