[Federal Register Volume 83, Number 52 (Friday, March 16, 2018)]
[Proposed Rules]
[Pages 11818-11843]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-05345]



[[Page 11817]]

Vol. 83

Friday,

No. 52

March 16, 2018

Part II





Department of Health and Human Services





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Food and Drug Administration





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21 CFR Part 1130





Tobacco Product Standard for Nicotine Level of Combusted Cigarettes; 
Proposed Rule

  Federal Register / Vol. 83 , No. 52 / Friday, March 16, 2018 / 
Proposed Rules  

[[Page 11818]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 1130

[Docket No. FDA-2017-N-6189]
RIN 0910-AH86


Tobacco Product Standard for Nicotine Level of Combusted 
Cigarettes

AGENCY: Food and Drug Administration, HHS.

ACTION: Advance notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is issuing this advance 
notice of proposed rulemaking (ANPRM) to obtain information for 
consideration in developing a tobacco product standard to set the 
maximum nicotine level for cigarettes. Because tobacco-related harms 
ultimately result from addiction to the nicotine in such products, 
causing repeated use and exposure to toxicants, FDA is considering 
taking this action to reduce the level of nicotine in these products so 
they are minimally addictive or nonaddictive, using the best available 
science to determine a level that is appropriate for the protection of 
the public health. FDA is using the term ``nonaddictive'' in this 
document specifically in the context of a potentially nonaddictive 
cigarette. We acknowledge the highly addictive potential of nicotine 
itself depending upon the route of delivery. As discussed elsewhere in 
this document, questions remain with respect to the precise level of 
nicotine in cigarettes that might render them either minimally 
addictive or nonaddictive for specific members or segments of the 
population. We envision the potential circumstance where nicotine 
levels in cigarettes do not spur or sustain addiction for some portion 
of potential smokers. This could give addicted users the choice and 
ability to quit more easily, and it could help to prevent experimenters 
(mainly youth) from initiating regular use and becoming regular 
smokers. The scope of products covered by any potential product 
standard will be one issue for comment in the ANPRM. Any additional 
scientific data and research relevant to the empirical basis for 
regulatory decisions related to a nicotine tobacco product standard is 
another issue for comment in the ANPRM.

DATES: Submit either electronic or written comments on the ANPRM by 
June 14, 2018.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before June 14, 2018. The https://www.regulations.gov electronic filing system will accept comments until 
midnight Eastern Time at the end of June 14, 2018. Comments received by 
mail/hand delivery/courier (for written/paper submissions) will be 
considered timely if they are postmarked or the delivery service 
acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2017-N-6189 for ``Tobacco Product Standard for Nicotine Level of 
Certain Tobacco Products.'' Received comments, those filed in a timely 
manner (see ADDRESSES), will be placed in the docket and, except for 
those submitted as ``Confidential Submissions,'' publicly viewable at 
https://www.regulations.gov or at the Dockets Management Staff between 
9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Gerie Voss, Center for Tobacco 
Products, Food and Drug Administration, 10903 New Hampshire Ave., 
Silver Spring, MD 20993, 1-877-CTP-1373, [email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the ANPRM
    B. Summary of the Major Issues Raised in the ANPRM
II. Background

[[Page 11819]]

    A. Purpose
    B. Legal Authority
III. Health Consequences of Combusted Tobacco Products
    A. Nicotine in Combusted Tobacco Products and Its Impact on 
Users
    B. Negative Health Effects of Combusted Tobacco Product Use
IV. Requests for Comments and Information
    A. Scope
    B. Maximum Nicotine Level
    C. Implementation (Single Target vs. Stepped-Down Approach)
    D. Analytical Testing Method
    E. Technical Achievability
    F. Possible Countervailing Effects
    G. Other Considerations
V. Potential Public Health Benefits of Preventing Initiation to 
Regular Use and Increasing Cessation
    A. Smoking Cessation Would Lead to Substantial Public Health 
Benefits for People of All Ages
    B. A Nicotine Tobacco Product Standard Could Lead to Substantial 
Improvement in Public Health
VI. References

I. Executive Summary

A. Purpose of the ANPRM

    Tobacco use causes a tremendous toll of death and disease every 
year, and these effects are ultimately the result of addiction to the 
nicotine in combustible cigarettes which causes repeated use of such 
products, thus repeatedly exposing users and non-users to toxicants. 
This nicotine addiction causes users to engage in compulsive tobacco 
use, makes quitting less likely, and, thus, repeatedly exposes them to 
thousands of toxicants in combusted tobacco products. This is 
especially true with respect to cigarette smoking. Through this ANPRM, 
FDA indicates that it is considering the issuance of a product standard 
to set a maximum nicotine level in cigarettes so that they are 
minimally addictive or nonaddictive, using the best available science 
to determine a level that is appropriate for the protection of the 
public health. The Agency seeks information and comment on a number of 
issues associated with such a potential product standard. Greatly 
reducing or eliminating the addictiveness of cigarettes would have 
significant benefits for youth, young adults, and adults. More than 
half of adult cigarette smokers make a serious quit attempt each year 
(quit for at least a day), many of whom do not succeed due to the 
addictive nature of these products (Ref. 1). The establishment of a 
maximum nicotine level in cigarettes not only could increase the 
likelihood of successful quit attempts, but it also could help prevent 
experimenters (mainly youth and young adults) from initiating regular 
cigarette smoking. Therefore, rendering cigarettes minimally addictive 
or nonaddictive (however that were achieved) could help current users 
quit and prevent future users from becoming addicted and escalating to 
regular use.

B. Summary of the Major Issues Raised in the ANPRM

    In this ANPRM, FDA is seeking information on a variety of issues 
regarding the development of a tobacco product standard that would 
limit the amount of nicotine in cigarettes. Specifically, FDA is 
seeking your comments, evidence, and other information supporting your 
responses to questions on the following topics:
     Scope--Cigarettes are the tobacco product category that 
causes the greatest burden of harm to public health given the 
prevalence of cigarette use, including among youth, and the toxicity 
and addictiveness of these products and the resulting tobacco-related 
disease and death across the population, including among non-users. If 
FDA were to establish a nicotine tobacco product standard that covered 
only cigarettes, some number of addicted smokers could migrate to other 
similar combusted tobacco products to maintain their nicotine dose (or 
engage in dual use with other combusted tobacco products), potentially 
reducing the positive public health impact of such a rule. Because the 
scope would impact the potential public health benefits of a nicotine 
tobacco product standard, FDA is seeking comment on whether the 
standard should cover any or all of the following products: Combusted 
cigarettes (which FDA has previously interpreted to include kreteks and 
bidis), cigarette tobacco, roll-your-own (RYO) tobacco, some or all 
cigars, pipe tobacco, and waterpipe tobacco. FDA intends that any 
nicotine tobacco product standard would cover all brands in a 
particular product category and, therefore, those products currently on 
the market and any new tobacco products would be expected to adhere to 
the standard.
     Maximum Nicotine Level--FDA has considered the existing 
peer-reviewed studies regarding very low nicotine content (VLNC) 
cigarettes and the likely effects of reducing nicotine in combusted 
tobacco products (i.e., cigarettes, cigars, pipe tobacco, roll-your-own 
tobacco, and waterpipe tobacco). A 2013 survey paper noted that 
researchers initially estimated that reducing the total nicotine 
content of cigarettes to 0.5 milligrams (mg) per rod would minimize 
addictiveness and that a ``more recent analysis suggests that the 
maximum allowable nicotine content per cigarette that minimizes the 
risk of central nervous system effects contributing to addiction may be 
lower'' (Ref. 2). The study authors concluded that ``[p]reventing 
children from becom[ing] addicted smokers and giving people greater 
freedom to stop smoking when they decide to quit by reducing the 
addictiveness of cigarettes is a policy that increasingly appears to be 
feasible and warranted'' (id.). We specifically request comment 
regarding this paper's conclusions and the possible impact of higher or 
lower maximum nicotine levels in a potential nicotine tobacco product 
standard. If FDA were to pursue a nicotine tobacco product standard, it 
would be important for FDA to consider what maximum nicotine level for 
such standard would be appropriate, how this maximum nicotine level 
should be measured (e.g., nicotine yield, nicotine in tobacco filler, 
something else), and how the threshold of nicotine addiction should be 
measured, using the best available science to determine a level that is 
appropriate for the protection of the public health. FDA seeks comment 
on a potential maximum nicotine level that would be appropriate for the 
protection of the public health, in light of scientific evidence about 
the addictive properties of nicotine in cigarettes. FDA is particularly 
interested in comments about the merits of nicotine levels like 0.3, 
0.4, and 0.5 mg nicotine/g of tobacco filler, as well as other levels 
of nicotine. FDA is also requesting any information on additional 
scientific data and research which would provide information about 
specific groups within the general population which may have an 
increased sensitivity to nicotine's reinforcing effects, or who may 
have otherwise not been captured in the literature on VLNC cigarettes. 
In addition, FDA is considering and requesting information on 
additional scientific data and research relevant to the empirical basis 
for regulatory decisions related to a potential nicotine product 
standard.
     Implementation--If FDA were to issue a product standard 
establishing a maximum nicotine level for cigarettes, such a standard 
could propose either a single target (where the nicotine is reduced all 
at once) or a stepped-down approach (where the nicotine is reduced 
gradually over time through a sequence of incremental levels and 
implementation dates) to reach the desired maximum nicotine level.
     Analytical Testing Method--As part of its consideration 
regarding a potential nicotine tobacco product standard, FDA is also 
considering whether such a product standard should specify a method for 
manufacturers to use to

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detect the level of nicotine in their products. FDA believes that the 
results of any test to measure the nicotine in such products should be 
comparable across different accredited testing facilities and products. 
It is critical that the results from the test method used demonstrate a 
high level of specificity, accuracy, and precision in measuring a range 
of nicotine levels across a wide variety of tobacco blends and 
products. FDA is aware of a variety of methods being developed that 
quantify nicotine in tobacco or tobacco product filler for various 
products.
     Technical Achievability--If FDA were to move forward in 
this area and proceed to the next step of issuing a proposed rule, 
section 907(b)(1) of the Federal Food, Drug, and Cosmetic Act (the FD&C 
Act) (21 U.S.C. 387g(b)(1) would require that FDA consider information 
submitted in connection with that proposed product standard regarding 
technical achievability of compliance. FDA continues to analyze the 
technical achievability of a maximum nicotine level for cigarettes as 
part of its broader assessment of how best to exercise its regulatory 
authority in this area. Significant nicotine reductions in cigarettes 
and other combusted tobacco products can be achieved principally 
through tobacco blending and cross-breeding plants, genetic 
engineering, and chemical extraction. Agricultural practices (e.g., 
controlled growing conditions, fertilization, and harvest) as well as 
more recent, novel techniques also can help to reduce nicotine levels. 
FDA is considering the feasibility of the current nicotine reduction 
techniques--for cigarette and other combusted tobacco product 
manufacturers of all sizes--to significantly reduce nicotine levels to 
levels similar to those in existing VLNC cigarettes. FDA also is 
considering the proper timeframe for implementation of a possible 
nicotine tobacco product standard to allow adequate time for industry 
to comply. In addition, FDA is seeking data and information regarding 
the potential costs, including possible costs to farmers, to implement 
such a standard.
     Possible Countervailing Effects--There may be possible 
countervailing effects that could diminish the population health 
benefits expected as a result of a nicotine tobacco product standard. 
As part of any subsequent rulemaking, FDA would need to assess these 
effects in comparison to the expected benefits, including among 
population subgroups. One possible countervailing effect is continued 
combusted tobacco product use. Current smokers of tobacco products 
subject to a nicotine tobacco product standard could turn to other 
combusted tobacco products to maintain their nicotine dependence, both 
in combination with cigarettes (i.e., dual use) or in place of 
cigarettes (i.e., switching). Coverage of other combusted tobacco 
products, as FDA is considering, is one way to significantly limit this 
product migration or transition to dual use with other combusted 
tobacco products.
    Another possible countervailing effect is the potential for 
increased harm due to continued VLNC smoking with altered smoking 
behaviors (e.g., increase in number of cigarettes smoked, increased 
depth of inhalation). Some studies of VLNC cigarettes with nicotine 
levels similar to what FDA may consider including in a nicotine tobacco 
product standard have not resulted in compensatory smoking and have 
demonstrated reductions in cigarettes smoked per day and in exposure to 
harmful constituents (e.g., Ref. 3; Ref. 4; Ref. 5).
    Another possible countervailing effect of setting a maximum 
nicotine level for cigarettes could be users seeking to add nicotine in 
liquid or other form to their combusted tobacco product. Therefore, FDA 
is considering whether any action it might take to reduce nicotine in 
cigarettes should be paired with a provision that would prohibit the 
sale or distribution of any tobacco product designed for the purposes 
of supplementing the nicotine content of the combusted tobacco product 
(or where the reasonably foreseeable use of the product is for the 
purposes of supplementing the nicotine content). FDA is also 
considering other regulatory options to address this concern.
    FDA is also considering whether illicit trade could occur as a 
result of a nicotine tobacco product standard and how that could impact 
the marketplace. In addition, FDA is considering how, if FDA were to 
issue a nicotine tobacco product standard that prompted an increase in 
the illicit market, comprehensive interventions could reduce the size 
of the illicit tobacco market through enforcement mechanisms and 
collaborations across jurisdictions.
     Other Considerations--FDA also recognizes that, if FDA 
were to proceed to the stage of proposing a rule in this area, 
potential costs and benefits from a possible nicotine tobacco product 
standard would be estimated and considered in an accompanying 
preliminary impact analysis, including the potential impacts on growers 
of tobacco and current users of potentially regulated products. Thus, 
FDA is also seeking comments, data, research results, and other 
information regarding economic impacts of a potential nicotine tobacco 
product standard.
    Further, this ANPRM briefly describes the potential public health 
benefits that could result from the increased cessation from and 
decreased initiation to regular use of cigarettes that FDA expects 
could occur with a nicotine tobacco product standard. FDA references 
findings from a population-based simulation model that projects the 
potential public health impact of enacting a regulation lowering 
nicotine levels in cigarettes and certain other combusted tobacco 
products to minimally addictive levels, utilizing inputs derived from 
empirical evidence and expert opinion (eight subject matter experts 
provided quantitative estimates for the potential outcomes of the 
policy on smoking cessation, initiation, switching, and dual use 
rates). Based on the experts' determinations that the reduction in 
nicotine levels in combusted tobacco products would create substantial 
reductions in smoking prevalence due to increased smoking cessation and 
reduced initiation of regular smoking, the model calculates that by the 
year 2100, more than 33 million youth and young adults who would have 
otherwise initiated regular smoking would not start as a result of a 
nicotine tobacco product standard. The model also projected that 
approximately 5 million additional smokers would quit smoking 1 year 
after implementation of the product standard, compared to the baseline 
scenario, which would increase to approximately 13 million additional 
former smokers within 5 years after policy implementation.

