Rev Environ Health 2016; aop

Aziemah Zulkifli, Emilia Zainal Abidin*, Najihah Zainol Abidin, Amer SiddiqAmerNordin,
Sarva Mangala Praveena, Sharifah Norkhadijah Syed Ismail, Irniza Rasdi,
KarmegamKaruppiah and Anita Abd Rahman

Electronic cigarettes: a systematic review of

available studies on health risk assessment
DOI 10.1515/reveh-2015-0075
Received December 10, 2015; accepted February 9, 2016

Abstract
Objective: This paper primarily aimed to review articles
which specifically quantified the risk of electronic cigarettes (e-cigarette) usage via the health risk assessment
(HRA) approach.
Methods: Systematic literature searches were conducted
using PubMed search engine databases. Search terms such
as electronic cigarette, e-cigarette, electronic nicotine
delivery systems, electronic cigarette liquid, electronic
cigarette vapors, and health risk assessment were
used to identify the relevant articles to be included in this
review. To enable comparison, hazard quotient (HQ) and
lifetime cancer risk (LCR) for the chemicals measured in
the selected articles were calculated for three of the articles
using the formula: [1] HQ=average daily dose (ADD)/reference dose (RfD) or exposure air concentration (EC)/reference concentration (RfC); [2] LCR=lifetime average daily
dose (LADD) cancer slope factor (CSF) or exposure air
concentration (EC) inhalation unit risk (IUR).
Results: Four articles pertaining to HRA of e-cigarettes
were critically reviewed, three of the papers focused on
specific chemicals namely nicotine, propylene glycol (PG),
glycerol and 1,2-propanediol, while one article evaluated

*Corresponding author: Emilia Zainal Abidin, Faculty of

Medicine and Health Sciences, Department of Environmental and
Occupational Health, Universiti Putra Malaysia, 43400, Serdang,
Selangor, Malaysia, Phone: +603 89472643, Fax: +603 89472395,
E-mail: za_emilia@upm.edu.my
Aziemah Zulkifli, Najihah Zainol Abidin, Sarva Mangala Praveena,
Sharifah Norkhadijah Syed Ismail, Irniza Rasdi and Karmegam
Karuppiah: Faculty of Medicine and Health Sciences, Department of
Environmental and Occupational Health, Universiti Putra Malaysia,
43400 Serdang, Selangor, Malaysia
Amer Siddiq Amer Nordin: Faculty of Medicine, Department of
Psychological Medicine, University of Malaya, 50603 Kuala Lumpur,
Malaysia
Anita Abd Rahman: Faculty of Medicine and Health Sciences,
Department of Community Health, Universiti Putra Malaysia, 43400
Serdang, Selangor, Malaysia

the health risks posed by heavy metals contained in

e-cigarettes. The calculated HQs for the chemicals in this
review had large variations. HQs of the six chemicals,
i.e. nicotine, PG, glycerol, cadmium, ethylene glycol,
nickel, aluminum and titanium, were found to have the
potential to contribute to non-carcinogenic health risks.
None of the LCR calculated had risks exceeding the
acceptable limit.
Conclusion: There are limited HRA studies and the ones
that were available provided inconsistent scientific evidences on the health risk characterization arising from the
usage of e-cigarettes. As such, there is a need to perform
more studies on HRA of e-cigarettes by using uniformed
and comprehensive steps and similar reference threshold
levels of exposures.
Keywords: electronic cigarettes (e-cigarettes); e-liquid;
hazard quotient; health risk assessment (HRA); margin of
exposure; risk characterization.

Background
Evidence from international studies reveal that the popularity of electronic cigarettes (e-cigarettes) is increasing
rapidly among the world population despite the controversies surrounding the e-cigarettes impact on health (1
3). This phenomenon should be considered as an issue of
concern by health organizations, such as the World Health
Organization (WHO), as the safety of e-cigarettes has yet
to be decisively established (4).
The users of e-cigarettes have increased in numbers in
many countries (1, 5, 6). Data provided by Regan etal. (5)
and King etal. (6) demonstrate increments in the percentage of e-cigarette users in the United States of America
(USA) from 0.6% in 2009 to 8.5% in 2013. Similarly, the
population-based Global Adult Tobacco Survey (GATS)
conducted from 2011 to 2013 reported high prevalence of
current e-cigarette users in four countries namely Greece
(2.2%), Qatar (1.8%), Malaysia (3.9%) and Indonesia
(2.5%) with Malaysia being the country with the highest

