E-cigarettes- what are the real ingredientsSandra Hodge

o E-cigarettes, E-cigs, EC, electronic nicotine delivery systems (ENDS) or electronic non-nicotine delivery system (ENNDS), electronic smoking device (ESD), personal vaporizer (PV).

o Invented in 2003 by Chinese pharmacist Hon Lik - entered the European and US market in 2006 and 2007.

o 1st generation ("cigalikes”): look like tobacco cigarettes although rigid and heavier. Low single voltage, short charge time, non refillable cartridges.

o 2nd gen: larger overall; look less like tobacco cigarettes; longer charge time, refillable.

o 3rd gen*: very long charge time, refillable, programmable to connection to PC.

o 4th gen*: small, compact.

Electronic cigarettes

*adjustable voltage/ wattage (many users push to and beyond power limits). Newer models allow user to set the airflow and coil temperature.

o Over 500 brands and rapidly increasing.

o E-cigarette profit could surpass tobacco cigarettes profit within 4y.

Tobacco Company E-cig Brand(s)

British American Tobacco Vype, e-voke, Ten Motives, Glo I Fuse, CHIC

Lorrillard (3rd largest cig manufacturer in US)

Blu, Ble Cig, Sky Cigs, Blue E-cigs

Japan Tobacco Int E-lites, PloomImperial Tobacco Puritane, Jai, RuyanFontem Ventures (Imperial Tobacco Member Company)

Dragonlite

Phillip Morris NicocigsAltria (includes Phillip Morris USA) Mark TenRJ Reynolds American VuseSwisher E-Swisher

Electronic cigarettes

o Battery-powered, with cartridges or refillable tanks containing an E- liquid (propylene glycol (PG) and glycerine (VG), typically 95%) + flavours.

oOften contain nicotine (one US study that only 1% of respondents used liquid without nicotine).Brands / models differ in nicotine yield, nicotine delivery is not uniformbetween puffs, brands or within a brand, actual nicotine levels may notmatch labelled amounts.

o Inhalation activates pressure-sensitive circuit that heats the element (E-cig coil / atomiser). The absorbent wick, cotton or wadding inside (along with wire) soaks up and heats the E-liquid and converts it to vapour (also vaporizes nicotine for inhalation).

o Power source: biggest component of an E-cig, frequently a rechargeable lithium-ion battery.

o Liquid heated at very high temperature:

200-800C depending on settings

Electronic cigarettes - basic components

Injuries from exploding E-cigarette device

Brownson et al. NEJM 2016;375;14

A, B: burns after a lithium-ion battery exploded in a

pocket.

C: burn and blast injury after an E-cig device

exploded during use, which led to traumatic tattooing

of the right cheek.

D: wound from an E-cig explosion, with a rim of

discoloration characteristic of an alkali chemical burn.

National Academy of Sciences Engineering Medicine (NASEM): 2018 Systematic Review of

>800 peer-reviewed scientific studies with the

aim of informing the understanding of public

health risks and benefits of E-cigs.

Conclusion 14-1. “There is conclusive evidence that e-cigarette devices can explode and cause burns and projectile injuries. Such risk is significantly increased when batteries are of poor quality, stored improperly, or modified by users”.

Who uses E-cigarettes?

o Predominantly male although E-cig use is rising among women.

o Many users middle-aged men who also smoke tobacco cigarettes.

Walsberger S, et al.: Cancer Council NSW; 2015 NZ Establishment Survey August 2017 – July 2018, n=11,280

‘Ever-users’ of E-cigs E-cig users – last 7 days

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Who uses E-cigarettes?

o Majority of people who try an E-cig end up using them at least semi-regularly.

o Most E-cig users have a history of smoking regular cigarettes.

o E-cig use among those who have never smoked is very low, but rapidly rising.

