In January 1964, then-US surgeon general Luther Terry released the first report identifying cigarettes as a cause of lung cancer. He knew his words wouldn’t be welcomed by Americans—42% of whom smoked at the time—or big tobacco companies. The report was reportedly published on a Saturday specifically to avoid causing a market crash.
In the intervening 50 years, Americans’ love of tobacco has waned, but not disappeared: Over 34 million US adults still use tobacco products. When e-cigarettes came to the US in 2007, they seemed like the solution smokers had waited decades for: a delivery system for the nicotine that addicted them without the tobacco that sickened them.
But a spate of recent illnesses, coupled with vaping’s popularity, is bringing longstanding questions about its health impact to the fore. As of late Friday (Sep. 6), 450 people in 33 states have been hospitalized with acute bouts of coughing, shortness of breath, nausea, and vomiting tied to vape use. Many have been placed on ventilators, and at least five people have died. Two weeks ago the US Centers for Disease Control and Prevention (CDC) issued an official warning for all e-cigarette products—a rarity for the organization, which typically shies away from commenting on consumer products.
“It’s buyer beware,” says Paul Scanlon, a pulmonologist at the Mayo Clinic in Rochester, Minnesota. “All people vaping should be aware this is a new exposure and there are some fairly significant health effects and we don’t know what causes it.”
For those who know the story of tobacco cigarettes, the news surrounding vapes sounds eerily familiar. Retailers once marketed cigarettes as beneficial, then as merely safe in different forms, and then, finally, begrudgingly acknowledged that they were dangerous—after the damage had already been done. If the same arc plays out with vapes, we’re right in the middle phase. The question on everyone’s mind, from doctors to researchers to regulators, is how to stop the story mid-act. To do that, they’ll need the benefit of historical hindsight and the ability to pull off some really, really hard science.
A heated history
Scientists knew about the dangers of cigarettes decades before the surgeon general released his official report. Beginning in the 1930s, researchers across Europe and the Americas began conducting studies of cells and animals, as well as observational studies of human lung cancer cases, that all pointed to the fact that tobacco tar is carcinogenic. By the 1950s, there was ample evidence of cigarettes’ harm—yet the public remained in the dark for another decade.
Part of the problem was centuries’ worth of street credibility: Archaeologists have found evidence of tobacco use in pipes going back 3,000 years.
And then there’s the fact that that smoking is fun. All kinds of people, including researchers themselves, wanted to show smoking was beneficial in order to justify their habit. “If the degree of association which has been established between cancer of the lung and smoking were shown to exist between cancer of the lung and, say, eating spinach, no one would raise a hand against the proscription of spinach from the national diet,” Charles Cameron, the medical and scientific director of the American Cancer Society, wrote in the Atlantic in 1956.
It’s also profitable. By the 1950s, industry researchers reportedly knew that smoking caused lung cancer, but kept the information a secret while aggressively advertising cigarettes. Tobacco companies worked with ad agencies to refute emerging evidence that cigarettes were lethal.
What’s old is new
There’s no evidence that vape manufacturers are similarly concealing evidence of the effects of their products. But in other ways, vapes look a lot like cigarettes did in the 1950s.
“E-cigarette marketing closely parallels cigarette marketing in the mid-1900s,” says Zainab Farzal, an otolaryngological surgeon at the University of North Carolina Chapel Hill. Before the 1970s, when the US began passing laws limiting cigarette advertising, such ads portrayed wealthy young, slim people smoking—not unlike some of the vaping ads we see today on social media, radio, and television. Cigarette ads, Farzal says, “seemed to suggest that smoking would in some way enhance these social aspects of their lives.”
Current e-cigarette advertising also plays up the fact that these products are safer than traditional cigarettes. It’s a strategy familiar to tobacco companies: When evidence of cigarettes’ health effects was emerging, manufacturers marketed some products as “light” or “mild” to telegraph their reduced risk. But the risks remained, and in 2017 the Food and Drug Administration (FDA) banned cigarette companies from using those words unless the FDA itself had cleared a product as having less tobacco.
It’s true that the biggest advantage of e-cigarettes is they don’t contain tobacco. They have also been found to contain lower levels of other known toxins than cigarettes. (Frankly, it would be hard not to.)
But they still contain addictive nicotine, and sometimes in much higher quantities than cigarettes. While research on the risks of nicotine itself is inconclusive, the bigger concern is that vapers who come back again and again for the fun stuff—nicotine, and also cannabis—are constantly exposing themselves to other aerosolized chemicals, which vary tremendously between cartridge types. For this reason, the medical community has always cautioned against e-cigarettes.
“[E-cigarettes are] heavy exposure to not only nicotine and designated ingredients, but solvents and combustion products and other flavoring that may be harmful,” says Scanlon.
