Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems Kathleen Stratton, Leslie Y. Kwan, and David L. Eaton, Editors Board on Population Health and Public Health Practice Health and Medicine Division A Consensus Study Report of
THE NATIONAL ACADEMIES PRESS â 500 Fifth Street, NW â 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:â 978-0-309-46834-3 International Standard Book Number-10:â 0-309-46834-5 Digital Object Identifier:â https://doi.org/10.17226/24952 Library of Congress Control Number:â 2018932760 Additional copies of this publication are available for sale from the National Acad- emies 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 Acad- emies Press. doi: https://doi.org/10.17226/24952.
The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institu- tion 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 char- ter 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.
Consensus Study Reports publishedÂ by the National Academies of Sciences, Engineering, and MedicineÂ document the evidence-based consensusÂ on the studyâs statement of task by an authoring committee of experts. Reports typi- cally include findings, conclusions, and recommendations based on information gathered by the committee and the committeeâs 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. ProceedingsÂ publishedÂ by the National Academies of Sciences, Engineering, and MedicineÂ chronicle the presentations and discussions at a workshop, symposium, or otherÂ eventÂ 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 visitÂ www.nationalacademies.org/about/whatwedo.
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 JOSÃ 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, Professor of Epidemiology, School of Public Health, Professor of Obstetrics and Gynecology and Pediatrics, Warren Alpert Medical School, Brown University GIDEON St.HELEN, Assistant Professor of Medicine, Division of Clinical Pharmacology, Department of Medicine, University of California, San Francisco v
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 WisconsinâMadison (until April 2017) vi
Reviewers This Consensus Study Report was reviewed in draft form by indi- viduals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical com- ments 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. GAÃA, 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 vii
viii REVIEWERS 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 conclu- sions 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.
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 âDeeming Regulationâ allows FDA to regulate the manufactur- ing, 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 âelectronic nicotine delivery systemsâ (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 combusti- ble tobacco cigarettes, e-cigarettes do not âburn,â 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 âsaferâ than combustible tobacco cigarettes, yet exposures to nicotine and a variety of other poten- tially harmful constituents do occur. Harm might also occur if youth who begin their âtobaccoâ use with e-cigarettes then transition to combustible tobacco cigarettes or if adult cigarette smokers use e-cigarettes to supple- ment 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 ix
x PREFACE 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-cig- arettes an effective means to quit smoking combustible tobacco cigarettes? Are e-cigarettes an âinitiation pathwayâ of youth to smoking combus- tible 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 surround- ing 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 iden- tified 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 pro- vided 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 study. David L. Eaton, Chair Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems
Contents SUMMARY 1 SUMMARY ANNEX 17 1 INTRODUCTION 23 Statement of Task, 23 A Note on Terminology: What Are E-Cigarettes?, 25 The Rapid Rise of E-Cigarette Use in the United States, 25 Potential Public Health Risks and Benefits of E-Cigarettes, 32 Regulatory Background, 34 Outline of the Report, 38 References, 39 2 COMMITTEE APPROACH 43 Literature Search, 44 Literature Review and Quality Assessment, 44 Approach to Assessing Causality, 46 Conclusions, 51 References, 51 xi
xii CONTENTS SECTION I: E-CIGARETTE DEVICES, CONSTITUENTS, AND EXPOSURES 3 E-CIGARETTE DEVICES, USES, AND EXPOSURES 55 Characteristics of E-Cigarette Devices, 55 E-Cigarette Use, 58 Exposure to Aerosols and Particulates, 69 Secondhand Exposure to E-Cigarette Aerosol, 77 References, 84 4 NICOTINE 89 Concentration of Nicotine in Commercial E-Cigarettes, 89 Nicotine Concentration in E-Cigarette Emissions, 92 pH of E-Liquids, 94 Nicotine Salts, 95 Toxicology and Modes of Action, 96 Exposure to Nicotine and Nicotine Derivatives from E-Cigarettes, 114 Relationship Between E-Cigarette Topography and Nicotine Exposure, 143 Synthesis, 144 References, 145 5 TOXICOLOGY OF E-CIGARETTE CONSTITUENTS 155 Humectants (Delivery Solvents), 156 Flavorings, 172 Carbonyl Compounds, 181 Minor Tobacco Alkaloids, 192 Tobacco-Specific Nitrosamines, 193 Free Radicals and Reactive Oxygen Species, 194 Other Toxicants, 195 Synthesis, 197 Metals, 198 References, 205 6 RESEARCH NEEDS: E-CIGARETTE DEVICES, CONSTITUENTS, AND EXPOSURES 217 Addressing Gaps in Substantive Knowledge, 218 Improving Research Methods and Quality, 219 Reference, 219
CONTENTS xiii SECTION II: EFFECTS OF E-CIGARETTES ON HEALTH 7 MODES OF ACTION 223 Endothelial Cell Dysfunction, 224 Oxidative Stress, 237 Conclusions, 250 References, 250 8 DEPENDENCE AND ABUSE LIABILITY 255 Characterization of Disease Endpoints and Intermediate Outcomes, 258 Optimal Study Design, 261 Questions Addressed by the Literature, 264 Epidemiology, 266 Human Laboratory Studies, 316 Conclusions, 333 References, 334 9 CARDIOVASCULAR DISEASE 339 Characterization of Disease Endpoints and Intermediate Outcomes, 341 Human Evidence from Studies of Cardiovascular Effects, 343 Conclusions, 377 References, 377 10 CANCERS 381 Characterization of Disease Endpoints and Intermediate Outcomes, 382 Optimal Study Design, 383 Epidemiology, 384 Case Reports and Other Clinical Studies, 386 In Vivo Animal Studies, 387 Studies of Effects of Major Components of E-Cigarettes on Cancer Outcomes, 395 Vulnerable/Susceptible Populations, 400 Synthesis, 401 References, 402 11 RESPIRATORY DISEASES 405 Characterization of Disease Endpoints and Intermediate Outcomes, 408 Optimal Study Design, 409 Questions Addressed by the Literature, 410 Clinical and Epidemiological Studies in Humans, 410
xiv CONTENTS In Vivo Animal Studies and In Vitro Mechanistic Studies, 441 Synthesis and Conclusions, 445 Vulnerable/Susceptible Populations, 447 References, 449 12 ORAL DISEASES 455 Characterization of Disease Endpoints and Intermediate Outcomes, 456 Optimal Study Design, 456 Questions Addressed by the Literature, 456 Studies in Humans (Clinical and Epidemiological), 456 In Vitro Studies, 458 Synthesis, 459 References, 459 13 DEVELOPMENTAL AND REPRODUCTIVE EFFECTS 461 Characterization of Disease Endpoints and Intermediate Outcomes, 462 Optimal Study Design, 464 Questions Addressed by the Literature, 464 Epidemiology, 464 Case Reports and Other Clinical Studies, 465 In Vivo Animal and In Vitro/Mechanistic Studies, 465 Studies on Combustible Tobacco and Nicotine, 465 Synthesis, 468 References, 468 14 INJURIES AND POISONINGS 473 Burns and Explosions, 474 Intentional and Unintentional Exposure to E-Liquid, 475 References, 476 15 RESEARCH NEEDS: EFFECTS OF E-CIGARETTES ON HEALTH 481 Addressing Gaps in Substantive Knowledge, 481 Improving Research Methods and Quality, 484 Reference, 485
