Education and Practice

The Potential Harmful Effects of E-cigarettes in Youth: It’s Not Just Vapor

Carolyn Ford Dominique L. McClain Trana Rashid

Introduction

“It’s not harmful, it’s just water vapor” is a common misconception about electronic cigarettes (EC) held by many American youth today.1 Because of this widespread belief, targeted marketing tactics, and other psychosocial factors, the use of EC has skyrocketed among adolescents and young adults.2 According to the 2016 National Youth Tobacco Surveys (NYTS) data analyzed by the Centers for Disease Control and Prevention (CDC), 4.3% of middle school students reported using EC over the past 30 days in 2016 compared to 0.6% in 2011.3 Similarly, 11.3% of high school students reported using EC over the past 30 days in 2016 compared to 1.5% in 2011. This sharp increase, rampant use in teens and young adults, and potentially harmful effects have prompted the U.S. Surgeon General to declare EC use a major public health concern.2 Accordingly, it is important that health professionals, especially pharmacists, become familiar with all aspects of EC use in this population.

Prevalence of E-Cigarettes in Adolescents

Electronic cigarettes are the most common form of tobacco used by youth in the United States.2 According to the 2016 NYTS CDC surveys, e-cigarette use among high and middle school students, respectively, was 11.3% (1.68 million users) and 4.3% (500,000 users) in comparison to traditional cigarettes, which was 8.0% (1.18 million users) and 2.2% (260,000 users).3 EC use has sharply increased from 1.5% to 16% among high school students and 0.6% to 5.3% among middle school students from 2011 to 2015.4 For the first time in 5 years, EC use dropped from 16.8% to 11.3% among high school students and 5.3% to 4.3% among middle school students between 2015 and 2016.3 However, it is important to note that over 2 million youth are EC users and that this rate exceeds the use of cigarettes and other tobacco products. Also, the same survey found that current use of any tobacco product in high school students was 20.2% (1 in 5) and 7.2% (1 in 14) in middle school students for a total of 3.9 million tobacco users. Moreover, the use of multiple tobacco products is also prevalent in youth. Nearly 10% of high school students (47.2% reporting the use of any tobacco product) and 3.1% of middle school students (42.4% reporting use of any tobacco product) reported use of two or more tobacco products in the past 30 days.

Prevalence of E-Cigarettes in North Carolina

North Carolina leads the nation in tobacco product growth and ranks #45 in state spending on tobacco prevention (equivalent to 1.2% of CDC recommended spending).5 Therefore, it is not surprising that NC youth have a higher tobacco use rate (including EC) than the national average.6 According to the North Carolina Youth Tobacco Survey, there was an 888% increase in EC use among high school students between 2011 and 2015.7 During the same time period, EC use increased 600% in middle school students. In comparison, the national EC use rate was 16% vs.16.8% among high school students and 5.3% vs. 6.99% among middle school students in 2015. Also, nearly 28% of NC high school students reported that they were considering using EC in 2016.7 The NC EC use data for 2016 is currently unavailable. Moreover, it is not possible to determine if NC witnessed a similar, significant decline in EC use among middle and high school students consistent with the national rates.

