The main objective of non-clinical studies is to determine the potential safety of ENDS in the short and long term by detecting potential target organs for toxicity, identifying safe dosage schemes and identifying parameters for clinical safety monitoring.
At the time of this writing, eight non-clinical studies had evaluated ENDS.5, 6, 14, 20–24
A study carried out by the FDA on two brands of ENDS found that they contained carcinogens, namely tobacco specific nitrosamines (TSNA), albeit at lower levels than in tobacco cigarettes and in similar levels to those found in nicotine medications25, 26
; that similarly labelled cartridges emitted markedly different amounts of nicotine with each puff (27–43 μg nicotine/100 ml puff); and that nicotine was detected in cartridges labelled as containing no nicotine.12
Moreover, one cartridge contained 1% diethylene glycol, a toxicant implicated in mass poisonings.27, 28
The second non-clinical investigation, conducted by a private company funded by an ENDS manufacturer, showed that the labelling of different ENDS approximately reflected their actual nicotine content.20
TSNAs and polycyclic aromatic hydrocarbons (potent, locally acting byproducts of the incomplete combustion of organic material) were detected in concentrations similar to those existing in nicotine medications.20, 26
Unlike tobacco cigarettes, the ENDS tested did not appear to interfere with monoamine oxidase enzyme A and B activity; a process involved in the regulation of mono-aminergic neurotransmitters that plays a pivotal role in mood and behaviour. Tests did not show detectable levels of heavy metals, propylene oxide and ethylene oxide, and found that ENDS probably incorporate lower concentrations of carcinogens than tobacco cigarettes.20
These results accord with the findings of the third study of no measurable levels of polycyclic aromatic hydrocarbons in ENDS aerosols.23
The fourth study compared the smoking properties of tobacco cigarettes and ENDS.5
Results showed that stronger puffing was required to smoke most ENDS brands than tobacco cigarettes. Moreover, the puff strength had to be increased and the aerosol density decreased as the puff number increased, while smoking characteristics, such as vacuum and density, varied considerably within and between ENDS brands.5
The potentially adverse effects on lungs if strong suction is required to smoke ENDS needs to be documented in the long term.5
The fifth study found hazardous aldehydes in a Japanese brand of ENDS (formaldehyde: 8.3 mg/m3
, acetaldehyde: 11 mg/m3
and acrolein: 9.3 mg/m3
) in concentrations respectively 1.2, 137 and 30 times less than from the tobacco cigarette brands also tested.22
However, these concentrations largely exceed international maximum exposure limits for formaldehyde (2.5 mg/m3
) and acrolein (0.8 mg/m3
Glycerol is used to improve mist generation, but if heated to 280°C can produce acrolein, a potentially critical toxicant in ENDS vapour, and other ENDS brands should be tested for it.
The sixth study tested the nicotine content in 2 brands of ENDS cartridges (3.2–4.1 mg/cartridge) and in the vapour of 1 brand (1 μg per puff for puffs 1–10, then <0.3 μg per puffs for puffs 11–50).14
This level was far below the levels found by FDA scientists,12
and suggests malfunctioning of ENDS, as the authors found.
The seventh study found that ENDS advertised as containing E-Cialis did not contain tadalafil (ie, Cialis) but contained its analogue amino-tadalafil, and that ENDS advertised as containing E-Rimonabant contained rimonabant and an oxidative impurity of rimonabant.6
These products contained nicotine, even though they were advertised as containing no nicotine.6
The eighth study evaluated five brands of ENDS and found that fluid leaked out of most cartridges, that the labelling of cartridges was poor and that most packs lacked warning information about potential risks.24
Thus, although some non-clinical research has been conducted that is relevant to predicting health effects in humans, much work remains to be done. For example, tests of pharmacokinetics and toxicokinetics should be conducted in animals (including absorption, distribution, metabolism and excretion of all compounds in ENDS vapour), and their toxicology and carcinogenicity should be characterised using standard tests of cytotoxicity and mutagenicity. Studies should also be conducted to explore the likely health effects of long-term ENDS use. The effect of good manufacturing practice in improving quality and minimising hazardous impurities needs to be assessed, and the effect of higher-voltage modified ENDS brands on hazardous volatiles should be monitored. Finally, there is a need to describe the variety of ENDS brands, models and refill liquids (‘juice’), and their evolution over time.