Methods to assess potential reduced exposure
Dorothy K. Hatsukami, Gary A. Giovino, Thomas Eissenberg, Pamela I. Clark,
Deirdre Lawrence, Scott Leischow
[Received 10 December 2004; accepted 30 June 2005]
The availability of tobacco products purported to reduce toxin exposure or potentially reduce health risks
necessitates the development of methods and identification of biomarkers that can be used to assess these products.
These assessments occur on multiple levels and stages, from identifying constituents in the tobacco products and
smoke, to human exposure and health effects trials, to postmarketing surveillance. A conference of
multidisciplinary experts was convened to present and discuss methods and biomarkers to assess these products
and to consider the infrastructure necessary to facilitate the evaluation process. Although no currently available set
of measures was thought to be sufficient for determining the relative health risk of potential reduced exposure
products, this paper provides a blueprint for future research toward this end.
Tobacco harm reduction, as a method to reduce
mortality and morbidity, has been receiving increas-
ing attention both in the United States and inter-
nationally. Harm reduction refers to ‘‘minimizing
harms and decreasing total morbidity and mortality,
without completely eliminating tobacco and nicotine
use’’ (Stratton, Shetty, Wallace, & Bondurant, 2001).
Although cessation and prevention should remain
the primary methods for tobacco control, several
reasons have been provided to support considering
lowering tobacco toxin exposure and addictiveness as
a strategy to reduce negative health consequences.
First, although smoking rates have been decreasing
consistently since the 1960s, the age-specific preva-
lence of cessation among ever-smokers (also known
as quit ratio) has leveled off in recent years (Giovino,
2002). Second, even though the majority of tobacco
users want to quit, few are successful on single quit
attempts, and only 10%–20% are ready to quit in the
immediate future (Etter, Paernegger, & Ronchi,
1997; Prochaska & Goldstein, 1991). Third, the
number of cigarettes smoked demonstrates a dose–
response relationship to disease (National Cancer
Institute, 1997; Stratton et al., 2001), and recent
modeling based on data from the American Cancer
Society’s Cancer Prevention Study I has suggested
that the greater the reduction and the earlier the age
of reduced smoking, the greater the number of years
of life saved (Burns, 1997). Methods that have been
proposed to reduce harm have ranged from modify-
ing tobacco to reduce toxicants to long-term use of
nicotine replacement products.
Because of the introduction of tobacco products
that were marketed with implied or direct claims of
reduced tobacco toxin exposure or reduced health
risks, the Institute of Medicine (IOM) was charged in
December 1999 by the U.S. Food and Drug
Administration (FDA) to address four questions
and to ‘‘formulate scientific methods and standards
by which potential reduced exposure products
(PREPs) could be addressed.’’ The four questions
were the following: (a) Does use of the product
decrease exposure to the harmful substances in
tobacco? (b) Is this decreased exposure associated
with decreased harm to health? (c) Are there
ISSN 1462-2203 print/ISSN 1469-994X online # 2005 Society for Research on Nicotine and Tobacco
Dorothy K. Hatsukami, Ph.D., University of Minnesota Cancer
Center, Minneapolis, MN; Gary A. Giovino, Ph.D., Roswell Park
Cancer Institute, Buffalo, NY; Thomas Eissenberg, Ph.D., Virginia
Commonwealth University, Richmond, VA; Pamela I. Clark, Battelle
Centers for Public Health Research & Evaluation, Baltimore, MD;
Deirdre Lawrence, Ph.D., Scott Leischow, Ph.D., National Cancer
Institute, Bethesda, MD.
Correspondence: Dorothy K. Hatsukami, Tobacco Use Research
Center, University of Minnesota, 2701 University Avenue SE, #201,
Minneapolis, MN 55414, USA. Tel: +1 (612) 627-1808; Fax: +1 (612)
627-4899; E-mail: firstname.lastname@example.org
Nicotine & Tobacco Research Volume 7, Number 6 (December 2005) 827–844
surrogate indicators of this effect on health that
could be measured in a time frame sufficient for
product evaluation? and (d) What are the public
health implications of tobacco harm reduction
After reviewing the scientific evidence, the IOM
report describedthe following
‘‘Reducing risk of disease by reducing exposure to
tobacco toxicants is feasible,’’ but it also stated that (b)
‘‘potential reduced exposure products (PREPs) have
not been evaluated comprehensively enough to pro-
vide a scientific base for concluding they are associated
with reduced risk of disease compared to conventional
tobacco use.’’ The report also concluded that (c)
‘‘surrogate biological markers that are associated with
tobacco related diseases could be used to offer
guidance as to whether or not PREPs are likely to be
risk-reducing,’’ (d) ‘‘currently available PREPs have
been or could be demonstrated to reduce exposure to
some of the toxicants in most conventional tobacco
products,’’ (e) ‘‘regulation of all tobacco products,
including conventional ones as recommend in IOM,
1994, as well as all other PREPs is a necessary
precondition for assuring a scientific basis for judging
the effects of using PREPs and for assuring that the
health of the public is protected,’’ and (f) ‘‘the public
health impact of PREPs is unknown. They are
potentially beneficial, but the net impact on popula-
tion health could, in fact, be negative.’’
These conclusions highlight the need for and
urgency in developing a comprehensive strategy to
evaluate these products and approaches. The cur-
rently existing PREPs include (a) modified tobacco
products that contain reduced levels of one or more
toxins (e.g., cigarettes with reduced tobacco-specific
nitrosamines through new curing processes, the
addition of catalysts to reduce polycyclic aromatic
hydrocarbon carcinogens produced by smoke, the
use of genetically modified plants to reduce nicotine
or nitrosamines, or the use of filters to selectively
reduce toxicants), (b) cigarette-like devices, such as
those that heat rather than burn tobacco, and (c)
oral noncombustible products, such as smokeless
tobacco, that are modified to reduce exposure to
specific toxicants. Other reduced exposure app-
roaches include reduced tobacco use either through
the use of medicinal products or other tobacco
products (e.g., oral tobacco for cigarette smoking)
and long-term maintenance on medicinal nicotine.
The urgency for evaluation of PREPs is also high-
lighted by past experiences with low-yield cigarettes.
Low-yield cigarettes were considered ‘‘safer’’ by
consumers, in some cases leading to continued
smoking and with no significant reductions in disease
(National Cancer Institute, 2001).
Evaluation of these products must involve con-
sideration of both individual risk and population
effects (Hatsukami, Henningfield, & Kotlyar, 2004;
Stratton et al., 2001). Individual risk involves
assessing toxin exposure, addictiveness, and disease
risk within individuals. Individual risk can be
determined by conducting both short- and long-term
clinical trials using biomarkers for exposure and for
health effects. Population effects involve assessing
tobacco use behavior such as the rate of uptake,
maintenance, cessation, and relapse as a result of the
introduction of the product and the effects of
product useon morbidity
Population effects can also be determined by
evaluating contributors to product use including
consumer perception of the product, product promo-
tion and placement in retail stores, cost, availability,
policies such as tobacco use bans, and changes in
Figure1 offers a heuristic model illustrating the
various components and steps in testing PREPs that
takes into account both individual and population
disease risk. This model is based on the principles for
evaluating PREPs described in the IOM report
(Stratton et al., 2001). Testing involves both pre-
market evaluation (step 1 and 2) and postmarket
evaluation (step 3). At each step of this three-step
model, testing results must be evaluated to determine
whether sufficient evidence supports an appropriate
risk–benefit ratio to permit proceeding to the next
step or to eventual market distribution. This ratio
can be based on the following:
N Extent of reductions in toxin exposure and
addictiveness and any other heath claims asso-
ciated with the product;
N Addictiveness or health risk compared with
conventional brands of tobacco, including mar-
keted brands with the lowest level of toxicity, and
N Adequateness and accuracy of information pro-
vided to the consumer about the extent of toxic
exposure from the product or relative health risk
(e.g., adequacy of the evidence to support claims
of reduced toxicity of a PREP, and if meaningful
reductions of exposure or risk are found, then
the accurate interpretation of the data by con-
N Effects of claims (if such claims are permitted),
marketing, and promotion efforts on consumer
perception of the product;
N Unintended and unwanted consequences such as
increased morbidity or mortality as a result of
increased prevalence of tobacco use or other
changes in tobacco use behavior.
When the product is being offered for consump-
tion, including in test marketing, evaluation of the
risk–benefit ratio must be performed by an indepen-
dent body of experts.
METHODS TO ASSESS PREPS
A comprehensive strategy for testing PREPs
initially involves testing for product toxicity or
hazard identification, and preclinical cell and animal
testing. According to the IOM report, hazard
identification involves some of the following compo-
nents: (a) Identifying toxicants in the PREP that are
known to cause adverse health effects, (b) determin-
ing the extent to which the compounds targeted for
reduced exposure are causally linked to tobacco-
related disease, (c) determining how the contents of
the PREP compare with those of conventional
tobacco products, (d) identifying unique toxicants
in the PREP compared with conventional tobacco
products, and (e) identifying unique toxicants that
may be associated with second-hand smoke. Once
these toxicants are identified, then extent of exposure
to toxicant ingredients (e.g., dose) should
measured based on machine-determined yields that
simulate human smoking behavior. The range of
doses that is observed can be applied to preclinical
testing on cells or in animals (e.g., tests for
cytotoxicity or mutagenicity) that will provide
qualitative information about the toxicity of these
ingredients. Future research goals should include the
development of preclinical tests that can quantita-
tively measure relative toxicity between the com-
parison compounds. Furthermore, the extent of
differences in exposure needed to result in mean-
ingful differences in risk is a critical question that
needs to be addressed. This task is made difficult and
complex because of the frequent need to quantify the
differences in risk between various highly toxic
products and the vast number of constituents that
need to be considered.
An independent group of scientists and regulators
should use available preclinical data (a) to assess
whether selected products are likely to substantially
reduce risk, taking into account the risk reduction
potential of products such as medicinal nicotine, and
(b) to assess whether further premarket testing is
worth pursuing (L. T. Kozlowski, Strasser, Giovino,
Erickson, & Terza, 2001). However, the role of
preclinical testing (animal or cell preparations) is
extremely limited. Because preclinical testing cannot
predict exposure or risk reduction when a product is
used by humans, the results must not be used as a
basis for advertising and promotion of PREPs.
After this first evaluation, human testing is neces-
sary. The primary aim of human clinical testing is to
determine individual risk, that is, the extent of
exposure to toxins and health effects or the potential
risk for disease resulting from use of the products, the
potential for persistent use of the products, and the
pattern of use of the products. Premarket consumer
perception testing can help to determine potential
individual as well as population harm. Perceptions of
the health risks or harms associated with products can
affect the individual’s decision to use them and the
extent to which the population participates in the
purchase of the products. Premarket consumer
an independent scientific panel or regulatory agency after each step.
Three step model for potential reduced exposure product (PREP) evaluation with assessment occurring by
NICOTINE & TOBACCO RESEARCH
perception testing involves determining how the
consumers perceive and interpret the information
and images delivered to them, and if these perceptions
and processing of information are accurate or
misleading. The purpose of consumer product testing
is to ensure that claims and marketing of a product
will lead the consumer to make an informed decision
based on an accurate understanding of valid informa-
tion, andto ensure thatthe product doesnot appeal to
youth, those who would have quit otherwise, or those
who have previously quit.
