Researchers call for retraction of NEJM paper showing dangers of e-cigarettes

NEJMResearchers and advocates are calling for the retraction of a 2015 letter in the New England Journal of Medicine that suggested that e-cigarettes are as harmful – if not more than – traditional cigarettes.

The NEJM paper reported that e-cigarettes expose smokers to significant amounts of formaldehyde, which the authors calculated could raise lifetime cancer risk by 5-15 fold compared to the risk for regular smokers. Critics, however, have claimed that to obtain such high levels of formaldehyde, the NEJM authors superheated the vapor from the e-cigs to levels that would create a well-known, acrid puff called a “dry puff.” This sensation, they say, is so terrible that no self-respecting “vaper” would consider repeating it. In other words, allege the e-cigarette supporters, the conditions described in the Letter—which was widely reported—were not relevant to human health.

This week, Addiction published a letter from critics of the NEJM paper, along with extensive supplementary materials, a reply from some of the NEJM Letter authors, and a response letter from the critics.

In their first Addiction letter, “Research letter on e-cigarettes was so misleading it should be retracted,” authors Clive Bates and cardiologist Konstantinos Farsalinos write:

There is a clear risk that extensive and alarming reporting will have persuaded many smokers that there is little to be gained by switching to e-cigarettes, despite the emerging expert consensus that vaping is likely to be at least 20 times lower risk than smoking.

We have documented the flaws in the experiment and cancer risk calculations and in the authors’ reply to criticisms of their work, and written to the editor of NEJM requesting the retraction of the letter.

NEJM editors have declined these requests. NEJM executive editor Edward W. Campion told Retraction Watch:

The research letter reported data on an important issue, namely the presence of a known carcinogen, at least at some device settings, in the vapor from e-cigarettes. We have seen no evidence of scientific misconduct, and we see no grounds for retraction. Disagreements about interpretation of data are not grounds for retraction. If disagreements about interpretation become a reason for retraction, the scientific community will be headed for real trouble.

Indeed, retraction guidelines from the Committee on Publication Ethics (COPE), of which NEJM is a member, lay out specific conditions under which papers should be retracted:

Journal editors should consider retracting a publication if:

• they have clear evidence that the findings are unreliable, either as a result of misconduct (e.g. data fabrication) or honest error (e.g. miscalculation or experimental error)

• the findings have previously been published elsewhere without proper crossreferencing, permission or justification (i.e. cases of redundant publication)

• it constitutes plagiarism

• it reports unethical research

In May, Farsalinos published an additional study in Addiction involving “seven experienced vapers,” with results suggesting that only “dry puff” conditions—i.e., overheated liquid—produced high levels of aldehydes, including formaldehyde.

As part of their latest commentary in Addiction, Farsalinos and Bates include supplementary information that describes earlier requests for a retraction of the NEJM paper “Hidden formaldehyde in e-cigarette aerosols,” including a list of signatories to a letter sent to NEJM.

In April, NEJM published three letters to the editor critiquing the original letter, along with a response from the original authors.

David H. Peyton, professor of chemistry at Portland State University and one of authors on the original NEJM letter, told Retraction Watch:

Bates & Farsalinos requested a retraction after their NEJM correspondence and our reply, and since that quickly failed they got Addiction to accept their request.

No one seems to be arguing with the science; they just seem very much to want the shading of the interpretation to match certain agendas.

E-cig proponents argue on behalf of public health, pointing to suggestions that because e-cigs are less dangerous than regular cigarettes, they should be welcomed. Indeed, proponents add, anyone who opposes e-cigarettes is simply playing into the hands—and marketing plans—of traditional cigarette makers by doing so.

And on the other side are those who see inherent health harms in e-cigarettes, with some data suggesting that while they might not be as bad as traditional smokes, they also aren’t anything to offer to the kiddies at Christmas.

We first learned about this spirited exchange around nicotine-carrying vapors from Michelle Ertischek, director of pharmaceutical risk management at PinneyAssociates, a health consulting firm that provides marketing support for pharmaceutical and healthcare products, among other services.

Ertischek said that PinneyAssociates does

currently provide consulting services to subsidiaries of Reynolds American, Inc., on products related to smoking cessation and tobacco harm minimization and one subsidiary, Niconovum, has purchased an option from JSR, LLC (an LLC consisting of key individuals from PinneyAssociates) for patented nicotine replacement therapy product technology.

