Japanese Study - Safety Assessment of Electrnic Cigarettes in Smokers
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I'm going to read the whole article, thanks for posting. Well, if I can find it in English hah.
Imagine how great the results would have been if the subjects had been allowed more than one cartridge per day. The manufacturers really need to stop perpetuating the "one cartridge = one pack " myth. I don't think I ever got close to 150 puffs from one cartridge.
Seriously, this is exactly the kind of honest, unbiased research we need.
Xerais, if you download the Japanese PDF file, you can then upload it to Google Translate. Then you can *Kind of* read it.
Seriously, this is exactly the kind of honest, unbiased research we need.
Xerais, if you download the Japanese PDF file, you can then upload it to Google Translate. Then you can *Kind of* read it.
I would think that's what it is. I was struck by the fact that they only put 0.25 g liquid in a cartridge. Since 1 ml = 1 gram, then they were only giving participants a tiny fraction of the average amount vaporized per day by a regular e-cigarette user.
Even if we assume that folks who buy pre-filled cartridges use only one a day, 0.25 g would be from 1/4 to 1/2 that amount (depending on cartridge capacity--most hold 0.5 or 1 ml).
But our CASAA survey showed that only 13.5% of the 2,200 respondents use less than 1 ml per day. The average falls somewhere around 2 ml (2 g).
I'm having trouble figuring out how they got 180 puffs per day from such a tiny amount of liquid. Maybe that's where the "trace amount of acrolein" came from...some poor sucker running his cartridge on empty. The abstract say nothing about the nicotine strength in their liquid. Has anyone translated the entire report?
Well I read the translated version, the main thing I got out of it was that the study did find acrolein.
"Detected in acrolein vapor generated from the electronic cigarette"
"Results were studied using two filter cartridges
As a result, each of acrolein 1 per cartridge
2.31μg, found 7.08μg"
The study went on to say that it was much less than a traditional cigarette and that it can be found in a normal human diet, so when compared to traditional cigarettes it was safer.
Acrolein - Wikipedia, the free encyclopedia
"Detected in acrolein vapor generated from the electronic cigarette"
"Results were studied using two filter cartridges
As a result, each of acrolein 1 per cartridge
2.31μg, found 7.08μg"
The study went on to say that it was much less than a traditional cigarette and that it can be found in a normal human diet, so when compared to traditional cigarettes it was safer.
Acrolein - Wikipedia, the free encyclopedia
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No need to be concerned by this level of acrolein. When you breathe the air in the kitchen during frying, you inhale much, much more acrolein.
I sent a link to this study to Dr. Laugesen who corresponded with the author of the study. In his email reply Dr. Miura put the acrolein issue into perspective:
If I'm working the math right, the acrolein in the e-cig is anywhere from 6.6% to 8.2% of what's in a Marlboro menthol Light.
The EPA has published a hazard sheet on acrolein. Acrolein | Technology Transfer Network Air Toxics Web site | US EPA
If I'm working the math right, the acrolein in the e-cig is anywhere from 6.6% to 8.2% of what's in a Marlboro menthol Light.
The EPA has published a hazard sheet on acrolein. Acrolein | Technology Transfer Network Air Toxics Web site | US EPA
Your math is excellent, Vocalek! (meaning - I've got the same result 
). That means that the level of acrolein is relatively small, although not totally negligible.
I wish they would conduct another study concerning PG and liquids containing various amounts of nicotine. If were were in their shoes, I'd multiply the cartridge contents by the factor of 10.
). That means that the level of acrolein is relatively small, although not totally negligible. I wish they would conduct another study concerning PG and liquids containing various amounts of nicotine. If were were in their shoes, I'd multiply the cartridge contents by the factor of 10.
Regardless if I need to be concerned about it, I think it is important to understand what we are ingesting with e-cigarettes. The study emphasizes how much healthier they are, through empirical study. I'm not going to discount a harmful toxin being present, I'd much rather know what is there instead of being ignorant to it.
You're right, Xerais, although we should also know the real levels of every chemical we inhale. As Paracelsus said: sola dosis facit venenum (only the dose makes the poison).
I am very happy that scientists started to explore the field. I hope they will provide us with solid facts.
I am very happy that scientists started to explore the field. I hope they will provide us with solid facts.
As I understand it, the formation of acrolein during use is more likely if VG is used as the base rather than PG, as was the case in this research. Also, it is a very good idea not to run your cartridges dry which might cause melting of the filling or the plastic casing.
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As a chemist I can tell you that acrolein does NOT form when PG is used. It's formed only when glycerin (or its derivatives, like oils) is heated.