II. Background

A. Purpose

    On July 28, 2017, FDA announced a comprehensive approach to the 
regulation of nicotine that includes the Agency's plan to begin a 
public dialogue about lowering nicotine levels in combustible 
cigarettes to minimally addictive or nonaddictive levels through 
achievable product standards, including the issuance of an ANPRM to 
seek input on the potential public health benefits and any possible 
adverse effects of lowering nicotine in cigarettes. Tobacco use causes 
a tremendous toll of death and disease every year, and these effects 
are ultimately the result of addiction to the nicotine contained in 
combustible cigarettes, leading to repeated exposure to toxicants from 
such cigarettes. This nicotine addiction causes users to engage in 
compulsive use, makes quitting less likely and, therefore,

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repeatedly exposes them (and others) to thousands of toxicants in 
combusted tobacco products. This is especially true with respect to 
cigarette smoking. Researchers have found that the mortality rate from 
any cause of death at any given age is 2 to 3 times higher among 
current cigarette smokers, compared to individuals who never smoked 
(Ref. 6).\1\ Through this ANPRM, FDA indicates that it is considering 
the issuance of a product standard to set a maximum nicotine level in 
cigarettes so that they are minimally addictive or nonaddictive, using 
the best available science to determine a level that is appropriate for 
the protection of the public health.\2\ The Agency seeks information 
and comment on a number of issues associated with such a potential 
product standard. Greatly reducing the addictiveness of cigarettes 
would have significant benefits for youth, young adults, and adults.\3\ 
More than half of adult smokers make a serious quit attempt each year 
(quit for at least a day), many of whom are not able to succeed due to 
the addictive nature of these products (Ref. 1). The establishment of a 
maximum nicotine level in cigarettes not only could increase the 
likelihood of successful quit attempts, but it also could help prevent 
experimenters (mainly youth) from initiating regular use. Therefore, 
FDA hypothesizes that making cigarettes minimally addictive or 
nonaddictive, using the best available science to determine a level 
that is appropriate for the protection of the public health, would 
significantly reduce the morbidity and mortality caused by smoking.
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    \1\ The discussion of scientific data discussed in this ANPRM is 
not intended to cover all available information on this subject 
matter. Rather, it is intended to provide only a sampling of some of 
the current research that could be relevant to consideration of a 
potential nicotine tobacco product standard.
    \2\ The Family Smoking Prevention and Tobacco Control Act 
specifically prohibits the Agency from ``requiring the reduction of 
nicotine yields of a tobacco product to zero'' but generally 
authorizes FDA to issue a tobacco product standard setting a maximum 
nicotine level. Section 907(C)(3)(B) of the FD&C Act.
    \3\ The definitions of ``youth,'' ``young adults,'' and 
``adults'' can vary in scientific studies. The term ``youth'' 
generally refers to middle school and/or high school age students. 
``Young adults'' generally refers to individuals 18 to 24 years of 
age. In some studies, ``adults'' may encompass individuals age 18 to 
24 but generally refers to those individual 24 to 65 years of age.
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    Preventing nonsmokers, particularly youth and young adults, from 
becoming regular smokers due to nicotine addiction would allow them to 
avoid the severe adverse health consequences of smoking and would 
result in substantial public health benefits. In 2014, the Surgeon 
General estimated that, unless this trajectory is changed dramatically, 
5.6 million youth aged 0 to 17 years alive today will die prematurely 
from a smoking-related disease (Ref. 7 at table 12.2.2). In 2009, 
Congress estimated that a 50 percent reduction in youth smoking would 
also result in approximately $75 billion in savings \4\ attributable to 
reduced health care costs (see section 2(14) of the Family Smoking 
Prevention and Tobacco Control Act; 21 U.S.C. 387 note). As further 
explained in this ANPRM, if cigarettes were minimally addictive or 
nonaddictive, it is expected that many fewer youth and young adults 
would be subjected to the impacts of nicotine (which has a 
significantly stronger effect on the developing brains of youth (e.g., 
Refs. 8 and 9)) from cigarettes, nor would they suffer from the health 
and mortality effects of cigarette use.
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    \4\ Congress' estimate of approximately $75 billion in savings, 
if adjusted for inflation, would amount to $83.63 billion in 2017.
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    Nicotine is powerfully addictive. The Surgeon General has reported 
that 87 percent of adult smokers start smoking before the age of 18 and 
half of adult smokers become addicted before the age of 18, which is 
before the age at which they can legally buy a pack of cigarettes (Ref. 
7). Nearly all smokers begin before the age of 25, which is the 
approximate age at which the brain has completed development (Ref. 8). 
Generally, those who begin smoking before the age of 18 are not aware 
of the degree of addictiveness and the full extent of the consequences 
of smoking when they begin experimenting with tobacco use (see, e.g., 
Ref. 10). Although youth generally believe they will be able to quit 
when they want, in actuality they have low success rates when making a 
quit attempt. For example, more than 60 percent of high school aged 
daily smokers have tried to quit but less than 13 percent were 
successful at quitting for 30 days or more (Ref. 11). In addition, one 
study found that 3 percent of 12th grade daily smokers estimated that 
they would ``definitely'' still be smoking in 5 years, while in reality 
63 percent of this population is still smoking 7 to 9 years later (Ref. 
12). Another survey revealed that ``nearly 60 percent of adolescents 
believe that they could smoke for a few years and then quit'' (Ref. 
13).
    Because it is such a powerful addiction, addiction to nicotine is 
often lifelong (Ref. 14). Among adolescent tobacco users in 2012, over 
half (52.2 percent) reported experiencing at least one symptom of 
tobacco dependence (Ref. 15). FDA expects that making cigarettes 
minimally addictive or nonaddictive (however that were achieved) may 
have significant benefits for youth by reducing the risk that youth 
experimenters progress to regular use of cigarettes as a result of 
nicotine dependence.
    The adolescent brain is more vulnerable to developing nicotine 
dependence than the adult brain; there are also data from animal 
studies that indicate that brain changes induced by nicotine may have 
long-term consequences (i.e., the long-term physical changes, caused by 
the adolescent nicotine exposure, prevent the brain from reaching its 
full potential, which could result in permanent deficiencies) (Refs. 8 
and 9). Adolescent tobacco users who initiated tobacco use at earlier 
ages were more likely than those initiating at older ages to report 
symptoms of tobacco dependence, putting them at greater risk for 
maintaining tobacco product use into adulthood (Ref. 15). Evidence from 
animal studies indicate that exposure to substances such as nicotine 
can disrupt brain development and have long-term consequences for 
executive cognitive function (such as task-switching and planning) and 
for the risk of developing a substance abuse disorder and various 
mental health problems (particularly affective disorders such as 
anxiety and depression) as an adult (Ref. 16). This exposure to 
nicotine can also have long-term effects, including decreased attention 
performance and increased impulsivity, which could promote the 
maintenance of nicotine use behavior (id.). Further, the 2010 Surgeon 
General's Report noted that symptoms of dependence could result from 
even a limited exposure to nicotine during adolescence (Ref. 17).
    For all these reasons, FDA is considering limiting the 
addictiveness of cigarettes by setting a product standard establishing 
a maximum nicotine level of cigarettes, to help prevent experimenters 
(who are mainly youth) from becoming addicted to tobacco and, thus, 
prevent them from initiating regular use and from increasing their risk 
of tobacco-related death and disease.
    FDA is also considering this action because age restrictions on the 
sale of tobacco products, by themselves, are not entirely effective in 
preventing youth from obtaining cigarettes or other combusted tobacco 
products. Youth smokers get their cigarettes from a variety of sources, 
including directly purchasing them from retailers, giving others money 
to buy them, obtaining them from other youth or adults (with

[[Page 11822]]

or without their knowledge), or using illegal means (i.e., shoplifting 
or stealing) (Ref. 18). The 2015 National Youth Risk Behavior 
Surveillance Survey (YRBS) of high school students in grades 9 through 
12 found that 12.6 percent of current cigarette smokers under age 18 
had purchased their cigarettes directly from stores or gas stations 
despite the Federal minimum age requirements for cigarettes (Ref. 19). 
While continued vigorous enforcement of youth access restrictions is 
critical to protecting public health, FDA is considering taking this 
additional step to ensure that even if youth do obtain access to 
cigarettes, they will be less likely to: (1) Become addicted to these 
products; (2) initiate regular use; and (3) increase their risk of the 
many diseases caused by, and debilitating effects of, combusted tobacco 
product use (Ref. 20).
    Similarly, limiting the nicotine in cigarettes could have 
significant benefits for adult tobacco product users, a large majority 
of whom want to quit but are unsuccessful because of the highly 
addictive nature of these products (see, e.g., Ref. 21). Data from the 
2015 National Health Interview Survey show that 68 percent of current 
adult cigarette smokers in the United States wanted to quit and 55.4 
percent of adult cigarette smokers made a past-year quit attempt of at 
least 1 day (Ref. 22). In high-income countries, about 7 of 10 adult 
smokers say they regret initiating smoking and would like to stop (Ref. 
23 at p. 2). Decreasing the nicotine in cigarettes so that they are 
minimally addictive or nonaddictive (using the best available science 
to determine a level that is appropriate for the protection of the 
public health) could help users quit if they want to--as the large 
majority of users say they do (e.g., Ref. 21).
    Although many factors contribute to an individual's initial 
experimentation with tobacco products, the addictive nature of tobacco 
is the major reason people progress to regular use, and it is the 
presence of nicotine that causes youth, young adults, and adult users 
to become addicted to, and to sustain, tobacco use (see, e.g., Refs. 24 
and 25). While nicotine is the primary addictive chemical in tobacco, 
sensorimotor stimuli that are repeatedly paired with nicotine through 
the process of smoking also develop into conditioned reinforcers that 
contribute to the persistent nature of nicotine dependence (Ref. 26). 
In cigarette users, the sensory aspects of smoking, such as taste and 
sensations of smoking (e.g., throat hit), are often reinforcing as they 
have been paired repeatedly with nicotine exposure and have been found 
to be reinforcing without concomitant nicotine exposure in experienced 
users (Ref. 27). Once tobacco users become addicted to nicotine, they 
require nicotine to avoid certain withdrawal symptoms. In the process 
of obtaining nicotine, users of combusted tobacco products are exposed 
to an array of toxicants in tobacco and tobacco smoke that lead to a 
substantially increased risk of morbidity and mortality (see, e.g., 
Ref. 10). Although most current U.S. smokers report that they want to 
quit smoking, have attempted to quit, and regret starting (see, e.g., 
Refs. 28 and 29), many smokers find it difficult to break their 
addiction and quit. Because of nicotine addiction, many smokers lack 
the ability to choose whether or not to continue smoking these toxic 
combusted products despite their stated desire to quit (see, e.g., Ref. 
17).
    Accordingly, FDA is considering whether to issue a tobacco product 
standard to: (1) Give addicted users of cigarettes the choice and 
ability to quit more easily by reducing the nicotine to a minimally 
addictive or nonaddictive level and (2) reduce the risk of progression 
to regular use and nicotine dependence for persons who experiment with 
the tobacco products covered by the standard. FDA hypothesizes that 
making cigarettes minimally addictive or nonaddictive, using the best 
available science to determine a level that is appropriate for the 
protection of the public health, could significantly reduce the 
morbidity and mortality caused by smoking.

B. Legal Authority

    The Family Smoking Prevention and Tobacco Control Act (Tobacco 
Control Act) was enacted on June 22, 2009, amending the FD&C Act and 
providing FDA with the authority to regulate tobacco products (Pub. L. 
111-31). Section 901 of the FD&C Act (21 U.S.C. 387a), as amended by 
the Tobacco Control Act, granted FDA authority to regulate the 
manufacture, marketing, and distribution of cigarettes, cigarette 
tobacco, RYO tobacco, and smokeless tobacco to protect the public 
health and to reduce tobacco use by minors. The Tobacco Control Act 
also gave FDA the authority to issue a regulation deeming other 
products that meet the statutory definition of tobacco product to be 
subject to FDA's tobacco product authority under chapter IX of the FD&C 
Act. On May 10, 2016, FDA issued the deeming rule (81 FR 28973), 
extending FDA's tobacco product authority to all tobacco products, 
other than the accessories of deemed tobacco products, that meet the 
statutory definition of tobacco product.
    Among the authorities included in chapter IX of the FD&C Act is the 
authority to establish tobacco product standards. The Act authorizes 
FDA to adopt a tobacco product standard under section 907 of the FD&C 
Act if the Secretary of Health and Human Services (HHS) finds that a 
tobacco product standard is appropriate for the protection of the 
public health. In making such a finding, the Secretary of HHS must 
consider scientific evidence concerning: (1) The risks and benefits of 
the proposed standard to the population as a whole, including users and 
nonusers of tobacco products; (2) the increased or decreased likelihood 
that existing users of tobacco products will stop using such products; 
and (3) the increased or decreased likelihood that those who do not use 
tobacco products will start using such products (section 
907(a)(3)(B)(i) of the FD&C Act).
    Section 907(a)(4) of the FD&C Act states that tobacco product 
standards must include provisions that are appropriate for the 
protection of the public health. Section 907(a)(4)(B)(i) provides that 
a product standard must include, where appropriate for the protection 
of the public health, provisions respecting the construction, 
components, ingredients, additives, constituents, including smoke 
constituents, and properties of the tobacco product. Further, section 
907(a)(4)(A)(i) states that provisions in tobacco product standards 
must include, where appropriate, provisions for nicotine yields. 
Section 907(a)(4)(B)(ii) also provides that a product standard must, 
where appropriate for the protection of public health, include 
``provisions for the testing (on a sample basis or, if necessary, on an 
individual basis) of the tobacco product.'' In addition, section 
907(a)(4)(B)(iv) provides that, where appropriate for the protection of 
public health, a product standard must include provisions requiring 
that the results of the tests of the tobacco product required under 
section 907(a)(4)(B)(ii) show that the product is in conformity with 
the portions of the standard for which the test(s) were required. 
Finally, section 907(d)(3)(B) of the FD&C Act prohibits the Agency from 
issuing a regulation that would require the reduction of nicotine 
yields of a tobacco product to zero.
    The FD&C Act also provides FDA with authority to issue regulations 
establishing restrictions on the sale and distribution of a tobacco 
product (section 906(d)(1) of the FD&C Act (21 U.S.C. 387f(d)(1))). 
These restrictions

[[Page 11823]]

may include restrictions on the access to, and the advertising and 
promotion of, the tobacco product, if the Secretary of HHS determines 
such regulation would be appropriate for the protection of the public 
health.
    FDA intends to use the information submitted in response to this 
ANPRM, its independent scientific knowledge, and other appropriate 
information, to further inform its thinking about options, including 
the scope, for a potential product standard that would set a maximum 
nicotine level for cigarettes, and restrictions prohibiting the sale 
and distribution of any product that violates such a standard.

