ECigarettes [1 ed.] 9781610022743, 9781610021692

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pediatric collections eCigarettes FEATURES: Flavored Electronic Cigarette Use and Smoking Among Youth Reasons for Trying E-cigarettes and Risk of Continued Use E-Cigarettes and Future Cigarette Use E-Cigarettes and “Dripping” Among High-School Youth Adolescent Risk Behaviors and Use of Electronic Vapor Products and Cigarettes

Pediatric Collections eCigarettes About AAP Pediatric Collections Pediatric Collections is a series of selected pediatric articles that highlight different facets of information across various AAP publications, including AAP Journals, AAP News, Blog Articles, and eBooks. Each series of collections focuses on specific topics in the field of pediatrics so that you can keep up with best practices, and make an informed response to public health matters, trending news, and current events. Each collection includes previously published content focusing on specific topics and articles selected by AAP editors. Visit http://collections.aap.org to view a list of upcoming collections.

Table of Contents 1 2 4

Introduction AAP Policy Cites Harms of E-Cigarettes; Urges Screening AAP News • Original Publication • October-26-2015 Electronic Nicotine Delivery Systems From the American Academy of Pediatrics • Original Publication • November-1-2015

13 Perfect Storm Can Spur Nicotine Addiction in Youths AAP News • Original Publication • December-19-2016

15

Nicotine and Tobacco as Substances of Abuse in Children and Adolescents From the American Academy of Pediatrics • Original Publication • January-1-2017

28 Public Policy to Protect Children From Tobacco, Nicotine, and Tobacco Smoke

From the American Academy of Pediatrics • Original Publication • November-1-2015

go.aap.org/connect

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Table of Contents 38 Clinical Practice Policy to Protect Children From Tobacco, Nicotine, and Tobacco Smoke

From the American Academy of Pediatrics • Original Publication • November-1-2015

48 Study Finds 1,500% Increase in Monthly Poison Center Calls Due to E-Cigarettes

AAP News • Original Publication • May-9-2016

49 E-Cigarettes, Nicotine, and Tobacco Product Poisonings in Children: A Problem We Need to Smoke Out

Journals Blog • Original Publication • June-2-2016

50 Pediatric Exposure to E-Cigarettes, Nicotine, and Tobacco Products in the United States

Article • Original Publication • June-1-2016

60 Study: 26% of Teen E-Cigarette Users “Dripping” E-Liquid AAP News • Original Publication • February-6-2017

61 E-Cigarettes and “Dripping” Among High-School Youth Article • Original Publication • March-1-2017

67 The Role of Flavored E-Cigarettes on Youth Cigarette Smoking: A Study That Leaves a Bad Taste in Your Mouth

Journals Blog • Original Publication • November-10-2016

68 Flavored Electronic Cigarette Use and Smoking Among Youth Article • Original Publication • December-1-2016

76 Smoking Out the Role of E-Cigarettes in Future Cigarette Use Journals Blog • Original Publication • July-8-2016

77

E-Cigarettes and Future Cigarette Use Article • Original Publication • July-1-2016

86 E-Cigarettes and Adolescents’ Risk Status Commentary • Original Publication • February-1-2017

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Table of Contents 88

Adolescent Risk Behaviors and Use of Electronic Vapor Products and Cigarettes Article • Original Publication • February-1-2017

98

Potential Solutions to Electronic Cigarette Use Among Adolescents Commentary • Original Publication • August-1-2016

101 E-cigarettes, Cigarettes, and the Prevalence of Adolescent Tobacco Use Article • Original Publication • August-1-2016

111 New Alternative Tobacco Products—A Threat to Adolescent Health In Brief • Original Publication • July-1-2016

114 E-Cigarettes and National Adolescent Cigarette Use: 2004–2014 Article • Original Publication • February-1-2017

124 Risk Factors for Exclusive E-Cigarette Use and Dual E-Cigarette Use and Tobacco Use in Adolescents

Article • Original Publication • January-1-2015

133 Exposure to Electronic Cigarette Television Advertisements Among Youth and Young Adults

Article • Original Publication • July-1-2014

141 Psychosocial Factors Associated With Adolescent Electronic Cigarette and Cigarette Use

Article • Original Publication • August-1-2015

154 High School Students' Use of Electronic Cigarettes to Vaporize Cannabis Article • Original Publication • October-1-2015

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Introduction P

ediatricians have been on the frontline of protecting their patients from the harm of tobacco, as they work to prevent initiation of smoking, implement cessation programs, and develop strategies

to protect children and families from secondhand smoke exposure. In recent years, a wide range of new tobacco products have become available, including e-cigarettes. To help all of us learn more about e-cigarettes, Pediatrics and other American Academy of Pediatrics (AAP) publications have

published articles that describe the patterns of use of these new products, the risk factors for initiation, and long-term health implications of using this method of smoking. The AAP has also published clinical care recommendations to address tobacco products with patients and their families. To help you better understand the issues surrounding the use of e-cigarettes in teens and young adults, we are now bringing together published articles on e-cigarettes in one custom collection, giving you easy access through this collection to a compendium of studies and findings on this important topic. This custom collection will be continually updated online as we publish more articles on e-cigarettes, so please check this collection frequently for new studies and information that we hope you will share with your patients when they ask about concerns regarding the safety and risks of using e-cigarettes.

—Alex Kemper, MD, MPH, MS Deputy Editor, Pediatrics

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:: October-26-2015

AAP Policy Cites Harms of E-Cigarettes; Urges Screening Susan C. Walley

Common questions from pediatricians How many children and adolescents are using electronic nicotine delivery systems (ENDS)? Surveys of youths show an 890% increase in ENDS use over the past four years. In 2013, as many as 29% of high school students had tried (ever used) e-cigarettes, with use in the past month (current use) of 18%. In contrast, 8.5% of U.S. adults reported having tried an e-cigarette in 2013. Why am I seeing ENDS commercials on television? Unlike conventional cigarettes, there are no current regulations on ENDS advertisements on television, print media or point-of-sale (advertisements where ENDS are sold). ENDS are being marketed heavily; in 2013, 80% of U.S. youths ages 12-17 years were exposed to 13 television advertisements for ENDS. What is in the ENDS solution (also known as e-juice or e-liquid)? ENDS solutions are advertised to contain concentrated nicotine, flavoring chemicals and propylene glycol and/or glycerin. There are 7,760 flavors of ENDS solutions advertised, many of which are candy and dessert flavored and appealing to children. In addition to what is advertised, however, ENDS solution has been shown to contain numerous toxicants and carcinogens. The ENDS refillable cartridges also allow for addition of other substances to the solution, including marijuana. What should I say when someone asks if I recommend ENDS? ENDS have been shown to pose harms for users and non-users and are not approved by the Food and Drug Administration (FDA) as smoking cessation devices. ENDS should not be recommended to youths or their parents/caregivers. Parents and youths who are interested in tobacco dependence treatment should be directed to evidence-based smoking cessation counseling and FDA-approved tobacco dependence treatments (See resources.).

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P

ediatricians should screen families and counsel them on the health risks of electronic nicotine delivery systems (ENDS), which include electronic cigarettes (e-cigarettes),

according to a new AAP policy statement. Electronic Nicotine Delivery Systems addresses pediatricians’ and pediatric health care providers’ questions about these products and the harms to youths. It is available at www.pediatrics.org/cgi/doi/10.1542/peds.2015-3222 and will be published in the November issue of Pediatrics. ENDS are handheld devices that produce an aerosol from a solution typically containing nicotine, flavoring chemicals and propylene glycol and/or glycerin to be inhaled by the user. ENDS include the wide range of products that are known as electronic cigarettes, e-cigs, e-hookah, vaping devices, vape pens and mechanical mods. In 2014, more youths reported using ENDS than any other tobacco product. The Academy is calling on pediatricians to ask about use of ENDS when screening for tobacco use and exposure. Pediatricians should counsel youths and parents on the following: • Harms for users. In addition to nicotine, ENDS solution has been shown to contain numerous toxicants and carcinogens harmful to human health. Nicotine is highly addictive and a known toxicant. Adolescents are more likely to become addicted even with sporadic use of tobacco. Use of nicotine-containing ENDS solution may lead adolescents to start smoking conventional cigarettes and other tobacco products. • Non-user exposure. ENDS secondhand aerosol and thirdhand aerosol (also known as vapor) have been shown to contain nicotine, toxicants, metal and silicate particles, and carcinogens that can pose harm to non-users. • Unintentional exposure. The ENDS solution can contain very concentrated nicotine, which can be lethal when ingested even in small quantities. There has been an astronomical increase in calls to poison control centers from ENDS exposures, and one child died after ingesting concentrated nicotine solution. • Renormalization of smoking behaviors. The increasing use of ENDs among youths and adults and lack of regulation threaten public health gains of successfully deglamorizing and restricting use and exposure of tobacco products.

Recommendations for pediatricians • Incorporate screening for ENDS use and exposure when screening for tobacco use and exposure. Provide prevention counseling in clinical practice.

Dr. Walley is a lead author of the AAP policy statement. Copyright © 2015, The American Academy of Pediatrics

• Counsel youths, parents and caregiv-

tobacco dependence pharmacothera-

• To reduce accidental poisonings,

ers about the harms of ENDS use and

pies approved by the Food and Drug

ENDS solution should be dispensed

exposure, and the importance of never

Administration.

in child-resistant packaging in

using nicotine-containing products. Parents should be advised to institute

• Become familiar with symptoms of acute nicotine poisoning.

amounts that would not be lethal to a young child. Ban all flavors in ENDS, as well as advertising of ENDS in

smoking bans that include ENDS (i.e., no ENDS use in home and cars)

Public policy recommendations

media and point-of-sale settings

to avoid secondhand and thirdhand

• The sale of ENDS and ENDS solution

that can be viewed by youths.

aerosol exposure and modeling of

to individuals younger than 21 years

Restrict depictions of ENDS in

smoking behavior.

should be banned (the Academy

movies, TV shows and video

• Counsel parents that children should

recommends 21 years as the minimum

games. • Local, state and federal regulation is

avoid contact with ENDS and

legal age of purchase for all tobacco

ENDS solution to avoid accidental

products), along with Internet sales of

needed to protect youths and others

poisonings.

ENDS and ENDS solutions.

from secondhand and thirdhand

• Parents and teens who use ENDS

• ENDS should be included in tobacco

aerosol exposure, as well as

should be offered or referred for

and smoke-free policies to reduce

unintentional nicotine exposure and

tobacco-cessation counseling and

youth ENDS use and exposure.

poisonings.