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2Zulkifli etal.: Electronic cigarettes

percentage of users (7). Notwithstanding the fact that
these four countries have already been recognized to have
a high baseline number of conventional cigarette smokers
to begin with [Greece (38.2%) (8), Indonesia (34.8%) (9)
and Malaysia (23.1%) (10)], the study was able to identify
that e-cigarette users in Malaysia are also made up of those
who has never taken up smoking in the first place. This
evidence calls forth reasonable concerns on the claims
where e-cigarettes might be useful as a smoking cessation device as high smoking prevalence as well as rapid
growth in the number of e-cigarette users were shown in
other similar countries (11).
Rapid market penetration of e-cigarettes has called
upon many public health experts to focus on studies
related to the detection of chemical constituents in e-liquids as well as the vapor. E-liquids or e-cigarette solutions
mainly contain propylene glycol, glycerol and/or vegetable glycerine, water and may or may not contain nicotine.
A comprehensive review demonstrated that there were 34
articles from 2008 till 2014 which specifically focused on
the investigation of chemical contents in e-liquid and/or
vapor of e-cigarettes (12). Nicotine, the major chemical
compound widely measured in e-liquids, was found in
concentrations of 0.1324 g/mL as detected in 16 samples
of e-liquids (13). Although nicotine is not categorized as
a component which causes cancer, its exposure has been
linked to addiction, respiratory and cardiovascular effects
by the International Agency for Research Cancer (IARC)
(14). The analysis of original e-cigarette cartridges and nicotine refill solutions revealed irregularities from the actual
nicotine content as the concentrations measured did not
correspond to the label on the products (15). The nicotine
contents differed up to more than 20% from the lower
values declared on the labels of the products. According
to the guidelines by the American E-liquid Manufacturing
Standards Association (AEMSA), nicotine concentrations
in e-liquids should be within the range of 10% from the
concentration indicated on the label (16) and inaccurate
labeling of chemical contents may possibly led to a greater
public health implication.
Tobacco-specific nitrosamine (TSNA) level was
another chemical widely measured in studies pertaining
to the evaluation of e-cigarette contents (1720). TSNA
is known as one of the most significant carcinogens in
smokeless tobacco products as well as in cigarette smoke
(18, 20, 21). Two of the TSNA derivatives, N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone (NNK) have been consistently demonstrated as
carcinogenic in experiments involving laboratory animals
and is classified as a group 1 carcinogen by IARC (22).
NNN causes esophageal and nasal tumors in rats and

respiratory tract tumors in mice and hamsters (23) while

NNK causes lung tumors in all species tested, i.e. rats, mice
and hamsters. Most of the e-liquids studied were found to
contain carcinogenic compounds of NNN within the range
of 0.3460.08 g/L and NNK within the range of 0.22
9.84 g/L (18).
At present, there is a lack of decisive conclusions on
the health implications of e-cigarettes usage by international health bodies. As such there is a growing interest
among researchers to focus on the health risk assessment
(HRA) of e-cigarettes (2426). HRAs on e-cigarettes were
performed by a number of studies using e-liquids produced by international companies, however, the types of
e-liquids used were not varied (27), considering that there
are an average of 242 new flavors of e-liquids produced
every month in the market (28). The methodology of HRA
introduced by the Environmental Protection Agency (EPA)
(29) has been widely used in studies to demonstrate carcinogenic and non-carcinogenic risks arising from the exposure of humans to toxic chemical substances. The agency
for Toxic Substances and Disease Registry (ATSDR) toxicology profiles was often used to aid in the calculations
of the risks of interests (2426). Even though HRA studies
on e-cigarette contents were available, the number of
studies were small and the methods used varied from one
to another.
This review was therefore designed to provide a
concise conclusion of HRA studies on e-cigarette and
e-liquid contents. This review is expected to assist policy
makers in drafting related laws and regulation pertaining to the usage of e-cigarettes. As there are many studies
that have only descriptively explained the human health
effects arising from the usage of e-cigarette, this review
was mainly aimed to provide the summary of the articles
which specifically quantified the risk of e-cigarette usage
via HRA approach.

