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595
R E V I E W P A P E R
Nofer Institute of Occupational Medicine, Łódź, Poland
International Journal of Occupational Medicine and Environmental Health 2019;32(5):595 – 634https://doi.org/10.13075/ijomeh.1896.01433
NEW IDEAS, OLD PROBLEMS?HEATED TOBACCO PRODUCTS –A SYSTEMATIC REVIEWMATEUSZ JANKOWSKI1, GRZEGORZ M. BROŻEK1, JOSHUA LAWSON2,3, SZYMON SKOCZYŃSKI4, PAULINA MAJEK1, and JAN E. ZEJDA1
1 Medical University of Silesia in Katowice, Katowice, PolandSchool of Medicine in Katowice, Department of Epidemiology2 University of Saskatchewan, Saskatoon, CanadaCollege of Medicine, Canadian Centre for Health and Safety in Agriculture3 University of Saskatchewan, Saskatoon, CanadaCollege of Medicine, Department of Medicine4 Medical University of Silesia in Katowice, Katowice, PolandSchool of Medicine in Katowice, Department of Pneumonology
AbstractHeated tobacco products (HTPs) are a form of nicotine delivery intended to provide an alternative to traditional cigarettes. The aim of this systematic review was to present the current state of knowledge on HTPs with an emphasis on the potential impact of HTP use on human health. During the preparation of this systematic review, the literature on HTPs available within Medline/PubMed, EMBASE, CINAHL, ScienceDirect, and Google Scholar was retrieved and examined. In the final review, 97 research papers were included. The authors specifically assessed the construction and operation of HTPs, as well as the chemical composition of HTP tobacco sticks and the generated aerosol, based on evidence from experimental ani-mal and cellular studies, and human-based studies. Heated tobacco products were found to generate lower concentrations of chemical compounds compared to traditional cigarettes, except for water, propylene glycol, glycerol, and acetol. The nicotine levels delivered to the aerosol by HTPs were 70–80% as those of conventional combustion. The results of in vitro and in vivo assessments of HTP aerosols revealed reduced toxicity, but these were mainly based on studies sponsored by the tobacco industry. Independent human-based studies indicated that there was a potentially harmful impact of the active and passive HTP smoking on human health. Currently, a large body of knowledge on HTP exposures and health effects is provided by the tobacco industry (52% of identified studies). Based on the available evidence, HTPs produce lower levels of toxic chemicals, compared to conven-tional cigarettes, but they are still not risk-free. Int J Occup Med Environ Health. 2019;32(5):595 – 634
Key words:smoking, systematic review, nicotine, tobacco industry, heat-not-burn tobacco products, heated tobacco products
Funding: this study was supported by the Medical University of Silesia (grant No. KNW-1-024/K/7/0).Received: January 16, 2019. Accepted: July 12, 2019.Corresponding author: Grzegorz M. Brożek, Medical University of Silesia in Katowice, School of Medicine in Katowice, Department of Epidemiology, Medyków 18, 40-752 Katowice, Poland (e-mail: gbrozek@sum.edu.pl).
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)596
taining propylene glycol or glycerol) which passes through a capsule made of granulated tobacco leaves [12,13].Tobacco companies claim that HTPs are less harmful than traditional cigarettes [14–18]. However, the potential im-pact of HTP use on human health has not been fully in-vestigated yet.The prevalence of HTP use has been increasing, espe-cially in highly developed countries such as Japan and Ita-ly [2,3,5,6]. Based on the growth of the e-cigarette market in recent years, it is expected that the popularity of HTPs will continue to increase rapidly.The aim of this systematic review is to examine the current state of knowledge on heated tobacco products. As a part of this process, the authors will: – review the chemical composition of HTP tobacco
sticks; – review the chemical composition of the aerosol gener-
ated during HTP use; – review evidence from experimental studies on animal
and cellular models; – review evidence from human-based studies; – describe the prevalence of HTP use. In addition, they
will also assess the marketing strategies of the tobacco industry as a way of considering the potential burden of the problem.
MATERIAL AND METHODSThe authors conducted a systematic review to complete the objectives outlined above. The search was carried out in Medline/PubMed, EMBASE, CINAHL, ScienceDirect, and Google Scholar. Combinations of the following key words: “IQOS,” “glo,” “Ploom TECH,” “heat-not-burn,” “heated to-bacco,” “novel tobacco products,” with “aerosol,” “chemical composition,” “cells,” “nicotine,” “safety,” “health effects,” “toxicity,” “secondhand exposure,” “addiction,” “frequency of use,” “marketing” and “safety” were used. Potentially rel-evant articles were selected based on their titles and abstracts. If an article was considered potentially relevant, the full paper
INTRODUCTIONHeated tobacco products (HTPs) are a form of nicotine de- livery intended to provide an alternative to traditional cig-arettes. These products were introduced for the first time in 1988, in the USA, as “Premier” from R.J. Reynolds [1]. As in the case of electronic cigarettes, this technology initially did not gain wide popularity and was discontinued shortly af-ter its introduction. Recently, the tobacco industry has made another attempt to introduce HTPs to the market [2–6]. In 2014, a heated tobacco system from Philip Morris In-ternational (PMI), marketed as IQOS (I-Quit-Ordinary-Smoking), was introduced [3–6]. Other tobacco companies introduced their own HTPs in 2016. British American To-bacco (BAT) created an HTP called “glo” [6], while a heat-ed tobacco and e-cigarette hybrid was developed by Japan Tobacco (JT) and marketed as “Ploom TECH” [6].The heated tobacco smoking technology is based on a unique electronic method of heating to generate aero-sols from tobacco sticks. Tobacco heating systems oper-ate at lower temperatures (240–350°C) than conventional cigarettes (> 600°C) [7].The IQOS tobacco heating system includes a “pen-shaped” electronically controlled heating element (holder) and a por-table charger for recharging the holder [4,8]. The IQOS uses a metal blade to penetrate tobacco sticks (called “HEETS”), thus heating tobacco from inside the stick up to 350°C [8,9]. The heating holder supplies heat for 6 min and allows up to 14 puffs. After this time, the holder needs to be re-charged [8]. Glo operates in a similar manner [9]. The device looks like a small simple box with an oval socket in the pe-riphery on top, where the tobacco stick is placed. After press-ing the button in the middle of the device, the tobacco stick (called “Kent Neostiks”) is heated to 240°C through a metal heating element surrounding the tobacco stick [10,11]. A sin-gle charge lasts for up to 30 smoking sessions [11].A slightly different heating technology is implemented by Ploom TECH [6,12]. In this case, the nicotine-containing aerosol is generated by heating an inhalation solution (con-
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 597
bacco industry is also working on a new form of HTPs called carbon heated tobacco products (CHTPs) [19]. Due to the different mode of operation, the early phase of the products (no general product sales), and the limited amount of re-search related to these products, they were not analyzed in detail in this review. Nevertheless, carbon-covered tobacco products are an alternative form of nicotine delivery and will require close monitoring in the future.The literature search and selection of articles were per-formed independently by 2 researchers. A comparison of the search results was made and, where there was a dis-crepancy, inclusion decisions were based on a consensus following discussion.The search process that led to the identification of 289 po-tential articles is summarized in Figure 1. Of these, 138 were
was printed for review. Reference lists from the selected arti-cles were checked for publications that may have been missed in the initial search. Manufacturer websites regarding data about the mode of use and all registration details were also reviewed. Finally, websites of leading health organizations were reviewed to identify their positions on HTPs. The final search was conducted on December 31, 2018.Articles were eligible to be included in the review if they were original, peer-reviewed articles, published in English. There was no limit regarding the time that had passed since publication other than the final date being December 31, 2018. Review and personal opinion papers were excluded. Papers that focused on other forms of smoking, such as elec-tronic cigarettes, smokeless tobacco such as chewing tobac-co or snus, shisha, and hookah, were also excluded. The to-
Iden
tifica
tion
Scre
enin
gEl
igib
ility
Incl
uded
Records excluded(N = 75)
49 studies about e-cigarette, chewing tobacco snus, shisha, or hookah9 conference abstracts12 studies not in English5 studies on carbon heated tobacco products
Records identified through databasesearching(N = 289)
Full-text articles excluded(N = 41)
24 review publications/commentaries2 studies not eligible2 studies protocols13 studies on the validation of selected analytical methods
Records after duplicatesremoved
(N = 166)
Full-text articles assessedfor eligibility(N = 138)
Studies includedin the qualitative synthesis
(N = 97)
Figure 1. PRISMA Flow Diagram [105]
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IJOMEH 2019;32(5)598
ing the manufacturer recommendations, cleaning of the device after each 20 tobacco sticks seems to be crucial to provide proper thermal regulation [8]. Moreover, Davis et al. showed that the heat produced by the device was enough to cause charring of the tobacco plug via pyrolysis and melting of the polymer-film filter [8]. This independent observation is in contrast to the manufac-turer’s claim that pyrolysis is minimized during IQOS use. Detailed information on the chemical composition of HTP tobacco sticks is presented in Table 1.
Chemical composition of generated aerosolThe tobacco industry claims that during HTP use, emis-sions of toxic chemicals are reduced due to the lower work-ing temperature of the devices [13–15,23,24]. The results of independent studies suggest that toxic compounds are not completely removed from the HTP aerosol and these products are still not risk-free (Table 1) [7,19,25–35].Uchiyama et al. compared the chemical composition of the aerosol from all 3 available heated tobacco products: IQOS with 4 different heat sticks, glo with 3 different heat sticks, and Ploom TECH with 3 different tobacco capsules, with smoke generated from 2 different reference ciga-rettes [7]. Water accounted for 75–85% of the total gas-eous and particulate matter generated during IQOS and glo use, compared to 17–27% in the smoke from tradition-al cigarettes [7]. Heated tobacco products generated fewer chemical compounds compared to traditional cigarettes, except for water, propylene glycol, glycerol, and acetol, where the concentration in mainstream smoke was higher in heated tobacco than in traditional cigarettes [7,27].Numerous studies, both independent and industry spon-sored, have shown that the levels of nicotine contained in the aerosol released by HTPs (both regular and menthol versions) were 70–80% as those of conventional combus-tion cigarettes [15,27,29,33,36]. Farsalinos et al. reported that HTPs delivered nicotine to the aerosol at levels high-er than e-cigarettes [9].
considered to be relevant after screening the titles and abstracts. After full-article review, 97 papers were consid-ered eligible and included in this review. Review papers, commentaries and opinions as well as studies on the vali-dation of selected analytical methods were excluded from the final analysis.For each paper, the funding source and authors’ conflict of interest declarations were analyzed. In this review, of the 97 identified papers, 50 (52%) had a potential conflict of interest. The presence of a conflict of interest in all pa-pers regarding the toxicity of HTP aerosols may indicate a potential risk of bias. To help assess this phenomenon, tobacco industry sponsored papers were separated from independent studies and visibly marked in this review. The authors also completed a brief sensitivity analysis summa-rizing the results of the tobacco company funded studies and independently funded studies separately.
RESULTSChemical composition of tobacco sticksSimilar to conventional cigarettes, heated tobacco products use real tobacco. Tobacco sticks are available in multiple flavors [10,20]. Among the multiple HTP tobacco sticks available on the market, only IQOS to-bacco sticks were tested in detail [8,9,21]. The chemi-cal composition of HEETS tobacco sticks includes processed tobacco, water, glycerin, guar gum, cellulose fibers, a polymer-film filter, and a cellulose-acetate mouthpiece filter [22]. According to the manufacturer data, the IQOS tobacco stick contains smaller amounts of tobacco compared to conventional cigarettes [20]. Independent studies by Farsalinos et al. [9] and Bek-ki et al. [21] showed that IQOS sticks contained 70–80% of the nicotine concentration found in conventional cigarettes. Davis et al. evaluated the performance of the IQOS system under various conditions [8]. The use of 1 IQOS stick left a significant amount of debris, fluid, and fragments of cast-leaf in the device holder. Follow-
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IJOMEH 2019;32(5) 599
Tabl
e 1. C
hem
ical c
ompo
sitio
n of
toba
cco
stick
s and
smok
e gen
erat
ed d
urin
g HTP
use
– a s
yste
mat
ic re
view,
2015
–201
8
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
yIn
depe
nden
t stu
dies
Dav
is et
al., U
SA
(201
8) [8
]to
evalu
ate t
he
perfo
rman
ce o
f the
IQO
S sy
stem
und
er va
rious
co
nditi
ons;
to te
st th
e ef
fects
of c
leani
ng o
n pe
rform
ance
and
pyro
lysis;
an
d to
det
erm
ine t
he
com
posit
ion
of, a
nd th
e po
tent
ial h
ealth
risk
from
, th
e pol
ymer
-film
filte
r of
IQO
S sti
cks
4 IQ
OS
devic
es, I
QO
S sti
cks (
stron
g m
enth
ol);
5 run
ning
cond
ition
s in
corp
orat
ing 2
diff
eren
t clea
ning
pr
otoc
ols;
a visu
al an
d ste
reom
icros
copi
c in
spec
tion
of IQ
OS
stick
s pre
-use
and
post-
use t
o de
term
ine t
he ex
tent
of
toba
cco
plug
char
ring (
from
pyr
olys
is)
and
polym
er-fi
lm fi
lter m
eltin
g, an
d to
eluc
idat
e the
effe
cts o
f clea
ning
on
char
ring;
unus
ed p
olym
er-fi
lm fi
lters
were
evalu
ated
by g
as ch
rom
atog
raph
y-m
ass s
pectr
omet
ry h
eads
pace
analy
sisto
det
erm
ine e
miss
ions
of p
oten
tial t
oxic
chem
icals
durin
g filte
r hea
ting
–th
e use
of 1
IQO
S sti
ck le
ft a s
ignifi
cant
amou
nt o
f deb
ris, fl
uid
and
fragm
ents
of ca
st-lea
f in
the d
evice
hol
der
–th
e im
plem
enta
tion
of m
anuf
actu
rer’s
clea
ning
instr
uctio
ns
incr
ease
d ch
arrin
g of t
he to
bacc
o pl
ug an
d m
eltin
g of t
he
polym
er-fi
lm –
the h
eat p
rodu
ced
by th
e dev
ice w
as en
ough
to ca
use c
harri
ng
of th
e tob
acco
plu
g via
pyro
lysis
and
melt
ing o
f the
pol
ymer
-film
fil
ter
–fo
rmald
ehyd
e cya
nohy
drin
was
relea
sed
from
the p
olym
er-fi
lm
filte
r at 9
0°C
(whi
ch is
well
belo
w th
e max
imum
tem
pera
ture
re
ache
d du
ring n
orm
al us
age)
–de
vice u
sage
lim
itatio
ns (o
nly o
pera
tes f
or 6
min
, max
14 p
uffs)
m
ay co
ntrib
ute t
o de
crea
ses i
n in
terp
uff i
nter
vals,
pot
entia
lly
incr
easin
g the
inta
ke o
f nico
tine a
nd o
ther
har
mfu
l che
mica
lsFa
rsalin
os et
al.,
Gre
ece (
2017
) [9]
to m
easu
re th
e nico
tine
levels
deli
vere
d du
ring
heat
ed to
bacc
o pr
oduc
t (IQ
OS)
use
, com
pare
d to
e-cig
aret
tes a
nd
conv
entio
nal c
igare
ttes;
to m
easu
re th
e am
ount
of
nico
tine i
n un
used
IQO
S sti
cks (
both
regu
lar an
d m
enth
ol fl
avor
)
2 typ
es o
f IQ
OS
stick
s (m
enth
ol an
d re
gular
), 3 d
iffer
ent t
ypes
of e
-ciga
rette
s (n
icotin
e con
cent
ratio
n 20
mg/m
l), an
d co
mm
ercia
lly av
ailab
le cig
aret
tes;
all
devic
es h
ad fu
lly ch
arge
d ba
tterie
s; th
e sm
oke a
nd ae
roso
ls fro
m al
l pro
ducts
we
re p
rodu
ced
usin
g the
Hea
lth
Cana
da In
tens
e (H
CI) p
uffin
g reg
ime
(55 m
L pu
ff vo
lum
e, 27
.5 m
L/s p
uff fl
ow
rate
, 2-s
puff
dura
tion,
30-s
inte
rpuf
f in
terv
al); i
n th
e cas
e of e
-ciga
rette
s and
IQ
OS,
the s
econ
d pu
ffing
regim
e (5
5 ml p
uff v
olum
e, 13
.75 m
L/s p
uff fl
ow
rate
, 4-s
puff
and
30-s
inte
rpuf
f int
erva
l) wa
s use
d to
asse
ss th
e res
ults
of
pro
long
ed p
uffs
on n
icotin
e deli
very
–IQ
OS
stick
s con
tain
ed a
com
para
ble n
icotin
e con
cent
ratio
n to
co
nven
tiona
l ciga
rette
s –
the l
evels
of n
icotin
e deli
vere
d to
the a
eros
ol b
y reg
ular
and
men
-th
ol IQ
OS
stick
s wer
e com
para
ble:
1.40±
0.16 m
g/12 p
uffs
and
1.38±
0.11 m
g/12 p
uffs,
resp
ectiv
ely –
an H
TP d
elive
rs ni
cotin
e to
the a
eros
ol at
leve
ls hi
gher
(1
.40±
0.16 m
g and
1.38
±0.1
1 mg a
t 2s)
than
an e-
cigar
ette
(0
.46±
0.06 m
g at 2
s) b
ut lo
wer t
han
a con
vent
iona
l ciga
rette
(1
.99±
0.20 m
g/ciga
rette
)
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)600
Bekk
i et a
l., Ja
pan
(201
7) [2
1]to
analy
ze th
e con
cent
ratio
n lev
els o
f bas
ic ha
rmfu
l co
mpo
nent
s [ni
cotin
e, ta
r, ca
rbon
mon
oxid
e (C
O) a
nd to
bacc
o-sp
ecifi
c ni
trosa
min
es (T
SNAs
] in
the m
ainstr
eam
smok
e an
d IQ
OS
stick
s, an
d to
co
mpa
re th
eir le
vels
with
th
ose e
mitt
ed d
urin
g th
e use
of c
onve
ntio
nal
com
busti
on ci
gare
ttes.