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POLICY STATEMENT

Organizational Principles to Guide and Define the Child Health Care System and/or Improve the Health of all Children

Electronic Nicotine Delivery Systems SECTION ON TOBACCO CONTROL

abstract

This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. The guidance in this statement does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. American Academy of Pediatrics Federal advocacy efforts should be coordinated with the AAP Department of Federal Affairs in Washington, DC, and with AAP chapters on state advocacy efforts to protect children from the harmful effects of tobacco use and secondhand smoke exposure. All policy statements from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

Electronic nicotine delivery systems (ENDS) are rapidly growing in popularity among youth. ENDS are handheld devices that produce an aerosolized mixture from a solution typically containing concentrated nicotine, flavoring chemicals, and propylene glycol to be inhaled by the user. ENDS are marketed under a variety of names, most commonly electronic cigarettes and e-cigarettes. In 2014, more youth reported using ENDS than any other tobacco product. ENDS pose health risks to both users and nonusers. Nicotine, the major psychoactive ingredient in ENDS solutions, is both highly addictive and toxic. In addition to nicotine, other toxicants, carcinogens, and metal particles have been detected in solutions and aerosols of ENDS. Nonusers are involuntarily exposed to the emissions of these devices with secondhand and thirdhand aerosol. The concentrated and often flavored nicotine in ENDS solutions poses a poisoning risk for young children. Reports of acute nicotine toxicity from US poison control centers have been increasing, with at least 1 child death reported from unintentional exposure to a nicotine-containing ENDS solution. With flavors, design, and marketing that appeal to youth, ENDS threaten to renormalize and glamorize nicotine and tobacco product use. There is a critical need for ENDS regulation, legislative action, and counter promotion to protect youth. ENDS have the potential to addict a new generation of youth to nicotine and reverse more than 50 years of progress in tobacco control.

DEFINITIONS • Secondhand aerosol: emissions from electronic nicotine delivery systems (ENDS) that are discharged into the surrounding environment with ENDS use, both directly from the ENDS and exhaled from the lungs of the user. • Thirdhand aerosol: ENDS emissions that remain on surfaces and in dust after ENDS use, which can be reemitted into the gas phase or react with oxidants in the environment to yield secondary pollutants. • ENDS alternate names: electronic cigarettes, e-cigarettes, e-cigs, electronic cigars, e-cigars, electronic hookah, e-hookah, hookah sticks, personal vaporizers, mechanical mods, vape pens, and vaping devices.

www.pediatrics.org/cgi/doi/10.1542/peds.2015-3222 DOI: 10.1542/peds.2015-3222

BACKGROUND

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

ENDS, including electronic cigarettes (e-cigarettes), are handheld devices that produce an aerosol from a solution typically containing nicotine,

Copyright © 2015 by the American Academy of Pediatrics

FROM THE AMERICAN ACADEMY OF PEDIATRICS

flavoring chemicals, and carrier solvents such as propylene glycol and vegetable glycerin (glycerol) for inhalation by the user. Wide variability exists in ENDS terminology, product design, and engineering. For the purposes of the current policy statement, the term ENDS encompasses devices that are typically battery operated and produce emissions for inhalation. Alternate names for these products include electronic cigarettes, e-cigarettes, e-cigs, electronic cigars, electronic hookah, e-hookah, hookah sticks, personal vaporizers, mechanical mods, vape pens, and vaping devices. Although commonly referred to as a vapor, the emission from ENDS is most accurately referred to as an aerosol, which is a suspension of fine particles in a gas.1 Despite variations in terminology, ENDS products generally have several common components that include a flow sensor, aerosol generator, battery, and solution storage area.2 When a user draws a breath (or “vapes”) from the device, a flow sensor detects the change in pressure and activates the aerosol generator. The generator draws the solution from the storage area and heats and/or mechanically disperses the solution, creating an aerosol. This aerosol is inhaled by the user, who then exhales it. Nonusers can be exposed to the emissions both from the aerosol that is exhaled as well as from the aerosol that is generated from the device. Some ENDS products have a light-emitting diode that simulates the lit end of a conventional cigarette. There are more than 460 different brands of ENDS, which vary considerably in price, quality, and design.3,4 ENDS can be purchased in various retail outlets, including vendors that sell tobacco, “vape” shops, mall kiosks, gas stations, convenience stores, grocery stores, and pharmacies, as well as through Internet vendors. ENDS can be

disposable or reusable; the reusable ENDS products have a rechargeable battery.4 The ENDS solution storage containers also vary widely, ranging from prefilled cartridges to tank-style, large refillable cartridges.4,5 Although many of the early “first-generation” ENDS were designed to resemble conventional cigarettes, newer ENDS models largely do not and may resemble other common objects such as a pen or flashlight.

dual use of ENDS and conventional cigarettes have been noted in both adults13,14 and youth.6,9,10,12,15 Among youth, self-reported e-cigarette use was also associated with higher odds of ever or current conventional cigarette smoking.15 Compared with nonusers, youth who used e-cigarettes perceived them as healthier than cigarettes10; however, youth using e-cigarettes were less likely to achieve abstinence from conventional cigarettes.15

EPIDEMIOLOGY OF YOUTH ENDS USE

Youth exposure to ENDS secondhand and thirdhand aerosol has also potentially increased with the increase in adult ENDS use. The percentage of e-cigarette ever use in adults rose from 3.3% in 2010 to 8.5% in 2013, and current use increased from 1% in 2010 to 2.6% in 2013.13 Adult conventional cigarette smokers exhibited the largest growth in ever use of ENDS, increasing from 9.8% in 2010 to 36.5% in 2013.

ENDS use has increased dramatically among youth. The National Youth Tobacco Survey (NYTS) began surveying ENDS use in 2011, asking questions only about e-cigarettes. Ever use (defined by the NYTS as having ever tried an e-cigarette) among middle school students increased from 1.4% in 2011 to 3% in 2013.6,7 Current use (defined by the NYTS as use of an e-cigarette at least 1 day in the past 30 days) among middle school students was 0.6% in 2011 and increased to 3.9% in 2014, a 650% increase.7,8 Among high school students, ever use increased from 4.7% in 2011 to 11.9% in 2013, and current use increased from 1.5% in 2011 to 13.4% in 2014, an 890% increase.6–9 Other surveys of high school students have found higher current use at 17% to 18%, with ever use as high as 29%.10,11 The 2014 NYTS and Monitoring the Future survey both documented for the first time that more teenagers used e-cigarettes in the past 30 days than any other tobacco products, including conventional cigarettes.8,11 ENDS use has been documented as highest among male subjects, non-Hispanic white youth, and Hispanic youth.8,12 A 2013 survey of high school students found that e-cigarette-only users had fewer social and behavioral risk factors than conventional cigarette users, raising concern that ENDS are attracting youth who may not otherwise have used tobacco products.10 In addition, high levels of

ENDS MARKETING AND SALES The increasing awareness, sales, and use of ENDS is being fueled by the marketing and promotion of ENDS in the media, including television, movies, video games, social media, the Internet, radio and print media, billboards, and point-of-sale advertising, as well as by celebrity role models. Advertisements and promotional efforts in broadcast media have been shown to promote youth initiation and progression of tobacco use.16 ENDS companies have marketed their products with claims of being “healthier” and “safer” than conventional cigarettes; these claims have not been scientifically validated.3,17 There are also unsubstantiated claims that ENDS can be used to “smoke anywhere” and both explicit and implicit claims that ENDS are smoking cessation aids (currently unapproved by the US Food and Drug Administration [FDA]). Among all media outlets, ENDS advertising expenditures increased from $6.4 million in 2011 to $18.3

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million in 2012, with the majority spent on magazine and television advertisements.18 Although tobacco advertisements on television have been legally banned since 1971 because of the Public Health Cigarette Smoking Act, there are no current regulations in place limiting ENDS advertisements.19 Although the current generation of children and adolescents had not previously been exposed to tobacco advertisements on television, youth exposure to television advertisements for ENDS increased by 256% from 2011 to 2013.20 In 2013, 80% of US youth aged 12 to 17 years were exposed to an average of 13 ENDS advertisements over the 1-year period. Driven in part by the significant increase in marketing and promotion, ENDS sales represented a billion-dollar industry in 2013, with some forecasters predicting they will eventually surpass sales for conventional cigarettes.21

ENDS SOLUTION COMPONENTS The solutions used in ENDS products (often referred to as e-liquid or e-juice) can be purchased in prepackaged cartridges or by volume to fill a refillable cartridge. ENDS solutions are also available through Internet vendors, in stores, and places where ENDS products are sold. In addition to concentrated nicotine, components of the ENDS solutions generally include flavoring chemicals and carrier solvents, such as propylene glycol and glycerol.1 Currently, there are no federal quality standards to ensure the accuracy of ENDS solution constituents as advertised or labeled. The refillable cartridges allow the user to deliver other psychoactive substances, including marijuana.4 In addition to nicotine, numerous toxicants and carcinogens harmful to human health have been found in ENDS solutions, including aldehydes, tobacco-specific nitrosamines, metals, tobacco alkaloids, and polycyclic

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AAP PEDIATRIC COLLECTIONS

aromatic hydrocarbons.1,22,23 These quantitative and qualitative studies illustrate that there are additional components in ENDS solutions that are unknown to users. Nicotine is the major psychoactive component of an ENDS solution.1 In a study of 35 ENDS cartridges and refill solutions, there were substantial discrepancies (as much as 89%) between the label and the actual nicotine content.24 The reported nicotine concentration in ENDS solutions ranges from 0 to 36 mg/mL with cartridges that vary in size.5,17 In comparison, a single conventional cigarette contains from 10 to 30 mg of nicotine, although the absorbed nicotine yield for a user is far less, from 0.05 to 3 mg per cigarette.25,26 The user’s actual nicotine exposure is affected by many factors, including the delivery system, nicotine pharmacokinetics, and individual consumption behavior.27,28 More than 7760 unique flavors of ENDS solutions are advertised, the majority of which are confectionary in nature and appealing to children.3,29 Popular options include fruit, candy, and dessert flavors such as “Belgian waffle” and chocolate.3,17 The most commonly offered flavors are tobacco and menthol, which are offered by 93% and 92%, respectively, of ENDS brands.3 Because cigarettes with candy and fruit flavoring encourage youth experimentation, regular use, and addiction,30 flavorings (other than menthol) have been banned in conventional cigarettes since the Family Smoking Prevention and Tobacco Control Act of 2009. Although the flavoring chemicals used in ENDS solutions have been cited as “food grade” and “generally recognized as safe,” under FDA guidelines, this certification relates only to ingestion, not inhalation.29 A study of ENDS solutions found that many of the flavoring chemicals contain aldehydes (known respiratory irritants) in sufficient concentrations to be of toxicological concern.29

The carrier solvents propylene glycol and vegetable glycerin (glycerol) are used in ENDS solutions to produce an aerosol that, when heated, simulates conventional cigarette smoke.1 Although these carrier solvents are used in other settings, insufficient data exist on the health effects of repeated long-term inhalation and exposure to these solvents.31

ENDS SECONDHAND AND THIRDHAND AEROSOL The aerosol generated by ENDS is inhaled and then exhaled by the user, and some of the generated aerosol may be directly discharged into the surrounding environment. This aerosol, also referred to as secondhand aerosol or secondhand vapor, can be inhaled by bystanders in a manner similar to secondhand cigarette smoke. Although ENDS advertisers often claim the secondhand aerosol is “harmless water vapor,” these claims are false: known harmful toxicants and carcinogens have been found in ENDS emissions.4 These include polycyclic aromatic hydrocarbons32 as well as nicotine, volatile organic compounds, ultrafine particles, and particulate matter.32–34 Metal and silicate particles, some of which occur at higher levels than in conventional cigarettes, have also been detected in ENDS aerosol.35,36 Thirdhand aerosol, as with thirdhand smoke, is the residual aerosol that remains on surfaces and in dust after ENDS use; this residual may react with oxidants in the environment to yield secondary pollutants or be reemitted into the gas phase.37 Because nicotine on surfaces has been shown to be increased after ENDS use,38 thirdhand aerosol is another potentially harmful unintentional source of nicotine exposure for youth. ENDS use exposes nonusers, including at-risk populations such as children and pregnant women, to nicotine and other harmful toxicants from secondhand and thirdhand aerosol.

