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Public Health Consequences of E-Cigarettes (2018)

Chapter: Front Matter

Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Pu ublic Health Cons H h sequen nces of E-Ciigarett tes Comm mittee on th Review of the Hea Effect of Electr he w alth ts ronic Nicot Delive tine ery Systems S Kathleen Stratton, Leslie Y. Kwan, and David L. Eaton, Ed n d ditors Boa on Popu ard ulation He ublic Heal Practice ealth and Pu lth e Health and Medicine D H Division A Consensus Study R Report of PR REPUBLICA ATION COP UNCO PY: ORRECTED PROOFS D

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by Contract No. HHSF223201610054C between the National Academy of Sciences and the U.S. Department of Health and Human Services: Food and Drug Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/24952 Library of Congress Control Number: Additional copies of this publication are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2018 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2018. Public health consequences of e-cigarettes. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/24952. PREPUBLICATION COPY: UNCORRECTED PROOFS

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. C. D. Mote, Jr., is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY: UNCORRECTED PROOFS

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY: UNCORRECTED PROOFS

COMMITTEE ON THE REVIEW OF THE HEALTH EFFECTS OF ELECTRONIC NICOTINE DELIVERY SYSTEMS DAVID L. EATON (Chair), Dean and Vice Provost, Graduate School, University of Washington ANTHONY J. ALBERG, Professor and Chair, Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina MACIEJ GONIEWICZ, Associate Professor of Oncology, Roswell Park Comprehensive Cancer Center ADAM LEVENTHAL, Director, USC Health, Emotion, & Addiction Laboratory, Professor of Preventive Medicine and Psychology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California JOSÉ E. MANAUTOU, Professor of Pharmacology & Toxicology, Interim Head, Department of Pharmaceutical Sciences, University of Connecticut SHARON MCGRATH-MORROW, Professor, Department of Pediatrics, Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine DAVID MENDEZ, Associate Professor, Health Management and Policy, University of Michigan RICHARD MIECH, Research Professor, Department of Youth and Social Issues, University of Michigan ANA NAVAS-ACIEN, Professor, Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University KENT E. PINKERTON, Professor and Director, Center for Health and the Environment, Department of Anatomy, Physiology, and Cell Biology, University of California, Davis NANCY A. RIGOTTI, Professor of Medicine, Harvard Medical School, Director, Tobacco Research and Treatment Center, Associate Chief, Division of General Internal Medicine, Massachusetts General Hospital DAVID A. SAVITZ, Vice President for Research, Professor of Epidemiology, Professor of Obstetrics and Gynecology, Brown University GIDEON ST.HELEN, Assistant Professor, Zuckerberg San Francisco General Hospital Study Staff KATHLEEN STRATTON, Study Director LESLIE Y. KWAN, Associate Program Officer AIMEE MEAD, Research Associate (from July 2017) ALEXIS WOJTOWICZ, Senior Program Assistant JORGE MENDOZA-TORRES, Senior Research Librarian REBECCA MORGAN, Senior Research Librarian DORIS ROMERO, Financial Associate (until March 2017) MISRAK DABI, Financial Associate (from April 2017) HOPE HARE, Administrative Assistant ROSE MARIE MARTINEZ, Senior Director, Board on Population Health and Public Health Practice Christine Mirzayan Science and Technology Policy Graduate Fellow ANDREW MERLUZZI, Ph.D. Candidate at the University of Wisconsin–Madison (until April 2017) v PREPUBLICATION COPY: UNCORRECTED PROOFS

REVIEWERS This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: R. GRAHAM BARR, Columbia University Medical Center NEAL L. BENOWITZ, University of California, San Francisco JOHN BRITTON, University of Nottingham CRISTINE D. DELNEVO, Rutgers, The State University of New Jersey JOANNA S. FOWLER, Brookhaven National Laboratory and National Institutes of Health MARIANNA D. GA A, British American Tobacco Research and Development Centre STEPHEN S. HECHT, University of Minnesota HARLAN R. JUSTER, New York State Department of Health PAULA M. LANTZ, University of Michigan RAFAEL MEZA, University of Michigan MEIR STAMPFER, Harvard Medical School and Harvard T.H. Chan School of Public Health THOMAS A. WILLS, University of Hawaii Cancer Center JUDITH T. ZELIKOFF, New York University School of Medicine SHU-HONG ZHU, University of California, San Diego Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by ERIC B. LARSON, Kaiser Permanente Washington Health Research Institute, and HUDA AKIL, University of Michigan. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies. vii PREPUBLICATION COPY: UNCORRECTED PROOFS