My concern with this is how was this vapor generated? Was the 'device' continually drawing vapor from the ecig? If so, chances are fairly good that the atomizer would get very hot, which would increase any acrolein generation. Or was the vapor generated for a few seconds, then wait while atty cools, repeat? I haven't read the report, yet. Does anyone who has read the report know the answer to this?
Just a curious old lab tech
The paper does not give much details about the analytical methods. Sampling or the vaping regime is certainly an issue that should have been taken great care of (to avoid overheating/running dry). Also interesting that the analysts collected 2 x 0.3g of condensed solution from two super-mini type cartridges, each reportedly holding 0.25g of e-liquid. Of course this could well be explained by additional liquid stored in the mesh of a primed atomizer (i.e. the cartridge was not necessarily dried to bone). However, I would feel more confident with the presented data, if the method section had actually documented that the authors had really understood what they have been analyzing.
Although the sampling conditions might well tend to err towards the worse side, the amount of produced acrolein is still notably less than what would be consumed from a single light cigarette (approaching the equivalent to one light cigarette, if we would extrapolate to a more realistic consumption of ~2ml liquid/day for an average e-cig user).
(find attached a very crude machine translation of the main text body of the article)
View attachment Miura et al. 2011 Safety assessment of e-cigs (translated).pdf
Although the sampling conditions might well tend to err towards the worse side, the amount of produced acrolein is still notably less than what would be consumed from a single light cigarette (approaching the equivalent to one light cigarette, if we would extrapolate to a more realistic consumption of ~2ml liquid/day for an average e-cig user).
(find attached a very crude machine translation of the main text body of the article)
View attachment Miura et al. 2011 Safety assessment of e-cigs (translated).pdf
Um, kind of reminds me of the assembly instructions that come with some imported products.
I went ahead and translated (most of) this. Hopefully it's not too long, and apologies if it's still hard to read - I did my best to preserve the Japanese sentences (which tend to run super long, as is often the case in Japanese). This is my first time ever translating material of a medical nature, so maybe some terminology is off and there was one part I didn't understand (the part in III.3 with urine proteins and sugars - I didn't get what the numbers meant). Also, I didn't do anything with the tables - it seemed too hard to deal with in Notepad.
HTML:
I. Introduction
Nicotine contained in tobacco is habit-forming and addictive. In addition
cigarettes have many carcinogens and toxins, so they are known to have a role
in the onset of various respiratory and circulatory ailments, and also, they are
known to increase the risk of a great number of malignancies leading to lung cancer.
Also, sidestream smoke contains toxins beyond even those in mainstream smoke, and
damage to health due to passive smoking has become a big problem [1]. Since 2004,
when they were first sold in China, electronic cigarettes as a nicotine delivery
system have amassed worldwide popularity [2]. These devices generally are made up
of a cartridge containing a liquid which includes nicotine, propylene glycol or
glycerin, and various flavorings. a heating element, and a battery, and by sucking
in the heating element is activated, and the solution is vaporized so that it can be
inhaled. As opposed to what one may call regular cigarettes, fire is not used, so
tar and carbon monoxide that accompany combustion and sidestream smoke from the tip
are not produced. Laugesen calls these nicotine-containing electronic cigarettes a
safer alternative to cigarette smoking [3]. On the other hand, the World Health
Organization has claimed that electronic cigarettes of this sort have not been
recognized as nicotine replacement therapy [4]. In addition, the U.S. Food and Drug
Administration has disassembled cartridges from two separate manufacturers and has
cited, in addition to nicotine, the presence of carcinogens such as tobacco-specific
nitrosamines, impurities characteristic of tobacco, and toxic diethylene glycol in
order to point out the danger of these devices [5]. In addition, because of the
flavors available, there is apprehension about young people getting their hands on
nicotine products [6]. Also, clinical trials concerning their safety have not been
done [7].
Against this background, electronic cigarettes free of nicotine were developed. The
object of this research is to test the safety of nicotine-free electronic cigarettes
developed by JBS Corporation when used by smokers. By sucking on these electronic
cigarettes, the glycerin-containing liquid inside the cartridge is heated and turns
into a vapor that is white in color. Through the inhalation of this vapor, the
devices are used as a tobacco-replacement product. In this study, subjects who were
smokers used these electronic cigarettes for 28 days, and tests were performed to
assess the devices' safety. Furthermore, as of October 2008, these devices were
already on the market.
