The Burgeoning Health Crisis of Youth and e-Cigarettes


RELEASE DATE:

May 1, 2019

EXPIRATION DATE:

May 31, 2021

FACULTY:

Elsen C. Jacob, PharmD, BCPS, BCGP, CPPS
Assistant Professor
Department of Clinical Health Professions
St. John's University College of Pharmacy and Health Sciences
Queens, New York

FACULTY DISCLOSURE STATEMENTS

Dr. Jacob has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-19-025-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To provide pharmacists an overview of electronic cigarettes (e-cigarettes) with a focus on their potential harms, impact on youth, and the current legislation surrounding them.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Define the term e-cigarettes and discuss the evolution of available products.
  2. Recognize the potential dangers of e-cigarette use, particularly in youth.
  3. Summarize the current legislation pertaining to e-cigarettes.
  4. Examine strategies to reduce youth use of e-cigarettes.

ABSTRACT: The use of electronic cigarettes (e-cigarettes) in youth has markedly increased in recent years. The risks associated with these products are multifold, including neurodevelopmental effects linked to tobacco exposure, increased risk for lifetime nicotine addiction, and exposure to toxic chemicals with negative effects that are only beginning to be understood. Manufacturers have used aggressive marketing strategies, such as introducing appealing flavors to promote e-cigarette usage in youth. Persistent public-health efforts to restrict youth access to these products are imperative. As such, it is important that pharmacists gain critical knowledge to inform the public about the potential harms of e-cigarettes.

Tobacco use is well recognized as the chief preventable cause of death in the United States.1 Diseases and conditions associated with tobacco use include various cancers, stroke, heart disease, diabetes, chronic obstructive pulmonary disease, pneumonia, blindness, hip fractures, ectopic pregnancies, and many others.2,3 In addition to the grave negative health consequences of tobacco use, there is an associated financial burden. In fact, the U.S. spends approximately $300 billion a year on medical care, lost productivity, and other factors related to tobacco usage.1

The relationship between cigarette smoking and preventable diseases was first highlighted in the 1964 Surgeon General's Report on Smoking and Health.3 Over the next 5 decades, many public-health initiatives, research, and policies informed the public on the health hazards linked to combustible cigarette smoking.3 Promisingly, this concerted effort led to a significant decline in cigarette smoking since the 1964 report as highlighted in the 2014 Report of the Surgeon General entitled "The Health Consequences of Smoking—50 Years of Progress."3 Indeed, tobacco use by youth had also been on a steady decline.3 In 1997, more than one in three high school students smoked tobacco products compared with one in five by 2011.3

Unfortunately, the once-steady decline in tobacco usage has since regressed.4 According to the CDC, 27.1% (4.04 million) high school students used tobacco products in 2018, compared with 24.2% (3.69 million) in 2011.5 This reemergence in tobacco use is primarily attributed to electronic nicotine delivery systems, or e-cigarettes.4 Although not highlighted, the 2014 Surgeon General report had remarked on the need to monitor the emergence of e-cigarettes.3 In 2016, the next Surgeon General report focusing on tobacco was entitled "E-cigarette Use Among Youth and Young Adults: A Report of the Surgeon General" and detailed the rise and prevalence of e-cigarettes among U.S. youth.4

Since the 2016 Surgeon General report, youth use of e-cigarettes has continued to rise at an alarming pace. The CDC reported that in 2018, 3.05 million, or 20.8%, of high school students disclosed e-cigarette use, a marked increase compared with 1.5%, or 220,000 students, who revealed usage in 2011.5 Even more shocking was that between 2017 and 2018, there was a 78% increase in e-cigarette use among high school students and a 48% increase in use among middle school students.5 This sharp increase in youth use of e-cigarettes has been attributed to flavors that appeal to youth, the discreet packaging of products, the misconception that e-cigarettes are safer than combustible cigarettes, and the lower cost of e-cigarettes compared with combustible cigarettes.4-6 This concerning trend of youth e-cigarette use has led to renewed public-health efforts to curb usage of these products, especially among children.4