As RAI’s subsidiary, RJ Reynolds Vapor Company, markets digital vapor products, we thus would have a legitimate basis and interest in these issues…

One of the company’s vice presidents, Jack Henningfield, and a senior scientific advisor with the company, Saul Shiffman, are among the signatories of the supporting letter that Bates sent to NEJM requesting a retraction.

In the April exchange of critical letters and the author reply in NEJM, only one letter included declarations:

Dr. Nitzkin reports receiving partial funding for some of his tobacco policy work from the R Street Institute. Dr. Farsalinos reports that some of his studies on electronic cigarettes were performed with unrestricted funds provided to the Onassis Cardiac Surgery Center by FlavourArt and Nobacco.

Farsalinos also runs a site called “E-cigarette Research.”

When asked about conflicts of interest, Bates (who did not write any of the April letters published in the NEJM) said that he does “sustainability consultancy,” most recently on opencast coal mining. His work, he said, is “not in this field at all, and I have no conflicts of interest with respect to tobacco, nicotine or pharma industries and have made these disclosure statements to Addiction and to NEJM when I complained to them.”

Bates and Farsalinos are currently listed as a volunteer “advisor to the grants committee” for the E-Research Foundation, whose website says that

The E-Research Foundation is a not for profit organization formed to further advance the scientific study of electronic cigarettes, related products and their use.

In their April letter responding to critiques, the authors of the original NEJM paper said they had no additional conflicts than those declared on the COI form published with the original letter. This form lists funding from, among other sources, Regina M. Dowd and Michael J. Dowd and from Patrick J. Coughlin. Michael Dowd, a former U.S. states attorney, is the founding partner of a law firm that has “led the fight against Big Tobacco since 1991,” according to the firm’s website.

Coughlin is also associated with the firm, and according to his biography on the firm’s website, he was involved in a

a large private RICO trial against the major tobacco companies on behalf of hundreds of thousands of Ohio Taft-Hartley health and welfare fund participants. Mr. Coughlin also helped end the Joe Camel ad campaign, a cartoon ad campaign that targeted children and secured a $12.5 billion recovery for the cities and counties of California in the landmark 1998 state settlement with the tobacco companies.

Also this week in Addiction, Peyton and two of his co-authors provide specific responses to science-related assertions Bates and Farsalinos made about the original NEJM study. They don’t address the retraction question.

Addiction’s editor-in-chief Robert West told Retraction Watch that the rationale for publishing this latest series of Letters was

that science should operate with maximum transparency and it is important for these kinds of discussions to be open to scrutiny by the research community and the public.

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19 thoughts on “Researchers call for retraction of NEJM paper showing dangers of e-cigarettes”

  1. It’s pretty sloppy, agenda focused editing on the part of the NEJM. In fact, the following sentence is a little second amendmenty:

    “Extrapolating from the results at high voltage, an e-cigarette user vaping at a rate of 3 ml per day would inhale 14.4±3.3 mg of formaldehyde per day in formaldehyde-releasing agents.”

    The editors/reviewers probably should have forced them to be explicit and stated:

    “… an e-cigarette user vaping at a rate of 3 ml per day” on high voltage (5.0 V) “would inhale…”

    Additionally, it would have been fair and responsible to state the cancer risk prediction for the low voltage setting based on their data. Retraction worthy? No. Poor reviewing/editing leading to a biased appearing article? Yes.

  2. All very well, but those addicted to tobacco would not find this (the original NEJM paper and the ensuing wrangling) very edifying.

    Can someone without an ax to grind provide the real-world truth about regular cigarettes versus e-sigs?

      1. Thanks for the link to the UK information. Good stuff.

        The UK Department of Public Health does have an axe to grind, as they spend taxpayer money on health maintenance. Their axe grinding therefore is to alert the UK government agencies that oversee delivery of public health about problems that could have a big impact on costs to the UK health delivery system. All that said, the UK reports do not suggest that e-cigarettes present any substantial risk, certainly as compared to cigarettes.

        I’ll take the UK reports over all the materials in the USA where corporate profits tend to sway the debates excessively.

        From page 78 of the report:

        There is no indication that EC users are exposed to dangerous levels of aldehydes.”

        They do review the NEJM study and its problems.

    1. Axe grinding aside, the only real research that has been done on aldehyde production in electronic cigarettes is the work done by Dr Farsilinos. In his research he carefully monitored the power used on the heating coil to find out how much of these chemicals are produced at temperatures they are really used at. Just because your toaster can burn toast and make a carcinogenic breakfast doesn’t mean that there’s a problem with eating toast. The so called research that is being criticised is just as rediculous as this example. It’s frustrating to hear of someone going back to a two pack per day habit because of this misinformation.

