FLAVOR CENTRAL Credit: Associated Press THE TRUTH ABOUT VAPING What we know, and what we don’t, about the safety of e-cigarettes. Credit: Kirk Zamieroski/ACS Productions

Inside a basement shop in Washington, D.C., on a bustling street filled with restaurants and nightclubs, a hazy cloud with the sweet scent of cotton candy and vanilla custard lingers in the air. Two men are sitting at a tasting bar smoking the latest flavors of “e-juice,” while the shop manager “vapes” on his electronic cigarette, or “box mod” device, behind the counter.

The back wall is lined with hundreds of 10–15-mL eyedropper bottles, each with a colorful, eye-catching label announcing an enticing flavor. Melon head, razzletaz, serious kiwi, Swedish fish, gummy bear, taste the rainbow—the list goes on. The vials contain e-juice, a liquid concoction of varying amounts of nicotine, propylene glycol, glycerin, and food-grade flavorings. The juice is heated inside battery-operated, refillable devices that come in myriad sizes, colors, shapes, and styles. Nicotine in the e-juice, as well as any flavors, is aerosolized and inhaled by the user.

Vaping shops and lounges such as this one are popping up all over the U.S., representing about one-third of the e-cigarette market, which was estimated at $2.2 billion in 2014. The devices they sell, called tanks or mods, are typically much larger and have stronger batteries than the slim first-generation e-cigarettes, or “cigalikes.” And unlike cigalikes, which come in traditional flavors such as tobacco and menthol, tanks and mods can be filled with any of the thousands of commercially available e-juice flavors.

A growing community of vapers and e-cigarette manufacturers is touting e-cigarettes as a way to help people quit smoking traditional cigarettes. There are lots of testimonials and anecdotal evidence that vaping has helped people quit smoking but little scientific data to back up the claim. Likewise, little is known about the long-term health risks of e-cigarettes or whether the multitude of candy and fruit flavors with catchy names will lead nonsmokers, particularly young people, to pick up a nicotine addiction. Most scientists say, however, that e-cigarettes are likely to be safer than cigarettes because compared with cigarette smoke, e-cigarette aerosol contains fewer toxic chemicals and at much lower concentrations.

As the vaping community rapidly grows, along with e-cigarette devices with increasingly powerful batteries and endless flavors, so do calls from public health advocates for federal oversight of the market. Some groups are urging the Food & Drug Administration to subject e-cigarettes to the same regulations as traditional cigarettes, including requiring health warnings on packages and prohibiting e-cigarettes from being sold to minors. Others are also calling for FDA to ban candy and other kid-friendly flavors.

FDA currently regulates only those e-cigarettes, e-juices, and other vaping supplies that make therapeutic claims. FDA proposed a rule last April, however, that would allow the agency to begin regulating e-cigarettes as tobacco products. The agency expects to finalize that rule later this year. In the meantime, various state and local governments are putting some restrictions on the sale and use of e-cigarettes in their jurisdictions, creating confusion and uncertainty for the industry.

Under FDA’s proposed rule, e-cigarette companies would have to register with the agency. In addition, manufacturers would have to file applications for all e-cigarettes marketed after Feb. 15, 2007, along with data about their potential health risks. That date was set by the Family Smoking Prevention & Tobacco Control Act, enacted in 2009, which gave FDA the authority to regulate tobacco products. Traditional cigarettes were already on the market in 2007, so they are “grandfathered” or exempt from being subject to the same requirements as new tobacco products. Very few e-cigarettes were on the market at that time—they were invented in China in 2003 but only began hitting the U.S. market around 2006 or 2007.

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The proposal would also prohibit sales of e-cigarettes to minors and require health warnings and disclosure of ingredients.

Small vaping businesses fear that tough new regulations will push them out of the e-cigarette market, particularly if they are required to test hundreds of flavors, each with four or five different strengths of nicotine, on dozens of different devices. They claim that big tobacco would benefit from the regulations because the only e-cigarettes that big tobacco companies produce are cigalikes with just a few flavors and nicotine concentrations.

“Big tobacco is trying to push through regulations so that the only flavors you would be able to have are tobacco, cream, and menthol,” says Ryan Bixby, a passionate vaper who manages the D.C. basement shop, DC Vape Joint. To comply with the proposed regulation, companies would have to pony up on average about $250,000 per flavor, per nicotine strength, he says. “The rules are completely designed to push the small companies out of the market.”

Bixby, 31, and other experienced vapers say that tanks and mods provide “a more satisfying experience” than cigalikes, and therefore can help tobacco smokers make the switch.

