Electronic Nicotine Delivery Systems (ENDS)

Electronic nicotine delivery systems (ENDS) are gaining in popularity in recent years. As a broad overview, an ENDS unit is a battery-powered device which heats up a metal resistive coil to produce an inhalable vapour of an e-liquid, without tobacco combustion. This e-liquid typically consists of Propylene Glycol (PG) and Vegetable Glycerin (VG) along with optional nicotine or flavourings. Originally designed to provide a perceived safer alternative and cessation tool for cigarette addition, the clinical risks associated with ENDS use, effectiveness for smoking cessation and overall toxicity are highly controversial.

ENDS mechanical designs are evolving over time to both deliver nicotine more efficiently and to maximize flavour. Since its emergence, both the design and the constituents (vehicle, nicotine concentration and flavouring) are highly variable with very little regulation.  Figure 1 describes the progression of the different generations of ENDS technology along with the new Pod-based devices, including the popular JUUL design.

Common to all generations of ENDS, is the use of PG/VG as a vehicle, along with nicotine and flavouring. Due to the vast difference in design and vape generation between ENDS devices, there is a large variability in the constituents of solvent used, along with the vapour produced, impacting particulate size and distribution, and ultimately affecting deposition. Studies show that power and temperature of ENDS units can have a significant effect on the size of the particulate generated from the vapour. For instance, an increase in power led to an increase in particle size generated and high temperature modes yielded the smallest particulate size1. Many hazardous biproducts of e-vapour have been identified as cardiovascular toxins such as Acetaldehyde, acrolein and formaldehyde2 along with heavy metal traces 3.

JUUL neon sign

There has been a dramatic rise in the use of the JUUL ENDS device over the past few years, particularly in the younger generation of previously non-smokers. The appeal of the JUUL initially is attributed from its compact nature and discrete design resembling a USB memory stick. The JUUL offers the highest nicotine content due to its integration in protonated salts rather than free-base in a PG/VG solution. The content of nicotine benzoate salts in JUUL pods can reach as high as 60 mg/mL, when compared to the classic first to third generation of ENDS ranging from 0-30 mg/mL. Despite this high level of nicotine, JUUL aerosols are perceived as being less abrasive and irritating to the user’s airways as a consequence of nicotine salts.

Additionally, the legalization of medical and recreational cannabis has enabled synthetic cannabinoids, cannabinol (CBD) and psychoactive Tetrahydrocannabinol (THC) to breach into the ENDS market for efficient cannabis delivery.

Clinical data has shown that ENDS delivery of cannabis, when compared to smoked cannabis leaf, leads to quicker absorption, greater cognitive impairment and overall psychomotor drug effect4. Not only is this dangerous due to the rapid absorption and exacerbation of behavioural consequences, but these black-market cannabis ENDS are highly unregulated.

The Center for Disease Control (CDC) and Food and Drug Administration (FDA) recently reported the presence of vitamin E acetate used in some of these ENDS units that led to e-cigarette, or vaping, product use associated lung injury (EVALI) and EVALI deaths. Vitamin E acetate is used in illegal-market products as both a thickening agent and as a THC oil diluent. While Vitamin E is identified as one of the culprits of EVALI, further diluents and fillers with potential toxic effects have yet to be identified.

Since ENDS units have only really increased in global popularity over the past 5 years, there is no conclusive, long-term clinical data yet following chronic exposures to e-cigarette aerosols and its constituents. There is an outpouring of resources and funding available to create relevant, translatable pre-clinical models of ENDS exposure in order to further delve into the potential toxicity.

To best create these translatable pre-clinical animal models, it is necessary to standardize factors such as puff frequencies and topographies, exposure concentrations, e-liquid composition and device generation/brand. Using the inExpose system, researchers create accurate and reproducible models of smoke exposure using automated generation of vapour, customizable puffing volumes and frequencies. A recent study5 by Dr. Crotty Alexander (2019) used the inExpose whole body exposure system to investigate the effects of daily JUUL intake on systemic inflammation. This lab exposed mice three times daily, for 20-minute expose sessions, to JUUL mango or mint flavouring led to significant inflammatory and weight changes in simply 4-weeks. This study along with other murine exposure studies show significant, alarming changes at the cell and protein levels following even acute exposures.

Further, there are groups working with in vitro studies of vape exposures in both aerosolized and condensed e-liquid exposures.

Aerosolized e-liquid exposures to an air-liquid interface is a more relevant approach rather than directly applying e-liquid or e-liquid condensate directly onto cells in-vitro, as condensate collecting methods can vary and certain particulates in condensate can be short-lived. In a recent publication of Toxicology and Applied Pharmacology5, Dr. Rahman’s group expose normal primary lung epithelial cells (BEAS-2B and NHBE) to aerosolized CBD oil using the inExpose to investigate the role of CBD on oxidative stress and lipopolysaccharide (LPS) induced inflammatory response. CBD demonstrates both pro- and anti-inflammatory effects by ROS levels, and significantly attenuates LPS-induced NF-kB activity along with IL-8 and MCP-1. An additional study in Scientific Reports6 uses the inExpose system for JUUL pod aerosolization to lung epithelial cells (16-HBE, BEAS-2B) and monocytes (U937). Exposures to different JUUL pod flavourings (tobacco, mint, coffee and fruit-based flavourings) leads to DNA damage, inflammatory responses, and oxidative stress on lung cells in vitro.

As the wealth of pre-clinical in vivo and in vitro knowledge increases, there is growing concern about the safety profile of these ENDS device and their potential cardiopulmonary toxicity. Further pre-clinical and clinical studies are needed to investigate both acute and chronic health consequences of e-cigarette use.



  1. Lechasseur, A., et al. (2019). Variations in coil temperature/power and e-liquid constituents change size and lung deposition of particles emitted by an electronic cigarettePhysiological Reports, 7(10): e14093. Doi.org/10.14814/phy2.14093
  2. Kosmider L, Sobczak A, Fik M, Knysak J, Zaciera M, Kurek J, Goniewicz ML. (2014). Carbonyl compounds in electronic cigarette vapors: effects of nicotine solvent and battery output voltageNicotine Tob Res,16: 1319-26.
  3. Williams., M, Villarreal A, Bozhilov K, Lin S, Talbot P. (2013). Metal and silicate particles including nanoparticles are present in electronic cigarette cartomizer fluid and aerosolPLoS One 2013;8: e57987.
  4. Spindle, T.R., Cone, E.J., & Schlienz, N.J. (2018). Acute Effects of Smoked and Vaporized Cannabis in Healthy Adults Who Infrequently Use CannabisSubstance Use and Addiction, 1(7): doi:10.1001/jamanetworkopen.2018.4841
  5. Crotty, A, et al. (2019). Inhalation of JUUL Aerosols and Flavor Choice Adversely Affects Inflammatory and Metabolic States. ATS, Effects of E-cigarettes and their Components on Respiratory Dysfunction, Inflammation and Repair, b107
  6. Muthumalage, T., et al. (2018). Inflammatiory and Oxidative Responses Induced by Exposure to Commonly Used e-Cigarette Flavouring Chemicals and Flavoured e-Liquids without NicotineFrontiers in Physiology, 11: doi.org/10/3389/fphys.2017.01130
  7. Muthumalage, T., Lamb, T., Friedman, M.R., & Rahman, I. (2019). E-cigarette flavored pods induce inflammation, epithelial barrier dysfunction, and DNA damage in lung epithelial cells and monocytes. Scientific Reports, 9:10935

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