Once the risk–benefit ratio is considered promis-
ing, then population effects of PREPs after they enter
into the market need to be assessed. This assessment
is accomplished through postmarketing surveillance
and epidemiological studies. Postmarketing evalua-
tion is conducted to ensure that PREPs do not result
in increased initiation of tobacco use, maintenance of
tobacco use in those who were interested in quitting,
or relapse to tobacco use in former tobacco users.
Furthermore, the use of PREPs should not result in
an increase in morbidity and mortality. It is not
acceptable to reduce individual risk at the expense of
increasing population harm. Therefore, through the
use of long-term, longitudinal surveys, the actual
reduction in harm through the use of PREPs can be
determined. An important point to remember is that
the different stages involved in testing these products
are bidirectional rather than unidirectional; that is,
results from human evaluation can inform preclinical
evaluation including product design. Similarly, post-
marketing surveillance results can inform clinical or
preclinical evaluation of products.
Because of the number of years required to
determine whether PREPs result in harm to health,
proxies for disease outcome are needed. Therefore,
essential measures for determining the impact of
PREPs are biomarkers for toxin exposure, injury,
and disease risk. When comparing the health effects
of a PREP, researchers must look for differences in
the levels of biomarkers associated with the PREP
and the currently used tobacco product, and ideally
the impact of this difference on health must be
determined. These biomarkers need to cover a broad
range of tobacco-related diseases to ensure that
products that decrease biomarkers for one disease
category do not increase them in another category.
In an effort to facilitate development of research
priorities and expand and update the IOM guide-
lines in the evaluation of PREPs, the National
Cancer Institute, National Institute on Drug Abuse,
National Institute on Alcoholism and Alcohol
Abuse, and the Centers for Disease Control and
Prevention convened a meeting to develop guidelines
for the evaluation of PREPs on both individual and
population levels. Both methods and biomarkers for
evaluation were addressed. Although evaluation of
product toxicity and preclinical evaluation of the
products is an important step in assessing PREPs,
this meeting focused primarily on human testing. A
steering committee (Table1) comprised of represen-
tatives from each of the government agencies and
two university-based scientists developed the meeting
agenda. Three topic were selected to examine
methods for evaluation: Human clinical testing;
premarket testing of consumer perceptions, product
marketing, and promotion; and postmarketing eva-
luation. Biomarkers for four categories of diseases
or negative health outcomes were also discussed:
Cardiovascular disease, pulmonary disease, cancer,
and fetal toxicity. A leader was selected for each
topic, and this leader subsequently selected the team
members for his or her topic (Table2).
The members of the methods groups were asked to
address the following questions for their assigned
topics: (a) What are the primary issues associated with
the evaluation of the products? (b) What are the
methods and measures to address these issues? (c)
What is the necessary infrastructure needed to
evaluate the PREPs? The biomarker groups were
asked to identify potential biomarkers that could be
used to evaluate PREPs based on their mechanistic
relationship to disease and evidence showing differ-
ences between smokers andnonsmokers, changes with
cessation, a dose–response relationship with number
of cigarettes per day, and changes with reduction in
smoking. Ideally, changes in the levels of biomarkers
should result in changes in the risks for disease.
Unfortunately, limiteddata areavailableontheextent
of biomarker change necessary to induce a beneficial
health effect. Therefore, predictive validity, one of the
hallmarks for determining a valid biomarker, was not
included as a criterion for assessing biomarkers. The
biomarkers groups also were asked to speculate on
potentially promising biomarkers.
Each group was asked to present its finding at
a meeting held on February 26 and 27, 2004, in
Washington, D.C. This meeting included an invited
expert panel (Table3) and representatives from
Table 1. Steering committee members.
David Ashley, Ph.D., Centers for Disease Control and
Prevention, Atlanta, GA
William Corrigall, Ph.D., National Institute on Drug Abuse,
Mirjana Djordjevic, Ph.D., National Cancer Institute, Bethesda,
Joanne Fertig, Ph.D., National Institute on Alcohol Abuse and
Alcoholism, Bethesda, MD
Dorothy Hatsukami, Ph.D., University of Minnesota, Minneapolis,
Stephen Hecht, Ph.D., University of Minnesota, Minneapolis, MN
Deirdre Lawrence, Ph.D., M.P.H., National Cancer Institute,
Scott Leischow, Ph.D., National Cancer Institute, Bethesda, MD
Celia Winchell, M.D., Food and Drug Administration, Rockville,
METHODS TO ASSESS PREPS
governmental agencies, and was also open to the
public. After each presentation, the audience raised
questions and provided feedback. After the meeting,
each workgroup was responsible for integrating these
comments into a written document. The final
document was then sent to the expert panel for their
review. The subsequent content of the two papers,
one on methods and one on biomarkers, represents
the deliberations of these groups. This article
discusses issues and methods associated with testing
PREPs, and a separate paper discusses biomarkers
for testing PREPs (Hatsukami, Benowitz, Rennard,
Oncken, & Hecht, in press). Note that the guidelines
and issues outlined here can be used for evaluating all
Human clinical trials
Issues in clinical trials of PREPs
Clinical trials are part of the essential second step of
evaluating PREPs (Figure1). As described below,
clinical trial design must account for moderating
factors that can influence a PREP’s impact, while
incorporating methods and measures that allow the
trial to address important questions such as (a) Does
the PREP result in reduction in toxin exposure/
uptake and harmful health effects? (b) What is the
abuse liability of the PREP? (c) How is the PREP
used? and (d) Does the PREP make future cessation
attempts less likely? These questions can be answered
in studies that approximate phase I–IV clinical trials,
as defined by the FDA.
Moderating factors that can influence the impact of a
PREP. Many moderating factors can influence the
effects of a PREP (Table4). These factors require
consideration because they may affect tobacco use
behavior and disease risk. Type of tobacco used is
Table 2. Topic leaders and workgroup members.
Human clinical trials
Dorothy Hatsukami, Ph.D.,aUniversity of Minnesota,
Thomas Eissenberg, Ph.D.,aVirginia Commonwealth
University, Richmond, VA
J Richard Crout, M.D., Crout Consulting, Bethesda, MD
Jack Henningfield, Ph.D., Pinney Associates, Bethesda, MD
Pamela Clark, Ph.D.,aBattelle Center for Public Health
Research & Evaluation, Baltimore
Paul Slovic, Ph.D., Decision Research, Eugene, Oregon
Neil Weinstein, Ph.D., Rutgers University, New Brunswick,
Gary Giovino, Ph.D.,aRoswell Park Cancer Institute,
Michael Cummings, Ph.D., Roswell Park Cancer Institute,
Steven Stellman, Ph.D., M.P.H., Columbia University, New
Neal Benowitz, M.D.,aUniversity of California,
San Francisco, CA
Anne Burke, Ph.D., University of Pennsylvania,
John Cooke, M.D., Ph.D., Stanford University, Stanford, CA
Stephen Rennard, M.D.,aUniversity of Nebraska, Omaha,
Mark Frampton, M.D., University of Rochester, Rochester,
David Riley, M.D., Robert Wood Johnson Medical School,
Stephen Hecht, Ph.D.,aUniversity of Minnesota,
Steven Belinsky, Ph.D., Lovelace Respiratory Research
Institute, Albuquerque, NM
Peter Shields, M.D., Georgetown University Lombardi
Cancer Center, Washington, DC
Steven Tannenbaum, Ph.D., Massachusetts Institute of
Cheryl Oncken, M.D., M.P.H.,aUniversity of Connecticut
Health Center, Farmington, CT
Peter Fried, Ph.D., Carleton University, Ottawa, Ontario
Theodore Slotkin, Ph.D., Duke University Medical Center,
Table 3. Expert panel members.
David Ashley, Ph.D., Centers for Disease Control and
Prevention, Atlanta, GA
David Burns, M.D., University of California, San Diego, CA
Greg Connolly, D.M.D., M.P.H., Massachusetts Department of
Public Health, Boston, MA
Mirjana Djordjevic, Ph.D., National Cancer Institute, Bethesda,
Jefferson Fowles, Ph.D., Institute of Environmental Science and
Research, Porirua, New Zealand
George Hammons, Ph.D., Philander Smith College, Little Rock,
Jonathan Samet, M.D., Johns Hopkins University, Baltimore, MD
David Shurtleff, Ph.D., National Institute on Drug Abuse,
Frank Vocci, M.D., National Institute on Drug Abuse, Bethesda,
Mitch Zeller, J.D., Pinney Associates, Bethesda, MD
Table 4. Moderating variables to consider for human clinical
Characteristics of tobacco user
Type of tobacco use
Degree of dependence
Amount of tobacco use
Duration of tobacco use
Interest in quitting
Recent cessation activity
Ethnicity or race
Physical and mental health status
NICOTINE & TOBACCO RESEARCH
one example, because oral tobacco confers less
tobacco (Hatsukami, Lemmonds, & Tomar, 2004).
Degree of dependence, indexed with biochemical
measures such as cotinine levels or self-report
scales, such as the Fagerstro ¨m Test for Nicotine
Dependence or the Nicotine Dependence Syndrome
Scale (Colby, Tiffany, Shiffman, & Niaura, 2000;
Stratton et al., 2001), may influence key variables
such as the extent or persistence of use and PREP-
induced changes in smoking behavior. Amount and
duration of tobacco use are also important; amount
serves as an indicator of frequency of behavior
whereas duration may be a better predictor of risk
for some diseases (Doll & Peto, 1978; Flanders,
Lally, Zhu, Henley, & Thun, 2003). Tobacco user
gender influences sensitivity to nicotine, treatment
outcomes, pharmacotherapy response, and extent
of uptake of carcinogens and disease risk and
outcome (Connett et al., 2003; Melikian et al.,
2004; Perkins, 2001). Ethnicity and race can also
affect the degree of dependence and disease outcome.
For example, African American tobacco users report
lower indicators of dependence and higher incidence
of tobacco-related disease (Caraballo, Giovino,
Pechacek, Mowery, & Richter, 1998; Emont, 1996;
Pe ´rez-Stable, Herrera, Jacob, & Benowitz, 1998; U.S.
Department of Health & Human Services, 1998;
Wagenknecht, Cutter, & Haley, 1990).
The effects of PREPs may differ based on users’
mental or physical health status, with potentially less
reduction in disease risk observed in populations
with a history of disease or a current disorder.
Concurrent medications may lead to induction of
enzymes that influence toxin exposure. Other mod-
erating variables include individual differences in
physiological phenotypes (e.g., individual differences
in metabolic activation or detoxification of toxins,
capacity and efficiency of DNA repair; Stratton et al.,
2001) and genotypes that confer susceptibility to
disease or addiction (Lerman & Niaura, 2002). In
sum, several potentially interrelated moderating
variables can influence PREP effects.
Methodological issues for evaluating PREPs. Several
methodological issues are relevant to assessing PREP
effects (Table5). First, the study population should
reflect the population of tobacco users likely to use
the PREP. For example, many smokers of light and
ultralight cigarettes are especially concerned about
the health risks from smoking (Giovino et al., 1996)
and thus may be most likely to use a PREP. Relative
to smokers trying to quit, smokers primarily inter-
ested in reducing their cigarette intake may have
more health, psychiatric, and alcohol use problems
(Lemmonds, Mooney, Reich, & Hatsukami, 2004),
which may limit the extent of beneficial effects from
using a PREP. The smoker’s cessation behavior, such
as interest in quitting or past quit attempts, is likely
to influence the use of the PREP and should be
controlled for or stratified in the comparisons.