  3. The real-world about e- versus regular cigarettes is that e-cigarettes likely present a far health lower risk. However, there are credible health professionals who are either for and or against e-cigarettes. Those against them worry that because they lack the negative stigma of smoked cigarettes, e-cigarettes could become extremely popular. In addition, whereas the risks of smoked cigarettes are known in-detail, our knowledge of the long-term risks of e-ones is limited.

    Others argue that e-cigarettes will allow smokers to stop an incredibly dangerous habit.

    As a toxicologist, because the material isn’t burned, I would expect lower risks from e-cigarettes. However, I think arguments from those both for & against e-cigs have merit.

    The formaldehyde issue is more of a red herring. Formaldehyde forms as a natural part of your metabolism. Your blood typically contains ~3 mg/l of it and the body metabolizes ~69 mg formaldehyde/MINUTE(!). It’s always part of your breath, your blood and in tissues. (See Mitkus et al., 2012 from USFDA).

    In contrast, using models the US Env Protection Agency sees formaldehyde as an incredibly incredibly dangerous carcinogen. Notably, they had proposed an airborne level that would be 1/50th to 1/500th of the natural formaldehyde level in your breath. At a Society for Risk Analysis meeting, a regulatory official from Texas gave a superb talk on the absurdity of this. If you follow EPA’s thinking (or lack thereof), the best way to avoid cancer from formaldehyde is to stop breathing.*

    Hence, considering that you naturally have 3 mg formaldehyde/l in your blood and that you are metabolizing 69 mg/minute – every minute all day, an additional 14 mg/DAY from inhalation is tiny by comparison.

    *EPA’s number comes from a blind use of models without assessment of the validity or real-world relevance.

    1. Your argument neglects issues surrounding the sensitivity of target tissues to high local formaldehyde concentrations, and also fails to address the significant pro-fibrotic potential of chronic, pulsatile exposure to high concentrations of vape juice contaminants. In other words, it’s a red herring.

      To me, the real danger of e-cigs is not from any dissolved or de novo generated toxicants, it’s the inherent “not a bug, a feature” socioeconomics of e-cigs. Specifically, young low-information consumers (i.e., “inexperienced vapers”) are likely to begin vaping under the carefully nurtured false pretense that vaping is a safe activity. Even the best of them will be at high risk for nicotine addiction. For many, when the real world eventually rises up and slaps them in the face, e-juice or other “safe” tobacco alternatives will become prohibitively expensive. What then? Tobacco, of course.

      Game, set, and match to the geniuses from Durham. It’s depressing, really.

      1. It’s the old “gateway” analogy that refuses to die. By this logic one should not permit the drinking of water because it is just a couple of steps away from becoming an alcoholic.

        1. No. Gateway theory implies a progression from less- to more intoxicating substances, most often with an accompanying increase in addictive potential and higher risk for morbidity. I am talking about a change in delivery system for the SAME addictive substance, nicotine. Given the increased profit margins and tighter market control associated with rolled tobacco, I guess e-juice could be considered a gateway to increased market share for Big Tobacco, but I’m pretty certain you weren’t going there.

          Meanwhile, it is well-established that Big Tobacco markets to children to create their next generation of customers/addicts. This “want some candy little girl?” approach has been around since I was a kid in the 1970’s and UST created their Happy Days ->Skoal ->Copenhagen addiction enhancement continuum. Candy flavored flavored e-juice is the obvious evolution of Joe Camel’s deadly legacy.

          My first high school class mate to succumb to this strategy was dipping Copenhagen by 9th grade, lost his lower jaw to cancer in 1992 and was dead from it 4 years later. I suspect there are several dozen others from my class who are at high risk of the same fate today. Middle school kids in my neighborhood are simply going to the local convenience store to snap up 5mL vials filled with made-in-China mystery liquids, “safely” and dutifully inhaling them deeply into their lungs for the sake of looking cool. Ka-CHING goes the cash drawer.

          Pure evil.

        2. This is not the same logic at all. There is no alcool in water. But there is nicotine in E-Cig. At start, the aim of E-cig, is to reduce progressively the amount of nicotine and then stop smoking (like nicotine patch in the old days). But nowadays, some people are starting smoking E-cig because it migt be deemed safe (opposed to regular smoking), and not to actually try to stop smoking. E-cig must presented as a medical product containing potential dangerous substance (nicotine and maybe other thing) meant to be taken to reduce addiction, not some fancy vapo to look cool.