PREFACE On May 10, 2016, the Food and Drug Administration (FDA) issued a rule to extend regulatory authority to all tobacco products, including e-cigarettes that meet the statutory definition of a tobacco product. This so-called “Deeming Regulation” allows FDA to regulate the manufacturing, distribution, and marketing of tobacco products such as e-cigarettes and includes automatic provisions such as youth access restrictions on sales. Although various forms of battery-powered “Electronic Nicotine Delivery Systems” (ENDS devices) have existed for more than a decade, their popularity, especially among youth, has increased in the past 5 years, although most recent data show a slight decline. In contrast to combustible tobacco cigarettes, e- cigarettes do not “burn,” and do not contain most of the estimated 7,000 chemical constituents present in tobacco smoke. Thus, it is generally believed that e-cigarettes are “safer” than combustible tobacco cigarettes, yet exposures to nicotine and a variety of other potentially harmful constituents do occur. Harm might also occur if youth who begin their “tobacco” use with e-cigarettes then transition to combustible tobacco cigarettes or if adult cigarette smokers use e-cigarettes to supplement their smoking, rather than quitting combustible tobacco cigarettes completely. In order to inform the public about the consequences of e-cigarettes and in support of future FDA and congressional action, a thorough and objective analysis of the state of scientific evidence relating to e-cigarettes and public health is needed. To that end, the ENDS Committee was established in December 2016 under the National Academies of Sciences, Engineering, and Medicine, with an ambitious timeline to complete a review of the science that can inform the understanding of public health risks and benefits of e-cigarettes. What are the short- and long- term health risks of regular use of e-cigarettes? What variables of the numerous types of devices and use patterns are important determinants of risk? Are e-cigarettes an effective means to quit smoking combustible tobacco cigarettes? Are e-cigarettes an “initiation pathway” of youth to smoking combustible tobacco cigarettes? These are just some of the important questions addressed by the committee in this report. Where feasible, the committee applied the most important attributes of systematic review methodology to the scientific literature to establish the strength of evidence surrounding the health risks (e.g., direct harmful effects, initiation of smoking) and benefits (e.g., smoking cessation) associated with e-cigarette use. Although the use of these products is relatively new, the committee identified more than 800 peer-reviewed scientific studies in this report. Based on this review, the committee has provided a summary of the current state of knowledge about the health risks and benefits of e-cigarette use, and has provided a series of research recommendations. I am deeply gratified by the remarkable hard work and insights provided by my fellow committee members and indebted to the tireless and thoughtful work of the National Academies staff that so ably kept us on task throughout the duration of this task. David L. Eaton, Chair Committee on the Health Effects of Electronic Nicotine Delivery Systems ix PREPUBLICATION COPY: UNCORRECTED PROOFS

CONTENTS SUMMARY S-1 SUMMARY ANNEX SA-1 1 INTRODUCTION 1-1 Statement of Task, 1-2 A Note on Terminology: What Are E-Cigarettes?, 1-3 The Rapid Rise of E-Cigarette Use in the United States, 1-3 Potential Public Health Risks and Benefits of E-Cigarettes, 1-8 Regulatory Background, 1-9 Outline of the Report, 1-12 References, 1-13 2 COMMITTEE APPROACH 2-1 Literature Search, 2-1 Literature Review and Quality Assessment, 2-2 Approach to Assessing Causality, 2-3 Conclusions, 2-6 References, 2-7 SECTION I: E-CIGARETTE DEVICES, CONSTITUENTS, AND EXPOSURES 3 E-CIGARETTE DEVICES, USES, AND EXPOSURES 3-1 Characteristics of E-Cigarette Devices, 3-1 E-Cigarette Use, 3-3 Exposure to Aerosols and Particulates, 3-7 Second-Hand Exposure to E-Cigarette Aerosol, 3-13 References, 3-22 4 NICOTINE 4-1 Concentration of Nicotine in Commercial E-Cigarettes, 4-1 Nicotine Concentration in E-Cigarette Emissions, 4-3 pH of E-Liquids, 4-4, Nicotine Salts, 4-6 Toxicology and Modes of Action, 4-6 Exposure to Nicotine and Nicotine Derivatives from E-Cigarettes, 4-20 Relationship Between E-Cigarette Topography and Nicotine Exposure, 4-41 Synthesis, 4-42 References, 4-43 5 TOXICOLOGY OF E-CIGARETTE CONSTITUENTS 5-1 Humectants (Delivery Solvents), 5-1 Flavorings, 5-13 xi PREPUBLICATION COPY: UNCORRECTED PROOFS