Second, unbiased assignment to carefully consid-
ered control conditions is critical. Control conditions
for PREP evaluation might include use of (a)
conventional tobacco products (Breland, Buchhalter,
Evans, & Eissenberg, 2002; Hecht et al., 2004), (b)
standardized products, although these types of
products are not considered sufficient (e.g., Eclipse
(Hatsukami, Lemmonds, Zhang et al., 2004), or (d)
no tobacco or nicotine products (i.e., abstinent users
or nonusers; Breland, Acosta, & Eissenberg, 2003).
These conditions provide valuable reference points
and allow consumers to understand the relative risks
associated with PREPs.
Third, both controlled and ad libitum use should
be consideredin assessing
tobacco use allows a direct comparison of the toxin
exposure associated with each PREP, whereas ad
libitum use provides a more accurate picture of toxin
uptake in the natural environment.
Fourth, a comprehensive battery of exposure,
injury, or disease biomarkers is essential in PREP
evaluation. Future research must identify a panel of
biomarkers that reflect different disease states so that
determinations can be made that reductions observed
in one area (e.g., carcinogen exposure) are not
achieved at the expense of increases in another (e.g.,
abuse liability or heart disease; Breland, Buchhalter et
al., 2002; Breland, Evans, Buchhalter, & Eissenberg,
2002; Fagerstro ¨m, Hughes, & Callas, 2002). A
thorough assessment panel should include a general
and uniform set of biomarkers that can be used in the
evaluation of all PREPs, in addition to biomarkers
that are specific to the products being assessed.
Fifth, it is important to consider goals, outcome
measures (e.g., metabolic half-life of biomarkers),
and in some cases, stabilization of PREP use
Table 5. General methodological issues in human clinical
Characterization of population
Random assignment of subjects to experimental conditions
Conventional brand of tobacco
Standardized brand of tobacco
Abstinent smokers or nonsmokers
Controlled vs. ad libitum smoking
Comprehensive set of biomarkers
Dictated by study goal and outcome measures
Stabilization of tobacco use behavior
Verification of product use or reduction in tobacco consumption
Monitoring of adverse events
Other unexpected or unintended consequences
METHODS TO ASSESS PREPS
behavior when determining study duration. For
example, in laboratory studies examining PREP
acute effects, study duration may be a few hours
(e.g., Breland, Buchhalter et al., 2002; Breland,
Evans etal.,2002; Buchhalter,
Eissenberg, 2001). However, if the goal of the study
is to examine human exposure and disease risk
measures in a naturalistic environment, then a study
may last days (e.g., Breland et al., 2003; Fagerstro ¨m,
2000; Hatsukami, Lemmonds, Zhang et al., 2004) or
months (Hecht et al., 2004; Keely, Hughes, & Hirsch,
Sixth, special attention should be given to assess-
ment and verification of compliance with protocol-
specific tobacco use restrictions. However, except in
inpatient settings, compliance can be difficult to
verify. On an outpatient basis, when the PREP
involves tobacco reduction or abstinence, biochem-
ical verification is possible (e.g., by assessing the
tobacco alkaloid anatabine, or tobacco-specific
nitrosamines such as total NNAL; Hecht et al.,
2004). For PREPs that specifically involve tobacco
use reduction, the extent to which anatabine, total
NNAL levels, or other biomarkers should be
lessened to indicate compliance is, to date, uncertain.
If the PREP involves a continued normal rate of
tobacco use (e.g., a tobacco-containing PREP
intended to reduce toxin exposure), then investiga-
tors may need to identify procedures that maximize
compliance while also encouraging accurate report-
ing of product intake (e.g., multiple compliance
measures, return of used and unused product,
Finally, adverse events (e.g., increased blood
pressure, higher than normal laboratory tests)
need to be monitored to assess for unintended or
unexpected consequences of PREP use.
Exposure and health effects. The measures related to
potential harm involve assessing toxin exposure or
health effects (Table6). With regard to assessing the
dose of toxin exposure, the most obvious measure is
actual tobacco use, complemented with topographi-
cal features such as (in smokers) puff number,
duration, volume, and velocity as well as interpuff
interval. Generally, self-report measures are common
(e.g., Bolliger et al., 2000; Carpenter, Hughes,
& Keely, 2003; Etter, Laszlo, Zellweger, Perrot,
& Perneger, 2002; Fagerstro ¨m, Tejding, Westin, &
Lunell, 1997; Hurt et al., 2000; Rennard et al., 2002;
Tonnesen, 2003) but can be confounded by changes
in use topography (e.g., Hecht et al., 2004). Thus
measures of actual toxin uptake, such as carbon
monoxide, nicotine or cotinine, anatabine, and
carcinogens, are essential (Breland et al., 2003;
Hecht et al., 2004). Exposure assessments could also
include examining PREP-delivered toxin pharmaco-
kinetics, including metabolism and clearance rates.
Biomarkers of health effects include early chemi-
cal, biological, and functional effects that are or
should be related mechanistically to disease outcome.
These measures incorporate biologically effective
dose, injury, or other disease-related outcomes
(Stratton et al., 2001). Examples of these measures
would include carcinogen-DNA adducts, lipid per-
oxidation, chromosomal aberrations, mitochondrial
mutations, lipids, F2 isoprostanes, white blood
count, blood pressure, or FEV1. These biomarkers
may describe components or mechanisms of the
disease process and may be used as tools for further
research to determine their relationship to disease
risk. In addition to these types of biomarkers,
directly observable measures such as visual inspec-
tion of airways or birth weight can be considered as
biomarkers of health effects.
Abuse liability of PREPs. Another important com-
ponent of assessing PREPs includes determining
their abuse liability, that is, the potential for
addiction (Table6). No PREP should have increased
abuse liability relative to existing conventional
products. Abuse liability may be measured in
several ways, including assessing the subjective
effects that it produces (Griffiths, Bigelow, & Ator,
Addiction Research Center Inventory (Houtsmuller,
Fant, Eissenberg, Henningfield, & Stitzer, 2002;
Jasinski, 1977; W. R. Martin, Sloan, Sapiro, &
Table 6. Measures for human clinical trials.
Exposure or chemical biomarkers
Frequency and amount of tobacco use
Tobacco use topography (e.g., number of puffs, puff duration,
puff volume, puff velocity)
Biomarkers for exposure (e.g., nicotine, cotinine, carbon
monoxide, carcinogen uptake)
Biomarkers of health effects
Early cellular or biological effects
Biologically effective dose
Other disease-related outcomes
Directly observed biomarkers
Abuse liability measures
Subjective responses to product
Behavioral responses to product
Drug choice paradigm
Duration of use
NICOTINE & TOBACCO RESEARCH
Jasinski, 1971; Schuh, Schuh, Henningfield, &
Stitzer, 1997), the Duke Cigarette Evaluation Scale
(Lee, Malson, Moolchan, & Pickworth, 2004; Rose,
Behm, Westman, & Johnson, 2000; Westman, Levin,
& Rose, 1992),the Profile
(McNair, Lorr, & Droppleman, 1992; Schuh et al.,
1997), and a variety of items assessing the valence
and magnitude of drug effects (e.g., Houtsmuller
et al., 2002, 2003). In these studies, subjective
responses have been compared across drugs or
products being tested. Other studies have asked
participants to indicate their preference for PREPs
(e.g., Schneider et al., 2004; Schuh et al., 1997). Other
measures have included assessment of palatability,
pleasantness, satisfaction, sensory effects, and extent
of feeling dependent
Houtsmuller et al., 2002, 2003; Lee et al., 2004;
Schneider et al., 2004; Schuh et al., 1997; West et al.,
2000). Another method of measuring abuse liability
involves determining behavioral responses, such as
asking participants to choose PREPs they would
like to self-administer after a sampling period (e.g.,
Fagerstro ¨m et al., 2002). The extent to which
participants use a PREP is presumed to be related
directly to the PREP’s abuse liability (Hughes et al.,
1991; West et al., 2000). Duration of use (‘‘How
long do participants persist in the use of the
product?’’) is also relevant (e.g., Shiffman, Hughes,
Di Marino, & Sweeney, 2003; West et al., 2000).
Finally, examining PREP effects on the suppression
of tobacco-related withdrawal symptoms or craving
thought to maintain tobacco use (e.g., Breland
et al., 2003; Breland, Buchhalter et al., 2002;
Houtsmuller et al., 2003; Pickworth, Fant, Nelson,
Rohrer, & Henningfield, 1999; Schneider et al., 2004;
West et al., 2000).
When examining PREP abuse liability, researchers
should consider testing different doses (Houtsmuller
et al., 2002, 2003; Hughes et al., 1991; Schuh et al.,
1997) and the use of appropriate negative and
positive control conditions (e.g., Houtsmuller et al.,
on the product(e.g.,
Patterns of use. Because using multiple products
(e.g., usual brand and a PREP) can lead to greater
toxicity, an examination of naturalistic use patterns
is important in assessing actual exposure (Keely et
al., 2001). For example, use of smokeless tobacco
instead of smoking may reduce individual disease
risk (e.g., Levy et al., 2004). However, this beneficial
effect may be lessened if smokeless products are
used in conjunction with cigarettes (Hatsukami,
Lemmonds, & Tomar, 2004) or are used to maintain
contrived tobacco use under circumstances in which
a smoker cannot smoke. Laboratory studies can also
reveal factors that might contribute to the extent to
which PREPs are used, compared with conventional
tobacco products (e.g., instructions and information
provided about the PREP, PREP cost and access,
availability of alternatives; Hughes et al., 1991).
Evaluating PREP effects on maintenance of tobacco
use. Understanding the extent to which long-term
abstinence from all tobacco products is hindered or
facilitated by PREPs is critical and can be ascer-
tained by (a) assessing changes in motivation to quit
on the Contemplation Ladder (Biener & Abrams,
1991; Carpenter et al., 2003; Kotlyar, Jensen, Li, &
Hatsukami, 2004) or similar measures (Etter et al.,
2002; Fagerstro ¨m, 2000), (b) assessing whether
subjects have progressed on their stages of change
(Etter et al., 2002; Prochaska, DiClemente, &
Norcross, 1992), (c) determining the number of quit
attempts in which abstinence has been sustained for
at least 24hr (e.g., Bolliger et al., 2000; Carpenter et
al., 2003), and (d) determining the total duration of
abstinence. The gold standard is the abstinence rate
associated with use of a PREP compared with
conventional products. Studies should not rely solely
on motivations to change as predictive of long-term
abstinence. The ideal PREP may well be one that
reduces toxin exposure and harmful health effects of
tobacco in the short term and does not compromise
complete tobacco abstinence in the long term.
Premarket consumer testing
Issues in premarket testing of product presentation
Premarket testing of consumer perceptions of PREPs
is important to ensure that claims conveyed about
these products or marketing efforts are accurate and
not misleading. The importance of this type of testing
is underscored by studies showing that many
smokers were misled about the health benefits
associated with light, mild, and ultralight cigarettes,
and by reports indicating that because of this
misperception, a number of smokers chose not to
quit smoking (National Cancer Institute, 2001).
