On 2016 Aug 30, Peter Hajek commented:

The length of exposure would be relevant if the dosing was comparable, but the damage to mice lungs was caused by doses of nicotine that were many times above anything a human vaper could possibly get. It is the dose that makes the poison. Many chemicals produce damage at large enough doses while lifetime exposure to small enough doses is innocent.

To justify the conclusions about toxicity of vaping, the toxic effect would need to be documented with realistic dosing, and then shown to actually apply to humans (who have much better nicotine tolerance than mice).

I agree that mice studies with realistic dosing could be useful, though data on changes in lung function in human vapers would be much more informative; and I do appreciate that the warnings of risks in the paper were phrased with caution.

On 2016 Aug 30, Robert Foronjy commented:

The study is NOT reassuring to e-cigarette consumers. On the contrary, it shows that nicotine exposure reproduced the lung structural and physiologic changes present in COPD. These changes occurred after only four months of exposure. Even adjusting for the differences in lifespans, this exposure in mice is much briefer than that of a lifelong e-cigarette consumer. I do agree, however, that carefully conducted studies are needed to determine whether there is a threshold effect of nicotine exposure.

On 2016 Aug 29, Peter Hajek commented:

Thank you for the explanation. The exposure however was not equivalent. Mice have much faster nicotine metabolism than humans which means that nicotine exposure in mice must be many times higher than in humans to produce the same blood cotinine levels. See the reference below that calculated that mice with comparable cotinine levels were exposed to an equivalent of at least 200 cigarettes per day. In addition to this, mice also have much lower tolerance to nicotine than humans which means that their organs would be much more severely affected even if the levels were comparable.

On 2016 Aug 29, Robert Foronjy commented:

Mortality was not reported in the manuscript since no deaths occurred. The exposure was well tolerated by the mice and no abnormal behavior or physiologic stress was noted. At the time of euthanasia, all the internal organs were grossly normal on exam. Cotinine levels in the mice were provided in the study and they are similar to what has been documented in humans who vape electronic cigarettes. We agree that both the mice and human consumers are exposing their lungs to toxic concentrations of nicotine. This is one of the essential points that is expressed by the data presented in the manuscript.

On 2016 Aug 26, Peter Hajek commented:

The authors propose a hypothesis that deserves attention, but the study findings need to be interpreted with caution.

The mice were severely overdosed with nicotine, up to the lethal levels for mice, and a huge amount above what any human vaper would get - see this comment on a previous such study:

http://journals.plos.org/plosone/article/comment?id=info:doi/10.1371/annotation/5dfe1e98-3100-4102-a425-a647b9459456

The report does not say how many mice were involved and if any died during the experiment; and whether effects of nicotine poisoning were detected in other organ systems. This could perhaps be clarified.

Regarding the relevance to human health, nicotine poisoning poses normally no risk to vapers or smokers because if nicotine concentrations start to rise above their usual moderate levels, there is an advance warning in the form of nausea which makes people stop nicotine intake long before any dangerous levels can accrue. (Mice in these types of experiments do not have that option).

The study actually provides a reassurance for vapers, to the extent that mice outcomes have any relevance for humans, in that in the absence of nicotine overdose, chronic dosing with the standard ingredients of e-cigarette aerosol (PG and VG) had no adverse effects on mice lungs.

Peter Hajek

On 2016 Aug 26, Peter Hajek commented:

The authors propose a hypothesis that deserves attention, but the study findings need to be interpreted with caution.

The mice were severely overdosed with nicotine, up to the lethal levels for mice, and a huge amount above what any human vaper would get - see this comment on a previous such study:

http://journals.plos.org/plosone/article/comment?id=info:doi/10.1371/annotation/5dfe1e98-3100-4102-a425-a647b9459456

The report does not say how many mice were involved and if any died during the experiment; and whether effects of nicotine poisoning were detected in other organ systems. This could perhaps be clarified.

Regarding the relevance to human health, nicotine poisoning poses normally no risk to vapers or smokers because if nicotine concentrations start to rise above their usual moderate levels, there is an advance warning in the form of nausea which makes people stop nicotine intake long before any dangerous levels can accrue. (Mice in these types of experiments do not have that option).

The study actually provides a reassurance for vapers, to the extent that mice outcomes have any relevance for humans, in that in the absence of nicotine overdose, chronic dosing with the standard ingredients of e-cigarette aerosol (PG and VG) had no adverse effects on mice lungs.

Peter Hajek

On 2016 Aug 29, Robert Foronjy commented:

Mortality was not reported in the manuscript since no deaths occurred. The exposure was well tolerated by the mice and no abnormal behavior or physiologic stress was noted. At the time of euthanasia, all the internal organs were grossly normal on exam. Cotinine levels in the mice were provided in the study and they are similar to what has been documented in humans who vape electronic cigarettes. We agree that both the mice and human consumers are exposing their lungs to toxic concentrations of nicotine. This is one of the essential points that is expressed by the data presented in the manuscript.

On 2016 Aug 29, Peter Hajek commented:

Thank you for the explanation. The exposure however was not equivalent. Mice have much faster nicotine metabolism than humans which means that nicotine exposure in mice must be many times higher than in humans to produce the same blood cotinine levels. See the reference below that calculated that mice with comparable cotinine levels were exposed to an equivalent of at least 200 cigarettes per day. In addition to this, mice also have much lower tolerance to nicotine than humans which means that their organs would be much more severely affected even if the levels were comparable.

On 2016 Aug 30, Robert Foronjy commented:

The study is NOT reassuring to e-cigarette consumers. On the contrary, it shows that nicotine exposure reproduced the lung structural and physiologic changes present in COPD. These changes occurred after only four months of exposure. Even adjusting for the differences in lifespans, this exposure in mice is much briefer than that of a lifelong e-cigarette consumer. I do agree, however, that carefully conducted studies are needed to determine whether there is a threshold effect of nicotine exposure.

On 2016 Aug 30, Peter Hajek commented:

The length of exposure would be relevant if the dosing was comparable, but the damage to mice lungs was caused by doses of nicotine that were many times above anything a human vaper could possibly get. It is the dose that makes the poison. Many chemicals produce damage at large enough doses while lifetime exposure to small enough doses is innocent.

To justify the conclusions about toxicity of vaping, the toxic effect would need to be documented with realistic dosing, and then shown to actually apply to humans (who have much better nicotine tolerance than mice).

I agree that mice studies with realistic dosing could be useful, though data on changes in lung function in human vapers would be much more informative; and I do appreciate that the warnings of risks in the paper were phrased with caution.