xii PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Carbonyl Compounds, 5-19 Minor Tobacco Alkaloids, 5-27 Tobacco-Specific Nitrosamines, 5-28 Free Radicals and Reactive Oxygen Species, 5-29 Other Toxicants, 5-29 Synthesis, 5-31 Metals, 5-32 References, 5-37 6 RESEARCH NEEDS: E-CIGARETTE DEVICES, CONSTITUENTS, AND EXPOSURES 6-1 Addressing Gaps in Substantive Knowledge, 6-1 Improve Research Methods and Quality, 6-2 Reference, 6-3 SECTION II: EFFECTS OF E-CIGARETTES ON HEALTH 7 MODES OF ACTION 7-1 Endothelial Cell Dysfunction, 7-2 Oxidative Stress, 7-12 Conclusions, 7-21 References, 7-22 8 DEPENDENCE AND ABUSE LIABILITY 8-1 Characterization of Disease Endpoints and Intermediate Outcomes, 8-3 Optimal Study Design, 8-5 Questions Addressed by the Literature, 8-8 Epidemiology, 8-9 Human Laboratory Studies, 8-40 Conclusions, 8-52 References, 8-53 9 CARDIOVASCULAR DISEASE 9-1 Characterization of Disease Endpoints and Intermediate Outcomes, 9-2 Human Evidence from Studies of Cardiovascular Effects, 9-4 Conclusions, 9-14 References, 9-32 10 CANCERS 10-1 Characterization of Disease Endpoints and Intermediate Outcomes, 10-1 Optimal Study Design, 10-2 Epidemiology, 10-3 Case Reports and Other Clinical Studies, 10-5 In Vivo Animal Studies, 10-5 Studies of Major Components of E-Cigarettes on Cancer Outcomes, 10-14 Vulnerable/Susceptible Populations, 10-17 PREPUBLICATION COPY: UNCORRECTED PROOFS

CONTENTS xiii Synthesis, 10-18 References, 10-19 11 RESPIRATORY DISEASES 11-1 Characterization of Disease Endpoints and Intermediate Outcomes, 11-3 Optimal Study Design, 11-4 Questions Addressed by the Literature, 11-4 Clinical and Epidemiological Studies in Humans, 11-5 In Vivo Animal Studies and In Vitro Mechanistic Studies, 11-7 Synthesis and Conclusions, 11-10 Vulnerable/Susceptible Populations, 11-12 References, 11-33 12 ORAL DISEASES 12-1 Characterization of Disease Endpoints and Intermediate Outcomes, 12-1 Optimal Study Design, 12-2 Questions Addressed by the Literature, 12-2 Studies in Humans (Clinical and Epidemiology), 12-2 In Vitro Studies, 12-3 Synthesis, 12-4 References, 12-4 13 DEVELOPMENTAL AND REPRODUCTIVE EFFECTS 13-1 Characterization of Disease Endpoints and Intermediate Outcomes, 13-2 Optimal Study Design, 13-3 Questions Addressed by the Literature, 13-3 Epidemiology, 13-4 Case Reports and Other Clinical Studies, 13-4 In Vivo Animal and In Vitro/Mechanistic Studies, 13-4 Studies on Combustible Tobacco and Nicotine, 13-4 Synthesis, 13-6 References, 13-6 14 INJURIES AND POISONINGS 14-1 Burns and Explosions, 14-1 Intentional and Unintentional Exposure to E-Liquid, 14-2 References, 14-3 15 RESEARCH NEEDS: EFFECTS OF E-CIGARETTES ON HEALTH 15-1 Addressing Gaps in Substantive Knowledge: Health Effects, 15-1 Improve Research Methods and Quality, 15-3 Reference, 15-5 PREPUBLICATION COPY: UNCORRECTED PROOFS