Methods
A systematic literature search was conducted to identify published
scientific studies related to e-cigarette usage and HRA. A set of relevant search terms were used separately or in combination in PubMed search engine. The following were the search terms included in
this study: electronic cigarette, e-cigarette, electronic nicotine
delivery systems, electronic cigarette liquid, electronic cigarette
vapors, and health risk assessment. The search date range was
restricted between the years 2000 and August 2015.
The inclusion criteria of the articles to be considered in the
review were the following: [1] written in English, [2] open access
journal [3] dealt mainly or partly with e-cigarette and/or health risk
assessment. The search yielded a total of 24 articles that met the

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Zulkifli etal.: Electronic cigarettes3

inclusion criteria. Article titles and abstracts were then screened

for relevance, which left a total of four studies suitable for full-text
review.

Calculation of Hazard Quotient (HQ) and Lifetime Cancer

Risk (LCR)
Further analysis of the data obtained from three studies was made in
order to compare and evaluate the health risk for each of the chemicals measured in e-cigarettes and e-liquids. No additional calculation was made for one study as the finding was already expressed in
a HQ value (27). In order to calculate HQ and LCR, the default body
weight of 70 kilograms (kg) was applied to the calculation of average daily dose (ADD) and lifetime average (LADD) as a representative average value for an adult as recommended by the EPA (30). The
information on the usage pattern of e-cigarette was obtained from the
study by Etter (31) which uses the assumption of 3 months exposure
duration (ED) and 100days of exposure frequency (EF). The reference
dose (RfD), reference concentration (RfC), cancer slope factor (CSF)
and minimal risk level (MRL) were chemical-specific values from the
Integrated Risk Information System (IRIS) EPA and the Agency for
Toxic Substances and Disease Registry (ATSDR).

Results and discussion

In total, there are four studies (2427) which performed
HRA from the use of e-cigarettes. Three studies measured
the health risks of specific chemicals in e-cigarettes namely
nicotine, propylene glycol (PG), glycerol and 1,2-propanediol, one study evaluated HRA for heavy metals. In brief,
the measurement in Exponent (27) were performed on a
disposable e-cigarette called NJOY, the measurement
by Kienhuis et al. (24) were performed for the nicotinefree shisha-pen, Farsalinos etal. (25) performed HRA of
13 e-cigarette products in the form of vapors and lastly,
Hahn etal. (26) determined the concentrations of several
elements in e-liquids. The summary of the studies are presented in Table1.
The approach of HRA in these studies (2427) consisted of four main steps: [1] analyze the concentration
of intended chemical contents in e-liquid or/and vapor;
[2] calculate the exposure that might be exposed by the
users; [3] compare the estimated exposure with established standards, i.e. non-observed adverse effect level
(NOAEL) or lowest observed adverse effect level (LOAEL)
and lastly [4] categorize the risk using margin of exposure
(MOE) or hazard quotation (HQ).
To predict the risk associated with the use of e-cigarettes, HRA was performed by integrating data of e-liquid
concentrations coupled with data on the usage patterns
of the e-cigarette. However, available studies focusing on

determination of chemical contents in e-cigarette coupled

with the usage of e-cigarettes were limited (25, 32, 33). The
common focus of these studies was only on the detection
of chemical compounds in e-cigarettes (34, 35) and did
not involve the determination of usage pattern of any particular population. On the other hand, there were small
numbers of studies which provided a significant amount
of data on specific usage patterns of e-cigarettes and did
not include the determinations of the e-liquid content as
one of its objectives (31, 32). Research to describe data of
e-cigarette usage patterns is crucial and is much needed
in order to enable HRA studies to be conducted considering evidence of usage patterns has yet to be established.
As the scientific knowledge on the implications of e-cigarettes usage is relatively minimal, HRA studies conducted
using specific usage patterns of specific populations will
give better risk estimates instead of using data on usage
patterns from other separate studies. Compared to conventional cigarettes, at present fewer studies regarding
the estimation of health risk has been conducted for the
usage of e-cigarettes (3639).
In order to determine whether e-cigarette pose a hazard
or is safe for its users, the estimated exposure of chemical
contents in e-cigarettes need to be compared with established threshold levels. There are a variety of standards
for threshold levels from professional bodies used in the
HRA studies in this review. In addition to the NOAEL and
LOAEL, the threshold levels used included average daily
index (ADI), permissible daily exposure (PDE), minimal
risk level (MRL) and recommended exposure limit (REL).
Out of the four HRA studies, studies by Kienhuis etal. (24)
and Hahn etal. (26) referred to NOAEL and LOAEL as the
threshold level of exposure. On the other hand, Farsalinos
etal. (25) used PDE, MRL and REL as the reference threshold level for the risk assessment of metals emitted from
e-cigarettes. ADI was also used by Hahn et al. (26) as
the toxicological threshold for certain chemicals namely
nicotine, 1,2-propanediol and thujone. For Exponent (27),
reference dose (Rfd) was used to compare with estimated
exposure of chemicals found in NJOY disposable e-cigarettes. However, for compounds with several threshold
levels, the lowest toxicological level was chosen (26).