2 con
vent
iona
l com
busti
on ci
gare
ttes
(3R4
F an
d 1R
5F),
and
2 IQ
OS
stick
s (re
gular
and
men
thol
); 4 s
ampl
es
(3R4
F, 1R
5F, m
enth
ol an
d re
gular
IQO
S sti
cks),
each
sam
ple i
nclu
ded
3 c
igare
ttes o
r stic
ks; s
mok
e and
aero
sols
from
all p
rodu
cts w
ere p
rodu
ced
usin
g th
e Hea
lth C
anad
a Int
ense
puf
fing
regim
e (55
mL
puff
volu
me,
2-s p
uff
dura
tion,
30-s
inte
rpuf
f int
erva
l), p
uff
num
ber:
9 tim
es fo
r a ci
gare
tte
and
11 ti
mes
for a
n IQ
OS
stick
–th
e con
cent
ratio
ns o
f nico
tine i
n IQ
OS
stick
s (re
gular
: 15.7
mg/g
; m
enth
ol: 1
7.1 m
g/g) w
ere a
lmos
t the
sam
e as i
n co
nven
tiona
l co
mbu
stion
ciga
rette
s (3R
4F: 1
9.7 m
g/g, 1
R5F:
15.9
mg/g
) –
the n
icotin
e lev
els in
the m
ainstr
eam
smok
e of I
QO
S (re
gular
: 1.1
mg/c
ig; m
enth
ol: 1
.2 m
g/cig)
wer
e low
er co
mpa
red
to co
nven
-tio
nal c
ombu
stion
ciga
rette
s (3R
4F: 1
.7 m
g/cig;
1R5F
: 1.0
mg/c
ig) –
durin
g IQ
OS
use,
the c
once
ntra
tion
of to
bacc
o-sp
ecifi
c nitr
osa-
min
es w
as o
ne-fi
fth an
d th
e con
cent
ratio
n of
CO
was
one
-hun
-dr
edth
of t
hose
of c
onve
ntio
nal c
ombu
stion
ciga
rette
s –
toxic
com
poun
ds ar
e not
com
plet
ely re
mov
ed fr
om th
e main
-str
eam
smok
e of I
QO
S
Prot
ano
et al
., Ita
ly (2
016)
[25]
and
(201
7) [2
6]
to ev
aluat
e em
issio
ns
of su
bmicr
onic
parti
cles
(SM
Ps) a
risin
g fro
m th
e “r
eal u
se” o
f a co
nven
tiona
l cig
aret
te, a
hand
-rolle
d cig
aret
te, a
n e-ci
gare
tte, a
nd
IQO
S, as
well
as to
estim
ate
the d
ose o
f SM
Ps de
posit
ed
in th
e res
pira
tory
syste
m
of in
divid
uals
(3 m
onth
s to
21 ye
ars o
f age
) exp
osed
to
seco
ndha
nd sm
oke
4 adu
lt sm
oker
s, ag
ed 37
–60;
a mod
el sm
okin
g roo
m 52
.7 m
2, 3 s
mok
ing s
essio
ns (1
ciga
rette
or I
QO
S sti
ck ea
ch) w
ith 1-
h in
terv
als fo
r eac
h sm
okin
g dev
ice; d
oses
dep
osite
d in
the
resp
irato
ry sy
stem
of p
assiv
e sm
oker
s we
re es
timat
ed u
sing a
mul
tiple-
path
pa
rticle
dos
imet
ry m
odel
–bo
th te
sted
non-
com
busti
on d
evice
s (an
e-cig
aret
te an
d IQ
OS)
em
itted
subm
icron
ic pa
rticle
s –
parti
cle em
issio
ns fr
om IQ
OS w
ere h
igher
than
from
an e-
cigar
ette
–du
ring I
QO
S us
e, 1-
h in
terv
al be
twee
n se
ssion
s, pa
rticle
valu
es
were
high
er, c
ompa
red
to th
e bas
eline
, dur
ing e
-ciga
rette
use
, 1-
h in
terv
als b
etwe
en se
ssion
s wer
e suf
ficien
t to
allow
par
ticle
deca
y to
reac
h ba
selin
e valu
es –
an es
timat
ed u
ptak
e of p
assiv
e sm
oker
s dec
reas
ed w
ith ag
e; hi
gher
dos
es w
ere e
stim
ated
for t
radi
tiona
l ciga
rette
s com
pare
d to
no
n-co
mbu
stion
dev
ices
–af
ter a
ll 3 s
mok
ing s
essio
ns, d
osim
etry
estim
ates
wer
e 50–
110%
hi
gher
for I
QO
S th
an fo
r an
e-cig
aret
teLi
et al
., Chi
na
(201
8) [2
7]– t
o ev
aluat
e the
chem
ical
subs
tanc
es em
itted
dur
ing
the u
se o
f IQ
OS;
– to
simul
ate p
yrol
ysis
of IQ
OS
stick
s and
to
mak
e com
paris
ons w
ith
conv
entio
nal c
igare
tte
Toba
cco
Hea
ting S
yste
m 2.
2 (TH
S2.2,
m
arke
ted
as IQ
OS)
and
the r
efer
ence
cig
aret
tes (
3R4F
); th
e tot
al pa
rticu
late
mat
ter,
wate
r, ta
r, ni
cotin
e, pr
opyle
ne
glyco
l, glyc
erin
, car
bon
mon
oxid
e, vo
latile
org
anic
com
poun
ds, a
rom
atic
amin
es, h
ydro
gen
cyan
ide,
amm
onia,
N-
nitro
sam
ines
, phe
nol, a
nd p
olyc
yclic
ar
omat
ic hy
droc
arbo
n we
re an
alyze
d un
der b
oth
the I
SO an
d H
CI re
gimes
;TH
S2.2
and
3 oth
er co
mm
ercia
l tob
acco
–th
e nico
tine a
nd ta
r lev
els em
itted
dur
ing t
he u
se o
f IQ
OS
were
alm
ost i
dent
ical t
o th
e ref
eren
ce ci
gare
tte (3
R4F)
–co
mpa
red
to a
conv
entio
nal c
igare
tte, I
QO
S de
liver
ed >
90%
fe
wer h
arm
ful a
nd p
oten
tially
har
mfu
l con
stitu
ents,
exce
pt fo
r ca
rbon
yls, a
mm
onia,
and
N-ni
troso
anab
asin
e, th
e lev
els o
f whi
ch
were
abou
t 50–
80%
lowe
r –
usin
g IQ
OS
relea
sed
muc
h m
ore w
ater
(154
1.67%
high
er u
nder
th
e ISO
regim
e, an
d 26
8.08%
high
er u
nder
the H
CI re
gime)
th
an 3R
4F –
a red
uctio
n of
har
mfu
l con
stitu
ents
resu
lts fr
om th
e low
er te
m-
pera
ture
of H
TPs d
urin
g the
ir us
e, ra
ther
than
from
the h
eatin
g sti
ck in
gred
ients
Tabl
e 1. C
hem
ical c
ompo
sitio
n of
toba
cco
stick
s and
smok
e gen
erat
ed d
urin
g HTP
use
– a s
yste
mat
ic re
view,
2015
–201
8 – co
nt.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 601
prod
ucts
were
hea
ted
in th
e pyr
olyz
er;
com
preh
ensiv
e gas
chro
mat
ogra
phy-
mas
s spe
ctrom
etry
was
use
d to
com
pare
di
ffere
nces
in em
itted
subs
tanc
esPa
citto
et al
., Ita
ly (2
018)
[20]
–to
char
acter
ize th
e emi
s-sio
n of I
QOS i
n ter
ms of
dif
feren
t aer
osol
metri
cs of
sub-
micro
n par
ticles
in –
main
strea
m sm
oke;
–to
evalu
ate t
he ef
fect
of
the I
QO
S sti
ck fl
avor
on
the c
once
ntra
tions
an
d siz
e dist
ribut
ions
of
parti
cles g
ener
ated
by
IQO
S; –
to ch
arac
teriz
e the
vola-
tility
of I
QO
S-em
itted
pa
rticle
s usin
g a th
erm
o-co
nditi
onin
g sys
tem
; –
to es
timat
e the
par
ticle
surfa
ce ar
ea d
oses
in
the h
uman
resp
irato
ry
appa
ratu
s by m
eans
of
a dep
ositi
on m
odel
mea
sure
men
ts of
the p
artic
le nu
mbe
r co
ncen
tratio
n an
d di
strib
utio
n in
the
main
strea
m ae
roso
l; 4 d
iffer
ent I
QO
S sti
cks fl
avor
s (co
mm
ercia
lized
with
the
nam
es “w
hite
,” “o
rang
e,” “b
lue”
and
“silv
er”)
;4 d
iffer
ent p
uff p
rofil
es (a
new
stick
ea
ch) i
n or
der t
o in
clude
pos
sible
diffe
renc
es in
the m
anuf
actu
ring o
f IQ
OS
stick
s;ea
ch p
uff p
rofil
e: 5 p
uffs;
leng
th o
f 2 s
, inte
r-puf
f tim
e of 1
0 s (e
ach
test
inclu
ded
a tot
al of
20 p
uffs)
–th
e par
ticle
(inclu
ding
bot
h vo
latile
and
non-
volat
ile p
artic
les)
num
ber c
once
ntra
tions
in th
e main
strea
m ae
roso
ls
were
< 1×
108 p
art.
cm–3
, and
lowe
r tha
n th
ose c
hara
cteris
tic
of tr
aditi
onal
cigar
ette
s and
e-cig
aret
tes
–th
e vol
atili
ty an
alysis
show
ed th
e high
amou
nt o
f vol
atile
frac
tion
of IQ
OS-
gene
rate
d pa
rticle
s –
the p
artic
le nu
mbe
r con
cent
ratio
n do
es n
ot st
atist
ically
dec
reas
e at
high
er sa
mpl
ing t
empe
ratu
res
Farsa
linos
et al
., G
reec
e/USA
(2
018)
[28]
to m
easu
re ca
rbon
yl em
issio
ns fr
om an
IQ
OS
in co
mpa
rison
wi
th an
e-cig
aret
te an
d a c
omm
ercia
l ciga
rette
a lab
orato
ry-ba
sed a
nalys
is of
the a
eros
ol cre
ated d
uring
the u
se of
: 1) r
egula
r and
m
enth
ol IQ
OS, 2
) an e
-ciga
rette
with
18
mg/m
l nico
tine,
and 3
) 1 w
idely
avail
able
conv
entio
nal c
igare
tte, a
n IQO
S dev
ice
with
stick
s (re
gular
), 1 p
opula
r bra
nd of
co
nven
tiona
l ciga
rette
s; a s
mok
ing de
vice
desig
ned t
o cap
ture
the m
ainstr
eam
smok
e; th
e ISO
stan
dard
s (35
ml)
at 2 p
uffs/
min
we
re ad
apted
; vola
tile o
rgan
ic co
mpo
unds
an
d nico
tine l
evels
wer
e ana
lyzed
by
gas c
hrom
atogr
aphy
coup
led to
a fla
me
ioniza
tion d
etecto
r; an
d poly
cycli
c aro
mati
c hy
droc
arbo
ns w
ere a
nalyz
ed us
ing hi
gh-
perfo
rman
ce liq
uid
–IQ
OS,
com
pare
d wi
th th
e con
vent
iona
l ciga
rette
, em
itted
lowe
r lev
els o
f for
mald
ehyd
e (on
aver
age b
y 91.6
%),
acet
aldeh
yde (
on
aver
age b
y 84.9
%),
acro
lein
(on
aver
age b
y 90.6
%),
prop
iona
l-de
hyde
(on
aver
age b
y 89.0
%),
and
crot
onald
ehyd
e (on
aver
age
by 95
.3%)
–IQ
OS
use e
mitt
ed su
bsta
ntial
ly lo
wer l
evels
of c
arbo
nyls
than
a c
omm
ercia
l tob
acco
ciga
rette
but
high
er le
vels
than
an
e-cig
aret
te
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)602
Auer
et al
., Sw
itzer
land
(201
7) [2
9], L
ette
rs to
the e
dito
r [30
–32]
to co
mpa
re th
e con
tent
s of
smok
e gen
erat
ed
durin
g IQ
OS
use w
ith th
e co
nten
ts of
smok
e fro
m
conv
entio
nal c
igare
ttes
chro
mat
ogra
phy c
oupl
ed to
a fl
uore
scen
ce d
etec
tor;
the t
empe
ratu
re
near
the h
eate
r blad
e ins
ide t
he IQ
OS
hold
er w
as m
onito
red
–vo
latile
org
anic
com
poun
ds, p
olyc
yclic
arom
atic
hydr
ocar
bons
, an
d ca
rbon
mon
oxid
e wer
e pre
sent
in IQ
OS
smok
e –
the s
mok
e rele
ased
by I
QO
S co
ntain
s elem
ents
from
pyr
olys
is an
d th
erm
ogen
ic de
grad
atio
n th
at ar
e the
sam
e har
mfu
l con
stitu
ents
of co
nven
tiona
l ciga
rette
smok
e –
adve
rtisin
g slo
gans
such
as “h
eat-n
ot-b
urn”
are n
o su
bstit
ute f
or
scien
ce –
IQO
S sm
oke h
ad 84
% o
f the
nico
tine f
ound
in co
nven
tiona
l ciga
-re
tte sm
oke
–th
e tem
pera
ture
of I
QO
S wa
s low
er (3
30°C
) tha
n th
at o
f the
con-
vent
iona
l ciga
rette
(684
°C)
Mall
ock e
t al.,
Ger
man
y (20
18) [
33]
chem
ical e
valu
atio
n of
sm
oke g
ener
ated
dur
ing
IQO
S us
e with
the
cont
ents
of sm
oke f
rom
co
nven
tiona
l ciga
rette
s
emiss
ion
of a
com
mer
cially
avail
able
HTP
(IQ
OS)
, fol
lowi
ng th
e HCI
regim
e; an
alysis
of t
he p
artic
ulat
e mat
ter (
TPM
), ni
cotin
e, wa
ter,
aldeh
ydes
, and
oth
er
volat
ile o
rgan
ic co
mpo
unds
(VO
Cs);
a lin
ear s
mok
ing m
achi
ne, 1
2 puf
fs
(4 in
terv
als o
f 3 p
uffs
each
)
–ni
cotin
e yiel
d wa
s com
para
ble t
o tra
ditio
nal c
ombu
stibl
e cig
aret
tes
–a s
ubsta
ntial
redu
ction
in th
e lev
els of
alde
hyde
s (ap
prox
. 80–
95%
) an
d VO
Cs (a
ppro
x. 97
–99%
) was
obs
erve
d –
the l
evels
of m
ajor c
arcin
ogen
s are
mar
kedl
y red
uced
in th
e em
is-sio
ns o
f the
analy
zed
HTP
in re
latio
n to
a co
nven
tiona
l ciga
rette
–th
e wat
er co
nten
t in
IQO
S sm
oke w
as h
igher
com
pare
d to
that
in
a co
nven
tiona
l ciga
rette
–co
mpa
rativ
ely h
igh le
vels
of ta
r wer
e fou
nd in
bot
h th
e HTP
an
d cig
aret
te sm
oke
Uch
iyam
a et a
l., Ja
pan
(201
8) [7
]to
analy
ze sm
oke f
rom
he
ated
toba
cco
prod
ucts
(IQO
S, gl
o, P
loom
TEC
H)
and
tradi
tiona
l ciga
rette
s (3
R4F
and
1R5F
)
3 HTP
ciga
rette
bra
nds:
IQO
S wi
th
4 typ
es o
f IQ
OS
stick
s (“r
egul
ar,”
“bala
nced
regu
lar,”
“min
t” an
d “m
enth
ol”)
; glo
with
3 typ
es o
f glo
sti
cks (
“brig
ht to
bacc
o,” “
fresh
mix”
an
d “in
tens
ely fr
esh”
); Pl
oom
TEC
H
with
3 typ
es o
f liq
uid
caps
ules
(“M
eviu
s Le
gular
,” “C
ooler
Gre
en” a
nd “C
ooler
Pu
rple”
); re
fere
nce c
igare
ttes (
3R4F
an
d 1R
5F);
smok
e was
colle
cted
usin
g a G
F-CX
572 s
orbe
nt ca
rtrid
ge an
d
a 9 m
m gl
ass-fi
ber fi
lter
–no
cons
ider
able
diffe
renc
e in
the t
otal
gase
ous a
nd p
artic
ulat
e co
mpo
unds
wer
e not
ed b
etwe
en H
TPs a
nd th
e tra
ditio
nal c
iga-
rette
(tot
al ga
seou
s and
par
ticul
ate m
atte
r: 42
mg/I
QO
S sti
ck;
29 m
g/glo
stick
; 18 m
g/Plo
om T
ECH
stick
and
31 m
g/tra
ditio
nal
cigar
ette
) –
fewe
r che
mica
l com
poun
ds w
ere g
ener
ated
by H
TPs t
han
by tr
a-di
tiona
l ciga
rette
s, ex
cept
for w
ater
, pro
pylen
e glyc
ol, g
lycer
ol,
and
acet
ol, t
he co
ncen
tratio
ns o
f whi
ch in
main
strea
m sm
oke
were
high
er in
HTP
s tha
n in
the t
radi
tiona
l ciga
rette
–wa
ter a
ccou
nted
for 7
5–85
% o
f the
tota
l gas
eous
and
parti
culat
e m
atte
r gen
erat
ed d
urin
g the
use
of b
oth
IQO
S an
d glo
(vs.