E-CIGARETTES

The modern version of the e-cigarette was invented in 2003 by a Chinese pharmacist, and by 2007 e-cigarettes exploded onto the U.S. market.4 Since then, manufacturers have developed a broad variety of e-cigarette products with varied design, appearance, and names.4

E-cigarettes utilize a battery-powered coil to vaporize a solution, commonly referred to as an e-liquid.7-9 E-cigarettes generally contain nicotine, propylene glycol, glycerol, metals, and depending on the product, flavored chemicals. When vaporized, all of these substances are inhaled by the user.7-9 Some commonly used products include cigalikes, vape pens, e-cigarettes, mods, and tank systems, with usage of e-cigarette products depending on user preference and geographic region.4 The habit of using an e-cigarette product is commonly referred to as vaping, which in 2014 was designated as the Oxford Dictionary Word of the Year.10

The increase in e-cigarette products is not without financial impact to the U.S. public. Market estimates in the U.S. are shocking, with public spending projected at approximately $6 billion in 2018.8 This is not surprising, considering that major tobacco companies, including Altria–Philip Morris, Reynolds American–Lorillard, and ITG Brands, have invested in the e-cigarette market.8 In fact, companies spent $125 million on e-cigarette marketing in 2014 alone.8

Due to the diversity of products, e-cigarettes can be divided into four generations: first, second, third, and JUUL and related products.11

First Generation

These older e-cigarette products are closed-system disposables that resemble cigarettes and are commonly referred to as cigalikes due to their resemblance to cigarettes.4,11,12 Included in this generation are also products that resemble pipes or cigars.4

Second Generation

These newer products are open-system, rechargeable devices that are generally pen-shaped and larger.11,12 They are also commonly referred to as tank systems due to their ability to hold large quantities of e-liquid.4

Third Generation

Products that fall into this category are often large, highly customizable, and refillable, earning them the name mods.11 Users are able to customize the e-liquid, heat settings, quantity of nicotine, and puff volume.12 These devices may also have various accoutrements, such as cartridges, refill bottles, and tanks.12

JUUL and Related Products

Products in this category are rechargeable and feature a high-tech design that is especially appealing to youth and young adults.11 These products also utilize nicotine salts in their e-liquid, which is intended to allow for the rapid delivery of a larger amount of nicotine.11 Of the many e-cigarette products available in the market, the fastest growing and highest selling e-cigarette brand in the U.S. is JUUL, a novel closedsystem e-cigarette product that was launched in 2015.13,14 This compact, easily concealable innovative product resembles a USB flash drive and contains two parts.14,15 The first is the body of the product, which is composed of a lithium-ion polymer battery, a temperature regulator, and sensors to detect inhalation and charge.14 The second part is the replaceable nicotine cartridge, referred to as a JUULpod, which contains the e-liquid, mouthpiece, and atomizer.14

JUUL can be charged using a USB port, and the pods are available in a variety of youth-appealing flavors, including Cool Mint, Mango, and Fruit Medley, among others.14,16 Users can also purchase skins, which are external adhesive covers intended to personalize these products.15 Each JUUL cartridge contains 0.7 mL of nicotine with 5% nicotine by weight, which is equivalent to 200 puffs or a pack of cigarettes.14 The use of JUUL is so popular that the act of using the device is now termed juuling, and the company reports a market share of over 50%, surpassing other e-cigarette products.14,16 Other products imitating JUUL have entered the market, including Suorin Drop and myblu, both of which are high-tech in design and also use nicotine salts in their e-liquid.11

YOUTH

Introduction to drugs and alcohol generally occurs during adolescence.17 This stage of transition from childhood to adulthood is a significant time of maturation of cognition and emotion.17 This developmental stage increases an individual's likelihood for risk-taking and other behavioral changes that allow for the development of autonomy as adults.17 Thus unsurprisingly, approximately 90% of adult tobacco users are reported to have developed their habit during adolescence.17

