Earlier this year, an 18-year-old woman was hospitalized for hypersensitivity pneumonitis—also known as wet lung. The patient’s pediatrician attributed her wet lung to lung damage and inflammation triggered by three weeks of e-cigarette (e-cig) use. Her lung damage was so severe that she was hospitalized on a ventilator. Over the past year, teen e-cig use has risen to include more than three million teens—that’s one in five high schoolers who are vaping, perhaps under the assumption that e-cigs are safer than cigarettes and don’t contain nicotine. Noticing this increase, the US Food and Drug Administration (US FDA) has demanded that five of the mainstream brands submit plans to prevent e-cig use in teens. As sales continue to increase, even in the adult population, one question remains unclear: What are the short- and long-term health effects of e-cig use?
Although e-cigs are touted as a “safer” alternative to and an aid to quit traditional smoking, the public health implications of e-cig use remain unclear. The belief that e-cigs are safer stems from fundamental differences between e-cigs and traditional tobacco cigarettes. Cigarettes utilize combustion of tobacco and additives to produce an inhalable smoke. E-cigs produce a vapor using a heating element that encounters the e-liquid solution. However, this heating element may also result in heavy metal exposure as it deteriorates due to high temperatures or over time from regular use. Acute effects of e-cig use have indicated that it can result in throat and mouth irritation, vomiting, nausea, and cough. These e-liquids contain many compounds in different combinations, making toxicity difficult to assess. Furthermore, the US FDA has not recognized e-cigs as a cessation device to quit smoking due to lack of evidence. However, a recent meta-analysis has demonstrated that adolescents who use e-cigs are at least three times more likely to initiate combustible cigarette use compared with those who do not use e-cigs.
When e-cigs first came onto the market, they were not regulated by the US FDA. With the increase of e-cig use, especially in teens, the US FDA finalized a rule on August 8, 2016, to regulate all tobacco products, including Electronic Nicotine Delivery Systems (ENDS). It requires health warnings and restricts sales to minors. However, it leaves one category of e-cigs unregulated: Electronic Non-Nicotine Delivery Systems (ENNDS). While the health impacts of nicotine are well established, the health effects of chemicals that are present and vary across flavorings are unknown.
Nicotine, a long-known brain stimulant, is present in traditional cigarettes and is known to affect brain development. This impact on brain development is the main reason the US FDA discourages its use in teens whose brains are still developing. Several studies have demonstrated that e-cig vaping with nicotine increases endothelial dysfunction, oxidative stress imbalance, and arterial stiffness. In ENDS, nicotine is vaporized using propylene glycol (PG) and glycerol (G). This combination makes it difficult to discern the effects of these individual components. One study demonstrated that high-temperature e-cig vehicle (PG and G) vaporization did not alter micro- or macrovascular function, and oxidative stress indicated that nicotine may be responsible for these dysfunctions. Another often overlooked route of exposure is dermal. Dermal exposure to e-cigarette liquid can cause dizziness, nausea, vomiting, or diarrhea. But while the health effects of nicotine have long been well established and include cardiovascular disease, potential birth defects, and poisoning, the health impact of ENNDS, which lack nicotine, needs to be studied further.
E-liquids are widely available in more than 7,700 flavors, and some are classified as Generally Recognized As Safe (GRAS) for food or oral ingestion. However, a distinction should be made between compounds safe for ingestion versus inhalation. In the early 2000s, food product flavorings gained public attention due to reports of serious lung disease in microwave popcorn workers. The flavoring chemicals were classified as GRAS, but exposures were occurring from inhalation and very little was known about inhalation hazards of these chemicals at that time. The main component of the flavoring was diacetyl, which was associated with bronchiolitis obliterans and other severe respiratory diseases in workers inhaling heated vapors containing diacetyl. This resulted in the condition being aptly named “popcorn lungs.” [Editor’s note: For more information on “popcorn lungs” and the toxicology research that resulted, read the SOT Tox Impact Statement “Popcorn Workers Lung: The Role of Diacetyl.”] Diacetyl has also been found in e-liquids and has been used in the formulation of a variety of flavorings. One study found diacetyl in 39 of 51 flavored e-cigs tested. The authors of this study contacted two of the e-liquid companies, and despite diacetyl being found in their flavors, the companies responded that their products did not contain the compound. Other chemicals found in e-cig flavorings, such as cinnamaldehyde, have been shown to impair the respiratory immune cell function. These potential health implications further emphasize the need for industry regulation of e-liquid compounds—regardless of their nicotine content.
Several other studies have investigated the detrimental health effects of ENNDS e-liquids. In in vitro experiments, human monocytic cell lines had an inflammatory response in monocytes mediated by cell-free reactive oxygen species (ROS) when exposed to e-liquids, and mixing e-liquid flavors resulted in a further increase in ROS levels, suggesting that mixing flavors may be more harmful to users. Other studies have demonstrated that e-cig vapor is cytotoxic and that the cytotoxicity of e-liquids correlates with the number and concentration of chemicals used in the e-liquid flavor. These findings were found in human embryonic cells, mouse neural stem cells, human pulmonary fibroblasts, human epithelial cells, and rat myocardial cells.
In humans, studies have indicated that e-liquids have the potential to drastically alter the immune response. Nasal scrapings from e-cig users showed decreases in more than 300 genes that regulate the immune system. The ability of e-cigs to widely alter immune genes suggests that they have the capability to suppress the immune system in the nasal mucosa. Furthermore, analysis of sputum from cigarette and e-cig users has indicated that this immune system suppression may leave e-cig users more susceptible to illnesses. Ultimately, more research is needed to determine the health impacts of long-term e-cig use. This is particularly important because e-cig use continues to be widespread, and regulations are needed to oversee the e-cig and e-liquid industry.
In addition to nicotine and flavoring additives, e-cig vapor contains a variety of other compounds, including small amounts of toxicants, carcinogens, heavy metals, and metal nanoparticles. Furthermore, chemicals found in e-cigarette aerosol can deposit particles like nickel, tin, and chromium into the lungs, causing local respiratory toxicity. Moreover, e-cigarettes deliver an aerosol of ultraﬁne particles to the distal airways and alveolus.
Ultimately, both ENDS and ENNDS have the potential to have adverse health effects but only time and research will be able to define with certainty the severity of their health impact. Only then will the US FDA be able to regulate ENNDS e-liquids. It may be years before we have this comprehensive view of e-cigs and health, which begs the question, “Is vaping e-cigs worth the potential long-term toxicological risk?”
The opinions or views expressed in this article are solely those of the author and not necessarily those of Covance or any of its affiliates. Covance makes no representations regarding the accuracy or reliability of the information provided herein.