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