In laboratory studies, neonatal mice exposed to the aerosol from a nicotine-containing ENDS solution had detectable levels of plasma cotinine, a metabolite of nicotine.39 The mice exposed to the ENDS solution containing nicotine had decreased weight gain and impaired postnatal lung growth compared with mice exposed to room air. ENDS solutions have also been shown to be cytotoxic to human embryonic stem cells.40 These studies raise concern for harm from in utero exposure and neonatal exposure to nicotinecontaining ENDS solution.

THE EFFECTS OF NICOTINE ON THE DEVELOPING BRAIN Nicotine is highly addictive and is the primary psychoactive component causing addiction in tobacco products.25 Nicotine has neurotoxic effects on the developing brain.41,42 In early adolescence, development of executive function and neurocognitive processes in the brain has not fully matured. Adolescents are more likely to engage in experimentation with substances such as cigarettes, and they are also physiologically more vulnerable to addiction.43 Particularly in adolescence, nicotine also has an effect on the brain as a “gateway” drug for cocaine and other illicit drugs.44

UNINTENTIONAL ENDS EXPOSURE AND TOXICITY Nicotine is derived from the tobacco plant and, in addition to being highly addictive, is toxic to humans.25 Nicotine is well absorbed from the respiratory tract, mucosal surfaces, skin, and intestines; thus, nicotine exposure can occur from inhaling, ingesting, or coming in physical contact with a nicotine-containing ENDS solution.25,45 Although symptoms of acute nicotine toxicity are generally mild and resolve within 12 hours with no treatment, large exposures can be fatal.46 Symptoms of acute nicotine toxicity are similar to those in a nicotine-naive user and

include fine tremor, nausea, tachycardia, and elevated blood pressure.25 Severe poisonings generally have a biphasic reaction. Early symptoms occur within the first hour of exposure and are characterized by cholinergic excess (increased salivation, vomiting, and diaphoresis); other signs may include cardiac dysrhythmias, seizures, and muscle fasciculations. Late symptoms of severe nicotine poisoning occur between 0.5 and 4 hours and include hypotension, bradycardia, lethargy, and respiratory failure secondary to neuromuscular blockade. Severe nicotine toxicity in children has been reported with nicotine doses as low as 2 mg.25 ENDS solutions have been advertised to contain as much as 36 mg/mL of nicotine (3.6%).17 The oral lethal dose of nicotine by body weight that is estimated to kill 50% of adults is projected at between 0.8 and 13 mg/kg.25,46 Using the mid-range estimate (6 mg/kg) of a lethal dose of nicotine, an ingestion of the contents of 2 mL (,0.5 teaspoon) of an ENDS concentrated nicotine solution could be fatal to the average 12-kg, 20-monthold child. There is significant risk of pediatric morbidity and mortality with the current unregulated packaging and volume of nicotine concentrations available in ENDS solutions. There has been an increase in unintentional exposures and poisonings from ENDS in the United States, including inhalations, eye and skin exposures, and ingestions. Calls to poison control centers for ENDS exposures increased from 1 exposure call per month in September 2010 to 215 calls in February 2014.45 The majority of ENDS exposures were among children 0 to 5 years of age, and 57.8% of ENDS exposures produced adverse health effects, most commonly vomiting, nausea, and eye irritation.45,47 As of publication date, there has been 1 reported child death in the United States from ingestion of a nicotine-containing ENDS solution.48 There has also been 1

adult death in the United States from an intentional injection of a nicotinecontaining ENDS solution.47 In addition, the lithium-ion batteries used in ENDS have reportedly caused explosions and fires, most commonly while the battery is charging. The US Fire Administration has cautioned that, because of the shape and construction of ENDS, battery failure may be more likely to result in an explosion that is propelled like a “flaming rocket.”49

DATA ON USE OF ENDS FOR SMOKING CESSATION ENDS products have been promoted by some manufacturers, either explicitly or implicitly, as a smoking cessation aid, although they are not approved by the FDA as a smoking cessation product.3,17 There have been limited studies on its use as a medical device. As of publication date, 1 randomized controlled clinical trial has compared nicotine-containing ENDS, nicotinereplacement therapy (21-mg nicotine patches), and placebo (no nicotine) ENDS.50 Six-month cessation rates were low overall, and no statistically significant difference was found among the 3 groups. Notable limitations to the study included inadequate behavioral support for all groups and poor participant adherence with study treatments, which was particularly low in the nicotine patch group. Because these results are from a single study, they should be interpreted with caution, considering the low overall tobacco cessation rates in all 3 study groups. An earlier meta-analysis of tobacco dependence treatments (which did not include ENDS) found that the nicotine patch was effective for the treatment of tobacco dependence, with cessation rates of 23% with the nicotine patch alone.51 Other population-based studies have found no association between ENDS use and successful cessation of conventional cigarette use.4,52 Overall, there is insufficient evidence to recommend the use of ENDS for smoking cessation.

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FEDERAL AND STATE ENDS REGULATION Although federal regulations ban the sale of conventional cigarettes to youth aged ,18 years, there are no current federal age restrictions for purchasing ENDS or ENDS products. The American Academy of Pediatrics (AAP) recommends 21 years as the minimum age of purchase for all tobacco products.53 In April 2014, the FDA issued a draft regulation that would extend the agency’s tobacco authority to cover the sale and distribution of ENDS and other tobacco products similar to conventional cigarettes. Final action on this regulation is pending. Federal regulations on the content, labeling, and packaging of ENDS and ENDS solutions also do not exist as of publication date. Federal legislation is pending that would give the Consumer Product Safety Commission the authority to require child-resistant packaging on liquid nicotine containers sold to consumers. Some states have already enacted legislation mandating child-resistant packaging for ENDS solutions. The majority of states have enacted laws prohibiting ENDS sales to minors, and a few states have enacted comprehensive laws that prohibit ENDS use in private worksites, restaurants, and bars.54 Updated information on state ENDS laws is available by contacting the AAP Division of State Government Affairs at [email protected]. There is no current federal regulation of Internet ENDS sales. No federal laws prevent ENDS and ENDS solutions from being purchased by anyone over the Internet, regardless of age.

RECOMMENDED ACTIONS FOR THE PEDIATRICIAN 1. Pediatricians should screen for ENDS use and provide prevention counseling in clinical practice. a. Screen children and adolescents, parents, and caregivers for ENDS use. Screening for ENDS use and exposure should be incorporated into the

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AAP PEDIATRIC COLLECTIONS

screening for tobacco use. Opportunities to screen include health supervision visits and visits for diseases that may be caused or exacerbated by tobacco smoke exposure, including ENDS secondhand or thirdhand aerosol. Because ENDS products vary widely and are referred to by many names, ask about use of these products by using specific names (eg, electronic cigarettes, e-cigarettes, e-cigs, electronic cigars, electronic hookah, e-hookah, hookah sticks, personal vaporizers, mechanical mods, vape pens, vaping devices). For more information (including an ENDS fact sheet), please refer to the AAP Julius B. Richmond Center of Excellence ENDS Web page (http://www2.aap. org/richmondcenter/ENDS.html). b. Counsel children and adolescents about the harms of ENDS and the importance of remaining a nonuser of ENDS and all nicotine-containing products. As part of tobacco use prevention counseling, pediatricians should include prevention counseling about the known hazards of ENDS and the importance of not initiating use of any nicotine-containing product. Personally relevant messages may include the severity and rapid development of nicotine addiction and health effects from ENDS use, lack of regulation of ENDS products and solutions, and the contaminants in the products.

2. ENDS use should not be recommended as a treatment product for tobacco dependence. No current evidence supports the efficacy or safety of ENDS as a tobacco dependence treatment product. Tobacco-dependent parents, caregivers, and adolescents should be offered behavioral counseling and support and should be educated on, offered, and/or referred to evidencebased, FDA-approved, tobacco dependence treatment medications as appropriate for the individual’s

severity of tobacco dependence and readiness to quit.51

3. Parents, caregivers, and adolescents who use ENDS should be offered or referred for tobacco cessation counseling and FDAapproved tobacco dependence pharmacotherapies appropriate to their level of addiction and readiness to change. For further information on tobacco cessation counseling and resources for adults and youth, please refer to the following:

• Clinical Practice Policy to Protect Children From Tobacco, Nicotine, and Tobacco Smoke55 • Treating Tobacco Use and Dependence (http://www.ahrq.gov/ professionals/clinicians-providers/ guidelines-recommendations/ tobacco/index.html) • Clinical Effort Against Secondhand Smoke Exposure (http://www2. massgeneral.org/ceasetobacco/) • American College of Chest Physicians Tobacco Dependence Treatment ToolKit (http:// tobaccodependence.chestnet.org/) 4. Pediatricians should recommend to ENDS users that children should avoid contact with ENDS and ENDS solutions as well as secondhand and thirdhand aerosol exposure. a. Counsel parents and caregivers that ENDS and ENDS solutions should be stored in childresistant packaging and out of the reach of children. Although some states have enacted legislation mandating childresistant packaging, no current federal regulations exist for childresistant packaging for ENDS and ENDS solutions. Although counseling should be targeted to prevention of ENDS use, if there are household users of ENDS, pediatricians should counsel parents and caregivers about childresistant packaging, handling, and storage.

b. Counsel parents and caregivers about strategies to reduce exposure to ENDS aerosol, such as instituting bans on ENDS use in the home and car. The best protection from exposure to ENDS aerosol is for parents and caregivers to not use ENDS. If that is not possible, pediatricians should recommend ENDS-free policies for their home and car.

5. Pediatricians should be familiar with symptoms of acute nicotine poisoning and consider acute nicotine poisoning from ENDS solutions when treating a child with symptoms consistent with acute nicotine poisoning unexplained by other etiologies. Although most exposures will not require treatment, medical management of severe acute nicotine ingestion is largely symptomatic and supportive. If an exposure occurs or there is concern for exposure, the American Association of Poison Control Centers (1-800-222-1222) should be contacted.