III. Health Consequences of Combusted Tobacco Products

A. Nicotine in Combusted Tobacco Products and Its Impact on Users

    Tobacco products are addictive, primarily due to the presence of 
nicotine, and the magnitude of public health harm caused by tobacco 
products is inextricably linked to their addictive nature (Ref. 13 at 
p. xi). Cigarettes are the most widely used tobacco products among 
adults and are responsible for at least 480,000 premature deaths in the 
United States each year (Ref. 7). Other combusted tobacco products that 
are possible targets of product migration (i.e., switch candidates for 
smokers to maintain their nicotine addiction) or dual use have similar 
adverse health effects and can cause nicotine dependence (Refs. 30 and 
31). For example, researchers have found that current exclusive cigar 
smokers and current exclusive pipe smokers have an increased risk for 
lung cancer and tobacco-related cancers overall, as compared to those 
who reported never using any type of combusted tobacco product (Ref. 
32). We note that there is a dose-response relationship between the 
number of cigars and pipes smoked and the risk of disease (i.e., the 
larger the number of cigars or pipes smoked, the higher the risk of 
disease) (Ref. 31 at 110), but cigar and pipe users are still subject 
to the addictive effects of nicotine through nicotine absorption (and 
to the health impacts of long-term use that may follow from regular use 
due to addiction) even if they report that they do not inhale (Refs. 
33-35).
    The Surgeon General has reported that ``most people begin to smoke 
in adolescence and develop characteristic patterns of nicotine 
dependence before adulthood'' (Ref. 36 at p. 29). Adolescents develop 
physical dependence and experience withdrawal symptoms when they try to 
quit smoking (id.). The 2014 Surgeon General's Report states that 5.6 
million youth currently 0 to 17 years of age are projected to die 
prematurely from smoking-related illnesses (Ref. 7 at pp. 666-667). 
Accordingly, using the best available science to determine a level that 
is appropriate for the protection of the public health, making 
cigarettes minimally addictive or nonaddictive would limit the number 
of youth and young adults who progress from experimentation to regular 
use and who, thereby, increase their risk for dangerous smoking-related 
diseases.
    Researchers have determined that almost one-third of adolescents 
aged 11 to 18 (31 percent) are ``early experimenters,'' meaning that 
they have tried smoking at least one puff of a cigarette (but smoked no 
more than 25 cigarettes in their lifetime) (Ref. 37). The Centers for 
Disease Control and Prevention (CDC) and other researchers have 
estimated that 30 percent or more of experimenters become established 
smokers (Ref. 37, citing Refs. 38 and 39). Given these past trends, if 
one applies the 30 percent estimate to the adolescents who were early 
experimenters in 2000, then 2.9 million of these early experimenters 
have now or will become established smokers (Ref. 37). Based on the 
number of persons aged 0 to 17 in 2012, the Surgeon General estimated 
that 17,371,000 of that group will become future smokers and 5,557,000 
will die from a smoking-related disease (Ref. 7 at T. 12.2.1). These 
high numbers speak to the extreme vulnerability of today's children and 
adolescents to the health harms of tobacco use resulting from 
addiction.
    Nicotine addiction is a critical factor in the transition of 
smokers from experimentation to sustained smoking and in the 
continuation of smoking for those who want to quit (Ref. 7 at p. 113; 
Ref. 17). Intermittent smokers, even very infrequent smokers, can 
become addicted to tobacco products (Ref. 40). Longitudinal research 
has shown that smoking typically begins with experimental cigarette use 
and the transition to regular smoking can occur relatively quickly by 
smoking as few as 100 cigarettes (Ref. 8). Other research found that 
among the 3.9 million middle and high school students who reported 
current use of tobacco products (including cigarettes and cigars) in 
2012, 2 million of those students reported at least one symptom of 
dependence (Ref. 15).
    Although the majority of adolescent daily smokers meet the criteria 
for nicotine dependence, one study found that the most susceptible 
youth lose autonomy (i.e., independence in their actions) regarding 
tobacco within 1 or 2 days of first inhaling from a cigarette (Refs. 41 
and 42). Another study found that 19.4 percent of adolescents who 
smoked weekly also were considered to be nicotine dependent (Ref. 43). 
In a study regarding nicotine dependence among recent onset adolescent 
smokers, individuals who smoked cigarettes at the lowest levels (i.e., 
smoking on only 1 to 3 days of the past 30 days) experienced nicotine 
dependence symptoms such as loss of control over smoking (42 percent) 
and irritability after not smoking for a while (23 percent) (Ref. 44). 
Researchers in a 4-year study of sixth grade students also found that 
``[e]ach of the nicotine withdrawal symptoms appeared in some subjects 
prior to daily smoking'' (Ref. 42) (emphasis added). Ten percent of the 
subjects showed signs of addiction to tobacco use within 1 or 2 days of 
first inhaling from a cigarette, and half had done so by the time they 
were smoking seven cigarettes per month (Ref. 42).
    It is clear that many adult cigarette smokers want to quit. Data 
from the 2015 National Health Interview Survey show that 68 percent of 
current adult smokers in the United States wanted to quit and 55.4 
percent of adult smokers made a past-year quit attempt of at least 1 
day (Ref. 22). According to an analysis of this survey, only 7.4 
percent of former adult cigarette smokers had recently quit (id.).
    For adult smokers who report quit attempts, many of these attempts 
are unsuccessful. For example, among the 19 million adults who reported 
attempting to quit in 2005, epidemiologic data suggest that only 4 to 7 
percent were successful (Ref. 28 at p. 15). Similarly, the Institute of 
Medicine (IOM), considering data from 2004, found that although 
approximately 40.5 percent of adult smokers reported attempting to quit 
in that year, only between 3 and 5 percent were successful (Ref. 13 at 
p. 82). Adult smokers may make as many as thirty or more quit attempts 
before succeeding (Ref. 45). FDA also notes that adults with education 
levels at or below the equivalent of a high school diploma have the 
highest smoking prevalence levels but the lowest quit ratios (i.e., the 
ratio of persons who have smoked at least 100 cigarettes during their 
lifetime but do not currently smoke to persons who report smoking at 
least 100 cigarettes during their lifetime) (Ref. 46). Nicotine 
addiction and associated withdrawal symptoms make it difficult for 
smokers to quit without using cessation counseling and/or cessation 
medications.

[[Page 11824]]

    Adolescents also experience low success rates when attempting to 
quit. As we have noted, most Americans who use tobacco products begin 
using when they are under the age of 18 and become addicted before 
reaching the age of 18 (Refs. 36 and 47). Although many adolescents 
believe ``they can quit [smoking] at any time and therefore avoid 
addiction,'' nicotine dependence can be rapidly established (Ref. 13 at 
p. 89; see also Ref. 28 at p. 158). Research has shown that some 
adolescents report symptoms of withdrawal and craving within days or 
weeks of beginning to smoke (Ref. 48). As a result, many adolescents 
are nicotine dependent despite their relatively short smoking histories 
(Ref. 11). An analysis of data from the 2015 YRBS found that, of those 
currently smoking cigarettes, 45.4 percent had tried to quit smoking 
cigarettes during the previous year (Ref. 19). Likewise, an analysis of 
the 2012 National Youth Tobacco Survey (NYTS) revealed that 51.5 
percent of middle and high school student smokers had sought to quit 
all tobacco use in the previous year (Ref. 49).
    Relapse is the principal limiting factor in the transition of 
smoking to nonsmoking status (Ref. 17). Relapse refers to the point 
after an attempt to stop smoking when tobacco use becomes ongoing and 
persistent (Ref. 17, citing Ref. 50). Most smokers who ultimately 
relapse do so soon after their quit attempt (Ref. 17). One study found 
that 80 to 90 percent of those individuals who were smoking at 6 months 
following a quit attempt had resumed smoking within 2 weeks following 
their quit attempt (Ref. 51). Long-term studies of individuals trying 
to quit smoking reveal that 30 to 40 percent of those who quit smoking 
for 1 year eventually relapsed (id.). In fact, one study following 840 
participants for more than 8 years found that approximately one-half of 
smokers who stopped smoking for 1 year relapsed to regular smoking 
within the subsequent 7 years (Ref. 52). Researchers have found that a 
higher frequency of smoking predicts more severe withdrawal symptoms 
and earlier relapse after an attempt to quit smoking and is associated 
with early lapses after cessation (Ref. 17 at p. 119). FDA specifically 
requests comment as to whether higher frequency smokers would 
experience more severe withdrawal symptoms from the use of VLNC 
cigarettes.
    FDA expects that, if cigarettes were minimally addictive or 
nonaddictive, the nicotine level in cigarettes would be self-limiting 
(i.e., smokers would be unable to obtain their nicotine dose from 
cigarettes no matter how they smoked them and eventually would stop 
trying to do so) (e.g., Refs. 4, 5, and 53), making it potentially 
easier for smokers to make more successful quit attempts and likely 
leading to a potentially substantial reduction in the rate of relapse 
compared to current levels.\5\ Former smokers that choose to switch 
completely to a potentially less harmful nicotine delivery product 
(e.g., electronic nicotine delivery systems (ENDS)) to maintain their 
nicotine dose also would, to the extent that those products result in 
less harm, significantly reduce their risk of tobacco-related death and 
disease. Accordingly, rendering cigarettes minimally addictive or 
nonaddictive (however that were achieved) would be expected to address 
the principal reason that smokers are unable to quit smoking.
---------------------------------------------------------------------------

    \5\ As stated throughout the document, FDA expects that, to 
maintain their nicotine dose, some number of addicted cigarette 
smokers could migrate to other similar, combusted products (or 
engage in dual use with such products) after the standard went into 
effect, reducing the benefits of the product standard. Since the 
scope would impact the potential public health benefits of such a 
nicotine tobacco product standard, FDA is seeking comment on whether 
the standard should cover any or all of the following products: 
Combusted cigarettes (which FDA has previously interpreted to 
include kreteks and bidis), cigarette tobacco, roll-your-own 
tobacco, some or all cigars, waterpipe tobacco, and pipe tobacco.
---------------------------------------------------------------------------

B. Negative Health Effects of Combusted Tobacco Product Use

    Nicotine is a powerfully addictive chemical. The effects of 
nicotine on the central nervous system occur rapidly after absorption 
(Ref. 25 at p. 12). Users of combusted tobacco products absorb nicotine 
readily from tobacco smoke through the lungs (id. at p. iii). Nicotine 
introduced through the lungs is rapidly distributed to the brain (id. 
at p. 12). With regular use, nicotine levels accumulate in the body 
during the day from the tobacco product use and then decrease overnight 
as the body clears the nicotine (id. at p. iii). Mild nicotine 
intoxication even occurs in first-time smokers (Ref. 25 at pp. 15-16). 
Tolerance to the effects of nicotine develops rapidly.
    The addiction potential of a nicotine delivery system varies as a 
function of its total nicotine dosing capability, the speed at which it 
can deliver nicotine, the palatability and sensory characteristics of 
the system, how easy it is for the user to extract nicotine, and the 
cost of the delivery system (Ref. 54). A cigarette is an inexpensive 
and extremely effective nicotine delivery device, which maximizes the 
cigarette's addicting and toxic effects (id.). The amount of nicotine 
delivered and the means through which it is delivered can either reduce 
or enhance a product's potential for abuse and physiological effects 
(Ref. 17 at p. 113). Quicker delivery, higher rate of absorption, and 
higher resulting concentration of nicotine increase the potential for 
addiction (id. at p. 113). The ultimate levels of nicotine absorbed 
into the blood for different tobacco products (e.g., cigarettes and 
cigars) can be similar in magnitude even though individuals may smoke 
them differently and the rate of absorption may be different (Ref. 25).
    The significant negative health effects from cigarettes are a 
consequence of long-term use. Children and adults continue using 
cigarettes primarily as a result of their addiction to nicotine (e.g., 
Ref. 7). Almost all adult smokers started smoking cigarettes as 
children or young adults, and half of adult smokers became addicted 
before turning 18 (id.).
    Cigarettes are responsible for hundreds of thousands of premature 
deaths every year from many diseases, put a substantial burden on the 
U.S. health care system, and cause massive economic losses to society 
(Ref. 7 at pp. 659-666; another perspective on this issue is provided 
by Sloan et al. (Ref. 55)). Cigarette smoking causes more deaths each 
year than AIDS, alcohol, illegal drug use, homicide, suicide, and motor 
vehicle crashes combined (Ref. 47). Every year, cigarette smoking is 
the primary causal factor for 163,700 deaths from cancer, 160,600 
deaths from cardiovascular and metabolic diseases, and 131,100 deaths 
from pulmonary diseases (Ref. 7 at p. 659). In the United States, about 
87 percent of all lung cancer deaths, 32 percent of coronary heart 
disease deaths, and 79 percent of all cases of chronic obstructive 
pulmonary disease (COPD) are attributable to cigarette smoking (id.). 
The 2014 Surgeon General's Report states that 5.6 million youth 
currently 0 to 17 years of age are projected to die prematurely from 
smoking-related illnesses (id. at pp. 666-667).
    Data from the CDC's Smoking-Attributable Mortality, Morbidity, and 
Economic Costs system for 2005-2009 (the most recent years for which 
analyses are available) indicate that cigarette smoking and exposure to 
cigarette smoke are responsible for at least 480,000 premature deaths 
each year (id. at p. 659). However, this estimate does not include 
deaths caused by other combusted forms of tobacco, such as cigars and 
pipes (id. at 665).\6\

[[Page 11825]]

The three leading causes of smoking-attributable death for current and 
former smokers were lung cancer, heart disease, and COPD (id. at p. 
660). For every person who dies from a smoking-related disease, 
approximately 30 more people will suffer from at least one smoking-
related disease (Ref. 58).
---------------------------------------------------------------------------

    \6\ As discussed in Ref. 56, regular cigar smoking was 
responsible for approximately 9,000 premature deaths and more than 
140,000 years of potential life lost among adults aged 35 years or 
older in 2010. The 2014 Surgeon General Report states that the 
methodology for estimating the current population burden for use of 
combusted tobacco products other than cigarettes remains under 
discussion, but the number of added deaths is expected to be in the 
thousands per year (Ref. 7 at 665, 14 SG; citing Ref. 57).
---------------------------------------------------------------------------

    Cigarettes also have deadly effects on nonsmokers. From 2005 to 
2009, an estimated 7,330 lung cancer and 33,950 heart disease deaths 
were attributable to exposure to secondhand smoke (Ref. 7 at p. 660). 
It is also well established that secondhand tobacco smoke causes 
premature death and disease in children and in adults who do not smoke 
(see, e.g., Ref. 59 at p. 11). According to the Surgeon General's 
Report, ``50 Years of Progress: A Report of the Surgeon General, 
2014,'' which summarizes thousands of peer-reviewed scientific studies 
and is itself peer-reviewed, smoking remains the leading preventable 
cause of disease and death in the United States, and cigarettes have 
been shown to cause an ever-expanding number of diseases and health 
conditions (Ref. 7 at pp. 107-621). As stated in the 2014 Report, 
``cigarette smoking has been causally linked to disease of nearly all 
organs of the body, to diminished health status, and to harm to the 
fetus . . . [and] the burden of death and disease from tobacco use in 
the United States is overwhelmingly caused by cigarettes and other 
combusted tobacco products'' (Ref. 7 at p. 7).
    Other combusted tobacco products, particularly those that could be 
cigarette alternatives if users were unable to continue smoking 
cigarettes, cause similar negative health effects. For example, there 
is a long-standing body of research, including reports from the Surgeon 
General and National Cancer Institute (NCI), demonstrating that cigar 
use can cause serious adverse health effects (Ref. 31 at 119-155; Refs. 
60, 61, and 33). NCI's Smoking and Tobacco Control Monograph No. 9 
(``Cigars: Health Effects and Trends''), which provides a 
comprehensive, peer-reviewed analysis of the trends in cigar smoking 
and potential public health consequences, as well as other research, 
demonstrates that cigar smoking leads to an increased risk of oral, 
laryngeal, esophageal, pharyngeal, and lung cancers, as well as 
coronary heart disease and aortic aneurysm, with the magnitude in risk 
a function of the amount smoked and depth of inhalation (Ref. 31 at 
119-155). Research indicates that most cigar smokers do inhale some 
amount of smoke, even when they do not intend to inhale, and are not 
aware of doing so (Refs. 33 and 34). Even when cigar smokers do not 
breathe smoke into their lungs, they are still subject to the addictive 
effects of nicotine through nicotine absorption (Refs. 33 and 35). This 
is because cigar smoke dissolves in saliva, allowing the smoker to 
absorb sufficient nicotine to create dependence, even if the smoke is 
not inhaled (Refs. 35 and 62).
    Regular cigar smoking (which, in this study, constituted use on at 
least 15 of the past 30 days) was responsible for approximately 9,000 
premature deaths and more than 140,000 years of potential life lost 
among adults aged 35 years or older in 2010 (Ref. 56). Researchers also 
have found that the risk of dying from tobacco-related cancers is 
higher from current exclusive pipe smokers and current exclusive cigar 
smokers than for those who reported never using combusted tobacco 
products (Ref. 32).

IV. Requests for Comments and Information

    To aid in its consideration regarding development of a nicotine 
tobacco product standard, FDA is seeking comments, data, research 
results, and other information related to questions under the following 
topics: Scope of products to be covered, maximum nicotine level for a 
nicotine tobacco product standard, implementation, analytical testing, 
technical achievability, possible countervailing effects (including the 
potential for an illicit market), and other considerations. We ask that 
commenters clearly identify the section and question associated with 
their responsive comments and information.

