E-Cigarettes & Electronic Nicotine Delivery Systems

Michael V. Burke EdD Program Director Mayo Clinic Nicotine Dependence Center

• At the end of the presentation the participants should be able to

• Describe the history and patterns of use of ENDS

• Summarize literature on health and safety concerns

• Discuss current regulatory and policy status and impact on tobacco control

©2016 MFMER | slide-‹#› History • Current iteration developed by Chinese pharmacist ‘Hon Lik; • marketed by ‘Ruyan’ in May 2004 • ‘resembling smoke’ • However, basic idea with similar structure/function researched by Big Tobacco going back at least 50 years • First patent in US 1965 • ‘Vaping’ described in a paper in 1979

To inhale vapor from an e-cigarette

A battery-powered device that provides inhaled doses of vaporized nicotine solution (usually) along with flavorants and solvents

Over 466 brands Replete with differences

• 7764 unique flavors • Nicotine amounts • Cartridge capacity • Toxicants in vapor • Heating element/battery

• Disposable • Re-chargeable with pre-filled cartridges

Refillable with liquids Starter Kits ~ $40 - $180

• Vapor CEO say “a generation from now, people may forget what a machine-rolled cigarette looks like.”

• “Consumption of e-cigs may overtake traditional cigarettes in the next decade” – Bonnie Herzog, Wells Fargo analyst

©2016 MFMER | slide-12 Family Smoking Prevention and Tobacco Control Act • Became law on June 22, 2009, first time tobacco regulated Gives the Food and Drug Administration (FDA) the authority to regulate the manufacture, distribution, and marketing of tobacco products to protect public health, including • Restricts tobacco advertising and sales to minors • Requires warning labels on tobacco (*challenged in court) • Manufacturing of products, including changes to reduce harm (cannot ban tobacco or nicotine completely) • New FDA Center that regulates and funds research • Does not regulate tobacco treatment (IND issues) • As a result of a court case, ENDS are considered ‘tobacco products’ even though they do not contain tobacco • FDA has indicated that they intend to regulate ENDS

Expected 2015 Vapor Market Size: $3.5 Billion

Vapors/Tanks/Mods & E-Cigarettes: $1.5B Personal Vaporizers: $2.0B

C-store, Food, C-Store, Food, Online and Other Online and Other Drug, Mass Drug, Mass Vape Shops: retail Channels: retail channels: Retail Channels: Retail Channels: $1.2B $800M $400M $700M $400M

*Other non-tracked outlets, e.g. tobacco-only outlets, etc. Online: $400M Other*: $400M

Herzog B, et al. Tobacco Talk: More Bullish Than Retailers-Suggesting Vapor Growth Remains Robust. Wells Fargo Securities Equity Research. Jan 23 2015. ©2016 MFMER | slide-15 ©2016 MFMER | slide-16 U.S. TOBACCO COMPANIES JOIN THE MARKET

©2016 MFMER | slide-21 How are ENDS Advertised? • ENDS advertising expenditures across media channels tripled from $6.4 million in 2011 to $18.3 million in 20121 • Blu ENDS: spent $12.4 million on advertising in the first quarter of Image from nytimes.com 20132 • Companies spent more than $15 million on television ads between Jan-Sept 20133

Image from facebook.com/gGreenSmokeRacing

• 1 in 2 exposed in retail stores

• 2 in 5 saw e-cigarette ads on line

% Ever tried e- cigarettes % Current use e- cigarettes

©2016 MFMER | slide-26 Prevalence of e-cigarette use in USA • Past 30 day use increased 9 fold among HS students • 1.5% in 2011 • 13.4% in 2014 • Middle school • 0.6% in 2011 • 3.9% in 2014 • In 2013 263,000 middle and high school students who had never smoked a cigarette and used an e-cigarette

• Leading form of nicotine use in adolescents (CDC,2014)

• E-Cigarette use influences intention to use and progression toward combustible tobacco use

• E-Cigarette using youth almost twice as likely to have intentions to smoke conventional cigarettes (CDC,2014)

• Over one year, use of e-cigarettes at baseline was significantly associated with progression along the trajectory to cigarette (Primack, et al., 2015. JAMA Pediatr).

