Heated tobacco products (HTP) represent the latest in a long line of products tobacco
companies have developed and marketed as less dangerous than conventional cigarettes,
beginning with so-called ‘safer cigarettes’ in the 1960s.
1
2
HTP (figure 1) heat tobacco to generate an inhaled nicotine aerosol and are marketed
using messages that explicitly or implicitly claim they are safer than cigarettes.
3–8
In 2018, HTP were available in many countries (table 1). In the USA, before marketing
new tobacco products, the Family Smoking Prevention and Tobacco Control Act
9
(FSPTCA) requires premarket review by the Food and Drug Administration (FDA) to demonstrate
that marketing them would be ‘appropriate for the protection of the public health’
(FSPTCA sections 910 and 905(j)). Additionally, to market any new tobacco product
in the USA with claims of reduced risk or reduced exposure to toxins compared to other
tobacco products (‘Modified Risk Tobacco Product’; MRTP), the company must first obtain
an MRTP marketing order from the FDA. In December 2016, Philip Morris International
(PMI) submitted an application to market IQOS, one of its HTP, with MRTP claims.
10
PMI’s MRTP application included extensive details about the product, the chemistry
of the aerosol it produces, related toxicology, effects on clinical measures in people,
perceptions of the product and its packaging (including warning labels), and behavioural
factors. This application sought FDA approval of PMI’s claims that smokers who switched
completely to IQOS would reduce their health risks or exposure to dangerous substances
compared with smoking cigarettes.
As of November 2017, there were 31 studies of HTP published in the peer reviewed literature,
20 of which were affiliated with the tobacco industry.
11
The 11 independent studies focused on awareness, use, and secondhand emissions of
HTP while the industry affiliated papers examined nicotine delivery and mainstream
emissions and exposures to selected toxicants. The fact that the literature has been
dominated by industry is particularly concerning because tobacco companies have a
record of publishing incomplete or manipulated information and presenting it to governments.
12-16
For example, PMI
17–20
and British American Tobacco
21–23
(BAT) conducted and published studies arguing that additives did not increase cigarettes’
toxicities. However, internal PMI documents and analysis of PMI’s data done by people
independent of the tobacco industry revealed that many toxicants increased when additives—notably
menthol—were present.
15
PMI’s IQOS MRTP application (the ‘application’) provides an opportunity to analyse
PMI’s data. This supplement to Tobacco Control includes eight papers that present
analyses of PMI’s application by researchers independent of the tobacco industry and
12 papers that provide independent assessments of HTP effects, including their political
and policy implications. Together, these papers provide insights into IQOS (and, in
broad terms, other HTP) and support the January 2018 vote by the FDA Tobacco Product
Scientific Advisory Committee that PMI’s application did not demonstrate it reduced
risk claims for IQOS
24
(online supplementary table S1). These papers also put HTP in the overall context
of the tobacco companies’ plans to maintain and grow their markets in the future and
outline regulatory responses.
HEALTH EFFECTS
The fundamental justification for introducing HTP is the claim that they are substantially
less dangerous than conventional cigarettes. PMI’s application includes PMI’s 3-month
study of 24 non-cancer biomarkers of potential harm (BOPH) in humans using IQOS compared
with conventional cigarettes. These biomarkers include measures of inflammation, oxidative
stress, cholesterol and triglycerides, blood pressure, and lung function. (PMI did
separate studies of biomarkers of exposure, several of which are carcinogens.) While
PMI’s application emphasises that these biomarkers generally changed in positive directions,
Glantz’s
25
examination of the data revealed no statistically detectable difference between IQOS
and conventional cigarettes for 23 of the 24 BOPH in Americans and 10 of 13 in Japanese.
Moreover, it is likely that the few significant differences were false positives.
Thus, despite delivering lower levels of some toxicants, PMI’s own data fail to show
consistently lower risks of harm in humans using IQOS compared with conventional cigarettes.
In June, 2018 PMI issued a press release
26
announcing that a 6-month human study comparing IQOS with conventional cigarettes
found eight biomarkers improved in those who switched to IQOS. PMI did not provide
specific results. In contrast to the application, PMI’s new study only examined six
BOPH (plus two biomarkers of exposure). Further, PMI did not report the full range
of biomarkers used in the earlier study although they can be measured in a blood sample
or simple physiological test. This additional study raises questions about PMI manipulating
the experimental design or data analysis as it and other companies have a history
of doing.