A. Scope

    A tobacco product standard limiting the nicotine level in 
cigarettes could address one of our nation's greatest public health 
challenges: The death and disease caused by cigarette use. 
Approximately 480,000 people die every year from smoking cigarettes 
(Ref. 7). Cigarettes are the tobacco product category that causes the 
greatest burden of harm to public health as a result of the prevalence 
of cigarette use and the toxicity and addictiveness of these products. 
FDA hypothesizes that a tobacco product standard limiting the nicotine 
level in cigarettes could significantly increase the number of 
successful quit attempts by the majority of smokers seeking to quit 
smoking every year and potentially prevent experimenters from becoming 
regular smokers. However, if a standard were to apply to cigarettes 
only, it could be substantially less effective. Specifically, FDA 
expects that, to maintain their nicotine dose, some number of addicted 
cigarette smokers could migrate to other similar, combusted products 
(or begin to engage in dual use with such other products) after the 
standard went into effect, reducing the benefits of the product 
standard. Former smokers that choose to switch completely to a 
potentially less harmful nicotine delivery product (e.g., ENDS) to 
maintain their nicotine dose also would, to the extent that those 
products result in less harm, significantly reduce their risk of 
tobacco-related death and disease. Since the scope would impact the 
potential public health benefits of such a nicotine tobacco product 
standard, FDA is seeking comment on whether the standard should cover 
any or all of the following products: Combusted cigarettes (which FDA 
has previously interpreted to include kreteks and bidis), cigarette 
tobacco, RYO tobacco, some or all cigars, pipe tobacco, and waterpipe 
tobacco. FDA intends that any nicotine tobacco product standard would 
cover all brands in a product category and, therefore, those products 
currently on the market and any new tobacco products would be expected 
to adhere to the standard.
    FDA is continuing to weigh several factors as it considers the 
scope of products that should be subject to any potential nicotine 
tobacco product standard--including the strength and breadth of the 
available data derived from studies of VLNC cigarettes on the likely 
effects of reducing nicotine \7\ (as discussed in section IV.B); 
current prevalence and initiation rates for different classes of 
tobacco products; the available data on the toxicity, addictiveness, 
and appeal of the products; the use topography of the products 
(including quantity, frequency, and duration of use); and the potential 
for migration to, and dual use of, different products. Current VLNC 
cigarette literature indicates that reduction of nicotine in cigarettes 
would make it more likely for smokers (even those not currently 
expressing a desire to quit) to cease cigarette use (e.g., Refs. 4, 5, 
63, and 64). In light of these data, FDA also believes that reduction 
of nicotine could help prevent

[[Page 11826]]

experimenters from becoming addicted to tobacco, resulting in regular 
tobacco use.
---------------------------------------------------------------------------

    \7\ VLNC cigarettes do not contain uniform amounts of nicotine.
---------------------------------------------------------------------------

    Based on these considerations, FDA is seeking comment on whether 
any nicotine tobacco product standard should cover any or all of the 
following products:
     Combusted cigarettes (which FDA has previously interpreted 
to include kreteks and bidis),
     Cigarette tobacco,
     RYO tobacco,
     Cigars (some or all categories; i.e., small cigars, large 
cigars, cigarillos, and/or so-called premium cigars),
     Pipe tobacco, and
     Waterpipe tobacco.
    Please explain your responses and provide any evidence or other 
information supporting your responses to the following questions:
    1. If FDA were to propose a product standard setting a maximum 
nicotine level, should such a standard cover other combusted tobacco 
products in addition to cigarettes? If so, which other products? If FDA 
were to propose to include additional categories of combusted tobacco 
products in a nicotine tobacco product standard, should the standard be 
tailored to reflect differences in these products? What criteria should 
be used to determine whether, and which, products should be covered?
    2. Some suggest that large cigars and those cigars typically 
referred to as ``premium'' cigars should be regulated differently from 
other cigars, asserting that they are used primarily by adults and 
their patterns of use are different from those of regular cigars (81 FR 
28973 at 29024). FDA requests information and data on whether large 
and/or so-called premium cigars should be excluded from a possible 
nicotine tobacco product standard based on asserted different patterns 
of use, and whether large and/or so-called premium cigars would be 
migration (or dual use) candidates if FDA were to issue a nicotine 
tobacco product standard that excluded premium cigars from its scope. 
FDA also requests data and information on whether and how there is a 
way that, if FDA were to exclude premium cigars from the scope of a 
nicotine tobacco product standard, FDA could define ``premium cigar'' 
to include only unlikely migration or dual use products and thereby 
minimize such consequences.
    3. Should waterpipe tobacco products, which are different from 
regular pipe tobacco, be included in such a standard? Are there data 
showing different use topographies or that they are not likely to be 
migration substitutes or dual use candidates? If FDA were to issue a 
nicotine tobacco product standard that did not include waterpipe 
tobacco products within the scope, what would be the likelihood that 
former smokers would switch to waterpipe tobacco to maintain their 
nicotine addiction? What are the relative risk consequences of 
switching to waterpipe tobacco?

B. Maximum Nicotine Level

    As discussed throughout this document, nicotine is addictive and is 
the primary reason why many smokers who want to quit are unable to do 
so. Accordingly, FDA is considering developing a proposed product 
standard to make cigarettes minimally addictive or nonaddictive by 
setting a maximum nicotine level, using the best available science to 
determine a level that is appropriate for the protection of the public 
health. FDA has considered several peer-reviewed studies regarding very 
low nicotine content (VLNC) cigarettes \8\ and the likely effects of 
reducing nicotine in combusted tobacco. A 2013 survey paper noted that 
researchers initially estimated that reducing the total nicotine 
content of cigarettes to 0.5 mg per rod would minimize addictiveness 
and that a ``more recent analysis suggests that the maximum allowable 
nicotine content per cigarette that minimizes the risk of central 
nervous system effects contributing to addiction may be lower'' (Ref. 
2). The study authors concluded that ``[p]reventing children from 
becom[ing] addicted smokers and giving people greater freedom to stop 
smoking when they decide to quit by reducing the addictiveness of 
cigarettes is a policy that increasingly appears to be feasible and 
warranted'' (id.). We specifically request comment regarding this 
paper's conclusions and the possible impact of higher or lower maximum 
nicotine levels in a potential nicotine tobacco product standard.
---------------------------------------------------------------------------

    \8\ Scientific studies regarding VLNC cigarettes use both 
``yield'' and ``content'' to describe the amount of nicotine in 
research cigarettes. ``Yield'' is the International Organization for 
Standardization (ISO) machine-generated nicotine smoke yield, and 
``content'' refers to the nicotine in the tobacco filler of the 
entire finished product. ``Yield'' and ``content'' are not 
interchangeable terms. If neither ``yield'' nor ``content'' is used, 
the nicotine levels in these studies refer to content.
---------------------------------------------------------------------------

    Early ``light'' cigarettes achieved a reduction in machine-measured 
nicotine yield through a variety of means, including through the use of 
ventilation holes (although the actual nicotine content was not low). 
This increase in ventilation led to lower yields of nicotine in smoke 
as measured by smoking machines, and these products were marketed as 
low nicotine delivery or ``light'' cigarettes. However, cigarette users 
could modify their use behaviors to compensate for this increase in 
ventilation. For example, the vent holes could be easily blocked by 
users' fingers or mouths, and larger or more frequent puffs could be 
taken by consumers (Ref. 65). As a result, these products were designed 
to make them ``appear'' light to the user but could deliver as much 
nicotine to the user as high nicotine delivery cigarettes. The 
compensatory behaviors of the cigarette user were able to overcome the 
changes in ventilation in these higher ventilated products.
    VLNC cigarettes, in contrast, have relied on reducing nicotine 
content in the tobacco filler rather than engineering changes to the 
cigarette. Patents reveal that more than 96 percent of nicotine can be 
successfully extracted while achieving a product that ``was 
subjectively rated as average in smoking characteristics'' (Ref. 66) 
and that up to a 75 percent reduction in the nicotine contained in a 
tobacco leaf can be achieved with an ``effective and economical system 
for producing tobacco products . . . while maintaining other desirable 
ingredients for good taste and flavor'' (Ref. 67).
    In conventional cigarettes manufactured in the United States, 
nicotine accounts for approximately 1.5 percent of the cigarette 
weight, or 10-14 mg of nicotine per cigarette (Refs. 68-71) and 
generally have nicotine yields in the 1.1 mg to 1.7 mg (Ref. 31 at p. 
67). Certain VLNC cigarettes have much lower nicotine yields than 
conventional cigarettes--in the 0.02-0.07 mg nicotine/cigarette range--
due to product changes that the user cannot overcome (Ref. 72). 
Reducing the nicotine in the finished tobacco product places an 
absolute maximum limit on the amount of nicotine that can be extracted 
by the user in a given cigarette, unlike modifications such as 
ventilation holes, which affect nicotine yield in smoke but can be 
overcome through user behavior. See section IV.C of this document for a 
discussion of possible compensatory smoking under a single target 
approach or a stepped down approach to nicotine reduction.
1. VLNC Cigarettes
    The first VLNC cigarettes studied by researchers were produced by 
Philip Morris and marketed under the brand name ``Next,'' which was 
reported to contain 0.4 mg nicotine/g of tobacco filler (Ref. 73). 
Later, the National Institute for Drug Abuse (NIDA) contracted with the 
Ultratech/Lifetech

[[Page 11827]]

Corporation \9\ to produce VLNC cigarettes for research purposes (Ref. 
74; Ref. 75). The two types of cigarettes produced were: (1) 1.1 mg/
cigarette (cig) ISO smoke nicotine (7.2 mg nicotine/cig in filler) and 
(2) 0.07 mg/cig ISO smoke nicotine (filler levels were reported as 0, 
but FDA has estimated these levels to be between 0.4 and 0.5 mg/cig) 
(Ref. 74).
---------------------------------------------------------------------------

    \9\ Both Ultratech and Lifetech have been reported as being the 
company through which NIDA manufactured research cigarettes.
---------------------------------------------------------------------------

    Researchers also have used Quest cigarettes, produced by Vector 
Tobacco, to study the impact of reduced nicotine (Ref. 76). To provide 
consumers with reduced risk tobacco products, companies like 22nd 
Century are using genetic engineering and plant breeding to produce 
very low nicotine tobacco for incorporation into cigarettes. In 2014, 
the company was granted patents for its process to virtually eliminate 
the nicotine in tobacco plants (Ref. 77). Further, low-nicotine 
cigarettes are produced and distributed for research purposes by 
Research Triangle Institute (RTI), under a contract for the NIDA's Drug 
Supply Program (Ref. 78). 22nd Century is acting as a vendor for RTI 
for this contract manufacturing Spectrum cigarettes that contain 0.4 mg 
nicotine/gram (g) of tobacco filler (id). Finally, Philip Morris 
manufactured cigarettes with varying nicotine levels for research only 
(Ref. 79). FDA requests data and information regarding the risks to 
smokers from inhalation of VLNC cigarette smoke.
    Table 1 includes a list of VLNC cigarettes used in research studies 
and their reported nicotine levels.

 Table 1--Filler Nicotine and ISO Nicotine Delivery for Low and Very Low
    (*) Nicotine Cigarettes Made Available Either Commercially or for
                                Research
------------------------------------------------------------------------
                                       Filler nicotine     ISO Nicotine
         Type of cigarette           level (mg/g or mg/    delivery (mg/
                                            cig)               cig)
------------------------------------------------------------------------
Quest 1...........................  12.5 mg/g; 8.9 mg/               0.6
                                     cig.
Quest 2...........................  6.4 mg/g; 5.1 mg/cig             0.3
Quest 3...........................  1.0 mg/g; 0.4 mg/cig            *0.5
Ultratech/Lifetech................  10.3 mg/g \1\; 7.2               1.1
                                     mg/cig.
Ultratech/Lifetech\2\.............  0.6-0.7 mg/g \1\;             *<0.06
                                     0.4-0.5 mg/cig.
Next..............................  0.4 mg/g............           *0.08
Spectrum high nicotine............  11.4-12.8 mg/g......         0.6-1.0
Spectrum intermediate nicotine....  5.7-5.8 mg/g........             0.3
Spectrum low nicotine.............  0.4 mg/g............          *<0.04
Philip Morris 12 mg (for research   14.4 mg/g \1\; 10.1              0.9
 only).                              mg/cig.
Philip Morris 8 mg (for research    10.6 mg/g \1\; 7.4               0.6
 only).                              mg/cig.
Philip Morris 4 mg (for research    5 mg/g \1\; 3.5 mg/              0.3
 only).                              cig.
Philip Morris 2 mg (for research    2.1 mg/g \1\; 1.5 mg/            0.2
 only).                              cig.
Philip Morris 1 mg (for research    0.9 mg/g \1\; 0.6 mg/            0.1
 only).                              cig.
------------------------------------------------------------------------
\1\ mg/g or mg/cigarette (cig) was calculated based on an estimate of
  0.7 g of tobacco per cigarette (Ref. 80).
\2\ Filler nicotine level was reported as 0 mg/cig, but FDA estimates
  the cigarette contained 0.4-0.5 mg/cig.

2. Estimate of Addiction Threshold Levels
    In 1994, certain scientists proposed the idea of federal regulation 
of nicotine content, which could result in lower intake of nicotine and 
a lower level of nicotine dependence (Ref. 81). However, FDA 
acknowledges that there is individual variability in dose sensitivity 
to all addictive substances, making it difficult to determine a single 
addiction threshold which would apply across the population. A proposal 
to lower the nicotine in conventional cigarettes, or any tobacco 
product, could merit consideration only if there were a threshold 
nicotine exposure level below which the nicotine did not produce 
significant reinforcing effects or sustain addiction in a majority of 
the population. FDA continues to assess VLNC cigarette studies 
analyzing addiction threshold levels, as discussed in this section.
    Four primary study types speak to the level of nicotine in tobacco 
that could significantly reduce product addictiveness. The first type 
uses indirect estimates based on information in humans regarding 
nicotine intake in smokers who appear not to be addicted to nicotine to 
estimate a likely threshold level. A second type includes studies of 
VLNC use by study participants that have reported increased quit 
attempts and cessation even in smokers not interested in quitting. A 
third type includes studies that have revealed reduced positive 
subjective effects and increased negative effects in VLNC smokers. The 
fourth type includes studies measuring nicotine receptor binding, which 
indicate that use of VLNC cigarettes yields significantly lower 
nicotinic acetylcholine receptor (nAChR) occupancy and cerebral 
response.
    a. Indirect estimates of an addiction threshold. In 1994, 
researchers conducted a review to explore indirect estimates of an 
addiction threshold by focusing on the smoking habits of a small 
population of smokers who demonstrate reduced nicotine dependence, as 
compared to other smokers (a group sometimes referred to as tobacco 
``chippers'') (Ref. 81, citing Ref. 82,). In the 1994 review, 
researchers suggested that a threshold level of nicotine per cigarette 
should be low enough to prevent or limit the development of nicotine 
addiction in most young people, while providing enough nicotine for 
taste and sensory sensation (e.g., Ref. 81). These researchers found 
that based on existing studies at the time, ``an absolute limit of 0.4 
to 0.5 mg of nicotine per cigarette should be adequate to prevent or 
limit the development of addiction in most young people. At the same 
time, it may provide enough nicotine for taste and sensory 
stimulation'' (id.), which FDA interprets to mean that there would be 
enough nicotine for an experienced user to tell that there is nicotine 
in the tobacco product.
    In another study seeking to estimate a reinforcement threshold, 
scientists reviewed several studies, including one in which abstinent 
smokers received intravenous nicotine injections by pulling a lever in 
a fixed ratio task (Ref.

[[Page 11828]]