The CDC has reported that although there has been a decline in youth use of combustible cigarettes, there is a dramatic increase in youth who acknowledge using e-cigarettes. E-cigarette use among high school students has risen from 1.5% in 2011 to 20.8% in 2018, and among middle school students, from 0.6% in 2011 to 4.9% in 2018.5 This rise of e-cigarette use by young people has been attributed to appealing flavors.5,6 The Populations Assessment of Tobacco and Health study stated that 81% of 12to 17-year-olds tried a flavored e-cigarette in their first use, and in the past 30-day use, 85.3% of this population reported utilizing flavored e-cigarettes.18

The trend of increasing use of flavored e-cigarettes is highly concerning in itself, but even more alarming is the recognition that flavored tobacco product use by youth is associated with the use of two or more tobacco products concurrently.19 In a recent study by Mantey and colleagues, it was noted that 48.6% of youth tobacco users consumed more than one tobacco product.19 Among the youth tobacco users, those who were classified as utilizing two forms of tobacco delivery (dual users) or multiple products (poly users) were significantly more likely to use flavored tobacco products.19 This emphasizes the correlation between flavored tobacco use and risks of utilizing multiple delivery forms of tobacco, including traditional cigarettes, and the need to create frameworks that severely restrict youth access to flavored tobacco products.19

It is important to educate youth about the risks for lifetime nicotine addiction and the dangers of e-cigarette products. Studies have revealed that e-cigarette products contain dangerous substances such as metals and carcinogenic compounds that are derived from flavoring agents.20 Even still, the targeted marketing of e-cigarette products present them to be safer than traditional cigarette products.20 In a recent survey of young people aged 15 to 24 years, 63% were unaware that all JUUL products contain nicotine.15 Compounding this, newer e-cigarette products such as JUUL that are popular with youth employ modified nicotine formulations, which are thought to contain two to 10 times the amount of nicotine compared with older e-cigarette products and are thus much more addictive.15

NICOTINE

Nicotine is a highly addictive alkaloid found in Nicotiana tabacum, the tobacco plant that is most widely cultivated.21,22 Tobacco is indigenous to the Americas, where native populations were utilizing tobacco long before the arrival of European immigrants to the New World.22 Following European conquest of the Americas, tobacco made its way out of the Americas and into other nations.22 In fact, nicotine earned its name from Jean Nicot de Villemain, a French ambassador who introduced tobacco to the French courts.22 The beginnings of the cultivation of tobacco as a cash crop can be traced back to Jamestown, Virginia.22 Commercialization of tobacco began in 1880 with the invention of a cigarette-rolling machine.22 Since its known beginnings, tobacco use has grown to become a global phenomenon.

The addiction to tobacco may involve the pharmacology of nicotine, environmental factors, and social influences, among others.2 When inhaled, nicotine is absorbed in the lungs and carried to the brain.2

Once in the brain, nicotine binds to the nicotinic cholinergic receptors, leading to the release of neurotransmitters such as dopamine, which manifests as the feeling of pleasure and mood modulation.2 With continued use, tolerance leads to physical dependence.2 Initially, sensory effects of the tobacco smoke increase users' fulfillment and reinforce behavior.22 Prolonged use advances addiction through neural plasticity and neuroadaptation that result in changes in brain circuitry.22 Individuals addicted to nicotine experience withdrawal when cessation is attempted.2 Withdrawal symptoms lead to a feeling of stress, anxiety, and anhedonia in users, which further decreases the likelihood of quitting.2,22 This likely explains why only 3% of smokers successfully quit smoking each year.2

Animal studies have noted that nicotine is a neuroteratogen and that exposure can lead to sustained and permanent negative effects at critical brain developmental stages.2,17 Some of these effects include increased levels of adult anxiogenesis and sustained and negative changes in the ability to learn, cognition, memory, and reward processing.23 In fact, studies report that post nicotine exposure, adolescents are noted to have an increased proclivity to other drugs and are more likely to engage in high-risk sexual behavior and develop psychiatric disorders.17 Although the dangers of nicotine addiction are well known, studies have shown that a significant number of youth are unaware that e-cigarette products contain nicotine.4

