Download Toxic and Cancer Causing Substances in the Urine of e

Toxic and Cancer Causing Substances
in the Urine of e-Cigarette Users vs.
Smokers
Stephen S. Hecht, Steven G. Carmella, Delshanee Kotandeniya, Makenzie
E. Pillsbury, Menglan Chen, Benjamin W.S. Ransom, Rachel Isaksson
Vogel, Bruce Lindgren, Elizabeth Thompson, Sharon E. Murphy, and
Dorothy K. Hatsukami
Tobacco Research Programs and Masonic Cancer Center
University of Minnesota
Toxic and Carcinogenic Compounds in Vapor from
e-Cigarettes
• A variety of potentially harmful compounds have been identified in e-cigarette vapor
Formaldehyde (human carcinogen)
Acetaldehyde (carcinogen related to alcohol drinking)
Acrolein (highly irritating and toxic)
Toluene (toxic)
NNN, NNK (tobacco carcinogens related to nicotine)
Metals (possible carcinogens and toxicants)
• Generally about 10 – 500 times less than in cigarette smoke
• A possible exception is the human carcinogen formaldehyde, levels of which can
increase drastically at high voltages.
Goniewicz et al, Tob. Control 2013; Kosmider et al, Nicotine Tob. Res. 2014;
Jensen et al, New. Engl. J. Med. 2015
Background
• No standard methods exist for measurement of e-cigarette
constituents.
• There are many different product types and variables.
• This is in contrast to established methodology for tobacco cigarettes.
• Machine measurement of constituents provides a method of
comparison but generally does not reproduce human smoking.
• Measurements of the toxicants or their ultimately excreted forms
(metabolites) can be an effective way of assessing exposure and
possible adverse effects.
Background
• Measurement of these metabolites in urine is known as the
“biomarker approach.”
• Limited studies to date have reported biomarkers in the urine of ecigarette users.
• Hecht et al, Nicotine Tob. Res., 2014
• Shahab et al, SRNT Proceedings, 2015
• Goniewicz et al, SRNT Proceedings, 2015
• We compared biomarkers in the urine of e-cigarette users and
cigarette smokers.
Study Design: e-Cigarette Users
• Inclusion criteria
•
•
•
•
18 years or older
Good physical and mental health
Stable on psychiatric medicines if using them
Did not smoke cigarettes for at least 2 months (CO < 6
ppm)
• Not knowingly exposed to secondhand cigarette smoke
• Using e-cigarettes for at least 1 month and 4 days per week
• Exclusion criteria
• Current use of medicinal nicotine or tobacco products
• Pregnant
• Subjects attended a clinic visit
• Completed a tobacco and e-cigarette use history
questionnaire
• Collected a spot urine sample
• Based on these criteria, there were 28 eligible e-cigarette
users.
e-Cigarette Brands Used
e-Cigarette Brand
Aqua
Aspire
Buck Naked Express
eGo
eQ
Green Smokeb
Green Smart Livingb
Hades
iGo
Itazte
JDTech
Kanger
MyVape
Origin
Provari
Sigelei
SMOKTech
V2b
Vapor4Life
Vision Spinner
Vmax
Number of
Usersa
2
2
1
8
1
1
1
1
1
5
1
7
1
1
4
1
2
1
1
3
1
a
Some users used more than one brand.
b.
Two subjects used cartridges (Green Smoke,
V2 and Green Smart Living); all others used
tank systems.