©2016 MFMER | slide-‹#› E-Liquid Solution Composition • Propylene glycol and/or vegetable glycerol • U. S. Food and Drug Administration • “Generally recognized as safe" (GRAS) for use as a direct food additive • Vapor that carries nicotine into body

• Nicotine • Varying amounts – Ex. 12 mg/ml same as 1.2% • Flavoring & coloring agents • Impurities & Additives

• Analyzed content of two leading e-cigarette brands • 18 varying types - flavoring, nicotine concentrations, and 0 mg/ml nicotine cartridges • Nicotine inhaler (control)

www.fda.gov ©2016 MFMER | slide-31 DPA's analysis: • Diethylene glycol in one cartridge @ 1% • Tobacco-specific nitrosamines (TSNA’s) in 1/2 of samples • As nicotine concentration increased, the number and concentration of TSNA’s increased. (Laugesen 2008, Health New Zealand Ltd.) • Tobacco-specific impurities detected in a majority of the samples tested • Anabasine • Myosmine • β-nicotyrine www.fda.gov ©2016 MFMER | slide-32 Nicotine Delivery

• “No nicotine” E-Cigarettes • Low levels of nicotine present in all cartridges tested, except one. • Three cartridges with same label • Markedly different amount of nicotine with each puff. • Range: from 26.8 to 43.2 mcg nicotine/100 mL puff

• One high-nicotine cartridge delivered 2 x as much nicotine as the nicotine inhaler

• Selected 16 brands

• Total nicotine level in 20 series of 15 puffs (300 total) • Nicotine delivered ranged from 0.5 to 15.4 mg • Effectively delivered nicotine in first 150 puffs • 50-60% of cartridge vaporized

©2016 MFMER | slide-34 Brand Model Labeled Nicotine in Nicotine in nicotine cartridge vapor (150 conc. (mg) puffs, mg) Trendy 808 18 16 3 Collins Age 18 11 4.7 Skycig Skycig 12 12 2.3 Liberro Black 18 19 6.1 Njoy Npro 18 16 5.0 Typical requires 12 x 46ml to deliver 1.5-2.6 mg cigarette puffs

Most brand cartridges contained less nicotine than labeled (18 of 35)

Seven brands contained more nicotine than labeled

©2016 MFMER | slide-35 Levels of selected carcinogens and toxicants in vapour (Goniewicz et al. 2013) • 12 brands of e-cigarettes tested • Compared with tobacco smoke and medicinal nicotine inhaler (10 sessions/15 puffs) • E cigarettes contained some cytotoxins & carcinogens • Carbonyls • VOC • PAH Levels 9–450 times lower than in cigarette smoke

Hyun-Ji Kim , et al. Journal of Chromatography A Volume 1291 2013 48 – 55. ©2016 MFMER | slide-37 Systematic Review of Health Effects of Electronic Cigarettes (Pisinger & Døssing, 2014) • High nicotine variability • Inter- and intra-brand • Inaccurate labels, ineffective delivery, etc. • Cytoxicity & carcinogens • Found in flavorants • TSNAs present in most samples (9-450 times lower than conventional cigarettes) • Metals & Particles • Particles of lead, tin, chromium, nickel and aluminum found in varying levels

• High levels of formaldehyde (Varlat, et al. 2015) • Formaldehyde within mixtures • Released when heated at high temperature (voltage)

• E-cigarettes associated with a significant increase in airway resistance (Vardavas, et al. 2011)

• Potential to induce inflammation in airway cells (Tartell, 2015) • Harmful effects similar to those observed in COPD

©2016 MFMER | slide-39 Nicotine Poisoning Cases on the Rise • Dec 2014 death of NY toddler who ingested liquid nicotine1 • 2014 CDC study found a dramatic increase in ENDS-related calls to poison centers from 2011-early 20142

1) ABC News, 2014 2) Chatham-Stephens K, et al. 2014 ©2016 MFMER | slide-40 Other Risk Concerns • Secondhand Exposure to ‘Vapor’ • Nicotine? • Other toxicants (recent press on formaldehyde)? • Long Term Impact of Propylene Glycol and other substances (eg Popcorn Lung?) • Flavorings (youth uptake risk?) • Lithium Ion batteries that can ignite/explode • No current standards for ingredients or product evaluation, so users do not know what they are ingesting

• 54 non-smoker volunteers from different homes: 25 living at home with conventional smokers, 5 living with nicotine ENDS users, and 24 from control homes (not using conventional cigarettes nor ENDS) • Measured airborne nicotine at home and biomarkers (cotinine in saliva and urine) during one week period • Results: • Mean of airborne nicotine was 0.74 μg/m3 (GSD1⁄44.05) in the smokers’ homes, 0.13 μg/m3 (GSD1⁄42.4) in the ENDS users’ homes, and 0.02 μg/m3 (GSD1⁄43.51) in the control homes. • Mean of salivary cotinine was 0.38 ng/ml (GSD1⁄42.34) in the smokers’ homes, 0.19 ng/ml (GSD1⁄42.17) in the ENDS users’ homes, and 0.07 ng/ml (GSD1⁄41.79) in the control homes • Cigarette exposure salivary cotinine > ENDS exposure & Control; No difference in salivary cotinine concentrations between ENDS exposure and Controls • Conclusion: Non-smokers passively exposed to ENDS absorb nicotine, but less than exposure to cigarettes