xiv PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES SECTION III: PUBLIC HEALTH IMPLICATIONS OF E-CIGARETTES 16 COMBUSTIBLE TOBACCO CIGARETTE SMOKING AMONG YOUTH AND YOUNG ADULTS 16-1 Conceptual Framework: Patterns of Use Among Youth and Young Adults, 16-1 Evidence Review: Levels of Evidence Available, 16-6 Evidence Review: Methods, 16-16 Evidence Review: Results, 16-17 Synthesis, 16-31 References, 16-33 17 SMOKING CESSATION AMONG ADULTS 17-1 Conceptual Framework: Patterns of E-Cigarette Use Among Established Smokers, 17-1 Evidence Review: Levels of Evidence Available, 17-4 Evidence Review: Methods, 17-5 Evidence Review: Results, 17-6 Synthesis, 17-14 Conclusions, 17-17 References, 17-36 18 HARM REDUCTION 18-1 Evidence Review: Levels of Evidence Available, 18-3 Evidence Review: Methods, 18-4 Evidence Review: Results, 18-6 References, 18-28 19 MODELING OF E-CIGARETTE USE 19-1 Model, 19-2 Modeling Assumptions, 19-3 Simulation Scenarios, 19-4 Results, 19-6 Summary, 19-15 References, 19-16 20 RESEARCH NEEDS: PUBLIC HEALTH IMPLICATIONS OF E-CIGARETTES 20-1 Addressing Gaps in Substantive Knowledge, 20-1 Improve Research Methods and Quality, 20-3 References, 20-3 21 CONCLUDING OBSERVATIONS 21-1 References, 21-3 APPENDIXES A Questions from the Center for Tobacco Products of the Food and Drug Administration Submitted for the Committee’s Consideration A-1 PREPUBLICATION COPY: UNCORRECTED PROOFS

CONTENTS xv B Search Strategy and Quality Assessment B-1 C Glossary of Terms Related to E-Cigarettes C-1 D Cytotoxicity Tables D-1 E Public Meeting Agenda E-1 F Committee Biosketches F-1 PREPUBLICATION COPY: UNCORRECTED PROOFS

BOXES, FIGURES, AND TABLES BOXES S-1 Statement of Task, S-10 S-2 Levels of Evidence Framework for Conclusions, S-11 S-3 Research Needs: E-Cigarette Devices, Constituents, and Exposures, S-12 S-4 Research Needs: Effects of E-Cigarettes on Human Health, S-13 S-5 Research Recommendations: Public Health Implications of E-Cigarettes, S-14 1-1 Statement of Task, 1-2 1-2 Major Provisions of the Food and Drug Administration Deeming Tobacco Products to Be Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act, 1-9 2-1 Level of Evidence Framework for Conclusions, 2-6 8-1 Criteria for Tobacco Use Disorder from the American Psychiatric Association’s Diagnostic and Statistical Manual for Mental Disorders, 5th Edition, 8-4 B-1A Search Strategy for E-Cigarettes in Human Populations, B-5 B-1B Search Strategy for E-Cigarettes in In Vivo Animal Populations, B-7 B-1C Search Strategy for E-Cigarettes in In Vitro Populations, B-8 B-1D Search Syntax for E-Cigarettes with No Population Limits, Excluding Results from Earlier Searches (BOXES B-1A, B-1B, B-1C) B-1E Search Syntax for E-Cigarettes and Dermal and Ingestion Exposure B-1F Search Syntax for E-Cigarettes with No Limit on Population or Publication, Excluding Results from Prior Searches (see BOXES B-1A, B-1B, B-1C, B-1D, B-1E), B-15 B-2 Inclusion Criteria for the Literature Review on the Health Effects of Electronic Cigarettes, B-16 B-3 Search Syntax for E-Cigarettes and Dependence, B-17 B-4 Search Syntax for Systematic Reviews and Meta-Analyses on E-cigarettes and Combustible Tobacco Cigarette Smoking Cessation, B-19 B-5 Search Syntax for Original Studies on E-cigarettes and Smoking Cessation, B-20 B-6 Search Syntax for E-Cigarettes and Combustible Tobacco Cigarette Smoking Initiation, B-22 B-7 Search Syntax for E-Cigarettes and Combustible Tobacco Cigarette Smoking Reduction, B-24 FIGURES 2-1 General and simplified conceptual framework of potential causal pathways by which e-cigarettes could affect health, 2-4 3-1 First, second, and third generation e-cigarette devices, 3-3 3-2 Mass frequency and cumulative mass distributions derived from impactor particle size distribution measurement of e-cigarette 1, 3-8 3-3 Temporal evolution of the number/size distribution of inhaled combustible tobacco cigarette smoke particles (panel A) and e-cigarette droplets (panel B) during puf ng, mouth-hold (MH), inhalation and exhalation, based on the same initial size distribution, 3-11 3-4 Photograph taken during a cloud competition at about 2 pm at a vaping convention, April 2016, Maryland, 3-13 xvi PREPUBLICATION COPY: UNCORRECTED PROOFS

