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New study in mice shows remarkably little acute toxicity, despite major methodology problems

05, Feb, 2015

By Tom Pruen

A new study published in the journal PLOS ONE, and conducted (surprisingly poorly) by John Hopkins University studied the effect of ecig vapour on mice.  They concluded that ecig use is associated with an increased likelihood of respiratory infection.

Sadly, there are two flaws in their methodology that make this result largely meaningless for human exposure. The first of these appears to be intentional: they exposed the mice to the same amount of ecig vapour as they expected an adult to use. This was done by exposing the mice (in a 2 litre chamber) to one, two second, puff every 10 seconds for 90 minutes, twice a day. This greatly exceeds the values derived from user surveys, which gives a spread of 80 to 200 puffs/day, since their experiment protocol works out to 1080 puffs/day. They also exposed the mice, which would have weighed about 40g each, to the same amount of vapour as that used by an adult consumer (of likely 70Kg -80Kg in weight) – a relative increase in exposure of 2000 times. It was also a whole body exposure.

It is not clear why they considered this an appropriate exposure from which to draw conclusions; this does not approximate the human exposure from an electronic cigarette. A better equivalent model would be using a fog machine to constantly fill a room with vapour, which a consumer would then occupy for several hours.

The lack of acute toxicity this abuse caused in the mice is a good indication of the low acute toxicity of both the nicotine, and the vapour as a whole, despite the next major methodology problem: dry hits.

The method used a rotary device fitted with 6 electronic cigarette cartomisers, each activated once per minute, for a total of 180 times day. The successful delivery from the cartomisers was assessed by detecting the vapour droplets generated, and cartomisers were replaced according to the following criteria:

“E-cig cartridges were replaced each week. The lifespan of each cartridge varied considerably, so they were also replaced whenever the real-time exposure monitor detected a decrease in output of a specific E-cig.”

Each cartomiser would have produced 1 puff per minute for 90 minutes, twice a day, for a total of 180 puffs per day. This suggests that the actual lifespan of a cartomiser would have been in the order of… one day. However, when a cartomiser starts to run dry, this is not always represented in a drop in vapour output, but by a decrease in flavour, and a decrease in the palatability of the vapour.

The upshot of this is that, as well as exposing the mice to the same dose as a human (a scale increase of about 2000 times), they also exposed them to significant amounts of thermal degradation products generated by empty cartomisers. Despite this, many of the mice survived to be infected with respiratory illnesses. It is not surprising that the poor mice did not fare very well at fighting off these infections after such abuse.


It has been pointed out to me that using the mass to estimate dose isn't a very reliable method, and this is actually an idea that has some merit. Although the mice were exposed to the same (or more) vapour than that used by a human consumer, this doesn't neccearily reflect the uptake. It is, without doubt, an oversimplification. Since the mice were in a chamber in which the vapour was part of the ambient enviroment during testing, it's actually quite difficult to directly relate it to human dose.

It's also actually arguable (although this isn't something my critics seem to have picked up on) that for respiratory effects, the concentration is probably more important than dose. Again the concentrations the mice were exposed to are not terribly similar to human exposures, due to the rapidity and long duration of the puff regime. Overall dose does however matter for deposition effects, and with 6 puffs/min with 1.05l/min flow, there is likely to be significant deposition from the vapour/aerosol phase.

It's also been suggested that the similar cotinine levels indicate a similar exposure, but this would, of course, require that no puffs were delivered after the cartomiser was empty, something which is implausible if cartomisers were changed weekly (or indeed anything other than daily). This flaw also raises the very real prospect that the vapour composition is also not comparable to human exposures.

*Edit 2*

It seems that matching the cotinine level is in itself a major methodology problem, as described in a comment to the original article.

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