Geoffrey M. Curtin

Safety assessment of diammonium phosphate and urea used in the manufacture of cigarettes

A tiered testing strategy has been employed to evaluate the potential for new ingredients, tobacco processes, and technological developments to alter the mainstream smoke or biological activity that results from burning cigarette tobacco. The foundation of this evaluation strategy is comparative testing, typically including chemical and biological assessments. In the manufacture of cigarettes, diammonium phosphate (DAP) and urea have been historically used as ingredients added to tobacco, to reconstituted tobacco sheet, and to other processed tobaccos. As part of ongoing stewardship efforts, a toxicological assessment of cigarettes with and without DAP and urea was conducted. Chemical and biological analyses were conducted for test cigarettes added 0.5% DAP and 0.2% urea in the final blend and also for those added 1.0% DAP and 0.41% urea in the final blend compared to reference cigarettes without added DAP or urea. Principal components of this evaluation included a determination of selected mainstream smoke constituent yields, an Ames assay in Salmonella typhimurium strains TA98 and TA100, a sister chromatid exchange assay in Chinese hamster ovary cells, a 13-week inhalation study of mainstream cigarette smoke in Sprague-Dawley rats, and a 30-week dermal tumor-promotion evaluation of mainstream cigarette smoke condensate in SENCAR mice. Comparative evaluations demonstrated that the addition of DAP and urea to cigarettes at up to 1% and 0.41%, respectively, does not alter the biological activity compared to reference cigarettes without DAP or urea.

Increased DNA methylation in the HoxA5 promoter region correlates with decreased expression of the gene during tumor promotion

Promoter‐region DNA methylation inhibits transcription. A two‐stage SENCAR (sensitive to mouse carcinogenesis) mouse skin carcinogenicity model was used to examine gene‐specific changes in methylation during skin tumor promotion. Analysis was performed on 7,12‐dimethylbenz[a]anthracene (DMBA)‐initiated skin promoted with 9, 18, 27, or 36 mg cigarette smoke condensate (CSC) for 9 wk, or 27 mg CSC for 9 wk and sacrificed 6 wk afterwards (recovery group). Additionally, tumors arising following promotion with 27 mg CSC for 29 wk were assessed. Gene array analysis identified differentially expressed genes. Expression of HoxA5, a tumor suppressor gene, was decreased following 9 wk of treatment with 27 mg CSC, and returned to control levels during recovery. HoxA5 promoter methylation was measured with the enzymatic regional methylation assay (ERMA). DNA was bisulfite‐modified, PCR‐amplified with primers containing dam sites, incubated with [14C‐methyl] S‐adenosyl‐l‐methionine (SAM) and dam methyltransferase for DNA quantification, then incubated with [3H‐methyl] SAM and SssI methylase to quantify methylation status. Higher 3H/14C ratios indicate increased methylation. The 3H/14C ratios of animals promoted with 27 or 36 mg CSC (48.2 ± 6.9 and 24.2 ± 6.1, respectively) were higher than the control or recovery group ratios (12.3 ± 0.1 and 12.6 ± 0.3, respectively); sequence analysis supported these findings. Increased methylation of p16 or O6 methylguanine methyltranferase (MGMT) was detected in 4/8 (50%) of the tumor samples from mice promoted with 27 mg CSC. These data suggest that increased DNA methylation contributes to the downregulation of HoxA5, and combined with hypermethylation of p16 or MGMT, this might facilitate the clonal expansion of increasingly aberrant cells during promotion.

Patterns of menthol cigarette use among current smokers, overall and within demographic strata, based on data from four U.S. government surveys.

The National Health and Nutrition Examination Survey, National Survey on Drug Use and Health, National Health Interview Survey and Tobacco Use Supplement to the Current Population Survey provide estimates of the proportions of U.S. smokers who currently use menthol cigarettes, overall and within demographic strata. Among adult past-month, regular and daily smokers, menthol cigarette use ranges from 26% to 30%, with statistically higher proportions of female versus male smokers (8-11 percentage points higher) currently using menthol cigarettes. Compared to adult smokers overall, statistically higher proportions of non-Hispanic Black smokers (72-79%) and statistically lower proportions of non-Hispanic White smokers (19-22%) currently use menthol cigarettes, with no differences among smokers of other race/ethnicity groups (18-20% to 28-30%, depending on the survey). Higher proportions of younger adult past-month, regular and daily smokers (aged 18-25years) currently use menthol cigarettes compared to older adult smokers (aged 26-29years and/or ⩾30years); however, differences are small in magnitude, with the vast majority of adult smokers (70-75%) who currently use menthol cigarettes being aged ⩾30years. Comparisons between youth and adult smokers are provided, although data for youth smokers are less available and provide less consistent patterns of menthol cigarette use.

Primary measures of dependence among menthol compared to non-menthol cigarette smokers in the United States.