PUBLIC POLICY RECOMMENDATIONS 1. Reduce youth access to ENDS. a. Ban the sale to and use of ENDS for children and youth younger than 21 years. Banning the sale of ENDS to youth younger than 21 years will decrease youth access and the potential for nicotine addiction. The AAP recommends 21 years as the minimum legal age of purchase for all tobacco products. b. Ban Internet sales of ENDS and ENDS solutions. Prohibition of Internet sales can help regulate the ability to restrict the sale of ENDS to youth. Internet sales of ENDS and ENDS solutions can easily be accessed by minors and used to evade local tobacco control regulations and taxes.

2. Reduce youth demand for ENDS. a. Ban all flavors in ENDS. Because flavors have been shown to promote tobacco product use among youth,30 flavoring chemicals, including menthol, should be banned in all ENDS products and solutions. Flavoring chemicals attractive to youth also have the potential to increase risk of ingestion of the ENDS solution by young children.

3. Ban advertising of ENDS in media/ Internet/point-of-sale settings that can be viewed by youth. ENDS advertisements in media, including television, radio and print, billboards, signage, Internet, and point-of-sale (advertisements located where ENDS are sold), promote a positive image of ENDS and encourage youth purchase and use of ENDS. Any promotional activities that can be accessed by children and/or adolescents should be considered advertising to youth.

4. Restrict depictions of ENDS and ENDS use in movies, television shows, and video games. Require any movie, television show, or video game with a depiction of ENDS or ENDS use to have an adult rating. Tobacco advertisements and promotional efforts in media promote youth tobacco initiation and progression of smoking. Movies, television shows, and video games that depict ENDS or ENDS use should be rated a minimum of R, TV-MA, or Mature, respectively.

learn, work, and play, including workplaces, restaurants, health care facilities, child care settings, schools, dormitories, entertainment venues, parks, athletic facilities, shopping malls, restaurants, and leisure facilities. School and college campuses should prohibit the sale and use of ENDS. Prohibitions of ENDS should be included as part of tobacco-free and smoke-free laws and policies. b. Protect children from unintentional nicotine exposure and poisonings. i. The size of ENDS concentrated nicotine solution prefilled cartridges and containers should be limited to amounts that would not be lethal to a young child if ingested. ii. ENDS solutions containing nicotine should be dispensed in childresistant packaging. iii. Child-resistant caps and other packaging technologies should be used to reduce the risk of exposure to children, including those that restrict the rate and amount of flow of liquid nicotine from a container.56 c. Tax ENDS at the same rate as conventional cigarettes. Smokers, particularly youth, are very price-sensitive57; therefore, ENDS and ENDS solutions should be taxed at a rate sufficient to discourage their use among youth and at a level not less than state and federal taxes on conventional cigarettes.

5. Protect youth from harms of involuntary ENDS, ENDS solution, and ENDS aerosol exposure.

d. Apply funds for public health initiatives to protect youth and to study the health effects of ENDS on users and nonusers.

a. Protect youth and other nonusers from secondhand and thirdhand aerosol exposure. Because ENDS secondhand and thirdhand aerosol contains nicotine and other harmful toxicants, ENDS use should be prohibited in all public spaces. ENDS use should also be prohibited in all locations where children and youth are cared for,

Research demonstrating the adverse health effects of conventional cigarette use and exposure took decades, while millions of youth and adults died of tobacco-related diseases. It is critical that the funding and development of research on ENDS, ranging from basic science of exposure to effects on public health and youth initiation, progress as

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quickly as the increase in youth ENDS use. Research funding should also focus on public health initiatives, including outcomes evaluations.

CONCLUSIONS ENDS use is rapidly increasing among youth and, according to the most recent data, ENDS are the most common tobacco product used among youth. ENDS use has the potential to addict youth to nicotine. There are potential health harms to nonusers of ENDS because of its toxicants, including nicotine, carcinogens, and metal particles found in the secondhand and thirdhand aerosol. There has been an increase in unintentional exposures of children with acute nicotine poisoning from a concentrated nicotine–containing ENDS solution, with at least 1 child death from unintentional ingestion of an ENDS solution. The increasing use of ENDS among youth threatens 5 decades of public health gains in successfully deglamorizing, restricting, and decreasing the use of tobacco products. Health claims of ENDS as smoking cessation aids are currently unsupported by scientific evidence. There is a crucial need for effective local, state, and federal regulation to protect children and youth from ENDS use and exposure to ENDS secondhand and thirdhand aerosol and concentrated nicotine solution. LEAD AUTHORS Susan C. Walley, MD, FAAP Brian P. Jenssen, MD, FAAP

PROVISIONAL SECTION ON TOBACCO CONTROL, 2014–2015 Ruth A. Etzel, MD, PhD, FAAP, Co-chairperson Karen M. Wilson, MD, MPH, FAAP, Co-chairperson Sophie J. Balk, MD, FAAP Harold J. Farber, MD, MSPH, FAAP Judith A. Groner, MD, FAAP John E. Moore, MD, FAAP

STAFF Janet Brishke, MPH

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ABBREVIATIONS AAP: American Academy of Pediatrics e-cigarettes: electronic cigarettes ENDS: electronic nicotine delivery systems FDA: US Food and Drug Administration NYTS: National Youth Tobacco Survey

REFERENCES 1. Cheng T. Chemical evaluation of electronic cigarettes. Tob Control. 2014; 23(suppl 2):ii11–ii17 2. Brown CJ, Cheng JM. Electronic cigarettes: product characterisation and design considerations. Tob Control. 2014; 23(suppl 2):ii4–ii10 3. Zhu SH, Sun JY, Bonnevie E, et al. Four hundred and sixty brands of e-cigarettes and counting: implications for product regulation. Tob Control. 2014;23(suppl 3): iii3–iii9 4. Grana R, Benowitz N, Glantz SA. E-cigarettes: a scientific review. Circulation. 2014;129(19):1972–1986 5. Collaco JM, Drummond MB, McGrathMorrow SA. Electronic cigarette use and exposure in the pediatric population. JAMA Pediatr. 2015;169(2):177–182 6. Arrazola RA, Neff LJ, Kennedy SM, HolderHayes E, Jones CD; Centers for Disease Control and Prevention (CDC). Tobacco use among middle and high school students—United States, 2013. MMWR Morb Mortal Wkly Rep. 2014;63(45): 1021–1026 7. Centers for Disease Control and Prevention (CDC). Notes from the field: electronic cigarette use among middle and high school students—United States, 2011-2012. MMWR Morb Mortal Wkly Rep. 2013;62(35):729–730

MMWR Morb Mortal Wkly Rep. 2013; 62(45):893–897 10. Wills TA, Knight R, Williams RJ, Pagano I, Sargent JD. Risk factors for exclusive e-cigarette use and dual e-cigarette use and tobacco use in adolescents. Pediatrics. 2015;135(1). Available at: www.pediatrics.org/cgi/content/full/135/ 1/e43 11. Johnston LD, O’Malley PM, Miech RA, Bachman JG, Schulenberg JE. Monitoring the Future: National Survey Results on Drug Use: 1975-2014. Overview, Key Findings on Adolescent Drug Use. Ann Arbor, MI: Institute for Social Research, The University of Michigan; 2015. Available at: www.monitoringthefuture. org/pubs/monographs/mtfoverview2014.pdf. Accessed July 8, 2015 12. Lippert AM. Do adolescent smokers use e-cigarettes to help them quit? The sociodemographic correlates and cessation motivations of US adolescent e-cigarette use. Am J Health Promot. 2015;29(6):374–379 13. King BA, Patel R, Nguyen KH, Dube SR. Trends in awareness and use of electronic cigarettes among US adults, 2010-2013. Nicotine Tob Res. 2015;17(2): 219–227 14. McMillen RC, Gottlieb MA, Shaefer RMW, Winickoff JP, Klein JD. Trends in electronic cigarette use among US adults: use is increasing in both smokers and nonsmokers. Nicotine Tob Res. 2015;17(10):1195–1202 15. Dutra LM, Glantz SA. Electronic cigarettes and conventional cigarette use among U.S. adolescents: a cross-sectional study. JAMA Pediatr. 2014;168(7):610–617

8. Arrazola RA, Singh T, Corey CG, et al; Centers for Disease Control and Prevention (CDC). Tobacco use among middle and high school students— United States, 2011-2014. MMWR Morb Mortal Wkly Rep. 2015;64(14):381–385

16. National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. Preventing Tobacco Use Among Youth and Young Adults: A Report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention; 2012. Available at: http:// pubmed.org/pubmed/?term=2012+ Surgeon+General%27s+Report%E2% 80%94Preventing+Tobacco+Use+Among+ Youth+and+Young+Adults. Accessed July 8, 2015

9. Centers for Disease Control and Prevention (CDC). Tobacco product use among middle and high school students—United States, 2011 and 2012.

17. Grana RA, Ling PM. “Smoking revolution”: a content analysis of electronic cigarette retail websites. Am J Prev Med. 2014; 46(4):395–403

18. Kim AE, Arnold KY, Makarenko O. E-cigarette advertising expenditures in the US, 2011-2012. Am J Prev Med. 2014; 46(4):409–412 19. Hodge JG Jr, Collmer V, Orenstein DG, Millea C, Van Buren L. Reconsidering the legality of cigarette smoking advertisements on television public health and the law. J Law Med Ethics. 2013;41(1):369–373 20. Duke JC, Lee YO, Kim AE, et al. Exposure to electronic cigarette television advertisements among youth and young adults. Pediatrics. 2014;134(1). Available at: www.pediatrics.org/cgi/content/full/ 134/1/e29 21. Robehmed N. E-cigarette sales surpass $1 billion as big tobacco moves in. Forbes. September 17, 2013. Available at: www.forbes.com/sites/natalierobehmed/ 2013/09/17/e-cigarette-sales-surpass-1billion-as-big-tobacco-moves-in/. Accessed July 8, 2015 22. Goniewicz ML, Knysak J, Gawron M, et al. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control. 2014;23(2): 133–139 23. Jensen RP, Luo W, Pankow JF, Strongin RM, Peyton DH. Hidden formaldehyde in e-cigarette aerosols. N Engl J Med. 2015 22;372(4):392–394 24. Goniewicz ML, Kuma T, Gawron M, Knysak J, Kosmider L. Nicotine levels in electronic cigarettes. Nicotine Tob Res. 2013;15(1):158–166 25. Soghoian S. Nicotine. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank’s Toxicologic Emergencies. 10th ed. New York, NY: McGraw-Hill Education; 2015:1138–1143 26. Federal Trade Commission. Report on Tar, Nicotine, and Carbon Monoxide, Covering 1998. Washington, DC: Federal Trade Commission; 2000. Available at: www.ftc.gov/reports/2000-report-tarnicotine-carbon-monoxide-covering-1998. Accessed September 15, 2015 27. Schroeder MJ, Hoffman AC. Electronic cigarettes and nicotine clinical pharmacology. Tob Control. 2014;23 (suppl 2):ii30–ii35 28. Evans SE, Hoffman AC. Electronic cigarettes: abuse liability, topography and subjective effects. Tob Control. 2014; 23(suppl 2):ii23–ii29