Calculated HQ and LCR

The calculated values of ADD, LADD and the threshold
chemical-specific toxicity value are presented in Table 2
while the calculated HQ and LCR values are presented in
Table 3. The health risks were then expressed as hazard
quotient (HQ) (risk characterization which indicates

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 Kienhuis etal. (24) Potential

harmful
health
effects of
inhaling
nicotine-free
shisha-pen
vapor: a
chemical
risk
assessment
of the main
components
propylene
glycol and
glycerol

Detection of constituents in liquid

and vapors of shisha-pens: gas
chromatography (GC) on a Varian GC 3900/
FID
Risk assessment:
1) Step 1: exposure assessment: using puff
volumes of e-cigarettes and normal
cigarettes and a 1-puff scenario (onetime exposure). Average conc. per
shisha-pen:
a) 1Calv;max=0.042 D1-puff shishapen/0.05=0.85 D1-puff shishapen=mg/L
b) 2Calv;max=0.042 D1-puff shishapen/0.07=0.6 D1-puff shishapen=mg/L
2) Step 2: compare the exposure estimated
with point of departure (POD) no
observed adverse effect level (NOAEL)
and lowest observed adverse effect level
(LOAEL) from previous study
3) Step 3: risk on local effects margin
of exposure (MOE) is a ratio of an
appropriate toxicological point of
departure (POD) divided with the
estimated human exposure (the smaller
the ration, the higher the risk)

NJOY
A risk was characterized using the following
e-cigarette
equation:
health risk
Hazard quotient (HQ):
assessment (Expected dose, mg/kg-day)/(dose criterion,
mg/kg-day)
*HQ <1 indicates that the expected exposure
does not exceed the dose criterion
(maximum level of exposure to a toxicant at
which no adverse effects are expected)

Exponent (27)

Concentration of;
i) propylene glycol: 54%
ii) glycerol: 46%
Vapor in shisha-pen comprised of:
i) 0.7 mg/puff of propylene glycol
ii) 0.6 mg/puff glycerol
Hazard assessment:
i) Propylene glycol: no evidence that PG is carcinogenic to human
Risk assessment:
i) Step 1:
a) propylene glycol:
Estimated maximum alveolar conc. in after one puff: 430603 mg/m3 (exceed peak acceptable
concentration) demonstrate that a risk of irritating effects on the respiratory tract epithelium due to
propylene glycol exist
b) glycerol: maximum alveolar concentration (1Calv; max)= 348495 mg/m3 (no MOE is calculated; due
to lack of relevant human inhalation studies)
ii) Step 2:
a) propylene glycol:
NOAEL (mg/m3):LOAEL: M
 in 176
Max 851
Mean 309
b) glycerol:
NOAEL: 165 mg/m3
LOAEL: 662 mg/m3
iii) Step 3: risk on local effects;
a) propylene glycol:
MOE for respiratory tract irritation=0.32 (LOAEL)
b) no MOE is calculated. However, inhaled concentration of glycerol in one puff: 348495 mg/m3 compared
to NOAEL (165 mg/mg3) and LOAEL (662 mg/m3) for local irritant effect to the respiratory tract in rats

Detected components in NJOY e-cigarette:

1) propylene glycol, glycerin, nicotine, acetaldehyde, 1-methoxy-2-propanol, 1-hydroxy-2-propanone,
acetic acid, 1-menthone, 2,3-butanediol, menthol, carvone, maple lactone, benzyl alcohol, 2-methyl2-pentanoic acid, ethyl maltol, ethyl cinnamate, myosamine, benzoic acid, 2,3-bipyridine, cotinine,
hexadecanoic acid, and 11-oxybis-2- propanol
Hazard quotient for each detected constituent: <1 (indicate low risk to adverse health effect if utilizes
one pack per day)

Risk assessment

Methodology

Title

No. Author/s (Year)

Table 1:Summaries of articles regarding the health risk assessment of e-cigarette.