FLAVORING CHEMICALS

The number of flavored e-cigarette products have more than doubled between 2013 and 2017, with e-cigarette users now having over 15,000 distinct flavors to choose from.4,24,25 The options range from (1) candy flavoring such as chocolate, cotton candy, peanut butter cup, and gummy bear to (2) fruit flavoring such as wild berry, watermelon, and lemonade to (3) unique flavors like crème brulee and Belgian waffle to (4) alcoholic drinks like strawberry daiquiri.4,9,14 There is great concern that the flavoring contained in e-cigarette products is enticing youth users.4

Flavoring compounds have been associated with respiratory diseases such as severe bronchiolitis obliterans, also known as popcorn lung, a condition that can lead to irreversible loss of lung function requiring lung transplants.24 This condition was first noted in workers at microwave popcorn production plants and was determined to be caused by inhalation of flavoring chemicals, including diacetyl, which gives food a creamy or buttery flavor, acetoin, and 2,3-pentanedione.24,26 As a consequence, the National Institute for Occupational Safety and Health issued recommendations to reduce inhalation exposures of workers to flavoring chemicals.27

Stemming from years of research, flavoring chemicals are nationally recognized as dangerous when inhaled, yet these same compounds have been noted in the flavoring of e-cigarettes.24 As e-cigarette products produce an ultrafine aerosol that penetrates into lungs, inhalation of flavoring chemicals can be dangerous for users.26 A study by Allen and colleagues demonstrated that of 51 e-cigarette flavors tested, 39 detected diacetyl and 47 detected either diacetyl, 2,3-pentanedione, or acetoin, compounds that were shown to have caused bronchiolitis obliterans.24 Of note, there have been several cases revealing negative pulmonary effects of e-cigarettes, including two recent case reports describing otherwise healthy adults presenting with bronchiolitis obliterans organizing pneumonia related to e-cigarette use.28,29

OTHER SAFETY CONCERNS

In a 2015 New England Journal of Medicine article, Jensen and colleagues reported that formaldehydecontaining hemiacetals can be formed while users are vaping.7 Formaldehyde is produced when propylene glycol is degraded and continues to react with additional propylene and glycerol to produce hemiacetals.7 Hemiacetals or formaldehyde-releasing agents (FRAs) are utilized as industrial biocides and are thought to be carcinogenic.7 According to Jensen and colleagues, FRAs may deposit into the lungs more efficiently than formaldehyde in the gaseous form, and may thus carry a higher risk for cancer than formaldehyde.7 In fact, when comparing the risk of cancer from long-term cigarette smoking based on the amount of inhaled formaldehyde exposure, long-term vaping likely carries a five to 15 times higher risk.7

Poison centers are also reporting increased numbers of acute health effects related to e-cigarette exposures. A 2016 study stated that most of the victims of nicotine exposure were children.30 In this investigation, when compared with cigarettes, a higher number of e-cigarette–exposure calls (11.7% vs. 5.9%) reported a moderate adverse effect, including seizure and severe vomiting, or major effects such as respiratory failure (0.3% vs. 0.1%).30

There have also been a growing number of e-cigarette–related fires and explosions.31 According to the U.S. Fire Administration, lithium batteries in e-cigarettes are hazardous.31 Between January 2009 and December 2016, there were 195 individual reports of fire and explosions related to e-cigarettes.31 Of these, 60 incidents occurred while the device was in use and 61 occurred while the device was in the user's pocket.31 Also, 38 of the events led to serious injuries to the users, which included hospitalization and potential loss of body parts, facial injuries, or third-degree burns.31 Eighty of the events were considered moderate, and patients were treated for second-degree burns, lacerations needing stitches, and smoke inhalation.31 In 10 of the events, the fire involved was major and involved significant building damage, and 27 incidents were considered moderate.31 This rising trend of fires and explosions involving e-cigarettes is highly concerning and requires further safety precautions.31

E-cigarettes are gaining some traction in the smoking cessation arena, especially with recent literature suggesting that they may be an effective option for smoking cessation in adult patients.32 In a recent smoking cessation study published in the New England Journal of Medicine by Hajek and colleagues, 18.8% of participants randomized to e-cigarettes reported 1-year abstinence compared with 9.9% of patients in the nicotine-replacement group.32 However, among the 1-year abstainers, 80% of those in the e-cigarette group continued to utilize e-cigarettes, compared with 9% in the nicotinereplacement group.32 This highlights that while e-cigarettes may be an effective option for combustible cigarette smoking cessation, these products could lead to long-term continued use.32 Prolonged use of e-cigarettes is concerning as there is a dearth of long-term data and as e-cigarette products also carry risk.