Recently, studies have been conducted on the
perception of claims that are made for PREPs. The
results are of concern. In a study conducted by
Shiffman, Pillitteri, Burton, and Di Marino (2004),
the aim was to assess smokers’ and ex-smokers’
perceptions of PREPs and how PREP claims may
affect interest in quitting among smokers or in
resuming smoking among ex-smokers. A random-
digit-dialed survey was used to contact 1,000 smokers
and 499 ex-smokers. Risk reduction claims asso-
ciated with R. J. Reynolds’s Eclipse were read to the
participants, and perception and potential effects of
these claims were assessed. Examples of these claims
METHODS TO ASSESS PREPS
include ‘‘Best choice for smokers is to quit but
Eclipse is the second best choice,’’ ‘‘May present less
risk of cancer,’’ and ‘‘Contains far less of the many
compounds found in cigarette smoke that are
believed to contribute to the risk of cancer and other
illnesses.’’ Between 81% and 91% of smokers and ex-
smokers thought Eclipse was safer than regular
cigarettes, and 24%–26%
completely safe (e.g., equivalent to not smoking).
About 57% of smokers were interested in using
Eclipse, with the greatest interest among contempla-
tors (i.e., smokers who expressed interest in quitting
within the next 6 months). The survey also showed
that 21% of smokers lost interest in quitting after
hearing about Eclipse, and 6.2% of ex-smokers were
interested in Eclipse, with even a higher rate of
interest (15.2%) among young adults who had
stopped smoking within the past 2 years. Although
one of the limitations of this study is that the survey
assessed intent rather than actual behavior, it raises a
cautionary note that promotion of PREPs, particu-
larly without regulatory oversight for the scientific
basis for making these claims, could have untoward
effects on public health.
Ideally, tobacco companies would not be able to
advertise their cigarette products, and it is debatable
whether they should be allowed to advertise any
claims for reduced exposure or reduced health risks.
However, given the lack of current restrictions on
advertisement and promotion, premarket testing is
an important component of evaluating PREPs.
Evaluation of these products may entail two
purposes: (a) Regulatory (i.e., Does this presentation
and promotion of the product adhere to an agreed-
upon standard including assurance that the claims
are not false or misleading?) or (b) public health (i.e.,
Are the presentation and promotion likely to lead to
beliefs or behaviors that tobacco control forces want
to prevent, such as maintenance of tobacco use in
those who would have quit otherwise?). The optimal
situation is when these two purposes merge.
Testing of consumer perceptions of PREPs includes
assessing reactions (a) to product characteristics
presented via advertising (e.g., newspaper, magazine,
Internet) and other promotional methods, images and
text, and packaging and (b) to implicit and explicit
reduced harm claims in these presentations. As a
preliminary step, decisions by a regulatory agency
must be made about what the science supports and
whether labels should reflect reduced exposure to
specific smoke constituents,based onhuman exposure
methods, or go so far as to provide estimates of
reduced risk of specific smoking-related diseases.
Furthermore determining the text, format, and
graphic representations of these data that best convey
information in a way that is interpreted accurately is
another important area of investigation. For example,
the use of visual scales that show exposure from
nonsmoking at one end and exposure to medium- or
high-yield conventional cigarettes at the other end
may be a readily comprehensible method of conveying
the data to laypersons. Lessons may be learned from
the experience of the FDA’s development and testing
of food labels. The necessity of this area of investiga-
tion is emphasized by studies showing that most
smokers are unaware of the tar yield of their own
cigarettes; could not correctly determine and under-
stand the implications of the relative tar levels of
cigarettes; and rely mostly on misleading labels such
as light, ultralight, or mild (Cohen, 1996; Etter,
Kozlowski, & Perneger, 2003; L. Kozlowski et al.,
1998). Also, accurately perceived information on
changes in specific components may nevertheless be
misleading if not accompanied by information about
components that have not changed.
describedfor testing consumer
tobacco products, several methodological issues bear
discussion. One important issue is the need to target
the testing in a population that is potentially
interested in these PREP products. Furthermore,
recruiting smokers or other tobacco users who have
diverse characteristics and describing these charac-
teristics is necessary to determine how these attri-
butes may influence their perceptions of PREPs. For
example, participants need to be characterized on
smoking status (e.g., never-smokers, former smo-
kers), stage of smoking (experimenters vs. regular
smoker), past and present efforts to reduce cigarette
consumption or switch to a lower-yield cigarette,
past quit attempts, difficulty in quitting smoking,
stage of change (thinking about quitting in the next
6 months or within the next month), or motivation
and intention to quit or decrease smoking. Perceived
pressure from peers, family, or health care providers
may also be a determinant of how PREPs are
perceived. Other characteristics that bear considera-
tion are the type of cigarettes currently smoked (e.g.,
ultra low yield, low yield, or regular), the degree of
tobacco dependence and extent of smoking (occa-
sional user vs. regular user), the degree of concern
about smoking-related health, and the general and
individual perceptions of risk associated with smok-
ing. Concerted effort should be made to include
individuals that represent a spectrum of ages
(adolescents, young adults, adults, and older adults)
and are from different ethnic and socioeconomic or
educational backgrounds. Most of these variables,
including gender, have been observed to influence
perceptions and use of low-yield and ultra-low-yield
cigarettes or PREPs (e.g., Etter et al., 2003; Gilpin,
NICOTINE & TOBACCO RESEARCH
Emery, White, & Pierce, 2002; Hamilton et al., 2004;
Shiffman et al., 2004; Shiffman, Pillitteri, Burton,
Rohay, & Gitchell, 2001a, 2001b).
Several avenues for consumer assessment of product
presentation and labeling include focus groups;
individual testing; mall-intercept interviews; and
Internet, mail, and telephone surveys. Focus groups
are most useful for initial exploration of the reactions
elicited in consumers in response to product character-
istics. Individual testing can be used for more in-depth
understanding of message processing and preferences.
It is recommended that some of the testing of the
product presentation characteristics be performed in
situ; that is, the content should be tested in the
environment in which the consumer will encounter it.
When consumers are explicitly directed to evaluate
PREP characteristics and messages, they are likely to
respond differently than if their attention had not been
directed to these issues. This distinction between
central and peripheral processing is well established
in the persuasion literature (Petty, Haugtvedt, &
Smith, 1995; Petty& Wegener,1999).Althoughtesting
of print advertising intended for magazines or the
Internet can be done in a laboratory setting, retail
advertising will need to be tested in an actual retail
environment, or within a virtual retail experience.
An innovative method of assessing the behavioral
impact of a product is described in a study conducted
by Shiffman, Burton, and associates (2001) using the
ARS Persuasion test, a method to test the effective-
ness of commercial television advertising. This test
involves presenting the advertisement, which is
embedded in a pilot television show that the
participants are presumably reviewing, and deter-
mining the pre-post shift in brand choice in an
environment that simulates product purchase. That
is, the participants’ shift in product choice offered as
prizes is determined before and after viewing the
advertisements. A control group that has no expo-
sure to the advertisement is used as a comparison
group. Ideally, the design should compare differences
in postmessage choice only between the exposed and
control groups. Making a premessage choice focuses
attention on the advertisement and alters the way in
which the message is processed. Conceivably, to
assess the effects of PREPs on quitting behaviors,
smokers who are in the preparation or action stage of
quitting can be exposed to a PREP advertisement
and the extent of PREP choices after exposure to the
advertisement can be compared with those of a
control group with no exposure to the advertisement.
Finally, population surveys can provide estimates
for population impact, as described in the aforemen-
tioned random-digit-dialed telephone survey con-
ducted to determine smoker and ex-smoker reactions
to PREP cigarettes claiming reduced risk (Shiffman
et al., 2004).
As an added area of research, product presentation
characteristics may influence smokers’ perceptions of
the sensory and reinforcing effects of the PREPs and
the experience of using them (Pollay & Dewhirst,
2002, 2003). For example, color, image, and exten-
sion of well-known brands may influence the
perception of product taste (Pollay & Dewhirst,
2002). On the other hand, if after trying a PREP, the
smoker rejects the sensory and hedonistic qualities of
the PREP, he or she is unlikely to adopt it, in spite
of any implicit or explicit reduced-harm claims.
Furthermore several studies have demonstrated that
the somatic or sensory sensations experienced by an
individual may shape his or her perception of
perceived health threat or protections (Brownlee,
Leventhal, & Leventhal, 2000; Leventhal et al.,
1997). Supporting the contributions of sensory
effects on product perception are two studies finding
that advertising information on the deceptiveness
about the sensory effects of smoking light cigarettes
had the greatest impact on changing beliefs about
safety and toxin delivery of light and ultralight
cigarettes, intent to quit, and preference for cigarettes
(Shiffman, Burton et al., 2001; Shiffman, Pillitteri
et al., 2001a). It is necessary then, in evaluating
consumer perceptions of a PREP, to consider how
the product presentation influences sensory and
reinforcing qualities of the PREP and how the
sensory experiences from the PREP influence percep-
tion of health benefits.
The assessment of consumer perceptions and assur-
ance of adequate interpretation of information
requires exposure to several methods of communica-
tion—print ads or packages, Internet, radio adver-
tisements, retail store advertisements, and product
placement. Participants in consumer testing should
be asked both general questions about the product
and specific questions about product presentation
characteristics. In other words, how the individual is
interpreting the information in the advertisement,
packaging, and labeling should be assessed. More
specifically, measures should include assessment of
comprehension, beliefs, and behavioral intention
(Bates, McNeill, Jarvis, & Gray, 1999; Cohen,
1996; Etter et al., 2003; Gilpin et al., 2002;
Hamilton et al., 2004; L. Kozlowski et al., 1998;
Pollay & Dewhirst, 2002; Shiffman, Burton et al.,
2001; Shiffman et al., 2004; Shiffman, Pillitteri et al.,
2001a, 2001b). Comprehension items include inquir-
ing about whether harmful toxins have been reduced,
to what extent, and the meaning of the reduction of
specific toxins; whether risk for disease has been
reduced, which diseases have been reduced, and to
what extent; the potential addiction of the PREP and
METHODS TO ASSESS PREPS
whether the PREP affects motivation to quit and
ease of cessation; and whether the product benefits
the health of others (e.g., reduces second-hand smoke
exposure to toxins). Belief items include asking if the
participants actually believe that using the PREP is
safer, healthier, or leads to beneficial health effects
and the type and degree of these benefits; if using the
PREP will make it easier for them to quit; if using the
PREP is just as good as quitting; if using the PREP
would lead to less harm or health benefits to
others; and if using the PREP would allay the
concerns of others over their tobacco use behaviors.
Comprehension and belief questions can be asked to
provide absolute or relative (compared with conven-
tional marketed products such as regular, light, and
ultralight cigarettes or compared with not smoking)
ratings of safety, delivery of toxins, and other
characteristics of the PREP. Behavioral intention
items include measurement of the extent to which
individuals are interested in trying the product,
changes in their interest in quitting when the product
becomes available, and if they would consider
switching to the PREP from their own brand of
cigarettes. Open-ended questions can also be asked,
including ‘‘What are your thoughts and feelings
about the PREP?’’, ‘‘What can you expect from this
product?’’, and ‘‘How would you use this product?’’
Finally, assessments can be conducted on the
credibility of the message, who the participants
believe the source of the message to be, and whether
they believe that the government has given the
product the stamp of approval.
