Friday, July 26, 2013

FDA Preliminary Scientific Evaluation of Menthol: Inadequate for Regulatory Action

The FDA Tobacco Products Scientific Advisory Committee in 2011 reported that menthol had a negative impact on public health.  This week, the FDA released a “Preliminary Scientific Evaluation of the Possible Public Health Effects of Menthol Versus Nonmenthol Cigarettes,” (available here) and announced a 60-day public comment period.  This is the opening salvo in FDA regulatory action that could eliminate or restrict around 30 percent of the American cigarette market (here). 

This post examines the evidence for regulating menthol provided in the preliminary scientific evaluation.

The FDA considered the effects of menthol on several smoking parameters, including smoke chemistry and toxicity, biomarkers, smoking patterns, marketing and consumer perception, smoking initiation and progression, nicotine dependence, and smoking cessation. 

Here are the report’s major findings (I have provided PubMed links to some of the important studies cited by the report):
Smoke Chemistry/Toxicity

There were no significant findings: “…menthol in cigarettes is not associated with increased or decreased smoke toxicity.”


There were no significant findings: “…menthol in cigarettes is likely not associated with increased or decreased levels of biomarkers of exposure.”

Smoking Patterns

The evaluation confirmed what is already widely acknowledged – that menthol cigarettes are more popular among certain groups, especially African Americans, women and, in some studies, younger smokers.

Marketing and Consumer Perception

There were no significant findings: “…a clear relationship cannot be drawn.”

Smoking Initiation and Progression

While the report concluded that “menthol in cigarettes is likely associated with increased initiation and progression to regular use of cigarette smoking,  this finding is based on remarkably mixed data, described in this passage:
“…There is no indication that menthol smokers first experience cigarette smoking any earlier or later than nonmenthol smokers (Pletcher et al., 2006; Okuyemi et al., 2004; Gandhi et al., 2009).  However, data regarding age of onset of regular smoking are mixed. Six studies found no difference (Hyland et al., 2002; Okuyemi et al., 2004; Okuyemi et al., 2007; Cubbin et al., 2010; Stahre et al., 2010; Lawrence et al., 2010 – males only), two found that menthol smokers began regular smoking at a later age (Fagan et al., 2010; Fernander et al., 2010), and two found that menthol smokers began regular smoking at an earlier age (Lawrence et al., 2010 – females only; Nonnemaker secondary data analysis).”
Nicotine Dependence

The report concluded that “…menthol in cigarettes is likely associated with increased dependence.”  This position defies some key research – “[Cigarettes per day] and [the Fagerstr√∂m Test for Nicotine Dependence], two measures that have historically been used to assess nicotine dependence, find no consistent effect of menthol” – and appears to be largely “based on findings of TTFC [time to first cigarette]” and other scales of dependence.  Let’s look at the “findings of TTFC.”

One of the main sources for such data is a 2010 study by Fagan) which found that only moderate menthol smokers (6-10 cigarettes per day, or cpd) were 22 percent more likely than regular smokers to have a cigarette within 5 minutes of waking.  Strangely, menthol had no effect among light (< 5 cpd) and heavy (11+ cpd) smokers.  A study by Collins and Moolchan in 2006 reported a higher percentage of 5-minute TTFC among adolescent menthol smokers seeking cessation treatment, a highly selective population that is not representative of all menthol smokers.  The FDA dismisses the results from four other studies, some positive and some negative, because they didn’t analyze the first five minutes after waking, which the FDA apparently views as the standard.  The report also discusses several studies that are not peer-reviewed, even though “…more consideration was given to peer-reviewed studies.”

The FDA conclusion conflicts with a 2012 study that was not included in the report (available here). It found that “Smoking behaviors may vary by menthol, but menthol was unassociated with dependence.”

Smoking Cessation

The FDA report concluded that “…menthol in cigarettes is likely associated with reduced success in smoking cessation, especially among African American menthol smokers.”  Once again, the finding was based on decidedly mixed results.

The report discussed nine cohort studies that had a vast range of outcomes.  Three found no differences in cessation between menthol and nonmenthol smokers (Hyland et al., 2002; Cropsey et al. 2009; Murray et al., 2007), and the report criticized two of them.  “A fourth study (Blot et al., 2011) found no difference between African American smokers but that White menthol smokers were more likely to have quit.  Of the remaining five cohort studies, four found worse cessation outcomes for menthol smokers compared to their nonmenthol counterparts ([only three references were cited here] Pletcher et al.,2006; Okuyemi et al., 2003; Harris et al., 2004), and one had a trend towards menthol smokers having worse outcomes (Foulds et al., 2006).”

Six cross-sectional studies had varied results regarding menthol and cessation: “…two (Fu et al., 2008; Muscat et al., 2002) failed to find significant differences between menthol and non-menthol smokers [The report appears to cite the wrong study by Fu et al., this one by the same author is more relevant  ]…three [studies] found that menthol smokers had worse cessation outcomes as compared to their nonmenthol smoking counterparts [references were not provided], while one (Gundersen et al., 2009), found that African-American and Latino menthol smokers had worse cessation outcomes as compared to their nonmenthol smoking counterparts while the reverse was true for White smokers.” 

The above FDA description of the Gundersen study is a disturbing misappropriation of research results.  The agency implies that the cessation outcome was worse in both African-American AND Hispanic menthol smokers.  Hispanic menthol smokers had worse cessation outcomes (adjusted odds ratio, AOR= 0.61, 95% Confidence Interval, CI=0.39-0.97), but the cessation rate for African American menthol smokers was NOT significantly lower (AOR=0.78, CI=0.56-1.09).  Statistical significance was reached only when both groups were combined as “Non-White”.  In fact, Gundersen describes the overall result for all menthol smokers: “The odds of being a former smoker does not differ statistically or substantially relative to nonmenthol smokers.”

The bottom line: Numerous studies showed mixed results for menthol and cessation, with some suggesting that menthol might be associated with reduced cessation among African Americans and with increased cessation among whites. 

The FDA preliminary evaluation – reflecting data from numerous studies – does not provide evidence of any significant differences between menthol and regular cigarettes with respect to smoking initiation, addiction to nicotine or cessation.  There is no justification for an evidence-based decision by the FDA to ban or otherwise restrict the menthol content in cigarettes.  

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