E-cigarettes are a topic of contentious debate. Are they an effective way to wean smokers off of traditional cigarettes? Are their dangers understated? Are they "gateway" devices to tobacco products? In short, all things considered, do e-cigs benefit or denigrate public health?

Earlier this month, a new PLoS ONE study entered into this contentious fray, and its results were fairly damning to claims that e-cigarettes are relatively safe.

To sum the study up: A research team primarily based out of Johns Hopkins University exposed mice to e-cigarette vapor in a small chamber for three hours a day for two weeks so that the levels of cotinine -- a metabolite of nicotine and biomarker for tobacco smoke exposure -- in their blood was roughly similar to the amount of cotinine seen in the blood of e-cig users. They found that mice which reached these levels of blood cotinine after exposure to e-cig vapor had compromised immune systems and were more susceptible to viral and bacteria infections compared to mice only exposed to normal air.

"Despite the common perception that E-cigs are safe, this study clearly demonstrates that E-cig use, even for relatively brief periods, may have significant consequences to respiratory health in an animal model; and hence, E-cigs need to be tested more rigorously, especially in susceptible populations," the researchers concluded.

Their cautionary message was blared across the web, in outlets like Discovery News, The Guardian, the BBC, and The Verge, and was widely shared on social media.

But it seems, however, there's a "little" problem with the study that escaped the scrutiny of early reporting. Mice have vastly higher rates of cotinine metabolism than humans. While the half-life of cotinine in mice is roughly 35 to 50 minutes, the half-life of cotinine in humans is approximately 20 hours! This massive disparity means that mice have to be exposed to much higher amounts of e-cigarette vapor at faster rates in order to reach comparable cotinine levels to humans.

In a detailed comment posted to the original study last Thursday, Drs. Alexey Mukhin and Jed Rose from the Center for Smoking Cessation at Duke University Medical Center pointed out this key tidbit of information, and subsequently calculated, based on the study's methods, how much nicotine the mice were exposed to. Then they translated that amount to a daily exposure for a human, which ended up being between 300mg and 370 mg per day.

That's a lot. To reach that level of nicotine, a human would have to take between 3,600 and 4,600 e-cig puffs per day. But that's just the low-end estimation. As Mukhin and Rose further explained (emphasis mine):

"It should be noted that in our calculations we postulated that the blood for cotinine measurement was taken immediately after the end of 90 min of exposure. In the results section the authors stated that “Blood was collected … within 1 h of the final exposure” but in the methods section they stated that “exposure was assessed by measuring serum cotinine at 1 h after exposure.” If the last statement is correct, because of the fast elimination of cotinine in mice the level of exposure in the study was 3 times higher (2^(60/37.5) ≈ 3) than the above-calculated values. In other words, to obtain the same exposure in humans the e-cig user should take 11000 – 13000 puffs per day. Assuming 8 hours of sleep per day, in order to acquire such a high number of puffs e-cig users would need to take 11-13 puffs per minute and thus practically take an e-cig puff with each breath."

That much vaping would undoubtedly compromise anybody's immune system!

In the wake of their convincing debunking, Mukhin and Rose stated, almost euphemistically, "We recommend that the results of the discussed study should be interpreted with caution and that more studies with more realistic levels of e-liquid exposure should be conducted."

Rose admitted that he does have a patent purchase agreement with Philip Morris International, which has an obvious stake in the e-cig market. But despite the apparent conflict of interest, he and Muhkin's analysis does seem sound.

RealClearScience reached out to Dr. Thomas Sussan and Dr. Shyam Biswal, the lead authors of the study, offering them a chance to respond to Mukhin and Rose's comment. *Sussan replied on March 1st:

For decades, animal studies have provided the basis for human studies, and this current study should provide rationale for future human studies. The mice in our study were allowed to breathe freely inside a chamber containing 20% e-cigarette vapor for 3 hours per day. This exposure is comparable to what a human e-cig user may be exposed to, after accounting for differences in lung capacity, and is well below one puff per breath.

*Article updated to include Sussan's reply

(Image: AP)