29. Tierney PA, Karpinski CD, Brown JE, Luo W, Pankow JF. Flavour chemicals in electronic cigarette fluids [published online ahead of print April 15, 2015]. Tob Control. doi: 10.1136/tobaccocontrol2014-052175 30. Deyton L, Sharfstein J, Hamburg M. Tobacco product regulation—a public health approach. N Engl J Med. 2010; 362(19):1753–1756 31. Callahan-Lyon P. Electronic cigarettes: human health effects. Tob Control. 2014; 23(suppl 2):ii36–ii40 32. Schober W, Szendrei K, Matzen W, et al. Use of electronic cigarettes (e-cigarettes) impairs indoor air quality and increases FeNO levels of e-cigarette consumers. Int J Hyg Environ Health. 2014;217(6):628–637 33. Schripp T, Markewitz D, Uhde E, Salthammer T. Does e-cigarette consumption cause passive vaping? Indoor Air. 2013;23(1):25–31 34. Czogala J, Goniewicz ML, Fidelus B, Zielinska-Danch W, Travers MJ, Sobczak A. Secondhand exposure to vapors from electronic cigarettes. Nicotine Tob Res. 2014;16(6):655–662 35. Williams M, Villarreal A, Bozhilov K, Lin S, Talbot P. Metal and silicate particles including nanoparticles are present in electronic cigarette cartomizer fluid and aerosol. PLoS One. 2013;8(3):e57987

40. Bahl V, Lin S, Xu N, Davis B, Wang YH, Talbot P. Comparison of electronic cigarette refill fluid cytotoxicity using embryonic and adult models. Reprod Toxicol. 2012;34(4):529–537 41. Dwyer JB, McQuown SC, Leslie FM. The dynamic effects of nicotine on the developing brain. Pharmacol Ther. 2009; 122(2):125–139 42. Schraufnagel DE. Electronic cigarettes: vulnerability of youth. Pediatr Allergy Immunol Pulmonol. 2015;28(1):2–6 43. Pentz MA, Shin H, Riggs N, Unger JB, Collison KL, Chou CP. Parent, peer, and executive function relationships to early adolescent e-cigarette use: a substance use pathway? Addict Behav. 2015;42: 73–78 44. Kandel ER, Kandel DB. Shattuck Lecture. A molecular basis for nicotine as a gateway drug. N Engl J Med. 2014; 371(10):932–943 45. Chatham-Stephens K, Law R, Taylor E, et al; Centers for Disease Control and Prevention (CDC). Notes from the field: calls to poison centers for exposures to electronic cigarettes—United States, September 2010-February 2014. MMWR Morb Mortal Wkly Rep. 2014;63(13): 292–293 46. Mayer B. How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious selfexperiments in the nineteenth century. Arch Toxicol. 2014;88(1):5–7

36. Saffari A, Daher N, Ruprecht A, et al. Particulate metals and organic compounds from electronic and tobaccocontaining cigarettes: comparison of emission rates and secondhand exposure. Environ Sci Process Impacts. 2014;16(10):2259–2267

47. Vakkalanka JP, Hardison LS Jr, Holstege CP. Epidemiological trends in electronic cigarette exposures reported to U.S. Poison Centers. Clin Toxicol (Phila). 2014; 52(5):542–548

37. Matt GE, Quintana PJE, Destaillats H, et al. Thirdhand tobacco smoke: emerging evidence and arguments for a multidisciplinary research agenda. Environ Health Perspect. 2011;119(9): 1218–1226

48. Hughes C. Tot’s fatal liquid nicotine ingestion brings call for action. Times Union. December 11, 2014. Available at: www.timesunion.com/local/article/CopsBoy-died-after-swallowing-liquid-nicotine5948066.php. Accessed July 8, 2015

38. Goniewicz ML, Lee L. Electronic cigarettes are a source of thirdhand exposure to nicotine. Nicotine Tob Res. 2015;17(2): 256–258

49. US Fire Administration. Electronic Cigarette Fires and Explosions. Washington, DC: Federal Emergency Management Agency, US Department of Homeland Security; October 2014. Available at: https://www.usfa.fema.gov/ downloads/pdf/publications/electronic_ cigarettes.pdf. Accessed July 8, 2015

39. McGrath-Morrow SA, Hayashi M, Aherrera A, et al. The effects of electronic cigarette emissions on systemic cotinine levels, weight and postnatal lung growth in neonatal mice. PLoS One. 2015;10(2):e0118344

50. Bullen C, Howe C, Laugesen M, et al. Electronic cigarettes for smoking

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cessation: a randomised controlled trial. Lancet. 2013;382(9905):1629–1637 51. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services. Public Health Service; 2008, Available at: www.ahrq. gov/professionals/clinicians-providers/ guidelines-recommendations/tobacco/ clinicians/update/treating_tobacco_ use08.pdf. Accessed July 8, 2015 52. McRobbie H, Bullen C, Hartmann-Boyce J, Hajek P. Electronic cigarettes for smoking cessation and reduction.

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Cochrane Database Syst Rev. 2014; 12(12):CD010216 53. American Academy of Pediatrics Section on Tobacco Control. Policy statement: public policy to protect children from tobacco, nicotine, and tobacco smoke. Pediatrics. 2015;136(5):998–1007 54. Marynak K, Holmes CB, King BA, Promoff G, Bunnell R, McAfee T; Centers for Disease Control and Prevention (CDC). State laws prohibiting sales to minors and indoor use of electronic nicotine delivery systems—United States, November 2014. MMWR Morb Mortal Wkly Rep. 2014;63(49):1145–1150

55. American Academy of Pediatrics Section on Tobacco Control. Policy statement: clinical practice policy to protect children from tobacco, nicotine, and tobacco smoke. Pediatrics. 2015;136(5): 1008–1017 56. Lovegrove MC, Hon S, Geller RJ, et al. Efficacy of flow restrictors in limiting access of liquid medications by young children. J Pediatr. 2013;163(4): 1134–9.e1 57. Chaloupka FJ, Yurekli A, Fong GT. Tobacco taxes as a tobacco control strategy. Tob Control. 2012;21(2): 172–180

:: December-19-2016

Perfect Storm Can Spur Nicotine Addiction in Youths Alyson Sulaski Wyckoff, Associate Editor

A

mong the reasons to keep youths from starting to smoke: Each year, only about 4% of 12- to 19-year-old smokers will successfully quit. While half of adult smokers try to quit

annually, less than 5% succeed. And the younger people are when they begin smoking, the less likely they will kick the habit. Tobacco exposure through personal use or second- or thirdhand smoke exposure remains the most important preventable cause of illness, disability and death among adults in the U.S. Internationally, tobacco use is the No. 1 cause of preventable death. After a gradual decline in smoking, the rate of decline has begun to slow for cigarettes. There also has been a significant rise in the use of nicotine products such as e-cigarettes, hookahs and smokeless tobacco, according to a new AAP technical report. Nicotine and Tobacco as Substances of Abuse in Children and Adolescents, from the Committee on Substance Use and Prevention, reviews the stages of use in progression to dependence on nicotine-containing products, as well as the physiologic characteristics, neurobiology, metabolism, pharmacogenetics and health effects of nicotine. The report is available at http://dx.doi.org/10.1542/peds.2016-3436 and will be published in the January issue of Pediatrics.

Multiple contributing factors While tobacco products contain more than 4,000 chemicals, nicotine is the major contributor to the development of dependence and the primary pharmacologic component of tobacco. Rapidly developing brains are especially susceptible to nicotine addiction, but behavioral, social, environmental and psychological factors also influence the development and maintenance of addiction. The urge to smoke occurs early on after kids first try it, the report notes, and then drives adolescents to smoke more often. A predictable sequence of events often unfolds: wanting to smoke, having cravings and then needing to smoke to avoid withdrawal symptoms. This “neurophysiologic dependence” leads to tolerance, and a greater amount of nicotine is needed to maintain equilibrium.

Appealing sensations Increasing the palatability of cigarettes are additives like menthol, with its candy-like taste and cooling properties. The sensory effects may result in the perception that cigarettes are less harmful than they really are and may drive up smoking frequency. Similarly, the sweeteners and fruit flavors in hookahs and the more than 7,000 flavors now available in electronic nicotine delivery systems including e-cigarettes also add to the products’ appeal. E-cigarette experimentation and recent use among middle and high school students in the U.S. doubled from 2011 to 2012, according to the report. About 1.78 million students had used e-cigarettes as of 2012.

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Toxic soup

Adverse effects of nicotine

Tobacco or nicotine also can have major

Although the delivery systems of products

There are not enough data to conclude

effects on early neurodevelopment. Infants

like e-cigarettes may reduce exposure to

that nicotine causes cancer, but evidence

born to mothers who smoked during

some of the toxic chemicals in cigarettes,

shows it may increase the risk for oral,

pregnancy had reduced weight, length

additional toxins are associated with

esophageal and pancreatic cancer.

and head circumference and exhibited

electronic delivery systems.

Among other effects, nicotine:

impulsivity, hyperactivity and significant impairments in cognitive functioning.

“Exposure to nicotine and its high addiction potential remain major concerns,” the report says.

• increases concentrations of dopamine,

The report addresses cessation

a neurotransmitter essential for boost-

measures, suggesting pharmacotherapy

ing attention, reward-seeking behaviors

to help moderately to severely tobacco-

e-cigarettes as smoking cessation aids,

and the risk of various addictions, from

dependent teens. However, there is

research has not documented their effec-

gambling to drug use;

concern that nicotine replacement therapy

Despite aggressive promotion of

tiveness in adults, according to the report.

• is at least partly responsible for the

use during adolescence may change the

Recent studies suggest that e-cigarette use

progression of chronic kidney disease

neurodevelopmental trajectory. Further

“may encourage, rather than discourage,

in cigarette smokers;

research is needed.

the use of conventional cigarettes among U.S. adolescents,” according to the report. Most of the adverse health consequences of tobacco use actually are the result of damage caused by tar, carbon monoxide, oxidizing chemicals and other constituents in the product rather than nicotine.

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• increases risk of osteoporosis and bone fractures;

Most research to date has been on behaviorally based interventions, which

• impacts body weight;

are most effective for youths with mild

• has a negative dose-related impact on

dependence. There are not enough data

both male and female fertility; and • significantly increases cortisol concentrations in daily smokers.

to support any one clinical approach to adolescent cessation of nicotine use, the report concludes.