‘Ever-users’ of E-cigs

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Walsberger S, et al. NSW Community Behaviours, Beliefs & Attitudes Towards E-cigarettes: Results of an Online Survey: Cancer Council NSW; 2015

E-cigarette use in Australia is on the rise

Fraser D, et al. Vapers’ perspectives on electronic cigarette regulation in Australia. Int J Drug Policy. 2015; Australian Bureau of Statistics,2013

Australia E-cig users are:1. Educated3. In high paying jobs

It’s not all about quitting

Walsberger S, et al. NSW Community Behaviours, Beliefs & Attitudes Towards E-cigarettes: Results of an Online Survey: Cancer Council NSW; 2015; Fraser D, et al. Vapers’ perspectives on electronic cigarette regulation in Australia. Int J Drug Policy. 2015

21% of Aussie E-cig users did not know if their E-liquid contained nicotine!

Attitudes about the safety and efficacy of E-cigarettes

Walsberger S, et al. NSW Community Behaviours, Beliefs & Attitudes Towards E-cigarettes: Results of an Online Survey: Cancer Council NSW; 2015

o Most E-cigs now made in China; Users find the products on the website and choose based on advertising, brand, service, images, highlights, prices…etc.

o Social website marketing also popular: Facebook, youtube, twitter and other foreign social networking sites. Payment methods: PayPal, TT and Western Union most common.

o Flavourings: Over 8,000 including tobacco, menthol, coffee, fruit, candy, alcohol, and unusual flavours such as cola and Belgian waffle.

o Many approved for oral ingestion but not for inhalation.

http://www.soarlogistics.com/en/worldnet.asp

E-cigarette marketing

Targeted advertising

And then

ADULT FOCUSSED FLAVOURS !!! Virginia tobaccoClassic tobaccoClassic menthol

Fruit medleyMango

Cool cucumberCool mint

Gottlieb: Thursday (13th Sep) - the agency has long commended e-cigarettes for their potential to move adults away from combustible products. BUT

"it cannot come at the expense of hooking a whole generation of kids on to nicotine and eventually onto tobacco products."

Many other chemicals reported in E-cig refill solutions, cartridges, aerosols and emissions.

E-cigarettes - other chemicals

Cheng T. Tob Control 2014;23:ii11–ii17.

o Superheated environment - can alter the structure of PG, VG and flavourings, generating aldehydes including formaldehyde, acetaldehyde and acrolein.

o Newer gen devices produce more aldehydes than 1st gen due to higher battery power output.

o Study of aldehyde emissions from two E-cig products at different power levels associated with normal and dry puff conditions (overheating).Experienced E-cig users took 4s puffs at 6.5, 7.5, 9 and 10W power levels.

o Formaldehyde, acetaldehyde and acrolein per 10 puffs were detected at 6.5W and 7.5 W with both products.

o Levels increased by 30-250 times in dry puff conditions, while acetone was detected only in dry puff conditions (that cause an unpleasant taste, which users learn to avoid).

E-cigarettes - aldehydes

Salamanca J, et al. E-cigarettes can emit formaldehyde at high levels under conditions that have been reported to be non-averse to users. Sci Rep. 2018;8:7559; Ogunwale M, et al. ACS Omega 2017;2:1207-14.

E-cigarettes - toxic heavy metals

The heating element, especially in new-generation high-power E-cigs, can decay or flake, releasing toxic heavy metals in the solution or aerosol.

2016: Elevated levels of nickel, chromium and aluminium reported in the urine and saliva of E-cig users.

2018: o E-cig vaporisers borrowed from 56 daily E-cig users - found many were being

exposed to potentially toxic levels of metals.o Assayed contents of the liquid surrounding the heating coil, as well as the

vaping liquid in the dispensary, and the aerosols the device produced.o Just under half of aerosols had lead levels that exceed EPA limits. o Average levels of nickel, chromium, and manganese also in unsafe margin.

Olmedo P, et al Metal Concentrations in e-Cigarette Liquid and Aerosol Samples: The Contribution of Metallic Coils. Environmental Health Perspectives 2018;126:10.1289/EHP2175

E-cigarettes and lung health

o The airway is especially vulnerable.

o The lung surface has the area of a tennis court.

E-cigarettes reduce bronchial epithelial cell viability

o Viability of NHBE48 and NHBE33 cells after exposure to air, E-cig vapour ±nicotine, PG, VG or cigarette smoke.

o * Sig. decrease in viability vs. clean air. # Sig. decrease vs. E-cig vapour without nicotine.