Descriptions of E-Cigarettes

E-cigarettes, also referred to as e-cigs, vapes, vaporizers, vape pens, e-hookah, hookah pens, tank systems, mods, and epipes, are a group of devices collectively known as electronic nicotine delivery systems (ENDS).8 These battery-powered devices produce an aerosol or vapor that usually contains nicotine. Inhalation of this aerosol is known as “vaping” and mirrors the smoking of a traditional cigarette. Despite the wide variability in design and appearance, EC typically have three primary components: 1) battery, 2) electronic heating element (atomizer, cartomizer, or clearomizer), and 3) fluid cartridge (Figure 1). The battery is the power source for the electronic heating element that heats the liquid in the cartridge and produces the aerosol or vapor for inhalation. EC devicescan be activated automatically where a flow sensor detects the air current created by the user puffing on the device or manually where the user presses a button. The cartridge or reservoir holds a liquid solution, commonly referred to as e-liquid or e-juice, which typically contains nicotine, humectants (such as propylene glycol and vegetable glycerin), flavorings, and other potentially harmful chemicals.9,10 The nicotine concentration in the e-liquid can range from 0 to 36 mg/ml in comparison to the 0.7-2.39 mg found in traditional cigarettes.11 The humectants serve as carrier solvents to generate the smokelike appearance of aerosol. Considering that most e-liquids are flavored, it’s estimated that approximately 8100 unique flavors exist with sweet and fruity flavors like candy and bubble gum being the most common and attractive to adolescents. There are approximately 500 brands of EC that can be divided into four major types or generations (Table 1)12. The first generation, referred to as “ciga-likes,” is relatively small and resembles a traditional cigarette in size and shape. Some may also have an LED light on the end that lights up to simulate smoking. Other versions of ciga-likes resemble a cigar or pipe. The disposable version is unusable after the battery dies. The non-disposable version has a rechargeable battery and a replaceable cartridge (cartomizer) that is pre-filled or refillable. The second-generation devices, typically shaped like pens or laser pointers, are referred to as vape pens. They are also called tank systems because of their transparent, cylindrical reservoir that holds much larger quantities of e-liquid than the first-generation models. These systems are reusable, allow any type of fluid, and have variable voltages. Some second generation devices called “mods” can be modified according to user preferences. Third and fourth generation devices--sometimes referred to as advanced personal vaporizers (APVs) or “mods”--vary significantly in shape and size and have very little resemblance to a traditional cigarette. They are customizable and vary in battery size, voltage and wattage. The fourth generation devices have added capacity to regulate temperature.

Harmful Effects of E-Cigarettes

The use of EC in youth has been declared a major health concern due to widespread use and the likelihood of harmful health effects attributable to aerosolized nicotine, flavorings, solvents, chemicals, and toxicants.2 This concern is further exacerbated by the current lack of FDA regulations that allow a wide variability of e-liquid constituents from prod-

uct to product and EC devices (regulation scheduled in 2018).13 Therefore, a review of how e-liquid constituents potentially lead to harmful health effects is warranted.

Nicotine

The negative consequences of nicotine (secondary to tobacco use) are well established. It is also known that young individuals are more susceptible to the adverse effects of nicotine than adults.14 As most EC contain nicotine and deliver concentrations equivalent to or higher than traditional cigarettes, similar adverse health effects are expected with these agents. This increased sensitivity to nicotine in youth correlates to its ability to impair brain development.15 During the period of adolescence up to age 25, the brain is undergoing major structural remodeling and rapid growth in circuitry that controls executive functioning (e.g. decision-making, self-discipline, impulse control, attention, learning, memory, reasoning, reward processing, and emotional maturation).16 Disruption of this neurobiological maturation by nicotine can result in long-lasting cognitive and behavioral impairments such as reduced impulse control, disruptive behaviors, decreased ability to learn and pay attention, reduced working memory, and increased mood disorders. Nicotine also impacts the brain reward processing center during this sensitive maturation period which can lead to drugseeking behaviors that result in a higher risk of addiction to nicotine and other drugs like alcohol, marijuana, cocaine, and methamphetamines.2 It has also been determined that the younger the age of nicotine initiation, the stronger and faster the rate of addiction. Additionally, nicotine use in adolescents may serve as a gateway to smoking traditional cigarettes which are significantly more toxic than EC.17 Research has shown that youth who use EC are more likely to start using other tobacco products like cigarettes. Another major concern is acute nicotine toxicity or poisoning that can result from ingestion of e-liquids.2 Commercially available e-liquid refill cartridges contain up to 36 mg of nicotine whereas cartridges purchased wholesale from the internet can contain up to 100 mg of nicotine. A lethal poisoning can occur, especially in children, if the contents of one nicotine refill cartridges is consumed, considering that the lethal dose in adults is 0.5-1.0 mg/ kg and 0.1-0.2 mg/kg in children, respectively. Young children under 6 years of age are the most vulnerable to poisonings, and the incidence of poisonings has increased significantly secondary to widespread EC use. According to National Poison Center calls, an average of one call per month for nicotine poisoning was reported in 2010 compared to an average of 215 per month reported in 2015.18 As of July 2016, the Child Nicotine Poisoning Prevention Law requires e-liquid refill containers be sold in child-resistant containers. Nicotine toxicity secondary to eye, skin, or mucous membranes exposure is usually limited to local irritation. A few cases of systemic toxicity (increased salivation, nausea, abdominal pain, vomiting and diarrhea, tachycardia, and elevated blood pressure) secondary to nicotine absorption through the skin have been reported.

