AACR-ASCO Joint Recommendations for Electronic Nicotine Delivery System Regulations
In a 2015 joint policy statement, the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) raised awareness about the rapidly growing epidemic of electronic nicotine delivery systems (ENDS), which includes e-cigarettes. The statement called on the U.S. Food and Drug Administration (FDA) to regulate ENDS similarly to other tobacco products as well as implement additional actions to protect youth and young adults who never previously used tobacco. The 2015 statement was born out of concern for the nearly 400 percent increase in ENDS use between 2012 and 2014 among U.S. high school and middle school students. By 2020, regular youth ENDS use increased by an additional 46 percent, a total of 3.6 million middle and high school students. This prompted AACR and ASCO to issue an updated ENDS statement to call for stronger action to address this dangerous trend.
While smoke from combustible tobacco contains far more carcinogens and other toxic chemicals than ENDS aerosols, there is growing evidence linking ENDS use to DNA damage and inflammation, key steps in cancer development. Additionally, nicotine itself increases blood pressure, weakens the immune system, and impairs memory and learning. However, long-term studies are needed to better understand the relationship between ENDS use and cancer.
ENDS have also been billed as a way to help adults quit smoking combustible tobacco, but the evidence of cessation efficacy remains insufficient. Additionally, no ENDS manufacturer has applied to the FDA to develop their products as a cessation therapy, a requirement to conduct clinical trials in the United States. Several other major health authorities have also determined that there is inadequate evidence to suggest ENDS help adults quit smoking, including the U.S. Surgeon General; the National Academies of Science, Engineering, and Medicine (NASEM); the U.S. Preventive Services Task Force (USPSTF); and the National Comprehensive Cancer Network.
The new policy statement describes advances in understanding how ENDS impact human biology and calls for urgent actions to protect public health. Importantly, the statement calls for an immediate ban on all non-tobacco-flavored ENDS products that contain natural or synthetic nicotine. Furthermore, the statement supports improved use of evidence-based smoking cessation treatments to reduce cancer incidence and improve public health.
Frequently Asked Questions
- How are ENDS regulated?
- Who uses ENDS?
- What is in “e-liquid”?
- How do flavors increase the appeal of tobacco products for youth?
- How does smoking combustible tobacco cause cancer?
- What do we know about the relationship between ENDS and cancer?
- Is nicotine harmful by itself?
- What evidence-based strategies can help someone quit smoking?
How are ENDS regulated?
The Family Smoking Prevention and Tobacco Control Act (TCA), enacted in 2009, provides FDA with the authority to regulate tobacco products, including cigarettes, e-cigarettes, and cigars, and requires manufacturers to provide enough evidence to prove to FDA that any new tobacco products are “appropriate for the protection of public health.” Beginning in 2020, manufacturers were required to submit Pre-Market Tobacco Product Applications (PMTAs) to FDA for each product in order to remain available for sale. FDA has received more than seven million PMTAs for ENDS products since 2020 and has only granted marketing orders to a select few. It is illegal to sell an ENDS product in the United States without a marketing order, but FDA can exercise discretion while applications are pending.
Many states, tribal nations, and local governments have also established regulations that are more stringent than at the federal level. For example, dozens of states and many jurisdictions explicitly prohibit the sale flavored ENDS.
Who uses ENDS?
ENDS are a driver of youth initiation to tobacco products. The 2022 National Youth Tobacco Survey estimated that more than 2.5 million youth regularly used ENDS, including 14 percent of all high school students. Additionally, 85 percent of youth who used ENDS used flavored products in 2022, with fruit and mint flavors being the most common. Youth who use ENDS disproportionately tend to identify as LGBTQ+, non-Hispanic white, Hispanic, and/or male.