TECHNICAL REPORT

Nicotine and Tobacco as Substances of Abuse in Children and Adolescents Lorena M. Siqueira, MD, MSPH, FAAP, FSAHM, COMMITTEE ON SUBSTANCE USE AND PREVENTION

Nicotine is the primary pharmacologic component of tobacco, and users of tobacco products seek out its effects. The highly addictive nature of nicotine is responsible for its widespread use and difficulty with quitting. This technical report focuses on nicotine and discusses the stages of use in progression to dependence on nicotine-containing products; the physiologic characteristics, neurobiology, metabolism, pharmacogenetics, and health effects of nicotine; and acute nicotine toxicity. Finally, some newer approaches to cessation are noted.

INTRODUCTION Tobacco exposure, whether through personal use, second- or thirdhand smoke exposure, or unintentional exposure, is the most important preventable cause of illness, disability, and death among adults in the United States.1 Worldwide, tobacco use is also the leading cause of preventable death.2 Many preventive measures have increased the perceived risk of smoking, which, along with the decreased access to cigarettes, has contributed to a gradual decline in use. However, the rate of decline has begun to slow for the use of cigarettes, and use has increased significantly for nicotine products such as hookahs and electronic nicotine delivery systems as well as for smokeless tobacco. As reported by the Centers for Disease Control and Prevention,2 e-cigarette experimentation and recent use among US middle and high school students doubled from 2011 to 2012 and has increased significantly since then. It is now estimated that 1.78 million students have ever used e-cigarettes. Of these, 9% (an estimated 160 000 students) have never used conventional cigarettes. The Monitoring the Future Study has also found that more teenagers report using electronic nicotine delivery systems in the past 30 days than any other tobacco product.3 Although these delivery systems may reduce exposure to some of the toxic chemicals in cigarettes, there are additional toxins associated with electronic nicotine delivery systems, and exposure to nicotine and its high addiction potential remain major concerns.4

abstract

This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. Technical reports from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external reviewers. However, technical reports from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent. The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. All technical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time. DOI: 10.1542/peds.2016-3436 PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The author has indicated she does not have a financial relationship relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The author has indicated she has no potential conflicts of interest to disclose.

To cite: Siqueira LM and AAP COMMITTEE ON SUBSTANCE USE AND PREVENTION. Nicotine and Tobacco as Substances of Abuse in Children and Adolescents. Pediatrics. 2017; 139(1):e20163436

FROM THE AMERICAN ACADEMY OF PEDIATRICS

It is well known that tobacco products contain more than 4000 different chemicals.5 Their effects, along with the sensory stimulation and the conditioning that develops with continued use, may contribute to the addiction process, but nicotine is the major contributor to the development of dependence. It is the primary pharmacologic component of tobacco, and its effects are sought after by users. Its highly addictive nature is responsible for the widespread use and difficulty with quitting.

HISTORICAL BACKGROUND Nicotine was originally isolated from the herbaceous plant Nicotiana tabacum, a native of tropical and subtropical America but now commercially cultivated worldwide. The plant was named after the diplomat Jean Nicot de Villemain, who, in 1556, brought tobacco seeds and leaves as a “wonder drug” to the French court from Brazil.6 Nicotine is a potent parasympathomimetic alkaloid and is now known to occur in the nightshade family of plants (Solanaceae). It is also present in minimal quantities in tomato, potato, eggplant (aubergine), green pepper, and cocoa leaves.7 Nicotine is produced in the roots and accumulates in the leaves of the tobacco plant, with the amount varying with position: that is, leaves harvested from higher stalk positions contain more nicotine than those from lower positions. Flue curing of the leaves changes the pH so that the smoke of the leaves is better inhaled and, as a result, both more addictive and more toxic. Leaves are usually combined so that, on average, cigarettes (in any of 15 different cigarette brands) contain approximately 1.5% nicotine by weight.8 Burning tobacco releases the nicotine, which is carried proximally on tar droplets and in the vapor when inhaled. Other alkaloids constitute

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8% to 12% of the total alkaloid content of tobacco products.

CRITERIA FOR DEPENDENCE Both the World Health Organization, in its International Classification of Diseases,9 and the American Psychiatric Association, in its Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,10 have issued diagnostic criteria to assess addiction. Currently, “substance use disorder” is the preferred term and includes dependence and withdrawal symptoms. Nicotine meets the established criteria for a drug that produces the symptoms of addiction, specifically, dependence, withdrawal, and craving. First use of tobacco most often occurs in young adolescents, and the earlier one begins, the less likely one is to be able to stop using tobacco products11 and the more likely use will continue with greater quantities.12 It has been estimated that two-thirds of children who smoke in sixth grade become regular adult smokers and almost half (46%) of smokers in the 11th grade become regular adult smokers.13 Even infrequent experimentation with smoking cigarettes can increase the risk of becoming a regular adult smoker; regular (defined as smoking at least monthly) smoking by an adolescent has been found to increase the risk of becoming an adult regular smoker by 16 times compared with nonsmoking adolescents.13 Of tobacco-dependent adults, 90% started smoking before 18 years of age and 99% started smoking before 26 years of age.14 A number of researchers have studied the development of nicotine addiction in adolescents. Even before any experimentation, adolescents’ exposure to advertising and the marketing of the range of tobacco products available can influence their attitudes about the risks and benefits of tobacco use. This initial preparatory stage is when individuals develop

attitudes and beliefs about the utility of tobacco and may then begin to experiment with a few cigarettes. A few will never use again, and some will smoke repeatedly but irregularly. Traditional theoretical models explaining nicotine addiction maintain that, beyond the role of nicotine as a key component required for the development of addiction, other behavioral, social, environmental, and psychological factors are also important for the development and maintenance of addiction.15 These include the attitude and behavior of friends and family members toward smoking, an underestimation of the addictive potential of nicotine, and an overestimation of the prevalence of peer smoking. Users also report that smoking alleviates anxiety, depression, and pain and that they, therefore, use it as a stress reliever. Although some of these effects may be related to the pharmacologic response along with the relief of withdrawal symptoms at times of smoking cessation, the belief that they are coping better with stress is a psychological effect that may lead to further use to control mood. Frequent dosing of nicotine is associated with hand-to-mouth movement that often becomes a social crutch that is difficult to do without after quitting. Other rituals associated with a particular device used may contribute to continued use. Smoking also becomes connected to specific times, experiences, and events, referred to as cues, and these become reinforcing of use over time. Light or intermittent smokers may be more influenced by these associated activities, such as after eating or drinking alcohol, than the need to use tobacco to relieve withdrawal symptoms.16 More recently, a newer model, the sensitization-homeostasis model, has been proposed as an alternative model, and a number of studies have supported this model to explain the development of nicotine addiction in

adolescents.17 This model suggests that, for adolescents, even infrequent smoking, such as at monthly intervals, is enough to put the individual at risk of dependence.18,19 With nondaily smoking, even after the first cigarette, early symptoms of dependence, such as wanting to smoke or craving a cigarette, can develop if adolescents go too long without a cigarette.20 One study has shown that monthly smoking can increase the likelihood of developing dependence by 10-fold.21 These researchers also found that there is a reciprocal relationship between diminished autonomy about smoking and the frequency of smoking. They suggest that the urge to smoke occurs early on after initiation and that this, in turn, drives the teenager to increase the frequency of smoking, which increases the risk of further dependence symptoms, such as a need to smoke. With increased frequency, the adolescent is more likely to experience a more rapid progression to addiction and the need for daily smoking, such as one would see in a dose-response effect. Researchers have also found that symptoms of dependence develop in a predictable sequence, beginning with wanting to smoke, followed by craving, and eventually needing to smoke to avoid withdrawal or abstinence symptoms, suggesting that the adolescent has neurophysiologic dependence.22 Neurophysiologic dependence may lead to tolerance, with a diminished effect experienced with continued use, resulting in an increased amount of nicotine needed to maintain equilibrium. This neuroadaptation within the brain may explain why teenagers report the need for nicotine to function normally.

PHYSIOLOGIC CHARACTERISTICS: FORMULATIONS, PREPARATIONS, AND ABSORPTION Nicotine is a weak base, and its absorption across biological membranes is pH dependent. It does

not rapidly cross membranes in an acidic environment when it is in an ionized form. The predominant form of tobacco in American cigarettes is flue cured. The initial puffs from these cigarettes have an acidic pH resulting in almost completely ionized nicotine that has little if any absorption across the buccal membranes. Air-cured tobacco, the predominant form in pipes, cigars, and a few European cigarettes, is alkaline. The released nicotine is largely nonionized and thus well absorbed through the mouth. Chewing tobacco, snuff, and nicotine polacrilex gum are also of alkaline pH, facilitating absorption through the oral mucous membranes. Nicotine can be absorbed through the skin, and toxicity has been documented in tobacco field-workers and those with skin contact with pesticides containing nicotine. In the lungs, the large surface area provided by the small airways and the alveoli as well as the local physiologic (slightly alkaline) pH of 7.4 allow for the rapid absorption of nicotine from cigarette smoke, where it reaches the systemic circulation without first passing through the liver. It is estimated to reach the brain in as little as 7 seconds after inhalation.23 The rapid onset of action with inhaled nicotine leads to a greater “high” and reinforces use, which leads to neuroadaptation, and continued use is related not only to the need to obtain nicotine but also to conditioning. Nicotine is poorly absorbed from the stomach because of the acidic pH but well absorbed from the small intestine. Reabsorption from the intestine may be a potential source for enterohepatic circulation. The dose of nicotine delivered cannot be determined solely by the nicotine content of the product because of these complexities. In addition, when smoking cigarettes, the actual amount of any alkaloid delivered depends on the puffing

characteristics: that is, the depth of the puff and the frequency. Smokers typically take 10 puffs within the span of 5 minutes and absorb 1 to 2 mg of nicotine (range: 0.5–3 mg).24 The elimination half-life of nicotine is 2 to 3 hours, meaning that the level of nicotine in the blood decreases by one-half after a smoker stops smoking for that length of time. This elimination half-life will decrease with repeated exposures to nicotine.