Under FDA’s proposal, however, “the higher-quality e-cigarette products that are crucial for many smokers to permanently quit will be eliminated from the legal market,” says Carl V. Phillips, scientific director of the Consumer Advocates for Smoke-free Alternatives Association, a group that promotes e-cigarettes and smokeless tobacco as reduced-harm products relative to traditional cigarettes. “The only products that stand any chance of successfully navigating the premarket tobacco application process will be the cigalike products,” he notes in comments submitted in August to FDA.

Republican leaders in Congress are also raising concerns about the impact of FDA’s proposed e-cigarette rule on small businesses. Speaker of the House of Representatives John Boehner (R-Ohio), House Majority Leader Kevin McCarthy (R-Calif.), and House Energy & Commerce Committee Chairman Fred Upton (R-Mich.) sent a letter in November to Sylvia Burwell, secretary of the Department of Health & Human Services, requesting that FDA change the grandfather date for tobacco products subject to its new rule. The lawmakers argue that because almost no e-cigarettes were on the market as of Feb. 15, 2007, the grandfather date would unfairly limit the growth of such products.

Several Democrats in Congress, on the other hand, are calling FDA’s proposal “timid and tepid.” Sen. Richard Blumenthal (D-Conn.), in particular, wants FDA to restrict the number of flavor options, advertising, and online sales of e-cigarettes. He and others, including 29 state attorneys general, are concerned about the growing use of e-cigarettes by youths under the age of 18.

Last year the Centers for Disease Control & Prevention reported that the number of youths in grades six through 12 who had never smoked a cigarette but had used e-cigarettes increased threefold, from about 79,000 in 2011 to more than 263,000 in 2013 (Nicotine Tob. Res. 2014, DOI: 10.1093/ntr/ntu166).

Many medical organizations, including the American Heart Association, the American College of Cardiology, the American Association for Cancer Research, and the American Society of Clinical Oncology (ASCO), are also worried about the rise in e-cigarette use by minors. They are pushing FDA to subject e-cigarettes to the same regulations as traditional cigarettes, including banning e-cigarette flavors that appeal to kids.

“We are concerned that e-cigarettes may encourage nonsmokers, particularly children, to start smoking and develop nicotine addiction,” Peter Paul Yu, ASCO president, said in a statement last month.

↑ Top Research Needs And Approaches THIRD GENERATION [+]Enlarge Credit: Shutterstock/C&EN

For now, FDA is not proposing to ban online e-cigarette sales, e-cigarette television commercials, or the thousands of e-juice flavorings. Such restrictions may ultimately come, but first FDA plans to gather the scientific evidence to determine whether there is a need for such regulations. And that could take several years.

To fill in some of the data gaps, FDA is funding a few dozen research projects, administered through the National Institutes of Health. The work includes characterizing e-cigarette devices, e-juices, and e-cigarette aerosols, as well as evaluating who is using e-cigarettes, why and how they are using them, and the potential health risks.

“E-cigarettes are evolving so quickly that we actually don’t know what people are smoking,” says Mirjana Djordjevic, program director for NIH’s Tobacco Control Research Branch, which is administering the grants. “We also don’t know how people are using them,” she notes. Such information is needed before “we can even think about potential health effects,” she says.

A few studies showing toxic carbonyl compounds such as formaldehyde and acrolein in e-cigarette aerosols have attracted widespread media attention. Such compounds are formed when propylene glycol and glycerin, components of e-juice, are heated in an e-cigarette. But for studies to be meaningful, they have to test devices the way people really use them, says Risa Robinson, a mechanical engineering professor at Rochester Institute of Technology, and that aspect of the tests has been questioned.

Studies that have reported high levels of carbonyls and other carcinogens in e-cigarette aerosols have been widely criticized by the vaping industry for using unrealistic conditions, including higher voltages than are typically used in real-world e-cigarette devices­—the higher the voltage, the higher the concentration of toxic chemicals in the aerosol. Tanks and mods do have increasingly powerful batteries, but the user can control the voltage on those devices.

Many other variables affect the emissions from e-cigarettes, including when the user pushes the fire button, how long the coil heats up, and the type of puff the user takes, Robinson says.

To get a better handle on how people actually use e-cigarettes, Robinson and colleagues are sending users home with personal monitoring devices that track every puff they take, as well as the flow rate and intensity of each puff. The team is hoping to use the data to program their smoking machines to better mimic vaping behavior.