      2. The body is chronically exposed to high local formaldehyde concentrations from natural metabolism. Do the math. 69 mg/min min from natural metabolism vs 14 mg/DAY from e-cigarettes. It’s not 14 mg in 1 vap, it’s 14 mg/day.

  4. Not all e-cigs have nicotine in them. In the USA, the states of Washington, Oregon and Colorado, and the District of Columbia, have recently legalized the posession, use, and sale of marijuana, available in e-cig form. The Supreme Court of Canada recently ruled that medical marijuana users should have access to marijuana in delivery systems other than a burning cigarette. So understanding e-cig health issues, beyond the issue of what the e-cig is advertised as containing, is important.

  5. We wish to point out an error in the recent posting on this site regarding the recent comments on our NEJM Letter.

    In particular, the 1st paragraph of the posting states that our NEJM Letter “suggested that e-cigarettes are as harmful – if not more than – traditional cigarettes.” This is wrong.

    Our Letter only compared the predicted formaldehyde-related lifetime cancer risk for chronic use of e-cigarettes vs. that of formaldehyde for chronic use of conventional cigarettes.

    There are many carcinogens present in tobacco smoke and in e-cigarette vapors, and so a calculation/prediction of the total risk would have required complete analyses for typical tobacco smoke and typical e-cigarette vapors for all carcinogens, including those known & unknown. Obviously, such analyses do not exist.

    Further, we only found a higher relative risk due to formaldehyde when the commercial e-cigarette system we tested was used at a higher power setting; a lower power setting produced much lower relative risk from formaldehyde and its related products, produced by the e-cigarette as compared to conventional cigarettes. This we also reported in the NEJM Letter.

    1. Thank you for your comment. We are leaving the first sentence of this story as it is because it reflects the conclusions of the NEJM Letter, particularly the last paragraph that makes a direct comparison between e-cigarettes and long-term cigarette smoking (one pack per day) and suggests a 5- to 15-fold greater lifetime cancer risk for e-cigarettes, i.e., suggests greater harm from the former:

      “If we assume that inhaling formaldehyde-releasing agents carries the same risk per unit of formaldehyde as the risk associated with inhaling gaseous formaldehyde, then long-term vaping is associated with an incremental lifetime cancer risk of 4.2×10−3. This risk is 5 times as high (as compared with the risk based on the calculation of Miyake and Shibamoto shown in Figure 1), or even 15 times as high (as compared with the risk based on the calculation of Counts et al. shown in Figure 1) as the risk associated with long-term smoking. In addition, formaldehyde-releasing agents may deposit more efficiently in the respiratory tract than gaseous formaldehyde, and so they could carry a higher slope factor for cancer.”

      1. Again, the context of what we said in the paper was all about formaldehyde and nothing else. That goes for Figure 1, which you quote above (from us), as well as in the papers we cited. The quote you have given should not be read without its context, and we hope that the readers keep in mind that all we were reporting on was formaldehyde, and that to imply anything else would be misleading; many others have fallen into this. Thank you for allowing us to clarify this point.

    2. Considering that all people exhale formaldehyde, which would seem to indicate that its cancer-causing properties are quite mild compared to other things in smoke, such narrow phrasing appears, to an outsider, to be calculated to cause most people to jump to exactly the conclusion that it is more cancer risk than cigarettes. If such a conclusion was not intended, more context would be expected to be provided in the original letter.

  6. A couple of other recent studies on harmful effects of vaping liquids and their contents (especially polyaromatic hydrocarbons used as flavoring agents), are here…

    There are also anecodota that the advertised temperatures achieved inside vaping devices (especially cheaper ones coming from a certain nation synonymous with crappy electronics) can vary widely. As scientists, are we really willing to believe that a $3 device bought at a gas station has exquisite control over such parameters? Have you ever bought a laser pointer at a flea market? That’s about the level of quality control we’re talking about here, and it doesn’t even include the counter-culture dedicated to hacking these devices!

    The notion that all vaping is equal (and equally safe), as seems to be pushed by this call for retraction, is not representative of reality in the Wild Wild West of the vaping market.

    1. Actually, they are not exquisitely controlled, they are simply not powerful-enough to cause the formaldehyde problem. It is like claiming a bicycle cannot be trusted to have a speed governor exquisite-enough to keep it from outpacing a formula racing car.

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