Demographics: e-Cigarette Users
• Age
34.0 ± 12.7 years
• Female
42.9%
• Non-Hispanic White
92.6%
• Education
89% some college
• Cigarettes per day
before switching to ecigarettes
21.1 ± 10.3
Comparison Groups – Cigarette Smokers
• Data from participants in some of our previous studies
• 165 smokers of “light cigarettes” interested in quitting
• 40 smokers who provided spot urine samples
• 17 smokers who provided 24h urine samples prior to quitting
• 18 smokers entering a nicotine reduction trial
• 86 smokers at baseline of a chemoprevention trial
• Demographics similar to e-cigarette users
• Essentially identical analytical methods used
Zarth et al, J. Chromatog B. 2014; Carmella et al, Chem. Res. Toxicol. 2009; Hatsukami et al, Addiction 2010
Urinary Biomarkers Analyzed
Biomarker
1-hydroxypyrene
Total NNAL
Total NNN
3-HPMA
HMPMA
2-HPMA
SPMA
Cotinine
PGF2α and PGEM
Source in e-Cigarette
PAH: Carcinogenic
combustion products
NNK: Cause of lung cancer
NNN: Cause of oral cancer
Acrolein: toxic
Crotonaldehyde: toxic
PO: Cause of cancers
Benzene: leukemia
Nicotine
Oxidants and
inflammation
Hecht SS, Yuan J-M, Hatsukami DK Chem. Res. Toxicol. 2010
Characteristics of the Cancer
Causing Agents and Toxicants
• PAH: Ubiquitous combustion products among which are strong
carcinogens (BaP: IARC group 1)
• NNK/NNN: Powerful tobacco carcinogens (IARC group 1)
• Acrolein/crotonaldehyde: Strong irritants and toxicants
• PO: A carcinogen which might be formed from propylene
glycol
• Benzene: cause of leukemia in humans (IARC group 1)
• Nicotine: addictive agent in tobacco products
• Oxidants and inflammation: involved in cancer causation
International Agency for Research on Cancer Monographs on the Evaluation of Carcinogenic Risks to Humans
U.S. National Toxicology Program Report on Carcinogens
Characteristics of the Carcinogens and Toxicants
• All appear on FDA’s list of harmful and potentially
harmful constituents of tobacco smoke.
• Some are recommended by WHO for mandated lowering
in tobacco smoke.
• They are considered to play an important role in cancer
induction by tobacco smoke.
Federal Register 76 (156) 2011; Burns, D. et al Tobacco Control, 2008
Exposure Biomarker Levels are Significantly Lower in
e-Cigarette Users Than in Cigarette Smokers
(Geometric means, pmol/ml urine)
e-Cigarette Users
Cigarette Smokers
(from our previous studies)
1-hydroxypyrene
Total NNAL
Total NNN
3-HPMA
HMPMA
2-HPMA
SPMA
Cotinine
0.38
0.02
0.005
1100
705
141
0.29
1880
0.97 (p<0.0001)
1.21 (p<0.0001)
0.073 (p<0.001)
4040 (p<0.0001)
4990 (p<0.0001)
399 (p = 0.006)
2.85 (p<0.0001)
1930-3930 NS
Exposure Biomarker Levels are Similar in
e-Cigarette Users vs. Non-Smokers
(pmol/ml urine)
e-Cigarette Users
1-hydroxypyrene
Total NNAL, NNN
3-HPMA
HMPMA
2-HPMA
SPMA
Typical non-smoker values
0.38
0.02
1100
705
141
0.29
0.37 (NHANES study)
Not detected (unless SHS)
750 – 1200 (literature range)
800 – 2100
370 – 480
0.11 – 2.1
All metabolites except NNAL are detected in virtually all human urine samples.
Grainger, J. Environ Res. 2006; Hecht, S. Chem. Res. Toxicol. 2010
Biomarkers of Oxidants and Inflammation are
Similar in e-Cigarette Users and Smokers
e-Cigarette
Users
(median)
Oxidants
(pmol/ml)
Inflammation
(pmol/ml)
a.
b.
Smokersa
(median)
0.80 (0.13 – 2.17)
N = 28
0.80 (0.18 –
2.74)
N = 83
P = 0.53b
32.1 (5.0 – 184)
N = 28
31.4 (3.0 – 149)
N = 86
P = 0.98
from an ongoing study
non-parametric Wilcoxon rank sum test
Summary
• Levels of several biomarkers of exposure to cancer causing and
toxic agents were significantly lower in e-cigarette users than in
cigarette smokers.
• Urinary nicotine metabolite levels were similar in the e-cigarette
users and cigarette smokers.
• Levels of oxidant and inflammation biomarkers were similar in
smokers and e-cigarette users. This observation requires further
study.
• Biomarker studies on formaldehyde exposure in e-cigarette users
need to be conducted.
Nicotine and Tobacco Research 2014 doi: 10.1093/ntr/ntu218
Summary
• In general, our studies demonstrate that e-cigarettes are
likely less harmful than tobacco cigarettes.
• This is logical because e-cigarettes do not contain tobacco
and do not produce combustion products.
• Nevertheless, allowing e-cigarette use in indoor spaces
could begin to reverse the significant progress that has
been made in regulation of indoor smoking
o Changes social norms
o Reduces cues for smoking
o An established method of tobacco control
Acknowledgements
Grant support from the U.S. National Cancer Institute:
U19 CA-157345 and R01 CA-81301
Mass spectrometry in the Analytical Biochemistry Shared
Resource, Masonic Cancer Center, University of Minnesota,
supported in part by Cancer Center Support Grant CA77598
Bob Carlson, editorial support