The huge variety of different types of e-cigarette devices, however, is making it difficult for researchers such as Robinson to assess the health risks of e-cigarettes. “We are looking at every device that we can get our hands on,” Robinson says. But, she adds, “they are being put on the market faster than we can test them.”

The lack of standard methods for measuring e-cigarette emissions also makes it difficult to compare one study with another and to compare e-cigarette emissions with cigarette smoke. “We need to establish standardized conditions under which the devices and their emissions could be compared to cigarettes,” says Stephen S. Hecht, a professor at the University of Minnesota College of Pharmacy and editor-in-chief of the journal Chemical Research in Toxicology.

“There are standardized conditions for smoking cigarettes that allow us to compare different types of cigarette smoke,” Hecht notes. “These conditions don’t replicate human smoking, but nevertheless they do allow you to compare different products,” he says.

Hecht and colleagues are evaluating the potential health effects of e-cigarettes by looking for biomarkers of exposure to tobacco-related cancer-causing compounds in the urine of e-cigarette users. As a first step, the researchers analyzed metabolites of six such carcinogens—nitrosamine ketone, polycyclic aromatic hydrocarbons, benzene, acrolein, crotonaldehyde, and propylene oxide—in e-cigarette users and compared them with levels of the same metabolites in cigarette smokers.

↑ Top Flavor Fears SLOW SCIENCE [+]Enlarge Credit: Roswell Park Cancer Institute

Levels of all of the metabolites are significantly lower in the e-cigarette users than in the smokers, Hecht says. The results suggest that “e-cigarettes have a more favorable toxicity profile than tobacco cigarettes,” at least as indicated by those compounds, he notes.

Other chemicals in e-cigarettes are also raising alarms, including a few of the flavoring agents. “Most of the flavors are taken from the food industry and have been tested for safety when we eat them,” says Maciej L. Goniewicz, a professor of oncology at Roswell Park Cancer Institute, in Buffalo. “We don’t know what the health effects are when these flavors are inhaled,” he says. It will be difficult to test all of the thousands of different combinations of flavors that are on the market. “Some of the flavors are just a single compound, but many are mixtures of different chemicals,” Goniewicz points out.


Preliminary evidence suggests at least some flavors pose cause for concern. A group of researchers led by cardiologist Konstantinos E. Farsalinos of the Onassis Cardiac Surgery Center, in Greece, evaluated 159 samples of sweet-flavored e-juice, purchased from 36 manufacturers in seven countries, for the presence of the creamy buttery flavorings diacetyl and acetyl propionyl. The two chemicals have been approved for food use but are associated with respiratory disease when inhaled. The researchers found both chemicals in 74.2% of the samples (Nicotine Tob. Res. 2014, DOI: 10.1093/ntr/ntu176). They detected the chemicals in both the e-juice and the aerosol generated by heating the liquid.

Another flavor to watch out for is cinnamon, warns Prue Talbot, a professor of cell biology at the University of California, Riverside. Talbot and colleagues exposed human embryonic stem cells and human adult pulmonary fibroblasts to 36 different e-juices. Cinnamon Ceylon was the most cytotoxic, she says.

The researchers determined that both cinnamaldehyde and 2-methoxycinna­maldehyde are cytotoxic (Toxicol. in Vitro 2014, DOI: 10.1016/j.tiv.2013.10.006). They quantified the amount of each chemical in the fluids by using high-performance liquid chromatography and found that cytotoxicity correlated with the amount of cinnamaldehyde in the product. The amount of 2-methoxycinnamaldehyde varied in the fluids, even in separate samples of the same product. The results suggest that the cinnamon flavorings in e-cigarette refill fluids could adversely affect users, Talbot says.

Right now it’s a “user beware” market for e-cigarettes, Talbot emphasizes. There are no regulations on manufacturing the devices or the flavored e-juices, and scientists who are evaluating the products are seeing wide variation in the quality and performance of the products. Research being conducted today may ultimately be used to inform regulations to make e-cigarettes safer, but Talbot and many other experts predict it may take a long time before such regulations are in place.

In the meantime, Bixby and other vaping advocates are working hard to create a vaping community and culture that is more accepted by society than tobacco smoking. Bixby holds classes two nights a week at the DC Vape Joint to teach people how to use the latest vaping gadgets and, for more experienced vapers, how to build their own devices. He’s proud to have recently celebrated his two-year “vapeversary”—meaning it’s been two years since he quit smoking cigarettes and switched to vaping. He’s not in the vaping business for the money, he tells C&EN. His goal is to help people quit smoking.