83). The authors found that studies using intravenous nicotine 
administration suggest that the nicotine reinforcement threshold (i.e., 
the minimum amount of nicotine intake required to initiate or maintain 
self-administration) is between 1.5 to 6.0 micrograms/kg in humans and 
3 to 10 micrograms/kg in rats (Ref. 84). Although the study's authors 
noted potential limitations (i.e., intravenous delivery does not mimic 
inhalation, administration of nicotine alone omits other psychoactive 
constituents in tobacco smoke, and other factors such as age, sex, and 
genetic variations may influence nicotine's reinforcing properties) 
(Ref. 84), the lowest dose in the study overlaps with the upper limit 
of an addiction threshold estimated by the 1994 study (Ref. 81). 
Despite the study limitations of both these estimates, they help 
provide a range on which to potentially base a nicotine level 
threshold.
    b. Findings of increased cessation for VLNC cigarettes. Several 
studies indicate that people using significantly reduced nicotine 
content cigarettes (as low as 0.4 mg nicotine/g of tobacco filler) are 
more likely to consider cessation (i.e., consider reducing cigarette 
intake as a step towards cessation or consider fully ceasing cigarette 
intake), even if they had not previously considered quitting (see, 
e.g., Refs. 4, 5, 63, and 64). These studies were not investigating 
VLNC cigarettes as cessation aids.
    Some studies showed that switching to VLNC cigarettes results in a 
reduced number of cigarettes smoked per day (Ref. 4; Ref. 76), reduced 
nicotine dependence (Refs. 4, 84, and 85), and minimal evidence of 
withdrawal distress and increased depression (Ref. 64, Ben 12; Refs. 
85-87). On the other hand, other researchers have reported the use of 
VLNC cigarettes did not change the number of cigarettes smoked per day 
(Refs. 86 and 88), but they did observe reductions in cotinine and 
carbon monoxide levels. For example, in the Benowitz et al. 2015 study 
(Ref. 86), where researchers progressively lowered nicotine content 
over 7 months, the authors found that, after the 7 months of VLNC 
cigarette use, nicotine intake remained below baseline (i.e., plasma 
cotinine at 149 ng/ml vs. 250 ng/ml). The Mercincavage et al. study 
(Ref. 88), a randomized study of smokers progressively decreasing 
nicotine content over three ten day periods, also yielded mixed results 
regarding harm exposure. The researchers found that certain biomarkers 
of exposure to toxic tobacco-related constituents (i.e., cotinine and 
NNAL) decreased with decreases in nicotine content, but there was no 
effect on the biomarker 1-hydroxpyrene (1-HOP) (Ref. 88). One 
limitation of these studies is that they were conducted in an 
unregulated environment in which smokers continued to have access to 
the normal nicotine content (NNC) cigarettes.
    One of the more recent studies (Ref. 85) on this issue was a 
double-blind, parallel, randomized clinical trial conducted between 
June 2013 and July 2014 that evaluated 840 participants (780 completed 
the 6-week study) who were not interested in quitting smoking. During 
the sixth week of the study, the average number of cigarettes smoked 
per day was lower for participants randomly assigned to cigarettes 
containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 
16.3, and 14.9 cigarettes per day, respectively) than for those 
assigned to their usual cigarette brand or those cigarettes containing 
5.2 or 15.8 mg per gram (22.2 and 21.3 cigarettes per day, 
respectively) (Ref. 85). Those participants using cigarettes with the 
lowest nicotine content (0.4 mg per gram nicotine/gram of tobacco 
filler, demonstrated reduced dependence, and use of reduced nicotine 
cigarettes, including the VLNC cigarettes, with minimal evidence of 
withdrawal-related discomfort or safety concerns (id.). The authors 
concluded that this study provides ``preliminary-short term data . . . 
[that] suggest that if nicotine content is adequately reduced, smokers 
may benefit by smoking fewer cigarettes and experiencing less nicotine 
dependence, with few negative consequences'' (id.).
    While these results, taken together with other studies, are 
promising, FDA acknowledges the inherent limitations of the available 
research on changes in smoking as a function of VLNC cigarettes use. As 
noted by the investigators of the 2015 double-blind, parallel, 
randomized clinical trial, ``no large-scale clinical trials of reduced 
nicotine cigarettes have been conducted. Furthermore, little is known 
about the dose-related effects of reduced nicotine. Data derived from 
trials assessing a range of reduced-nicotine cigarettes are critical 
for providing an empirical basis for regulatory decisions pertaining to 
nicotine product standards'' (Ref. 85). As a result, FDA requests 
submission of additional data that may be used to explore further the 
hypotheses presented in this ANPRM (e.g., extended duration studies) 
and supports the development of additional studies to further analyze 
these conclusions.
    c. Subjective effects and relief of withdrawal symptoms associated 
with VLNC cigarettes. Individuals who smoke VLNC cigarettes experience 
some of the same subjective effects as those individuals who smoke 
traditional, NNC cigarettes. For example, VLNC users report 
experiencing reductions in certain physiological withdrawal symptoms 
(e.g., craving, anxiety, irritability, depression) but do not 
experience other symptoms associated with full nicotine content 
cigarettes (e.g., relief of physical withdrawal symptoms, increased 
stimulation and alertness, reduction in restlessness) (Refs. 44, 72, 
74, 75, 89-93). Exposure over multiple days generally leads to a 
reduction in cigarettes smoked per day (Ref. 87). Furthermore, 
physiological responses after VLNC cigarettes, such as the increase in 
heart rate that is typically observed following nicotine 
administration, are less than those seen with higher nicotine 
cigarettes and are absent in some cases (Ref. 74, 94, and 95). Thus, it 
appears that transitioning to VLNC cigarettes (from NNC cigarettes) may 
result in some behavioral and physiological responses commonly 
experienced when using standard NNC cigarettes (e.g., reduced appetite, 
increased alertness). These responses, where present, are lower than 
those seen with standard nicotine cigarettes and get progressively 
lower over time.
    d. Lower nAChR occupancy and cerebral response from the use of VLNC 
cigarettes. VLNC cigarettes contain some nicotine, albeit at very low 
levels. Although there is enough nicotine in VLNC cigarettes to bind to 
acetylcholine receptors in the brain, there is not enough to 
consistently produce the full range of subjective responses (i.e., 
those responses based on or influenced by individual, internal 
perceptions or experiences) observed following use of NNC cigarettes 
(Refs. 74, 92, 96, and 97). Therefore, VLNC cigarettes may not produce 
the full range of subjective effects as NNC cigarettes. This supports 
the hypothesis that many subjective and physiological effects observed 
following exposure to smoke from VLNC cigarettes could be due to 
repeated pairing of nicotine with sensory and conditioned cues or to 
other psychoactive chemicals. Given that these subjective and 
physiological effects have been directly linked to nicotine, it is 
likely that they are learned responses through repeated pairing with 
nicotine and not due to other chemicals in the smoke.
    Please explain your responses and provide any evidence or other 
information supporting your responses to the following questions:
    1. The Tobacco Control Act prohibits FDA from reducing nicotine 
yields in any combusted tobacco product to zero

[[Page 11829]]

(section 907(d)(3) of the FD&C Act). If FDA were to propose a maximum 
nicotine level for cigarettes, what should be the maximum level to 
ensure that the product is minimally addictive or nonaddictive, using 
the best available science to determine a level that is appropriate for 
the protection of the public health? Rather than establishing a 
nicotine target to make products ``minimally addictive'' or 
``nonaddictive,'' should FDA consider a different threshold (e.g., less 
addictive than current products on the market)? How should the maximum 
level be measured (e.g., nicotine yield, nicotine in cigarette filler, 
something else)? What would be the potential health impacts of 
requiring a maximum nicotine level such as 0.4 mg nicotine/g of tobacco 
filler? FDA is interested in public health impacts of requiring 
different maximum nicotine levels, such as 0.3, 0.4, and 0.5 mg 
nicotine/gram of tobacco filler, as well as other maximum nicotine 
levels and solicits comments about the potential health impacts of 
different maximum levels.
    2. FDA lists four types of studies to estimate the threshold of 
nicotine addiction (i.e., indirect estimates; findings of increased 
cessation for VLNC cigarettes; subjective effects, craving, and 
withdrawal associated with VLNC cigarettes; and lower nAChR occupancy 
and cerebral response from the use of VLNC cigarettes). Should FDA rely 
on some or all of these types of studies? Why or why not? Is there a 
different method that FDA should investigate or use to determine the 
threshold for nicotine addiction?
    3. In addition to nicotine, minor tobacco alkaloids (including 
nornicotine, cotinine, anabasine, anatabine, and myosamine) and tobacco 
smoke aldehydes (such as acetaldehyde) are pharmacologically active and 
may contribute to addiction (see, e.g., Refs. 98 and 99). Researchers 
have investigated the abuse potential of nornicotine, cotinine, 
anabasine, and acetaldehyde in animals (Ref. 100). However, many of 
these compounds are only present in tobacco smoke at low levels and are 
likely less potent than nicotine in mediating pharmacological response 
and, therefore, reinforcement (Refs. 101 and 102). In addition to 
setting a maximum nicotine level, should the product standard also set 
maximum levels of other constituents (e.g., nornicotine, acetaldehyde, 
anabasine) that may have the potential to produce dependence and be 
addictive? If so, at what levels?
    4. If FDA were to finalize a nicotine tobacco product standard, 
what is the potential that adults and adolescents would perceive these 
VLNC cigarettes as ``safe''--and how could youth and adult risk 
perceptions of these cigarettes impact initiation, use, and cessation 
habits of combusted tobacco products?

C. Implementation (Single Target vs. Stepped-Down Approach)

    If FDA were to issue a product standard establishing a maximum 
nicotine level for cigarettes, such a standard would need to either 
propose a single target (where the nicotine is reduced all at once) or 
a stepped-down approach (where the nicotine is gradually reduced over 
time through a sequence of incremental levels and implementation dates) 
to reach the desired maximum nicotine level. Some have suggested that 
any maximum nicotine level should be established as a single target 
(rather than a stepped-down approach) to limit exposure to harmful 
tobacco while providing similar cessation rates to those that could 
occur with a stepped-down approach. Some level of compensatory smoking 
behavior (i.e., smokers seeking to obtain the amount of nicotine they 
need to sustain their addiction by smoking more cigarettes per day, 
taking more and deeper puffs, and/or puffing with a faster draw rate) 
theoretically could occur under either a single target or stepped-down 
approach and could impact the public health benefits of a possible 
nicotine tobacco product standard. According to studies involving VLNC 
cigarettes and other reduced nicotine cigarettes, researchers expect 
there could be very little or no compensatory smoking with a single 
target approach and that it would be self-limiting (i.e., smokers would 
be unable to obtain their nicotine dose from cigarettes no matter how 
they smoke them and eventually would stop trying to do so), which could 
maximize the benefits of such a tobacco product standard (Refs. 3-5). 
If individuals were to engage in compensatory smoking with a single 
target approach, researchers find that any compensatory smoking at the 
maximum nicotine levels that FDA is considering here could only be 
minimal and transient (e.g., Refs. 103, 104, 92, and 93).
    In contrast, during a stepped-down approach, tobacco users may 
attempt to compensate for the loss of nicotine during the early stages 
of a stepped-down approach by smoking additional tobacco products or by 
smoking more intensely, since the intermediate-stage products could 
allow for extraction of nicotine through such efforts in a way that 
VLNC cigarettes would not (e.g., Refs. 64, 76, and 105).\10\
---------------------------------------------------------------------------

    \10\ However, the IOM has cited one study showing that when 
nicotine content is stepped down, smokers do not engage in 
compensatory smoking when nicotine is extracted from tobacco and, 
therefore, do not increase their toxic exposures (Ref. 13 at p. 
349).
---------------------------------------------------------------------------

    FDA is aware of several studies that have demonstrated the impact 
of an immediate (e.g., Refs. 53, 106-108) or a stepped-down approach 
(Ref. 64) to nicotine reduction on smoking cessation outcomes. 
Researchers have found that the single target approach may be 
associated with better cessation outcomes. Data from the International 
Tobacco Control Policy Evaluation 4-Country Survey, a telephone survey 
of more than 8,000 adult smokers in the United States, the United 
Kingdom, Canada, and Australia, illustrates the cessation benefits from 
abrupt abstinence from cigarettes (``cold turkey'') when compared to a 
gradual reduction of smoking prior to complete abstinence (``cut 
down'') (Ref. 109). While this differs from the approaches considered 
in this ANPRM, it provides helpful insight into the effects of a 
gradual vs. single change in nicotine intake. Researchers concluded 
that immediate nicotine cessation was ``clearly associated with more 
successful outcomes'' (Ref. 109). Scientists also found higher 
abstinence rates for those using the single target approach in studies 
comparing two levels of commercial low-yield nicotine cigarettes and 
nicotine lozenges (Ref. 4).
    Nevertheless, some studies have found that both reduction 
strategies increase a smoker's probability of cessation. For example, 
in a study of smokers with no strong preference for a quitting method 
who were randomly assigned to study arms requiring either that they 
quit immediately or gradually reduce their cigarette consumption over 2 
weeks, both the immediate and gradual cessation methods produced 
similar results (Ref. 110). Likewise, in a meta-analysis of 10 studies 
to determine the impact of stepped reduction of nicotine versus a 
single nicotine target in participants interested in quitting smoking, 
scientists determined that a stepped reduction in nicotine ``provides 
similar quit rates to abrupt quitting with no evidence that one method 
is significantly superior to the other in adults trying to quit 
smoking'' (Ref. 111 at p. 13) and concluded that there were no 
additional cessation benefits for the stepped-down approach (Ref. 111 
at p. 2).
    FDA understands the argument that a stepped-down approach to 
limiting the nicotine levels in tobacco products

[[Page 11830]]

could undermine the public health goals of such a standard by allowing 
for prolonged exposure to tobacco-related toxicants during the step-
down period. Although both approaches likely would result in comparable 
quit rates eventually, some studies have indicated a greater likelihood 
of cessation success with the use of a single target. In addition, 
preliminary studies show that a single target approach could limit 
further exposure to harmful tobacco (when compared with the stepped-
down approach to limiting nicotine levels). FDA continues to weigh 
these factors, and will consider the information submitted in response 
to this ANPRM, as it decides the appropriate approach for a potential 
nicotine tobacco product standard.
    Please explain your responses and provide any evidence or other 
information supporting your responses to the following questions:
    1. What data are available to demonstrate that a single target 
approach to reach a maximum nicotine level would or would not result in 
any unintended consequences?
    2. In the alternative, what data are available to demonstrate that 
a stepped-down approach involving a sequence of incremental levels and 
implementation dates to reach a proposed nicotine level would or would 
not result in any unintended consequences?
    3. If FDA were to select a stepped-down approach for a nicotine 
tobacco product standard, what scientific evidence exists to support 
particular interim nicotine levels and the appropriate number of steps 
that would be needed to reach the target level?
    4. Would a single target and a stepped-down approach for 
implementation result in comparable quit rates or reduced initiation 
rates?
    5. What would be the likely implementation differences, including 
implementation timelines and transition costs, between a single target 
approach or a stepped-down approach involving a sequence of incremental 
levels and implementation dates?

D. Analytical Testing Method

    As part of its consideration regarding a potential nicotine tobacco 
product standard, FDA is also considering whether such a product 
standard should specify a method for manufacturers to use to detect the 
level of nicotine in their tobacco products. FDA believes that the 
results of any test method to measure the nicotine in combusted tobacco 
products should be comparable across different accredited testing 
facilities and products. It is critical that the results from the test 
method demonstrate a high level of specificity, accuracy, and precision 
in measuring a range of nicotine levels across a wide variety of 
tobacco blends and products.
    A variety of methods have been in development that allows nicotine 
in tobacco or tobacco product filler to be quantified for various 
products. For example, two Cooperation Centre for Scientific Research 
Relative to Tobacco (CORESTA) methods have undergone round-robin method 
validation studies in accordance with ISO 5725-1 through ISO 5725-2: 
(1) Continuous flow analysis (CFA) and (2) gas chromatography-flame 
ionization detector (GC-FID). The CFA method measured a nicotine range 
of 0.69-3.30 percent (or 6.9-33 mg/g) in burley and flue-cured tobaccos 
and exhibited a repeatability range of 0.03-0.17 and a reproducibility 
range of 0.12-0.67, dependent on the mean (Ref. 112). A GC-FID method 
for determining nicotine in fermented extractions from tobacco leaves 
was validated in accordance with FDA and International Council for 
Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use specifications, including specificity, 
linearity, precision, accuracy, and robustness (Ref. 113). Gas 
chromatography-mass spectrometry (GC-MS) was used as the confirmation 
technique in this study, in which a recovery of 117.8 percent was 
achieved; recovery was within FDA guidelines (<120 percent) (Ref. 113). 
Nicotine content of 0.43 percent (4.3 mg/g) in the extract was reliably 
measured and stability testing on this same extract was conducted for 
360 days (id.). In addition, the WHO's Tobacco Laboratory Network 
(TobLabNet) has developed a standard operating procedure for 
determination of nicotine in cigarette tobacco filler using gas 
chromatography (Ref. 114). The WHO's TobLabNet determined that this 
method is suitable for the quantitative determination of nicotine in 
cigarette tobacco filler by gas chromatography (GC) (id.).
    We also note that ISO 10315 and CORESTA Method No. 62 have been 
used in substantial equivalence reports submitted to the Agency. ISO 
10315 is a method for analyzing nicotine in smoke. With this method, 
conditioned cigarettes are smoked under ISO 4387 conditions and smoke 
is captured on a Cambridge filter pad and extracted in propan-2-ol 
containing internal standard such as n-heptadecane or quinaldine 
(carvone or n-octadecane are other alternatives to internal standards) 
and analyzed immediately using GC coupled with flame ionization 
detection (Ref. 115).
    CORESTA Method No. 62 is a standard method used to analyze nicotine 
in tobacco filler and smokeless tobacco products (Ref. 116). This 
method describes extraction of nicotine in solid tobacco in basified 
extraction solution (using sodium hydroxide to deprotonate the nicotine 
in solution) of either hexane containing n-heptadecane or quinaldine 
internal standards or basified extraction solution (using sodium 
hydroxide) of methyl-t-butyl ether solution containing quinoline 
internal standard (id.).
    FDA is also aware of other methods that have been used to analyze 
nicotine levels. Such methods include GC combined with various 
detectors, GC-MS with solid-phase microextraction as a preconcentration 
step for low detection, other formats of GC-FID, capillary 
electrophoresis combined with either ultraviolet (UV) or 
electrochemical detection, and alternative chromatography techniques 
including supercritical fluid chromatography-ion mobility detection 
(Ref. 117), reversed phase ion-pair liquid chromatographic extraction 
(Ref. 118), and high-pressure liquid chromatography with UV detection 
(Ref. 119).
    Please explain your responses and provide any evidence or other 
information supporting your responses to the following questions:
    1. If FDA were to issue a product standard, should the Agency 
require a standard method of product testing to analyze the nicotine 
levels in products subject to the standard? If so, what method or 
methods should FDA use?
    2. Should the Agency require manufacturers to sample their products 
in a specific manner to ensure that products do not contain excess 
levels of nicotine? Should manufacturers be required to test each 
manufactured batch to ensure compliance with a product standard 
limiting nicotine levels? What criteria should be used to determine if 
a batch passes or fails testing?