4Zulkifli etal.: Electronic cigarettes

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 Title

Methodology

Risk assessment

Electronic
cigarettes:
overview of
chemical
composition
and
exposure
estimation

Determination of concentration of

elements in e-liquid using NMR:

1. Nicotine
2. Glycerol
3. 1,2-Propanediol
4. Ethylene glycol
5. 1,3-Propanediol
6. Thujone
7. Ethyl vanillin
Risk assessment:
Use probabilistic exposure estimate using
Monte Carlo analysis (10,000 Iteration)
1) Exposure= risk function of
concentration* risk function of
e-liquid concentration*risk function of
vaporization percentage/risk function of
bodyweight (kg)
2) Generate margin of exposure (MOE) of
each elements:a) MOEs derived from animal studies (for
all elements excepts for nicotine):
i) <10: high risk
ii) <100: risk
iii) 100: acceptable
b) MOEs derived from human studies:
i) >10: acceptable
ii) <1: high risk

Concentration of elements in e-liquid (meanSD):

1. Nicotine: 1113 mg/mL
2. Glycerol: 3723 g/100 g
3. 1,2-Propanediol: 5730 g/100 g
4. Ethylene glycol: 1018 g/100 g
5. 1,3-Propanediol: 0.61.7 g/100 g
6. Thujone: 6.734 mg/L
7. Ethyl vanillin: 3068 mg/L
Estimated exposure (mg/kg bw/day) (meanSD):
1. Nicotine: 0.380.39 (exceed ADI proposed by EFSA)
2. Glycerol: 9.0 (< NOAEL)
3. 1,2-Propanediol: 14.512.4 (< NOAEL)
4. Ethylene glycol: 2.16.7 (< BMDL10)
5. 1,3-Propanediol: 0.14 0.51 (< NOAEL)
6. Thujone: 1.6E-49.7E-4 (< ADI)
7. Ethyl vanillin: 7.2E-42.0E-3 (< ADI)
Margin of exposure:
1. Nicotine: <10 (high risk category)
2. 1,2-Propanediol: <100 (risk category)
3. Ethylene glycol: <100 (risk category)

Farsalinos etal. (25) Are metals i) Two studies from literature in measuring I)Average daily exposure from 13 e-cigarette: 2.6387 times lower than the safety cut-off point of PDEs,
emitted from metals emitted to the aerosol from 13
325 times lower than MRL, 66577,514 times lower than safety cut-off point of RELs
electronic
e-cigarette products were chosen.
II) One of 13 products: exposure 10% higher than PDE for cadmium at the extreme daily use of 1200 puffs
cigarettes
i) Estimated exposure (600 puffs/day)
a reason
were compared with chronic permissible
for health
daily exposure (PDE) (cadmium,
concern?
chromium, copper, lead and nickel),
A riskminimal risk level (MRL) (manganese),
assessment
and recommended exposure limit (REL)
analysis of
(aluminum, barium, iron, tin, titanium,
currently
zinc and zirconium)
available
literature

4. Hahn etal. (26)

No. Author/s (Year)

Table 1(continued)

Zulkifli etal.: Electronic cigarettes5

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1-methoxy-2-propanol (PGME)

1-hydroxy-2-propanone

Acetic acid

menthol

Carvone

Benzoic acid

5E-01
2.8E-01
1.7
1E-02

0.0001
8.5E-03
5E-05
9E-03
3.3

5c

0.0001b

0.1c

5E-4a

5E-03a

5E-05a

6.3E+00

2E-05a

2.2E-06

4.8E-04

8.4E-02

1.8E-03

IUR
(mg/m3)