Scheffler S, et al. Int J Environ Res Public Health. 2015;12:3915-25. Evaluation of E-Cigarette Liquid Vapor and Mainstream Cigarette Smoke after Direct Exposure of Primary Human Bronchial Epithelial Cells

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o 16HBE cells ±control media, CSE, E-cig vapour, Paclitaxel for 24h.

o N ≥ 3; mean ± SD. * Sig increase vs. media treated cells.

Ween M et al. The effects of E-cigarettes on bronchial epithelial cells- looking beyond the toxic effects. Respirology 2018 in press

E-cigarettes reduce bronchial epithelial cell viability

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Scheffler S, et al. Evaluation of E-Cigarette Liquid Vapor and Mainstream Cigarette Smoke after Direct Exposure of Primary Human Bronchial Epithelial Cells. Int J Environ Res Public Health. 2015;12:3915-25.

o ROS-Glo™ H2O2 Assayo *Significant difference vs. clean air exposed cells. o # vs. E-cig vapour with 0% nicotine.

E-cigarettes increase oxidative stress

E-cigarettes increase inflammatory responses

E-liquid induces IL-6 production in primary human airway epithelial cells.Normal human tracheobronchial epithelial cells from young healthy non-smokers: E-liquid at various concentrations ± nicotine 24h.IL-6 protein levels in cell culture supernatants measured by ELISA.

Wu Q, et al. Electronic Cigarette Liquid Increases Inflammation and Virus Infection in Primary Human Airway Epithelial Cells. PLoS One 2014;9: e108342.

Research bronchoscopies on healthy non-smokers; smokers and E-cig users -bronchial brush/ BAL

Airways friable and inflamed in smokers, mostly in E-cig users.

E-cigarettes increase inflammatory responses

Ghosh A, et al. Chronic E-Cigarette Exposure Alters the Human Bronchial Epithelial Proteome. Am J Respir Crit Care Med. 2018;1198:67-76.

o Bronchial brush epithelial cells (51 subjects) –Proteomics: 300 proteins differentially expressed in smoker and E-cig user airways.

o E-liquids rapidly entered cells.

o Only 78 proteins commonly altered in both groups.

o 113 uniquely altered in E-cig users.o Confirmed in vitro in human airway epithelial

cultures, and murine nasal epithelia in vivo.

o Biological effects in part mediated by PG/VG base.

E-cigarettes and tobacco cigarettes are different

These changes are likely not harmless and may have clinical implications for the development of chronic lung disease.

Further studies are required to determine the full extent of E-cig use on the lung

The greatest similarity that E-cigs and combustible cigs have is that they are both designed to be deeply inhaled. They are very different otherwise.

Ghosh A, et al. Chronic E-Cigarette Exposure Alters the Human Bronchial Epithelial Proteome. Am J Respir Crit Care Med. 2018;1198:67-76.

Ween M et al, Phagocytosis and Inflammation: Exploring the effects of the components of E-cigarette vapor on macrophages. Physiol Reports 2017;e13370.

THP-1 macrophages + control media, 10% CSE, or E-cig vapour for 24h prior to exposure to apoptotic bronchial epithelial cell targets

*sig decrease vs. control; +vs. CSE

E-cigarettes reduce macrophage capacity to phagocytose apoptotic bronchial epithelial cells (efferocytosis)

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What’s the relevance of these findings to human lung disease?

ABNORMAL epithelial repair in COPD and asthma

Oxidative stress, respiratory pathogens, inflammation, inhaled environmental stimuli, cigarette smoke, E-Cig Vapour

o Mice were exposed to 8 wk tobacco smoke, air (control), or one of fourdifferent types of E-cig aerosol ± nicotine (0 or 12 mg/mL), PG or glycerine.

o No increase in inflammation but significant impairments in lung function.

o Mice also hyperresponsive to methacholine, regardless of the presence orabsence of nicotine.

Murine studies- E-cigarettes cause decreased lung function

o E-cig vapour containing nicotine caused more inflammation and reducedflexibility of the offspring’s airways, compared to vapour without nicotine.

McAlinden K, et al. Maternal E-cigarette Vaping Enhances Development Of Allergic Asthma In The Offspring, in 2017, Am Thoracic Soc. p. A7333

Maternal E-cigarette use enhances and worsens allergic asthma in offspring

Larcombe A, et al. The effects of electronic cigarette aerosol exposure on inflammation and lung function in mice. AJP (Lung), 2017:00203.2016.