15
While HTP are presented as ‘new’, they are simply the latest incarnation of a technology
tobacco companies have been developing for decades. Elias et al
2
analysed previously secret PMI documents, public communications and the application
to compare IQOS to Accord, an earlier HTP that PMI unsuccessfully marketed in the
USA and Japan in 1998 and 2006, respectively. PMI’s public statements seemed contradictory,
claiming that Accord reduced exposure to harmful constituents while consistently emphasising
that the reductions did not mean Accord was safer than conventional cigarettes. In
terms of aerosol chemistry, Accord had lower levels than IQOS of some toxicants and
higher levels of others. PMI appears to be capitalising on the MRTP process to make
reduced exposure claims for IQOS despite the fact that overall toxicant exposures
are not, on average, different than Accord.
Discussion of HTP (as well as e-cigarettes) has focused on cancer even though cardiovascular
and metabolic disease kill about as many smokers as cancer.
27
Unlike cancer, the dose–response relationship for cardiovascular effects is highly
non-linear, with large effects at low doses.
28
An important pathway through which tobacco use increases the risk of heart disease
is by impairing the ability of arteries to enlarge when needed to accommodate increases
in blood flow (flow mediated dilation, FMD). Nabavizadeh et al
29
tested whether exposure to IQOS aerosol impaired FMD in a well-established experimental
model in which rats inhale IQOS aerosol from a single HeetStick (the IQOS tobacco
stick), mainstream smoke from a single Marlboro Red cigarette, or clean air. In contrast
with PMI’s application claiming that IQOS causes less impairment than conventional
cigarettes, Nabavizadeh et al
29
showed IQOS aerosol’s acute effects impaired vascular endothelial function (measured
with FMD) comparably with cigarette smoke.
Moazed et al
30
found data in PMI’s application raising significant concerns about IQOS’ pulmonary
effects. Rats exposed to IQOS suffered pulmonary inflammation and immunomodulation.
Although PMI did not report any direct measures of pulmonary inflammation in humans,
they measured pulmonary function and found no evidence of improvement in cigarette
smokers who switched to IQOS. PMI’s application also ignores the effect of dual use
and secondhand aerosol exposure.
Independent research confirmed adverse effects of IQOS aerosol on lung cells. Leigh
et al
31
exposed human bronchial epithelial cells in vitro to aerosols from three PMI products:
IQOS (tobacco flavour), an e-cigarette (MarkTen, tobacco flavour) and a conventional
cigarette (Marlboro Red) at comparable nicotine levels at the air–liquid interface.
IQOS showed significantly higher cytotoxicity than e-cigarettes, but less than combustible
cigarettes. These observations have important legal implications in the USA because
to authorise marketing IQOS with reduced risk claims, the FDA would have to find that
IQOS would benefit the public health and significantly reduce harm or reduce exposure
to harmful substances ‘compared to the similar types of tobacco products then on the
market’ (FSPTCA section 911(g)(2)(B)(ii)), and e-cigarettes were currently on the
market at the time that PMI submitted its application.
Reinforcing the need to compare HTP to e-cigarettes rather than cigarettes, Leigh
et al
32
compared the levels of carcinogenic tobacco specific nitrosamines (TSNA) in IQOS aerosols
to MarkTen e-cigarettes and Marlboro Red 100 conventional cigarettes at comparable
nicotine delivery levels. TSNA yields per puff in IQOS aerosol was an order of magnitude
lower than in Marlboro cigarette smoke, but an order of magnitude higher than in MarkTen
e-cigarettes. In short, IQOS does not reduce exposure to these important carcinogens
nearly as much as e-cigarettes.
Most discussion of the toxicants in non-cigarette tobacco products compare them to
cigarettes on the assumption that if the non-cigarette products deliver lower levels
of toxicants than cigarettes, the products would be less dangerous. However, St Helen
et al
33
found that PMI’s data only support its claim that IQOS reduces exposure to some (40
of 93) harmful and potentially harmful constituents (HPHCs) identified by the FDA.
PMI’s data also show significantly higher levels of many toxicants not on the FDA
HPHC list in IQOS aerosol compared with cigarette smoke, with 22 over twice as high
and 7 over 10 times higher. Therefore, it is important to expand chemical assessment
of emissions from HTP and other new tobacco products beyond those found in cigarette
smoke.
