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UK E-Cigarette Summit 2017
Relative risks of cancer posed by combustible
and vapourising forms of nicotine delivery:
Evidence from chemical exposures
University of St Andrews
Ed Stephens
Scope of presentation
• Focus on cancer
• Carcinogenic potential of different
nicotine aerosols assessed
• Use published data from many labs
• Aim to create a potency spectrum for
comparing tobacco smoke, heat-not-
burn emissions, e-cigarette vapour and
other nicotine-delivering aerosols
• Convert potencies to risk via exposure
• Use tobacco smoke as basis for
comparing relative risk From Tobacco Atlas, 4th edition
Projected global tobacco-
attributable deaths in 2015
Carcinogens in tobacco
• US Food & Drug Administration (FDA) list of Harmful & Potentially Harmful Constituents (HPHC) in tobacco products
• 93 chemical compounds in list, including
75 carcinogens
25 respiratory toxicants
12 cardiovascular toxicants
• Others have added toxicants specifically for e-cigarettes (HPHC+)
• Full HPHC+ analysis well beyond the capability of most labs (>20 separate analytical procedures)
• Major tobacco companies use Labstat Inc. for independent analyses of HPHC or HPHC+ suite in their products, along with QA monitors (3R4F). Now publishing results in peer review journals
• Inhalation unit risk is the increased cancer risk from inhalation exposure to 1 µg/m3 of a compound for a lifetime
• Unit risks for 44 HPHC carcinogens found in various sources
Prioritising Carcinogens
Cancer Potency (individual compound) = Unit risk x Concentration
Cancer Potency (aerosol) = sum of individual potencies
10-7 10-6 10-5 10-4 10-3 10-2 10-1 10010-5 10-6 10-710-410-310-2
Carcinogen unit risk (µg m -3)-1 3R4F concentration (µg mL -1)
Several carcinogens
not yet assigned unit risks Several carcinogens not quantifable
CONCENTRATION IN SMOKEUNIT RISK
0 10 20 4030
Cancer potency %
3R4F reference
cigarettes
1,3-Butadiene
Formaldehyde
AcrylonitrileAcetaldehyde
Acrylamide
BenzeneEthylene oxide
HPHC data
from Margham et al.
(2016)
increasing unit risk increasing concentration
Comparing Priority Carcinogens R
an
ked
po
ten
cy
E-CIGARETTE
ePen (BAT)
0 10 20 4030
Cancer potency % Cancer potency % Cancer potency % Cancer potency %
HPHC data
from Margham et al.
(2016)
HPHC data
from Breheny et al.
(2017)
HPHC data
from Forster et al.
(2017)
HPHC data
from Margham et al.
(2017)
>5% potency
1,3-Butadiene
Acrylonitrile
Acetaldehyde
Acrylamide
Benzene
>5% potency
Acrylamide
Acetaldehyde
Chromium
>5% potency
Acetaldehyde
Chromium
Formaldehyde
>5% potency
Formaldehyde
Acetaldehyde
COMBUSTED
TOBACCO 3R4F
HEAT-NOT-BURN TOBACCO
c-THP (BAT) THS (PMI)
Carbonyl
Volatile
Metal
Semivolatile
Amine
Nitrosamine
PAH
Other
1,3-Butadiene Acrylamide AcetaldehydeFormaldehyde
Acetaldehyde
0 10 20 30 40 50 60 0 10 20 30 40 50 0 10 20 30 40 50 60 70 80
Range of Cancer Potency in Tobacco Smoke
Cancer potency
Counts et al. (2005)
Pazo et al. (2016)
Bodnar et al. (2012)
PMI: global (n=48)
CDC: US (n=52)
RJR: US (n=61)
TOBACCO SMOKE
BRANDS
6.1x10-5 7.7x10-54.5x10-5
PROTOCOL
Health Canada
+2s-2s
Cancer potency calculated
on basis of concentration,
e.g. µg/mL
E-cigarettes usually
reported as µg/N puffs of
fixed volume
Tobacco smoke & HnB
reported as µg/consumable
Detailed procedures for
resolving incompatibilities
and for calculating potency
& risk described by
Stephens, (2017) Tobacco
Control
(doi:10.1136/tobaccocontro
l-2017-053808)
Cancer Potency Spectrum: From Fresh Air to Smoke
Cancer potency (normalised to tobacco smoke)
Indoo
r a
ir(O
ldh
am
et
al. 2
017
)
Ou
tdoo
r a
ir
Nicotineinhaler
Tobaccosmoke
Ambientair
10010-110-210-310-410-510-6
To
ba
cc
o s
mo
keAmbient
air
Nicotine
inhaler
Cancer potency (normalised to tobacco smoke)
10010-110-210-310-410-510-6
Cancer Potency Spectrum: Tobacco Products
Tobacco blends for THS
THS Schaller et al. (2017)
THS Forster et al. (2017)
THP Forster et al. (2017)
Cancer Potency Spectrum: E-Cigarettes
Analyses of E-cigarette emissions collected from 16 publications
ePen has full HPHC, others have fewer analytes (mainly carbonyls)
To
ba
cco
sm
ok
e
He
at-
no
t-B
urn
Nicotine
inhaler
ePen:
Margham et al.