E. Technical Achievability

    FDA continues to analyze the technical achievability of a maximum 
nicotine level for cigarettes as part of its overall assessment of how 
best to implement this authority and is seeking comments from 
interested parties regarding this issue, including with respect to the 
technical achievability of such a standard for small cigarette and/or 
small combusted tobacco product manufacturers.

[[Page 11831]]

    The industry and consumer product companies have developed versions 
of denicotinized cigarettes and a range of brands with differing 
nicotine levels. By blending tobaccos based on nicotine levels, tobacco 
companies have manufactured their products to specifications that 
ensure the final product will have precise levels of nicotine and have 
ensured that nicotine levels vary only minimally within cigarette packs 
and from pack to pack (60 FR 41453 at 41505, 41509, August 11, 1995). 
In fact, the tobacco industry has had programs in place since the 1960s 
to obtain ``any level of nicotine desired'' (Ref. 120, citing Ref. 
121). The industry also has recognized that the techniques it has used 
to increase nicotine levels can be used to reduce nicotine levels as 
well (60 FR 41453 at 41722).
    As previously described, VLNC cigarettes have been produced since 
the 1970s. During this time, NCI contracted for production of a line of 
cigarettes with widely varying nicotine concentrations (Ref. 122, 81 
SG). In the late 1980s, a major cigarette manufacturer had plans to 
develop VLNC cigarettes with a reduction in mainstream nicotine yields 
of greater than 95 percent (Ref. 123). More recently, 22nd Century, 
acting as vendor for RTI's contract with NIDA, has developed 
cigarettes, not currently commercially available, that are similar in 
many sensory characteristics to conventional cigarettes but with 
extremely low nicotine levels (Refs. 54, 124, and 125).
    Significant reductions of nicotine in combusted tobacco products 
can be achieved principally through tobacco blending and cross-breeding 
plants, genetic engineering, and chemical extraction. Agricultural 
practices (e.g., controlled growing conditions, fertilization, harvest) 
as well as more recent, novel techniques also can help to reduce 
nicotine levels. One or a combination of these processes could be used 
to achieve the nicotine levels that FDA is considering for a nicotine 
tobacco product standard.
1. Tobacco Blending/Cross Breeding
    Most of the cigarettes sold in the United States are blended 
cigarettes (Ref. 126). A tobacco industry executive previously 
testified that the main component of a cigarette that contributes to 
nicotine delivery is the tobacco blend and that year-to-year crop 
variation does not determine the nicotine content in a cigarette (Ref. 
127). The term ``leaf blending'' describes the selection of tobaccos to 
be used in a product by tobacco type (e.g., flue-cured, burley, 
oriental), geographical origin, year, and grade of the tobacco (Ref. 
128). Blend differences can produce significant variations in nicotine 
concentration in the tobacco rod, leading to differences in smoke 
composition and yield (Ref. 120 at p. 469). Grading, which is used to 
evaluate and identify differences within tobacco types and is a 
function of both plant position (i.e., higher or lower on the stalk) 
and of quality (i.e., ripeness), and segregation of grades by nicotine 
content, already has become common practice (Ref. 128 at p. 2-3).
    Many tobacco lines are available, including approximately 1,000 
different tobacco varieties (Ref. 126). The tobacco industry has used 
breeding and cultivation practices to develop high nicotine tobacco 
plants to give manufacturers greater flexibility in blending and in 
controlling the amount of nicotine to be delivered (60 FR 41453 at 
41694). These practices could be used to develop low nicotine plants as 
well. In fact, tobacco industry documents show that in the 1960s, 
tobacco companies recognized the increasing demand for low nicotine 
tobacco and began instituting projects that found that low nicotine 
cigarettes can be made by selecting grades of tobacco with low nicotine 
content (Ref. 128; citing Ref. 129; Ref. 130).
    Because the nicotine content of tobacco plants varies, 
manufacturers could replace more commonly used nicotine-rich varieties 
like Nicotiana rustica with lower nicotine varieties (Ref. 131). 
Oriental Turkish-type cigarettes also deliver substantially less 
nicotine than cigarettes that contain air-cured Burley tobacco (Ref. 
120; citing Ref. 132). In addition, manufacturers could select specific 
tobacco seedlings that are low in nicotine and plant only those low 
nicotine seedlings (Ref. 133). Even without this selective breeding, 
manufacturers could use careful tobacco leaf purchasing plans to 
control the nicotine content in their products (60 FR 41453 at 41694). 
By maintaining awareness of the differences and monitoring the levels 
in purchased tobacco, companies could produce cigarettes with nicotine 
deliveries consistent to one-tenth of one percent (despite variations 
of up to 25 percent in the nicotine content of the raw material grown 
in the same area, from year to year) (60 FR 41453 at 41694).
    The position of leaves on the plant stalk also affects nicotine 
levels; tobacco leaves located near the top of the plant can contain 
higher concentrations of nicotine and lower stalk leaves generally 
contain lower nicotine levels (Ref. 114; Ref. 120). For example, flue-
cured tobacco leaves harvested from the lowest stalk position may 
contain from 0.08 to 0.65 percent nicotine, whereas leaves from the 
highest positions may contain between 0.13 and 4.18 percent nicotine 
(Ref. 126, citing Ref. 134). Therefore, substituting leaves found lower 
on the plants could reduce the nicotine content of tobacco products 
(Ref. 131).
    A number of internal tobacco industry documents describe the use of 
leaf blending and tobacco selection to control the nicotine content of 
cigarettes (Ref. 128 at p. 3). For example, one company project 
determined that low nicotine cigarettes can be made by selecting grades 
of tobacco with low nicotine content (Ref. 128 at p. 3, citing Ref. 
135). Another observed that the demand for low nicotine tobacco has 
increased worldwide and necessitated a shift in purchasing standards 
(Ref. 128 at p. 3, citing Ref. 136).
2. Chemical Extraction
    Nicotine also can be removed from tobacco via chemical extraction 
technology. By the 1970s, tobacco manufacturers regularly practiced 
nicotine extraction as a method to control nicotine delivery (Ref. 128, 
citing Ref. 137; Refs. 138 and 139). Extraction methods include water 
extraction (coupled with steam or oven drying), solvent extraction, and 
extractions of nicotine without usable leaf (Ref. 128). Supercritical 
fluid extraction also yielded success in the 1990s, allowing for 
optimum extraction times and the elimination of more time-consuming 
steps (Refs. 140 and 141). FDA notes that there are existing patents 
for chemical extraction of nicotine in tobacco, which reveal that more 
than 96 percent of nicotine can be successfully extracted while 
achieving a product that ``was subjectively rated as average in 
nicotine characteristics'' (Refs. 142 and 66).
    In addition, a major tobacco manufacturer has used a high-pressure 
carbon dioxide process similar to the process used to decaffeinate 
coffee. In this process, tobacco leaf is treated with ammonium salt, 
then treated with carbon dioxide/water vapor, which has achieved a 95 
to 98 percent reduction in nicotine (Ref. 133, citing Ref. 143) 
Although some manufacturers believe that previous water extraction 
practices may have rendered the tobacco ``unsuitable for use,'' other 
water extraction projects yielded suitable smoking material with 
sizeable nicotine reductions (80 to 85 percent reduction in leaf 
nicotine) (Ref. 128, citing Ref. 144; Refs. 145 and 146).

[[Page 11832]]

3. Genetic Engineering
    Tobacco industry scientists have long recognized the potential for 
genetic engineering to control nicotine content (Ref. 147). The first 
practical application of biotechnology by a major tobacco manufacturer 
was the development of low nicotine tobacco in the 1980s, which led to 
the receipt of a patent for biotechnology for altering nicotine in 
tobacco plants (Refs. 133 and 148). Other tobacco researchers and major 
manufacturers also recognized the value of biotechnology for developing 
low nicotine tobacco for cigarettes, including for use as part of a 
smoking cessation program (Ref. 149).
    Several American and international tobacco companies genetically 
engineered low nicotine varietals in the 1960s and 1970s, including a 
strain with nicotine levels as low as 0.15 percent (Ref. 128; citing 
Refs. 150-155). During that time period, the Kentucky Tobacco Research 
Board worked on genetic strains of low nicotine tobacco (with a 
nicotine content of 0.2 percent) to be used for experimental studies on 
the role of nicotine in smoking behavior (Ref. 128, citing Refs. 156-
159). In addition, Canadian researchers examined low nicotine strains 
of tobacco, particularly in association with efforts to develop a 
strain of flue-cured or air-cured tobacco that would be suitable as the 
base material for reconstituted tobacco (Ref. 128, citing Refs. 151 and 
160). In 2003, Vector Tobacco began marketing the Quest cigarette, 
which was produced from genetically modified tobacco and contained only 
trace amounts of nicotine (Ref. 133) (this product is no longer on the 
market). Genetic engineering has resulted in reductions of nicotine 
levels in the range of 80 to 98 percent (id.). In 2014, the U.S. Patent 
and Trademark Office granted two patents for two genes that may be 
suppressed to achieve a substantial decrease in nicotine in tobacco 
plants (Ref. 161).
4. Other Practices
    Industry studies have shown that changes to growing and harvesting 
practices affect the development of tobacco chemistry, including 
nicotine content (Ref. 128). Some manufacturers have revised their 
agricultural practices specifically to meet new product development 
goals, such as the production of low nicotine tobacco (id.). For 
example, one manufacturer evaluated various experimental agricultural 
practices that could affect the tobacco's chemistry, including bulk-
curing, once-over harvesting, and high plant density (id., citing Ref. 
162). In other cases, chemical agents were observed to reduce nicotine 
content (Ref. 128 citing Refs. 163-165).
    After growers harvest tobacco, it is cured and aged before use in 
tobacco products. The aging process naturally changes the chemistry of 
the tobacco, including some reduction in nicotine content (Ref. 128). 
At least one manufacturer has explored efforts to speed up the process 
of aging tobacco, in part to alter or limit the changes in chemistry 
that naturally occur (id., citing Ref. 166). Other approaches to curing 
and fermenting tobacco were explored as a method for altering nicotine 
content (Ref. 128). For example, in one manufacturer's report, 
researchers observed that the properties of tobacco, including nicotine 
content, could be altered without the need for nontobacco additives by 
modifying curing practices (id., citing Ref. 167). In addition, 
manufacturers have explored approaches to identify microbial bacteria 
that actively degraded nicotine while leaving other components of the 
leaf intact (Ref. 128, citing Refs. 168 and 169). Consumer product 
testing showed that the ``product acceptability'' of that tobacco was 
equal to that of untreated tobacco (Ref. 128, citing Ref. 170).
    Researchers have developed novel approaches to reducing the 
nicotine in tobacco products in recent years. For example, a salivary 
excretion produced by a caterpillar (containing the enzyme glucose 
oxidase) is applied to tobacco plant leaves and can reduce the nicotine 
in tobacco leaf by up to 75 percent and provide an ``effective and 
economical system for producing tobacco products which contain about 
0.01 mg nicotine per cigarette or less . . . while maintaining the 
other desirable ingredients for good taste and flavor'' (Ref. 67).
    Please explain your responses and provide any evidence or other 
information supporting your responses to the following questions:
    1. What methods are tobacco product manufacturers currently using 
to maintain consistency of the nicotine in their products, given the 
variability of nicotine levels over growing seasons and crop type? How 
could these methods be adapted to ensure that certain combusted tobacco 
products meet a potential nicotine tobacco product standard?
    2. What is the feasibility of using the techniques discussed in 
this section, or other nicotine reduction techniques, to reduce the 
nicotine in cigarettes?
    3. What is the feasibility of using the techniques discussed in 
this section, or other nicotine reduction techniques, for non-cigarette 
combusted tobacco products (e.g., cigarette tobacco, RYO tobacco, 
little cigars, large cigars, cigarillos, pipe tobacco, and waterpipe 
tobacco) that FDA is considering covering under a nicotine tobacco 
product standard?
    4. If FDA were to propose a tobacco product standard setting a 
maximum nicotine level, how, if at all, would such a product standard 
impact tobacco farmers' growing and/or curing practices? If FDA were to 
finalize a nicotine tobacco product standard, what would be the costs 
and benefits for tobacco farmers and tobacco processors, particularly 
regarding how any such rulemaking might affect them in light of new 
technologies and business opportunities that are foreseeable, but not 
now in place? In addition, if FDA were to finalize a nicotine tobacco 
product standard, what would be the costs for farmers in light of such 
a standard?
    5. Section 907(d)(2) of the FD&C Act provides that a tobacco 
product standard must set forth the effective date of the standard, 
which may not be less than 1 year after publication of a final rule 
unless FDA determines that an earlier effective date is necessary for 
the protection of the public health (and that such effective date be 
established ``to minimize, consistent with the public health, economic 
loss to, and disruption or dislocation of, domestic and international 
trade''). This section also provides that the effective date be a 
minimum of 2 years after publication of a final rule if the tobacco 
standard can be met only by requiring ``substantial changes to the 
methods of farming the domestically grown tobacco used by the 
manufacturer.'' Therefore, if FDA were to propose a product standard 
setting a maximum nicotine level, when should this standard become 
effective? What implementation timeframe would allow adequate time for 
industry to comply? Should the same timeframe be required for all 
tobacco product manufacturers, regardless of their number of employees 
and/or annual revenues? \11\ Given the currently available processes to 
reduce the nicotine in tobacco products (e.g., chemical processes, 
genetic engineering), what do manufacturers

[[Page 11833]]

and others with relevant expertise consider an appropriate timeframe to 
implement a product standard to reduce nicotine? Would a 2-year, 4-
year, or 6-year timeframe be appropriate?
---------------------------------------------------------------------------

    \11\ The Tobacco Control Act defines ``small tobacco product 
manufacturer'' to be a tobacco product manufacturer that employs 
fewer than 350 employees (21 U.S.C. 387(16)). In the preamble to the 
deeming rule, FDA defined ``small-scale tobacco product 
manufacturers'' to be a manufacturer of any regulated tobacco 
product with 150 employees or fewer and annual total revenues of $5 
million or less (81 FR 28973 at 28980). If you are providing 
comments or information relevant to these definitions or a different 
definition, please note that definition in your comments.
---------------------------------------------------------------------------

    6. Should the standard include provisions that would allow 
manufacturers, distributors, or retailers to sell off existing 
nonconforming inventory of manufactured combusted tobacco products? If 
so, what would be a reasonable sell-off period?
    7. What are the potential outcomes of implementing methods to 
reduce nicotine content in cigarettes in terms of impact on 
characteristics of cigarettes (flavor, taste, aroma, etc.) and user 
experience?