CONTENTS xv SECTION III: PUBLIC HEALTH IMPLICATIONS OF E-CIGARETTES 16 COMBUSTIBLE TOBACCO CIGARETTE SMOKING AMONG YOUTH AND YOUNG ADULTS 493 Conceptual Framework: Patterns of Use Among Youth and Young Adults, 494 Evidence Review: Levels of Evidence Available, 499 Evidence Review: Methods, 513 Evidence Review: Results, 515 Synthesis, 532 References, 536 17 SMOKING CESSATION AMONG ADULTS 541 Conceptual Framework: Patterns of E-Cigarette Use Among Established Smokers, 542 Evidence Review: Levels of Evidence Available, 544 Evidence Review: Methods, 546 Evidence Review: Results, 558 Synthesis, 579 Conclusions, 584 References, 584 18 HARM REDUCTION 589 Evidence Review: Levels of Evidence Available, 592 Evidence Review: Methods, 593 Evidence Review: Results, 595 References, 623 19 MODELING OF E-CIGARETTE USE 631 Model, 632 Modeling Assumptions, 633 Simulation Scenarios, 636 Results, 636 Summary, 649 References, 650 20 RESEARCH NEEDS: PUBLIC HEALTH IMPLICATIONS OF E-CIGARETTES 653 Addressing Gaps in Substantive Knowledge, 653 Improving Research Methods and Quality, 655 Reference, 656
xvi CONTENTS 21 CONCLUDING OBSERVATIONS 657 References, 659 APPENDIXES A Questions from the Center for Tobacco Products of the Food and Drug Administration Submitted for the Committeeâs Consideration 661 B Search Strategy and Quality Assessment 665 C Glossary of Terms Related to E-Cigarettes 697 D Cytotoxicity Tables 703 E Public Meeting Agenda 741 F Committee Biosketches 745
Boxes, Figures, and Tables BOXES S-1 Statement of Task, 4 S-2 Levels of Evidence Framework for Conclusions, 5 S-3 Research Needs: E-Cigarette Devices, Constituents, and Exposures, 13 S-4 Research Needs: Effects of E-Cigarettes on Human Health, 14 S-5 Research Recommendations: Public Health Implications of E-Cigarettes, 15 1-1 Statement of Task, 24 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, 35 2-1 Levels of Evidence Framework for Conclusions, 50 8-1 Criteria for Tobacco Use Disorder from the American Psychiatric Associationâs Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, 259 B-1A Search Strategy for E-Cigarettes in Human Populations, 668 B-1B Search Strategy for E-Cigarettes in In Vivo Animal Populations, 670 xvii
xviii BOXES, FIGURES, AND TABLES B-1C Search Strategy for E-Cigarettes in In Vitro Populations, 672 B-1D Search Syntax for E-Cigarettes with No Population Limits, Excluding Results from Earlier Searches (Boxes B-1A, B-1B, B-1C), 674 B-1E Search Syntax for E-Cigarettes and Dermal and Ingestion Exposure, 680 B-1F Search Syntax for E-Cigarettes with No Limit on Population or Publication, Excluding Results from Prior Searches (Boxes B-1A, B-1B, B-1C, B-1D, B-1E), 681 B-2 Inclusion Criteria for the Literature Review on the Health Effects of E-Cigarettes, 682 B-3 Search Syntax for E-Cigarettes and Dependence, 683 B-4 Search Syntax for E-Cigarettes and Combustible Tobacco Cigarette Smoking Initiation, 685 B-5 Search Syntax for Systematic Reviews and Meta-Analyses on E-Cigarettes and Combustible Tobacco Cigarette Smoking Cessation, 687 B-6 Search Syntax for Original Studies on E-Cigarettes and Smoking Cessation, 689 B-7 Search Syntax for E-Cigarettes and Combustible Tobacco Cigarette Smoking Reduction, 691 FIGURES 2-1 General and simplified conceptual framework of potential causal pathways by which e-cigarettes could affect health, 47 3-1 First-, second-, and third-generation e-cigarette devices, 57 3-2 Mass frequency and cumulative mass distributions derived from impactor particle size distribution measurement of e-cigarette 1, 70 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 pufï¬ng, mouth-hold (MH), inhalation, and exhalation, based on the same initial size distribution, 74 3-4 Photograph taken during a cloud competition at about 2 pm at a vaping convention, April 2016, Maryland, 78 3-5 Event room PM2.5 concentrations before, during, and after an e-cigarette convention, 81