McGrath-Morrow S, et al. The effects of electronic cigarette emissions on systemic cotinine levels, weight and postnatal lung growth in neonatal mice. PLoS One 2015;e0118344.

E-cigarettes inhibit mouse growth

Effects of E-cigarettes on comorbid conditions-cardiovascular disease and lung infection

Schweitzer K, et al. Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures. AJP(lung) 2015; Farsalinos K, et al. Comparison of the cytotoxic potential of cigarette smoke and electronic cigarette vapour extract on cultured

myocardial cells. Int J Envir Res Pub Health. 2013

E-cigarettes disrupt lung endothelial function

Cells treated with tobacco-flavoured E-cigs.Viability (mean % ±SD) vs. untreated cells.

..and reduce myocardial cell viability

Wu Q et al. Electronic Cigarette Liquid Increases Inflammation and Virus Infection in Primary Human Airway Epithelial Cells. PLoSOne 2014; e108342.

o Normal human tracheobronchial epithelial cells from healthy non-smokers pre-exposed to E-liquid without (NO-NIC) or with nicotine for 24h.

o Then infected with HRV-16 (104 TCID50/well) for 6 or 24h.o Viral RNA levels - RT-PCR.

E-cigarettes may predispose users to HRV infection

Ween et. al, unpublished data

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E-cigarettes reduce macrophage capacity to phagocytose lung bacteria

o Recent case of respiratory bronchiolitis interstitial lung disease in a 33-year-old male with history of a mixed germ cell tumour.

o Vaping 10-15 times a day alongside smoking traditional cigarettes.

o After 3 months of this regimen, multiple new areas of interstitial lung damage were identified.

o These areas of damage resolved after ceasing the use of a personal vaporiser.

Flower M, et al. Respiratory bronchiolitis-associated interstitial lung disease secondary to electronic nicotine delivery system use confirmed with open lung biopsy. Respirology case reports, 2017;5(3).

Case studies on the effects of E-cigarettes are beginning to emerge

No longitudinal studies into long term health risks of E-cigs… yet!

E-cigarettes as smoking cessation tools

o E-cigs have been described as potential smoking cessation aids for thosesmokers who have been unable to quit using other methods.

o While some (mostly population-based) surveys have reported supportiveevidence, others have found that E-cigs were ineffective as smoking cessationaids.

El Dib Review:o Systematic Review and Meta-Analysis 3 randomised trials (1,007 participants)

and 9 cohorts (13,115 participants) followed smokers over a long period toassess the effectiveness of different methods of quitting smoking.

o Concluded that based on available evidence it was not possible to ‘verify norexclude the hypothesis’ that E-cigs were more effective than other nicotinereplacement strategies.

Also stated there was a need for more ‘well designed trials in this field’.

El Dib R, et al. Electronic Nicotine Delivery Systems and/or Electronic Non-Nicotine Delivery Systems for Tobacco Smoking Cessation or Reduction: A Systematic Review and Meta-Analysis, BMJ Open 2017;7

E-cigarette as smoking cessation aids

National Academy of Science “Are e-cigarettes an effective means to quit smokingcombustible tobacco cigarettes?”

NASEM Conclusions:o 17-1. “Overall, there is limited evidence that e-cigarettes may be effective aids to

promote smoking cessation…..but subject to significant uncertainty”.

o 17-2. “There is moderate evidence from randomized controlled trials that e-cigarettes with nicotine are more effective than e-cigarettes without nicotine forsmoking cessation”.

o 17-3. “There is insufficient evidence from randomized controlled trials aboutthe effectiveness of e-cigarettes as cessation aids compared with notreatment or to Food and Drug Administration - approved smoking cessationtreatments”.

Stratton K, et al. Public Health Consequences of E-cigarettes, National Academy of Sciences 2018;17:15.

o A key issue for public health policy makers is whether E-cigs could create anew pathway into smoking for young people.

NASEM [17,389 adolescents and young adults].Are e-cigarettes an “initiation pathway” of youth to smoking combustible tobaccocigarettes?