Postmarketing surveillance and evaluation
Issues in postmarketing surveillance and evaluation of
problems before a product goes to market, unantici-
pated developments are likely. A postmarketing
system of surveillance and evaluation is needed to
assess the actual population impact of the marketing
of PREPs on the perceptions, behaviors, and health
outcomes of relevant populations. The main con-
cern in the tobacco control community is whether
the marketing of PREPs will slow the decline in the
use of conventional cigarettes and other tobacco
products that has been observed since the 1950s
(Giovino, 2002; Husten, Jackson, & Lee, 2004;
Joseph, Hennrikus, Thoele, Krueger, & Hatsukami,
2004; E. G. Martin, Warner, & Lantz, 2004;
Mendez & Warner, 2004; Warner & Martin,
2003). The ultimate question is whether tobacco-
attributable morbidity and mortality will eventually
be lower than they would have been had PREPs not
been introduced into the market (Ferrence, Slade,
Room, & Pope, 2000; Hatsukami et al., 2002). This
is an extremely difficult question to resolve, partly
because any conclusions drawn will rely on assump-
tions made when making projections. Nevertheless,
a comprehensive postmarketing surveillance and
evaluation system that provides information on
product characteristics, environmental influences,
relevant perceptions and behaviors, biological expo-
sures, and health outcomes (Figure2) for both the
United States and comparison countries will max-
imize feedback potential and permit corrective
action as early in the process as possible.
The ideal postmarketing surveillance and evalua-
tion system will incorporate principles of public
health surveillance. These principles include the
ongoing, systematic collection, analysis, interpreta-
tion, and dissemination of data regarding a health-
related event for use in public health action to reduce
morbidity and mortality and to improve health. Data
disseminated by a public health surveillance system
can be used for immediate public health action,
program planning and evaluation, and formulation
of research hypotheses (Centers for Disease Control
and Prevention, 2001a).
Many attributes are used to evaluate surveillance
systems, including representativeness, timeliness, sim-
plicity, flexibility, and sensitivity (Centers for Disease
perceptions, uptake of constituents, and disease risk.
Elasticity/compensation model of policies influencing product design and chemistry and user behaviors,
NICOTINE & TOBACCO RESEARCH
Control and Prevention, 2001a). A representative
system will accurately describe the distribution of
health events (e.g., behavior, disease) in a popula-
tion by person, place, and time. A timely system
minimizes the delay between the occurrence of an
event and the collection of data and reporting of
findings. The simplicity of a given system is a
function of its structure and ease of operation.
Ideally, a surveillance system will be as simple as
possible and still meet all of its objectives. A flexible
system can economically adapt to changing operat-
ing conditions or information needs. Sensitivity
refers to the ability of a system to detect relevant
health behaviors, perceptions, diseases, and condi-
tions of interest.
Surveillance systems can be either passive or active.
Passive systems generally collect information on
health events reported by interested health profes-
sionals and others. Two examples of passive systems
are the reporting of adverse drug events to the FDA
via the Medwatch program and the Substance Abuse
and Mental Health Services Administration via the
Drug Abuse Warning Network (Arfken & Cicero,
2003; FDA, 2004; Substance Abuse and Mental
Health Services Administration, 2004). Active surveil-
lance systems are more resource intensive and for this
application would involve data collection on the
PREPs themselves; the people who use them, as well
aspotentialusers;theways theproducts aremarketed;
and the environment in which they are marketed.
Systems would need to monitor both pro- and anti-
tobacco influences. An active surveillance system is
urgently needed to properly assess the impact of
PREPs at the population level (Stratton et al., 2001).
Numerous surveys at the federal and state levels
monitor tobacco-related variables, but their purposes
differ, and none is dedicated to assessing the popula-
tion impact of PREPs on tobacco use perceptions and
behaviors and tobacco-attributable morbidity and
Key topics that need to be addressed include
initiation and cessation rates, tobacco consumption
patterns, and patterns of PREP use (e.g., whether they
facilitate initiation to conventional cigarettes and
whether they facilitate quitting). It is vital that we
understand the characteristics of persons who adopt
PREP use, for health outcomes will be influenced by
factors such as age, duration of previous use of
conventional tobacco products, and exposure to
environmental tobacco smoke. We will need to know
if current and potential users are adequately informed
about the relative harms posed by various products
(Cummings et al., 2004). Such assessments will be
enhanced with adequate product surveillance (includ-
ing the characteristics of the products themselves
and how they are experienced by users), marketing
surveillance (e.g., of both words and images), and
environmental surveillance (of both pro- and anti-
tobacco forces). Given that most, if not all,PREPs will
would most likely be implemented at the federal level,
multinational comparisons will be needed to monitor
PREP use, PREP users, and their environment.
Table7 describes some of the methodological chal-
lenges associated with postmarketing surveillance.
Table8 details existing and new measures and
methods needed for postmarketing surveillance.
The current system of data collection on tobacco is
complex and sophisticated. However, the integration
and coordination needed to prevent unanticipated
deleterious consequences of the marketing of PREPs
Currently, information on the consumption of
various tobacco products is available from the U.S.
Department of Agriculture (2004) and from Federal
Trade Commission (FTC) reports of aggregated data
on the characteristics (e.g., length, menthol status) of
cigarettes consumed in the United States (FTC,
2003a). However, none of this information is
available on a variety-specific basis (i.e., at the sub-
brand level), nor by geographic locale. Use of
pharmaceutical aids to quitting is reported by a
proprietary firm and used by researchers to under-
stand patterns of quitting (Centers for Disease
Control and Prevention, 2000).
No useful surveillance is conducted on the design
of products, constituents in their tobacco, added
ingredients, and the smoke they generate (Stratton
et al., 2001). Until 1998, the FTC (2000) reported tar,
nicotine, and carbon monoxide (TNCO) levels in the
smoke of domestic varieties of cigarettes, but the
testing system was not indicative of actual human
smoking practices (National Cancer Institute, 2001).
TNCO and additional constituents need to be
measured in a manner that reflects how cigarettes
are actually smoked.
Tobacco product marketing also is monitored
inadequately. The FTC collects brand-specific mar-
keting data for cigarettes and smokeless tobacco but
Table 7. General methodological issues in postmarketing
Testing products under conditions that mimic actual human
Validity of self-reports of historical events (e.g., age at first use
and first daily use, timing of use of various products and dose
administered when using)
Declining response rates of telephone surveys in the United
Finding biomarkers that predict disease outcomes
Comparability of American Cancer Society Cancer Prevention
Study (CPS)-III to CPS-I and CPS-II
Adequate comparison groups (i.e., from other countries)
METHODS TO ASSESS PREPS
can legally report only aggregated national marketing
expenditures (FTC, 2003a, 2003b). Self-reported
exposures to various media messages are obtained in
several surveys (Bachman, Johnston, & O’Malley,
2001; Centers for Disease Control and Prevention,
2001b; Farrelly et al., 2002). Proprietary data on
television and magazine advertising can be purchased,
as can data on newspaper stories and prices of various
products (Clegg Smith et al., 2002; Stillman, Cronin,
Wakefield, & Chaloupka, 2003). The state of
California supports activities that monitor sponsor-
ship and promotions (Cruz & Jouharzadeh, 2003).
Resources to expand these efforts are needed. Further
monitoring needs involve work on text and images in
newspapers and magazine advertising; direct mail
marketing; retail environment advertisement and
promotions; placement and portrayals of products in
movies and on television; Internet messages (e.g.,
marketing, sales, chat rooms, corporate Web sites);
product packaging; newspaper and magazine articles,
editorials, and op-ed pieces; television stories and
commentaries; tobacco industry anti-tobacco efforts;
and tobacco industry efforts to counter tobacco
control activities (G. A. Giovino et al., unpublished
Monitoring of anti-tobacco activities will permit
assessment of factors that reduce prevalence. For
example, both media advocacy and paid media
should be monitored, as should the availability of
strength of smoke-free airs laws, ordinances, and
policies (Strattonet al.,
Individual tobacco product use is assessed in
numerous national surveys (Stratton et al., 2001).
Although each survey is necessary for various
components of public health surveillance, none of
them collects all of the information needed to
properly assess possible risks and benefits associated
with the introduction of PREPs; further, all are
cross-sectional in design (Stratton et al., 2001). Only
limited information on perceptions regarding PREPs
and other tobacco products (e.g., optimism bias) and
on comorbidities is available from representative
surveys. Therefore, a population-based surveillance
system with adequate measures of variables needed
to assess possible risks and benefits of PREP use is
needed. This system would ideally be longitudinal
in nature and provide comparisons with other
English-speaking countries in the same stage of
the tobacco use epidemic (e.g., Canada, United
Kingdom, Australia) (Lopez, Collishaw, & Piha,
1994), similar in design to the International Tobacco
Control Policy Evaluation Survey (Fong, Borland,
response rates in telephone surveys conducted in
the United States will need to be adequately
accounted for and appropriate incentives provided
to maximize participation rates.
Biological markers that are predictive of disease
outcome need to be identified, perhaps by conduct-
ing follow-up studies of serum and urine from the
Third National Health and Nutrition Examination
Survey (conducted from 1988 to 1994; Stratton et al.,
2001). The American Cancer Society’s Cancer
Prevention Study (CPS)-I and CPS-II have made
enormous contributions to tobacco epidemiology,
partly because of comparisons made between the two
cohorts (Thun et al., 1997; Thun & Heath, 1997). The
voluntary nature of this study facilitated the enroll-
ment of large numbers of current, former, and never-
smokers, yielding rates for a large number of diseases
for each category of smokers. A third CPS wave is
being planned. The recruitment and retention of
smokers, particularly as smoking becomes propor-
tionately more prevalent in lower socioeconomic
groups (Husten et al., 2004), is a challenge for future
cohort studies (Michael Thun, personal communica-
tion, June 28, 2004). A partnership between the
federal government and the private sector may help
solve this dilemma.
Table 8. Existing and new measures and methods for postmarketing surveillance.
Product consumption: U.S. Department of Agriculture, Federal Trade Commission reports
Tobacco product marketing: Federal Trade Commission; surveys on exposure to media messages such as the Youth Tobacco
Survey, Monitoring the Future, Legacy Media Tracking Survey, and various state-based evaluations
Individual product use: Monitoring the Future, National Health Interview Survey, National Survey on Drug Use and Health, Tobacco
Use Supplement to Current Population Survey
Health outcomes: Third National Health and Nutrition Examination Survey, American Cancer Society Cancer Prevention Survey I and
II, national vital statistics system, cancer registries, hospital discharge survey, medical expenditure surveys
New methods and surveys that need developing
Product consumption: potential reduced exposure products (PREPs) and geographic locale of product consumption
Surveillance of tobacco product design, constituents of tobacco products, and actual human exposure
Surveillance of tobacco product marketing including television and magazine advertising, newspaper stories and editorials, television
coverage and commentaries, sponsorship and promotions, text and images across various media outlets, product packaging and
Surveillance on antitobacco activities including cessation, school programming, ordinances, and policies
Surveillance on individual product use including a population-based surveillance that specifically measures who, what, when, and
where of PREP use and how the products are perceived
Addition of biomarkers to existing surveys on health outcomes
NICOTINE & TOBACCO RESEARCH
Sources of data on disease outcomes include the
national vital statistics system, cancer registries,
hospital discharge surveys, medical expenditures
surveys, and the ACS Cancer Prevention Studies
(Stratton et al., 2001). To facilitate reporting by
consumers, a telephone number for reporting rele-
vant symptoms (e.g., sore throat, coughing, irrita-
tion) could be placed on every package. These
systems can be used to help calculate the population
impact of PREPs.