tradi
-tio
nal t
obac
co: 1
7–27
%)
–th
e mos
t abu
ndan
t che
mica
l com
poun
ds ge
nera
ted
durin
g H
TP u
se w
ere g
lycer
ol, m
enth
ol, n
icotin
e, pr
opyle
ne gl
ycol
, an
d ac
etol
Tabl
e 1. C
hem
ical c
ompo
sitio
n of
toba
cco
stick
s and
smok
e gen
erat
ed d
urin
g HTP
use
– a s
yste
mat
ic re
view,
2015
–201
8 – co
nt.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 603
–th
e mea
n he
atin
g tem
pera
ture
s wer
e 210
°C fo
r IQ
OS;
170°
C fo
r glo
; 23°
C fo
r Plo
om T
ECH
; and
460°
C fo
r tra
ditio
nal c
igare
ttes
–th
e lev
els o
f gen
erat
ed ch
emica
l com
poun
ds d
epen
ded
on th
e te
mpe
ratu
re o
f tob
acco
stick
s in
HTP
sRu
prec
ht et
al., I
taly/
USA
/Hon
g Kon
g (2
017)
[34,
35]
to co
mpa
re th
e en
viron
men
tal p
ollu
tion
gene
rate
d by
e-cig
aret
tes,
IQO
S, an
d tra
ditio
nal
cigar
ette
s, in
a sta
ndar
d in
door
envir
onm
ent
the c
hara
cteriz
atio
n of
blac
k car
bon,
m
etal
parti
cles,
orga
nic c
ompo
unds
, an
d th
e size
-segr
egat
ed p
artic
le m
ass,
and
the c
once
ntra
tions
emitt
ed fr
om
IQO
S; a
room
48 m
2 ; 13 s
mok
ing/
vapi
ng se
ssion
s: an
e-cig
aret
te (1
6 mg/m
l ni
cotin
e, 1 p
uff e
very
min
for 7
min
, fo
llowe
d by
3 m
in p
ause
), IQ
OS
(with
10
men
thol
and
14 w
ithou
t men
thol
IQ
OS
stick
s, 3-
h sm
okin
g ses
sion,
av
erag
e sm
okin
g tim
e – 7
min
, fol
lowe
d by
a sh
ort 3
-min
pau
se),
conv
entio
nal
cigar
ette
(9 ci
gare
tte p
er ea
ch se
ssion
, av
erag
e sm
okin
g tim
e – 7
min
, fol
lowe
d by
a sh
ort 3
-min
pau
se)
–th
e IQ
OS
side-
strea
m sm
oke i
ndica
ted
that
the p
artic
ulat
e em
is-sio
n of
org
anic
mat
ter f
rom
thes
e dev
ices i
s sign
ifica
ntly
diffe
rent
, de
pend
ing o
n th
e org
anic
com
poun
d –
IQO
S sm
oke w
as m
ostly
free
from
arom
atic
hydr
ocar
bons
(PAH
s) –
IQO
S us
e stil
l em
itted
subs
tant
ial le
vels
(up
to 2–
6 mg/h
dur
ing
a reg
ular
smok
ing r
egim
en) o
f cer
tain
n-a
lkan
es, o
rgan
ic ac
ids
(such
as su
beric
acid
, aze
laic a
cid, a
nd n
-alk
anoi
c acid
s with
car-
bon
num
bers
10–1
9) an
d lev
oglu
cosa
n –
com
pare
d to
bot
h e-
cigar
ette
s and
conv
entio
nal c
igare
ttes,
met
al em
issio
ns w
ere r
educ
ed in
IQO
S sm
oke,
and
thes
e em
issio
ns w
ere
mos
tly si
mila
r to
the b
ackg
roun
d lev
els –
carc
inog
enic
aldeh
yde c
ompo
unds
, inclu
ding
form
aldeh
yde,
acet
aldeh
yde,
and
acro
lein,
whe
re p
rese
nt in
IQO
S sm
oke (
but
their
leve
ls we
re su
bsta
ntial
ly lo
wer c
ompa
red
to co
nven
tiona
l cig
aret
tes)
–alt
houg
h IQ
OS
smok
e has
subs
tant
ially
lowe
r em
issio
ns o
f the
m
ost t
oxic
com
poun
ds, c
ompa
red
to tr
aditi
onal
cigar
ette
s, th
ey
are s
till n
ot ri
sk-fr
eeLe
igh et
al., U
SA
(201
8) [3
7]to
det
erm
ine t
obac
co-
spec
ific n
itros
amin
e (T
SNA)
yield
s in
the
aero
sol e
mitt
ed fr
om
HTP
s in
com
paris
on to
the
e-cig
aret
tes a
nd to
bacc
o cig
aret
tes
IQO
S (A
mbe
r, to
bacc
o fla
vor),
an e-
cigar
ette
(3.5%
nico
tine,
toba
cco
flavo
red)
and
a wid
ely av
ailab
le to
bacc
o cig
aret
te; a
smok
ing m
achi
ne w
as u
sed
to ge
nera
te p
uffs:
IQO
S (1
2 puf
fs),
an e-
cigar
ette
(55 p
uffs)
and
a sin
gle
toba
cco
cigar
ette
(8 p
uffs)
, the
aver
age
TSNA
yield
s wer
e calc
ulat
ed p
er p
uff
and
per p
uffin
g ses
sion
–IQ
OS
use e
mits
subs
tant
ial le
vels
of to
bacc
o-sp
ecifi
c car
cinog
enic
subs
tanc
es –
IQO
S em
its 8–
22 lo
wer a
mou
nts o
f TSN
A (n
g/puf
f) th
an co
mbu
s-tib
le cig
aret
tes,
but s
ignifi
cant
ly hi
gher
than
e-cig
aret
tes
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)604
Salm
an et
al.,
Leba
non/
USA
(2
018)
[38]
to in
vesti
gate
the t
oxici
ty an
d ni
cotin
e deli
very
po
tent
ial o
f IQ
OS
IQO
S an
d a w
idely
avail
able
toba
cco
cigar
ette
; sm
oke/a
eros
ol w
as ge
nera
ted
unde
r 2 re
gimes
: HCI
and
ISO
, usin
g a s
mok
ing m
achi
ne; r
eacti
ve o
xyge
n sp
ecies
, car
bony
l com
poun
ds, f
ree-
base
an
d pr
oton
ated
nico
tine e
miss
ions
wer
e m
easu
red
–IQ
OS
emits
sign
ifica
nt le
vels
of re
activ
e oxy
gen
spec
ies
(6.26
±2.7
2 nm
ol H
2O2/se
ssion
) and
carb
onyl
com
poun
ds
(472
±19
μg/s
essio
n), b
ut th
ey ar
e 85%
and
77%
lowe
r tha
n th
e lev
els em
itted
by c
ombu
stibl
e ciga
rette
s –
IQO
S em
its h
arm
ful c
onsti
tuen
ts th
at ar
e lin
ked
to ca
ncer
, pul
-m
onar
y dise
ases
, and
addi
ction
in ci
gare
tte sm
oker
s –
IQO
S de
liver
s sim
ilar l
evels
and
free-
base
frac
tions
of n
icotin
e at
the m
outh
piec
e as c
ombu
stibl
e ciga
rette
sSt
udies
with
a po
tent
ial
confl
ict of
inte
rest
Prat
te et
al.,
Switz
erlan
d (2
017)
[23]
PMI
to co
mpa
re th
e sol
id
parti
cles l
evels
in th
e m
ainstr
eam
aero
sol
from
TH
S2.2
and
the
main
strea
m sm
oke o
f th
e ref
eren
ce ci
gare
tte
(3R4
F)
IQO
S (T
HS2
.2), t
he re
fere
nce c
igare
tte
(3R4
F), a
com
mer
cially
avail
able
ther
mod
enud
er o
pera
ting a
t 300
°C,
coup
led to
a 2-
stage
impa
ctor,
was u
sed
to tr
ap so
lid p
artic
les; a
ny co
llecte
d pa
rticle
s wer
e sub
sequ
ently
analy
zed
by
elec
tron
micr
osco
pe sc
anni
ng
and
an el
ectro
n di
sper
sive X
-ray
–th
e main
strea
m ae
roso
l fro
m T
HS2
.2 wa
s fre
e fro
m so
lid ca
rbon
pa
rticle
s, wh
ich co
nfirm
s the
thes
is th
at n
o co
mbu
stion
pro
cess
take
s plac
e dur
ing T
HS2
.2 us
e
Bura
tto et
al.,
Switz
erlan
d (2
018)
[24]
PMI
to an
alyze
the
conc
entra
tion
of 8
carb
onyl
com
poun
ds in
TH
S2.2
aero
sols
3R4F
ciga
rette
s and
TH
S2.2;
smok
e/ae
roso
l was
gene
rate
d un
der t
he H
CI
regim
e con
ditio
ns, u
sing a
30-p
ort
caro
usel
smok
ing m
achi
ne;
–in
TH
S2.2
aero
sols,
carb
onyl
conc
entra
tions
(for
mald
ehyd
e, ac
-et
aldeh
yde,
acet
one,
acro
lein,
pro
pion
aldeh
yde,
crot
onald
ehyd
e, m
ethy
l-eth
yl-ke
tone
, and
but
yrald
ehyd
e) w
ere l
ower
com
pare
d to
th
ose m
easu
red
in ci
gare
tte sm
oke
Mito
va et
al.,
Switz
erlan
d (2
016)
[14]
PMI
to as
sess
the i
mpa
ct of
TH
S2.2
use o
n in
door
air
quali
ty
THS2
.2 an
d a w
idely
avail
able
toba
cco
cigar
ette
, an
envir
onm
enta
lly
cont
rolle
d ro
om, 3
scen
ario
s: “O
ffice
,” “R
esid
entia
l” an
d “H
ospi
talit
y;”
selec
ted
indo
or ai
r con
stitu
ents
were
m
easu
red
–th
e con
cent
ratio
ns o
f res
pira
ble s
uspe
nded
par
ticles
, ultr
avio
let
parti
culat
e mat
ter,
fluor
esce
nt p
artic
ulat
e mat
ter,
solan
esol
, 3-
ethe
nylp
yrid
ine,
form
aldeh
yde,
acro
lein,
crot
onald
ehyd
e, ac
ry-
loni
trile,
ben
zene
, 1,3-
buta
dien
e, iso
pren
e, to
luen
e, CO
, NO
and
NOx af
ter t
he u
se o
f TH
S2.2
unde
r 3 en
viron
men
tal c
ondi
tions
we
re eq
uiva
lent t
o th
e con
cent
ratio
ns fo
und
in b
ackg
roun
d
indo
or ai
r –
THS2
.2 us
e res
ulte
d in
incr
ease
d ac
etald
ehyd
e and
nico
tine c
on-
cent
ratio
ns in
indo
or ai
r, bu
t the
se co
ncen
tratio
ns w
ere c
onsid
er-
ably
lowe
r tha
n th
ose f
ound
in co
nven
tiona
l ciga
rette
s
Tabl
e 1. C
hem
ical c
ompo
sitio
n of
toba
cco
stick
s and
smok
e gen
erat
ed d
urin
g HTP
use
– a s
yste
mat
ic re
view,
2015
–201
8 – co
nt.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 605
The tobacco industry claims that the aerosol formed dur-ing the heating process has around 90–95% lower levels of toxicants than conventional cigarette smoke [13–15,23,24]. This was partially confirmed by independent stud-ies [27,28]. Li et al. reported that, compared to convention-al cigarettes, IQOS delivered a > 90% lower concentration of harmful and potentially harmful constituents (HPHCs) except for carbonyls, ammonia, and N-nitrosoanabasine, where the levels were about 50–80% lower [27]. Farsali-nos et al. showed that IQOS use emitted substantially lower levels of carbonyls than a commercial cigarette but higher levels than an e-cigarette [28]. Mallock et al. observed sub-stantially lower levels of aldehydes (approx. 80–95%) and volatile organic compounds (approx. 97–99%) in the IQOS aerosol compared to cigarette smoke [33]. Pacitto et al. also showed lower volatile and non-volatile particle con-centrations in the mainstream IQOS aerosols compared to traditional cigarette smoke [20].Protano et al. compared the emission of submicronic par-ticles (SMPs) from IQOS and e-cigarettes [25,26]. Both devices emitted SMPs but the particle emissions from IQOS were higher than those from e-cigarettes. Rup-recht et al. noted that the IQOS aerosol was free from metal emissions, in contrast to cigarette and e-cigarette aerosols [34,35]. However, toxic compounds were not completely removed from the heated tobacco aerosol [15]. Li et al. and Mallock et al. showed that IQOS emitted comparable levels of tar to the reference cigarette [27,33]. Bekki et al. observed that the concentration of tobacco-specific nitrosamines were one-fifth of those of conven-tional cigarettes [21]. Leigh et al. also observed that IQOS emitted lower amounts of tobacco-specific nitrosamines than combustible cigarettes, but a significantly higher amount than e-cigarettes [37]. Salman et al. reported that the use of IQOS emitted significant levels of reactive oxy-gen species and carbonyl compounds, but these were still 85% and 77% lower than the levels emitted by combus-tible cigarettes [38].
Jacc
ard
et al
., Sw
itzer
land
(201
7) [1
5]PM
I
to co
mpa
re th
e che
mica
l co
mpo
sitio
n an
d to
xicity
of
TH
S2.2
aero
sols
with
sm
oke f
rom
the r
efer
ence
cig
aret
te (3
R4F)
THS2
.2, th
e ref
eren
ce ci
gare
tte (3
R4F)
; a s
mok
ing m
achi
ne; a
nalys
es o
f the
co
nstit
uent
s of m
ainstr
eam
smok
e fro
m
the r
efer
ence
ciga
rette
(3R4
F ) a
nd th
e ae
roso
l of T
HS2
.2 un
der t
he H
CI re
gime
–ex
cept
for n
icotin
e, ha
rmfu
l and
pot
entia
lly h
arm
ful c
onsti
tuen
ts we
re re
duce
d by
90%
in th
e TH
S2.2
aero
sol i
n co
mpa
rison
wi
th th
e ref
eren
ce ci
gare
tte (3
R4F)
smok
e
Ichi
tsubo
et al
., Jap
an
(201
8) [1
3]Ja
pan
Toba
cco
to an
alyze
the i
mpa
ct of
us
ing a
nov
el to
bacc
o va
por
prod
uct (
the P
loom
TEC
H
prot
otyp
e) o
n in
door
air
quali
ty
the P
loom
TEC
H p
roto
type;
an
envir
onm
enta
lly co
ntro
lled
cham
ber;
3 env
ironm
ents:
2 no
n-sm
okin
g ar
eas a
nd 1
smok
ing a
rea;
indo
or ai
r qu
ality
was e
valu
ated
by:
1) m
easu
ring
the c
onsti
tuen
ts in
main
strea
m
emiss
ions
, 2) b
y det
erm
inin
g the
clas
sic
envir
onm
enta
l tob
acco
smok
e and
3)
by r
epre
sent
ative
air q
ualit
y mar
kers
–th
e main
strea
m em
issio
ns o
f vap
or fr
om P
loom
TEC
H w
ere
chem
ically
sim
pler
than
thos
e of c
igare
tte sm
oke
–en
viron
men
tal t
obac
co sm
oke m
arke
rs, vo
latile
org
anic
com
-po
und
(tolu
ene)
, car
bon
mon
oxid
e, pr
opyle
ne gl
ycol
, glyc
erol
, and
tri
acet
in w
ere b
elow
the l
imit
of d
etec
tion,
or t
he li
mit
of q
uant
ifi-
catio
n, in
bot
h th
e non
-smok
ing a
nd sm
okin
g env
ironm
ents
afte
r us
ing t
he P
loom
TEC
H –
no si
gnifi
cant
incr
ease
in th
e lev
els o
f for
mald
ehyd
e, ac
eton
e or
amm
onia
in th
e exh
aled
air w
ere o
bser
ved
follo
wing
Pl
oom
TEC
H u
se –
Ploo
m T
ECH
had
no
mea
sura
ble e
ffect
on th
e ind
oor a
ir qu
ality
CO –
car
bon
mon
oxid
e; H
CI –
Hea
lth C
anad
a In
tens
e; H
TPs
– he
ated
tob
acco
pro
ducts
; ISO
– I
nter
natio
nal O
rgan
izatio
n fo
r St
anda
rdiza
tion;
SM
Ps –
sub
micr
onic
parti
cles;
THS2
.2 – t
obac
co h
eatin
g sys
tem
2.2 (
IQO
S); T
SNA
– tob
acco
-spec
ific n
itros
amin
es; P
MI –
Phi
lip M
orris
Inte
rnat
iona
l; VO
Cs –
volat
ile o
rgan
ic co
mpo
unds
; 3R4
F – r
efer
ence
ciga
rette
.
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)606
from the HTP aerosol. Moreover, some independent studies have suggested that pyrolysis processes can still be present during HTP use. On the one hand, the levels of some toxicants can be reduced during HTP use but, on the other hand, HTP users can be exposed to higher levels of other toxic chemical and harmful substances compared to tobacco smoke.
Evidence from the experimental animal and cellular studiesThe tobacco industry has performed multiple [22,37–70] in vitro studies on human bronchial epithelial cells, coro-nary arterial endothelial cells, a 3-D nasal culture model, gingival epithelial organotypic cultures, monocytic cells, and in vivo mouse models (Table 2). The results of these studies have indicated that the aerosol from HTPs has lower toxicity and no new hazards compared to cigarette smoke [10,11,22,39–68].The aqueous aerosol extract from IQOS has reduced ef-fects on the adhesion of monocytic cells to human coro-nary endothelial cells compared to the aqueous refer-ence cigarette smoke extract [55]. The aerosol extracts from IQOS were also found to induce less inflammation and migration, and to be less cytotoxic than those from burning conventional cigarettes [56]. The IQOS aerosol exerted a weaker biological impact on human organo-typic bronchial epithelial cells than cigarette smoke at similar nicotine concentrations [57]. Compared to ciga-rette smoke, there was a substantially lower impact of the IQOS aerosol in terms of alterations in tissue morphol-ogy, secretion of pro-inflammatory mediators, impaired ciliary function, increased perturbed transcriptomes, and miRNA expression profiles [58]. Exposure to IQOS aero-sols had a lower impact on the pathophysiology of human gingival organotypic cultures than conventional cigarette smoke [59]. Cigarette smoke caused significant discolor-ation of dental composite resins [60] while this effect was minimized during IQOS use [60].
Controversial results were presented by Auer et al. who showed that in the IQOS aerosol, volatile organic com-pounds, polycyclic aromatic hydrocarbons, and carbon monoxide were detected [29]. Moreover, the smoke re-leased during the use of IQOS contained elements from pyrolysis and thermogenic degradation, similar to the harmful constituents of conventional cigarette smoke [29]. These findings significantly differed from those presented by the tobacco industry and gave rise to heated discussions among the experts [30–33]. Independent experts [31] and industry representatives [32] concluded that the results presented by Auer et al. could be misinterpreted due to the absence of a standardized protocol for emission gener-ation and specifically validated analytical measurements.Some authors suggest that, even without such combus-tion as in the case of traditional cigarettes, HTPs still release harmful compounds which can then expose by-standers [25,26,34,35]. Ruprecht et al. showed that IQOS emitted detectable and substantial levels (up to 2–6 mg/h during a regular smoking regimen) of several organic com-pounds, including n-alkanes, organic acids, and aldehyde species such as formaldehyde, acetaldehyde, and acro-lein [34,35]. Protano et al. estimated the dose of submi-cronic particles deposited in the respiratory system of indi-viduals exposed to secondhand smoke from a combustible cigarette, an e-cigarette, and IQOS [25,26]. The highest doses were reported to originate from combustible ciga-rettes compared to non-combustion devices. However, the dosimetry estimates were 50–110% higher for IQOS than for e-cigarettes [25,26]. Although the IQOS aerosol has substantially lower emissions of toxic compounds com-pared to traditional cigarettes, it is still a source of passive exposure [25,26].Based on evidence from studies not sponsored by the to-bacco company, in general, the results have shown that HTP use releases lower levels of most toxic chemicals and harmful substances compared to conventional cigarettes. However, toxic compounds are not completely removed
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 607
Tabl
e 2. E
viden
ce fr
om th
e exp
erim
enta
l ani
mal
and
cellu
lar st
udies
– a s
yste
mat
ic re
view,
2015
–201
8
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
yIn
depe
nden
t stu
dies
Naba
vizad
eh et
al.,
USA
(201
8) [7
1]to
det
erm
ine t
he p
oten
tial
impa
ct of
expo
sure
to th
e IQ
OS
aero
sol o
n ar
teria
l flo
w-m
ediat
ed d
ilatio
n
8 male
rats;
anae
sthet
ized
rats
were
ex
pose
d to
the I
QO
S ae
roso
l fro
m si
ngle
Hea
tStic
ks, m
ainstr
eam
smok
e fro
m
single
ciga
rette
s or c
lean
air fo
r a se
ries
of co
nsec
utive
30-s
cycle
s ove
r 1.5
–5 m
in; e
ach
cycle
– 15
or 5
s
of ex
posu
re, f
ollo
wed
by re
mov
al
from
the n
ose c
one;
mea
sure
men
t:
pre-
expo
sure
and
post-
expo
sure
flo
w-m
ediat
ed d
ilatio
n,
and
post-
expo
sure
seru
m n
icotin
e an
d co
tinin
e
–ac
ute e
xpos
ures
to th
e IQ
OS
aero
sol i
mpa
ir th
e flow
-med
iated
di
latio
n in
rats
–th
e main
strea
m IQ
OS
aero
sol f
rom
a sin
gle H
eatS
tick c
an ra
pidl
y an
d su
bsta
ntial
ly im
pair
the e
ndot
helia
l fun
ction
in ra
ts, co
mpa
ra-
bly t
o cig
aret
te sm
oke
–th
e pos
t-exp
osur
e ser
um n
icotin
e lev
els w
ere 4
.5-fo
ld h
igher
in th
e ra
ts ex
pose
d to
IQO
S th
an in
thos
e exp
osed
to ci
gare
ttes
Leigh
et al
., USA
(2
018)
[72]
to ex
amin
e the
pot
entia
l cy
toto
xic ef
fects
of i
nhali
ng
emiss
ions
from
an H
TP,
in co
mpa
rison
with
the
electr
onic
and
com
busti
ble
cigar
ette
s.
hum
an b
ronc
hial
epith
elial
cells
ex
pose
d di
rectl
y to
1) 55
puf
fs fro
m an
e-
cigar
ette
, 2) 1
2 puf
fs fro
m an
HTP
, and
3)
8 pu
ffs fr
om a
conv
entio
nal c
igare
tte;
neut
ral r
ed u
ptak
e and
tryp
an b
lue
assa
ys w
ere u
sed
to m
easu
re cy
toto
xicity
–em
issio
ns fr
om th
e HTP
dam
aged
bro
nchi
al ep
itheli
al ce
lls; h
ow-
ever
, the
HTP
show
ed re
duce
d cy
toto
xicity
relat
ive to
a co
mbu
sti-
ble c
igare
tte b
ut h
igher
toxic
ity th
an an
e-cig
aret
te –
com
pare
d wi
th ai
r con
trols,
a sig
nific
ant i
ncre
ase i
n cy
toki
nes
levels
was
obs
erve
d po
st-ex
posu
re to
toba
cco
smok
e but
not
to th
e H
TP o
r e-ci
gare
tte ae
roso
lsCh
un et
al., U
SA
(201
8) [7
0]to
asse
ss th
e pos
sible
hepa
toto
xicity
of I
QO
San
inde
pend
ent r
evisi
on o
f pre
clini
cal
and
clini
cal d
ata o
n IQ
OS
subm
itted
by
PMI t
o FD
A, in
ord
er to
iden
tify t
he
pote
ntial
relat
ions
hip
betw
een
IQO
S ex
posu
re an
d un
expe
cted
liver
toxic
ity
–a c
ombi
natio
n of
anim
al da
ta an
d hu
man
-bas
ed d
ata r
evea
ls a p
at-
tern
of I
QO
S he
pato
toxic
ity w
hich
is w
orth
care
ful c
onsid
erat
ion
–PM
I’s p
recli
nica
l and
clin
ical d
ata c
onsti
tute
a co
ncer
ning
pat
tern
of
pos
sible
hepa
toto
xicity
, esp
ecial
ly co
nsid
erin
g the
shor
t per
iod
of ex
posu
re –
IQO
S m
ay h
ave u
nexp
ecte
d or
gan
toxic
ity th
at h
as n
ot b
een
as-
socia
ted
with
ciga
rette
s
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)608
Stud
ies w
ith a
pote
ntial
co
nflict
of i
nter
est
a cyc
le of
9 to
bacc
o in
dustr
y pub
licat
ions
ab
out T
obac
co
Hea
ting S
yste
m 2.
