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Comment from Brad Rodu

February 14, 2017

The is a Comment on the Food and Drug Administration (FDA) Proposed Rule: Tobacco Product Standard for N-Nitrosonornicotine Level in Finished Smokeless Tobacco Products

February 14, 2017

Stephen Ostroff, M.D.
Acting Commissioner
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852

Re: Docket No. FDA-2016-N-2527 Tobacco Product Standard for N-Nitrosonornicotine (NNN) Level in Finished Smokeless Tobacco Products, 82 Fed. Reg. 8,004 (Jan. 23, 2017)

Dear Dr. Ostroff:

The proposed rule cited above would require that the mean level of N-nitrosonornicotine (NNN) in smokeless tobacco (ST) products not exceed 1.0 microgram per gram (one part per million) of tobacco (on a dry weight basis).

The FDA asserts “that establishing a NNN limit in finished smokeless tobacco products is appropriate for the protection of the public health.” Justification for the proposed rule is based on an FDA estimate that ST use in the U.S. causes 276 deaths from oral and pharyngeal cancer yearly (this number was rounded to 300 in the proposed rule) – 268 in men and eight in women. The agency estimates that “in the 20 years following implementation of the proposed product standard… approximately 2,200 oral cancer deaths would be prevented in the United States because of this rule.”

Following is evidence demonstrating that FDA estimates of ST-associated oral and pharyngeal cancer deaths are incorrect. Corrected estimates indicate that the proposed rule is irrelevant to moist snuff and loose leaf chewing tobacco products, and that the rule, therefore, is unjustified.

FDA staff used a standard population attributable risk formula to estimate the number of oral and pharyngeal cancer deaths attributable to ST. However, they incorrectly used a relative risk (RR) of 2.16, which was based on a 2008 report (1). This RR is invalid because it combines different RRs for men and women; those RRs have been established by numerous epidemiologic studies conducted over the past 35 years (2,3). Those studies document that men, who primarily use moist snuff or loose leaf chewing tobacco, do not have significantly elevated risks for oral and pharyngeal cancer (RR ~ 1). In contrast, women, who primarily use powdered dry snuff, have significantly elevated risks (RR ~ 4-6).

The established differences in risk among men and women were confirmed by research published last year by Annah Wyss at the National Institute of Environmental Health Sciences and colleagues at the National Cancer Institute and over a dozen international universities and health centers (4). This study determined odds ratios (ORs, interpreted the same as RRs) among snuff and chew users for head and neck cancer – which includes laryngeal cancer in addition to cancers of the oral cavity and pharynx (the risk estimates are applicable to the current issue). The OR among all snuff users, men and women combined, was 3.0, which is similar to the estimate that the FDA incorrectly used for both sexes. However, in the Wyss study, the OR among men (who primarily use moist snuff) was 0.86, while the OR among women (who primarily use powdered dry snuff) was 8.89; these figures are consistent with estimates published in 2002 (2). The ORs for chewing tobacco in the Wyss study were not significantly elevated for men or women.

Using the population attributable risk formula from the proposed rule, I will show how the application of risks specific to men and women change the FDA estimates. First, the following table (adapted from Table 5 in the proposed rule) summarizes the data that the FDA used (ST prevalence, RRs and total numbers of deaths from oral and pharyngeal cancer in the U.S.) and the estimates of deaths attributable to ST (last column). Note that agency staff appropriately applied different prevalence rates for men and women, but they did not apply sex-specific RRs.

Table 1. FDA Estimate of Annual Deaths From Oral and Pharyngeal Cancer Attributable to Smokeless Tobacco (ST), Men and Women in the U.S.
Number of Percent Number [Found in PDF]

The next table illustrates how the death estimates change if ORs specific for men and women are used. As noted above, I base my revised estimates on the risks of snuff use. Different forms of snuff are the most popular smokeless products among both men (moist snuff) and women (powdered dry snuff). The risks for chewing tobacco in the Wyss study are not significantly elevated for men or women, so that product would add zero deaths. In addition, the ORs I used from the Wyss study are for oral, pharyngeal and laryngeal cancers, but these are unlikely to be very different from oral and pharyngeal cancer.

Table 2. Corrected Estimate of Deaths From Oral and Pharyngeal Cancer Attributable to Snuff Use Among Men and Women in the U.S.
Number of Percent Attrib. Number Attrib. [Found in PDF]

In summary, the FDA failed to use risk estimates specific to men and women, resulting in overestimation of cancer deaths in the former and underestimation in the latter. By using the same FDA formula and assigning accurate risks, I estimate that there are 52 deaths among women using ST (primarily powdered dry snuff) each year from oral and pharyngeal cancer. The number of deaths among men using ST (moist snuff or loose leaf chewing tobacco) is zero.

The proposed rule is therefore irrelevant and unjustified with respect to moist snuff or loose leaf chewing tobacco, and it is not appropriate for the protection of public health.

Brad Rodu
Professor of Medicine
Endowed Chair, Tobacco Harm Reduction Research
School of Medicine
University of Louisville
505 South Hancock Street
Louisville, KY 40204
Phone 502-852-7793
Fax 502-852-7979

1. Boffetta P, Hecht S, Gray N, Gupta P, Straif K. Smokeless tobacco and cancer. Lancet Oncology 2008; 9(7):667-75. PMID 18598931
2. Rodu B, Cole P. Smokeless tobacco use and cancer of the upper respiratory tract. Oral Surgery Oral Medicine Oral Pathology 2002; 93(5):511-5. PMID 12075196
3. Winn DM, Blot WJ, Shy CM et al. Snuff dipping and oral cancer among women in the southern United States. New England Journal of Medicine 1981; 304(13):745-9. PMID 7193288
4. Wyss AB, Hashibe M, Lee YA, et al. Smokeless tobacco use and the risk of head and neck cancer: pooled analysis of US studies in the INHANCE consortium. American Journal of Epidemiology 2016 Oct 15. [Epub ahead of print]. PMID 27744388

Brad Rodu is a senior fellow of The Heartland Institute and holds the Endowed Chair in Tobacco Harm Reduction Research at the University of Louisville’s James Graham Brown Cancer Center.