When glycerin is heated, the toxic substance acrolein may be produced. This
substance is produced in the process of cooking food, and is also found in the
atmosphere [8]. With this in mind, the production of acrolein in the vapor emitted
by these electronic cigarettes was tested.
II. Methodology
1. Test equipment
Product name: Mild Smoker Next (JBS Corp.)
Device construction (Figure 1)
--
Filter Cartridge
Joint (atomizer)
Main unit (rechargeable battery)
--
Figure 1 Test equipment (electronic cigarette) configuration
--
Main unit (rechargeable battery)
Joint (atomizer)
Filter Cartridge
Contents of filter cartridge used in tests
Aqueous glycerin solution (approx. 0.25 g.)
Composition: Food-additive-grade glycerin, purified water
2. Subjects
Male and female volunteers 20 or older who were habitual smokers using 20 or more
cigarettes per day were chosen as subjects. Further, those who had used electronic
cigarettes before, those with an existing history of heart and/or respiratory
conditions, those with a predisposition for allergies or chronic dermatitis, and
others who were judged by the doctors in charge of testing to be unfit for this
study were excluded. Ultimately, 34 people who met the above conditions were
selected. The age of the participants was 44.9±13.7 (mean±standard deviation), with
26 males and 8 females. This study was carried out with the approval of the Osaka
City University Graduate Medical Research Ethics Committee (approval number 1794),
and the study was carried out upon receiving the written consent of participants
after thoroughly explaining the goals and content of the study in accordance with
the Declaration of Helsinki (revised 2008).
3. Testing Schedule
The testing schedule is shown in figure 2. First, prescreening using an advance
checklist was carried out, and those who were found to be suitable were requested to
enter the clinic as candidate subjects. The period of electronic cigarette use was
set for July 10 - August 6, 2010, with participants coming to the clinic a total of
three times - once before use began, once one week into use, and once the day after
the last day of use. The first time they came to the clinic, participants were
informed of testing procedures and their written consent was acquired.
--
Ethics Committee approval -> Recruitment and prescreening of subjects -> Entry and
acquisition of consent / Screening / Assessment of eligibility (First visit [before
beginning testing]) -> Electronic cigarette use - 28 days (Second visit [after one
week of use]) (Third visit [upon completion])
--
Figure 2 Testing schedule
--
At the first and third visits subjects were given a physical examination, and blood
and urine samples were collected. Further, intake of anything other than water was
prohibited from 9 P.M. of the night before these visits. It was recognized that a
single cartridge did not produce much smokelike vapor after 150 puffs. Based on
this, participants were instructed to replace the filter cartridge with a new one
every day, and after taking 150 puffs in a day or upon experiencing a sharp decline
in vapor output. No particular restrictions were placed on subjects' smoking during
the course of the study.
4. Checkup Provisions
1) Physical examination: Weight, BMI, blood pressure, pulse
During the first visit, heights were measured, and BMI was calculated using weight
measurements obtained at each visit. Also, blood pressure and pulse were measured on
an individual basis after 5-10 minutes of rest using an automatic sphygmomanometer.
2) Hematological analysis
Leukocyte count, erythrocyte count, platelet count, hemoglobin, hematocrit, MCV
(mean corpuscular volume), MCH (mean cell hemoglobin), MCHC (mean corpuscular
hemoglobin concentration)
3) Biochemical blood analysis
Albumin, blood urea nitrogen, creatinine, total bilirubin, AST, ALT, γ-GTP, total
cholesterol, triglyceride, HDL cholesterol, blood sugar (empty stomach)
4) Urinalysis
D-glucose, protein, and urobilinogen were assessed qualitatively on urinalysis
forms.
5) Interview examination
Interviews were given during the three visits. At the first visit, history of
illness, present health condition, and history of allergies was confirmed, and upon
completion of the study subjects were interviewed about any changes in physical
condition due to use of the test devices. Also, at the second visit, along with an
interview concerning changes in physical condition, consumption was determined by
measuring the change in the weight of spent filter cartridges, and in the case of
conspicuously low consumption of glycerin, guidance was given on inhalation
technique.
6) Journal
Participants were requested to keep a journal noting frequency of use of the test
device, changes in physical condition, and use of pharmaceuticals over the course of
the four weeks of use of the test devices.
5. Tests Concerning Acrolein Production
The toxic substance acrolein can be produced by heating glycerin. Therefore,
acrolein formation in the vapor emitted by electronic cigarettes was tested. For
this test, a chemical assessment research group was consulted. Vapor produced by
electronic cigarettes was trapped and cooled with liquid nitrogen, and 0.3 g. of the
resulting liquid was kept at a constant volume with methanol and subjected to
analysis by gas chromatography.