It is possible that HTP could cause some diseases not caused by conventional cigarettes.
Chun et al
34
identified animal and human studies in PMI’s application suggesting that IQOS may
cause liver toxicity not observed in cigarette users. PMI compared liver toxicity
in rats exposed to IQOS or cigarette smoke, and found that several measures of liver
toxicity (liver weights, blood levels of alanine aminotransferase and hepatocellular
vacuolisation) increased more in female (but not male) rats exposed to IQOS than cigarettes.
PMI’s human clinical data also suggested the possibility of increased liver injury
in one of their studies: following 5 days of using IQOS, conventional cigarettes,
or smoking abstinence, plasma bilirubin was higher in IQOS users than conventional
smokers or abstainers. PMI Science posted a response to this paper on its website
stating that “based on an analysis of our toxicological studies and clinical studies
performed according to international standards of good practice, there is no evidence
that IQOS use leads to hepatotoxicity [emphasis added].”
35
In contrast to this unequivocal statement, the point that Chun et al make is not that
the data PMI submitted to the FDA prove hepatotoxicity, but that the combination of
animal data and some of the human data constitute a pattern worth careful consideration,
especially in light of the short duration of the studies and lack of additional potential
insults to the liver including alcohol use and other drug use that is common in smokers.
IQOS (and likely HTP generally) are simply different from conventional cigarettes
and deliver less of some toxicants and more of others, so that IQOS may pose lower,
the same or higher health risks than cigarettes depending on the disease. IQOS emits
more of several important toxins with more adverse health effects than e-cigarettes.
PERCEPTIONS OF THE PRODUCT AND WARNING LABELS
Despite the evidence discussed above, in 2018 IQOS and other HTP were being marketed
around the world with claims that they are less harmful than cigarettes because they
expose users to lower levels of some toxicants. Popova et al
36
examined the qualitative and quantitative Perception and Behavior Assessment Studies
in PMI’s application which revealed that consumers perceive even reduced exposure
claims as reduced risk claims. Allowing PMI to promote IQOS with reduced exposure
claims would amount to permitting the kind of ‘light’ and ‘mild’ fraud that the FSPTCA
and WHO Framework Convention on Tobacco Control (FCTC) expressly prohibit for other
tobacco products.
This misunderstanding of reduced exposure as reduced risk bears directly on how IQOS
should be labelled so as not to mislead consumers. McKelvey et al
37
examined PMI’s application focusing on the statements that switching completely from
cigarettes to IQOS reduces risk. PMI failed to demonstrate that current smokers will
understand what ‘switching completely’ means, and therefore failed to demonstrate
that their IQOS will not decrease smokers’ intentions to quit smoking, or that IQOS
users will ‘switch completely’ (PMI’s other studies showed most people use IQOS and
cigarettes concurrently, so-called dual users.) Additionally, PMI’s study design and
measurement instruments suffered design flaws, and their reporting of associated findings
is misleading. Experience with other products such as e-cigarettes suggests consumers
will not understand that they must completely quit smoking cigarettes to achieve the
claimed health benefits of IQOS. Rather, consumers will likely misunderstand unsupported
claims of reduced risks to mean IQOS are risk-free.
Independently confirming PMI’s results, El-Toukhy et al
38
examined the impact of reduced exposure and reduced harm MRTP claims in a national
sample of US adults and adolescents. They found that communicating lower risk in MRTP
claims led to lower perceived risk among adults and adolescents and increased the
likelihood that adults would use the product. Reduced exposure claims led to lower
perceived chemical quantity and lower perceived risk, but had no effect on likelihood
of product use. Adults and adolescents misinterpreted reduced exposure claims as communicating
lower risk, even when no explicit reduced risk claims were made. Because reduced exposure
MRTP claims are not permissible under US law if they mislead the public to believe
the product presents less risk of harm, these studies demonstrate that reduced exposure
claims for IQOS are impermissible.
These concerns are particularly acute for adolescents who are susceptible to using
novel tobacco products. E-cigarettes provide a cautionary tale for any new tobacco
product coming to market: e-cigarettes have attracted youth at low risk of initiating
nicotine use with cigarettes,
39
many of whom then proceed to cigarettes.