2 (T
HS2
.2, m
arke
ted
as IQ
OS)
in R
egul
ar
Toxic
ol P
harm
acol
[2
2,39–
47],
Switz
erlan
d (2
016)
PMI
to as
sess
the p
oten
tial f
or
THS2
.2 to
be a
cand
idat
e m
odifi
ed ri
sk to
bacc
o pr
oduc
t
8 lab
orat
ory e
xper
imen
tal i
nves
tigat
ions
or
chem
ical a
nalys
es, a
nd 1
early
clin
ical
inve
stiga
tion
on T
HS2
.2; co
mpa
rison
to
the r
esul
ts ob
serv
ed af
ter t
he re
fere
nce
cigar
ette
(3R4
F) u
se
–in
vitro
and
in vi
vo as
sessm
ents
of T
HS2
.2 sm
oke r
evea
led re
duce
d to
xicity
and
no n
ew h
azar
ds co
mpa
red
to ci
gare
tte sm
oke,
as w
ell
as a
redu
ced
impa
ct on
smok
ing-
relat
ed d
iseas
e net
work
s –
smok
ers w
ho h
ad sw
itche
d to
TH
S2.2
pres
ente
d re
duce
d ex
posu
re
to h
arm
ful a
nd p
oten
tially
har
mfu
l con
stitu
ents
(HPH
Cs)
–th
e cyto
toxic
ity o
f TH
S2.2
aero
sols
was r
educ
ed b
y > 90
% co
m-
pare
d wi
th th
e ref
eren
ce ci
gare
tte sm
oke,
the T
HS2
.2 ae
roso
l fra
ction
was
not
mut
agen
ic in
the A
mes
mut
agen
icity
assa
y –
ther
e was
no
chan
ge in
the H
PHC
yield
s or i
n vit
ro to
xicol
ogy
findi
ngs f
or th
e diff
eren
t tob
acco
blen
ds u
sed
in IQ
OS
toba
cco
stick
s; th
e aer
osol
s pro
duce
d by
toba
cco
blen
ds in
the T
HS2
.2 co
ntain
ed si
gnifi
cant
ly lo
wer c
once
ntra
tions
of H
PHCs
than
the
3R4F
main
strea
m sm
oke
–a 9
0-da
y nos
e-on
ly in
halat
ion
study
in ra
ts sh
owed
that
ther
e wer
e no
appa
rent
new
toxic
ity ef
fects
in th
e TH
S2.2
aero
sol, c
ompa
red
with
the r
efer
ence
ciga
rette
(3R4
F) sm
oke
–af
ter 9
0-da
y exp
osur
e the
alan
ine a
min
otra
nsfe
rase
leve
ls an
d liv
er w
eight
s wer
e sign
ifica
ntly
high
er in
fem
ale an
imals
expo
sed
to IQ
OS
than
in th
e cas
e of c
onve
ntio
nal c
igare
ttes
–he
pato
cellu
lar va
cuol
izatio
n wa
s sign
ifica
ntly
incr
ease
d
in IQ
OS-
expo
sed
fem
ale ra
ts, an
effe
ct no
t see
n in
ciga
rette
-ex
pose
d an
imals
–th
e TH
S2.2
aero
sol i
n co
ntra
ry to
the 3
R4F
cigar
ette
smok
e, di
d no
t cau
se gl
obal
miR
NA d
ownr
egul
atio
n –
a 90-
day n
ose-
only
inha
latio
n stu
dy in
rats
show
ed th
at sy
stem
ic to
xicity
and
alter
atio
ns in
the r
espi
rato
ry tr
act w
ere s
ignifi
cant
ly lo
wer i
n th
e rat
s exp
osed
to th
e men
thol
ated
varia
nt o
f TH
S2.2
than
in th
e gro
ups e
xpos
ed to
trad
ition
al (3
R4F)
and
men
thol
ated
re
fere
nce c
igare
ttes
–cig
aret
te sm
oke i
nduc
ed an
infla
mm
ator
y res
pons
e, tri
gger
ed ce
l-lu
lar st
ress
resp
onse
s, an
d af
fecte
d sp
hing
olip
id m
etab
olism
whi
le th
ese e
ffects
wer
e red
uced
or a
bsen
t dur
ing e
xpos
ure t
o
the T
HS2
.2 ae
roso
l (th
e men
thol
ated
varia
nt)
Tabl
e 2. E
viden
ce fr
om th
e exp
erim
enta
l ani
mal
and
cellu
lar st
udies
– a s
yste
mat
ic re
view,
2015
–201
8 – co
nt.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 609
–in
a 5-
day c
ontro
lled o
pen-
label
clini
cal s
tudy
(N =
160 a
dults
) all
biom
arke
rs of
HPH
C ex
posu
re (e
xcep
t for
nico
tine)
wer
e sign
ifi-
cant
ly re
duce
d in T
HS2
.2 us
ers,
com
pare
d to c
igare
tte sm
oker
s, an
d ap
proa
ched
the l
evels
obse
rved
in th
e sm
okin
g abs
tinen
ce gr
oup
–th
e tes
ted
signa
ture
of 1
1 gen
es o
n th
e blo
od tr
ansc
ripto
me o
f the
su
bjec
ts en
rolle
d in
the c
linica
l stu
dy sh
owed
a re
duce
d ex
posu
re
resp
onse
in th
e sub
jects
who
stopp
ed sm
okin
g or s
witch
ed to
TH
S2.2,
com
pare
d to
thos
e who
cont
inue
d tra
ditio
nal c
igare
tte
smok
ing
a cyc
le of
9 to
bacc
o in
dustr
y pub
licat
ions
ab
out T
obac
co
Hea
ting P
rodu
ct 1.0
(T
HP1
.0, m
arke
ted
as
glo) i
n Re
gular
Toxic
ol
Phar
mac
ol [1
0,11,4
8–54
], U
nite
d Ki
ngdo
m
(201
8)BA
T
to as
sess
the p
oten
tial f
or
THP1
.0 to
be a
cand
idat
e m
odifi
ed ri
sk to
bacc
o pr
oduc
t
7 pre
-clin
ical s
tudi
es o
n th
e saf
ety a
nd
toxic
olog
ical a
ssessm
ent o
f TH
P1.0;
2 t
ypes
of t
obac
co st
icks (
regu
lar
toba
cco
and
men
thol
flav
ors);
co
mpa
rison
to th
e res
ults
obse
rved
afte
r th
e ref
eren
ce ci
gare
tte (3
R4F)
use
–ae
roso
l for
med
dur
ing t
he h
eatin
g pro
cess
had
arou
nd 90
–95%
fe
wer t
oxica
nts t
han
the s
mok
e of c
onve
ntio
nal c
igare
ttes
–du
ring T
HP1
.0 us
e, th
e aer
osol
was
gene
rate
d in
a m
echa
nism
of
disti
llatio
n or
evap
orat
ion;
ther
e was
very
littl
e or n
o co
mbu
stion
du
ring T
HP1
.0 us
e –
in th
e aer
osol
of T
HP1
.0, th
e lev
els o
f tox
icant
s wer
e sub
stant
ially
lowe
r tha
n in
3R4F
smok
e: a r
educ
tion
of 96
.1% o
n av
erag
e fo
r 9 su
bsta
nces
prio
ritize
d fo
r low
erin
g in
cigar
ette
s, an
d 96
.8%
for 1
8 sub
stanc
es p
riorit
ized
by th
e FDA
–th
e lev
els o
f nico
tine,
acet
aldeh
yde,
form
aldeh
yde a
nd p
artic
ulat
e m
atte
r em
itted
dur
ing T
HP1
.0 us
e exc
eede
d am
bien
t air
mea
s-ur
emen
ts, b
ut w
ere >
90%
redu
ced
relat
ive to
ciga
rette
smok
e, m
arke
rs of
toba
cco
com
busti
on w
ere n
ot o
bser
ved;
the r
esid
ual
toba
cco
smok
e odo
r was
sign
ifica
ntly
lowe
r fro
m T
HP1
.0 th
an
from
a co
nven
tiona
l ciga
rette
–TH
P1.0
dem
onstr
ated
sign
ifica
ntly
redu
ced
cyto
toxic
ity co
mpa
red
to th
e ref
eren
ce ci
gare
tte ex
posu
re –
THP1
.0 sh
owed
redu
ced
activ
ity (l
ittle
or n
o ac
tivity
) in
all
10 d
iffer
ent t
oxici
ty an
d ox
idat
ive-st
ress
endp
oint
s, as
sesse
d us
ing n
orm
al hu
man
bro
nchi
al ep
itheli
al ce
lls, c
ompa
red
to
the r
efer
ence
ciga
rette
–TH
Ps d
emon
strat
ed si
gnifi
cant
ly re
duce
d in
vitro
toxic
olog
ical
activ
ity co
mpa
red
to th
e ref
eren
ce ci
gare
tte –
the p
uffin
g beh
avio
rs fo
r naiv
e and
regu
lar H
TP u
sers
were
sim
i-lar
(the
mea
n pu
ff du
ratio
n wa
s 1.8
s; th
e mea
n pu
ff in
terv
al
was 7
.4–9.9
s) –
THP1
.0 sh
owed
subs
tant
ially
redu
ced
resp
onse
s in
pre-
clini
cal
tests
, in co
mpa
rison
to ci
gare
ttes,
so th
e aut
hors
conc
lude
d th
at
THP1
.0 co
uld
have
the p
oten
tial t
o be
a re
duce
d ris
k pro
duct
com
pare
d to
ciga
rette
s
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)610
Pous
sin et
al.,
Switz
erlan
d (2
016)
[5
5]PM
I
to as
sess
the e
ffects
of
aque
ous e
xtrac
ts fro
m
THS2
.2 ae
roso
ls, an
d th
e re
fere
nce c
igare
tte (3
R4F)
sm
oke o
n th
e adh
esio
n of
mon
ocyti
c cell
s to
hum
an co
rona
ry ar
teria
l en
doth
elial
cells
hum
an co
rona
ry ar
teria
l end
othe
lial
cells
; hum
an m
onoc
ytic c
ells;
a dire
ct an
d in
dire
ct ex
posit
ion
to th
e aqu
eous
3R
4F sm
oke o
r the
TH
S2.2
aero
sol
extra
ct
–th
e aqu
eous
aero
sol e
xtrac
t fro
m T
HS2
.2 ha
d re
duce
d ef
fects
on
the a
dhes
ion
of m
onoc
ytic c
ells t
o hu
man
coro
nary
endo
theli
al ce
lls, c
ompa
red
to th
e aqu
eous
ciga
rette
(3R4
F) sm
oke e
xtrac
t –
the a
utho
rs su
gges
ted
that
TH
S2.2
had
a pot
entia
l to
redu
ce
the r
isk fo
r car
diov
ascu
lar d
iseas
es co
mpa
red
to co
mbu
stibl
e cig
aret
tes
van
der T
oorn
et al
., Sw
itzer
land
(201
5)
[56]
PMI
to in
vesti
gate
the e
ffect
from
TH
S 2.2
on
the
migr
ator
y beh
avio
r of
mon
ocyte
s, in
com
paris
on
with
the r
efer
ence
cig
aret
tes (
3R4F
)
the a
eros
ol ex
tract
from
TH
S2.2
and
the s
mok
e extr
act f
rom
3R4F
; the
m
onoc
ytic c
ell li
ne an
d hu
man
coro
nary
ar
teria
l end
othe
lial c
ells w
ere u
sed
to
analy
ze ch
emot
axis
and
trans
endo
theli
al m
igrat
ion;
flow
cyto
met
ry an
d EL
ISA
assa
ys
–th
e inh
ibito
ry ef
fects
of t
he T
HS2
.2 ex
tract
for c
hem
otax
is we
re
appr
ox. 1
8 tim
es le
ss ef
fecti
ve co
mpa
red
to th
e 3R4
F ex
tract
–ex
tracts
from
TH
S2.2
indu
ced
less i
nflam
mat
ion
and
migr
atio
n,
and
were
less
cyto
toxic
than
thos
e fro
m b
urni
ng co
nven
tiona
l cig
aret
tes (
3R4F
) –
heat
ed to
bacc
o pr
oduc
ts (T
HS2
.2) h
ave a
pot
entia
l to
redu
ce
the r
isk fo
r car
diov
ascu
lar d
iseas
es co
mpa
red
to co
mbu
stibl
e cig
aret
tes
Iskan
dar e
t al.,
Switz
erlan
d (2
017)
[5
7]PM
I
to p
erfo
rm a
com
para
tive
asse
ssmen
t of t
he b
iolo
gical
impa
ct of
the T
HS2
.2 ae
roso
l and
the r
efer
ence
cig
aret
te sm
oke
THS2
.2, th
e ref
eren
ce ci
gare
tte (3
R4F)
; hu
man
org
anot
ypic
bron
chial
epith
elial
cultu
res e
xpos
ed to
an ae
roso
l fro
m
THS2
.2 or
ciga
rette
smok
e at s
imila
r ni
cotin
e con
cent
ratio
ns; t
he as
sessm
ent
inclu
ded
cultu
re h
istol
ogy,
cyto
toxic
ity,
secr
eted
pro
-infla
mm
ator
y med
iator
s, cil
iary b
eatin
g, an
d ge
nom
e-wi
de
mRN
A/m
iRNA
pro
files
–th
e TH
S2.2
aero
sol e
xerte
d a w
eake
r bio
logic
al im
pact
than
ciga
-re
tte sm
oke a
t sim
ilar n
icotin
e con
cent
ratio
ns –
no m
orph
olog
ical c
hang
e was
obs
erve
d fo
llowi
ng ex
posu
re to
th
e TH
S2.2
aero
sol
–ex
posu
re to
the T
HS2
.2 ae
roso
l evo
ked
lowe
r lev
els o
f sec
rete
d m
ediat
ors a
nd fe
wer m
iRNA
alte
ratio
ns th
an th
e ref
eren
ce ci
ga-
rette
(3R4
F) sm
oke
Iskan
dar e
t al.,
Switz
erlan
d (2
017)
[5
8]PM
I
to in
vesti
gate
the
appl
icatio
n of
in vi
tro
hum
an 3-
D n
asal
epith
elial
cultu
re m
odels
for t
he
toxic
olog
ical a
ssessm
ent o
f in
halat
ion
expo
sure
THS2
.2, th
e ref
eren
ce ci
gare
tte (3
R4F)
; a h
uman
3-D
nas
al cu
lture
mod
el;
a sys
tem
s tox
icolo
gy ap
proa
ch w
as
impl
emen
ted,
a se
ries o
f 5 ex
perim
enta
l re
petit
ions
, for
each
repe
titio
n
3 ind
epen
dent
expo
sure
runs
, wer
e pe
rform
ed (2
8-m
in co
ntin
uous
expo
sure
to
the s
mok
e/aer
osol
each
)
–th
e ref
eren
ce ci
gare
tte (3
R4F)
smok
e was
subs
tant
ially
grea
ter
than
that
of t
he T
HS2
.2 ae
roso
l in
term
s of c
ytoto
xicity
leve
ls,
alter
atio
ns in
tissu
e mor
phol
ogy,
secr
etio
n of
pro
-infla
mm
ator
y m
ediat
ors,
impa
ired
ciliar
y fun
ction
, and
incr
ease
d pe
rturb
ed
trans
crip
tom
es an
d m
iRNA
expr
essio
n pr
ofiles
Tabl
e 2. E
viden
ce fr
om th
e exp
erim
enta
l ani
mal
and
cellu
lar st
udies
– a s
yste
mat
ic re
view,
2015
–201
8 – co
nt.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 611
Zane
tti et
al.,
Switz
erlan
d/ U
SA/
Ger
man
y (20
17) [
59]
PMI
to co
mpa
re th
e exp
osur
e ef
fects
of t
he re
fere
nce
cigar
ette
(3R4
F) an
d TH
S2.2
on h
uman
ging
ival
epith
elial
orga
notyp
ic cu
lture
s usin
g a sy
stem
s to
xicol
ogy a
ppro
ach
a hum
an gi
ngiva
l epi
theli
al or
gano
typic
cultu
re m
odel;
a sm
okin
g mac
hine
; 10
3R4F
ciga
rette
s (10
–11 p
uffs
each
) an
d 10
TH
S2.2
stick
s (up
to 12
puf
fs ea
ch);
the s
tudy
des
ign in
acco
rdan
ce
with
the H
ealth
Can
ada s
mok
ing
regim
e; re
peat
ed ex
posu
re (3
day
s)
for 2
8 min
at 2
mat
chin
g con
cent
ratio
ns
of th
e ref
eren
ce ci
gare
tte (3
R4F)
smok
e or
the T
HS2
.2 ae
roso
l
–ex
posu
re to
the T
HS2
.2 ae
roso
l had
a lo
wer i
mpa
ct on
the p
atho
-ph
ysio
logy
of h
uman
ging
ival o
rgan
otyp
ic cu
lture
s tha
n cig
aret
te
smok
e –
the T
HS2
.2 ae
roso
l cau
sed
min
or h
istop
atho
logic
al alt
erat
ions
an
d m
inim
al cy
toto
xicity
com
pare
d to
ciga
rette
smok
e (1
% fo
r the
TH
S2.2
aero
sol v
s. 30
% fo
r ciga
rette
smok
e, at
a hi
gh
conc
entra
tion)
–TH
S2.2
had
a red
uced
impa
ct on
the r
eleas
e of p
roin
flam
mat
ory
med
iator
s: TH
S2.2
expo
sure
caus
ed si
gnifi
cant
alte
ratio
ns
in 5
of 14
pro
infla
mm
ator
y med
iator
s ana
lyzed
, ciga
rette
use
alt
ered
11 o
f 14 p
roin
flam
mat
ory m
ediat
ors
Zhao
et al
., USA
/Ch
ina/
Switz
erlan
d (2
017)
[60]
PMI
to ev
aluat
e the
effe
cts
of ci
gare
tte sm
oke o
n th
e di
scol
orat
ion
of d
enta
l re
sin co
mpo
site c
ompa
red
with
the a
eros
ol fr
om
a hea
ted
toba
cco
prod
uct
(TH
S2.2)
60 d
iscs f
rom
3 co
mm
ercia
l res
in
com
posit
es; 2
0 disc
s of e
ach
com
posit
e we
re d
ivide
d in
to 2
grou
ps an
d ex
pose
d to
ciga
rette
smok
e fro
m 20
refe
renc
e cig
aret
tes (
3R4F
) or t
he ae
roso
l fro
m
20 IQ
OS
toba
cco
stick
s per
day
for
3 wee
ks; t
he co
lor,
gloss
and
surfa
ce
roug
hnes
s of t
he co
mpo
site d
iscs w
ere
mea
sure
d at
bas
eline
and
afte
r exp
osur
e an
d br
ushi
ng w
ith a
toot
hpas
te
in 3
cons
ecut
ive w
eeks
–co
lor d
iffer
ence
s rela
tive t
o th
e bas
eline
(ΔE)
wer
e on
aver
age
27.1
(±3.6
) in
the 3
R4F
grou
p an
d 3.9
(±1.5
) in
the T
HS2
.2 gr
oup
afte
r 3 w
eeks
of e
xpos
ure (
p <
0.00
01)
–th
e ref
eren
ce ci
gare
tte (3
R4F)
smok
e cau
sed
signi
fican
t disc
olor
a-tio
n of
den
tal c
ompo
site r
esin
s whi
le th
is ef
fect
was m
inim
ized
durin
g the
use
of T
HS2