Previously published studies provide somewhat inconsistent evidence on whether menthol in cigarettes is associated with increased dependence. The National Health and Nutrition Examination Survey, National Survey on Drug Use and Health, National Health Interview Survey, and Tobacco Use Supplement to the Current Population Survey collect data on current cigarette type preference and primary measures of dependence, and thus allow examination of whether menthol smokers are more dependent than non-menthol smokers. Analyses based on combined data from multiple administrations of each of these four nationally representative surveys, using three definitions for current smokers (i.e., smoked ⩾1day, ⩾10days and daily during the past month), consistently demonstrate that menthol smokers do not report smoking more cigarettes per day than non-menthol smokers. Moreover, two of the three surveys that provide data on time to first cigarette after waking indicate no difference in urgency to smoke among menthol compared to non-menthol smokers, while the third suggests menthol smokers may experience a greater urgency to smoke; estimates from all three surveys indicate that menthol versus non-menthol smokers do not report a higher Heaviness of Smoking Index. Collectively, these findings indicate no difference in dependence among U.S. smokers who use menthol compared to non-menthol cigarettes.

Evaluating the association between menthol cigarette use and the likelihood of being a former versus current smoker.

Menthol in cigarettes has been examined for its potential to affect smoking dependence, measured primarily as number of cigarettes smoked per day and time to first cigarette after waking; the ability to quit smoking constitutes an additional measure of dependence. Successful quitting among menthol compared to non-menthol cigarette smokers is difficult to determine from the literature, due in part to the various definitions of quitting used by researchers. Nevertheless, intervention and follow-up studies of smoking cessation treatments generally indicate no differences in quitting success among menthol compared to non-menthol smokers, while cross-sectional studies suggest some differences within race/ethnicity groups. The association between menthol cigarette use and likelihood of being a former versus current smoker was examined based on data from the National Health Interview Survey and Tobacco Use Supplement to the Current Population Survey. Analyses stratified by race/ethnicity and limited to smokers who had quit at least one year prior to survey participation provided inconsistent results with regard to menthol cigarette use and quitting, both within surveys (i.e., comparing race/ethnicity groups) and between surveys (i.e., same race/ethnicity group across surveys). Evidence suggesting the existence or direction of an association between menthol in cigarettes and quitting depended on the data source.

Assessing the Likelihood and Magnitude of a Population Health Benefit Following the Market Introduction of a Modified‐Risk Tobacco Product: Enhancements to the Dynamic Population Modeler, DPM(+1)

Researchers and those responsible for evaluating and implementing policies intended to reduce population harm must assess the potential for both intended and unintended consequences associated with those policies. Such assessments should be based on the combined dimensions of magnitude, and thus likelihood, of shifts in exposure patterns needed to produce a population benefit or harm, and magnitude of the expected population benefit or harm. In response to this assessment need, we provide a conceptual description of the dynamic population modeler, DPM(+1), as well as illustrative analyses that estimate the effects on all-cause mortality, life expectancy, and quality of life-adjusted life expectancy if exposure patterns in the population shift from a higher risk product (e.g., cigarettes) to a lower, or modified, risk tobacco product (MRTP) in specified ways. Estimates from these analyses indicate that, within a single birth cohort, switching completely from cigarette smoking to MRTP use is more likely to lead to a population-level survival benefit than initiating tobacco use with an MRTP instead of cigarettes. This is because tobacco initiation rarely occurs beyond young adulthood, whereas continuing smokers exist in all subsequent age categories, leading to a greater cumulative effect. In addition, complete switching to MRTP use among a small proportion of smokers in each age category offsets the survival deficit caused by unintended shifts in exposure patterns, such as MRTP initiation among never tobacco users followed by transitioning to cigarette smoking and/or cigarette smokers switching to MRTP use instead of quitting.

Measures of initiation and progression to increased smoking among current menthol compared to non-menthol cigarette smokers based on data from four U.S. government surveys

There are no large-scale, carefully designed cohort studies that provide evidence on whether menthol cigarette use is associated with a differential risk of initiating and/or progressing to increased smoking. However, questions of whether current menthol cigarette smokers initiated smoking at a younger age or are more likely to have transitioned from non-daily to daily cigarette use compared to non-menthol smokers can be addressed using cross-sectional data from U.S. government surveys. Analyses of nationally representative samples of adult and youth smokers indicate that current menthol cigarette use is not associated with an earlier age of having initiated smoking or greater likelihood of being a daily versus non-daily smoker. Some surveys likewise provide information on cigarette type preference (menthol versus non-menthol) among youth at different stages or trajectories of smoking, based on number of days smoked during the past month and/or cigarettes smoked per day. Prevalence of menthol cigarette use does not appear to differ among new, less experienced youth smokers compared to established youth smokers. While there are limitations with regard to inferences that can be drawn from cross-sectional analyses, these data do not suggest any adverse effects for menthol cigarettes on measures of initiation and progression to increased smoking.

Data on cardiovascular and pulmonary diseases among smokers of menthol and non-menthol cigarettes compiled from the National Health and Nutrition Examination Survey (NHANES), 1999–2012

This Data in Brief contains results from three different survey logistic regression models comparing risks of self-reported diagnoses of cardiovascular and pulmonary diseases among smokers of menthol and non-menthol cigarettes. Analyses employ data from National Health and Nutrition Examination Survey (NHANES) cycles administered between 1999 and 2012, combined and in subsets. Raw data may be downloaded from the National Center for Health Statistics. Results were not much affected by which covariates were included in the models, but depended strongly on the NHANES cycles included in the analysis. All three models returned elevated risk estimates for three endpoints when they were run in individual NHANES cycles (congestive heart failure in 2001-02; hypertension in 2003-04; and chronic obstructive pulmonary disease in 2005-06), and all three models returned null results for these endpoints when data from 1999-2012 were combined.