Solvents

Propylene glycol and vegetable glycerin are solvents used in EC. Per the Agency for Toxic Substances and Disease Registry (ASTDR), propylene glycol is an additive found in foods, medications, and cosmetics.19 It is safe for ingestion, injection, and topical administration. However, it has not been addressed whether it is safe for inhalation. Other names for propylene glycol are 1,2-propanediol, 1,2-dihydroxypropane, methyl glycol, and trimethyl glycol. Aerosolized propylene glycol has been used during military exercises and fire simulations because of its ability to produce a dense smoke without open flames. The ASTDR reports that people who receive a rapid intravenous infusion of the substance or have increased contact time with the substance are at the highest risk for toxic exposure to propylene glycol. Propylene glycol has a similar chemical structure to ethylene glycol. While these two compounds have similar structure, ethylene glycol exposure is more hazardous to the body. Vegetable glycerin is a food additive that is also referred to as glycerol, glycerin, 1,2,3-propanetriol, and 1,2,3-trihydroxypropane.20 There are currently no sufficient data on health hazards that can result from direct inhalation of vegetable glycerin.20

Flavorings were originally created to mask the tobacco flavor and increase the appeal to younger users. When youth are asked why they started using ecigarettes, curiosity, flavoring and perceived low harm compared to other tobacco products top the list. In a study performed by Population Assessment of Tobacco and Health (PATH), 13,651 youth were surveyed on their use of flavored tobacco products. 81.5% of the e-cigarette users in this study stated that they use e-cigarettes because of the flavoring options as they selected “because they come in flavors I like” as one of the eleven options available on the survey.21 The study ultimately confirms flavorings as a reason for e-cigarette usage in the youth. The 2009 Family Smoking Prevention and Tobacco Control Act prohibits flavorings other than menthol in cigarettes.22 The US. Food and Drug Administration is currently attempting to regulate e-cigarettes, but new legislation has been introduced to weaken FDA oversight despite strong evidence of the link between flavored tobacco products and e-cigarette use among the youth. The popularity of flavored e-cigarettes is very concerning as usage increases among youth and facilitates addiction. This addiction can lead to the use of other tobacco products causing additional harm. It has been documented that tobacco companies marketed flavored mini-cigars (and cigarillos) to intentionally facilitate youth uptake of cigarettes. Companies have also intended for their flavored smokeless tobacco product users to move onto unflavored products that deliver more nicotine.23 Lastly, there is apprehension regarding the safety of inhaling flavorings without sufficient data on their long-term health effects.24 E-liquid manufacturers have claimed that the flavoring ingredients are recognized as safe when labeled “food grade”, but the Flavor Extracts Manufacturers Association has declared that safety warning only applies for ingestion, not inhalation.25

Adulterants

Researchers have found adulterants in EC that can result in unhealthy consequences. Nicotine, nornicotine, anabasine, and anatabine are all alkaloids found in a cured tobacco leaf.26 Nicotine makes up the majority of all the alkaloids. The other alkaloids will eventually become tobacco specific N-nitrosamines (TSNAs) during the curing process after undergoing nitrosation. TSNAs include 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone (NNK), N’-nitrosonornicotine (NNN), N’nitrosoanabasine (NAB), and Nnitrosoanatabine (NAT). The International Agency for Research on Cancer (IARC) deemed that both NNK and NNN are human carcinogens. TSNAs like NNN and NNK are found in tobacco cigarettes sold in the United States.27 Consumers often assume that because they are not actually smoking tobacco while using EC they are avoiding these TSNAs; however, that is incorrect. A study was done to determine the concentration of TSNAs in EC produced by four different U.S. companies.28 Researchers used Cambridge filter pads to collect the aerosol released by the EC. Contents of the pads were then extracted with methanol so they could be analyzed using liquid chromatography and mass spectrometry. The study found traces of the TSNAs that were below the limit of quantification designated to be 90 ng/g by researchers. This evidence does suggest that TSNAs are present in the EC; however, the quantities found are lower than what would be discovered in actual tobacco-containing products. Another study was done to determine how much of the alkaloids were present in EC.29 In this study, researchers purchased several nicotine-containing EC online. The cartridges were removed from the smoking devices and mixed in methanol for extraction. High performance liquid chromatography was used to analyze the extractions. One brand in particular had concentrations of anatabine well above the set quantification limit. This is concerning because the alkaloids in EC can potentially undergo nitrosation while being manufactured or if the product is stored incorrectly (which would result in TSNAs being formed).2