BOXES, FIGURES, AND TABLES xvii 3-5 Event room PM2.5 concentrations before, during, and after an e-cigarette convention, 3-15 3-6 Real-time changes of PM10, CO2, and TVOC concentrations during a vaping convention in Maryland. During the vaping competition (section 4 of the graph), TVOCs and PM10 increased, although for PM10 the monitor stopped before the end of the competition, 3-16 3-7 Estimated disability-adjusted life years (DALYS) lost due to exposure to secondhand e-cigarette aerosol, 3-18 4-1 Nicotine metabolic pathways, 4-12 5-1 Postulated pathways and byproducts formed during thermal dehydration of propylene glycol and glycerin, 5-23 5-2 Effects of nicotine solvent and battery output voltage on levels of carbonyl compounds released from electronic cigarettes, 5-25 5-3 Scanning electron microscopy and energy dispersive X-ray spectroscopy analysis of disposable EC/EH wires and joints, 5-34 5-4 Distribution of metal concentrations within and across brands of disposable e-cigalike devices, 5- 35 7-1 Publications by year on e-cigarettes and in vitro systems, 7-1 7-2 Endothelial cell dysfunction by tobacco smoke, 7-3 7-3 Proposed signaling cascade triggered by nicotine that partially overlaps with that used by combustible tobacco cigarette smoke extracts to disrupt the endothelial cell barriers and cell proliferation, 7-11 7-4 Publications by year on e-cigarettes and oxidative stress, 7-13 7-5 Principal component analysis of top 2000 genes by median absolute deviation. Human bronchial epithelial cells exposed to combustible tobacco cigarette smoke, e-cigarette aerosol, or air, 7-18 7-6 Changes in GSH status and generation of reactive oxygen species, 7-20 8-1 Distribution of tobacco dependence among each tobacco product use group in the Population Assessment on Tobacco and Health Study Wave 1, 8-34 8-2 Dependence score as a function of nicotine concentration, 8-37 8-3 Subjective reward responses for the nicotine e-cigarette and the placebo (non-nicotine) e- cigarette, 8-46 8-4 Interactions between time and condition (Hydro e-cigarette, NPRO e-cigarette, own-brand combustible tobacco cigarette, and sham [unlit combustible tobacco cigarette]) for subjective effects, 8-51 9-1 Conceptual framework of plausible pathways, including mechanisms and intermediary outcomes, by which exposure to e-cigarettes influences cardiovascular disease, 9-2 9-2 Endothelial progenitor cells (EPCs) during e-cigarette inhalation and control, 9-12 10-1 Conceptual framework of plausible pathways, including mechanisms and intermediary outcomes, by which exposure to e-cigarettes influence cancer outcomes, 10-3 11-1 Conceptual framework of plausible pathways, including mechanisms and intermediary outcomes, by which exposure to e-cigarettes influences respiratory disease, 11-2 16-1 Conceptual framework for transition from e-cigarette use to cigarette use initiation and progression, 16-2 PREPUBLICATION COPY: UNCORRECTED PROOFS

