Menthol and Tobacco Smoke Menthol and Tobacco Smoke Exposure: Exposure:

Second Conference on Menthol Cigarettes

Washington, DC October 19 – 20, 2009

What We Know; What We Don’t What We Know; What We Don’t And Where to GoAnd Where to Go

James R. Hébert, Sc.D., Health SciencesJames R. Hébert, Sc.D., Health SciencesDistinguished Professor of EpidemiologyDistinguished Professor of EpidemiologyDirector, Cancer Prevention and Control Director, Cancer Prevention and Control

Principal Investigator, SCCDCNPrincipal Investigator, SCCDCN

South Carolina Statewide South Carolina Statewide Cancer Prevention & Control ProgramCancer Prevention & Control Program

Review of the Motivation for the 1Review of the Motivation for the 1stst Paper on Mentholated Cigarettes & CAPaper on Mentholated Cigarettes & CA

In Western countries, conventional view is that 95% of Squamous Cell Cancers of the Esophagus Squamous Cell Cancers of the Esophagus (SCCE) are attributable to tobacco and alcohol

Within the U.S., rates for Blacks are about 4 times those of Whites, yet the use rates of tobacco and alcohol are about equal

Also see:1. Hebert JR. Differences in biological responses to cigarette smoking remain unexplained.

Am J Pub Health 1991; 81:1679-1680.2. Hebert JR, Kabat GC. Menthol cigarette smoking and oesophageal cancer: Results of a

case-control study. Int J Epidemiol 1989; 18:37-44.

Menthol Cigarette Sales and Age-Adjusted Esophageal Cancer Rates in Blacks

As noted by Dr. Joshua Muscat:As noted by Dr. Joshua Muscat:

Despite suggestion of effect, none of the studies conducted thus far have implicated mentholated cigarettes as a materially important cause of cancer

Our early study did show an increase in esophageal CA in women

Most of the studies are hospital-based; Many of them (e.g., by Stellman, Kabat, Muscat, Hebert, et al.) use the same (AHF) dataset

Generally Null Results in These Studies Have Generally Null Results in These Studies Have Not Resolved the Issue Definitively!Not Resolved the Issue Definitively!

The lack of representativeness of Blacks in study populations

The inability to define menthol cigarette exposure unambiguously

The lack of data on potential effect-modifiers; e.g., dietary factors, thermal damage from hot beverages

Hebert JR, Kabat GC. Menthol cigarette smoking and Oesophageal cancer: results of a case-control study. Int J Epidemiol 1989;18:37-44.

Why?

Total Area: 31,113 mi2

Total Population: ~4.2mProportion AA: 31% >40% of rural population is AA

The Picture in SC

SCCE in South Carolina

Incidence among AA men is 7.63 times that observed in EA men (vs. the US national differential of ~ 4)

The tobacco use rate in AAs is about 2/3 that of EAs

1. Hebert JR. Invited commentary: menthol cigarettes and risk of lung cancer. Am J Epidemiol 2003;158(7):617-20.

2. Hebert JR, Adams SA, Daguise VG, Hurley D, Smith EW, Purdon C, Lawson A, Mitas M, Reed CE. Esophageal cancer disparities in South Carolina: Early detection, special programs, and descriptive epidemiology. J South Carolina Med Assoc 2006;102:201-9.

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Squamous Cell Carcinoma Adenocarcinoma

Histologic Type of Esophageal Cancer by Race; SC 1997-2002

South Carolina County-by-State Comparison of Black vs. White Incidence Rates of Squamous Cell Esophageal Cancer (age-adjusted 1997-2002 Male incidence)

How Could Menthol Explain these Differences (thinking circa 1988)?

Pyrollized menthol could exert a direct carcinogenic effect

Anesthetic properties could lead to changes in smoking behavior

Anesthetic properties may allow smokers to consume beverages at a higher temperature

Menthol may modify specific nutrient effects1. Hebert JR. Differences in biological responses to cigarette smoking remain unexplained. Am

J Pub Health 1991; 81:1679-1680.2. Hebert JR, Kabat GC. Menthol cigarette smoking and oesophageal cancer: Results of a

case-control study. Int J Epidemiol 1989; 18:37-44.

Direct Action of Menthol Direct Action of Menthol UnderUnder FireFire

Despite that menthol might be able to pyrolyze during smoking, there is no good evidence that the normal process of smoking in humans actually results in increased concentration of carcinogens or pro-carcinogens

Problem: conventional view confuses/equates pyrolysis of menthol (whose products do not appear to function as materially relevant carcinogens) with increases in exposure to known carcinogens [which does appear to occur when (esophageal) membrane is exposed simultaneously to NNK or B[a]P and menthol (or menthol + EtOH)]

References:

Werley MS, Coggins CRE, Lee PN. Possible effects on smokers of cigarette mentholation: a review of the evidence relating to key research questions. Regulatory Toxicol Pharmacol 2007;47(2):189-203.

Hébert, R., 2004. What’s new in “Nicotine & Tobacco Research?” Nicotine Tobacco Res. 6, S1–S4.