There is currently a lack of literature on e-cigarette cessation. There is also a paucity of literature surrounding medication therapy for combustible cigarette cessation in youth. To broaden our understanding of effective electronic cessation strategies and youth use of e-cigarette products, it is important that research in these areas is encouraged and funded. Furthermore, research to expand our understanding of nonpharmacologic strategies to assist with cessation efforts may also play a crucial role in cessation of e-cigarette products in youth and thus should also be encouraged.

HISTORICAL PERSPECTIVE

In the past 5 decades, several public-health measures have aimed to reduce tobacco use in the U.S. TABLE 1 highlights these major actions. Legislation surrounding e-cigarette products is evolving rapidly. A growing number of states have augmented federal restrictions placed on e-cigarette products and have developed more robust regulation.40 For example, states including California, Hawaii, New Jersey, and Oregon, as well as the District of Columbia, have increased the minimum age required to purchase e-cigarette products to 21 years.40 Also, while most states have yet to include special taxes on e-cigarette products, a few states, including California, Delaware, Kansas, Louisiana, Minnesota, New Jersey, North Carolina, Pennsylvania, West Virginia, and the District of Columbia impose special taxes on e-cigarette products.40 Furthermore, several states now have requirements for product packaging as well as places and times with smoke-free restrictions.40


tbl1

MARKETING

E-cigarette companies have come under pressure for heavily marketing their products to reach youth.4 They have utilized the historical strategies of cigarette companies, which included flavored products that are appealing to young people, sexual content, and endorsements by celebrities.4,9 Companies have also exploited television, magazines, radio, the Internet, social media, and other means to entice youth.4 Studies reviewing online marketing have noted direct or indirect claims suggesting that their product is cleaner, cheaper, less regulated in public spaces, and more socially acceptable.25 Companies that target youth in their marketing and make false claims to the public must be fined and prosecuted.

RECOMMENDATIONS

There is an immediate need to ensure that youth use of e-cigarette products is curtailed and that the youth who are addicted to e-cigarette products receive assistance to achieve cessation. The following are some recommendations:

  1. Ban all flavored nicotine products.
  2. Implement state and national tax on e-cigarettes that are comparable to traditional cigarettes.4
  3. Enact government regulation of e-cigarette companies' marketing platforms, such as social media and television.
  4. Ensure that all e-cigarette products list ingredients, including nicotine, and state the harms, including cancer, in plain language.
  5. Ban all accessories, such as skins, for e-cigarette products.
  6. Fund long-term studies on implications of e-cigarette use.
  7. Fund long-term studies on youth e-cigarette–cessation strategies.

PHARMACIST'S ROLE

Pharmacists have a unique opportunity to play a major role in ensuring that the public is educated about the risks associated with combustible cigarettes and e-cigarettes. As one of the healthcare professionals most accessible to the public, pharmacists may be in a position to answer questions from the public regarding e-cigarettes, to create cessation initiatives, and to counsel parents and youth on the harms associated with use of e-cigarettes. As pharmacotherapy experts, pharmacists can also educate other healthcare professionals on current literature pertaining to cessation of traditional cigarettes and e-cigarettes and advocate for further regulation related to sale of tobacco products and access to both adults and youth.

CONCLUSION

The rise in youth use of e-cigarettes is alarming. Thus, it is important that strong public-health measures are crafted to eliminate youth use of these products. The general public must be informed about the dangers of e-cigarettes and other nicotinecontaining products. It is vital that pharmacists and other health professionals are equipped to counsel patients, especially youth, on the dangers of e-cigarette products.