Product design features can be assessed using visual
inspection (e.g., for cigarette diameter and length,
tobacco weight, filter type and weight, structural
materials); optical scanning to assess blending; and
machines for assessing characteristics such as ventila-
tion, pressure drop, and paper porosity. Appropriate
chemical analyses should be conducted on the
products themselves and the smoke generated by
those that are burned (or heated). Candidates for
surveillance include TNCO, free nicotine, polycyclic
aromatic hydrocarbons, and tobacco-specific nitrosa-
mines. Ideally, variety-specific parameters for smok-
ing-machine settings that mimic consumer behaviors
should be determined and used in assessments.
Representative surveys of youth and adults should
measure use (e.g., daily dose, brand history, topo-
graphy); dependence; age and incidence of initiation
and cessation; susceptibility to start; motivations and
intentions to quit; perceptions of the risks and
benefits associated with tobacco products and cessa-
tion treatments; awareness, use, and perceptions of
and interest in PREPs; media exposures (e.g.,
cigarette advertising and promotions, anti-tobacco
messages); home or work smoking bans; support and
advice for quitting; health beliefs; alcohol and illicit
drug use; mental health indicators; perceived stress;
physical health; other risk factors; demographics;
and biological fluids for biomarkers and genetic
testing. One methodological concern raised in all
epidemiological studies is the validity of documenta-
tion of exposure. Notably, age at initiation and the
duration and dosage of each tobacco product used
would need to be assessed accurately. Biomarkers
should be measured as indicated by the science. For
example, cancer biomarkers would include NNAL
and NNAL-Gluc in urine and aromatic amine-Hb
adducts (Hatsukami, Benowitz, Rennard, Oncken, &
Hecht, in press). In sum, the proposed comprehen-
sive surveillance system would do much more than
monitor PREPs. It would also assess whether
introduction of PREPs had any influence on smok-
ing attitudes and behaviors in general.
Research will be needed to develop, test, and
validate various environmental measures and indices
of both tobacco promotional and tobacco control
activities (e.g., state and local programs, media)
across various communication channels (G. A.
Giovino et al., unpublished manuscript). A coordi-
nated system will be required to assess the nature,
scope, intensity, and effectiveness of these strategies
(G. A. Giovino et al., unpublished manuscript).
Measures of health status would include symptoms
Eclipse),biologicalfunction,years of potentiallifelost,
and health-related quality of life (Stratton et al., 2001).
Recommendations and conclusions
The recommendations put forward by this group are
similar to those proposed by the World Health
Organization Scientific Advisory Committee on
Tobacco Regulation (2003) in a document entitled
‘‘Statement of Principles Guiding the Evaluation
of New or Modified Tobacco Products.’’ In the
conclusions of that document, one of the principles
stated, ‘‘Regulatory oversight of cigarette and
cigarette-like products should include examination
of at least five separate aspects of the new products:
Physical chemical characteristics of the tobacco and
tobacco smoke, uptake of toxicants (both by smokers
and by non-smokers), toxicity, addiction potential,
and disease risk (across a spectrum of disease
states).’’ Similar aspects were proposed for the
evaluation of smokeless tobacco products. These
principles described the need for adequate scientific
evidence to support the claims made on these
products, with an independent regulatory agency
Demonstration of reduction of smoke emissions or
reduced uptake in toxins was not considered
sufficient for a claim or implication that the product
reduces toxicity or harm. Of final note, the principles
described a need for postmarketing surveillance to
monitor and further assess consumer perceptions of
claims made on these PREPs.
Another document was developed by the World
Health Organization Study Group on Tobacco
Product Regulation (2003), formerly the Scientific
entitled ‘‘Guiding Principles for the Development
of Tobacco Product Research and Testing Capacity
and Proposed Protocols for the Initiation of Tobacco
Product Testing.’’ The purpose of this document was
to promulgate principles to implement articles of the
WHO Framework Convention on Tobacco Control
(FCTC) that are related to tobacco products testing.
This document proposed guidelines for testing and
measurement and for the regulation of the contents
and emissions from tobacco products (Article 9 of
FCTC), for the regulation of tobacco disclosures to
both governmental authorities and the public about
of the claims.
METHODS TO ASSESS PREPS
the contents and emissions of tobacco products
(Article 10), and for the packaging and labeling of
tobacco products (Article 11), including assurance
that packaging and labeling do not promote false or
misleading impressions about the health effects or
harmfulness of the products. The principles called for
empirically verified standardized testing protocols
and methods to assess product performance. It also
emphasized that these methods must remain flexible
and can be modified by the evolving research in
product testing, by ongoing changes in tobacco
products, and by assessing the impact of marketing
messages and health effects of these products on
populations. Further, the document described spe-
cific principles for testing and research as well as
specific testing protocols particularly as they relate to
measuring tobacco ingredients, emissions, and pro-
duct design features.
The recommendations made by the panel of
experts for this paper as well as the World Health
importance of an infrastructure that allows for an
integrated, comprehensive, and systematic evaluation
of tobacco products, both conventional and PREPs
(Table9). This system would include a product
registry, which would have necessary information
on all nicotine-delivery products on the market.
Optimal coordination of data collection and analyses
will be facilitated by the creation and long-term
support of a transdisciplinary research network that
would include experts from both the public and
private sectors (G. A. Giovino et al., unpublished
manuscript). A comprehensive premarket evaluation
program will likely require multiple testing sites, with
each site using a valid, reliable, and uniform or
coordinated set of measures (with additional mea-
sures as needed or desired).
The network also could facilitate the development
and implementation of a multilevel cohort design
dedicated to assessing the impact of PREPs on
perceptions of these products and tobacco use
behaviors. Such a study could involve multiple
country controls and be based on a theory-driven
mediational model to test hypotheses and answer
research questions about the effects of product
innovations and regulatory policies that influence
the design of tobacco products (Fong, Borland,
Hastings, & Cummings, 2004).
In addition to a set of planned evaluation and
surveillance activities, the system would have the
capacity to conduct rapid-response surveillance.
Such a capability would permit flexible response to
emerging developments that could limit possible
untoward effects of the marketing and use of
PREPs (G. A. Giovino et al., unpublished manu-
script). Legislation that would provide marketing
data disaggregated by variety and geographic locale
would facilitate analyses of marketing influences.
The research network should have access to a core
group of methodological expertise to inform the data
collection and analysis work (G. A. Giovino et al.,
Funding for this initiative could come from a
modest increase in the federal excise tax. Given that
about 20 billion packs of cigarettes were sold in the
United States in 2003, a 1-cent per pack increase
would raise $200 million. Approximately one-half of
that amount could be dedicated to surveillance and
evaluation, with the other half used for research
on reducing tobacco use and associated harms.
Furthermore, the information on product character-
istics and industry marketing would be provided by
the industry, with enough funds made available to
have an independent panel of expert scientists verify
industry reports. The oversight of this infrastructure
would best be served by an independent regulatory
body, such as the FDA. However, should FDA
regulation over tobacco products not occur, other
governmental agencies can provide appropriate
forums for independently assessing these products
and verifying the industry reports. With the growing
introduction of PREPs, it is imperative that research
and action be undertaken now to ensure that the
public will be protected and to avoid a potential
public heath disaster. But more important, to have a
significant impact on public health, all tobacco
products should be regulated and undergo compre-
The conference on which this paper is based was funded by the
National Cancer Institute, National Institute on Drug Abuse, and
National Institute on Alcohol Abuse and Alcoholism. The authors
thank all the members of the workgroup who contributed to the
manuscript. They also thank David Ashley, David Burns, Neil
Weinstein, and Jonathan Samet for their invaluable comments on the
Arfken, C. L., & Cicero, T. J. (2003). Postmarketing surveillance for
drug abuse. Drug and Alcohol Dependence, 70(Suppl. 3), S97–S105.
Bachman, J. G., Johnston, L. D., & O’Malley, P. M. (2001).
Monitoring the Future: Questionnaire responses from the nation’s
Table 9. Infrastructure needs.
Transdisciplinary research network of independent researchers
Multisite clinical and premarketing testing centers
Valid, reliable, and uniform or coordinated test measures
Linked survey data
Multilevel cohort designs assessing potential reduced
exposure products (PREPs)
Independent monitoring of data within a regulatory framework
Independent panel of expert reviewers
NICOTINE & TOBACCO RESEARCH
high school seniors. Ann Arbor, MI: Survey Research Center,
Institute for Social Research.
Bates, C., McNeill, A., Jarvis, M., & Gray, N. (1999). The future of
tobacco product regulation and labeling in Europe: Implications for
the forthcoming European Union directive. Tobacco Control, 8,
Biener, L., & Abrams, D. (1991). The Contemplation Ladder:
Validation of a measure of readiness to consider smoking cessation.
Health Psychology, 10, 360–365.
Bolliger, C. T., Zellweger, J.-P., Danielsson, T., van Biljon, X.,
Robidou, A., Westin, A., Perruchoud, A. P., & Sawe, U. (2000).
Smoking reduction with oral nicotine inhalers: Double blind,
randomised clinical trial of efficacy and safety. British Medical
Journal, 321, 329–333.
Breland, A. B., Acosta, M. C., & Eissenberg, T. (2003). Tobacco
specific nitrosamines and potential reduced exposure products for
smokers: A preliminary evaluation of Advance. Tobacco Control,
Breland, A. B., Buchhalter, A. R., Evans, S. E., & Eissenberg, T.
(2002). Evaluating acute effects of potential reduced-exposure
products for smokers: Clinical laboratory methodology. Nicotine
& Tobacco Research, 4(Suppl. 2), 131–140.
Breland, A. B., Evans, S. E., Buchhalter, A. R., & Eissenberg, T.
(2002). Acute effects of Advance: A potential reduced exposure
product for smokers. Tobacco Control, 11, 376–378.
Brownlee, S., Leventhal, E. A., & Leventhal, H. (2000). Regulation,
self regulationand regulation
physical health. In M. Boekartz, P. R. Pintrich & M. Zeidner
(Eds.), Handbook of self-regulation (pp. 369–416). San Diego:
Buchhalter, A. R., Schrinel, L., & Eissenberg, T. (2001). Withdrawal-
suppressing effects of a novel smoking system: Comparison with
own brand, not own brand, and de-nicotinized cigarettes. Nicotine &
Tobacco Research, 3, 111–118.
Burns, D. (1997). Estimating the benefits of a risk reduction strategy.
Poster presented at the Society for Research on Nicotine and
Tobacco third annual scientific conference, Nashville, TN.
Caraballo, R. S., Giovino, G. A., Pechacek, T. F., Mowery, P. D., &
Richter, P. A. (1998). Racial and ethnic differences in serum cotinine
levels of cigarette smokers: Third National Health and Nutrition
Examination Survey, 1988–1991. The Journal of the American
Medical Association, 280, 135–139.
Carpenter, M., Hughes, J., & Keely, J. (2003). Effect of smoking
reduction on later cessation: A pilot experimental study. Nicotine &
Tobacco Research, 5, 155–162.
Centers for Disease Control and Prevention. (2000). Use of FDA-
approved pharmacologic treatments for tobacco dependence in the
United States: 1984–1998. Morbidity and Mortality Weekly Report,
Centers for Disease Control and Prevention. (2001a). Updated
guidelines for evaluating public health surveillance systems:
Recommendations from the guidelines working group. Morbidity
and Mortality Weekly Report, 50(RR-13), 1–35.