40
McKelvey et al
41
found that PMI’s application failed to provide any evidence regarding the effect IQOS
and its marketing will have on the likelihood that adolescents who are not tobacco
users or who are former tobacco users will start nicotine use with IQOS. Instead,
PMI conducted studies of adults that relied on ‘behavioural intention’ as a proxy
to predict IQOS use, ignoring evidence that these models do not accurately predict
tobacco use. Of added concern, the IQOS name, packaging and retail shops resemble
popular cell phones that attract youth.
42
PMI’s data and independent scientific studies regarding novel tobacco products (including
e-cigarettes) marketing suggest IQOS will attract adolescent and young adult non-users
to initiate tobacco use with IQOS and could also increase polyuse of different tobacco
products.
Hair et al
43
examined IQOS marketing in Japan and Switzerland and studied consumer perceptions,
attitudes and behaviours. Expert interviews and IQOS packaging and marketing analyses
revealed that IQOS was marketed as a clean, chic and pure product which resonated
in cultures that value cleanliness, exclusivity and high-tech appearances. Japanese
consumers used IQOS for socialising with non-smokers. Focus group participants in
both Japan and Switzerland reported lower levels of satisfaction with IQOS than cigarettes,
although many found the packaging appealing. Few participants reported potential health
benefits compared with cigarettes.
PMI introduced IQOS to Korea in May 2017. Three months later, Kim et al
44
conducted an online survey of young adults including current, ever and non-users.
Rather than switching from conventional cigarettes to IQOS, all current IQOS users
continued to use cigarettes or e-cigarettes. There were no IQOS-only users. Current
users believed IQOS less harmful or useful to stop smoking. The observation that all
the current IQOS users were dual users of conventional cigarettes or e-cigarettes
contradicts PMI’s assumption that cigarette smokers would switch to HTP.
As of July 2018, the FDA had not authorised HTP for sale in the USA, but awareness
and use were increasing. Nyman et al
45
assessed awareness and use of HTP in the USA. From 2016 to 2017, adult awareness of
HTP increased from 9.3% to 12.4%, ever use increased from 1.4% to 2.2% and current
use doubled from 0.5% to 1.1%. Non-white adults, cigarette smokers, and both current
and former users of e-cigarettes were more likely to use HTP.
POLICY, POLITICS AND LAW
Tobacco companies have promoted ‘harm reduction’ for decades. Although tobacco harm
reduction proponents take British psychologist Michael Russell’s 1976 idea that ‘people
smoke for nicotine but they die from the tar’
46
as an article of faith, he simply presented it as a ‘hypothesis’. Elias and Ling
47
examined tobacco industry documents and found that Russell collaborated with BAT on
two ‘safer cigarette’ studies and received £55 000 (£300 850 or $398 000 in 2018)
to study medium-nicotine low-tar cigarettes. The most prominent early HTP was RJ Reynolds’
(RJR) Premier, introduced in the USA in 1988. Russell engaged extensively with RJR
about Premier’s ‘positive aspects’ and published an unsigned 1991 Lancet editorial
48
endorsing Premier as a ‘near-perfect low tar cigarette’ 2 years after RJR stopped
marketing Premier without disclosing his conflict of interest. Although Premier failed,
RJR saw future business opportunities for novel products if endorsed by health authorities,
making conflicts of interest highly important considerations in assessing product
endorsements, including those published by high-impact medical journals.
It is important to consider HTP in the context of multinational tobacco companies’
product mix and response to the tightening regulatory environment promoted by FCTC.
Bialous and Glantz
49
describe how HTP extend the industry’s strategies to undermine government regulation
by reframing tobacco companies from part of the problem to part of the solution. Under
the ‘harm reduction’ moniker, companies are attempting to rehabilitate their reputations
to more effectively influence governments to roll back existing tobacco control policies
or create exemptions for HTP. Where regulations are absent or loopholes exempt HTP
from existing regulations, companies’ market HTP to increase social acceptability
for all their tobacco products. Governments must ensure that HTP are regulated or
banned, and reject partnerships with tobacco companies to promote ‘harm reduction’.
Doing so requires governments in countries where HTP are not available to keep them
out or, if allowed in the market, strictly regulate them under the FCTC.
Israel illustrates how PMI took advantage of regulatory ambiguity to implement an
aggressive campaign promoting IQOS as safer than conventional cigarettes. Rosen and
Kislev
50
describe how PMI promoted IQOS as part of its ‘Smoke-Free Israel vision’ after launching
IQOS in December 2016. The campaign began with quiet pre-market meetings with government
officials, followed by meetings in Israel’s Parliament and an intense campaign in
the printed press to promote harm reduction and PMI’s ‘Smoke-Free Israel vision’.