INCREASING PALATABILITY Several additives are used in the manufacture of cigarettes to reduce the harshness of the smoke.25 Menthol is an additive that is actively promoted by the tobacco industry for its perceived sensory benefits. A large number of young people and occasional users of cigarettes use menthol cigarettes because it helps reduce harshness. The specific candylike taste of menthol and its cooling, anesthetic, and analgesic properties make it appealing to these smokers.26 The sensory effects of menthol serve as conditioned stimuli, increasing the reinforcing effects of nicotine and thus the addiction potential of menthol cigarettes. As users become tolerant of this flavor, some actively seek even stronger sensory attributes in a cigarette, and beginning with a mentholcontaining product may facilitate an adolescent’s progression to daily smoking. Smokers who prefer and choose menthol-containing products tend to be disproportionately black and male.25 The perceived reduction in harshness may result in the intake of more cigarettes, and therefore more toxic and dependence-causing substances, increasing the difficulty in quitting cigarette use.27 The perceived reduced harshness also contributes to the perception that cigarettes are less harmful than they actually are. Similarly, other products have additives that increase their

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palatability. The tobacco used in hookahs (shisha, maassel, tumbak, or jurak) is moist and shredded. It is mixed with sweeteners such as honey, molasses, or fruit, and many have candy or fruit flavoring added. Bidis, hand-rolled, thin, filterless cigarettes, are sold unflavored or flavored (eg, with vanilla, strawberry, or mango). Kreteks, clove-flavored cigarettes, have a particularly pungent smell. Kreteks, used in Indonesia, contain eugenol, which has an anesthetic effect, allowing for deeper inhalation. Chewing tobacco is used all over the world; and in 1 form used in India, referred to as pan masala, areca nuts, slaked lime, and other flavoring agents and sweeteners are added. Electronic nicotine delivery systems also have >7760 unique flavors, including fruit, candy, and dessert flavors, raising concerns about the strong appeal of all these products to children.28

MECHANISM OF ACTION: NEUROBIOLOGY Nicotine acts on nicotinic acetylcholine receptors (nAChRs) in the peripheral nervous system (autonomic ganglia and adrenal medulla; neuromuscular junction) and the central nervous system (CNS). The nAChRs are ligand-gated ion channels made up of 5 subunits that assemble around an ion pore. When nicotine or acetylcholine binds, a change occurs in their conformation that renders the ion pore permeable to cations, which, in turn, excite the cell. There are 12 isoforms, 9 α-subunits labeled from α2 to α10 and 3 β-subunits labeled from β2 to β4. The mix of these subunits in each receptor gives the receptor its distinct pharmacologic properties and its response to nicotine stimulation. The activation of some receptors promotes the reinforcing effects, whereas the activation of others limits reinforcement and possibly mediates the aversive effects. An understanding of these

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subunits is helping researchers develop antismoking medications. In the human brain, the most widely expressed nAChR is the α4,β2 subunit, which has a central function in the mediation of the physiologic effects of nicotine. With repeated exposure, there is an increase in the number of nAChRs. This upregulation is believed to be the response to nicotine-mediated desensitization of the receptors and may play a role in the development of dependence. Overnight, when these receptors become unoccupied, it has been suggested that they recover to a responsive state, which creates the craving and withdrawal symptoms experienced by many in the morning. Functional imaging studies of the brain have detected differences in brain structure between smokers and nonsmokers. Smokers have been found to have differences in the microstructural order in white matter areas of the brain, specifically the anterior cingulate bundle.29 Studies also have found that smokers reporting more subjective symptoms of dependence, by using standardized measures, had a decreased density of neural connections, or streamlines, between the anterior cingulate bundle and the precuneus and increased connections between the anterior cingulate bundle and the superior-frontal cortex. These areas of the brain and specific circuits are those correlated with memory, motivation, executive function, and mood. These studies support the connection between subjective symptoms of nicotine dependence and white matter structure and suggest that nicotine dependence over time can result in neuroplastic changes in a number of brain systems. In addition, various neurotransmitters are involved, including acetylcholine, dopamine, noradrenaline, serotonin, glutamate, opioids, and γ-aminobutyric acid; and the overall physiologic effect

of nicotine may result from the interactions of these various neurotransmitters. Nicotine receptors in the CNS are located mainly in presynaptic membrane, and in that way, they regulate the release of several neurotransmitters. Nicotine increases concentrations of dopamine, a neurotransmitter essential for boosting attention, reward-seeking behaviors, and the risk of various addictions, from gambling to drug use.30 Dopamine is released in the mesolimbic system, the corpus striatum, and frontal cortex and is critical for the drug-induced reward effect. Nicotine receptors in the striatum, where movements are planned and controlled, are located near the terminals that regulate and emit dopamine. In animal studies, even a small dose of nicotine stimulates the release of dopamine in the striatum, stopping movements that otherwise would go uncontrolled. This finding has led to research examining the role of nicotine in the prevention and treatment of a variety of neurologic disorders, including Parkinson disease, mild cognitive impairment, Tourette syndrome, schizophrenia, and attention-deficit/ hyperactivity disorder. The available research suggests that youth with mental illness are at increased risk of tobacco use.31 The direction of causation remains unclear. Epidemiologic studies have contributed to the development of the gateway drug model that suggest that previous use of the legal drugs tobacco and alcohol increases the vulnerability to the subsequent use of illicit drugs. Studies indicate that ethanol potentiates the response of high-affinity nAChRs to both acetylcholine and nicotine.32 Even small amounts of alcohol are known to boost nicotine effects, inducing subjects to smoke more. A recent study in a mouse model examining the effects of nicotine on cocaine abuse has provided a

biological mechanism to support the gateway theory by showing that nicotine increases the expression of the FosB gene (which has been related to addiction) and increases the vulnerability to cocaine dependence.33 This finding suggests that the prevention and cessation of nicotine use may decrease the future risk of addiction to illicit drugs.

NICOTINE METABOLISM Nicotine is mainly metabolized by the liver (85%–90%), and the metabolites are then excreted through the kidneys. Only 10% of nicotine is excreted unchanged. Nicotine metabolism involves a 2-step process mediated by the cytochrome P450 system, mainly by the hepatic enzymes CYP2A6 and CYP2B6. The first step produces the metabolite cotinine, which is then converted to multiple products, the most abundant being 3′-hydroxycotinine. The ratio of 3′-hydroxycotinine to cotinine is a reflection of in vivo nicotine clearance and is referred to as the nicotine metabolic rate. Some data from patients with chronic kidney disease indicate that the excretion of cotinine is minimally affected.34 Cotinine has a long half-life (18–20 hours), and on average, it takes approximately 72 hours to eliminate 90% of the cotinine.35 Although this long half-life makes it difficult to assess the most recent cigarette intake/smoking pattern, cotinine’s concentration in the urine correlates well with blood concentration. The measurement of urinary cotinine concentration is a useful method to distinguish smokers from nonsmokers and is a marker for long-term nicotine intake, although an increased urinary cotinine concentration can be observed in people exposed to secondhand smoke (SHS). Because employer-based insurance is now affected by the use of tobacco, an understanding of the

utility of nicotine and cotinine testing is important for employers. Although not commonly tested for, cotinine can also be used for screening adolescents who use these products or those who are exposed to SHS. Cotinine can be measured in serum, urine, saliva, and hair. Nonsmokers exposed to typical levels of SHS have serum cotinine concentrations less than 1 ng/mL. People with heavy exposure to SHS have serum cotinine concentrations in the range of 1 to 10 ng/mL, whereas active smokers almost always have serum cotinine concentrations higher than 10 ng/mL and occasionally higher than 500 ng/mL.36

PHARMACOGENETICS OF NICOTINE The variation in nicotine response can be understood to be the result of the interaction between drug metabolism and drug receptor genotypes.37 This variation in response is still an area of active investigation, and new data are adding to our understanding.

Drug Receptor Genotypes Each of the nAChRs is encoded for by a single CHRN gene. Large genomewide association study meta-analyses have brought to light the variations in the nAChR subunit genes that make the strongest genetic contribution to smokingrelated habits.40 The gene locus on chromosome 15q25.1 contains a dense set of highly correlated single nucleotide polymorphisms, in the CHRNA5-CHRNA3-CHRNB4 gene cluster.41 These may influence the age of initiation, the amount smoked, the development of nicotine dependence, and adverse effects such as lung cancer and chronic obstructive pulmonary disease. These associations appear to be more important in early-onset smokers, suggesting an age-associated relationship. In addition to smoking quantity and nicotine dependence, variants in nAChR genes have also been associated with alcohol and other substance dependencies as well as with a predisposition to schizophrenia.41,42

Drug Metabolism Genetic variation in the CYP2A6 gene can increase or decrease this enzyme’s activity through altering the protein’s expression level or its structure and function and thus nicotine metabolism. Multiple alleles of the CYP2A6 enzyme have been identified (www.cypalleles.ki.se/cyp2a6. htm), including single nucleotide polymorphisms, duplications, deletions, and conversions, which have allowed for grouping people into slow, intermediate, and normal metabolizers.38 People who carry reduced or null activity CYP2A6 alleles are more likely to be nonsmokers or smoke fewer cigarettes per day, are less likely to progress to nicotine dependence, and may have an easier time quitting smoking and have a lower risk of lung cancer.39 The opposite is the case for fast metabolizers.

NICOTINE METABOLISM AND RACE, SEX, AND AGE The rate of nicotine metabolism has been found to vary by sex and race, which may influence susceptibility to addiction and ability to quit. Differences in the CYP2A6 allele frequencies may underlie this variability across sexes and ethnic groups. Up to 90% of white smokers are fast metabolizers. Latino smokers have rates of metabolism similar to white smokers. AfricanAmerican smokers are more likely to be slow metabolizers, and Asian smokers have the slowest nicotine metabolic rates.36 On average, slow metabolizers smoke fewer cigarettes than fast metabolizers and have higher quit rates, and the slower nicotine metabolism may account for their lower risk of nicotine addiction in studies in African-American smokers.43

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Women metabolize nicotine faster than men, which may explain why women have more difficulty in quitting.44 It is important to use caution in the clinical application of these data to individual patients because of heterogeneity and thus limitations of how racial categories are defined in the literature and the unique diversity of use and addiction trajectories of each patient. It is anticipated that further research will make individual-level assessments available in the future. Another factor affecting nicotine metabolism is the use of hormonal contraception. Studies indicate that these medications may accelerate cotinine metabolism in women, probably by an estrogen induction of CYP2A6 that is independent of ethnicity and cigarette consumption.45

of the adverse health consequences of tobacco use are the result of damage caused by tar, carbon monoxide, oxidizing chemicals, and other constituents in the product rather than nicotine.14 Although smoking affects almost every system in the body, only some effects have been found to be directly related to nicotine use.

In the adolescent years, recent studies have confirmed differences in metabolic rate by race but not by sex.46 However, the use of oral contraceptive pills, as in women, has been found to accelerate nicotine metabolism in adolescent tobaccodependent smokers.47 Another study by the same authors assessed the rate of nicotine metabolism in adolescents by using the nicotine metabolic rate as a reflection of the rate of clearance of nicotine. Slow metabolizers, because they have nicotine present for a longer time, are expected to smoke less. However, the findings were the opposite among slower metabolizers. They smoked more cigarettes per day and had higher addiction scores. These authors hypothesized that the brains of these slower metabolizers are exposed to greater amounts of nicotine for a longer period of time, and therefore, slower metabolizers may be more likely to develop addiction in early stages of smoking.48

As noted previously, nicotine stimulates the release of various neurotransmitters in the CNS. Nicotine users endorse a reduction in pain, anxiety, and other negative emotional symptoms along with positive feelings of a mild euphoria, alertness, increased memory, and learning. Nicotine also has many neuroendocrine responses.50 Although smokers say they smoke to control stress, studies show a significant increase in cortisol concentrations in daily smokers compared with occasional smokers or nonsmokers.51 These findings suggest that, despite the subjective effects, smoking may actually worsen the negative emotional states. The effects of nicotine on the sleep-wake cycle through nicotine receptors may have a functional significance. Nicotine receptor stimulation promotes wake time and reduces both total sleep time and rapid eye movement sleep. Dopamine release in the CNS inhibits prolactin secretion from the anterior pituitary. However, decreased concentrations are only seen with long-term use, possibly because of desensitization of the nAChRs. Acute nicotine use increases prolactin secretion.