6. Statistical Analysis
All data were arranged based on mean value ± standard deviation. For assessment of
safety, weight, BMI, blood pressure, pulse, and the values from clinical blood tests
from before the test began and from after four weeks of use were analyzed using a
paired t-test, and a risk rate below 5% was considered significant. SPSS 15.0J for
Windows (SPSS Inc., Chicago, IL) was used for statistical analysis.
III. Results
34 people consented to this study, and up to the second visit, all were still
participating, but by the third visit, two participants had dropped out of the study
due to personal reasons, so 32 subjects successfully completed the study. As for the
test devices, weight of filter cartridges before and after use were compared on an
electronic scale (that measures in grams to up to three decimal places), and
compliance was confirmed based on these measurements and on the journal entries. All
subjects who successfully completed the study had used the device on over 90% of
days (proportion of days: 97.7±4.4%). Mean amount consumed was 0.181±0.040 g., and
compared with filter cartridges used in preliminary testing where 150 puffs used an
amount of 0.235±0.021 g. (n=13), compliance was judged to be good at over 70%.
1. Influence on blood pressure and body weight
Table 1 displays the changes before and after electronic cigarette use in body
weight, BMI, systolic blood pressure, diastolic blood pressure, and pulse. No change
was seen in weight and BMI. Both systolic and diastolic blood pressure showed a
statistically significant increase after four weeks of using the test devices, but
it was slight and judged to be within the normal physiological range of
fluctuation.
2. Blood tests
Table 2 shows the values from hematological analysis before and after use of
electronic cigarettes. Leukocyte count, erythrocyte count, platelet count,
hemoglobin, and MCHC were not affected by use of the test devices. On the other
hand, hematocrit, MCV, and MCH showed a statistically significant decrease over the
four weeks using the test devices, but it was a very small change and was within the
normal physiological rate of fluctuation.
Table 3 shows the values from biochemical blood analysis before and after electronic
cigarette use. Stasistically significant changes in blood albumin density,
creatinine content, AST, and HDL cholesterol were registered after the four weeks of
use, but they were slight and judged to be within the normal physiological range of
fluctuation.
3. Urinalysis
Out of the 32 subjects, irregularities were noticed in urinalysis results for two
subjects. One showed an increase of one in urine proteins, while the other showed an
increase of three in urine proteins and an increase in urine sugars of two, but
there were no fluctuations over the study period and electronic cigarettes had no
influence (Table 4).
4. Interviews and journals
Five subjects complained of throat irritation, one complained of lip irritation, and
two complained of coughing or phlegm due to use of the test devices. These symptoms
went away after testing was completed (Table 5).
5. Testing related to acrolein production
Results of testing two filter cartridges showed per-cartridge acrolein levels of
2.31 μg and 7.08 μg.
IV. Observations
This study targeted smokers and tested the safety of electronic cigarettes when used
with glycerin as an ingredient at the rate of one cartridge per day for 28 days.
Urine and blood analysis, subject journals, interviews by physicians, and also
physical examinations were done before using the test devices and again after four
weeks of use, but abnormal fluctuations in clinically tested variables and critical
signs of harm that could be considered to have a causal relationship to these test
devices were not found. While it was found that 7 out of 32 subjects (22%)
experienced mild symptoms of upper respiratory irritation while using the test
devices, these symptoms disappeared after the study's conclusion. Subjects continued
to smoke ordinary cigarettes during the study period. Accordingly, there is the
possibility that use of these devices can give upper respiratory irritation to a
certain proportion of people. When Bullen et al. compared the frequency of oral
cavity and throat irritation for groups of users of nicotine-free electronic
cigarettes, nicotine-containing electronic cigarettes, and the Nicorette® inhaler,
they reported finding 22%, 38%, and 88% respectively for the three groups [9].
These results match those of this study, and there were not thought to be any
problems with tolerability.
That acrolein is produced from the application of heat to the aqueous glycerin
solution in the test cartridges was evident from testing. Acrolein is formed when
cooking foods containing carbohydrates, vegetable oils, and animal fats and amino
acids, and is also obtained from the burning of petroleum and biodiesel fuels [8].