F. Possible Countervailing Effects

    Section IV. B discusses some of the potential benefits that FDA 
expects could occur as a result of one possible nicotine tobacco 
product standard. There may be possible countervailing effects that 
could diminish the population health benefits expected as a result of a 
nicotine tobacco product standard. As part of any subsequent rulemaking 
FDA would need to assess these effects in comparison to the expected 
benefits, including among population subgroups.
    One possible countervailing effect is continued combusted tobacco 
product use. Current smokers of tobacco products covered by a nicotine 
tobacco product standard could turn to other tobacco products to 
maintain their nicotine dependence, both in combination with cigarettes 
(i.e., dual use) or in place of cigarettes (i.e., switching). For those 
users seeking to switch to a potentially less hazardous tobacco product 
(e.g., electronic nicotine delivery systems), FDA expects that the 
increase in consumer demand for such other products likely would be met 
by the tobacco industry, which has a history of being responsive to 
market shifts (see FDA's Draft Concept Paper published elsewhere in 
this issue of the Federal Register). For example, traditional cigarette 
manufacturers began to expand into the smokeless market when 
restrictions on where smokers were allowed to smoke were in enacted in 
the 1980s, 1990s, and early 2000s (id., citing Ref. 171). FDA also 
wishes to better understand whether users would switch to premium 
cigars if these products were excluded from the scope of a nicotine 
tobacco product standard. FDA has requested data and information on 
whether large and/or so-called premium cigars would be migration or 
dual use candidates, or whether and how there is a way to define 
``premium cigar'' to minimize such consequences.
    While FDA believes that some consumers would be satisfied with VLNC 
cigarettes, the Agency expects that there would be a subset of 
consumers uninterested in switching to VLNC cigarettes or quitting 
tobacco products altogether. This subset of consumers may seek to 
obtain illicit tobacco products after a standard becomes effective (see 
FDA's Draft Concept Paper). As a result, FDA is considering whether an 
increase in illicit trade might occur as a result of a nicotine tobacco 
product standard and how that could impact the marketplace and public 
health. The analysis of possible illicit trade includes considerations 
regarding the sources of tobacco, how illicit tobacco products might be 
manufactured, possible workarounds (such as adding nicotine in liquid 
or other form to a product with minimally addictive or nonaddictive 
nicotine levels), the ability to distribute illicit products, the 
development of consumer awareness, and how illicit trade sales might 
take place (id.). The capacity to produce illicit tobacco products 
would depend upon a variety of factors, including the ease of acquiring 
the raw materials (particularly tobacco), the sophistication required 
to construct the desired product, and the purpose (whether it is for an 
individual's personal use, or for wider distribution and sale). Large, 
commercial, tobacco product manufacturers have the resources, 
sophistication, and ability to manufacture illicit tobacco products 
(id.). Illicit tobacco products also may be smuggled and sold through 
the internet. It is unclear, however, to what extent such companies 
would be willing to risk their businesses (and resulting profits) to 
manufacture illicit tobacco products (id.). Tribal manufacturers are an 
additional source of tobacco products, having relatively high 
sophistication and machinery in some instances, but they are also 
subject to the same disincentives as large manufacturers and generally 
lack widespread distribution and sales capabilities (id.).
    The IOM has explored the issue of possible illicit trade if FDA 
were to issue a tobacco product standard limiting the levels of 
nicotine in cigarettes. The IOM found that although there is 
insufficient evidence to draw firm conclusions regarding how the U.S. 
illicit tobacco market would respond to regulations requiring a 
reduction in the nicotine content of cigarettes, limited evidence 
suggests that the demand for illicit conventional cigarettes would be 
``modest'' (Ref. 172). The IOM suggests that demand would be limited, 
because some smokers may quit and other will use modified products or 
seek legal alternatives (id.). Although some smokers may seek to 
purchase illicit products if available and accessible, the IOM finds 
that this ``would require established distribution networks and new 
sources of product (which would either have to be smuggled from other 
countries or produced illegally) to create a supply of cigarettes with 
prohibited features'' (id.). Given that individuals have utilized 
distribution networks to smuggle cigarettes and avoid higher taxes, FDA 
is considering whether there might be additional incentive to create or 
obtain the prohibited cigarettes that are not available elsewhere in 
the United States. In addition, the report explains that comprehensive 
interventions by several countries show that it is possible to reduce 
the size of the illicit tobacco market through enforcement mechanisms 
and collaborations across jurisdictions (id.).
    If a nicotine tobacco product standard were to prompt the 
development of an illicit market, FDA would have the authority to take 
enforcement actions regarding the sale and distribution of illicit 
tobacco products. The FD&C Act provides FDA with several tools that it 
may use against noncompliant parties. For example, FDA could issue a 
Warning Letter, an advisory action in which FDA notifies a regulated 
entity that FDA has found evidence that the party violated the law. A 
Warning Letter is used to achieve prompt voluntary compliance. In a 
Warning Letter, FDA informs the regulated entity that failure to comply 
with the requirements of the FD&C Act and its implementing regulations 
may result in FDA enforcement action. These actions may include 
initiating administrative actions or referring cases to the Department 
of Justice for initiation of judicial action. FDA may seek to initiate 
an administrative legal action against a regulated entity that can 
result in the imposition of a fine or civil money penalty. Possible 
judicial actions may include seizures, injunctions, and criminal 
prosecution.
    Another possible countervailing effect is the potential for 
increased harm due to continued VLNC smoking with altered smoking 
behaviors. Some studies of VLNC cigarettes with nicotine levels similar 
to what FDA is considering have not found compensatory smoking behavior 
and have found reductions in the number of cigarettes smoked per day 
and, consequently, decreased exposure to harmful constituents (as 
discussed in

[[Page 11834]]

section IV.B of this document). If FDA decides to pursue a proposed 
nicotine product standard, FDA will continue to consider this potential 
countervailing effect.
    Another possible countervailing effect of setting a maximum 
nicotine level for cigarettes could be that users would seek to add 
nicotine in liquid or other form to their combusted tobacco products. 
Therefore, FDA is considering whether any action it might take to 
reduce nicotine in combusted tobacco products should be paired with a 
provision that would prohibit the sale or distribution of any tobacco 
product designed for the purposes of supplementing the nicotine content 
of a combusted tobacco product (or any product where the reasonably 
foreseeable use is for the purposes of supplementing this nicotine 
content). FDA is also considering what other regulatory options may be 
available to address this concern and requests comments on such 
options.
    Please explain your responses and provide any evidence or other 
information supporting your responses to the following questions:
    1. In addition to a nicotine tobacco product standard, should FDA 
consider any additional regulatory action to address the possibility of 
migration to, or dual use with, other tobacco products?
    2. If FDA were to issue a product standard setting a maximum 
nicotine content for cigarettes, would smokers seek to add liquid 
nicotine to their VLNC cigarettes? Therefore, should such a regulation 
include provisions prohibiting the sale or distribution of any tobacco 
product designed for the purposes of supplementing the nicotine content 
of a combusted tobacco product (or any product where the reasonably 
foreseeable use is to supplement this nicotine content)? How could such 
a provision be structured to efficiently and effectively achieve this 
purpose? Should FDA consider other means to prevent supplementing the 
nicotine content of a combusted tobacco product subject to a nicotine 
tobacco product standard?
    3. Would a nicotine tobacco product standard affect the current 
illicit trade market, and, if so, to what extent? How would users 
obtain their sources of tobacco in an illicit market? How would 
manufacturers distribute their illicit products and develop consumer 
awareness of such products? How would such sales take place?
    4. FDA hypothesizes that, based on currently available research, 
nicotine levels like those levels that FDA would consider with a 
possible nicotine tobacco product standard would be self-limiting 
(i.e., smokers would be unable to obtain their nicotine dose from 
cigarettes no matter how they smoke them and eventually would stop 
trying to do so). Do any peer-reviewed studies demonstrate that 
lowering the nicotine content of cigarettes to minimally addictive 
levels might encourage consumers to smoke more VLNC cigarettes to 
achieve the higher nicotine doses currently delivered by NNC 
cigarettes?
    5. If a nicotine tobacco product standard were in effect, the 
following outcomes could occur: (1) Smokers could continue to smoke but 
use the low nicotine products; (2) smokers could completely switch to, 
or dual use low nicotine products with, other legal tobacco or nicotine 
products; (3) smokers could quit using any nicotine or tobacco product; 
or (4) smokers could seek to buy illegal cigarettes in an illicit 
market. Are there data that would provide information on which of these 
outcomes is most likely? Is there some other outcome that could occur?
    6. If an illicit market developed, what percentage of current 
smokers would switch to illicit conventional cigarettes rather than 
quitting or switching to other legal products? How would this change if 
illicit conventional cigarettes were more expensive and/or harder to 
obtain? How would this change with the implementation of improved 
monitoring and enhanced enforcement by FDA and its partners?
    7. If a nicotine tobacco product standard prompted growth of an 
illicit market, how long would it likely last? Would demand likely 
decrease over time, stay the same, or increase?
    8. If a nicotine tobacco product standard prompted growth of an 
illicit market, what effect, if any, would this have on the market for 
illegal drugs? Are there data showing a relationship between illicit 
tobacco use and illegal drug use?
    9. What mechanisms may be used to prevent, control, or contain 
illicit markets in conventional cigarettes that may develop if FDA 
establishes a product standard? What State and Federal entities may be 
responsible for these mechanisms, and how much would they cost?

G. Other Considerations

    To aid in its consideration regarding development of a nicotine 
tobacco product standard, FDA is seeking data, research results, and 
other information regarding the following:
    1. What data may be helpful to assess the universe of tobacco 
products that are currently available to consumers and their relevant 
characteristics, such as nicotine levels? How can available sources of 
information, such as manufacturer registrations and/or product listings 
with FDA, be used in this assessment?
    2. How should potential consumer surplus or utility loss from the 
removal of nicotine in cigarettes be considered, given the availability 
of other sources of nicotine such as ENDS and the continued 
availability of combustible tobacco products?
    3. What sources of information could be used to estimate the change 
in demand for VLNC cigarettes? What factors should we consider in 
estimating the changes in demand for other tobacco products?
    4. What factors should be considered in estimating changes in 
experimentation and initiation that may occur as a result of a 
potential nicotine tobacco product standard?
    5. In what ways might a change in nicotine levels in cigarettes 
spur innovation in the market for both combusted and noncombusted 
tobacco products?
    6. What factors should be considered in estimating the impacts of 
externalities that might exist for VLNC cigarettes, such as secondhand 
smoke, litter, and pollution? How could the impact of externalities for 
VLNC cigarettes be compared to the impacts from NNC cigarettes?
    7. What factors should we consider in estimating the impact of 
changes in demand for other tobacco products?
    8. If FDA were to finalize a nicotine tobacco product standard, 
what might be the costs to current smokers?
    9. Are there any other relevant comments or information that would 
be helpful for FDA to consider in analyzing the economic impacts of a 
proposed nicotine tobacco product standard?

V. Potential Public Health Benefits of Preventing Initiation to Regular 
Use and Increasing Cessation

    If FDA were to issue a proposed tobacco product standard setting a 
maximum nicotine level, FDA would provide an analysis explaining how 
the proposed rule would be appropriate for the protection of the public 
health (section 907(a)(3)(A) of the FD&C Act). For the purposes of this 
ANPRM, this section briefly describes the potential public health 
benefits FDA believes could result from the increased cessation and 
decreased initiation to regular use that FDA expects could occur if 
cigarettes and possibly some other combusted tobacco products were 
minimally addictive or nonaddictive. It also references findings from a

[[Page 11835]]

population-based simulation model that quantified the potential public 
health impact of enacting a regulation lowering nicotine levels in 
cigarettes and some other combusted tobacco products to minimally 
addictive levels, utilizing inputs derived from empirical evidence and 
expert opinion. We are seeking public comment regarding the inputs that 
should be used for modeling the impact of a nicotine tobacco product 
standard.

A. Smoking Cessation Would Lead to Substantial Public Health Benefits 
for People of All Ages

    Significant declines in the deaths caused by the use of combusted 
tobacco products can be achieved by reducing the prevalence of smoking 
cigarettes and other combusted tobacco products. Smoking cessation has 
major and immediate health benefits for men and women of all ages, 
regardless of health status (Ref. 173 at p. i). Smoking cessation 
decreases the risk of the health consequences of smoking, and former 
smokers live longer than continuing smokers. For example, persons who 
quit smoking before age 50 have one-half the risk of dying in the next 
15 years compared with continuing smokers (id. at p. v).
    Smoking cessation reduces the risk of cancers throughout the body 
(Ref. 173). For example, although the risk of dying from lung cancer is 
22 times higher for male smokers than male nonsmokers (and 12 times 
higher for female smokers than female nonsmokers), the risk of lung 
cancer after 10 years of abstinence is 30 to 50 percent that of 
continuing smokers (id.; Refs. 174 and 175).
    Smoking cessation also reduces the risk of other life-threatening 
illnesses that occur in smokers. In addition to reducing the risk of 
cancers and the mortality rates of smoking-related diseases, smoking 
cessation substantially reduces the risk of other dangerous diseases 
that can lead to death or disability and cause a financial strain on 
health care resources. For example, smoking cessation substantially 
reduces risk of peripheral artery occlusive disease (which can cause 
complications that lead to loss of limbs) (Ref. 173). Former smokers 
also have half the excess risk of experiencing an abdominal aortic 
aneurysm compared to current smokers (id.). Cigarette smoking also 
complicates many diseases (e.g., smokers with diabetes have higher risk 
of complications, including heart and kidney disease, poor blood flow 
in the legs and feet, retinopathy and peripheral neuropathy), and 
smoking cessation can alleviate those complications as well (Ref. 17).
    Youth and young adults would experience the greatest benefits from 
a nicotine tobacco product standard, because many of them may not 
progress beyond experimentation and, therefore, may not experience 
dangerous and deadly tobacco-related health effects. Fetuses and 
children also would benefit if their parents quit smoking, given the 
negative health consequences to the fetus of a smoking mother and the 
dangers of secondhand smoke. In addition, children of parents who 
smoke, when compared with children of nonsmoking parents, have an 
increased frequency of respiratory infections like pneumonia and 
bronchitis (Ref. 173). Smoking cessation reduces the rates of these 
respiratory symptoms and of respiratory infections (Ref. 176 at p. 
467). Children exposed to tobacco smoke in the home also are more 
likely to develop acute otitis media (middle ear infections) and 
persistent middle ear effusions (thick or sticky fluid behind the 
eardrum) (Ref. 173). If parents were more able to quit because these 
products become minimally addictive or nonaddictive, youth would 
experience these health problems much less frequently.
    Although the health benefits are greater for people who stop 
smoking at earlier ages (Refs. 173 and 176), researchers estimate that 
smokers can gain years of additional life expectancy no matter when 
they quit (Ref. 177). In addition, scientists using data from the 
Cancer Prevention Study (CPS-II), but accounting for bias caused by 
smoking cessation after baseline, found that even smokers who quit at 
age 65 had an expected life expectancy increase of 2 years for men and 
3.7 years for women (Ref. 178).
    The benefits continue for those who remain smoke free. At year one, 
an individual's added risk of coronary heart disease becomes half that 
of a smoker's (Ref. 175). Between 2 and 5 years after cessation, an 
individual's stroke risk is reduced to that of a nonsmoker (id.). In 
addition, a former smoker's risk of cancers of the mouth, throat, 
esophagus, and bladder is halved within five years (id.). By 10-years 
post cessation, an individual's risk of cancers of the kidney and 
pancreas decreases (id). The risk of coronary heart disease becomes 
that of a nonsmoker after 15 years of abstinence (id.).