7.2E-04d

1.6E-04d

0.14d

2.1d

14.5d

9.0d

0.38d

603d

495d

0.2893
0.0000069
0.000535

0.0300

0.0258d

0.00032e

0.00070e

0.00006e

0.00057e

Hahn Kienhuis Farsalinos

etal. (26) etal. (24) etal. (25)

0.0023d

0.00084e

0.00054e

0.00024e

0.062
0.0044e

0.0042d

0.0145d

0.2571d

0.3582
d

Exponent
(27)

0.00011e

0.047e

0.00002e

0.00187
e

0.00032
e

0.00070
e

0.00006
e

0.00057e

Hahn Kienhuis Farsalinos

etal. (26) etal. (24) etal. (25)

1.83E-05d

Exponent
(27)

Average daily dose (ADD) (mg/kg/day)d or Lifetime Average daily dose (LADD) (mg/kg/day)d
Exposure air concentration (mg/m3)e
or Exposure air concentration (mg/m3)e

RfD, Reference dose; RfC, reference concentration; MRL, minimal risk level; CSF, Cancer slope factor; IUR, Inhalation Unit Risk; a RfD value by IRIS EPA, b MRL value of by ATSDR, ccould not be estimated due to the absence of threshold toxicity value of the chemical, , not measured; , non-carcinogenic, , unavailability of the value.

3E-01

6E-01

7E-01

2E-01

Zirconium

Barium

Aluminum

1.4E-01

Zinc

Manganese

Ethyl vanilin

10
0.11

Titanium

Thujone

1,3-Propanediol

4E-01

Ethylene glycol

25

Iron

1,2-Propanediol @ PG

100

0.0008

5E-02

0.0035

3.0E-03

1.8E-03

Tin

Glycerol

4E-02

Acetaldehyde

Nickel

Lead

Copper

Chromium

Nicotine

Cadmium

CSF
(mg/kg/day)

Chemical-specific threshold toxicity value

RfD RfCa/MRLb RELc

(mg/kg/day)
(mg/m3)

Chemical constituents
ine-cigarette

Table 2:Additional analysis of estimated Average Daily Dose (ADD), Lifetime Average Daily Dose (LADD) and chemical-specific threshold toxicity value.

6Zulkifli etal.: Electronic cigarettes

Zulkifli etal.: Electronic cigarettes7

Table 3:Additional analysis in estimating HQ for non-carcinogenic health risk and LCR for carcinogenic health risk for each of chemical
constituents measured in all included studies.
Chemical constituents in
e-cigarette

E-liquid Shisha pen E-cig aerosol

Hahn
Kienhuis
Farsalinos
etal. (26)
etal. (24)
etal. (25)

HQ
LCR

NJOY E-cig
E-liquid Shisha pen E-cig aerosol NJOY E-cig

Exponent
Hahn
Kienhuis
Farsalinos Exponent
(27) etal. (26)
etal. (24)
etal. (25)
(27)

Cadmium

28.5

1.03E-06

Chromium

0.6

5.04E-06

Lead

3.57E-08
1.54E-07

Nickel

1.6

Acetaldehyde

0.3582

Nicotine

475

0.2571

Glycerol

0.09

1,2-Propanediol @ PG

0.58

Ethylene glycol

5.25

1,3-Propanediol

0.014

4.95

24.1

0.0145

0.0042

Thujone

1.45E-03

Ethyl vanilin

1.44E-04

Copper

5.67E-04

Manganese

0.4

Aluminum

9.4

Barium

0.22

Iron

Tin

0.044

Titanium

2.4

Zinc

Zirconium

1.68E-04

1-methoxy-2-propanol (PGME)

0.0258

1-hydroxy-2-propanone

0.0023

Acetic acid

0.0300

menthol

0.2893

Carvone

0.0000069

Benzoic acid

0.000535

1.83E-07

HQ, Hazard quotient; LCR, lifetime cancer risk; acould not be estimated due to the absence of threshold toxicity value of the chemical; bold,
HQ value more than 1 (unacceptable risk for non-carcinogenic health effects), , non-carcinogenic; , not measured.