.2 (IQ
OS)
Mali
nska
et al
., Po
land/
Switz
erlan
d (2
018)
[61]
PMI
to ev
aluat
e the
m
itoch
ondr
ial fu
nctio
n an
d ox
idat
ive st
ress
afte
r ex
posu
re to
HTP
and
cigar
ette
smok
e
hum
an b
ronc
hial
epith
elial
cells
, fo
llowi
ng 1-
and
12-w
eek e
xpos
ures
to
the t
otal
parti
culat
e mat
ter f
rom
the
TSH
2.2 an
d re
fere
nce c
igare
tte (3
R4F)
ae
roso
l
–th
e tot
al pa
rticu
late m
atte
r fro
m T
HS2
.2 ha
d a l
ower
effe
ct on
ox
idat
ive p
hosp
hory
latio
n, ge
ne ex
pres
sion
and
prot
eins i
nvol
ved
in o
xidat
ive st
ress
than
the t
otal
parti
culat
e mat
ter f
rom
the r
efer
-en
ce ci
gare
tte
van
der T
oom
et al
., Sw
itzer
land
(201
8)
[62]
PMI
to ev
aluat
e fun
ction
al an
d m
olec
ular
chan
ges i
n hu
man
bro
nchi
al ep
itheli
al ce
lls fo
llowi
ng a
12-w
eek
expo
sure
to th
e tot
al pa
rticu
late m
atte
r fro
m
THS2
.2 co
mpa
red
to th
e re
fere
nce c
igare
tte (3
R4F)
THS2
.2, th
e ref
eren
ce ci
gare
tte (3
R4F)
; hu
man
bro
nchi
al ep
itheli
al ce
ll lin
e, 12
-wee
k exp
osur
e, th
e asse
ssmen
t of
endp
oint
s lin
ked
to lu
ng ca
rcin
ogen
esis
–lo
ng-te
rm ex
posu
re to
the t
otal
parti
culat
e mat
ter f
rom
the
THS2
.2 ha
d a l
ower
bio
logic
al im
pact
on h
uman
bro
nchi
al ep
i-th
elial
cells
com
pare
d wi
th th
e tot
al pa
rticu
late m
atte
r fro
m th
e re
fere
nce c
igare
tte sm
oke
–sh
ort-t
erm
expo
sure
to th
e tot
al pa
rticu
late m
atte
r fro
m th
e ref
er-
ence
ciga
rette
resu
lted
in ce
llular
crisi
s and
epith
elial-
mes
ench
y-m
al tra
nsiti
on –
long
-term
expo
sure
to th
e tot
al pa
rticu
late m
atte
r fro
m th
e ref
er-
ence
ciga
rette
resu
lted
in ce
llular
tran
sform
atio
n
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)612
Has
well
et al
., Uni
ted
King
dom
(201
8) [1
6]BA
T
to co
mpa
re th
e tra
nscr
ipto
mic
pertu
rbat
ions
follo
wing
an
acut
e exp
osur
e of a
3D
airwa
y tiss
ue to
the a
eros
ols
from
2 co
mm
ercia
l TH
Ps
and
the r
efer
ence
ciga
rette
(3
R4F)
2 Tob
acco
Hea
ting P
rodu
cts (T
HP
and
THP1
.0), t
he re
fere
nce c
igare
tte
(3R4
F), a
3D ai
rway
cell
mod
el an
d RN
A-se
quen
cing w
ere u
sed
to as
sess
trans
crip
tom
ic pe
rturb
atio
ns af
ter
expo
sure
–TH
Ps h
ad a
redu
ced
impa
ct on
gene
expr
essio
n co
mpa
red
to
3R4F
–th
ere w
as n
o pr
o-in
flam
mat
ory e
ffect
obse
rved
afte
r TH
P us
e
Croo
ks et
al., U
nite
d Ki
ngdo
m (2
018)
[17]
BAT
to d
eter
min
e whe
ther
th
e inc
lusio
n of
pot
entia
l fla
vorin
gs in
the T
HP
woul
d ad
d to
the l
evels
of
toxic
ants
in th
e em
issio
ns
or al
ter i
n vit
ro re
spon
ses
glo, t
obac
co gl
o sti
cks (
Neos
tik),
both
fla
vore
d an
d un
flavo
red,
a co
mpa
rison
wi
th th
e ref
eren
ce ci
gare
tte (3
R4F)
sm
oke
–th
e lev
els o
f mea
sure
d to
xican
ts we
re si
mila
r in
the fl
avor
ed an
d un
flavo
red
toba
cco
stick
s (Ne
ostik
) em
issio
ns, a
nd si
gnifi
cant
ly lo
wer t
han
in th
e em
issio
ns fr
om th
e ref
eren
ce ci
gare
tte (3
R4F)
–th
e TH
P ae
roso
l was
not
mut
agen
ic in
the A
mes
mut
agen
icity
assa
y or i
n th
e mou
se ly
mph
oma a
ssay
–we
ak ge
noto
xic re
spon
ses i
n th
e in
vitro
micr
onuc
leus t
est w
ere
obse
rved
, usin
g Chi
nese
ham
ster l
ung fi
brob
lasts,
from
bot
h fla
-vo
red
and
unfla
vore
d Ne
ostik
s, an
d th
ese w
ere w
eake
r tha
n fo
r th
e ref
eren
ce ci
gare
tteIsh
ikaw
a et a
l., Ja
pan
(201
8) [1
8]Ja
pan
Toba
cco
to an
alyze
the b
iolo
gical
effe
cts o
f aer
osol
s fro
m th
e re
fere
nce c
igare
tte (3
R4F)
an
d a n
ovel
toba
cco
vapo
r pr
oduc
t (th
e Plo
om T
ECH
pr
otot
ype)
the P
loom
TEC
H p
roto
type,
the
refe
renc
e ciga
rette
(3R4
F), M
ucilA
ir or
gano
typic
bron
chial
epith
elial
cultu
res;
a dire
ct ae
roso
l exp
osur
e sy
stem
, 5 ex
posu
re co
nditi
ons f
or
cigar
ette
smok
e and
3 fo
r Plo
om T
ECH
–th
e ref
eren
ce ci
gare
tte (3
R4F)
smok
e inc
reas
ed cy
toto
xicity
, cy-
toki
ne se
cret
ion,
and
diffe
rent
ial ge
ne ex
pres
sion,
dep
endi
ng o
n th
e exp
osur
e dos
e –
no ch
ange
s wer
e obs
erve
d in
any o
f the
analy
zed
endp
oint
s fol
-lo
wing
the P
loom
TEC
H va
por e
xpos
ure
–th
e aut
hors
conc
lude
d th
at th
e bio
logic
al ef
fects
of P
loom
TE
CH va
por w
ere l
ower
than
thos
e of c
onve
ntio
nal c
ombu
stibl
e cig
aret
tes
Taka
hash
i et a
l., Ja
pan/
Switz
erlan
d (2
018)
[63]
Japa
n To
bacc
o
to ex
amin
e the
emiss
ion
levels
for s
electe
d cig
aret
te
smok
e con
stitu
ents,
and
in
vitro
toxic
ity o
f the
aero
sol
from
a no
vel t
obac
co va
por
prod
uct (
the P
loom
TEC
H
prot
otyp
e) an
d to
com
pare
th
em to
the r
efer
ence
cig
aret
te (3
R4F)
smok
e
the P
loom
TEC
H p
roto
type,
the
refe
renc
e ciga
rette
(3R4
F); “
Hof
fman
n an
alyte
s” w
ere c
ondu
cted,
the A
mes
as
say a
nd th
e in
vitro
Micr
onuc
leus
Assa
y wer
e per
form
ed to
asse
ss cy
to-
and
geno
toxic
ity
–a c
hem
ical a
nalys
is of
the P
loom
TEC
H p
roto
type a
eros
ol d
emon
-str
ated
that
the H
offm
ann
analy
te le
vels
were
subs
tant
ially
lowe
r th
an in
the 3
R4F
smok
e and
that
they
wer
e mos
tly b
elow
quan
tifi-
able
levels
–no
mea
sura
ble g
enot
oxici
ty or
cyto
toxic
ity fe
atur
es w
ere o
bser
ved
durin
g Plo
om T
ECH
pro
totyp
e use
Tabl
e 2. E
viden
ce fr
om th
e exp
erim
enta
l ani
mal
and
cellu
lar st
udies
– a s
yste
mat
ic re
view,
2015
–201
8 – co
nt.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 613
Szos
tak e
t al.,
Switz
erlan
d (2
017)
[6
4]PM
I
to ev
aluat
e the
impa
ct of
expo
sure
to ci
gare
tte
smok
e and
the T
HS2
.2 ae
roso
l on
mice
hea
rt tis
sues
the r
efer
ence
ciga
rette
(3R4
F),
a TH
S2.2
heat
ed to
bacc
o sy
stem
(IQ
OS)
; fem
ale A
poe–/–
mice
; exp
osur
e to
ciga
rette
smok
e or t
he T
HS2
.2 ae
roso
l for
up
to 8
mon
ths
–th
e ciga
rette
smok
e exp
osur
e ind
uced
the d
ownr
egul
atio
n of
ge
nes i
nvol
ved
in th
e cyto
skele
ton
orga
niza
tion
and
the c
on-
tracti
le fu
nctio
n of
the h
eart
(main
ly ge
nes t
hat e
ncod
e β-a
ctin,
ac
tinin
-α-4
, and
filam
in-C
) and
dow
nreg
ulat
e gen
es re
lated
to th
e in
flam
mat
ory r
espo
nse
–th
ese e
ffects
wer
e not
obs
erve
d in
the g
roup
expo
sed
to
the T
HS2
.2 ae
roso
lLo
Sas
so et
al.,
Switz
erlan
d/
Sing
apor
e/ G
erm
any
(201
6) [6
5]PM
I
to in
vesti
gate
the e
ffects
of
expo
sure
to th
e TH
S2.2
aero
sol, t
he re
fere
nce
cigar
ette
smok
e or fi
ltere
d air
on
the l
ivers
of
Apoe
–/– m
ice
an 8-
mon
th in
halat
ion
study
with
Apo
e–/–
mice
, exp
osur
e to
1) th
e TH
S2.2
aero
sol,
2) th
e ref
eren
ce ci
gare
tte (3
R4F)
sm
oke,
or 3)
filte
red
air; a
fter 2
mon
ths
som
e mice
expo
sed
to ci
gare
tte sm
oke
were
switc
hed
to T
HS2
.2 or
filte
red
air
expo
sure
–sig
ns o
f ove
rt he
pato
toxic
ity w
ere a
bsen
t in
all 3
grou
ps –
com
pare
d wi
th ci
gare
tte sm
oke,
the T
HS2
.2 ae
roso
l had
redu
ced
biol
ogica
l effe
cts o
n th
e live
rs of
Apo
e–/– m
ice –
the l
ivers
of th
e Apo
e–/– m
ice ex
pose
d to
ciga
rette
smok
e did
ex-
hibi
t mol
ecul
ar re
spon
ses (
such
as d
ysre
gulat
ion
of li
pid,
xeno
bi-
otic
and
possi
bly i
ron
hom
eosta
sis) w
hich
wer
e muc
h les
s affe
cted
in th
e TH
S2.2,
cessa
tion
and
switc
hing
grou
psPh
illip
s et a
l., Si
ngap
ore/
Switz
erlan
d/ G
erm
any
(201
6) [6
6,67]
PMI
to in
vesti
gate
feat
ures
of
chro
nic o
bstru
ctive
pu
lmon
ary d
iseas
e (CO
PD)
and
card
iova
scul
ar
dise
ase (
CVD
) am
ong t
he
apol
ipop
rote
in E
-defi
cient
(A
poe–/–
) mice
expo
sed
to ci
gare
tte sm
oke o
r the
TH
S2.2
aero
sol f
or u
p
to 8
mon
ths
(Apo
e–/–) m
ice ex
pose
d to
ciga
rette
sm
oke (
3R4F
) or t
he ae
roso
l fro
m
THS2
.2 fo
r up
to 8
mon
ths;
som
e gro
ups
expo
sed
to ci
gare
tte sm
oke w
ere e
ither
sw
itche
d to
the T
HS2
.2 ae
roso
l or
unde
rwen
t ces
satio
n af
ter 2
mon
ths;
the
expo
sure
effe
cts w
ere i
nves
tigat
ed u
sing
phys
iolo
gy an
d hi
stolo
gy, c
ombi
ned
with
tran
scrip
tom
ics, li
pido
mics
, and
pr
oteo
mics
–cig
aret
te sm
oke i
nduc
ed n
asal
epith
elial
hype
rplas
ia an
d m
etap
la-sia
, lung
infla
mm
atio
n, an
d em
phys
emat
ous c
hang
es (i
mpa
ired
pulm
onar
y fun
ction
and
alveo
lar d
amag
e) –
cigar
ette
smok
e exp
osur
e had
an at
hero
geni
c effe
ct in
cludi
ng
alter
ed li
pid
profi
les an
d ao
rtic p
laque
form
atio
n –
expo
sure
to th
e TH
S2.2
aero
sol n
eithe
r ind
uced
lung
infla
mm
a-tio
n or
emph
ysem
a, no
r con
siste
ntly
chan
ged
the l
ipid
pro
file o
r en
hanc
ed p
laque
form
atio
n –
cessa
tion
or sw
itchi
ng to
TH
S2.2
reve
rsed
the i
nflam
mat
ory
resp
onse
s and
halt
ed th
e pro
gres
sion
of in
itial
emph
ysem
atou
s ch
ange
s and
the a
ortic
plaq
ue ar
eaTi
tz et
al., S
witze
rland
/Si
ngap
ore/F
inlan
d (2
016)
[68]
PMI
to in
vesti
gate
the T
HS2
.2 ex
posu
re ef
fects
on
lung
lip
id m
etab
olism
in
an ap
olip
opro
tein
E-
defic
ient (
Apoe
–/–)
mou
se st
udy
mice
expo
sed
to h
igh co
ncen
tratio
ns o
f th
e ref
eren
ce ci
gare
tte (3
R4F)
smok
e, th
e aer
osol
from
TH
S2.2
or fi
ltere
d air
, for
up
to 8
mon
ths;
som
e gro
ups
expo
sed
to ci
gare
tte sm
oke w
ere e
ither
sw
itche
d to
the T
HS2
.2 ae
roso
l or
unde
rwen
t ces
satio
n af
ter 2
mon
ths
–th
e ref
eren
ce ci
gare
tte (3
R4F)
smok
e ind
uced
a co
ordi
nate
d lip
id
resp
onse
cont
rolle
d by
tran
scrip
tion
regu
lator
s (su
ch as
SRE
BP
prot
eins)
and
supp
orte
d by
oth
er m
etab
olic
adap
tatio
ns; m
ost o
f th
ese c
hang
es w
ere a
bsen
t in
the m
ice d
urin
g exp
osur
e to
THS2
.2,
in th
e ces
satio
n gr
oup,
and
the i
n sw
itchi
ng gr
oup
–th
e Apo
e−/−
mice
expo
sed
to T
HS2
.2 fo
r 3 m
onth
s sho
wed
som
e do
wnre
gulat
ion
of se
vera
l sph
ingo
lipid
s, a r
espo
nse o
ppos
ite to
th
at o
bser
ved
in th
e gro
up ex
pose
d to
the r
efer
ence
ciga
rette
(3
R4F)
smok
e
Apoe
–/– m
ouse
– a
polip
opro
tein
E-d
eficie
nt m
ouse
; BA
T –
Briti
sh A
mer
ican
Toba
cco;
ELI
SA –
enz
yme-
linke
d im
mun
osor
bent
assa
y; FD
A –
Food
and
Dru
g Ad
min
istra
tion;
H
PHCs
– ha
rmfu
l and
pot
entia
lly h
arm
ful c
onsti
tuen
ts; H
TPs –
hea
ted
toba
cco
prod
ucts;
miR
NA –
micr
o rib
onuc
leic a
cid; P
MI –
Phi
lip M
orris
Inte
rnat
iona
l; TH
P1.0
– tob
acco
hea
ting
prod
uct (
glo);
THS2
.2 – t
obac
co h
eatin
g sys
tem
2.2 (
IQO
S); 3
R4F
– ref
eren
ce ci
gare
tte.
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)614
were published in 1 journal that had a history of concealed pro-industry bias [69].An independent review of industry sponsored preclini-cal and clinical data on IQOS, performed by Chun et al., points to the potential hepatotoxic effects of IQOS use [70]. A combination of animal data and human-based data reveals a concerning pattern of possible hepatotox-icity, especially considering the short period of exposure. Chun et al. suggested that IQOS might have unexpected organ toxicity, not observed during cigarette smoking.Independent experimental animal and cellular studies on HTPs are very limited. Nabavizadeh et al. showed that the mainstream IQOS aerosol from a single tobacco stick might rapidly and substantially impair the endothelial function in rats, comparable to smoke from a cigarette. The use of IQOS does not necessarily avoid the adverse cardiovascu-lar effects of cigarette smoking [71]. Leigh et al. reported that the aerosol emitted from IQOS damaged human bronchial epithelial cells; however, IQOS cytotoxicity was lower compared to that of a combustible cigarette, but it exhibited higher toxicity than an e-cigarette, which was consistent with tobacco industry data [72].
Potential impact of heated tobacco on human healthBased on studies sponsored by the tobacco industry (Table 3), among healthy Japanese adult smokers, the results have shown that HTPs effectively deliver nicotine and achieve similar pharmacokinetic profiles to combus-tible cigarettes [12,36,73]. Brossard et al. showed that the nicotine pharmacokinetic profile of IQOS was close to that of conventional cigarettes with similar urge-to-smoke levels [36]. The use of IQOS or glo reduced the exposure to smoke toxicants in a manner comparable to quitting tobacco use [74,75]. After switching from conventional cigarettes to HTPs (IQOS or glo), a sig-nificant reduction in the levels of biomarkers of expo-sure to harmful and potentially harmful constituents was observed [76–78].
