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).

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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]

R E V I E W P A P E R M. JANKOWSKI ET AL.

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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