non-carcinogenic health risk) and lifetime cancer risk

(LCR) (risk characterization which indicates carcinogenic
health risk) as presented in Table 4. HQ of equal or <1
indicates that there is no appreciable risk that non-cancer health effects will occur while it is believed that the
exposed person/population would encounter non-carcinogenic health risk when HQ value is found to be more
than 1. In assessing the carcinogenic health risk, the US
EPA has stated that LCR value of 1E-06 to be negligible or
clearly acceptable while the risk within the range of 1E-06
and 1E-04 are generally considered to be acceptable. On
the other hand, value of more than 1E-04 would be considered as unacceptable (40).
The calculated HQ between the studies showed inconsistencies between several studies (26, 27). The largest

inconsistency was demonstrated for HQ of nicotine. HQ

value for nicotine as reported by Exponent (27) was lower
than 1 while HQ calculated from the data of Hahn et al.
(26) were more than a 1000-fold higher. Unlike the study
by Exponent (27), Hahn et al. (26) used outcome measures of MOE (values <100 represents risk and values <1
represents high-risk) instead of HQ. Both of these studies
provide the basis for the need of further study because
of the inconsistent results and the large variation in the
conclusion that were obtained from the HRA of the same
chemical contents.
HQ of glycerol and propylene glycol (PG) were available
for three studies (24, 26, 27). The estimated HQ of g
lycerol
and PG calculated from the study by Kienhuis et al. (24)
were the highest (4.95 and 24.1, respectively) between the

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8Zulkifli etal.: Electronic cigarettes

Table 4:Calculation of ADD, LADD, HQ and LCR of exposure to chemicals constituents in e-cigarette.
Non-carcinogenic health risk
Average daily dose: ADD (mg/kg-day) @ (mg/m )
3

Carcinogenic health risk

Lifetime average daily dose: LADD(mg/kg-day) @ (mg/m3 )

CpIR Ed EF
BW ATNC

Cp=Average concentration of chemical in e-liquid (mg/mL)

IR=Inhalation rate (m3); 20 m3 /day, @ Ingestion rate (mg/day)
Ed=Exposure duration (year)
EF=Exposure frequency (day)
BW=Body weight (kg);70 kg [EPA (30)]
ATNC=Averaging time (EDx365days/year)
Hazard quotient (HQ)
ADD
=
RfD

CpIR EdEF
BW ATC

Cp=Average concentration of chemical in e-liquid (g/mL)

IR=Inhalation rate (m3); 20 m3 /day@ Ingestion rate (mg/day)
Ed=Exposure duration (year)
EF=Exposure frequency (day)
BW=Body weight (kg)
ATC=Averaging time (25,550 days/year)
Lifetime cancer risk ( LCR ):
LADDCSF
LCR=Lifetime cancer risk
LADD=Lifetime average daily dose (mg/kg-day)
CSF=Cancer slope factor (mg/kg-day)

HQ=Hazard quotient
ADD=Average daily dose (mg/kg-day)
RfC=Reference dose (mg/kg-day)
For inhalation:
EC (mg/m3 )
HQ =
RfC (mg/m3 )

For inhalation:
LCR=EC (mg/m3)URF (mg/m3)-1

HQ=Hazard quotient
EC=Exposure air concentration (mg/m3)
RfC=Reference concentration (mg/m3)
Interpretation:

<1

Acceptable

>1

Unacceptable

Interpretation:

<106

Clearly acceptable

106 to 104

Acceptable

>104

Clearly unacceptable

three studies. Similar to nicotine, Exponent (27) exhibited

the lowest value of HQ for both chemicals. The HQ for other
chemical constituents measured by Exponent (27) continues to exhibit the same pattern. HQ of exposure to ethylene
glycol in e-cigarettes was only measured in one study and
was found to be higher than 1 (26) as such no comparison
can be made. Farsalinos etal. (25) measured the concentration of heavy metal contained in e-cigarettes and found
that the calculated HQ of exposure to cadmium, nickel,
aluminum and titanium was higher than 1 (28.5, 1.6, 9.4
and 2.4, respectively). The source of cadmium is possibly
from the components of the e-cigarette itself as cadmium
has been known to be the element used in e-cigarette
structure. Nichrome heating wire and other parts of the
atomizer could also be the potential source of nickel in
e-cigarette (25). In the context of titanium, Farsalinos etal.
(25) have stated that it is extremely unlikely that the metal
was emitted from the e-cigarette usage as titanium is not
found naturally in the air, and is very unstable and enters
the environment primarily as air emissions from facilities
that make or use it in various chemical processes or as