BOXES, FIGURES, AND TABLES xix 3-6 Real-time changes of PM10, CO2, and TVOC concentrations during a vaping convention in Maryland, 82 3-7 Estimated disability-adjusted life-years (DALYs) lost due to exposure to secondhand e-cigarette aerosol, 83 4-1 Nicotine metabolic pathways, 102 5-1 Postulated pathways and by-products formed during thermal dehydration of propylene glycol and glycerol, 186 5-2 Effects of nicotine solvent and battery output voltage on levels of carbonyl compounds released from e-cigarettes (Âµg/15 puffs; n = 3; puff duration = 1.8 seconds, puff volume = 70 ml, puff intervals = 17 seconds), 189 5-3 Scanning electron microscopy and energy-dispersive X-ray spectroscopy analysis of disposable e-cigarette/e-hookah wires and joints, 200 5-4 Distribution of metal concentrations within and across brands of disposable e-cigalike devices, 202 7-1 Publications by year on e-cigarettes and in vitro systems, 224 7-2 Endothelial cell dysfunction by tobacco smoke, 225 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, 236 7-4 Publications by year on e-cigarettes and oxidative stress, 238 7-5 Principal component analysis of top 2,000 genes by median absolute deviation, 245 7-6 Changes in glutathione status and generation of reactive oxygen species, 248 8-1 Distribution of tobacco dependence among each tobacco product use group in the Population Assessment on Tobacco and Health Study Wave 1, 309 8-2 Dependence score as a function of nicotine concentration, 313 8-3 Subjective reward responses for the nicotine e-cigarette and the placebo (non-nicotine) e-cigarette, 324 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, 331
xx BOXES, FIGURES, AND TABLES 9-1 Conceptual framework of plausible pathways, including mechanisms and intermediate outcomes, by which exposure to e-cigarettes influences cardiovascular disease, 340 9-2 Endothelial progenitor cells (EPCs) during e-cigarette inhalation and control, 374 10-1 Conceptual framework of plausible pathways, including mechanisms and intermediate outcomes, by which exposure to e-cigarettes influences cancer outcomes, 382 11-1 Conceptual framework of plausible pathways, including mechanisms and intermediate outcomes, by which exposure to e-cigarettes influences respiratory disease, 406 III-I Smoking transitions between e-cigarette use, combustible tobacco cigarette smoking, and non-use, 488 16-1 Conceptual framework for transition from e-cigarette use to combustible tobacco cigarette use initiation and progression, 495 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 non-current e-cigarette users at baseline, 519 16-3 Past 30-day use of e-cigarettes and combustible tobacco cigarettes among high school and middle school students in the 2011â2016 National Youth Tobacco Survey, 530 17-1 Conceptual framework of smoking cessation and e-cigarette use, 542 18-1 Changes in select carcinogen levels over 2 weeks of electronic cigarette use among 20 smokers (mean Â± SD), 601 18-2 Urinary metabolite levels for selected toxins and carcinogens, by group, 603 18-3 Forced expiratory volume (FEV1) at the four time points of assessment for all 18 patients, 609 18-4 Changes in diastolic blood pressure from baseline, follow-up 1 (6 Â± 1 month) and follow-up 2 (12 Â± 2 months) separately for e-cigarette users (exclusive and dual) and exclusive combustible tobacco cigarette smokers, 610
BOXES, FIGURES, AND TABLES xxi 18-5 Changes in the number of chronic obstructive pulmonary disease exacerbations from baseline, at follow-up visit 1 (12 Â± 1.5 months) and visit 2 (24 Â± 2.5 months) separately for e-cigarette users and controls, 611 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, 622 TABLES 1-1 Percentage of High School and Middle School Students Who Have Ever Used E-Cigarettes; National Youth Tobacco Survey (NYTS) 2011â2016, 27 1-2 Summary of the Key Events in the History of E-Cigarette Regulation, 36 3-1 Summary of E-Cigarette Puffing Topography Studies, 60 3-2 Particle Size Distribution Parameters Determined from Cascade Impactor Analysis, 71 4-1 Pharmacokinetic Parameters of (S)-Nicotine and (3Â´R,5Â´S)-Trans- 3Â´-Hydroxycotinine After