Toxins

The potential hazards associated with e-cigarette inhalation are complicated due to multiple factors: battery voltage, temperature, nicotine concentration, flavoring chemicals and other e-liquid contents.30 These factors vary widely and produce aerosol-

ized components at different temperatures. E-liquids are normally labeled with nicotine content and a propylene glycol/vegetable glycerin ratio. However, the list of toxic chemicals produced during the atomizer heating process is not directly labeled.31 A study was performed to identify different chemicals in 30 different e-cigarette fluids. A significant number of the chemicals used for flavorings were irritants like aldehydes which can cause damage to the respiratory tract.25 Another study detected the presence of pharmaceutical ingredients amino-tadalafil and rimonabant in e-liquids; some users of the pharmaceutical drug rimonabant reported instances of psychiatric adverse events and neurologic symptoms and seizures. The presence of such chemicals can pose a threat to e-cigarette users due to their unknown effects.32 E-liquids were also found to have diethyl phthalate and diethylhexyl phthalate which both have estrogenic and antiandrogenic effects. Diethylhexyl phthalate is also classified as a suspected carcinogen in humans. The liquids used for e-cigarette refills were also found to have chemical compounds diacetyl and acetyl propionyl (adds a buttery flavor to the product). The National Institute for Occupational Safety and Health declared these compounds safe for ingestion for flavoring but has not declared them safe for inhalation. A study was performed testing 159 samples from 36 different manufacturers and both compounds were found in 74% of the samples tested. Out of the 74%, approximately half of the samples exposed consumers to levels higher than approved safety limits.33 E-liquid aerosols were also found to have traces of heavy metals such as tin, silver, iron, nickel, cadmium, aluminum and silicate. Concentrations of these heavy metals were found to be higher than or equal to concentrations in original cigarette smoke. Lead and cadmium are specifically linked to respiratory disease.34 The battery voltage is also a component that affects the toxicity of inhalants. Carbonyls like formaldehyde, acetaldehyde and acrolein are found in e-cigarettes with increased voltage.35 These carbonyls are the outcomes from the oxidation of propylene glycol and vegetable glycerin due to high temperatures. Formaldehyde is classified as carcinogenic to humans according to the U.S. Environmental Protection Agency with the maximum allowable daily intake of 0.2 mg/kg.36 Acrolein is toxic in all forms and has been a common factor in several pulmonary diseases like lung cancer, asthma, and chronic obstructive pulmonary disease.37 Increased chances of generating these carbonyls were found at voltages at or above 5 volts. 38 E-cigarette aerosol is misconceived as harmless water vapor to many users. However, e-cigarette users are exposed to several compounds like carbonyl compounds or organic compounds that can cause adverse effects. The effects are still unknown for some of the chemical compounds and will continue to be difficult to research as more diDevice Malfunction

Bodily injury and property damage are common results of EC device explosions and fires. According to the U.S. Fire Administration, 195 separate cases of EC-related explosions and fires were reported between 2009 and 2016.39 Of these incidents, 68% caused bodily injuries and 66% ignited a fire in bedding, clothing, drapes and vehicle seats. 29% of these individuals suffered potentially life-threatening injuries like severe chemical burns, fractured neck vertebrae, finger loss, and nicotine overdose.

The U.S. Fire Administration has also determined that the root cause of EC device malfunction is lithium ion battery thermal runaway which causes the battery (or container) to behave like a “flaming rocket.” While the device’s battery is being charged, thermal runaway occurs when the internal battery temperature overheats to explosive levels. The overcharging of the lithium ion battery stems from user error, confusing charging instructions, manufacturing flaws or defects secondary to lack of regulation, poor design, faulty charging units, and counterfeit batteries. In addition to properly charging the battery in accordance with the manufacturer’s instruction, using devices that protect from overcharging, regulate thermal power, and relieve internal overpressure can help prevent thermal runaway.