Centers for Disease Control and Prevention. (2001b). Youth tobacco
surveillance—United States, 2000. Morbidity and Mortality Weekly
Report, 50(SS-4), 1–84.
Clegg Smith, K., Wakefield, M., Siebel, C., Szczypka, G., Slater, S.,
Terry-McElrath, Y., Emery, S., & Chaloupka, F. J. (2002). Coding
the news: The development of a methodological framework for
coding and analyzing newspaper coverage of tobacco issues. Retrieved
June29, 2004, from www.impacteen.org/generalarea_PDFs/
Cohen, J. (1996). Smokers’ knowledge and understanding of advertised
tar numbers: Health policy implications. American Journal of Public
Health, 86, 18–24.
Colby, S. M., Tiffany, S. T., Shiffman, S., & Niaura, R. (2000).
Measuring nicotine dependence among youth: A review of available
approaches and instruments. Drug and Alcohol Dependence,
59(Suppl. 1), S23–S39.
Connett, J. E., Murray, R. P., Buist, A. S., Wise, R. A., Bailey, W. C.,
Lindgren, P. G., Owens, G. R.; Lung Health Study Research
Group. (2003). Changes in smoking status affect women more than
men: Results of the Lung Health Study. American Journal of
Epidemiology, 157, 973–979.
Cruz, T., & Jouharzadeh, P. (2003). Sampling, coupons, and other free
stuff: What is the industry up to? Presented at the 2003 National
Conference on Tobacco or Health, Boston, MA.
of the selfin maintaining
Cummings, K. M., Hyland, A., Giovino, G. A., Hastrup, J., Bauer, J.,
& Bansal, M. (2004). Are smokers adequately informed about the
health risks of smoking and medicinal nicotine. Nicotine & Tobacco
Research, 6(Suppl. 3), 333–340.
Doll, R., & Peto, R. (1978). Cigarette smoking and bronchial
carcinoma: Dose and time relationships among regular smokers
and lifelong non-smokers. Journal of Epidemiology and Community
Health, 32, 303–313.
Eclipse Expert Panel. (2000). A safer cigarette? A comparative study. A
consensus report. Inhalation Toxicology, 12(Suppl. 5), 1–48.
Emont, S. (1996). Racial differences in the impact of smoking-
attributable disease on health care costs in Indiana. Indiana
Medicine, 89, 161–164.
Etter, J., Kozlowski, L. T., & Perneger, T. V. (2003). What smokers
believe about light and ultralight cigarettes. Preventive Medicine, 36,
Etter, J., Laszlo, E., Zellweger, J. P., Perrot, C., & Perneger, T. V.
(2002). Nicotine replacement to reduce cigarette consumption in
smokers who are unwilling to quit: A randomized trial. Journal of
Clinical Psychopharmacology, 22, 487–495.
Etter, J., Paernegger, T., & Ronchi, A. (1997). Distributions of
smokers by stage: International comparison and association with
smoking prevalence. Preventive Medicine, 26, 580–585.
Fagerstro ¨m, K.O.(2000).Nicotine-replacement
R. Ferrence, J. Slade, R. Room & M. Pope (Eds.), Nicotine and
public health (pp. 199–207). Washington, DC: American Public
Fagerstro ¨m, K. O., Hughes, J., & Callas, P. (2002). Long term effects
of the Eclipse cigarette substitute and the nicotine inhaler in
smokers not interested in quitting. Nicotine & Tobacco Research,
Fagerstro ¨m, K. O., Tejding, R., Westin, A., & Lunell, E. (1997).
Aiding reduction of smoking with nicotine replacement medica-
tions: Hope for the recalcitrant smoker? Tobacco Control, 6,
Farrelly, M. C., Healton, C. G., Davis, K. C., Messeri, P.,
Hersey, J. C., & Haviland, M. L. (2002). Getting to the truth:
American Journal of Public Health, 92, 901–907.
Federal Trade Commission. (2000). ‘‘Tar,’’ nicotine, and carbon
monoxide of the smoke of 1,294 varieties of domestic cigarettes for
the year 1998. Washington, DC: Author.
Federal Trade Commission. (2003a). Federal Trade Commission
cigarette report for 2001. Washington, DC: Author.
Federal Trade Commission. (2003b). Federal Trade Commission
smokeless tobacco report for the years 2000 and 2001. Washington,
Ferrence, R., Slade, J., Room, R., & Pope, M. (Eds.). (2000). Nicotine
and public health. Washington, DC: American Public Health
Flanders, W. D., Lally, C. A., Zhu, B. P., Henley, S. J., & Thun, M. J.
(2003). Lung cancer mortality in relation to age, duration of
smoking, and daily cigarette consumption: Results from Cancer
Prevention Study II. Cancer Research, 63, 6556–6562.
Fong, G. T., Borland, R., Hastings, G., & Cummings, K. M. (2004,
February). Evaluating and building an evidence base for the
Framework Convention on Tobacco Control: Recent findings from
the International Tobacco Control Policy Evaluation Survey. Paper
presented at the symposium presented at the Society for Research
on Nicotine and Tobacco annual meeting, Scottsdale, AZ.
Food and Drug Administration. (2004). Medwatch. Retrieved June 28,
2004, from www.fda.gov/medwatch.
Gilpin, E. A., Emery, S., White, M. M., & Pierce, J. P. (2002). Does
tobacco industry marketing of ‘light’ cigarettes give smokers a
rationale for postponing quitting? Nicotine & Tobacco Research,
4(Suppl. 4), S147–S155.
Giovino, G. A. (2002). Epidemiology of tobacco use in the United
States. Oncogene, 21, 7326–7340.
Giovino, G. A., Tomar, S., Reddy, M., Peddicord, J., Zhu, R.-P.,
Escobedo, L., & Eriksen, M. P. (1996). Attitudes, knowledge, and
beliefs about low-yield cigarettes among adolescent and adults. In
The FTC cigarette test method for determining tar, nicotine, and
carbon monoxide yields of U.S. cigarettes. Report of the NCI Expert
Committee. (Smoking and Tobacco Control Monograph No.7;
NIH Publication No.96-4028; pp.39–57). Rockville, MD: U.S.
Department of Health and Human Services, Public Health Service,
National Institutes of Health, National Cancer Institute.
METHODS TO ASSESS PREPS
Griffiths, R. R., Bigelow, G. E., & Ator, N. A. (2003). Principles of
initial experimental drug abuse liability assessment in humans. Drug
and Alcohol Dependence, 70, S41–S54.
Hamilton, W. L., diStefano Norton, G., Ouellette, T. K., Rhodes,
W. M., Kling, R., & Connolly, G. N. (2004). Smokers’ responses
to advertisements for regular and light cigarettes and potential
reduced-exposure tobacco products. Nicotine & Tobacco Research,
6(Suppl. 3), S353–S362.
Hatsukami, D., Benowitz, N. L., Rennard, S. I., Oncken, C., &
Hecht, S. S. (in press). Biomarkers to assess potential reduced
exposure tobacco products. Nicotine & Tobacco Research.
Hatsukami, D., Henningfield, J., & Kotlyar, M. (2004). Harm
Annual Review of Public Health, 25, 1–19.
Hatsukami, D., Lemmonds, C., & Tomar, S. (2004). Smokeless
tobacco use: Harm reduction or induction approach? Preventive
Medicine, 38, 309–317.
Hatsukami, D., Lemmonds, C. A., Zhang, Y., Murphy, S. E., Le, C.,
Carmella, S. G., & Hecht, S. S. (2004). Evaluation of carcinogen
exposure in people who used ‘‘reduced exposure’’ tobacco products.
Journal of the National Cancer Institute, 96, 844–852.
Hatsukami, D., Slade, J., Benowitz, N., Giovino, G., Gritz, E.,
Leischow, S., & Warner, K. (2002). Reducing tobacco harm:
Research challenges and issues. Nicotine & Tobacco Research,
4(Suppl. 2), S89–S101.
Hecht, S. S., Murphy, S. E., Carmella, S. G., Zimmerman, C. L.,
Losey, L., Kramarczuk, I., Roe, M. R., Puumala, S. S., Li, Y. S.,
Le, C. T., Jensen, J., & Hatsukami, D. K. (2004). Effects of reduced
cigarette smoking on uptake of a tobacco-specific lung carcinogen.
Journal of the National Cancer Institute, 96, 107–115.
Houtsmuller, E. J., Fant, R. V., Eissenberg, T. E., Henningfield, J. E.,
& Stitzer, M. L. (2002). Flavor improvement does not increase
Biochemistry, and Behavior, 72, 559–568.
Houtsmuller, E. J., Henningfield, J. E., & Stitzer, M. L. (2003).
Subjective effects of the nicotine lozenge: Assessment of abuse
liability. Psychopharmacology, 167, 20–27.
Hughes, J. R., Gust, S. W., Keenan, R. M., Fenwick, J. W., Skoog, K.,
& Higgins, S. T. (1991). Long-term use of nicotine vs. placebo gum.
Archives of General Medicine, 151, 1993–1998.
Hurt, R. D., Croghan, G. A., Wolter, T. D., Croghan, I. T., Offord,
K. P., Williams, G. M., Djordjevic, M. V., Richie, J. P., Jr., &
Jeffrey, A. M. (2000). Does smoking reduction result in reduction of
biomarkers associated with harm? A pilot study using a nicotine
inhaler. Nicotine & Tobacco Research, 2, 327–336.
Husten, C., Jackson, K., & Lee, C. (2004). Cigarette smoking among
adults—United States, 2002. Morbidity and Mortality Weekly
Report, 53, 427–431.
Jasinski, D. R. (1977). Assessment of the abuse potentiality of
morphine-like drugs (methods used in man). In W. R. Martin
(Ed.), Drug addiction I. Morphine, sedative-hypnotic and alcohol
dependence. Handbook of experimental pharmacology (Vol.45,
pp.197–258), Heidelberg: Springer.
Joseph, A. M., Hennrikus, D., Thoele, M. J., Krueger, R., &
Hatsukami, D. (2004). Tobacco control leaders’ perceptions of
harm reduction. Tobacco Control, 13, 108–113.
Keely, J. P., Hughes, J. R., & Hirsch, T. S. (2001). Effects of a cigarette
substitute on ongoing smoking. Poster presented at the Society for
Research on Nicotine and Tobacco annual meeting, Seattle, WA.
Kotlyar, M., Jensen, J., Li, S., & Hatsukami, D. (2004). Effect of
smoking reduction on cardiovascular biomarkers and subjective
measures. Poster presented at the Society for Research on
Nicotine and Tobacco Annual Meeting, Scottsdale, AZ.
Kozlowski, L., Goldberg, M., Yost, B., White, E., Sweeney, C., &
Pillitteri, J. (1998). Smokers’ misperceptions of light and ultra-light
cigarettes may keep them smoking. American Journal of Preventive
Medicine, 15, 78–79.
Kozlowski, L. T., Strasser, A. A., Giovino, G. A., Erickson, P. A., &
Terza, J. V. (2001). Applying the risk/use equilibrium: Use medicinal
nicotine now for harm reduction. Tobacco Control, 10, 201–203.
Lee, E., Malson, J., Moolchan, E., & Pickworth, W. (2004).
Quantitative comparisons between a nicotine delivery device
(Eclipse) and conventional cigarette smoking. Nicotine & Tobacco
Research, 6, 95–102.