The variability in those ingredients is really where cigarettes and vapes diverge. In terms of composition, cigarettes are all relatively similar, says Michael Blaha, a cardiologist and clinical researcher at Johns Hopkins University. In the late 1930s, when researchers in Germany began comparing lung cancer cases in smokers and non-smokers, the smokers had such a markedly higher risk of developing the disease the trend was clear even in studies of fewer than 100 people. In other words, it didn’t matter what cigarettes they were smoking for the effect to be obvious.
Not only do vape cartridges greatly differ from one another, but many of the chemicals within each of them are of unknown safety. This, Blaha says, is what makes studying vapes the “wild west of epidemiology.”
The frontiers of medicine
On Sept. 5, health officials identified vitamin E acetate, an oil, as an ingredient associated with some of the acute respiratory syndrome hospitalizations. It was the first flicker of light after weeks of reports vaguely linked to vape pens, but far from a definitive answer. (Indeed, a Sept. 6 CDC report noted that “no consistent e-cigarette product, substance, or additive has been identified in all cases.”)
The link to this specific ingredient makes some biological sense. “Lungs don’t have a good mechanism for inhaling oil,” explains Scanlon. Exposure to oils like vitamin E acetate causes the lungs to mount an immune response, which can lead to something called lipoid pneumonia. Like pneumonia caused by an infection, lipoid pneumonia causes the lungs to fill with fluids—except with no pathogen to blame. Steroids can calm the immune reaction, Scanlon says, but the New York Times reported that a third of patients with this kind of sudden-onset lung disease have had to be put on ventilators while their lungs recovered.
Given the severity of the recent reactions, whatever is happening in these cases may have nothing to do with your average e-cigarette’s risk profile. But the uncertainty surrounding cartridge ingredient safety applies across the board, and is a major obstacle to definitive research.
In addition to oils, vape cartridges can contain all kinds of other chemicals for flavorings—many of which have never been studied in their aerosolized form. Early evidence has suggested that some flavorings can damage the body’s white blood cells, which would presumably cause an inflammatory reaction. And even though many of these chemicals are “generally regarded as safe“ for ingestion by the FDA, there’s no telling how much of them will be present in any given cartridge, says Esther Omaiye, a PhD candidate in environmental toxicology at the University of California, Riverside. Omaiye and her group have found that a flavorant called cinnamaldehyde, which should not be above 1% in perfumes and body care products, made up 36% of one type of e-cigarette cartridge.
The FDA requires e-cigarette companies to provide ingredient lists when they register their products. But even if these identified and unidentified chemicals are safe in the short term, there haven’t been any studies of their long-term effects—because people haven’t been vaping long enough yet.
On top of all those unknowns, there’s no way for researchers to know exactly what study participants are smoking. In at least some of the recent cases of acute lung disease, patients likely used cartridges that contained marijuana, which, as a schedule 1 drug, is not regulated by the FDA, or cartridges they had modified themselves for new flavors or higher nicotine content. Plus, because some studies have shown that e-cigarette users are likely to also use cigarettes (especially if they’re trying to quit smoking) or cannabis, it’s difficult to account for the consequences of vape use exclusively.
The list of variables that would pop up in a longitudinal study of vaping is so long that some scientists have debated whether it’s even worth trying, Blaha says. The fear is that ultimately, it would be a waste of funding—because it’d be impossible to pick out which health outcomes were a result of which chemical in vape devices.
The million-dollar question
While a longitudinal study of lung disease incidence in vapers will take decades, intermediate answers can be had by looking at markers of disease rather than diagnoses. Some longer-term clinical trials looking at pulmonary effects are already underway.
One, run by researchers at the University of Southern California, will look for early biomarkers of cancer among current smokers interested in switching to e-cigarettes over five years; it began earlier this month. Another, run by researchers based in Italy, has for five years followed bladder and stomach cancer rates among vapers, in addition to lung disease, and should finish this December.
In some ways, the dramatic spate of vaping-associated lung disease in the US may help researchers by narrowing their focus. Instead of broadly asking what vaping does to the body, they can focus on what vaping does to the lungs.
PET scans can reveal inflammation in the lungs, for example, that might precede symptoms. Researchers can also look at lung volumes and flow rates in vapers for signs of their overall effects, along with traditional treadmill tests for cardiovascular performance. It could be that some people are predisposed to sudden-onset, severe illness, and others aren’t—but researchers won’t know unless they have more data.
To be sure, all of these studies are going to be complicated by the wide variety of vape cartridges, both legal and on the black market. The challenges of studying and regulating e-cigarettes are beyond an uphill battle—it’s more like up several mountains. If public health specialists have learned anything from the saga of cigarettes, though, it’s that people are going to keep vaping regardless of whether or not scientists study it. Some data are always better than none.