REFERENCES

  1. Smoking and tobacco use fast facts. Center for Disease Control and Prevention. www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/index.htm. Published 2018. Accessed January 11, 2019.
  2. Benowitz NL. Nicotine addiction. N Engl J Med. 2010;362(24): 2295-2303.
  3. U.S. Department of Health and Human Services. The health consequences of smoking—50 years of progress: a report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014.
  4. E-cigarette use among youth and young adults: a report of the Surgeon General; 2016. www.cdc.gov/tobacco. Accessed January 18, 2019.
  5. Cullen KA, Ambrose BK, Gentzke AS, et al. Notes from the field: increase in use of electronic cigarettes and any tobacco product among middle and high school students—United States, 2011–2018. MMWR Morb Mortal Wkly Rep. 2018;67(45):1276-1277.
  6. Livingston CJ, Freeman RJ, Costales VC, et al. Electronic nicotine delivery systems or e-cigarettes: American College of Preventive Medicine's practice statement. Am J Prev Med. 2019;56(1):167-178.
  7. Jensen RP, Luo W, Pankow J, et al. Hidden formaldehyde in e-cigarette aerosols. NEJM. 2015;372(4):392-394.
  8. Electronic cigarettes: an overview of key issues. 2018. www.tobaccofreekids.org/assets/factsheets/0379.pdf. Accessed January 18, 2019.
  9. The flavor trap–how tobacco companies are luring kids with candyflavored e-cigarettes and cigars. 2017. www.tobaccofreekids.org/microsites/flavortrap/full_report.pdf. Accessed January 18, 2019.
  10. Word of the year 2014. Oxford Dictionaries. https://en.oxforddictionaries.com/word-of-the-year/word-of-the-year-2014. Accessed January 26, 2019.
  11. E-cigarettes: facts, stats and regulations. https://truthinitiative.org/ sites/default/files/Truth_E-Cigarette_FactSheet_FINAL.pdf. Published 2018. Accessed January 28, 2019.
  12. Cantrell J, Huang J, Greenberg M, et al. History and current trends in the electronic cigarette retail marketplace in the United States. Nicotine Tob Res. 2018 Oct 12; Epub ahead of print.
  13. Willett JG, Bennett M, Hair EC, et al. Recognition, use and perceptions of JUUL among youth and young adults. Tob Control. 2019;28:115-116.
  14. Juul and the guinea pig generation–public health concerns about use by young people; 2018. www.publichealthlawcenter.org. Accessed January 18, 2019.
  15. Barrington-Trimis JL, Leventhal AM. Adolescents' use of "Pod Mod" e-cigarettes—urgent concerns. New Engl J Med. 2018;379(12): 1099-1102.
  16. Chu KH, Colditz JB, Primack BA, et al. JUUL: spreading online and offline. J Adolesc Health. 2018;63:582-586.
  17. Yuan M, Cross SJ, Loughlin SE, et al. Nicotine and the adolescent brain. J Physiol. 2015;593:3397-3412.
  18. Ambrose BK, Day HR, Rostron B, et al. Flavored tobacco product use among US youth aged 12-17 years, 2013-2014. JAMA. 2015;314(17):1871-1873.
  19. Mantey DS, Omega-Njemnobi O, Montgomery L. Flavored tobacco use is associated with dual and poly tobacco use among adolescents. Addict Behav. 2019 Mar 4; Epub ahead of print.
  20. Rubinstein ML, Delucchi K, Benowitz NL, Ramo DE. Adolescent exposure to toxic volatile organic chemicals from e-cigarettes. Pediatrics. 2018;141(4):e20173557.
  21. Goldenson NI, Leventhal AM, Stone MD, et al. Associations of electronic cigarette nicotine concentration and subsequent cigarette smoking and vaping levels in adolescents. JAMA Pediatr. 2017;171(12):1192-1199.
  22. Dani JA, Balfour DJK. Historical and current perspective on tobacco use and nicotine addiction. Trends Neurosci. 2011;34(7):383-392.