The public campaign included digital and print marketing aimed at young people to
promote PMI’s ‘Smoke-Free Israel vision’ and harm reduction using the theme ‘IQOS
Changes Everything’, that stressed IQOS was clean with less smell and no ash. PMI’s
campaign initially resulted in IQOS’ exemption from tobacco regulations. These policies
were later reversed after three petitions to the Supreme Court, pressure from health
organisations and leading politicians, and wide press coverage of PMI’s influence
on Parliament’s decision-making process. Israel’s weak and poorly enforced advertising
restrictions, however, have allowed PMI to continue its marketing claims.
In determining whether any new tobacco product may be sold, including HTP the FDA
must consider the product’s overall population health impact. Importantly, in addition
to any changes in specific toxicity for current smokers who switch from cigarettes
to HTP, the availability of HTP affects nicotine and cigarette initiation and cessation.
For products that have not been on the market to empirically answer these questions,
modelling is an important element of the decision-making process. Max et al
51
evaluated PMI’s Population Health Impact Model (PHIM), as used in its application,
in comparison with other available models. Although similar to many published models,
PHIM includes assumptions likely to lead to a positive assessment of IQOS’ population
health impact. PHIM does not consider impacts on morbidity, underestimates mortality,
does not include impacts on non-users, ignores the impact of IQOS on nicotine product
initiation among never smokers and does not use the latest US data to set the model’s
parameters. Because PHIM systematically underestimates the impact of IQOS on the population
as a whole, it cannot adequately justify marketing IQOS as ‘appropriate to protect
public health’.
The most important change in the policy environment since the tobacco companies were
last actively promoting HTP in the 1980s and 1990s is the advent of formal regulatory
regimes for tobacco products through the FSPTCA in the USA and the FCTC globally.
Lempert and Glantz
52
analysed laws and obligations that apply to the introduction, labelling and marketing
of IQOS under FSPTCA and FCTC. PMI’s premarket tobacco application and MRTP application
for IQOS do not meet FSPTCA requirements on reduced harm or net public health benefit.
The FDA can only authorise sale of new products through the new tobacco product pathway
that are better for public health than products currently on the market, and e-cigarettes,
currently sold in the USA, should probably be the comparator product. FCTC obligates
parties to implement laws to reduce tobacco use and nicotine addiction, and the introduction
of any new tobacco product must be assessed against this goal. PMI’s aggressive marketing
techniques for IQOS using targeted customer interventions and sophisticated technologies
to capture data and monitor use directly from the IQOS device via the internet
53
should concern privacy and public health advocates. Moreover, nothing in the US law
or FCTC prevents authorities from prohibiting HTP. If not banned, all HTP components
should be regulated as stringently as tobacco products, including restrictions on
labelling, advertising, sales to minors, price and taxation policies, and smoke-free
measures, and these laws should be aggressively enforced.
CONCLUSION
HTP are the latest effort by tobacco companies to adapt to a changing regulatory landscape
to maintain and expand their customer base amid declining social acceptability of
tobacco use and declining cigarette consumption. IQOS and other HTP are the newest
in a long string of products designed to retain customers and protect tobacco companies’
reputations and political influence. Because US law required PMI to provide detailed
results of their IQOS research for its MRTP application, it was possible to independently
assess their research. PMI’s own data do not support its claims that IQOS is less
dangerous than cigarettes. While IQOS may expose users to lower levels of some toxicants
than cigarettes, they also expose users to higher levels of other toxicants. Likewise,
IQOS likely exposes users to lower risks of some diseases and higher risks of others.
PMI’s research, confirmed by independent research, also highlights the fact that reduced
exposure claims are misunderstood as reduced harm claims. These facts raise serious
concerns that HTP and their marketing will harm youth and young adults and undermine
cessation among smokers without providing health benefits to smokers who use them.
Fortunately, regulatory tools are in place to make rational, evidence-based decisions
about these products. The question is whether public health advocates will ensure
that policy-makers prioritise protecting public health and prevent tobacco companies
from again using their extensive public relations and political resources to avoid
regulation and protect profits. Policy makers should give greater weight to the advice
provided by public health scientists than to submissions from industry when it comes
to regulating tobacco products such as HTP.
Supplementary Material
Supplemental Table