Intravenous Administration, 101 4-2 Summary of Clinical Studies Examining Nicotine Exposure from E-Cigarette Use, 116 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, 159 5-2 Plasma Pharmacokinetics of Propylene Glycol Given as a 4-Hour Intravenous Infusion, 160 5-3 Acute Lethal Dose (LD50) of Propylene Glycol in Rats, Mice, Guinea Pigs, and Rabbits, 164 5-4 Overview of Common Flavorings and Their Inhalation Toxicity, 176 5-5 Summary of Experimental Studies Determining Carbonyl Compounds in E-Cigarette Aerosols, 184 5-6 Volatile Compounds Detected in E-Cigarette Aerosol, 188 8-1 Epidemiological Studies on E-Cigarettes and Dependence, 268 8-2 Laboratory/Experimental Studies on Dependence and Abuse Liability, 284
xxii BOXES, FIGURES, AND TABLES 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, 306 8-4 Product Liking for Vuse Solo E-Cigarettes with Different Nicotine Concentrations Compared with Usual Brand Combustible Tobacco Cigarette and Nicotine Gum, 328 9-1 Clinical Studies of Short-Term Effects of E-Cigarette Use on Cardiovascular Endpoints, 344 9-2 Epidemiological Studies on Chronic E-Cigarette Use and Cardiovascular Endpoints, 362 10-1 In Vitro Mutagenicity/DNA Damage Assessment of E-Cigarette Liquids and Aerosols, 388 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, 395 10-3 Formaldehyde and Acrolein Levels Generated from Five E-Cigarette Devices at Different Power Levels, 396 10-4 Occurrence of Tumors in Female Sprague-Dawley Rats Exposed to Nicotine for Up to 24 Months and Controls, 399 11-1 Clinical and Epidemiological Studies in Humans, 412 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 Non-Smokers at Baseline, 502 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, 504 16-3 DOSEâRESPONSE: Summary of Prospective Cohort Studies of the Association Between E-Cigarette Use Frequency and Subsequent Risk of Smoking of Combustible Tobacco Cigarettes Among Youth/Young Adults, 508 16-4 Meta-Analysis of Unadjusted and Adjusted Odds of Ever Smoking Combustible Tobacco Cigarettes Among Combustible Tobacco CigaretteâNever Smokers at Baseline and E-Cigaretteâ Ever Users at Baseline Compared with E-CigaretteâNever Users at Baseline, 517
BOXES, FIGURES, AND TABLES xxiii 17-1 Systematic Reviews of E-Cigarettes and Smoking Cessation Identified by Literature Search, 548 17-2 Characteristics of Three Randomized Controlled Trials Testing the Efficacy of E-Cigarettes for Smoking Cessation, 560 17-3 Selected Systematic Reviews: Part 1, 562 17-4 Selected Systematic Reviews: Part 2, 568 18-1 Comparison of Toxicant Levels Among Combustible Tobacco Cigarette Smoke and E-Cigarette Aerosol, 597 18-2 Comparison of In Vitro Studies That Compared Toxicity of E-Cigarettes and Combustible Tobacco Cigarettes, 613 18-3 Comparison of Animal Studies That Compared Toxicity of E-Cigarettes and Combustible Tobacco Cigarettes, 616 19-1 Summary of Simulation Runs Considered by the Committee, 637 19-2 Model-Estimated Life-Years Lost During 2015â2050 Due to E-Cigarettes, 640 19-3 Model-Estimated Life-Years Lost During 2015â2070 Due to E-Cigarettes, 642 19-4 Model-Estimated Life-Years Lost During 2015â2050 Due to E-Cigarettes, 643 19-5 Model-Estimated Life-Years Lost During 2015â2070 Due to E-Cigarettes, 644 19-6 Model-Estimated Life-Years Lost During 2015â2050 Due to E-Cigarettes, 645 19-7 Model-Estimated Life-Years Lost During 2015â2070 Due to E-Cigarettes, 646 19-8 Model-Estimated Life-Years Lost During 2015â2050 Due to E-Cigarettes, 647 19-9 Model-Estimated Life-Years Lost During 2015â2070 Due to E-Cigarettes, 648 D-1 Summary of Exposure, Comparison, and Control Conditions and Cell or Tissue Type Used in In Vitro Studies of E-Cigarettes Assessing Cytotoxicity, 704 D-2 Summary of Test Agents, Cell or Tissue Type Used, and Assays Employed in In Vitro Studies of E-Cigarettes Assessing Cytotoxicity, 710 D-3 Summary of Results from In Vitro Studies of E-Cigarettes Assessing Cytotoxicity, 727