Ballbe, M. et al. (2014) Cigarettes vs. E-cigarettes: Passive Exposure at Home Measured by Means of Airborne Marker and Biomarkers. Environmental Research 135 76-80 ©2016 MFMER | slide-43 ©2016 MFMER | slide-44 Safety Conclusions

• No firm conclusions can be drawn on safety • Inconsistencies, methodological problems • Conflicts by authors • Lacking long-term research • ‘While likely safer than conventional cigarettes, they cannot be regarded as safe’ • Risk to public health should continue to me monitored • Concerns of renormalization of smoking

©2016 MFMER | slide-‹#› Randomized Trials of E-cigs Caponnetto, 2013 Bullen, 2013 (PlosOne) (Lancet) Population Unmotivated to quit Motivated to quit Inclusion criteria ≥10cpd for at least 5 years ≥10cpd for last year 18-70 years ≥18 years

Sample size 300 657

Intervention 7.2 mg E-cig 16 mg E-cig 7.2-5.4 mg E-cig 21 mg NRT patch 0 mg E-cig 0mg E-cig

No behavioral support Minimal behavioral support Intervention period 12 weeks 13 weeks (1 wk pre-quit)

Outcomes 6 months 6 months

• Reductions in cigarettes/day use and eCO levels were observed at each study visits in all three study groups • P < 0.001 vs baseline • No differences between groups • Smoking reduction: • 22.3% at week 12 • 10.3% at week 52 • Abstinence: • 10.7% at week 12 • 8.7% at week 52

• Smoking abstinence • E-cig 7.3% • Nicotine patches 5.8% • Placebo e-cig 4.1% • Not statistically different • 16 mg E-cig increased time to first relapse compared to nicotine patch (35 days vs. 14 days, P < 0.0001) • No significant differences in adverse events

©2016 MFMER | slide-49 Summary of E-cig RCTs • In smokers who use E-cigarettes for 12-13 weeks with little to no behavioral support • Six month quit rates are low (5-12%) • Quit rates are similar for nicotine vs nicotine-free e- cigs • Cigarette consumption is reduced • Mild, self-limiting side effects are reported • E-cigarettes are highly acceptable to users • In those motivated to quit: • E-cigs are not superior to nicotine patches • Nicotine e-cigs delay relapse back to regular smoking

©2016 MFMER | slide-50 FDA Proposed Regulation – November 2014 • Register with the FDA and report product and ingredient listings • Only make claims of reduced risk if the FDA confirms that scientific evidence supports it • Minimum age and identification restrictions to prevent sales to underage youth • Requirements to include health warnings • Not distribute free samples • Prohibition of vending machine sales, unless in a facility that never admits youth

©2016 MFMER | slide-51 What Can We Say About ENDS? • Lack of Scientific Consensus On: • Health Risks • Youth Addiction Potential • Potential to Cause Smokers to Continue Smoking • Effectiveness for Smoking Cessation • What We Know: • Less Harmful Than Combustible Cigarettes • Use by Non-Smokers is Uncommon • Nicotine Delivery Is Highly Variable, but Can Comparable to a Cigarette • Secondhand Exposure to Nicotine & Other Constituents Can Occur • Rapidly Changing Products and Regulatory Environment

http://www.smokinginengland.info/downloadfile/?type=report&src=6 ©2016 MFMER | slide-52 What to Tell Patients • We do not know: • If ENDS are safe • Which chemicals ENDS contain • How much nicotine users are inhaling • If ENDS are effective for smoking cessation based on controlled studies • Advice for Smoking Cessation? • Use FDA-approved medication • Behavioral treatment to improve medication adherence and address addiction challenges

Electronic Cigarettes. www.etobaccofree.gov ©2016 MFMER | slide-53 Key Points • Battery-powered device that vaporizes nicotine or non-nicotine solutions for inhalation • Rapidly gaining in popularity • No industry or public health standards established • Lack of evidence for safety and efficacy, though research is growing • Impact upon tobacco control/public health is to be determined