Lemmonds, C., Mooney, M., Reich, B., & Hatsukami, D. (2004).
Characteristics of cigarette smokers seeking treatment for cessation
vs. reduction. Addictive Behaviors, 29, 357–364.
Lerman, C., & Niaura, R. (2002). Applying genetic approaches to the
treatment of nicotine dependence. Oncogene, 21, 7412–7420.
Leventhal, H., Benyamini, Y., Brownlee, S., Diefenbach, M.,
Leventhal, E., Patrick-Miller, L., & Robitaille, C. (1997). Illness
representations: Theoretical foundation. In K. J. Petrie & J. A.
Weinman (Eds.), Perceptions of health and illness: Current research
and application (pp.19–45). Amsterdam, The Netherlands: Harwood
Levy, D. T., Mumford, E. A., Cummings, K. M., Gilpin, E. A.,
Giovino, G., Hyland, A., Sweanor, D., & Warner, K. E. (2004). The
relative risks of a low-nitrosamine smokeless tobacco product
compared with smoking cigarettes: Estimates of a panel of experts.
Cancer Epidemiology, Biomarkers & Prevention, 13, 1–8.
Lopez, A. D., Collishaw, N. E., & Piha, T. (1994). A descriptive model
of the cigarette epidemic in developed countries. Tobacco Control, 3,
Martin, E. G., Warner, K. E., & Lantz, P. M. (2004). Tobacco harm
reduction: What do the experts think? Tobacco Control, 13,
Martin, W. R., Sloan, J. W., Sapiro, J. D., & Jasinski, D. R. (1971).
Physiologic, subjective, and behavioral effects of amphetamine,
methamphetamine, ephedrine, phenmetrazine and methylphenidate
in man. Clinical Pharmacology and Therapeutics, 12, 245–258.
McNair, D. M., Lorr, M., & Droppleman, L. F. (1992). Profile of
Mood States (manual) (Revised ed.). San Diego: Educational and
Industrial Testing Service.
Melikian, A. A., Djordjevic, M., Hosey, J., Zhang, J., Chen, S.,
Muscat, J. E., Zang, E., Stellman, S. D., & Richie, J. P. (2004).
Influence of gender on delivered toxins from cigarette smoke and
metabolism. Poster presented at the Society for Research on
Nicotine and Tobacco annual meeting, Scottsdale, AZ.
Mendez, D., & Warner, K. E. (2004). Adult cigarette smoking
prevalence: Declining as expected (not as desired). American
Journal of Public Health, 94, 251–252.
National Cancer Institute. (1997). Changes in cigarette-related disease
risk and their implication for prevention and control. (Smoking and
Tobacco Control Monograph No. 8; NIH Publication No. 97-
4213). Rockville, MD: National Institutes of Health.
National Cancer Institute. (2001). Risks associated with smoking
cigarettes with low machine-measured yields of tar and nicotine.
(Smoking and Tobacco Control Monograph No. 13; NIH
Publication No. 02-5074). Bethesda, MD: U.S. Department of
Health and Human Services, National Institutes of Health, National
Pe ´rez-Stable, E., Herrera, B., Jacob, P., III., & Benowitz, N. (1998).
Nicotine metabolism and intake in black and white smokers. The
Journal of the American Medical Association, 280, 152–156.
Perkins, K. A. (2001). Smoking cessation in women. Special
considerations. CNS Drugs, 15, 391–411.
Petty, R., Haugtvedt, C., & Smith, S. C., Jr. (1995). Elaboration as a
determinant of attitude strength: Creating attitudes that are
persistent, resistant, and predictive of behavior. In R. E. Petty &
J. A. Krosnick (Eds.), Attitude strength: Antecedents and con-
sequences (pp. 93–130). Mahwah, NJ: Lawrence Erlbaum.
Petty, R., & Wegener, D. (1999). The elaboration likelihood model:
Current status and controversies. In Y. Trope & S. Chaiken (Eds.),
Dual process theories in social psychology (pp. 37–72). New York:
Pickworth, W. B., Fant, R. V., Nelson, R. A., Rohrer, M. S., &
Henningfield, J. E. (1999). Pharmacodynamic effects of new de-
nicotinized cigarettes. Nicotine & Tobacco Research, 1, 357–364.
Pollay, R. W., & Dewhirst, T. (2002). The dark side of marketing
seemingly ‘‘light’’ cigarettes: Successful images and failed fact.
Tobacco Control, 11(Suppl. 1), i18–i31.
Pollay, R. W., & Dewhirst, T. (2003). A Premiere example of the
illusion of harm reduction cigarettes in the 1990s. Tobacco Control,
Prochaska, J. O., DiClemente, C. C., & Norcross, J. C. (1992). In
search of how people change: Applications to addictive behaviors.
American Psychologist, 47, 1102–1114.
Prochaska, J. O., & Goldstein, M. G. (1991). Process of smoking
cessation. Implications for clinicians. Clinics in Chest Medicine, 12,
Rennard, S. I., Umino, T., Millatmal, T., Daughton, D. M.,
Manouilova, L. S., Ullrich, F. A., Patil, K. D., Romberger, D. J.,
Floreani, A. A., & Anderson, J. R. (2002). Evaluation of subclinical
respiratory tract inflammation in heavy smokers who switch to a
NICOTINE & TOBACCO RESEARCH
cigarette-like nicotine delivery device that primarily heats tobacco. Download full-text
Nicotine & Tobacco Research, 4, 467–476.
Rose, J. E., Behm, F. M., Westman, E. C., & Johnson, M. (2000).
Dissociating nicotine and nonnicotine components of cigarette
smoking. Pharmacology, Biochemistry, and Behavior, 67, 71–81.
Schneider, N. G., Olmstead, R. E., Nides, M., Mody, F. V., Otte-
Colquette, P., Doan, K., & Patel, S. (2004). Comparative testing of 5
nicotine systems: Initial use and preferences. American Journal of
Health Behavior, 28, 72–86.
Schuh, K., Schuh, L., Henningfield, J., & Stitzer, M. (1997). Nicotine
nasal spray and vapor inhaler: Abuse liability
Psychopharmacology, 130, 352–361.
Shiffman, S., Burton, S. L., Pillitteri, J. L., Gitchell, J. G., Di Marino,
M.E.,Sweeney,C.T.,Wardle,P. A.,& Koehler,G. L. (2001).Test of
‘‘light’’ cigarette counter-advertising using a standard test of
advertising effectiveness. Tobacco Control, 10(Suppl. 1), i33–i40.
Shiffman, S., Hughes, J. R., Di Marino, M. E., & Sweeney, C. T.
(2003). Patterns of over-the-counter nicotine gum use: Persistent use
and concurrent smoking. Addiction, 98, 1747–1753.
Shiffman, S., Pillitteri, J. L., Burton, S. L., & Di Marino, M. E. (2004).
Smoker and ex-smoker reactions to cigarettes claiming reduced risk.
Tobacco Control, 13, 78–84.
Shiffman, S., Pillitteri, J. L., Burton, S. L., Rohay, J. M., & Gitchell,
J. G. (2001a). Effect of health messages about ‘‘light’’ and ‘‘ultra
light’’ cigarettes on beliefs and quitting intent. Tobacco Control,
10(Suppl. 1), i24–i32.
Shiffman, S., Pillitteri, J. L., Burton, S. L., Rohay, J. M., & Gitchell,
J. G. (2001b). Smokers’ beliefs about ‘‘light’’ and ‘‘ultra light’’
cigarettes. Tobacco Control, 10(Suppl. 1), i17–i23.
Stillman, F. A., Cronin, K. A., Evans, W. D., & Ulasevich, A. (2001).
Can media advocacy influence newspaper coverage of tobacco:
Measuring the effectiveness of the American Stop Smoking
Intervention Study’s (ASSIST) media advocacy strategies. Tobacco
Control, 10, 137–144.
Stratton, K., Shetty, P., Wallace, R., & Bondurant, S. (Eds.). (2001).
Clearing the smoke: Assessing the science base for tobacco harm
reduction. Washington, DC: Institute of Medicine, National
Substance Abuse and Mental Health Services Administration. (2004).
Drug abuse warning network. Retrieved June 28, 2004, from http://
Szczypka, G., Emery, S., Wakefield, M. A., & Chaloupka, F. J. (2003).
The adaptation and use of Neilsen media research commercials ratings
data to measure potential exposure to televised smoking-related
advertisements. Retrieved June 29, 2004, from www.impacteen.org/
Thun, M. J., Day-Lally, C., Myers, D. G., Calle, E. E., Flanders,
W. D., Zhu, B. P., Namboodiri, M. M., & Heath, C. W. (1997).
Trends in tobacco smoking and mortality from cigarette use in
Cancer Prevention Studies I (1959 through 1965) and II (1982
through 1988). In D. R. Shopland, D. M. Burns, L. Garfinkel, & J.
M. Samet (Eds.), Changes in cigarette-related disease risks and their
implication for prevention and control (Smoking and Tobacco
Control MonographNo.8; NIH
Rockville, MD: National Cancer Institute.
Thun, M. J., & Heath, C. W., Jr. (1997). Changes in mortality from
smoking in two American Cancer Society prospective studies since
1959. Preventive Medicine, 26, 422–426.
U. S. Department of Agriculture. (2004). Tobacco outlook (No. TBS-
257). Washington, DC: Author, Economic Research Service.
U. S. Department of Health and Human Services. (1998). Tobacco use
among U.S. racial/ethnic groups—African Americans, American
Indian and Alaska Natives, Asian Americans and Pacific Islanders,
and Hispanics: A report of the surgeon general. Atlanta, GA: U.S.
Department of Health and Human Services, Centers for Disease
Control and Prevention.
Wagenknecht, L. E., Cutter, G. R., & Haley, N. J. (1990). Racial
differences in serum cotinine levels among smokers in the Coronary
Artery Risk Development in (Young) Adults Study. American
Journal of Public Health, 80, 1053–1056.
Wakefield, M. A., & Chaloupka, F. J. (1998). Improving the
measurement and use of tobacco control ‘‘inputs.’’ Tobacco
Control, 7, 333–335.
Warner, K. E., & Martin, E. G. (2003). The U.S. tobacco control
community’s view of the future of tobacco harm reduction. Tobacco
Control, 12, 383–390.
Wennike, P., Danielsson, T., Landfeldt, B., Westin, A., & Tonnesen, P.
(2003). Smoking reduction promotes smoking cessation: Results
from a double blind, randomized, placebo-controlled trial of
nicotine gum with 2-year follow-up. Addiction, 98, 1395–1402.
West, R., Hajek, P., Foulds, J., Nilsson, F., May, S., & Meadows, A.
(2000). A comparison of the abuse liability and dependence
Psychopharmacology, 149, 198–202.
Westman, E. C., Levin, E. D., & Rose, J. E. (1992). Smoking while
wearing the nicotine patch: Is smoking satisfying or harmful?
Clinical Research, 40, 871A.
World Health Organization Scientific Advisory Committee on
Tobacco Product Regulation. (2003). Statement of principles guiding
the evaluation of new or modified tobacco products. Retrieved from
World Health Organization Study Group on Tobacco Product
Regulation. (2003). Guiding principles for the development of tobacco
product research and testing capacity and proposed protocols for the
initiation of tobacco product testing. Retrieved from www.who.int/
gum,spray and inhaler
METHODS TO ASSESS PREPS