Effect of menthol flavor in cigarettes on addiction and toxicant exposure
Open Access
- Author:
- Lin, Wenxue
- Graduate Program:
- Epidemiology (PhD)
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- April 27, 2022
- Committee Members:
- Duanping Liao, Professor in Charge/Director of Graduate Studies
John Hayes, Outside Unit Member
Joshua Muscat, Co-Chair, Major Member & Dissertation Advisor
Junjia Zhu, Outside Field Member
John Richie, Co-Chair, Major Member & Dissertation Advisor - Keywords:
- Menthol
cigarettes
carcinogen
biomarkers
NHANES
very low nicotine content cigarette - Abstract:
- The United States Food and Drug Administration (FDA) is considering two tobacco product standards in cigarettes including banning menthol and reducing nicotine content. In April 2022, FDA proposed product standards to prohibit menthol as a characterizing flavor in cigarettes. The overall goal of this dissertation is to provide novel information on whether menthol in cigarettes modifies the addiction potential in cigarettes and exposure to toxic constituents. While the health effects of menthol have been studies for decades, there remains unanswered questions on aspects of its effects. These include whether menthol affects exposure to tobacco smoke carcinogens and nicotine metabolism. Menthol cigarette smoking may impact nicotine metabolite ratio (NMR) and facilitate exposure to tobacco smoke. Few studies have examined the differences in urine NMR and biomarkers of tobacco smoke between menthol and non-menthol cigarette smokers. We used data from the National Health and Nutrition Examination Survey (NHANES) 2015-2016 special sample to compute urine NMR by menthol status. NHANES 2015-2016 special sample data were also used to compare markers of FDA’s 26 Harmful and Potentially Harmful Constituents (HPHCs) in tobacco smoke. These markers include urinary metabolites of polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs) and metals. Urinary metabolites of 7 PAHs, 15 VOCs and 4 metal biomarkers were compared between exclusive menthol (n=162) and non-menthol (n=189) cigarette smokers. Multivariable analysis was conducted on creatinine-adjusted concentrations. We found that adjusted geometric means (GMs) of urine NMR were 1.8 and 1.6 for menthol and non-menthol cigarette smokers, respectively. There was no difference in NMR by cigarette flavor (Ratio of GMs [Menthol/Non-menthol]: 1.1; 95% CI: 0.8,1.6; p>0.1). Menthol did not affect the nicotine metabolite ratio in urine. There were no significant differences in cotinine levels and in 22 of the HPHCs. Among the metabolites of PAHs, the levels of 1-hydroxyphenanthrene were about 16% lower in menthol smokers. Among the metabolites of VOCs, menthol cigarette smokers presented significantly lower concentrations of acrylamide (115.6 µg/g creatinine vs.154.6 µg/g creatinine; Ratio of GMs [95% CI]: 0.7 [0.6,0.9]; p-value: 0.02), N, N-dimethylformamide and acrylonitrile. Menthol and non-menthol smokers presented similar levels of metals. In addition to menthol flavor, nicotine reduction is another possible strategy considered by FDA to decrease prevalence of cigarette smoking. In 2018, the U.S. FDA issued an Advanced Notice of Proposed Rulemaking (ANPRM) to reduce nicotine in tobacco products to make them minimally addictive or nonaddictive. The present dissertation evaluated whether menthol modifies the treatment effect of a gradual reduction from fully nicotinized cigarettes to very low nicotine cigarette (VLNC 0.4mg/cig) over a 5-month period of time. Two parallel randomized clinical trials of gradually reduced nicotine in cigarettes from 11.6 mg down to 0.2 mg nicotine (very low nicotine content; VLNC) over an 18-week period in smokers with low socioeconomic status (SES) and mental health conditions. Menthol did not modify the pooled association between nicotine content treatment (VLNC vs. UNC [Usual Nicotine Content]) and cigarettes per day, expired carbon monoxide levels, nicotine dependence and symptomology. Menthol did not have a differential impact on multiple subjective ratings of VLNC cigarettes, except harshness. The odds ratio for being compliant for non-menthol vs. menthol users is 2.6 (95% CI:1.0, 6.4; p-value: 0.04). In summary, the impact of menthol on nicotine metabolism is not significant between menthol and non-menthol cigarette smokers. Menthol and non-menthol cigarettes deliver similar levels of HPHC. Findings on toxicity are similar for menthol and non-menthol cigarettes. The pooled analysis of clinical trials indicated that lowering nicotine content in cigarettes had similar beneficial effects by flavor status, except menthol smokers were less likely to smoke VLNC cigarettes without supplementation with usual cigarettes. These findings provide support for a menthol ban if nicotine content in cigarettes is reduced to very low levels. The information from these studies should be informative to the FDA on whether to implement a final ruling on a ban and respond to potential challenges on any proposed ban.