HEALTH CONSEQUENCES OF EXPOSURE TO NICOTINE Although there are adverse health effects attributable to nicotine, most

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The data are insufficient to conclude that nicotine causes cancer, but there is evidence that it may increase the risk of oral, esophageal, and pancreatic cancer. In women, the intensity of current smoking has been noted to be an independent risk factor for high-grade cervical intraepithelial neoplasia, after controlling for cervical human papillomavirus infection.49

The cardiovascular effects of nicotine are mainly the result of stimulation of the sympathetic nervous system. In humans, nicotine has a biphasic physiologic response. In low concentrations, it acts as a stimulant by increasing adrenal catecholamines, but high doses of nicotine have the opposite effect, with hypotension and slowing of the heart rate.52 nAChRs are found not only in neuronal and muscle cells but also in endothelial and immune cells. Nicotine induces proliferation of vascular smooth muscle cells and the migration of cells into blood vessels. Nicotine also increases lipolysis, resulting in the release of free fatty acids; over time, these effects cause an acceleration of coronary and peripheral vascular disease as well as an increase in the risk of strokes. A relationship has been found between nicotine and inflammatory bowel disease. Although smoking has a deleterious effect on those with Crohn disease, it protects those with ulcerative colitis.53,54 The risk of developing ulcerative colitis is lower in smokers (odds ratio: 0.41; 95% confidence interval:, 0.34–0.48). People who stop smoking and then resume smoking experience clinical improvement.54 Many possible explanations have been proposed; these include the effects of smoking on cellular and humoral immunity, cytokines, eicosanoid-mediated inflammation, antioxidant and oxygen free radicals, endogenous glucocorticoids, colonic mucus, mucosal blood flow, thrombosis, gut permeability, and motility.55 Recent research on microbiota changes with smoking may also help explain the influence of smoking on inflammatory bowel disease. Additional research on whether other chemicals in cigarettes may also be involved in this process is underway. However, no advantages over standard therapy have been advanced, and adverse effects of nicotine preclude a therapeutic recommendation.

Recent studies indicate that the parasympathetic nervous system controls innate immune responses through the modulation of the production of multiple inflammatory cytokines. Acetylcholine, as the principal neurotransmitter for the parasympathetic nervous system, has been shown to have antiinflammatory effects mediated through the nicotinic receptors on macrophages, inhibiting the proinflammatory cytokines from these macrophages.56 The finding of distinct nAChR subtypes expressed on immune cells now suggests that this regulation is based on receptor affinity; evidence has been found for a crucial role for an α7 nAChR subtype in this process. Clinical and experimental evidence indicates that nicotine is at least partly responsible for the progression of chronic kidney disease in cigarette smokers.57 Nicotine also exacerbates acute kidney injury by various mechanisms.58 The bone marrow is innervated by cholinergic nerve fibers and macrophages, and other cytokineproducing cells express the α7 receptor and are functionally responsive to nicotine, which indicates a probable mechanism for control of inflammation. Similarly, microglial cells represent the largest class of phagocytes in the CNS and are regulated by acetylcholine. The activation of these microglia can be neurotoxic or neuroprotective and thus are important in CNS pathology. Several nicotinic agonists specifically targeting the α7 nAChR have been developed and are being studied for the treatment of neurologic, inflammatory, and infectious diseases. Long-term exposure to nicotine increases the risk of osteoporosis and bone fractures by creating an imbalance in bone remodeling through nicotine’s effects on osteoclasts and osteoblasts.59 Nicotine also has an effect on body weight through mechanisms that

are complex and not completely understood. The acute response is suppression of appetite and an increase in the metabolic rate, but chronic administration activates systems that increase appetite and decrease metabolic rate.60 Many chronic smokers are overweight and have the metabolic syndrome with increased visceral adiposity. However, the reduction in appetite and the weight control are important effects that are more likely to appeal to younger females than males.61 The increased appetite and weight gain that occur after stopping smoking can serve as a deterrent to smoking cessation for women.62 Women who stop are also at greater risk of relapse to avoid the weight gain. Adequate pharmacotherapy of tobacco dependence may decrease or eliminate the weight gain associated with stopping. One study found that soon after abstinence from tobacco smoking, an increase in the plasma concentration of the appetitestimulating peptide acetylated ghrelin occurs.63 This finding could explain the increased food craving during nicotine withdrawal and subsequent weight gain. Nicotine has a negative dose-related impact on both male and female fertility. In men, nicotine affects both gametogenesis and steroidogenesis. Nicotine also impairs nitric oxide synthesis, leading to erectile dysfunction. Although cigarette smoking has been associated with decreased fertility rates, adverse pregnancy outcomes, and higher risk of in vitro fertilization failure, the precise role of nicotine is still being evaluated both for the woman and for the fetus. The short-term safety of nicotine replacement therapy during pregnancy has been evaluated in a limited number of studies, but long-term effects on the fetus warrant further studies. Animal studies suggest that there may be an increased incidence of obesity, hypertension, type 2

diabetes, respiratory dysfunction, neurobehavioral effects, and impaired fertility.64 Two key studies have documented the developmental effects on offspring of women who smoked cigarettes prenatally and support concerns that tobacco or nicotine can have significant effects on early neurodevelopment in humans.65,66 These studies have found that infants born to mothers who smoked during their pregnancies had reduced weight, length, and head circumference but also showed significant impairments in cognitive functioning, impulsivity, hyperactivity, and increased risk of developing an addiction disorder. These effects were seen throughout early childhood and persisted through adolescence and into young adulthood. The neurobiological systems that are related to these behavioral problems are found in the dopamine, opioid neuropeptide, and cannabinoid systems in the amygdala and striatal regions of the brain and are important for the regulation of processes relevant to the behaviors noted previously.67 Numerous studies that used animal models have identified the effects of both cigarette smoke or nicotine on brain development during fetal development, such as altered expression of nicotinic acetylcholine receptors in critical brainstem areas involved in autonomic function and altered excitability of neurons in brainstem areas involved in sensory integration.68,69 Functional correlates of nicotine exposure include hypoventilation and apnea, as well as blunted chemoreflexes in response to hypoxia.70–72 Studies in human fetal subjects who have been exposed to nicotine have provided a better understanding of the molecular mechanisms underlying the developmental behaviors seen with prenatal nicotine exposure. For example, researchers have found that prenatal cigarette

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exposure is associated with a decrease in the expression of the genes related to the endogenous opioid system in areas of the brain, the nucleus accumbens, that have been implicated in behavior motivation and mood regulation.73 Prenatal tobacco exposure also alters both nicotinic and muscarinic receptors of the cholinergic systems in the brainstem and cerebellar regions.67 Nicotinic acetylcholine receptors are strongly associated with serotonergic (5-HT receptors) in the brainstem during fetal development, and abnormalities of serotonergic neurotransmission in the brainstem have been consistent with neuropathologic findings in cases of sudden unexpected and unexplained death in infancy.74,75 In first-trimester human fetuses, abnormal nicotinic receptor subunit levels have also been detected in the brainstem regions associated with sudden infant death syndrome.76 Dysfunction of these brainstem regions, which can be associated with sudden infant death syndrome, is strongly associated with maternal cigarette use during pregnancy, and the alterations that are seen with gene expression in these cholinergic receptor subunits may be a contributing factor to the brainstem abnormalities seen in these infants.77 These molecular alterations in gene expression as a result of prenatal nicotine exposure may be explained by epigenetic mechanisms, which is currently an area of active research.67 The reader is referred to the American Academy of Pediatrics’ technical report “SIDS and Other Sleep-Related Infant Deaths: Evidence Base for 2016 Updated Recommendations for a Safe Infant Sleeping Environment” for a comprehensive review on this subject.78

ACUTE TOXICITY Children can ingest nicotine from the tobacco in cigarettes, chewing

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tobacco, pipe tobacco, nicotine gum and patches, and some insecticides. Most such incidents occur in children younger than 6 years, and the frequency and severity of outcomes are generally benign because of the ensuing emesis.79,80 Recently, the newer electronic nicotine delivery systems with refillable cartridges that contain liquid nicotine have become a source of accidental exposure to a concentrated nicotine solution. The Centers for Disease Control and Prevention has reported a marked increase in e-cigarette liquid-related calls to poison control centers, from 1 per month (September 2010) to 215 per month (February 2014). More than half (51.1%) of calls involved children younger than 5 years.81 A death of a child who ingested the concentrated nicotine solution used with electronic nicotine delivery systems was reported recently.82 Early symptoms of nicotine ingestion include a burning sensation in the mouth and throat, nausea, vomiting, confusion, dizziness, weakness, and drooling from increased salivation. Signs include tachycardia, tachypnea, hypertension, and agitation followed by bradycardia, hypotension, and respiratory depression. Severe poisoning leads to arrhythmias, coma, convulsions, and cardiac arrest. Skin or eye contact with concentrated liquid may cause irritation followed by variable absorption. Systemic signs or symptoms may follow. The lethal dose of nicotine has been estimated to be as little as 50 to 60 mg in adults, although this number is disputed. The lethal dose in children is probably much lower, between 1 and 13 mg/kg, and severe toxic reactions have been reported in children with doses as low as 2 mg. Nicotine liquid refills are available in various strengths ranging from 6 (0.6%) to 36 (3.6%) mg/mL. Assuming there are 20 drops in 1 mL of solution, 1 drop of 3.6% nicotine liquid will contain 1.8 mg nicotine. The dose of nicotine that

has been estimated to be lethal for 50% of adults is between 0.8 and 13.0 mg/kg.83 It has been estimated that 1 teaspoon (5 mL) of a 1.8% nicotine solution could be lethal to a 90-kg person.84 The ingestion of a few drops of concentrated solution is enough to cause severe symptoms in young children.85 For example, the ingestion of 1 to 2 drops of a 3.6% solution (1.8–3.6 mg) will put most children younger than 5 years in this category. With the use of a midrange of this lethal dose (6 mg/ kg), the ingestion of 0.5 teaspoon (or 2 mL) of a concentrated nicotine solution could even be lethal to an average 12-kg, 20-month-old child.4 Thus, children who have ingested ≥0.2 mg/kg of nicotine would be expected to be symptomatic and will need medical assessment. The refill liquids also contain unknown concentrations of oil of wintergreen (methyl salicylate), glycerin, and propylene glycol, which could also cause multiple toxidromes, including salicylism and cholinergic crisis.86 The risk posed by nicotine liquid to children is an important anticipatory guidance topic to discuss with parents and caregivers. Preventive measures to reduce toxic ingestions include public education and legislation to improve the safety profile of electronic nicotine delivery system containers through limited volumes in available containers and child-proof packaging.

CESSATION Although nearly half of adult smokers attempt to stop each year,