Conclusion 16-1. “There is substantial evidence that e-cigarette useincreases risk of ever using combustible tobacco cigarettes among youthand young adults”.

Conclusion 16-2. “Among youth and young adult e-cigarette users who ever usecombustible tobacco cigarettes, there is moderate evidence that e-cigarette useincreases the frequency and intensity of subsequent combustible tobaccocigarette smoking”.

E-cigarette use and smoking in youth

Stratton K, et al. Public Health Consequences of E-cigarettes, National Academy of Sciences 2018;17:15.

What about the risks to others?

o Measured cotidine (a nicotine by-product) in blood of non-smokers afterspending 1h in in a room with E-cig useror cigarette smoker.

o Like tobacco, the only way cotinineappears in the blood of non-users isthrough second-hand exposure.

White = baseline, black = immediately after a session grey = 1h after a session

Flouris A, et al. Inhal Toxicol 2013;25(2):91-101. Acute impact of active and passive electronic cigarette smoking on serum cotinine and lung function.

Passive Vaping, does it exist?

Compounds listed in California’s Safe Drinking Water and Toxic EnforcementAct.

Side Stream Vapouro Benzene: in pesticides and gasoline, emissions from burning coal and oil,and motor vehicle exhaust. Carcinogen, aplastic anemia, leukaemia,reproductive effects.

o Diethylene Glycol: used in antifreeze and capable of causing eye irritationand respiratory tract irritation.

o Isoprene: used to make synthetic rubbers, probable carcinogen.o Formaldehyde: carcinogen.o Nicotine: effects the nervous system and the heart.o Nnitrosonornicotine (NNN): carcinogen.o Propylene Glycol: solvent for food colours and flavours, used in the paintand plastics industries; causes respiratory, throat and nose irritations.

o Toluene: poisonous industrial solvent. CNS dysfunction, possiblecarcinogen, URT irritation.

Compounds in side stream vapour

Czogala J, et al. Secondhand exposure to vapors from electronic cigarettes. Nicotine Tob Res 2014;16:655-62; Ingebrethsen, B, et al. Electronic cigarette aerosol particle size distribution measurements. Inhalation Toxicology 2012;24:976-84.

a = by machine b = exhaled by user

Side stream vapour contains particles

E-cigarette aerosol particulate matter size comparable to cigarette smoke thus similar potential to penetrate and deposit in the lung tissue. Particles ≤ than 2.5μm can adversely affect the respiratory and circulatory systems of humans.

NICOTINE Particulate matter 2.5 (PM2.5)

NASEM conclusionsConclusion 14.2 “There is conclusive evidence that intentional or accidental

exposure to e-liquids (from drinking, eye contact, or dermal contact) can result in

adverse health effects including but not limited to seizures, anoxic brain injury,

vomiting, and lactic acidosis”.

Conclusion 14.3 “There is conclusive evidence that intentionally orunintentionally drinking or injecting e-liquids can be fatal.”

Potential effects of E-cigarettes on the ‘non-user’

o Australia: Number of calls to the four Poison Information centres regarding E-

cigs: 2 to 54 between 2009 and 2013, most relating to children’s exposure.

o USA: Number of calls to poison centers for

E-cig exposures, by month 2010–2014.

Calls to Poison Information Centres

Stratton K, et al. Public Health Consequences of E-cigarettes, National Academy of Sciences 2018;17:15; Schripp T, et al. Does e-

cigarette consumption cause passive vaping? Indoor Air 2013;23:25-31.

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There isn’t enough information!

PubMed –

Tobacco Cigarettes 52,801 (8,118 Reviews)

E-cigarettes 1,007 (96 Reviews)

NHMRC CEO made a statement in March 2015:

“Electronic cigarettes…….. have recently gained prominence in Australia and

around the world, and are marketed online as a method to assist smokers to quit,

or a ‘safe alternative’ to conventional tobacco cigarettes.

However, there is currently insufficient evidence to support these claimsand further research is needed to enable the safety, quality and efficacy of

e-cigarettes to be assessed”.

There isn’t enough information!

There are real doubts in relation to efficacy and

concerning data on harms.

A precautionary approach to regulation is wise.

The genie will never be able to be put back in the bottle !