Public Health
Consequences of
E-Cigarettes
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
Washington, DC
www.nap.edu
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: 978-0-309-46834-3
International Standard Book Number-10: 0-309-46834-5
Digital Object Identifier: https://doi.org/10.17226/24952
Library of Congress Control Number: 2018932760
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.
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.
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.
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, 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
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)
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. GAÇA, 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.
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 study.
David L. Eaton, Chair
Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems
SECTION I: E-CIGARETTE DEVICES, CONSTITUENTS, AND EXPOSURES
3 E-CIGARETTE DEVICES, USES, AND EXPOSURES
Characteristics of E-Cigarette Devices
Exposure to Aerosols and Particulates
Secondhand Exposure to E-Cigarette Aerosol
Concentration of Nicotine in Commercial E-Cigarettes
Nicotine Concentration in E-Cigarette Emissions
Toxicology and Modes of Action
Exposure to Nicotine and Nicotine Derivatives from E-Cigarettes
Relationship Between E-Cigarette Topography and Nicotine Exposure
5 TOXICOLOGY OF E-CIGARETTE CONSTITUENTS
Humectants (Delivery Solvents)
Free Radicals and Reactive Oxygen Species
6 RESEARCH NEEDS: E-CIGARETTE DEVICES, CONSTITUENTS, AND EXPOSURES
Addressing Gaps in Substantive Knowledge
SECTION II: EFFECTS OF E-CIGARETTES ON HEALTH
8 DEPENDENCE AND ABUSE LIABILITY
Characterization of Disease Endpoints and Intermediate Outcomes
Questions Addressed by the Literature
Characterization of Disease Endpoints and Intermediate Outcomes
Human Evidence from Studies of Cardiovascular Effects
Characterization of Disease Endpoints and Intermediate Outcomes
Case Reports and Other Clinical Studies
Studies of Effects of Major Components of E-Cigarettes on Cancer Outcomes
Vulnerable/Susceptible Populations
Characterization of Disease Endpoints and Intermediate Outcomes
In Vivo Animal Studies and In Vitro Mechanistic Studies
Vulnerable/Susceptible Populations
Characterization of Disease Endpoints and Intermediate Outcomes
Questions Addressed by the Literature
Studies in Humans (Clinical and Epidemiological)
13 DEVELOPMENTAL AND REPRODUCTIVE EFFECTS
Characterization of Disease Endpoints and Intermediate Outcomes
Questions Addressed by the Literature
Case Reports and Other Clinical Studies
In Vivo Animal and In Vitro/Mechanistic Studies
Studies on Combustible Tobacco and Nicotine
Intentional and Unintentional Exposure to E-Liquid
15 RESEARCH NEEDS: EFFECTS OF E-CIGARETTES ON HEALTH
Addressing Gaps in Substantive Knowledge
SECTION III: PUBLIC HEALTH IMPLICATIONS OF E-CIGARETTES
16 COMBUSTIBLE TOBACCO CIGARETTE SMOKING AMONG YOUTH AND YOUNG ADULTS
Conceptual Framework: Patterns of Use Among Youth and Young Adults
Evidence Review: Levels of Evidence Available
17 SMOKING CESSATION AMONG ADULTS
Conceptual Framework: Patterns of E-Cigarette Use Among Established Smokers
Evidence Review: Levels of Evidence Available
Evidence Review: Levels of Evidence Available
19 MODELING OF E-CIGARETTE USE
20 RESEARCH NEEDS: PUBLIC HEALTH IMPLICATIONS OF E-CIGARETTES
Addressing Gaps in Substantive Knowledge
Boxes, Figures, and Tables
BOXES
S-2 Levels of Evidence Framework for Conclusions
S-3 Research Needs: E-Cigarette Devices, Constituents, and Exposures
S-4 Research Needs: Effects of E-Cigarettes on Human Health
S-5 Research Recommendations: Public Health Implications of E-Cigarettes
2-1 Levels of Evidence Framework for Conclusions
