publication date: Oct. 18, 2019

E-cigarette smoke associated with lung cancer, inflammation, as federal agencies respond to vaping deaths

By Alex Carolan and Matthew Bin Han Ong

E-cigarette smoke, like tobacco smoke, may, in fact, cause cancer, new studies suggest.

According to one just-reported study, mice exposed to e-cigarette smoke were five times more likely to develop lung cancer, and 10 times more likely to develop precancerous lesions of the bladder.

Another study found that a specific vaping component led to lung inflammation, a result of short-term e-cigarette use on the lungs. Inflammation often presages medical conditions that include bronchitis, asthma, heart disease, and cancer.

Peter Shields, thoracic oncologist at The Ohio State University Comprehensive Cancer Center and a study author, said this study is the first experimental demonstration of an impact of e-cigarette use on inflammation in the human lung among never-smokers.

Researchers specifically studied e-cigarette users who were healthy, non-smokers. This is an important aspect of the study design as e-cigs were developed originally to be a smoking cessation tool, but have since been widely adopted by non-smokers.

“The rise in electronic cigarette use is quickly becoming a public health crisis that the scientific community is rushing to address so that the FDA has the information it needs to regulate this industry to protect public health,” Shields said in a statement.

The e-cigarette smoke mice study was published Oct. 7 in Proceedings of the National Academy of Sciences. The inflammation pilot study was published Oct. 16 in the journal Cancer Prevention Research.

“This work and other mouse studies show that e-cigarette aerosols have adverse health effects,” Ron Johnson, program director of the DNA and Chromosome Aberrations Branch in the Division of Cancer Biology at NCI, said to The Cancer Letter. “E-cigarette aerosols are known to contain other carcinogens (e.g. heavy metals and formaldehyde) and it is unclear how these carcinogens and other constituents may contribute to toxicity. A recent publication has shown that e-cigarette aerosols without nicotine disrupt normal lung function and cause lung tissue damage in exposed mice.”

These new studies are being reported at a time when young adults are smoking more e-cigarettes and when a string of vaping-related deaths often associated with e-cigarettes containing THC has brought national attention to the issue. FDA, NIH, the Centers for Disease Control and Prevention, and state and local departments are investigating a multi-state outbreak of lung injury associated with the use of e-cigarettes.

The new vaping-related illness recently received a name—“e-cigarette, or vaping, product use associated lung injury”—and acronym EVALI. As of Oct. 8, CDC has received reports of 1,299 cases of EVALI, including 26 deaths, which occurred in 21 states.

Recent studies show that while fewer teenagers are using conventional cigarettes, more are using e-cigarettes.

Fewer eighth, 10th, and 12th graders are using conventional cigarettes, according to a study from the National Institute on Drug Abuse. In eighth graders, 13% reported using cigarettes in 2015, compared to about 9.1% in 2018. In 10th graders these rates fell from 19.9% to 16%, and in 12th graders these fell from 31.1% to 23.8%, respectively (The Cancer Letter, Sept. 27).

Though cigarette use fell from 8.1% to 5.5% overall, vaping rates increased from 21% to 27%, according to CDC’s Tobacco Survey published in early 2019.

E-cigarettes contain a lower number of toxic substances than conventional cigarettes, but their long-term health effects are not yet clear, the National Academies of Sciences, Engineering, and Medicine concluded in a report published Jan. 23, 2018 (The Cancer Letter, Jan. 26, 2018).

Tobacco companies are losing customers of products that involve burning tobacco and are increasingly emerging as dominant players in the market for alternative products, which include electronic cigarettes and similar devices. Meanwhile, mainstream tobacco control organizations say that while new products may present safer alternatives, their prevalence and harms must be studied.

The NASEM report does not say, “e-cigarettes are saving lives,” David Eaton, chair of the NASEM committee that authored the report, said at the time (The Cancer Letter, Feb. 9, 2018).

Vaping-related illness, where most patients report having used e-cigarettes containing THC, has prompted former FDA Commissioner Scott Gottlieb  to examine the impasse on federal regulation of marijuana.

“The Justice Department remains unwilling or unable to enforce existing federal laws, even on matters not specifically mentioned by the congressional budget riders,” Gottlieb wrote in a commentary for the Wall Street Journal. “The feds are also reluctant to regulate this market. Exerting partial oversight over the riskiest products would effectively signal the end of federal marijuana prohibition. Justice officials see such a step as politically controversial, even as it becomes clear that a blanket ban is no longer politically practicable.