B. A Nicotine Tobacco Product Standard Could Lead to Substantial 
Improvement in Public Health

    As stated throughout this document, nicotine at levels currently 
found in tobacco products is highly addictive, and addiction to 
nicotine is the ``fundamental reason that individuals persist in using 
tobacco products'' (Ref. 17 at p. 105). Although nicotine itself is not 
the direct cause of most tobacco-attributable disease, addiction to the 
nicotine in tobacco products is the proximate cause of these conditions 
because it sustains tobacco use (Refs. 54 and 179). Addiction caused by 
nicotine in tobacco is critical in the transition of smokers from 
experimentation to sustained smoking and in the maintenance of smoking 
for those who want to quit (Ref. 7 at p. 113; Ref. 17). As a result, 
FDA expects that making cigarettes minimally addictive or nonaddictive 
would reduce tobacco-related harms by promoting smoking cessation or 
complete migration to alternative, potentially less harmful 
noncombusted products and by reducing initiation. In this section, we 
summarize the approach used to describe the possible impact of a 
potential nicotine tobacco product standard to the population as a 
whole and present the findings of this analysis.
    As discussed elsewhere in this document, FDA is considering the 
scope of a potential product standard, and has asked for public 
comment. To assess the impact of one potential option that might 
maximize the potential public health impact, it may be appropriate to 
consider the Apelberg et al. 2018 publication, which presented 
simulation modeling of a policy scenario in which the scope of a 
potential product standard restricted the nicotine level in cigarettes, 
cigarette tobacco, RYO tobacco, cigars (including little cigars, large 
cigars, and cigarillos, but not so-called ``premium'' cigars), and pipe 
tobacco (other than waterpipe/hookah tobacco). As part of a formal 
expert elicitation process (this process centered around three online 
conferencing sessions held during January and February 2015, following 
a written protocol designed to elicit opinions using a structured, 
standardized approach (see Ref. 181 for more details)), eight subject 
matter experts were asked to provide their individual estimates of the 
anticipated impacts of a hypothetical policy (setting a ``maximum limit 
on the amount of nicotine in cigarette tobacco filler'' for the purpose 
of reducing nicotine in cigarettes ``to minimally addictive levels'') 
and to develop subjective probability distributions for parameters of 
interest.
    A more detailed description of the methodology, data sources and 
inputs, and results from this analysis can be

[[Page 11836]]

found in two peer-reviewed publications (Refs. 180 and 181).
1. Approach to Estimating Impacts to the Population as a Whole
    As described in this document, FDA expects that making cigarettes 
minimally addictive or nonaddictive (however that were achieved) would 
impact currently addicted smokers by increasing their ability to quit 
smoking and affect nonsmokers by reducing the likelihood that they 
would become established and addicted smokers. Apelberg et al. 2018 
updated a previously published discrete system dynamic population model 
to compare projected outcomes for a status-quo scenario (in which no 
maximum nicotine level is implemented) with outcomes for a policy 
scenario in which a hypothetical regulation lowering nicotine in 
cigarettes, and selected other combusted tobacco products, to minimally 
addictive was implemented \12\ (Ref. 181).
---------------------------------------------------------------------------

    \12\ The policy scenario presented in Apelberg et al. 2018 (Ref. 
181) did not define a specific level of nicotine as minimally 
addictive. Rather, the policy scenario simulated implementation of a 
hypothetical standard in which cigarettes and certain other 
combusted tobacco products were made minimally addictive, informed 
by a formal expert elicitation process (Ref. 181), used to estimate 
the impact of decreasing the addictiveness of cigarettes on certain 
tobacco use behaviors. Given the lack of specificity in the 
hypothetical scenario posed in the Apelberg et al. study, caution is 
warranted in extrapolating its results to the assessment of a 
particular policy.
---------------------------------------------------------------------------

    The model incorporated, based on estimates of subject matter 
experts, the following tobacco use transitions to estimate the impact 
of the policy: (1) Cigarette smoking cessation; (2) cigarette smokers 
switching to noncombusted tobacco products (e.g., smokeless tobacco 
and/or electronic cigarettes) rather than quitting tobacco use 
entirely; (3) continuing smokers becoming dual users of cigarettes and 
noncombusted tobacco products; (4) nonsmokers initiating regular 
cigarette smoking; and (5) nonsmokers who have been dissuaded from 
smoking cigarettes and certain other combusted tobacco products, who 
may instead initiate use of a noncombusted tobacco product. The model, 
based on input parameters derived from expert estimates, projected the 
impact of the policy on four main outcomes: (1) Prevalence of cigarette 
smoking and noncombusted tobacco product use; (2) the number of 
individuals dissuaded from cigarette smoking; (3) cumulative number of 
tobacco-attributable deaths avoided; and (4) cumulative life years 
gained as a result of a regulation setting a maximum nicotine level.
    The methodology implemented in this analysis has been detailed 
elsewhere (Refs. 180 and 181). Briefly, the simulation begins with an 
initial population that reflects the sex, age, and tobacco use 
distribution (i.e., never, current, and former use of cigarettes and 
noncombusted products) of the U.S. population in 2015, based on U.S. 
Census Bureau estimates. The analysis projects population changes for 
2016-2100 in 1-year increments, while accounting for births, net 
migration (which accounts for immigration and emigration) and deaths, 
the last of which is a function of age, sex, and tobacco use status. 
Baseline estimates for tobacco use status (combinations of current, 
former, and never use for cigarettes and noncombusted products) by sex, 
age, and time since cessation (for cigarettes only) were obtained from 
the 2015 National Health Interview Survey (NHIS) for adults (Ref. 1) 
and the 2015 NYTS for youth (Ref. 182). Mortality rates and relative 
risks by tobacco use status were obtained from U.S. vital statistics 
data, NHIS data linked for mortality followup (for never smoker 
mortality rates and cigarette smoking relative risks), and the CPS-II 
(for smokeless tobacco product relative risks). In the absence of data 
on the long-term health risks of ENDS, Apelberg et al. assumed that the 
ENDS products carried the same risks associated with traditional 
smokeless tobacco (see Ref. 181 for more detail).
    Quantitative inputs for rates of post-policy smoking cessation, 
switching, and dual use in the hypothetical policy scenario were 
obtained through a formal expert elicitation process. The methodology 
used to identify experts, develop the protocol, conduct the 
elicitation, and summarize the findings has been described in detail 
elsewhere (Ref. 181 at Appendix). Briefly, elicitation candidates with 
expertise in tobacco science and policy were identified, ranked, and 
recruited in accordance with a pre-specified protocol, based on 
publication history and accounting for potential conflicts of interest. 
Candidates were required to self-certify that they were free of any 
actual, apparent, or potential conflicts of interests. The elicitation 
process centered around three online conferencing sessions held during 
January and February 2015, following a written protocol designed to 
elicit opinions using a structured, standardized approach (see Ref. 181 
for more details). Briefing books with key papers on the topics of 
interest as well as background data on tobacco use and policy were 
provided to a panel of eight experts prior to the conference sessions. 
Experts were asked to identify any other relevant information to share 
with the panel. Detailed written questionnaires were completed by each 
expert as independent take-home exercises. To maintain the independence 
of the experts and encourage open discussion, involvement of FDA staff 
was limited.
    To explore the potential impact of a product standard that would 
maximally benefit population health, the experts were asked to assume 
that combusted tobacco products that could be viewed as highly likely 
to serve as substitutes for traditional cigarettes (i.e., RYO tobacco, 
pipe tobacco, nonpremium cigars) would be included in the policy, while 
other tobacco products (i.e., premium cigars, waterpipe/hookah, ENDS, 
smokeless tobacco) would be excluded.\13\ The eight experts were asked 
to predict and quantify the anticipated impact of the policy on the 
following model parameters: (1) Cigarette smoking cessation rates; (2) 
switching from cigarette smoking to other tobacco products excluded 
from the hypothetical policy scenario; (3) dual use rates; (4) 
cigarette smoking initiation rates; and (5) initiation rates for other 
tobacco products excluded from the hypothetical policy scenario. Each 
of the eight experts was asked to provide his or her best estimate of 
the parameters' true value, estimates of the minimum and maximum 
plausible values, and estimates of the 5th, 25th, 75th and 95th 
percentile values. Experts were asked first about impacts in the first 
year immediately following the potential product standard's 
implementation and then about the impacts in the years following the 
first full year of implementation. Experts had the option of providing 
separate estimates of impacts for males and females for the initial and 
subsequent years. For each question, experts were asked to provide the 
factors they considered pertinent to answering the question, including 
the studies and research findings most influential to informing their 
views, and to rate their familiarity with the relevant literature. The 
elicitation process provided the experts with opportunities to interact 
and discuss divergent views, from

[[Page 11837]]

which each expert generated his/her initial and final estimates.
---------------------------------------------------------------------------

    \13\ While the policy scenario presented in Apelberg et al., 
2018 (Ref. 181) is based on reduction in nicotine level in 
cigarettes, cigarette tobacco, RYO tobacco, certain cigars and pipe 
tobacco, the estimated population impact is based on reductions in 
cigarette smoking. FDA notes that not accounting for reductions in 
the use of other combusted tobacco products may underestimate the 
overall impact of this policy scenario.
---------------------------------------------------------------------------

    The eight experts' judgments about the potential values of these 
parameters are published in Apelberg et al. 2018 (Ref. 181). While 
parameter estimates and their probability distributions varied somewhat 
between participants, most experts had the view that making cigarettes 
and certain other combusted tobacco products minimally addictive would 
lead to substantial initial and long-term increases in smoking 
cessation among cigarette smokers and decreased initiation among 
nonsmokers. Distributions provided by the eight experts' parameter 
estimates were substantially broad in range. For example, for both male 
and female non-smokers, the median minimum and maximum estimates from 
the eight experts on the ``percent of reduction in annual smoking 
initiation rates'' after the first year in response to the policy 
ranged from 10 percent to 90 percent. For both male and female smokers, 
the median minimum and maximum estimates from the eight experts on the 
``percent of current smokers who quit smoking as a result of the 
policy'' within the first year after policy implementation ranged from 
4 percent to 50 percent.
    To account for uncertainty associated with the expected impact of 
the policy scenario, Apelberg et al. 2018 used the distributions of the 
experts' estimates in a Monte Carlo simulation. A Latin Hypercube 
sampling with 1,000 sample values was performed for each of the 
expert's response distributions. For each simulation, the policy 
scenario was compared to the baseline scenario to estimate changes in 
the outcomes described above. A summary of distribution responses are 
provided in Apelberg et al. 2018.
2. Projected Impacts to Users, Nonusers, and the Population as a Whole
    As illustrated in Figure 1 (Ref. 181), using the experts' input 
estimates for the parameters described previously, and assuming that 
the policy is implemented in 2020, the simulation model projected that 
cigarette smoking prevalence declines substantially in the policy 
scenario within the first year of implementation of the hypothetical 
policy scenario to a median value of 10.8 percent compared with 12.8 
percent in the baseline scenario. In subsequent years, the simulation 
model projects that the difference in cigarette smoking prevalence 
between the scenarios continues to grow due to the experts' estimates 
of sustained increases in cessation and decreases in initiation in the 
policy scenario. The projected smoking prevalence drops to a median 
value of 1.4 percent (5th and 95th percentile projections range from 
0.2 percent to 5.9 percent) under the policy scenario by 2060 compared 
to 7.9 percent under the baseline. Smoking prevalence estimates for the 
year 2100 are comparable to those for 2060.
    Concurrent with a projected reduction in cigarette smoking is a 
projected increase in noncombusted product use. Adult noncombusted 
tobacco product use is higher in the hypothetical policy scenario 
compared to the baseline scenario within the first year of 
implementation of the potential product standard (Ref. 181 at Figure 
1), due to estimated increases in switching from cigarette smoking and 
transitions to dual cigarette and noncombusted product use as a result 
of the hypothetical policy scenario. The prevalence of noncombusted 
tobacco product use remains higher in the policy scenario over time due 
to the experts' predictions that there would be both increased uptake 
among smokers (through either complete switching or dual use) and 
increased initiation due to some dissuaded cigarette initiators taking 
up noncombusted products instead.
    Table 2 provides a projection of the number of individuals who 
would not become cigarette smokers over time as a result of the 
hypothetical policy scenario. Since it is assumed, based on expert 
input, that there would be a sustained decrease in cigarette smoking 
initiation rates, the model projects that the cumulative number of 
dissuaded smoking initiates continues to increase over time. By 2100, 
the median estimate from the model, based on the experts' estimates of 
potential initiation rates as a result of the policy, is that more than 
33 million youth and young adults who would have otherwise initiated 
regular smoking would not start as a result of the hypothetical policy 
scenario (5th and 95th percentile projections range from 8.0 million to 
64.1 million).
    Using the eight experts' estimates for the percent of current 
smokers who would quit smoking after implementation of the policy, 
approximately 5 million additional smokers are estimated to quit 
smoking within one year after implementation of the product standard 
(5th and 95th percentile projections range from 110,000 to 19.7 
million), compared to the baseline scenario. The number of additional 
smokers quitting would increase by approximately 13 million within 5 
years after policy implementation (5th and 95th percentile projections 
range from 430,000 to 30.5 million), compared to the baseline scenario.

 Table 2--Projected Number of Individuals Who Would Not Initiate Regular
 Smoking as a Result of a Nicotine Tobacco Product Standard Implemented
                                 in 2020
------------------------------------------------------------------------
                                        Cumulative new smoking initiates
                                             avoided (in millions)
                 Year                 ----------------------------------
                                           5th                   95th
                                        percentile   Median   percentile
------------------------------------------------------------------------
2040.................................          2.0      8.1         15.6
2060.................................          3.9     16.0         31.0
2080.................................          5.9     24.4         47.2
2100.................................          8.0     33.1         64.1
------------------------------------------------------------------------

    Table 3 presents the estimated cumulative number of tobacco-
attributable deaths potentially avoided and life years gained due to 
the experts' determinations that smoking rates would decrease as a 
result of the hypothetical policy scenario. By 2060, it is estimated 
that a median value of almost 3 million deaths due to tobacco would be 
avoided (5th and 95th percentile projections range from 0.7 million to 
4.3 million), rising to 8.5 million by the end of the century (5th and 
95th percentile projections range from 2.2 million to 11.2 million). 
The reduction in premature deaths attributable to the hypothetical 
policy scenario would result in approximately 33 million life years 
gained by 2060 (5th and 95th percentile projections range from 7.8 
million to 53.9 million) and over 134 million life years gained by 2100 
(5th and 95th percentile projections range from 31.6 million to 183.0 
million).

[[Page 11838]]



 Table 3--Projected Number of Tobacco-Attributable Deaths Avoided and Life Years Gained Due to Reduced Smoking as a Result of a Nicotine Tobacco Product
                                                              Standard Implemented in 2020
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                          Cumulative tobacco attributable deaths avoided      Cumulative life years gained (millions)
                                                                            (millions)                   -----------------------------------------------
                          Year                           ------------------------------------------------
                                                                                               95th       5th percentile      Median           95th
                                                          5th percentile      Median        percentile                                      percentile
--------------------------------------------------------------------------------------------------------------------------------------------------------
2040....................................................             0.3             0.9             1.4             2.5             6.8            11.5
2060....................................................             0.7             2.8             4.3             7.8            33.1            53.9
2080....................................................             1.3             5.6             7.9            16.5            79.6           118.0
2100....................................................             2.2             8.5            11.2            31.6           134.4           183.0
--------------------------------------------------------------------------------------------------------------------------------------------------------

3. Request for Comments
    Based on the experts' judgments that reducing nicotine levels in 
combusted tobacco products would increase smoking cessation and 
decrease smoking initiation, and calculations from the simulation model 
describing the potential impact of reducing nicotine to minimally 
addictive levels in cigarettes and selected other combusted tobacco 
products, FDA anticipates a significant public health benefit to the 
United States. This hypothesis is based on the assumption that the 
reduction in nicotine levels in combusted tobacco products would create 
substantial reductions in smoking prevalence due to increased smoking 
cessation and reduced initiation of regular smoking. Given that 
research studies cannot easily replicate the condition of a nationally 
enforced restriction on nicotine to minimally addictive levels in 
cigarettes, FDA sought expert opinion through an established 
elicitation process to provide the best estimates for the potential 
values and associated ranges of the likely impact of a hypothetical 
reduction in cigarettes' nicotine content (to be achieved by a 
potential product standard) on tobacco use behaviors. FDA requests 
data, evidence, and other information regarding the potential public 
health benefits (or risks) if FDA were to move forward in this area. 
Specifically, FDA is seeking data, evidence, and other information that 
could inform the following five parameter inputs that would be helpful 
in determining the public health impact of a nicotine tobacco product 
standard:
     Percent of current cigarette smokers who would quit 
cigarette smoking as a result of a standard restricting nicotine to 
minimally addictive levels.
     Percent of quitters switching to other combusted or 
noncombusted tobacco products.
     Percent of continuing smokers who become dual product 
users of cigarettes and noncombusted tobacco products.
     Percent reduction in annual smoking initiation rates.
     Percent of dissuaded smoking initiates who initiate 
noncombusted tobacco product use instead.

Please include your assumptions about the scope of the standard and 
data that supports your estimates.
4. Additional Public Health Benefits
    While the projections from the simulation model calculating the 
potential impact from reducing nicotine to minimally addictive levels 
in cigarettes suggest a significant public health benefit to the United 
States resulting from substantial reductions in smoking prevalence 
(based on the model's inputs, which reflect the experts' assessments 
that the reduction in nicotine levels in combusted tobacco products 
would create substantial increases in smoking cessation and reductions 
in initiation of regular smoking), the analysis does not address 
certain potential added benefits. First, the model does not account for 
increased quality of life from decreased tobacco-related morbidity, nor 
does it account for cost savings from medical care averted. Second, the 
analysis does not account for the impacts of secondhand smoke exposure 
on public health in the United States. Third, the analysis does not 
account for reductions in harms caused by smoking-related fires. 
Fourth, the potential impact described does not account for the 
potential impact on population health from use of the other combusted 
products (e.g., cigars, pipes) if the assumed rule were to cover such 
products. Finally, these projections do not assess whether there could 
be potential health benefits associated with smokers cutting down on 
the number of cigarettes smoked as a result of the standard.

VI. References

    The following references are on display in the Dockets Management 
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persons between 9 a.m. and 4 p.m. Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

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    Dated: March 12, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-05345 Filed 3-15-18; 8:45 am]
BILLING CODE 4164-01-P