EC devices produce an aerosol that is exhaled by the user into the environment. This aerosol contains harmful (and potentially harmful substances) like nicotine, heavy metals, TSNAs, VOCs and glycols that can be inhaled, ingested, and absorbed through direct dermal contact by bystanders in a similar manner to traditional cigarette smoke (second-hand exposure). Third-hand exposure can occur when bystanders come in contact with EC aerosol constituents deposited on surfaces. The aerosol produced by EC contains ultra-fine particles that are similar in size and present in higher concentrations than particles found in traditional cigarette smoke. Due to this small size, these nanoparticles can penetrate deeply into the lungs and cross into the systemic circulation of users and bystanders resulting in potentially harmful effects. The FDA has determined that even though the concentration of most harmful substances is lower in EC than traditional cigarette smoke, they can accumulate inside indoor environments.

The amount of EC aerosol inhaled by bystanders is unknown and currently under investigation. The concentration of EC aerosol released into the environment is dependent on many factors that include the type of device, e-liquid concentration, number of puffs, depth of inhalation, and the number of users in the room. There is evidence that passive exposure to EC aerosol can result in increased serum nicotine levels (measured as the metabolite cotinine) that are similar from passive exposure to traditional cigarette smoke which can adversely impact long-term lung function. Passive EC aerosol may also produce allergic reactions in bystanders due to exposure to allergens like propylene glycol and nuts used in some flavorants. This potential risk for allergic reactions and other health concerns (secondary to EC aerosol) should be further investigated based on underlying factors like the high incidence of food allergies in the U.S. Until the long-term health effects are determined, the use of EC in indoor environments should be included in smoke-free regulations.40

Conclusions

EC are the most commonly used form of tobacco among youth today. Consequently, youth usage has become so widespread that the U.S. Surgeon General has declared it a major public health concern. Other reasons for this alarming trend are increased nicotine sensitivity (and a greater risk for addiction), delayed brain development, gateway use to other tobacco products like traditional cigarettes, increased unintentional nicotine poisonings, and harmful effects due to inhaling or ingesting aerosol toxicants.41 This problem is further complicated by unregulated aggressive marketing on mainstream media channels that specifically target youth. safety and limit the use in youth, the FDA has approved regulations similar to other forms of tobacco. It is important to note that many EC regulations have not been implemented due to judicial delays. Until such time when regulations are fully implemented to include smoke-free policies, a major public health effort that includes education, prevention, and youth advocacy is warranted to protect vulnerable populations from potential harm.

Carolyn Ford, PharmD. (Corresponding Author) is Professor and Director of Community Healthcare Outreach, Wingate University School of Pharmacy. cford@wingate.edu

Dominique L. McClain and Trana Rachid are PharmD Students, Wingate University School of Pharmacy.

None of the authors have a conflict of interest.

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Figure 1: Variety of E-Cigarettes Shapes and Sizes

Photo Reproduced from CDC: Mandie Mills.

DIFFERENT TYPES OF E-CIGARETTES

1st Generation 2nd Generation 3rd Generation 4th Generation

Common Names

General Description

Refillable

Cartridge-type Ciga-like Ciga-like Vape pens Mods* Mods or APV Mods or APV

Looks & feels like a traditional cigarette Can look like pipe or cigar Size, shape, &

color varies widely Clear fluid cartridge, cylindrical in shape Variable size & shape

customizable

Unregulated battery power Variable size & shape

customizable

Variable voltage and power Variable size & shape

customizable

Variable voltage, power, and temperature

Pre-filled Pre-filled and refillable Refillable

Tank-based Refillable

Tank-based Refillable

Tank-based Refillable

Tank-based

Rechargeable Disposable Single unit Rechargeable Rechargeable Separate battery and tank Rechargeable Separate battery and Rechargeable Separate battery and Rechargeable Separate battery and

• From the CDC, Influenza Vaccination Update. Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. For the full report, https://www. cdc.gov/mmwr/volumes/66/rr/rr6602a1.htm

• Update on CMM Grant at UNC, as published in Septeber 2017 ACCP Report. https://www.accp.com/report/index. aspx?iss=0917&art=6