“The result is an impasse. Federal agencies exert little oversight, and regulation is left to a patchwork of inadequate state agencies. The weak state bodies sanction the adoption of unsafe practices such as vaping concentrates, while allowing an illegal market in cannabis to flourish.

“Any federal regulation would need to be backed up with oversight and vigorous enforcement to keep a black market from continuing to flourish and causing these lung injuries,” Gottlieb wrote. “Expanding access to marijuana for legitimate medical research would allow more scientists either to validate or dispel the myriad claims about marijuana’s therapeutic usefulness. Whatever medical claims are made should be subject to the same federal standards applied to other drugs.

“The protracted hand-wringing over federal cannabis policy must stop,” Gottlieb said. “The tragic spate of fatalities related to vaping of pot concentrates means the time has come for Congress and the White House to stop blowing smoke and clear the air.”

At this time, FDA and CDC have not identified the cause or causes of the lung injuries among EVALI cases, and the only commonality among all cases is that patients report the use of e-cigarette, or vaping, products.

 

CDC, FDA statements

“CDC recommends that persons should not use e-cigarette, or vaping, products that contain tetrahydrocannabinol,” CDC officials said in an Oct. 11 interim guidance for health care providers. “At present, CDC recommends persons consider refraining from using e-cigarette, or vaping, products that contain nicotine. Irrespective of the ongoing investigation, e-cigarette, or vaping, products should never be used by youths, young adults, or women who are pregnant. Persons who do not currently use tobacco products should not start using e-cigarette, or vaping, products.

“This outbreak might have more than one cause, and many different substances and product sources are still under investigation,” the CDC interim guidance states. “To date, national and state data suggest that products containing THC, particularly those obtained off the street or from other informal sources (e.g., friends, family members, or illicit dealers), are linked to most of the cases and play a major role in the outbreak. Therefore, CDC recommends that persons should not use e-cigarette, or vaping, products that contain THC.”

FDA, too, has issued a public health warning that uses similar language.

“A majority of the samples tested by the states or by the FDA related to this investigation have been identified as vaping products containing THC,” the agency states in the Oct. 4 warning. “Through this investigation, we have also found most of the patients impacted by these illnesses reported using THC-containing products, suggesting THC vaping products play a role in the outbreak.

“Do not use vaping products that contain THC. Do not use vaping products—particularly those containing THC—obtained off the street or from other illicit or social sources. Do not modify or add any substances, such as THC or other oils, to vaping products, including those purchased through retail establishments.”

The signals coming from the mice study are concerning, researchers say. Mice exposed to smoke for about a year developed cancer and precancerous lesions at a significantly higher rate.

“What we have found is that mice exposed to e-cigarette smoke for 54 weeks developed lung cancer and precancer change[s] in bladder tissue,” the study’s first author Moon-Shong Tang, professor in the Department of Environmental Medicine, Department of Medicine, and Department of Pathology at NYU Langone Health, said to The Cancer Letter.

The mice were separated into three groups:

  • Group one (45 mice) was exposed to ECS generated from e-juice, containing 36 mg/mL of nicotine dissolved in isopolypropylene glycol and vegetable glycerin at a one-to-one ratio.

  • Group two (20 mice) was exposed to isopolypropylene glycol and vegetable glycerin (Veh), the ingredients found in e-juice. This group did not include nicotine.

  • Group three (20 mice) was exposed to filtered air.

Most notably, the study found that:

  • Nine of 40 (22.5%) mice from the first group exposed to ECS for 54 weeks developed lung adenocarcinomas,

  • Twenty-three of these 40 (57.5%) mice developed bladder urothelial hyperplasia. 

Comparatively:

  • Lung cancer jumped from 5.6% to 22.5% in the control group versus the ECS group. None of the mice in the Veh group developed lung tumors.

  • Bladder urothelial hyperplasia jumped from 6.3% in the group exposed to Veh versus 57.5% of mice in the ECS group. None of the control group developed bladder urothelial hyperplasia.

“That’s a precancerous change—a very high percentage,” Tang said of the mice who developed hyperplasia. “Bladder hyperplasia is a jump from 6% jump to almost 60%. That’s a ten-fold jump.”