Menthol as a PenetrantMenthol as a Penetrantl-menthol and other substituted terpenes, such as thiomenthol, enhance dermal absorption of pharmaceutical agents; so, menthol, alone or in combination with EtOH, may modify permeability and solubility of tobacco carcinogens

References:

Werley MS, Coggins CRE, Lee PN. Possible effects on smokers of cigarette mentholation: a review of the evidence relating to key research questions. Regulatory Toxicol Pharmacol 2007;47(2):189-203.

Azzi C, Zhang J, Purdon CH, Chapman JM, Nitcheva D, Hebert JR, Smith EW. Permeation and reservoir formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BAP) across porcine esophageal tissue in the presence of ethanol and menthol. Carcinogenesis 2006;27(1):137-45.

Static Franz cell for testing Static Franz cell for testing esophageal permeationesophageal permeation

Confocal ResultsConfocal Results

Control (untreated esophagus) showing (red) autofluorescence

BAP-exposed membrane (at 6h) showing the foci of fluorescence (green) due to carcinogen reservoir formation

Histological staining, showing BAP presence (green) in esophageal tissue, blue fluorescence indicates nuclei, and red demarcates smooth muscle cells below the basal mucosal layer

Perinuclear localization of the BAP (green), closely associating with squamous cell nuclei (blue)

20µm 20µm

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20µm

Lung Cancer & MentholLung Cancer & MentholIn an invited commentary on the Brooks et al. 2003 article on lung cancer1 to which Dr. Muscat refers, I concluded that “it is becoming clear that if there is an elevation in risk of lung cancer from smoking mentholated cigarettes beyond that from smoking regular, filter-tipped brands, it is either subtle or refractory to the methods we have used thus far.”2

References

1. Brooks DR, Palmer JR, Strom BL, Rosenberg L. Menthol cigarettes and risk of lung cancer. Am J Epidemiol 2003;158:609-16.

2. Hebert JR. Invited commentary: menthol cigarettes and risk of lung cancer. Am J Epidemiol 2003;158(7):617-20.

Considering Actions of Considering Actions of MentholMenthol

Epidemiology is concerned with both space and time, raising the issue of simultaneous exposures

It is recognized that cigarette-derived exposures represent mixtures that are very complex

Our results, which focus on menthol and well-known carcinogens, are consistent with menthol acting in combination with NNK and B[a]P to elevate risk – but only in situations where exposures happen in combination; and this would be expected to be much more likely in the esophagus than in the lungs

More recent work, focusing on mucin, indicate > permeation than the combination (of menthol and tobacco carcinogens) in a simple aqueous solution (findings under review)

What Else Do We Know What Else Do We Know About Menthol?About Menthol?

Although there may be an effect on the function of cold receptors, with cooling affecting airflow, there is no good evidence that menthol increases overall tobacco exposure through an effect such as modifying air passageways, patterns of inhalation, puff volume, etc.

Effects on physiology, if any, appear to be subtle and small; however, the effect on solubility, membrane permeability, and access to cellular machinery (e.g., nuclear DNA) appear to be large and the largest of these is observed in the upper digestive portion of the aerodigestive tract; i.e. the proximal esophagus (because this is where the mixtures would tend to be the richest)

What else to consider?What else to consider? We already know that some of these cancers,

especially SCCE, evince strong effect modification by other factors (lung cancer much less so)

Menthol may modify nicotine/ carcinogen metabolism

In relation to menthol, 2nd-hand smoke is a non-issue – exposures are too small to create very dangerous mixtures

Explore the possibility of subsets of susceptible of individuals (adding to a line of research that began >30 years ago)

Where to go?Where to go? Large, and in some instances (e.g., for SCCE)

huge, racial disparities in rates of cancers of the upper aerodigestive tract remain unexplained

Even though it is a rare cancer, it makes sense to focus on SCCE, as it is deadly (MIR>0.90), much more common in Blacks, and is the place where we would expect to see the most mixing (i.e., menthol with tobacco carcinogens)

Thanks to the Many People and Institutions that have influenced my thinking, especiallyUniversity of Washington• Cole P. Dodge (UNICEF)• Ross Prentice (FHCRC)Harvard University• Glorian Sorensen (DFCC)• Karen Peterson (U Michigan)• Mohamed el Lozy• Walter Willett• Larry Kushi (Kaiser P.)Bombay University – Healis• Prakash C. GuptaBoston University – Bedford VA• Donald MillerTata Memorial Centre• Rajiv Sarin

American Health Foundation• Ernst Wynder (deceased)• Geoffrey Kabat (AECOM)University of Massachusetts• Ira Ockene (Prev Cardiology)• Judy Ockene (Prev & Behav Med) University of South Carolina• John Ureda (Insights Consulting)• Tom Hurley (EPID-BIOS)• Bill Hrushesky (Dorn VA)• Jane Teas (CCUSC)• Harris Pastides (EPID-BIOS)• John Vena (UGA)• CPCP Junior Faculty