B-1A Search Strategy for E-Cigarettes in Human Populations
B-1B Search Strategy for E-Cigarettes in In Vivo Animal Populations
B-1C Search Strategy for E-Cigarettes in In Vitro Populations
B-1E Search Syntax for E-Cigarettes and Dermal and Ingestion Exposure
B-2 Inclusion Criteria for the Literature Review on the Health Effects of E-Cigarettes
B-3 Search Syntax for E-Cigarettes and Dependence
B-4 Search Syntax for E-Cigarettes and Combustible Tobacco Cigarette Smoking Initiation
B-6 Search Syntax for Original Studies on E-Cigarettes and Smoking Cessation
B-7 Search Syntax for E-Cigarettes and Combustible Tobacco Cigarette Smoking Reduction
FIGURES
3-1 First-, second-, and third-generation e-cigarette devices
3-5 Event room PM2.5 concentrations before, during, and after an e-cigarette convention
3-6 Real-time changes of PM10, CO2, and TVOC concentrations during a vaping convention in Maryland
4-1 Nicotine metabolic pathways
5-4 Distribution of metal concentrations within and across brands of disposable e-cigalike devices
7-1 Publications by year on e-cigarettes and in vitro systems
7-2 Endothelial cell dysfunction by tobacco smoke
7-4 Publications by year on e-cigarettes and oxidative stress
7-5 Principal component analysis of top 2,000 genes by median absolute deviation
7-6 Changes in glutathione status and generation of reactive oxygen species
8-2 Dependence score as a function of nicotine concentration
9-2 Endothelial progenitor cells (EPCs) during e-cigarette inhalation and control
17-1 Conceptual framework of smoking cessation and e-cigarette use
18-2 Urinary metabolite levels for selected toxins and carcinogens, by group
18-3 Forced expiratory volume (FEV1) at the four time points of assessment for all 18 patients
TABLES
1-2 Summary of the Key Events in the History of E-Cigarette Regulation
3-1 Summary of E-Cigarette Puffing Topography Studies
3-2 Particle Size Distribution Parameters Determined from Cascade Impactor Analysis
4-2 Summary of Clinical Studies Examining Nicotine Exposure from E-Cigarette Use
5-2 Plasma Pharmacokinetics of Propylene Glycol Given as a 4-Hour Intravenous Infusion
5-3 Acute Lethal Dose (LD50) of Propylene Glycol in Rats, Mice, Guinea Pigs, and Rabbits
5-4 Overview of Common Flavorings and Their Inhalation Toxicity
5-5 Summary of Experimental Studies Determining Carbonyl Compounds in E-Cigarette Aerosols
5-6 Volatile Compounds Detected in E-Cigarette Aerosol
8-1 Epidemiological Studies on E-Cigarettes and Dependence
8-2 Laboratory/Experimental Studies on Dependence and Abuse Liability
9-1 Clinical Studies of Short-Term Effects of E-Cigarette Use on Cardiovascular Endpoints
9-2 Epidemiological Studies on Chronic E-Cigarette Use and Cardiovascular Endpoints
10-1 In Vitro Mutagenicity/DNA Damage Assessment of E-Cigarette Liquids and Aerosols
17-1 Systematic Reviews of E-Cigarettes and Smoking Cessation Identified by Literature Search
17-3 Selected Systematic Reviews: Part 1
17-4 Selected Systematic Reviews: Part 2
18-1 Comparison of Toxicant Levels Among Combustible Tobacco Cigarette Smoke and E-Cigarette Aerosol
19-1 Summary of Simulation Runs Considered by the Committee
19-2 Model-Estimated Life-Years Lost During 2015–2050 Due to E-Cigarettes
19-3 Model-Estimated Life-Years Lost During 2015–2070 Due to E-Cigarettes
19-4 Model-Estimated Life-Years Lost During 2015–2050 Due to E-Cigarettes
19-5 Model-Estimated Life-Years Lost During 2015–2070 Due to E-Cigarettes
19-6 Model-Estimated Life-Years Lost During 2015–2050 Due to E-Cigarettes
19-7 Model-Estimated Life-Years Lost During 2015–2070 Due to E-Cigarettes
19-8 Model-Estimated Life-Years Lost During 2015–2050 Due to E-Cigarettes
19-9 Model-Estimated Life-Years Lost During 2015–2070 Due to E-Cigarettes
D-3 Summary of Results from In Vitro Studies of E-Cigarettes Assessing Cytotoxicity