The Tang et al. study is an important initial finding indicating that exposure of mice to e-cigarette aerosols containing nicotine may be carcinogenic, said NCI’s Johnson.

“This study used a small number of animals, and strong statistical significance for lung tumors was achieved only by combining control groups,” Johnson said to The Cancer Letter. “A larger effect was seen for bladder hyperplasia but it’s not known whether this early stage of premalignancy would progress to more advanced stages.

“As the authors acknowledge, a larger size animal study is needed to determine how well these preliminary results repeat. While the amount of aerosol exposure over the course of the mouse study may have been much higher than the amount in typical e-cigarette users, the study does suggest that e-cigarette aerosols could be carcinogenic.”

In a 2017 study, Tang and colleagues found that nicotine induces DNA damage and inhibits DNA damage repair in human cells. The most recent study concludes that nicotine, though widely thought to be non-carcinogenic, in addition to e-cigarette smoke, “may induce lung and bladder cancer.”

“Nicotine getting into the cell transforms and becomes nitrosamine. And nitrosamine, further metabolized, becomes a DNA damaging agent, and DNA damage. All of these effects are mediated by the nitrosamine. That’s a crucial step,” Tang said.

“The human, the policy-maker, has to consider this very seriously. Because the mechanism, the chemical from nicotine, causes lung cancer in mice.”

 

Implications for cancer

Former FDA Commissioner Gottlieb said the animal study attempts to isolate nicotine’s effects on cancer, and “is subject to extensive prior studies, many more rigorous than this one,” he wrote in a tweet.

As to the risk from vaping, Gottlieb said that “it should be assumed that vapor alone causes some lung injury, a reason why these products should be used by adults and be positioned as an alternative for currently addicted adult smokers. They are less harmful than cigarettes, but they are not safe.”

Anthony Alberg, professor and chair in the Department of Epidemiology and Biostatistics at the University of South Carolina Arnold School of Public Health, said this research is important to document the potential for harm in humans.

“Eventually we need human data to characterize specifically the human effects. But these studies are particularly important now when we don’t have that kind of human evidence,” Alberg said to The Cancer Letter.

It took decades to demonstrate that tobacco smoke in traditional combustible cigarettes causes cancer in humans, resulting in the landmark 1964 Surgeon General’s report that linked smoking with lung cancer and heart disease.

Alan Blum, director of The University of Alabama Center for the Study of Tobacco and Society, said researchers and policymakers don’t need to wait that long to act on e-cigarettes.

“I don’t think we need to wait for three generations to see whether this is going to cause even a fraction of the problems that smoking has taken,” Blum said to The Cancer Letter. “I don’t think an infinite number of studies are ever going to show that vaping is worse than cigarette smoking, but what we’re finding seems to surprise a lot of people that it’s worse than just inhaling water vapor or glycerin vapor and some flavorings and some nicotine.”

Blum said it’s harmful to continue to defend these products as part of a harm-reduction strategy. The best way to quit smoking is to go cold turkey, he said.

“Although it’s very early, and, frankly, sad to say, we do need more research, I think it’s caused me to stop and say, ‘Why are we wasting our time defending e-cigarettes because of the industry’s claim [about harm reduction]?’” Blum said.

The American Cancer Society agrees that more research is needed.

“In this study, mice who inhaled e-cigarette aerosol, including nicotine, developed more lung cancers than expected. It is unclear what this study means for people who use nicotine-containing e-cigarettes, including JUUL products, which always contain nicotine,” said Victoria Stevens, scientific director of epidemiology research at ACS.

“Firm conclusions about cancer risk in people cannot be made from only one animal study—more research in both animals and people is needed,” Stevens said. “The bottom line is that we already know e-cigarette use should not be considered safe. The best choice is to avoid using any tobacco product, including e-cigarettes.”

Tobacco companies have been funding research ventures into harm reduction. Philip Morris, for example, committed $1 billion over 12 years through the Foundation for a Smoke-Free World, prompting critics to describe the venture as a cynical strategy to coerce scientists and market new ways of consuming tobacco (The Cancer Letter, Oct. 6, 2017).

Alas, the talk of the danger of e-cigarettes may contribute to their allure.

“If you keep on saying how dangerous it is, they love it,” Blum said. “The manufacturers really sort of love it because that feeds into the danger point of view as opposed to the stupid point of view.”

Copyright (c) 2019 The Cancer Letter Inc.