The total particulate matter from IQOS had a lower ef-fect on oxidative phosphorylation, gene expression, and proteins involved in oxidative stress, compared to the total particulate matter from the reference cigarette [61]. Long-term exposure to the total particulate matter from IQOS had a lower biological impact on the human bronchial epi-thelial cells line compared to the total particulate matter from cigarette smoke [62].The aerosol from glo also demonstrated significantly re-duced in vitro toxicological activity compared to conven-tional cigarettes [16,17]. There was no pro-inflammatory effect observed after the use of glo [16]. The glo aerosol was not mutagenic in the Ames mutagenicity assay or in the mouse lymphoma [17]. Similarly, no measurable geno-toxicity or cytotoxicity features were observed after Ploom TECH use [63], and the biological effects of the Ploom TECH aerosol were also lower than those of conventional cigarette smoke [18].Most in vivo studies were performed on apolipoprotein E-deficient (Apoe–/–) mouse models exposed to cigarette smoke or the IQOS aerosol for 8 months (Table 2). In con-trast to traditional cigarette smoke, IQOS aerosols did not affect the downregulation of genes involved in the cyto-skeleton organization, contractile function of the heart, or genes related to the inflammatory responses [64]. The IQOS aerosol had reduced biological effects on the livers of the Apoe–/– mice [65]. However, Wong et al. observed a significant increase in alanine aminotransferase (ALT), liver weights, and hepatocellular vacuolization in female rats exposed to IQOS. These effects were lower or absent in the case of cigarette-exposed rats [42]. Exposure to the IQOS aerosol did not induce lung inflammation or em-physema, nor did it consistently change the lipid profile or enhance the aortic plaque formation [66,67]. There was no relevant IQOS aerosol exposure effect on lung lipid me-tabolism either [68].All the studies presented above were performed or spon-sored by the tobacco industry. Moreover, most of them
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 615
Tabl
e 3. H
uman
-bas
ed st
udies
– a s
yste
mat
ic re
view,
2015
–201
8
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
yIn
depe
nden
t stu
dies
Adria
ens e
t al.,
Belgi
um (2
018)
[79]
to in
vesti
gate
the e
ffect
of u
sing a
n IQ
OS
on th
e ex
haled
CO
, acu
te ci
gare
tte
crav
ing,
with
draw
al sy
mpt
oms,
and
subj
ectiv
e po
sitive
and
nega
tive
expe
rienc
es af
ter o
vern
ight
smok
ing a
bstin
ence
, co
mpa
red
to u
sing a
n e-
cigar
ette
or a
regu
lar
cigar
ette
30 p
artic
ipan
ts (a
ged
22±
3.09 y
ears;
67
% m
ale),
3 con
secu
tive m
easu
rem
ent d
ays
afte
r bein
g ove
rnigh
t sm
okin
g abs
tinen
t; 3 d
iffer
ent p
rodu
cts: a
conv
entio
nal
cigar
ette
, an
e-cig
aret
te, I
QO
S; d
urin
g ea
ch se
ssion
1 pr
oduc
t was
use
d fo
r 5 m
in; t
he ex
haled
CO
mea
sure
men
ts an
d de
dica
ted
ques
tionn
aires
wer
e ad
min
ister
ed th
roug
hout
each
sessi
on
–cig
aret
te sm
okin
g for
5 m
in re
sulte
d in
a sig
nific
ant i
ncre
ase
in th
e exh
aled
CO, w
here
as u
sing I
QO
S re
sulte
d in
a sm
all
but r
eliab
le in
crea
se (0
.3 pp
m)
–cig
aret
te cr
avin
g was
redu
ced
signi
fican
tly af
ter t
he p
rodu
ct us
e, wi
th th
e dec
line b
eing s
trong
er fo
r tob
acco
smok
ing t
han
for e
-ciga
rette
s or I
QO
S –
a sho
rt-te
rm u
se o
f IQ
OS
can
be ef
fecti
ve to
mom
enta
rily
redu
ce th
e acu
te ci
gare
tte cr
avin
g and
with
draw
al sy
mpt
oms
–IQ
OS
is m
ore p
opul
ar w
ith n
ovice
use
rs th
an an
e-cig
aret
te
Tabu
chi e
t al.,
Japa
n (2
017)
[5]
to as
sess
the s
ympt
oms
indu
ced
by se
cond
hand
ex
posu
re to
the H
TP
(IQO
S, P
loom
or g
lo)
toba
cco
aero
sol i
n Ja
pan
a fol
low-
up 3-
year
long
itudi
nal I
nter
net
surv
ey o
f 824
0 sub
jects
(age
d 15
–69 y
ears
in 20
15; 4
9.6%
male
) to
evalu
ate t
he
prev
alenc
e of H
TP u
se an
d sy
mpt
oms
indu
ced
by se
cond
hand
expo
sure
to th
e HTP
to
bacc
o ae
roso
l
–99
7 (12
%) o
f sub
jects
repo
rted
seco
ndha
nd ex
posu
re
to H
TP sm
oke
–am
ong a
ll pe
ople
expo
sed
to se
cond
hand
smok
e, 37
% ex
peri-
ence
d at
leas
t 1 h
ealth
sym
ptom
of e
xpos
ure t
o pa
ssive
H
TP sm
okin
g, m
ost o
f the
m re
porte
d fe
eling
ill (
25%
), ey
e pa
in (2
2.3%
), an
d so
re th
roat
(20.6
%)
Step
hens
, Uni
ted
King
dom
(201
7) [8
0]to
com
pare
canc
er
pote
ncies
of v
ario
us
nico
tine d
elive
ring a
eros
ols
the c
ance
r pot
encie
s of v
ario
us n
icotin
e de
liver
ing p
rodu
cts (c
igare
ttes,
e-cig
aret
tes,
a nico
tine i
nhale
r, th
e HTP
pro
totyp
e)
aero
sols
were
mod
eled
usin
g pub
lishe
d ch
emica
l ana
lyses
of e
miss
ions
and
their
as
socia
ted
inha
latio
n un
it ris
ks; t
he sm
oke
and
vapo
r wer
e exp
resse
d in
com
mon
uni
ts;
the l
ifetim
e can
cer r
isks w
ere c
alcul
ated
from
th
ese p
oten
cies u
sing d
aily c
onsu
mpt
ion
estim
ates
–he
ated
toba
cco
devic
es h
ad lo
wer c
ance
r pot
encie
s tha
n tra
-di
tiona
l tob
acco
smok
e by a
t lea
st 1 o
rder
of m
agni
tude
, but
hi
gher
pot
encie
s tha
n m
ost e
-ciga
rette
s –
the m
ean
lifet
ime c
ance
r risk
s dec
lined
in th
e seq
uenc
e: co
m-
busti
ble c
igare
ttes >
hea
ted
toba
cco
prod
ucts
> e-
cigar
ette
s ≥
nico
tine i
nhale
r
Kam
ada e
t al.,
Japa
n (2
016)
[81]
to re
port
the fi
rst ca
se
of ac
ute e
osin
ophi
lic
pneu
mon
ia ca
used
by
smok
ing I
QO
S
a cas
e rep
ort;
a 20-
year
-old
man
who
had
sm
oked
20 IQ
OS
stick
s dail
y for
6 m
onth
s, an
d do
ubled
stick
cons
umpt
ion
2 wee
ks
befo
re th
e hos
pita
lizat
ion
–he
ated
toba
cco
cigar
ette
use
caus
ed ac
ute e
osin
ophi
lic p
neu-
mon
ia in
an ad
ult m
ale sm
oker
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)616
Aoka
ge et
al., J
apan
(2
018)
[82]
to re
port
the c
ase s
tudy
of
fulm
inan
t acu
te
eosin
ophi
lic p
neum
onia
caus
ed b
y HTP
s
a cas
e rep
ort;
a 16-
year
-old
man
with
a h
istor
y of c
rusta
cea a
llerg
y and
bro
nchi
al as
thm
a in
child
hood
, who
had
star
ted
HTP
us
e 2 w
eeks
bef
ore t
he h
ospi
taliz
atio
n an
d su
bseq
uent
ly su
ffere
d fro
m sh
ortn
ess o
f br
eath
that
grad
ually
wor
sene
d
–H
TP u
se in
duce
d fu
lmin
ant a
cute
eosin
ophi
lic p
neum
onia
–th
e pat
ient w
as su
cces
sfully
trea
ted
with
veno
veno
us ex
traco
r-po
real
mem
bran
e oxy
gena
tion
for s
ever
e res
pira
tory
failu
re
Stud
ies w
ith
a pot
entia
l con
flict
of
inte
rest
Yuki
et al
., Jap
an
(201
7) [1
2]Ja
pan
Toba
cco
to in
vesti
gate
the
phar
mac
okin
etics
of
nico
tine f
ollo
wing
the
use o
f a p
roto
type n
ovel
toba
cco
vapo
r pro
duct
(the
Ploo
m T
ECH
pro
totyp
e)
in co
mpa
rison
to a
conv
entio
nal c
igare
tte
24 su
bjec
ts (a
ged
21–6
3 yea
rs; 10
0% m
ale),
the P
loom
TEC
H p
roto
type,
a con
vent
iona
l cig
aret
te; h
ealth
y Jap
anes
e adu
lt m
ale
smok
ers;
the p
lasm
a nico
tine c
once
ntra
tions
in
blo
od sa
mpl
es an
d th
e nico
tine i
ntak
e we
re es
timat
ed b
ased
on
the m
outh
leve
l ex
posu
re
–th
e pha
rmac
okin
etics
of n
icotin
e, fo
llowi
ng th
e Plo
om T
ECH
pr
otot
ype u
se, w
ere n
ot m
arke
dly d
iffer
ent f
rom
thos
e fol
low-
ing t
he co
nven
tiona
l ciga
rette
use
, whi
le th
e Plo
om T
ECH
pr
otot
ype p
rovid
ed le
ss ni
cotin
e fol
lowi
ng a
cont
rolle
d sin
gle
use
–th
e esti
mat
ed n
icotin
e mou
th le
vel e
xpos
ure,
follo
wing
the
Ploo
m T
ECH
pro
totyp
e use
, was
appr
oxim
ately
two-
third
s of
that
obt
ained
follo
wing
the c
onve
ntio
nal c
igare
tte sm
okin
gBr
ossa
rd et
al.,
Switz
erlan
d (2
017)
[3
6]PM
I
to in
vesti
gate
the s
ingle
-use
ni
cotin
e pha
rmac
okin
etic
profi
le of
TH
S2.2,
co
mbu
stibl
e ciga
rette
s an
d ni
cotin
e rep
lacem
ent
ther
apy (
a gum
)
62 h
ealth
y adu
lt Ja
pane
se sm
oker
s (ag
ed
23–6
5 yea
rs; 52
.5–55
% m
ale);
THS2
.2 (th
e re
gular
and
men
thol
varia
nt),
a com
mer
cially
av
ailab
le br
and
of ci
gare
ttes,
and
nico
tine
repl
acem
ent t
hera
py (g
um);
the p
lasm
a ni
cotin
e con
cent
ratio
ns w
ere m
easu
red
in
16 b
lood
sam
ples
colle
cted
over
24 h
afte
r a s
ingle
use
–TH
S2.2
deliv
ered
nico
tine a
s effe
ctive
ly as
com
busti
ble c
iga-
rette
s and
faste
r tha
n th
e nico
tine g
um –
the u
rge-
to-sm
oke t
otal
scor
es w
ere c
ompa
rabl
e bet
ween
TH
S2.2
and
com
busti
ble c
igare
ttes
–TH
S2.2
can
satis
fy sm
oker
s and
be a
n alt
erna
tive t
o co
m-
busti
ble c
igare
ttes f
or ad
ult s
mok
ers w
ho d
o no
t wan
t to
quit
smok
ing
Pica
vet e
t al.,
Switz
erlan
d (2
016)
[7
3]PM
I
to co
mpa
re th
e ph
arm
acok
inet
ics o
f ni
cotin
e TH
S2.1
and
com
busti
ble c
igare
ttes
28 h
ealth
y sm
oker
s (ag
ed 23
–65 y
ears
); TH
S2.1
(the p
roto
type
of I
QO
S)
and
a com
mer
cially
avai
labl
e bra
nd
of ci
gare
ttes;
the a
sses
smen
t of t
he
phar
mac
okin
etics
of n
icotin
e afte
r a s
ingl
e and
ad
libitu
m u
se o
f TH
S2.1
or
the r
efer
ence
ciga
rette
; a 7-
day
confi
nem
ent p
erio
d; b
lood
sam
ples
wer
e dr
awn
for p
harm
acok
inet
ic an
alys
is
–th
e nico
tine d
elive
ry ra
te w
as si
mila
r for
TH
S2.1
and
the
com
busti
ble c
igare
tte af
ter a
sing
le an
d ad
libitu
m u
se –
THS2
.1 ef
fecti
vely
deliv
ers n
icotin
e and
achi
eves
sim
ilar
phar
mac
okin
etic
profi
les to
com
busti
ble c
igare
ttes
–TH
S2.1
redu
ces t
he u
rge t
o sm
oke i
n a m
anne
r sim
ilar t
o co
mbu
stibl
e ciga
rette
s
Tabl
e 3. H
uman
-bas
ed st
udies
– a s
yste
mat
ic re
view,
2015
–201
8 – co
nt.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 617
Lüdi
cke e
t al.,
Switz
erlan
d (2
018)
[7
4,75]
PMI
to ex
amin
e the
impa
ct of
switc
hing
to m
enth
ol
THS2
.2 on
the b
iom
arke
rs of
expo
sure
to H
arm
ful
and
Pote
ntial
ly H
arm
ful
Cons
titue
nts (
HPH
Cs),
and
the c
linica
lly re
levan
t ris
k mar
kers
of sm
okin
g-re
lated
dise
ases
, rela
tive
to m
enth
ol co
mbu
stive
cig
aret
tes a
nd sm
okin
g ab
stine
nce
160 J
apan
ese a
dult
smok
ers (
aged
23
–65 y
ears;
57.5%
male
): 78
use
d m
enth
ol
THS2
.2, 42
smok
ed m
enth
ol ci
gare
ttes,
40
wer
e clas
sified
to th
e sm
okin
g abs
tinen
ce
grou
p; 5
days
of u
se in
confi
nem
ent
and
85 d
ays i
n am
bulat
ory s
ettin
gs, f
ollo
w up
on
day
90
–sw
itchi
ng fr
om m
enth
ol co
mbu
stibl
e ciga
rette
s to
men
thol
TH
S2.2
signi
fican
tly re
duce
d H
PHC
expo
sure
, with
con-
cent
ratio
ns si
mila
r to
thos
e obs
erve
d fo
llowi
ng sm
okin
g ab
stine
nce
–sw
itchi
ng fr
om m
enth
ol co
mbu
stibl
e ciga
rette
s to
men
thol
TH
S2.2
resu
lted
in re
duce
d bi
omar
kers
of ex
posu
re to
ciga
-re
tte sm
oke,
and
chan
ges w
ere o
bser
ved
in cl
inica
lly re
levan
t bi
omar
kers
of o
xidat
ive st
ress
(8-e
pi-p
rosta
gland
in F
2α),
plat
elet a
ctivit
y (11
-deh
ydro
-thro
mbo
xane
B2)
, end
othe
lial
func
tion
(solu
ble i
ntra
cellu
lar ad
hesio
n m
olec
ule-
1), li
pid
met
abol
ism (h
igh-d
ensit
y lip
opro
tein
chol
este
rol)
and
lung
fu
nctio
n (fo
rced
expi
rato
ry vo
lum
e in
1 s),
simila
r to
the
smok
ing a
bstin
ence
grou
p –
the a
utho
rs su
gges
t tha
t swi
tchin
g to
THS2
.2 ha
s the
pot
en-
tial t
o re
duce
the a
dver
se h
ealth
effe
cts o
f sm
okin
g-re
lated
di
seas
esLü
dick
e et a
l., Sw
itzer
land
(201
7)
[76]
PMI
to as
sess
the p
atte
rns o
f TH
S2.1
use,
as w
ell as
to
evalu
ate t
he b
iom
arke
rs of
ex
posu
re to
toba
cco
smok
e to
xican
ts am
ong a
dult
smok
ers
40 sm
oker
s (ag
ed 24
–56 y
ears;
45%
male
) us
ing t
he p
roto
type o
f IQ
OS
– TH
S2.1
(N
= 20
) or t
heir
own
bran
d of
com
mer
cially
av
ailab
le cig
aret
tes (
N =
20) f
or 5
days
; the
bi
omar
kers
of ex
posu
re w
ere m
easu
red
at
base
line a
nd o
n da
y 1 th
roug
h da
y 5; p
uffin
g to
pogr
aphy
was
obs
erve
d
–th
e bio
mar
kers
of ex
posu
re to
toba
cco
smok
e tox
icant
s wer
e sig
nific
antly
redu
ced
with
TH
S2.1
use c
ompa
red
to ci
gare
tte
smok
ing
–TH
S2.1
was p
erce
ived
as le
ss re
ward
ing i
n te
rms o
f sen
sory
an
d ph
ysica
l effe
cts th
an co
nven
tiona
l ciga
rette
s –
THS2
.1 us
ers a
dapt
ed th
eir p
uffin
g beh
avio
r ini
tially
thro
ugh
long
er p
uff d
urat
ion
and
mor
e puf
fs; h
owev
er, o
n da
y 5 th
e to
tal p
uff v
olum
e ret
urne
d to
bas
eline
leve
ls –
the u
se o
f TH
S to
bacc
o sti
cks i
ncre
ased
by 2
7% o
ver t
he
study
per
iod
Haz
iza et
al.,
Switz
erlan
d (2
016)
[7
7]PM
I
to d
emon
strat
e red
uced
ex
posu
re to
har
mfu
l an
d po
tent
ially
harm
ful
cons
titue
nts a
mon
g the
su
bjec
ts wh
o sw
itche
d fro
m
cigar
ette
s to
THS2
.2, as
co
mpa
red
to co
ntin
ued
cigar
ette
smok
ing a
nd
smok
ing a
bstin
ence
fo
r 5 d
ays
160 h
ealth
y adu
lt Ja
pane
se sm
oker
s (ag
ed
23–6
5 yea
rs; 50
% m
ale):
THS2
.2 us
ers
(N =
80);
cigar
ette
smok
ers (
N =
40),
absta
in
from
smok
ing (
N =
40);
5-da
y exp
osur
e; ea
ch d
ay 24
-h u
rine w
as co
llecte
d
–th
e lev
els o
f bio
mar
kers
of ex
posu
re to
har
mfu
l and
pot
en-
tially
har
mfu
l con
stitu
ents
were
sign
ifica
ntly
redu
ced
in th
e pa
rticip
ants
switc
hing
to T
HS2
.2 co
mpa
red
to co
nven
tiona
l cig
aret
te sm
oker
s –
THS2
.2 re
duce
d th
e urg
e to
smok
e in
a man
ner s
imila
r to
com
busti
ble c
igare
ttes
–TH
S2.2
was s
light
ly les
s sat
isfac
tory
than
conv
entio
nal
cigar
ette
s
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)618
Independent studies performed with the aim of assessing the health impact of HTP use are very limited (Table 3). Adri-aens et al. showed that 5 min of IQOS use resulted in a small but reliable increase (0.3 ppm) in the exhaled CO level [79]. Stephens et al. compared cancer potencies of various nico-tine delivering aerosols [80]. Performed estimations revealed that HTPs had lower cancer potencies than traditional ciga-rettes, but higher potencies than most e-cigarettes [80].Tabuchi et al. showed that among 8240 subjects who par-ticipated in a 3-year longitudinal survey, 12% (N = 997) reported secondhand exposure to heated tobacco aero-sols [6]. Among all people exposed to secondhand smoke, 37% had experienced at least 1 health symptom. The most common reported symptoms after secondhand exposure to IQOS smoke were: feeling ill (25%), eye pain (22.3%) and sore throat (20.6%) [6]. The highest prevalence of symp-toms caused by secondhand exposure to HTP smoke was observed among never-users of any tobacco products [6].Researchers from Japan reported 2 cases of acute eosino-philic pneumonia following HTP use [81,82]. The first case of acute eosinophilic pneumonia was diagnosed in a 20-year-old man who had smoked 20 IQOS sticks daily for 6 months and doubled stick consumption 2 weeks before the hospital-ization [81]. The second case of fulminant acute eosinophilic pneumonia was diagnosed in 16-year-old man with bronchial asthma in childhood, who had used HTPs for 2 weeks [82]. There were no available human-based studies assessing the potential impact of HTP use on lung physiology.Moazed et al. reviewed the PMI modified risk tobacco product (MRTP) application to the U.S. Food and Drug Administration in 2016 [83]. An assessment of industry data revealed that IQOS use was associated with signifi-cant pulmonary and immunomodulatory toxicities, with no detectable differences between cigarette smokers and those who were switched to IQOS [83]. Furthermore, the analysis of the same PMI MTRP application by Glantz [84] suggested that, in human testing, IQOS did not reveal de-tectably better measures of the biomarkers of potential
Gale
et al
., Uni
ted
King
dom
/Swi
tzerla
nd
(201
8) [7
8]BA
T
to ev
aluat
e cha
nges
in th
e bi
omar
kers
of to
xican
t ex
posu
re o
n sw
itchi
ng fr
om
conv
entio
nal c
igare
ttes t
o H
TPs
180 J
apan
ese a
dult
smok
ers (
aged
33±
9.0
year
s; 50
% m
ale);
THP1
.0 (g
lo), T
HS2
.2 (IQ
OS)
, a co
mbu
stible
ciga
rette
; the
smok
ers
smok
ed co
mbu
stible
ciga
rette
s for
2 da
ys; a
fter
this
perio
d, th
ey w
ere s
witch
ed to
the f
ollow
ing
grou
ps: 1
) con
tinue
smok
ing,
2) sw
itch t
o the
m
enth
olated
or no
n-m
enth
olated
varia
nt of
glo
, 3) s
witch
to no
n-m
enth
olated
IQO
S, or
4)
quit
nico
tine a
nd to
bacc
o pro
duct
use;
each
gr
oup u
sed t
heir
dedi
cated
prod
ucts
for 5
days
; th
e bas
eline
and p
ost-r
ando
miza
tion 2
4-h u
rine
sam
ples w
ere c
ollec
ted, c
arbo
n mon
oxid
e in
exha
led br
eath
was
mea
sure
d dail
y
–glo
or I
QO
S us
e for
5 da
ys re
duce
d th
e exp
osur
e to
smok
e to
xican
ts in
a m
anne
r com
para
ble t
o qu
ittin
g tob
acco
use
–on
day
5 af
ter s
witch
ing,
the u
rinar
y bio
mar
kers
of to
xican
ts (e
xcep
t the
nico
tine)
and
exha
led C
O le
vels
were
sign
ifica
ntly
redu
ced
by m
edian
s 21–
92%
, com
pare
d wi
th th
e bas
eline
in
all gr
oups
usin
g glo
or I
QO
S, o
r qui
tting
toba
cco
use
BAT
– Brit
ish A
mer
ican T
obac
co; C
O –
carb
on m
onox
ide;
ppm
– pa
rts pe
r milli
on; H
PHCs
– ha
rmfu
l and
pote
ntial
ly ha
rmfu
l con
stitu
ents;
HTP
s – he
ated
toba
cco p
rodu
cts; P
MI –
Phi
lip M
orris
In
tern
atio
nal; T
HP1
.0 – t
obac
co he
atin
g pro
duct
(glo
); TH
S2.1
– tob
acco
heat
ing s
yste
m 2.
1 (th
e pro
totyp
e of I
QO
S); T
HS2
.2 – t
obac
co he
atin
g sys
tem
2.2 (
IQO
S); 3
R4F
– ref
eren
ce ci
gare
tte.