a result of spills. For aluminum, the main sources of the

metal in e-cigarette aerosol might have originated from the
atomizers of e-cigarette as well as from heating coils (25).
In terms of the carcinogenic effects of heavy metals,
LCR for the study by Farsalinos et al. (25) was within
the acceptable limit (of <104). The estimated LCR for
cadmium, chromium, lead, nickel and acetaldehyde were
not more than 104 (1.03E-06, 5.04E-06, 3.57E-08, 1.54E-07,
1.83E-07, respectively) which indicated that the exposure
to these chemicals were not likely to pose cancer health
risk to the users. In addition to the LCR calculated for the
four metals, this review also presents the LCR for acetaldehyde. The LCR was reported by Exponent (27) and was
within the acceptable limit. The comparison of LCR value
of these chemicals could not be performed as it was not
measured by the other two studies (24, 26).
The additional HQ analysis clearly indicates that
concern needs to be given to chemical constituents such
as nicotine, cadmium, PG, glycerol and aluminum as all
of these elements had among the highest value of HQ than
any others chemicals. Although the estimated LCR value

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Zulkifli etal.: Electronic cigarettes9

was <1E-04 and was unlikely to develop any carcinogenic

health risk to the user, more studies related to the calculation of LCR of chemical constituents in e-liquids should
be performed in order to be able to have a comprehensive
conclusion pertaining to the possibility of e-cigarettes and
its link to cancer in human. It is also noted that important carcinogenic compounds frequently associated with
tobacco, such as TSNA were not measured by any of the
studies.
In evaluating the quality of research articles included
in this review, few elements were assessed. Overall, all
the studies included have the constructive structure of a
strong research article. There was detailed presentation
of the results and concise discussion of study findings
and the limitation of studies were also addressed by the
authors of three studies (2426). Hahn et al. (26) noted
that the adoption of toxicological threshold for oral exposure instead of inhalation exposure in calculating the
risk associated with the usage of e-cigarette was seen as
the limitation of their approach. The limited information
on the topography profile of the usage of shisha-pens
has contributed to the use of assumption in estimating
the risk upon exposure. As the health risk of exposure to
heavy metals may be affected by the solubility of different
metal particle forms (41), no further assessment could be
performed by Farsalinos et al. (25) as they were lacking
data on the form of metals detected in the e-cigarette
aerosol.
It was also noted that the declarations of interest
were mentioned in three articles except for one (27). Even
though the HQ value of all chemical contents of e-cigarette
samples from this study showed that the exposure to these
chemicals were unlikely to cause non-carcinogenic health
risks to the users, the findings needs to be interpreted cautiously due to the possible bias arising from the source of
funding for the study.

Conclusion
From the further analysis of estimating the health risks of
all measured chemicals, there were six types of e-cigarette
constituents namely nicotine, PG, glycerol, cadmium, ethylene glycol, nickel, aluminum and titanium, which were
found to have the potential to contribute to the non-carcinogenic health risks to its users. There are limited HRA
studies and the ones available provide inconsistent scientific evidence on the health risk characterization arising
from the usage of e-cigarette. As such, there is a need to
perform more studies on HRA of e-cigarettes by using uniformed and comprehensive steps and similar reference

threshold levels of exposures. Furthermore, findings of

HRA was more relevant to a particular population of interest based on the specific usage patterns of e-cigarette
rather than integrating findings from other studies which
did not reflect the actual pattern of e-cigarette usage. Sufficient scientific conclusions of e-cigarettes will assist to
provide a reason or act as a force for many countries to
regulate e-cigarette usage.
Acknowledgments: This review paper was made possible
because of the financial support from the Fundamental
Research Grant Scheme (FRGS) Ministry of Education
Malaysia, under the Vote 5524532 and Ministry of Higher
Education Malaysia (MyBrain). AZ, NZA, EZA, ASAN,
SNSI, IR, SMP, and KK conceptualized the idea of this
paper. AZ developed the full manuscript and NZA, EZA,
ASAN, and SMP suggested corrections and amended the
manuscripts. All authors approved the final manuscript
for publication.

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