In addition to youth, 5.1 percent of U.S. adults (approximately 13 million) were estimated to regularly use ENDS in 2020. ENDS use is most common among adults younger than 24 years, roughly 15 percent of whom regularly used ENDS in 2020. Concerningly, 45 percent of adults (approximately 6 million) who used ENDS in 2020 have never smoked cigarettes. This study also estimated that 33 percent (approximately 4.4 million) of adults who use ENDS “dual use” combustible tobacco, such as cigarettes. Adults who dual use ENDS and combustible tobacco experience similarly high levels of carcinogens as adults who exclusively smoke cigarettes.
What is in “e-liquid”?
E-liquid contains a solvent (usually a mixture of propylene glycol, glycerin, and water) that dissolves nicotine, flavorings, and other additives designed to increase the appeal of e-cigarettes. Most flavoring molecules have only been tested for safety when consumed in food or drink, but not by inhalation. Additionally, e-liquid often contains unintentionally added toxicants either naturally derived from tobacco plants or residues from the manufacturing process. Heating up and aerosolizing e-liquid also can result in the formation of additional carcinogens and release carcinogenic metals from the heating coils. However, it is important to note that e-cigarettes generally emit far fewer carcinogens than from smoking traditional cigarettes.
How do flavors increase the appeal of tobacco products for youth?
Flavorings and cooling agents, like menthol, reduce the irritation and harsh taste from ENDS aerosols. Youth who are offered to try fruit flavored ENDS are 6.49-fold more likely to try the product compared to being offered a tobacco-flavored ENDS. In fact, 71 percent of youth who use ENDS do so because they “come in flavors I like.” Flavors also inappropriately reduce perceptions of how harmful the products are. Flavored ENDS products are often advertised and packaged with bright colors that appeal to youth. In comparison to youth, adults who use ENDS are 21-fold more likely to use tobacco-flavored ENDS exclusively.
How does smoking combustible tobacco cause cancer?
While cigarettes inherently contain numerous carcinogens, many of the carcinogen molecules inhaled when smoking are created by the process of burning. Many of these carcinogens bind to and chemically alter DNA inside cells all over the body, not just the lungs. If this damage is not repaired, mutations form when cells try to replicate the DNA. Some mutations will pre-dispose cells to become cancerous by altering vital cellular functions, such as DNA repair proteins, growth suppressing proteins, and/or enhancing pro-growth signals. Additionally, tobacco smoke and toxicants dissolved in the blood are irritating and result in inflammation. Inflammation processes release chemicals that promote cellular growth and replication, which amplify existing DNA mutations. Eventually, enough DNA mutations and pro-growth environments can lead to uncontrollable cellular growths, known as cancer.
What is known about the relationship between ENDS and cancer?
While ENDS aerosols contain far fewer carcinogens and other toxic chemicals than smoke from traditional tobacco products, some carcinogens and metabolites of carcinogens have been found in the urine of individuals who exclusively use ENDS. There is also evidence that ENDS may cause DNA damage and promote rapid cellular replication through inflammation. Cancer can take years or decades to develop. Therefore, long-term studies are needed to better understand the relationship between ENDS use and cancer risks.
Is nicotine harmful by itself?
What evidence-based strategies can help someone quit smoking?
There are several FDA-approved medications as well as behavioral therapy that are demonstrated to improve the chances of successfully quitting tobacco. FDA-approved medications fall into two categories: nicotine replacement therapies, such as patches or gum, and medication that alters the impact of nicotine on the brain, such as varenicline. Additional free evidence-based resources for smoking cessation can be found at SmokeFree.gov, and by calling 1-800-QUIT-NOW or 1-855-DEJELO-YA (Español).
1. Ban all non-tobacco-flavored products that contain natural or synthetic nicotine; flavors may only be used for research purposes or FDA-approved tobacco cessation therapies.
2. Tax all products that contain natural or synthetic nicotine in a manner that reduces tobacco use and promotes public health
3. Increase funding for evidence-based tobacco control programs and campaigns such as the CDC’s Office on Smoking and Health, state tobacco control programs, and Quit Lines.