Tabl
e 3. H
uman
-bas
ed st
udies
– a s
yste
mat
ic re
view,
2015
–201
8 – co
nt.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 619
IQOS users were triple users of conventional cigarettes and e-cigarettes, as well as HTPs [86]. HTPs have also gained popularity in the USA [87,88]. From 2016 to 2017, the awareness of HTPs among U.S. adults increased from 9.3% to 12.4%, ever use increased from 1.4% to 2.2%, and the current use doubled, from 0.5% to 1.1%, among U.S. adults [87]. In the USA, the highest awareness of HTPs was observed among current smokers as well as younger adults, under the age of 30 [88].Tabuchi et al. pointed to the power of mass media and TV broadcasting as a tool to promote the use of IQOS [6]. The highest prevalence of ever IQOS use was observed among people who had seen a TV program where Japa-nese comedians discussed their IQOS use, compared to those who had not seen it. The willingness to use IQOS was significantly higher among current tobacco smokers with the intention to quit than among those with no inten-tion to quit [6]. Experience with electronic cigarette use indicates that most smokers who reach for an e-cigarette to quit traditional cigarettes are dual users who ultimately use both forms of cigarettes [89]. A risk of dual use ex-ists also in the case of heated tobacco products. Miyaza-ki et al. indicated a higher tendency (but not statistically significant) to ever use heated tobacco products among former smokers with lower education levels [89].The study from Italy by Liu et al. also revealed that the highest prevalence of ever HTP users was among current e-cigarette users and current cigarette smokers [2,3]. Only 1% of those who had never smoked cigarettes and 1.2% of those who were never e-cigarette users had tried IQOS [2]. These findings were supported by a study from Great Brit-ain, conducted by Brose et al [85]. Current e-cigarette users were more likely to use HTPs (6.2%) compared to subjects who had never used e-cigarettes (0.3%, p < 0.05). Ever e-cigarette users were also more likely to be aware of HTPs [85]. In Korea and the USA, the highest aware-ness and ever or current use of HTPs were also observed among current smokers or e-cigarette users [86,87].
harm than traditional cigarettes. Glantz pointed out that there were no statistically significant differences in the biomarkers of potential harm between IQOS and conven-tional cigarette users among American adults (for 23 of the 24 biomarkers) and Japanese adults (for 10 of the 13 biomarkers) [84].Although tobacco industry sponsored studies have mostly shown health benefits of switching from conventional ciga-rette use to HTP use, independent studies indicate some potentially harmful consequences of exposure to HTP aerosols. Currently there is no evidence regarding the long-term health effects of HTP use. The potential role of HTPs as a tool in smoking cessation is also unknown.
The frequency of using heated tobacco productsHeated tobacco products have been widely available for only a few years. The data on the frequency of use of these products are mainly from Japan and Italy, the test markets where these products were first introduced (Table 4). Tabuchi et al. reported that the number of current IQOS users in Japan was consistently increas-ing, from 0.3% in 2015 to 0.6% in 2016, and up to 3.6% in 2017 [5,6]. The prevalence of Ploom TECH use in 2015–2017 increased 4-fold (from 0.3% to 1.2%) [5,6]. Among 8240 surveyed subjects, 0.8% declared the current use of glo [5,6]. Face-to-face interviews with 3086 Italians aged ≥ 15 years showed that 19.5% of respondents were aware of heated tobacco products [2,3]. Ever use of HTPs was reported by 1.4% of subjects and 2.3% of subjects in-tended to try HTPs in the near future.Brose et al. estimated the awareness and prevalence of HTP use in Great Britain [85]. Among 12 696 adult par-ticipants, 9.3% were aware of heated tobacco products. Ever use of HTPs was declared by 1.7% of respondents and 0.8% were current users [85]. Kim et al. reported that among 228 young Korean adults, more than one-third (38.1%) were aware of IQOS [86]. The current IQOS use was declared by 3.5% of respondents, wherein all current
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)620
Tabl
e 4. T
he fr
eque
ncy o
f usin
g hea
ted
toba
cco
prod
ucts
– a sy
stem
atic
revie
w, 20
15–2
018
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
yIn
depe
nden
t stu
dies
Tabu
chi e
t al.,
Japa
n (2
016)
[5]
to es
timat
e the
awar
enes
s an
d us
e of e
-ciga
rette
s an
d H
TPs i
n th
e Jap
anes
e po
pulat
ion
an In
tern
et su
rvey
, inclu
ding
8240
re
spon
dent
s (ag
ed 15
–69 y
ears)
in th
e fin
al an
alysis
, the
stud
y per
form
ed
in 20
15
–as
man
y as 6
.6% o
f res
pond
ents
ever
use
d e-
cigar
ette
s or H
TPs
–am
ong t
he 55
4 sub
jects
who
ever
use
d e-
cigar
ette
s or h
eat-n
ot-
burn
(HNB
) tob
acco
, 7.8%
ever
tried
Plo
om T
ECH
, an
d 8.4
% ev
er u
sed
IQO
STa
buch
i et a
l., Ja
pan/
Italy/
USA
(201
7) [6
]to
asse
ss th
e pre
valen
ce,
pred
ictor
s of u
se an
d sy
mpt
oms o
f sec
ondh
and
expo
sure
to H
TP (I
QO
S,
Ploo
m T
ECH
or g
lo)
toba
cco
aero
sols
in Ja
pan
2 dat
a sou
rces
:G
oogle
sear
ch q
uery
dat
a to
asse
ss th
e pop
ulat
ion’
s int
eres
t in
HTP
sa f
ollo
w-up
3-ye
ar lo
ngitu
dina
l Int
erne
t su
rvey
of 8
240 s
ubjec
ts (a
ged
15–
69 ye
ars i
n 20
15) t
o ev
aluat
e the
pr
evale
nce o
f the
curre
nt H
NB to
bacc
o us
e
–th
e num
ber o
f cur
rent
IQO
S us
ers w
as co
nsta
ntly
incr
easin
g,
from
0.3%
in Ja
nuar
y–Fe
brua
ry 20
15 to
0.6%
in 20
16,
and
up to
3.6%
in 20
17 –
the h
ighes
t pre
valen
ce o
f eve
r IQ
OS
use w
as am
ong p
eopl
e who
ha
d se
en a
telev
ision
pro
gram
(10.3
%) p
rom
otin
g IQ
OS,
com
-pa
red
to th
e peo
ple w
ho h
ad n
ot se
en it
(2.7%
) –
the p
reva
lence
of P
loom
TEC
H fo
r 2 ye
ars i
ncre
ased
4 tim
es
(from
0.3%
in 20
15 to
1.2%
in 20
17)
–in
2017
0.8%
of s
ubjec
ts we
re cu
rrent
glo
user
s –
the w
illin
gnes
s to
use I
QO
S wa
s sign
ifica
ntly
high
er am
ong c
ur-
rent
smok
ers w
ith an
inte
ntio
n to
qui
t tha
n am
ong t
hose
with
no
inte
ntio
n to
qui
t (AO
R: 13
.3 vs
. 6.7,
resp
ectiv
ely)
Liu
et al
., Ita
ly (2
018)
[2,3]
to in
vesti
gate
the a
ware
ness
and
use o
f HTP
s in
Italy
a fac
e-to
-face
surv
ey o
f 308
6 sub
jects,
fro
m a
repr
esen
tativ
e pop
ulat
ion
aged
≥
15 ye
ars
–as
man
y as 1
9.5%
of r
espo
nden
ts we
re aw
are o
f HTP
s –
as m
any a
s 1.4%
of r
espo
nden
ts ha
d ev
er u
sed
HTP
s,
and
2.3%
inte
nded
to tr
y HTP
s –
the h
ighes
t pre
valen
ce o
f eve
r HTP
use
rs wa
s am
ong c
urre
nt
e-cig
aret
te sm
oker
s (7.7
%),
and
curre
nt ci
gare
tte sm
oker
s (3.1
%);
only
1% o
f the
resp
onde
nts w
ho h
ad n
ever
smok
ed ci
gare
ttes
and
1.2%
of n
ever
e-cig
aret
te u
sers
had
tried
IQO
S Br
ose e
t al.,
Uni
ted
King
dom
(201
8) [8
5]to
estim
ate t
he aw
aren
ess
and
use o
f HTP
s in
Gre
at
Brita
in
a cro
ss-se
ction
al on
line s
urve
y, Fe
brua
ry–M
arch
2017
, invo
lving
12
696 a
dults
–as
man
y as 9
.3% o
f res
pond
ents
were
awar
e of H
TPs
–as
man
y as 1
.7% o
f res
pond
ents
had
ever
use
d H
TPs,
of
who
m 0.
8% w
ere c
urre
nt u
sers
–ne
ver e
-ciga
rette
use
rs we
re m
ore l
ikely
to b
e una
ware
of H
TPs
–cu
rrent
e-cig
aret
te u
sers
were
mor
e lik
ely to
use
HTP
s (6.2
4%)
com
pare
d to
the s
ubjec
ts wh
o ha
d ne
ver u
sed
e-cig
aret
tes (
0.33%
, p
< 0.
05)
–am
ong t
he 17
3 sub
jects
who
had
ever
tried
HTP
s, 38
.7% h
ad tr
ied
them
up
to 2
times
, 17.3
% u
sed
them
wee
kly,
and
12.7%
wer
e da
ily H
TP u
sers
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 621
Kim
et al
., Rep
ublic
of
Kor
ea (2
018)
[86]
to in
vesti
gate
the
awar
enes
s, ex
perie
nce
and
curre
nt u
se o
f IQ
OS
amon
g you
ng K
orea
n ad
ults
228 y
oung
adul
ts, ag
ed 19
–24 y
ears,
an
onlin
e sur
vey p
erfo
rmed
3 m
onth
s afte
r th
e int
rodu
ction
of I
QO
S to
the K
orea
n m
arke
t
–as
man
y as 3
8.1%
of r
espo
nden
ts we
re aw
are o
f IQ
OS,
whe
rein
th
e IQ
OS
awar
enes
s was
sign
ifica
ntly
high
er fo
r con
vent
iona
l cig
aret
te sm
oker
s (57
.5%) c
ompa
red
to n
on-ci
gare
tte sm
oker
s (4
2.5%
) –
as m
any a
s 5.7%
of r
espo
nden
ts ha
d tri
ed IQ
OS
–th
e cur
rent
use
of I
QO
S wa
s dec
lared
by 3
.5% o
f res
pond
ents,
wh
erein
all c
urre
nt IQ
OS
user
s wer
e trip
le us
ers o
f con
vent
iona
l cig
aret
tes a
nd e-
cigar
ette
s –
curre
nt ci
gare
tte sm
oker
s wer
e muc
h m
ore l
ikely
to b
e awa
re
of IQ
OS
(OR
= 4.
49) a
nd to
ever
be I
QO
S us
ers (
OR
= 11
.64)
than
non
-smok
ers
Nym
an et
al., U
SA
(201
8) [8
7]to
inve
stiga
te th
e aw
aren
ess a
nd u
se o
f HTP
s in
the U
SA
a nat
iona
l pro
babi
lity s
ampl
e of U
.S.
adul
ts, o
nlin
e Pro
ducts
and
Risk
Pe
rcep
tions
Sur
veys
, dat
a fro
m 20
16
(N =
6014
) and
2017
(N =
5992
)
–in
2016
–201
7 the
awar
enes
s of H
TPs a
mon
g U.S
. adu
lts in
crea
sed
from
9.3%
to 12
.4% (p
< 0.
001)
, eve
r use
incr
ease
d fro
m 1.
4%
to 2.
2% (p
= 0.
005)
and
curre
nt u
se in
crea
sed
2-fo
ld, f
rom
0.5%
to
1.1%
(p =
0.00
4) –
the h
ighes
t awa
rene
ss of
HTP
s was
amon
g men
and
youn
ger
adul
ts –
form
er an
d cu
rrent
e-cig
aret
te u
sers
were
mor
e lik
ely to
be a
ware
of
, to
have
ever
use
d or
to b
e cur
rent
use
rs of
HTP
s tha
n th
ose
who
had
neve
r use
d e-
cigar
ette
sM
aryn
ak et
al., U
SA
(201
8) [8
8]to
asse
ss th
e awa
rene
ss an
d ev
er u
se o
f hea
ted
toba
cco
prod
ucts
amon
g U.S
. adu
lts
an In
tern
et su
rvey
cond
ucte
d in
June
–Jul
y 201
7 am
ong U
.S. a
dults
ag
ed ≥
18 ye
ars (
N =
4107
)
–as
man
y as 5
.2% o
f U.S
. adu
lts w
ere a
ware
of H
TPs,
inclu
ding
9.9
% o
f cur
rent
ciga
rette
smok
ers
–as
man
y as 0
.7% o
f U.S
. adu
lts, in
cludi
ng 2.
7% o
f cur
rent
smok
-er
s, ha
d ev
er u
sed
HTP
s –
curre
nt sm
oker
s wer
e mor
e lik
ely to
be a
ware
of H
TPs (
aOR
=
6.18)
than
nev
er sm
oker
s, an
d yo
unge
r adu
lts (a
ged
< 30
year
s [a
OR
= 3.
35])
were
mor
e lik
ely to
be a
ware
of H
TPs t
han
thos
e ag
ed ≥
30 ye
ars
Miya
zaki
et al
., Jap
an
(201
8) [8
9]to
analy
ze th
e rela
tions
hip
betw
een
educ
atio
nal
atta
inm
ent a
nd e-
cigar
ette
an
d H
TP u
se
7338
resp
onde
nts (
rand
omly
sam
pled
, a n
atio
nal r
epre
sent
ative
sam
ple)
aged
18
–69 y
ears
in 20
15 (3
706 w
omen
);
–th
e asso
ciatio
n be
twee
n ed
ucat
iona
l atta
inm
ent a
nd ev
er u
se
of H
TPs w
as n
ot st
atist
ically
sign
ifica
nt –
form
er sm
oker
s with
a lo
wer e
duca
tiona
l lev
el in
dica
ted
the
tend
ency
to h
igher
ORs
(but
not
stat
istica
lly si
gnifi
cant
) for
bot
h e-
cigar
ette
and
HTP
s eve
r use
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)622
Given the consistent growth and development of the e-cigarette market, it is expected that the popularity of HTPs will also increase rapidly. The 10-fold increase in the frequency of IQOS use in Japan, observed within 3 years, indicates the rapidly growing magnitude of the problem [6]. Caputi et al., assessing the growth potential of heated tobacco products, compared trends in the popu-larity of HTPs with historical trends for e-cigarette use in Japan [1,90]. The monthly Google query trends monitor-ing revealed that the average monthly searches for HTPs rose by 1,426% between 2015 and 2016 [90]. Moreover, the change in the average monthly queries for HTPs in Japan in 2015–2017 was approx. 399 times larger than the change in the average monthly queries for e-cigarettes in the USA over the same time period [90].Due to the increase in the frequency of HTP use and the growing number of countries where these products are being introduced, the prevalence of heated tobacco use requires constant monitoring.
Marketing strategies of HTP promotionIn many countries, heated tobacco products are under dif-ferent laws and jurisdiction than conventional cigarettes, which has implications on the marketing strategies and promotion of these products (Table 5). In Japan, heated tobacco products are sold as tobacco products and regu-lated by the Tobacco Industries Act [5]. In South Korea, heated tobacco products are regulated as a variant of e-cigarettes [4]. In the EU, advertising for IQOS and oth-er heated tobacco devices (except for the tobacco stick) is not regulated under the European Union Tobacco Prod-ucts Directive (2014/40/EU) [3]. Elias et al. analyzed inter-nal PMI documents [91]. After a comparison of the prod-uct design, exposure data, and safety claims, the authors concluded that IQOS appeared to be a variant of Accord without consistent improvements in exposure to aerosol toxic compounds [91]. Elias et al. suggested that the in-dustry’s reduced risk claim was an effect of the marketing
Capu
ti et
al., J
apan
/U
SA (2
017)
[1,90
]to
des
crib
e tre
nds i
n th
e po
pular
ity o
f HTP
s in
their
Ja
pane
se te
st m
arke
t, an
d to
com
pare
thes
e tre
nds
with
hist
orica
l tre
nds f
or
e-cig
aret
tes t
o un
derst
and
the g
rowt
h po
tent
ial o
f thi
s ne
w pr
oduc
t glo
bally
mon
thly
Goo
gle q
uery
tren
ds
mon
itorin
g (fro
m 1.
01.20
10 th
roug
h 13
.09.20
17);
all q
uerie
s inc
ludi
ng H
NB
toba
cco
and/
or th
e mos
t pop
ular
bra
nds
in Ja
pan;
a co
mpa
rison
of t
he Ja
pane
se
HTP
s sea
rch
trend
s aga
inst
sear
ches
for
e-cig
aret
tes i
n th
e Uni
ted
Stat
es
–se
arch
es fo
r HNB
pro
ducts
hav
e inc
reas
ed su
bsta
ntial
ly –
aver
age m
onth
ly se
arch
es ro
se b
y 1,42
6% (9
5% C
I: 74
6±3,5
74)
betw
een
the fi
rst (2
015)
and
seco
nd (2
016)
com
plet
e yea
rs sin
ce
HTP
s wer
e mar
kete
d –
quer
ies fo
r HTP
s con
tinue
d to
grow
in 20
16–2
017 (
to S
epte
mbe
r):
an ad
ditio
nal 1
00%
(95%
CI:
60±
173)
–qu
eries
for H
NB p
rodu
cts in
Japa
n oc
cur m
ore f
requ
ently
than
qu
eries
for e
-ciga
rette
s in
the U
SA –
the c
hang
e in
aver
age m
onth
ly qu
eries
for H
TPs i
n Ja
pan
in 20
15–
2017
was
399 (
95%
CI:
184±
1,490
) tim
es la
rger
than
the c
hang
e in
the a
vera
ge m
onth
ly qu
eries
for e
-ciga
rette
s in
the U
SA o
ver
the s
ame t
ime p
erio
dSt
udies
with
a po
tent
ial
confl
ict o
f int
eres
tno
ne av
ailab
le
AOR
– adj
uste
d od
ds ra
tio; C
I – co
nfide
nce i
nter
val;
HTP
s – h
eate
d to
bacc
o pr
oduc
ts; O
R – o
dds r
atio
.
Tabl
e 4. T
he fr
eque
ncy o
f usin
g hea
ted
toba
cco
prod
ucts
– a sy
stem
atic
revie
w, 20
15–2
018 –
cont
.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 623
Tabl
e 5. H
TP m
arke
ting s
trate
gies a
nd p
rodu
ct pr
omot
ion
– a sy
stem
atic
revie
w, 20
15–2
018
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
yIn
depe
nden
t stu
dies
Kim
, USA
(201
7) [4
]to
des
crib
e PM
I’s
mar
ketin
g of I
QO
S
in S
outh
Kor
ea
news
mon
itorin
g, di
rect
obse
rvat
ion
– stu
dy vi
sits b
y the
auth
or to
the 2
flag
-sh
ip st
ores
in S
eoul
(Jun
e 201
7) an
d th
e pu
rcha
se o
f an
IQO
S de
vice f
rom
1 sto
re
–th
e man
ufac
ture
r enc
oura
ges c
usto
mer
s to
regis
ter o
n a d
edica
ted
webs
ite to
obt
ain a
limite
d-tim
e disc
ount
for t
heir
first
devic
e pu
rcha
se an
d to
exte
nd th
e war
rant
y fro
m 6
to 12
mon
ths
–a p
rofe
ssion
al pr
esen
tatio
n by
an “I
QO
S co
ach”
: all
store
custo
m-
ers t
ake p
art i
n a 1
5-m
in in
form
atio
n se
ssion
bef
ore b
uyin
g the
ir fis
t IQ
OS
devic
e –
desig
ns o
f the
stor
e, de
vice a
nd p
acka
ging,
and
the p
rodu
ct pu
r-ch
asin
g pro
cess
give a
n im
pres
sion
that
IQO
S is
a high
-dem
and,
up
scale
pro
duct
for t
ech-
savv
y use
rs –
due t
o th
e Kor
ean
IQO
S re
gulat
ion
(as a
varia
nt o
f e-ci
gare
ttes)
IQO
S sti
cks p
acks
hav
e onl
y lab
els w
arni
ngs a
bout
nico
tine a
ddic-
tion,
with
out s
howi
ng va
rious
neg
ative
cons
eque
nces
of s
mok
ing
–th
e tax
on
IQO
S sti
cks i
s onl
y half
of t
hat o
n re
gular
ciga
rette
s –
the p
rice o
f IQ
OS
stick
s is s
imila
r to
regu
lar ci
gare
ttes
Mat
hers
et al
., Can
ada
(201
8) [9
2]to
des
crib
e PM
I’s
mar
ketin
g of I
QO
S
in C
anad
a
data
on
IQO
S pr
omot
ion
in 49
reta
il ou
tlets,
inte
rview
s with
cler
ks an
d ob
serv
atio
ns o
utsid
e an
IQO
S sto
re
–th
e dom
inan
t mar
ketin
g cha
nnel
was v
isibl
e ava
ilabi
lity o
f IQ
OS
in a
large
num
ber o
f tob
acco
reta
il ou
tlets
(102
9 acr
oss O
ntar
io)
–IQ
OS
bout
ique
stor
es w
ere t
he lo
cus o
f agg
ressi
ve p
rom
otio
n,
inclu
ding
exch
angin
g a p
ack o
f stic
ks o
r a li
ghte
r for
an IQ
OS
devic
e, lau
nch
parti
es, “
mee
t and
gree
t” la
unch
es an
d af
ter-h
ours
even
ts –
the p
rom
inen
t IQ
OS
signs
and
a san
dwich
boa
rd si
gn re
adin
g “B
uild
ing a
Sm
oke-
Free
Fut
ure”
wer
e wid
ely av
ailab
le ou
tside
the
store
s –
sales
repr
esen
tativ
es re
gular
ly us
ing I
QO
S m
ade a
sign
ifica
nt
cont
ribut
ion
to th
e dire
ct pr
omot
ion
of th
at p
rodu
ct –
IQO
S us
ers w
ere i
nvite
d to
regis
ter a
s cus
tom
ers o
n a d
edica
ted
webs
ite, w
here
they
rece
ived
custo
mer
supp
ort,
dedi
cate
d m
arke
t-in
g cam
paign
s and
a m
ap o
f ret
ail lo
catio
ns –
regis
tere
d IQ
OS
user
s wer
e reg
ular
ly in
vited
to co
mpl
ete s
urve
ys
abou
t IQ
OS
use,
for w
hich
they
wer
e com
pens
ated
with
an o
ppor
-tu
nity
to w
in p
rizes
R E V I E W P A P E R M. JANKOWSKI ET AL.