  23. Holliday E, Gould TJ. Nicotine, adolescence, and stress: a review of how stress can modulate the negative consequences of adolescent nicotine abuse. Neurosci Biobehav Rev. 2016;65:173-184.
  24. Allen JG, Flanigan SS, LeBlanc M, et al. Flavoring chemicals in e-cigarettes: diacetyl, 2,3-pentanedione, and acetoin in a sample of 51 products, including fruit-, candy-, and cocktail-flavored e-cigarettes. Environ Health Perspect. 2016;124(6):733-739.
  25. Hsu G, Sun JY, Zhu SH. Evolution of electronic cigarette brands from 2013-2014 to 2016-2017: analysis of brand websites. J Med Internet Res. 2018;20(3):e80.
  26. Barrington-Trimis JL, Samet JM, McConnell R. Flavorings in electronic cigarettes: an unrecognized respiratory health hazard? JAMA. 2014;312(23):2493-2494.
  27. NIOSH Alert–Preventing lung disease in workers who use or make flavorings. Cincinnati, OH; 2003. www.cdc.gov/niosh. Accessed January 26, 2019.
  28. Khan MS, Khateeb F, Akhtar J, et al. Organizing pneumonia related to electronic cigarette use: a case report and review of literature. Clin Respir J. 2018;12(3):1295-1299.
  29. Mantilla RD, Darnell RT, Sofi U. Vapor lung: bronchiolitis obliterans organizing pneumonia (BOOP) in patient with e-cigarette use. Am Thorac Soc 2016 Int Conf. 2016;(193):A6513.
  30. Chatham-Stephens K, Law R, Taylor E, et al. Exposure calls to U.S. poison centers involving electronic cigarettes and conventional cigarettes—September 2010–December 2014. J Med Toxicol. 2016;12(4):350-357.
  31. McKenna LA Jr. Electronic cigarette fires and explosions in the United States 2009-2016. U.S. Fire Administration. 2017. www.usfa.fema.gov/downloads/pdf/publications/electronic_cigarettes.pdf. Accessed April 18, 2019.
  32. Hajek P, Phillips-Waller A, Przulj D, et al. A randomized trial of e-cigarettes versus nicotine-replacement therapy. N Engl J Med. 2019;380(7):629-637/
  33. History of the Surgeon General's reports on smoking and health. CDC. www.cdc.gov/tobacco/data_statistics/sgr/history/index.htm. Published 2006. Accessed January 16, 2019.
  34. Smoking and tobacco use: legislation. Centers for Disease Control and Prevention. www.cdc.gov/tobacco/data_statistics/by_topic/policy/legislation/index.htm. Published 2018. Accessed January 31, 2019.
  35. Astor RL, Urman R, Barrington-Trimis JL, et al. Tobacco retail licensing and youth product use. Pediatrics. 2019;143(2):e20173536.
  36. U.S. racketeering verdict–big tobacco guilty as charged. Campaign for tobacco-free kids. www.tobaccofreekids.org/what-we-do/industrywatch/doj. 2018. Accessed February 1, 2019.
  37. Hickey B. The PACT Act–Preventing illegal internet sales of cigarettes and smokeless tobacco. Campaign for tobacco-free kids. www. tobaccofreekids.org. Published 2016. Accessed February 1, 2019.
  38. Deeming tobacco products to be subject to the Federal Food, Drug, and Cosmetic Act, as amended by the Family Smoking Prevention and Tobacco Control Act; restrictions on the sale and distribution of tobacco products and required warning statements for tobacco products; final rule. Fed Regist. 2016;81(90):28974-29106w.
  39. Press announcements–statement from FDA Commissioner Scott Gottlieb, M.D. On proposed new steps to protect youth by preventing access to flavored tobacco products and banning menthol in cigarettes. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm625884.htm. 2018. Accessed January 6, 2019.
  40. U.S. e-cigarette regulations: a 50-state review. Saint Paul, MN; 2018. www.publichealthlawcenter.org. Accessed February 24, 2019.