4. Prohibit the use of ENDS in places where combustible tobacco use is prohibited by federal, state, or local laws. All tobacco use should be prohibited at medical facilities.
6. Limit the sale of tobacco products to stores or areas within stores that require age verification upon entrance.
7. Require health insurance plans, including Medicare/Medicaid, to cover all FDA-approved cessation therapies, expand coverage limits, and reimburse healthcare providers, including cessation specialists, for time helping patients quit smoking and vaping.
1. Regulate predatory tobacco advertising practices including packaging, product designs, and labeling appealing to youth; misleading statements about cessation efficacy; athletic, musical, social, or cultural event sponsorship; giveaways when buying tobacco products; branded clothing; social media, digital, and print advertising; and tobacco use in movies and television.
2. The FDA should enforce removal of ENDS products from the market that have not received a marketing order, publish pre-market tobacco product applications with confidential information redacted, and update PMTA review progress with a publicly available database.
3. The FDA should develop product standards for tobacco products to improve public health, including but not limited to minimizing appeal to youth; capping the amount of nicotine delivery to minimize addictiveness; eliminating or substantially reducing human exposure to known carcinogens (e.g., heavy metals) and other toxicants (e.g. additives, contaminants, and manufacturing residues); and regulating the power and operating temperature of ENDS products.
4. PMTAs should require information regarding: composition of ENDS and e-liquid components; appeal to people who have never used tobacco products; impacts on health; geotracking or biometric capabilities; and steps taken to protect consumer privacy.
5. Require health warning and safety labels on ENDS packaging and advertising; these labels should contain ENDS/e-liquid composition information from PMTAs.
6. The FDA and/or NCI should provide evidence-based, non-stigmatizing definitions for categories of tobacco use for human studies, for example no tobacco history; no smoking history; no ENDS history; currently smoking; currently using ENDS; former smoking history. The FDA and/or NCI should provide guidance on best practices for measuring tobacco use data in human studies. The FDA should require all oncology clinical trials to assess tobacco use and report findings.
7. The FDA should increase enforcement of the minimum age to legally purchase tobacco products
Additional Research Needs
1. Research is needed to determine effective ENDS cessation therapies for youth, young adults, and adults, as well as cessation therapies for youth combustible tobacco users.
2. Large prospective epidemiological studies are needed to investigate the long-term health impacts of ENDS use and disparities in tobacco-related illness.
3. Additional research is needed for a comprehensive understanding of the acute and long-term biologic effects of ENDS use, carcinogen exposures, and the use of ENDS in the context of smoke exposure.
4. Additional research is needed on how patients diagnosed with cancer use tobacco products, their reasons for use, perceptions of health impacts, impact of cessation on cancer-related outcomes, and interactions with anticancer therapies.
5. Randomized clinical trials are needed to investigate the cessation efficacy of ENDS compared to FDA-approved cessation therapies. Investigational New Drug applications are necessary to facilitate such trials.
6. Research is needed to monitor the impacts of federal, state, and local tobacco policies on youth and adult use patterns, as well as the use of evidence-based approaches to develop policy.
This Updated Policy Statement was developed by a joint Writing Group composed of members from the Tobacco Products and Cancer Subcommittee of the American Association for Cancer Research (AACR) Science Policy and Government Affairs (SPGA) Committee and the American Society of Clinical Oncology (ASCO) Tobacco Cessation and Control Subcommittee of the Health Equity and Outcomes Committee (HEOC). The Updated Statement was reviewed by both parent committees (i.e., the AACR SPGA Committee and the ASCO HEOC), and was approved by the AACR Board of Directors on April 8, 2022 and the ASCO Executive Committee on April 21, 2022. This Updated Policy Statement was published jointly by invitation and consent in both Clinical Cancer Research and Journal of Clinical Oncology. Copyright 2022 American Association for Cancer Research and American Society of Clinical Oncology. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or storage in any information storage and retrieval system, without written permission by the American Association for Cancer Research and the American Society of Clinical Oncology.