IJOMEH 2019;32(5)624
Hair
et al
., USA
/U
nite
d Ki
ngdo
m
(201
8) [9
3]
to ex
amin
e con
sum
er
perc
eptio
ns, a
ttitu
des a
nd
beha
viors
rega
rdin
g the
he
ated
toba
cco
prod
uct
(IQO
S); t
o do
cum
ent
the p
rodu
ct m
arke
ting
strat
egies
to d
eter
min
e its
pote
ntial
for a
ppea
ling t
o yo
ung a
dults
in Ja
pan
and
Switz
erlan
d
expe
rt in
terv
iews;
a sem
iotic
analy
sis
of th
e IQ
OS
pack
ing a
nd m
arke
ting
mat
erial
s; 12
focu
s gro
ups w
ith ad
ults
in
Switz
erlan
d an
d Ja
pan
(N =
68 fo
r bot
h gr
oups
)
–IQ
OS
user
s fro
m Ja
pan
and
Switz
erlan
d re
porte
d lo
wer l
evels
of
satis
facti
on w
ith th
e pro
duct
relat
ive to
com
busti
ble c
igare
ttes
–Ja
pane
se IQ
OS
user
s use
d th
e pro
duct
for s
ocial
izing
with
no
n-sm
oker
s –
bran
d am
bassa
dors
were
empl
oyed
to sh
owca
se th
e pro
duct
and
answ
er q
uesti
ons w
ith fr
ee sa
mpl
es –
the p
rodu
ct m
arke
ting e
xhib
ited
4 key
mes
sage
s: cle
anlin
ess,
custo
miza
tion,
com
paris
ons w
ith co
mbu
stibl
e sm
okin
g, an
d so
ciabi
lity
Rose
n et
al., I
srael
(201
8) [9
4]to
des
crib
e the
entry
of
IQO
S to
Isra
el, an
d its
m
arke
ting c
ampa
ign
data
on
IQO
S en
try to
Isra
el –
2 dist
inct
cam
paign
s: th
e Pol
icy M
aker
s Cam
paign
(the
lobb
ying
of in
tend
ed le
gal r
egul
atio
ns) a
nd th
e Pub
lic C
ampa
ign
(a d
igita
l mar
ketin
g cam
paign
, pho
tos o
f the
pro
duct
and
shor
t te
xt m
essa
ges t
o pr
omot
e the
pro
duct
in p
ublic
) –
5 cam
paign
elem
ents:
PM
I’s “S
mok
e-fre
e Isra
el Vi
sion,
” the
ha
rm-re
ducti
on cl
aim, p
ropo
sing d
iffer
ent r
egul
atio
ns fo
r “no
n-co
mbu
stibl
e pro
ducts
,” at
tem
ptin
g to
tax I
QO
S at
a di
ffere
nt ra
te
than
ciga
rette
s; ad
verti
sing s
loga
ns (e
.g., N
o fir
e/No
smok
e/No
ash)
Kreit
zber
g et a
l., U
SA
(201
8) [9
6]to
des
crib
e HTP
mar
ketin
g str
ateg
ies o
n In
stagr
am
the I
nsta
gram
pro
gram
min
g int
erfa
ce
was u
sed
to ex
amin
e the
imag
e con
tent
of
HTP
pos
ts, ge
nera
l tex
tual
topi
cs
and
large
r the
mes
relat
ed to
thes
e te
xtual
topi
cs, p
ublic
hea
lth re
levan
t to
pics
, and
diff
eren
t typ
es o
f Ins
tagr
am
user
s who
pos
ted
HTP
s; IQ
OS
relat
ed
hash
tags
(e.g.
, #IQ
OS,
#IQ
OSF
amily
, #I
QO
SFrie
nds)
were
use
d to
iden
tify
HTP
cont
ent
–th
ere w
ere 1
2 774
pos
ts an
d co
mm
ents
relat
ed to
IQO
S id
entifi
ed –
posts
asso
ciate
d H
TPs w
ith #
luxu
ry, #
fash
ion,
and
#sup
erio
rity
–po
sts co
mpa
red
heat
ed to
bacc
o de
vices
with
ciga
rette
s and
sug-
geste
d th
eir u
se fo
r sm
okin
g ces
satio
n –
HTP
use
rs cu
stom
ized
their
IQO
S ca
ses,
tips,
and
skin
s, an
d th
e fra
min
g of t
hese
dev
ices,
as fa
shio
n ac
cesso
ries
–In
stagr
am m
ay in
crea
se th
e soc
ial ac
cept
ance
of t
obac
co u
se
Stud
ies w
ith a
pote
ntial
co
nflict
of i
nter
est
none
avail
able
HTP
s – h
eate
d to
bacc
o pr
oduc
ts; P
MI –
Phi
lip M
orris
Inte
rnat
iona
l.
Tabl
e 5. H
TP m
arke
ting s
trate
gies a
nd p
rodu
ct pr
omot
ion
– a sy
stem
atic
revie
w, 20
15–2
018 –
cont
.
Stud
y typ
e and
refe
renc
eAi
m o
f the
stud
ySt
udy d
esign
Sum
mar
y
HEATED TOBACCO PRODUCTS — A SYSTEMATIC REVIEW R E V I E W P A P E R
IJOMEH 2019;32(5) 625
the IQOS classification as a variant of e-cigarettes implies taxation and, in Korea, taxes on IQOS tobacco sticks are only half of that of traditional cigarettes [4]. In Israel, IQOS is taxed at the same rate as cigarettes [94].Kreitzberg et al. identified 12 774 posts and comments re-lated to IQOS on Instagram (a photo and video-sharing social networking service) [96]. The analysis of the IQOS users’ behavior in social media has shown that they are customizing IQOS devices and accessories dedicated to HTPs [96]. Sharing content related to the use of IQOS in social media, such as Instagram (photos when using the device or photos of customized devices), is used to build a community identified by such hashtags as #IQOSFamily or #IQOSFriends. Kreitzberg et al. suggested that Insta-gram might increase the social acceptability of tobacco use and, due to this fact, there should be an age restriction on the content promoting HTPs [96].Furthermore, in many countries, heated tobacco products may be used in public places, in contrast to traditional cigarettes. All these activities have the potential to change social norms and attitudes towards tobacco use, and sug-gest to the public that HTPs are a safe form of tobacco use. Elias and Ling emphasized the key role of respected health leaders in shaping public attitudes towards novel tobacco products and their impact on the commercial fate of HTPs [97]. The authors encouraged public health ex-perts to carefully formulate opinions, bearing in mind the past experience with the industry-backed “safer tobacco products,” such as filtered and low-tar cigarettes, which served to undermine and delay the global tobacco control efforts [97]. Lempert and Glantz pointed out legal uncer-tainties regarding HTPs, especially electronic devices used to heat up tobacco sticks [98]. The authors concluded that in the USA and parties to the WHO Framework Conven-tion on Tobacco Control (FCTC) all components of HTPs should be regulated at least as stringently as tobacco prod-ucts and should be subject to all tobacco control laws that apply to other tobacco products [98].
strategy focused on the social and regulatory landscape rather than the result of toxicological differences between IQOS and its precursor, Accord [91].According to Italian law, advertising and promotions of heated tobacco products are not banned [3]. Dedicated shops called an “IQOS embassy” or an “IQOS boutique” are present in several strategic Italian cites [3]. Simi-lar shops are present in Japan, South Korea, and Cana-da [4,92]. In these fancy concept stores (designed similar to electronics stores), people can try IQOS for free [3,4]. Mathers et al. noted that sales representatives in Canada, by regularly using IQOS, made a significant contribution to the direct promotion of this product [92]. A similar marketing strategy was launched in Japan where “brand ambassadors” were employed to showcase the products and answer questions with free samples [93]. In South Korea, each IQOS-store customer takes part in a 15-min professional presentation by an “IQOS coach” before buy-ing their first IQOS device [4]. Rosen et al. identified 5 ele-ments of a marketing campaign of IQOS in Israel, includ-ing the following: 1) Philip Morris’s “Smoke-free Israel Vision”; 2) the harm-reduction claim; 3) the proposition of a different regulation for “non-combustible products”; 4) attempts to tax IQOS at a different rate from that ap-plicable to cigarettes; and 5) catchy advertising slogans (e.g., No fire/No smoke/No ash) [94].Liber reported that, in most of the countries where HTPs were sold, these products had received tax advantages and its tax rates were lower than those of conventional cigarettes [95]. The differences between regulations for traditional cigarettes and HTPs can also be seen in the packaging of these products. For example, in Italy, health warnings are required to cover only 30% of the HTP pack-ing in contrast to the traditional cigarette packing where warnings are required to cover 65% of cigarette packs [3]. In South Korea, the IQOS tobacco stick packs only have labels warning about nicotine addiction, without showing various negative consequences of smoking [4]. Moreover,
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totoxicity associated with IQOS use [70]. Chun et al. sug-gested that HTP use might have unexpected organ toxicity not observed when smoking traditional cigarettes [70].Following the manufacturer recommendations, especially proper cleaning of the device after each 20 tobacco sticks seems to be crucial to provide proper thermal regulation and reduce emissions of harmful substances. Most of the research regarding the chemical composition of generated aerosol was carried out on brand new, never used devic-es [39–54]. Independent researchers showed that the use of 1 IQOS tobacco stick left a significant amount of debris, fluid, and fragments of cast-leaf in the device holder [8]. It can be assumed that the lack of proper cleaning can lead to the accumulation of undesirable substances in the holder, influencing the heating conditions and chemical composition of the generated aerosol.The tobacco industry has performed multiple studies re-garding health consequences of HTP use. The results of in vitro and in vivo studies indicate that HTP aerosols have lower toxicity and no new hazards compared to conven-tional cigarette smoke [39–54]. The results of human-based studies also suggest that switching from conven-tional cigarettes to IQOS or glo leads to reductions in exposure to smoke toxicants in a manner comparable to quitting tobacco use [74–78]. However, there have been no independent studies regarding short-term and long-term health consequences of HTP use.Data provided by the tobacco industry did not convince the leading health organizations to recognize HTPs as “re-duced risk products” [99–101]. In December 2016, PMI applied to the FDA (U.S. Food and Drug Administration) to consider IQOS as a modified risk tobacco product [83]. In January 2018, the FDA Tobacco Products Scientific Ad-visory Committee concluded that there was no conclusive scientific evidence that IQOS use was less risky than con-tinuing tobacco smoking and PMI should not claim that IQOS use cut the risk of tobacco-related diseases [86,102]. Furthermore, the FDA experts were not convinced that
DISCUSSIONThe heated tobacco smoking technology has become in-creasingly popular [6,79]. The most popular HTP prod-uct – IQOS from PMI – is widely available in 33 countries worldwide, including 21 European countries [93]. Other popular HTPs – glo and Ploom TECH – are also gaining new markets [6]. The source of the aerosol is a tobacco stick made of processed tobacco [12,13]. Tobacco sticks are avail-able in multiple flavors [10,20]. The variety of flavors, and especially the introduction of sweet fruit variants of tobacco sticks, may encourage young people to reach for HTPs be-cause of their attractive taste. The chemical composition of HTP tobacco sticks differs from traditional cigarettes [22]. However, both of them have a comparable nicotine concen-tration [9,21]. Therefore, the levels of nicotine contained in the HTP aerosol have been 70–80% as those of conven-tional combustion cigarettes [15,27,29,33], based on the re-sults of both independent and industry studies. This finding may suggest that HTPs were launched in response to the dissatisfaction with the lack of rapid nicotine delivery by e-cigarettes. However, further research is needed to describe the profile and characteristics of HTP users.According to the tobacco industry data, aerosols formed during the heating process have around 90–95% lower levels of toxicants than conventional cigarette smoke [13–15,23,24]. Independent studies have confirmed that the concentration of chemical compounds generated by HTPs is lower than that generated by traditional ciga-rettes [27,28,33]. However, toxic compounds are not com-pletely removed from the HTP aerosol [7,19,25–35]. The results of independent studies have shown that IQOS emit substantially lower levels of carbonyls and submicronic particles than a commercial cigarette but higher levels than an e-cigarette [25,26,28]. The emission of reactive ox-ygen species during IQOS use points to potentially harm-ful effects of IQOS use, such as cancer or pulmonary dis-eases [38]. Moreover, an independent review of preclinical and clinical data on IQOS has revealed the possible hepa-
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companies use dedicated hashtags and advertising slogans to promote HTPs on their websites [96]. The use of social media for the promotion of HTPs can make it more difficult to monitor the marketing activities which may contradict the WHO Framework Convention on Tobacco Control.Current knowledge on HTP exposures and health effects is often based on data provided by the tobacco industry (52% of identified studies). There is a need for future in-dependent research, especially human-based studies as-sessing short-term as well as long-term health effects of HTP use. Future studies will provide more information about passive HTP smoking and the impact of HTP sec-ondhand smoke on bystanders, which will be crucial to implement proper regulations regarding HTPs, especially HTP use in public places. Currently, there is no evidence that HTPs can be used as an effective tool for smoking ces-sation. This topic also needs further investigation.There are a few limitations to this study. This review was restricted to peer-reviewed articles available in English. Most of them focused only on data from 5 countries, which limits the external validity of this research. There was also substantial variation in the study designs of in vitro and in vivo studies, especially the conditions of exposure and the length of follow up. Sample sizes also varied substantially between studies. Nevertheless, this study is the most up-to-date systematic review regarding heated tobacco products and addresses several different aspects of HTP use.
CONCLUSIONSHeated tobacco products are gradually gaining in popular-ity. A chemical analysis of aerosols has revealed that heat-ed tobacco products release lower levels of toxic chemicals compared to conventional cigarettes. However, toxic com-pounds are not completely removed from the HTP aero-sol and these products are still not risk-free. The nicotine levels delivered to the aerosol by heated tobacco products were almost the same as those of conventional combus-tion. Health consequences of HTPs as well as their role in
smokers would use IQOS alone and stated that there was a high to medium risk of dual use of IQOS and conven-tional cigarettes [86,102].According to the World Health Organization (WHO) statement, there is no evidence that HTPs are less harm-ful than conventional cigarettes [99]. The WHO has also emphasized that conclusions about the HTP ability to as-sist with quitting smoking cannot yet be drawn. The WHO has concluded that all forms of tobacco use are harmful and new tobacco products should be regulated under the WHO Framework Convention on Tobacco Control (FCTC) [99].The European Respiratory Society (ERS) has stated that, as with regular tobacco smoking, heated tobacco products are addictive and carcinogenic to humans [100]. Accord-ing to the ERS statement, there is no evidence that heated tobacco products are efficient tools to aid in smoking ces-sation. Moreover, the ERS cites some strong evidence sug-gesting that studies performed or sponsored by tobacco industry companies cannot be trusted [100]. The ERS has concluded that it cannot recommend any products which can be harmful to the lungs and human health [100].A more liberal position is presented by Public Health Eng-land (PHE) [101]. This organization has concluded that available evidence suggests that heated tobacco products may be considerably less harmful than conventional ciga-rettes, but more harmful than e-cigarettes [101]. Despite this fact, PHE emphasizes the urgent need to provide more research independent of commercial interests [101].The prevalence of HTP use is constantly growing, espe-cially among current cigarette or e-cigarette smokers [6]. Such a high interest in HTPs among current smokers may pose a risk of dual use in this group. In many countries, the advertising and promotion of HTPs are not banned [3,98]. The marketing strategies and promotion of these products, such as fancy concept stores, brand ambassadors, and free samples testing, can support the increase in the number of HTP users [4,92,93]. Like e-cigarettes [103,104], HTPs are advertised via the Internet and social media [92–94]. Tobacco
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8. Davis B, Williams M, Talbot P. iQOS: evidence of pyrolysis and release of a toxicant from plastic. Tob Control. 2019;28(1): 34–41, https://doi.org/10.1136/tobaccocontrol-2017-054104.
9. Farsalinos KE, Yannovits N, Sarri T, Voudris V, Poulas K. Nicotine Delivery to the Aerosol of a Heat-Not-Burn To-bacco Product: Comparison With a Tobacco Cigarette and E-Cigarettes. Nicotine Tob Res. 2018;20(8):1004–9, https://doi.org/10.1093/ntr/ntx138.
10. Proctor C. Assessment of tobacco heating product THP1.0. Part 1: Series introduction. Regul Toxicol Pharmacol. 2018; 93:1–3, https://doi.org/10.1016/j.yrtph.2017.09.010.
11. Eaton D, Jakaj B, Forster M, Nicol J, Mavropoulou E, Scott K, et al. Assessment of tobacco heating product THP1.0. Part 2: Product design, operation and thermophysi-cal characterisation. Regul Toxicol Pharmacol. 2018;93:4–13, https://doi.org/10.1016/j.yrtph.2017.09.009.
12. Yuki D, Sakaguchi C, Kikuchi A, Futamura Y. Pharmaco-kinetics of nicotine following the controlled use of a proto-type novel tobacco vapor product. Regul Toxicol Pharmacol. 2017;87:30–5, https://doi.org/10.1016/j.yrtph.2017.05.005.
13. Ichitsubo H, Kotaki M. Indoor air quality (IAQ) evaluation of a Novel Tobacco Vapor (NTV) product. Regul Toxicol Pharma-col. 2018;92:278–94, https://doi.org/10.1016/j.yrtph.2017.12.017.
14. Mitova MI, Campelos PB, Goujon-Ginglinger CG, Maed-er S, Mottier N, Rouget EG, et al. Comparison of the impact of the Tobacco Heating System 2.2 and a cigarette on in-door air quality. Regul Toxicol Pharmacol. 2016;80:91–101, https://doi.org/10.1016/j.yrtph.2016.06.005.
15. Jaccard G, Tafin Djoko D, Moennikes O, Jeannet C, Kondy-lis A, Belushkin M. Comparative assessment of HPHC yields in the Tobacco Heating System THS2.2 and commercial cig-arettes. Regul Toxicol Pharmacol. 2017;90:1–8, https://doi.org/10.1016/j.yrtph.2017.08.006.
16. Haswell LE, Corke S, Verrastro I, Baxter A, Banerjee A, Adamson J, et al. In vitro RNA-seq-based toxicogenomics assessment shows reduced biological effect of tobacco heat-ing products when compared to cigarette smoke. Sci Rep. 2018;8(1):1145, https://doi.org/10.1038/s41598-018-19627-0.
smoking aid are unknown. Among the currently available data on HTPs, most papers (52%) have been sponsored by the tobacco industry. There is a need for the future in-dependent and standardized investigations of the poten-tial health effects associated with heated tobacco use and HTP potential in smoking cessation aid.
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