xviii PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES 16-2 Meta-analysis of adjusted odds of current (past 30-day) combustible tobacco cigarette smoking at follow-up among non-current combustible tobacco cigarette smokers at baseline and current e- cigarette users at baseline compared with noncurrent e-cigarette users at baseline, 16-21 16-3 Past 30-day use of e-cigarettes and cigarettes among high school and middle school students in the 2011-2016 National Youth Tobacco Survey, 16-28 17-1 Past 30-day use of e-cigarettes and cigarettes among high school and middle school students in the 2011-2016 National Youth Tobacco Survey, 17-2 18-1 Changes in select carcinogen levels over 2 weeks of electronic cigarette use among 20 smokers (mean ± SD), 18-10 18-2 Urinary metabolite levels for selected and toxic carcinogens, by group, 18-12 18-3 Forced expiratory volume (FEV1) at the four timepoints of assessment for all 18 patients, 18-17 18-4 Changes in diastolic blood pressure from baseline, follow-up 1 (6 ± 1 months) and follow-up 2 (12 ± 2 months) separately for e-cigarette users (exclusive and dual) and exclusive regular smokers, 18-18 18-5 Changes in the number of chronic obstructive pulmonary disease (COPD) exacerbations from baseline, at follow-up visit 1 (12 ± 1.5 months) and visit 2 (24 ± 2.5 months) separately for electronic cigarette users and controls, 18-19 18-6 Comparison of indoor air nicotine (left) and aerosol particle (right) concentrations released from e-cigarette with background values and combustible tobacco cigarette smoking reported, 18-27 TABLES 1-1 Percentage of High School and Middle School Students Who Have Ever Used E-Cigarettes; National Youth Tobacco Survey (NYTS) 2011-2016, 1-4 1-2 Summary of the Key Events in the History of E-Cigarette Regulation, 1-11 3-1 Particle Size Distribution Parameters Determined from Cascade Impactor Analysis, 3-8 3-2 Summary of 14 E-Cigarette Puffing Topography Studies, 3-19 4-1 Pharmacokinetic Parameters of (S)-Nicotine and (3´R,5´S)-trans-3´-hydroxycotinine After Intravenous Administration, 4-9 4-2 Summary of Clinical Studies Examining Nicotine Exposure from E-Cigarette Use, 4-21 5-1 Dose Limits of Commonly Used Drugs to Avoid Propylene Glycol Intoxication Based on a Maximum Amount of PG Equal to 69 g/day, 5-4 5-2 Plasma Pharmacokinetics of Propylene Glycol Given as a 4-H Intravenous Infusion, 5-6 5-3 Acute Lethal Dose (LD50) of Propylene Glycol in Rats, Mice, Guinea Pigs, and Rabbits, 5-8 5-4 Overview of Common Flavorings and Their Inhalation Toxicity, 5-16 5-5 Overview Table Comparing Experimental Set-Ups and Results of the Current Study with Comparable Studies Conducted in the Past, 5-22 5-6 Volatile Compounds Detected in E-Cigarette Aerosol, 5-24 8-1 Epidemiologic Studies on E-cigarettes and Dependence, 8-10 8-2 Laboratory/Experimental Studies on Dependence and Abuse Liability, 8-19 8-3 Tobacco Dependence Instruments and Questions Included, Examined in Response Models, and Retained on a Final Common Tobacco Dependence Instrument in the Population Assessment on Tobacco and Health Study Wave 1, 8-32 PREPUBLICATION COPY: UNCORRECTED PROOFS