When administered orally to mice, rats, and dogs, acrolein did not show
carcinogenicity in tests for the same. Tests with exposure through inhalation were
also reported, but there were problems with the number of animals and with the
duration of the study, and data sufficient for evaluation were not obtained. As a
result, it is classified as Group 3 (agents not classifiable as to their
carcinogenicity to humans) by the International Agency for Research on Cancer (IARC)
[10]. Nevertheless, acrolein is found in nature, and human daily intake is 4.6 μg
from the atmosphere, 0.30 μg from drinking water, and 88 μg from dietary sources
[10]. In the case of tobacco, mainstream smoke from one cigarette contains
9.93-116 μg of acrolein, and sidestream smoke from one cigarette contains 288-348 μg
[10,11]. To give specific examples, Mild Sevens contain 47.6-110 μg per cigarette
and Frontier Lights contain 9.9-38.0 μg [11]. The filter cartridges used in this
study can be used over 150 times, and this is thought to be equal to a pack of (20)
cigarettes. Considering this carefully, while one cannot completely deny the
potential harm of acrolein, the amount of acrolein inhaled from one filter
cartridge in the test device is roughly equivalent to the amount humans are exposed
to from the atmosphere, and is less than the lowest amounts of acrolein found in the
mainstream smoke from one cigarette, so when one considers that these devices are
used by smokers for the purpose of reducing smoking, we may come to think of this
toxicity as unproblematic.
--
y-axis: cigarettes smoked (number / day)
x-axis: [left] before beginning the study [right] fourth week of the study
--
Figure 3 Change in number of cigarettes smoked as a result of using the test devices
--
This study showed a statistically significant decrease in cigarettes consumed while
the test devices were being used (figure 3). Since the filter cartridges used did
not contain nicotine, it cannot be simply thought that it was because of a decrease
in the desire for cigarettes that accompanies nicotine dependence, but a correlation
between use of the device and a decrease in cigarettes consumed was evident. The
reason for the decrease in cigarettes consumed is unclear, but it is possible that
compulsion to inhale from the device at least 150 times per day cut into
opportunities to smoke. Among 45 flavors offered under 25 brand names domestically,
nicotine was detected in 15 flavors under 11 brand names [12]. These cartridges and
devices that vaporize nicotine are in violation of the Pharmaceutical Business Law
[13]. Similar issues have been raised by the U.S. Food and Drug Administration, and
this can be considered a problem that should be given heed [6].
V. Summary
The safety of electronic cigarettes employing an aqueous glycerin solution for four
weeks was tested for smokers (of more than 20 cigarettes per day). In addition, the
change in amount smoked over the period the electronic cigarettes were used was
investigated. Blood tests, urinalysis, subject journals, and physician interviews
took place both before and after use, but abnormal fluctuations in clinically tested
variables and critical signs of harm that could be considered to have a causal
relationship to these test devices were not found, and the safety of the electronic
cigarettes used in this study was confirmed. Acrolein was detected in the vapor
produced by the electronic cigarettes, but it was less than the lowest amounts found
in the mainstream smoke from a single cigarette, and when used by smokers this is
not considered problematic. In addition, consumption of cigarettes declined
appreciably in correlation with use of these electronic cigarettes. Consequently,
the possibility that the electronic cigarettes tested are a safer alternative for
smokers is suggested.
Japanese sources:
10) Shin enerugī sangyō gijutsu sōgō kaihatsu kikō. Akurorein. Kagaku busshi�tsu no
shoki risuku hyōka sho 2006.
[New Energy and Industrial Technology Development Organization. Acrolein.
Preliminary chemical risk assessment paper. 2006.]
11) Kōsei rōdō shō. Heisei 11-12 nendo tabako-en no seibun bunseki ni tsuite
(gaiyō).
[Ministry of Health, Labour, and Welfare. Concerning constituent analysis of tobacco
smoke, Heisei 11-12 {1999-2000} (Outline)]
12) Dokuritsu gyōsei hōjin kokumin seikatsu sentā. Denshi tabako no anzensei o
kangaeru. http://www.kokusen.go.jp/news/data/n-20100818_1.html
[National Consumer Affairs Center. Considering the safety of electronic cigarettes.
http://www.kokusen.go.jp/news/data/n-20100818_1.html ]
13) Yaku shoku kan ma hatsu 0818 dai 5 gō (Heisei 22-nen 8-gatsu 18-nichi tsuki).
Nikochin o gan'yū suru denshi tabako ni kansuru yakuji kanshi no tettei ni tsuite
(irai).
[Pharmaceutical and Food Safety Bureau - Compliance and Narcotics Division report
No. 0818 Volume 5 (Heisei 22 {2010} August 18th)
Concerning thoroughness of the Pharmaceutical Business Law oversight of electronic
cigarettes containing nicotine (request).]
(Cited URLs were accessed in September 2010)
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