(2016)
Am
bie
nt
air
Cancer potency (normalised to tobacco smoke)
10010-110-210-310-410-510-6
Cancer Potency of E-cigarettes by Generation
10-1
10-2
10-3
10-4
10-5
100
101
Ca
nce
r p
oe
tncy
rela
tiv
e t
o t
ob
ac
co
sm
ok
e
4th3rd2nd1st
e-cigarette generation
potency of tobacco smoke
GENERATION
1st
2nd
3rd
4th
Formaldehyde–power–user experience 1
Farsalinos et al. (2017) Food and Chemical
Toxicology 109, 90-94
Experiment: 26 former smokers now e-cigarette users recruited
Same device & liquid vaped (CE4, Innokin iTaste VV, 6 mg/mL nicotine)
Voltage increased in steps and users reported taste responses
3.5 4.0 4.5 5.0
Volts
0.001
0.01
0.1
1
Fo
rmald
eh
yd
e (
µg
/mL
)
data from Farsalinos et al. (2017)
Total aversion
Some aversion
No aversion
(r2 = 0.98)
Formaldehyde–power–user experience 2
To
bac
co
sm
oke
He
at-
no
t-B
urn
em
iss
ionNicotine
inhaler
Ambient
air
No aversion
Some aversion
Total aversion
Cancer potency (normalised to tobacco smoke)
10010-110-210-310-410-510-6
Unexplained Potency Variation in Same Brand & Flavour
Solid lines connect the same
brand & flavour in 2nd
generation disposable
cartomisers (US).
Voltage/power was not varied.
(data from Klager et al., 2017)
Cancer potency (normalised to tobacco smoke)10010-110-210-310-410-510-6
Vivid VanillaBerryPina ColadaOriginal TobaccoJava JoltMenthol
To
bac
co
sm
oke
He
at-
no
t-B
urn
Ambient
air
Other factors?
METALS IN EMISSIONS • E-cigarette devices of all generations are
largely constructed of metal
• Coils most commonly nichrome (NiCr alloy) or
kanthal (FeAlCr)
• Very few measurements of metals in vapour
• No studies of metal speciation in e-cigarette
emissions, e.g. Cr(0), Cr(III) & Cr(IV) have low
toxicities whereas Cr(VI) is highly carcinogenic
AEROSOL SIZE DISTRIBUTIONS Mikheev et al. (2016) Real-Time Measurement of Electronic Cigarette
Aerosol Size Distribution and Metals Content Analysis. Nicotine &
Tobacco Research 18,1895-1902
Scungio et al. (2018) Measurements of electronic cigarette-generated
particles for the evaluation of lung cancer risk of active and passive
users. Journal of Aerosol Science 115, 1-11
From Potency to Risk
Risk = Potency x Exposure
In this model exposure is a simple function of the volume of aerosol inhaled
Cigarettes: 15 cigs/day x 10 puffs x 50 mL/puff = 7.5 L smoke/day
e-cigarettes: Robinson et al. (2015) report 30L/day as the mean inhaled vapour
across a sample (n=21) i.e. x4 greater exposure - consistent with Behar et al. (2014)
Cancer potency (normalised to tobacco smoke)10010-110-210-310-410-510-6
Ambient
air
Nicotine
inhaler
He
at-
no
t-B
urn
To
bac
co
sm
ok
e
No aversion
Some aversion
Total aversion
POTENCY
POTENCY x4
Effect of emissions on other medical conditions
RESPIRATORY & CARDIOVASCULAR
DISEASE
Cancer potential appears to be dominated
by carbonyls - most studies of emissions
have focused on carbonyls (aldehydes)
Carbonyls are implicated in respiratory
but not CV disease. Also volatiles (VOCs),
metals, carbonyls, PAHs and other
compounds involved
Applying analogous approaches to
respiratory and cardiovascular diseases is
currently limited by the very small number
of studies with e-cigarette emissions data
for the wider range of HPHC+ toxicants