BOXES, FIGURES, AND TABLES xix 8-4 Product Liking for Vuse Solo E-Cigarettes with Different Nicotine Concentrations Compared with Usual Brand Combustible Tobacco Cigarette and Nicotine Gum, 8-49 9-1 Clinical Studies of Short-Term Effects of Electronic Cigarette (EC) Use on Cardiovascular Endpoints, 9-15 9-2 Epidemiologic Studies on Chronic E-Cigarette (EC) Use and Cardiovascular Endpoints, 9-28 10-1 In Vitro Mutagenicity/DNA Damage Assessment of E-Cigarette Liquids and Aerosols, 10-8 10-2 Comparison of Formaldehyde and Acrolein Levels in Smoke from One Combustible Tobacco Cigarette and in Aerosol from 15 Puffs of an E-Cigarette, 10-13 10-3 Formaldehyde and Acrolein Levels Generated from 5 E-Cigarette Devices at Different Power Levels, 10-14 10-4 Occurrence of Tumors in Female Sprague-Dawley Rats Exposed to Nicotine for Up to 24 Months and Controls, 10-16 11-1 Clinical and Epidemiological Studies in Humans, 11-14 16-1 INITIATION: Summary of Prospective Cohort Studies of the Association Between Ever Use of E-Cigarettes (versus Never Use) and Subsequent Risk of Ever Smoking of Combustible Tobacco Cigarettes Among Youth/Young Adults Who Were Nonsmokers at Baseline, 16-9 16-2 PROGRESSION: Summary of Prospective Cohort Studies of the Association Between E- Cigarette Use and Subsequent Risk of Recent Smoking/Heavier Smoking of Combustible Tobacco Cigarettes Among Youth/Young Adults, 16-11 16-3 DOSE–RESPONSE: Summary of Prospective Cohort Studies of the Association Between E- Cigarette Use Frequency and Subsequent Risk of Smoking of Combustible Tobacco Cigarettes Among Youths/Young Adults, 16-14 16-4 Meta-Analysis of Unadjusted and Adjusted Odds of Ever Smoking Combustible Tobacco Cigarettes Among Never Combustible Tobacco Cigarette Smokers at Baseline and Ever E- Cigarette Users at Baseline Compared with Never E-Cigarette Users at Baseline, 16-19 17-1 Systematic Reviews of E-Cigarettes and Smoking Cessation Identified by Literature Search, 17- 19 17-2 Characteristics of Three Randomized Controlled Trials Testing the Efficacy of E-Cigarettes for Smoking Cessation, 17-27 17-3 Selected Systematic Reviews: Part 1, 17-29 17-4 Selected Systematic Reviews: Part 2, 17-32 18-1 Comparison of Toxicant Levels Among Combustible Tobacco Cigarette Smoke and E-Cigarette Aerosol, 18-7 18-2 Comparison of In Vitro That Compared Toxicity of E-Cigarettes and Combustible Tobacco Cigarettes, 18-20 18-3 Comparison of Animal Studies That Compared Toxicity of E-Cigarettes and Combustible Tobacco Cigarettes, 18-23 19-1 Summary of Simulation Runs Considered by the Committee, 19-5 19-2 Model-Estimated Life-Years Lost During 2015-2050 Due to E-Cigarettes, 19-7 19-3 Model-Estimated Life-Years Lost During 2015-2070 Due to E-Cigarettes, 19-9 19-4 Model-Estimated Life-Years Lost During 2015-2050 Due to E-Cigarettes, 19-10 19-5 Model-Estimated Life-Years Lost During 2015-2070 Due to E-Cigarettes, 19-11 19-6 Model-Estimated Life-Years Lost During 2015-2050 Due to E-Cigarettes, 19-12 19-7 Model-Estimated Life-Years Lost During 2015-2070 Due to E-Cigarettes, 19-13 PREPUBLICATION COPY: UNCORRECTED PROOFS

xx PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES 19-8 Model-Estimated Life-Years Lost During 2015-2050 Due to E-Cigarettes, 19-14 19-9 Model-Estimated Life-Years Lost During 2015-2070 Due to E-Cigarettes, 19-15 D-1 Summary Table of Exposure, Comparison, and Control Conditions and Cell or Tissue Type Used in In Vitro Studies of E-cigarettes assessing Cytotoxicity, D-2 D-2 Summary Table of Test Agents, Cell or Tissue Type Used, and Assays Employed in In Vitro Studies of E-cigarettes assessing Cytotoxicity, D-7 D-3 Summary of Results from In Vitro Studies of E-cigarettes assessing Cytotoxicity, D-17 PREPUBLICATION COPY: UNCORRECTED PROOFS

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Millions of Americans use e-cigarettes. Despite their popularity, little is known about their health effects. Some suggest that e-cigarettes likely confer lower risk compared to combustible tobacco cigarettes, because they do not expose users to toxicants produced through combustion. Proponents of e-cigarette use also tout the potential benefits of e-cigarettes as devices that could help combustible tobacco cigarette smokers to quit and thereby reduce tobacco-related health risks. Others are concerned about the exposure to potentially toxic substances contained in e-cigarette emissions, especially in individuals who have never used tobacco products such as youth and young adults. Given their relatively recent introduction, there has been little time for a scientific body of evidence to develop on the health effects of e-cigarettes.

Public Health Consequences of E-Cigarettes reviews and critically assesses the state of the emerging evidence about e-cigarettes and health. This report makes recommendations for the improvement of this research and highlights gaps that are a priority for future research.

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