What's really in the vapes?
Vaping has established itself within the cultures of schools, workplaces and home lives throughout Aotearoa. Between 2019/20 and 2020/21 alone, the proportion of New Zealanders above age fifteen who vape regularly has more than doubled, to approximately 356,000 people.1 With vaping being very recently emergent, the risks of this still-juvenile practice are brought to the fore – and reasonably so. We are still in the dark as to the effects of vaping on the body, and this will take years of intensive and comprehensive study; what we can look into in lieu of systems-level research are the components in isolation.
The inhalation of vapour into the lungs from the now commercially-recognised devices called “vapes” is a complex process. During a single hit of a vape, an inhalation of air pulls together two microscopic prongs inducing a current to flow that provides energy to a coil to vaporise surrounding ‘juice’. The user inhales this vapour which then recondenses in the alveoli of their lungs - this ‘juice’ now resides within the microscopic air sacs of their lungs.
Is this a problem? Within this juice is found a variety of different compounds including glycerin, propylene glycol, nicotine benzoate and various flavouring compounds. Of course, each of these compounds have their own journeys once inside the body of the user - chemically as well as anatomically - and it is the biochemical legacy of these compounds that engender the broader effects of vaping as a practice.
While in Aotearoa - as globally - there are a diversity of vape brands and flavours available to consumers, the vast majority contain the same few compounds, as aforementioned. The primary distinction between various vapes - for chemists and consumers alike - are the flavouring compounds present in the juice of the vape. The flavours on the market are profligate, and to look into each subsequent one would become less and less relevant. As such, I’m looking into two flavours in particular: tobacco and mint/menthol. Each flavour requires a distinct chemistry for the taste buds of the user’s mouth to discern flavour, and as such are chemically distinct. This article will follow the chemical and anatomical pathways of these common vape chemicals once they enter the body.
The chemicals involved
Propylene glycol
Propylene glycol is the primary compound found in vaping products in Aotearoa. Propylene glycol - propane-1,2-diol - is used as the base solvent in a majority of vape juices and carries a faint sweet taste. As a diol, the chemical pathways undergone by this compound in the cells of human bodies involve oxidation of the hydroxyl groups by enzymes alcohol and aldehyde dehydrogenase to, ultimately, lactic acid. Propylene glycol has a boiling point of 188.2ºC. Industrially, propylene glycol is made from the hydration of propylene oxide. Propylene oxide is formed by either the oxidation or hydrochlorination of propene, and is a recognised carcinogen.
Glycerol
Glycerol is another common compound found in vape juices. Similar to propylene glycol, but with an additional hydroxyl group on the third carbon, glycerol - propane-1,2,3-triol - undergoes a comparable metabolic processing, involving oxidation of the hydroxyl groups. Glycerol has a boiling point of 280ºC. Industrially, glycerol is made from triglycerides which occur naturally in (particularly fatty) foods. These triglycerides are esters with three carboxylic acid chains of varying length bonded to a single triol. These carboxylic acid chains can be removed from the triglyceride via a variety of processes - hydrolysis, saponification, transesterification - resulting (upon distillation) in the isolation of the triol: glycerine.
Both glycerol and propylene glycol act as effective solvent bases for vape juices due to the presence of hydroxyl groups within their structures. The electronegativity of the oxygen draws electron density away from the hydrogen atom, polarising it. The emergence of these regions of partial charge about both molecules provide sites for solute anions to be attracted to the polarised hydrogen, and cations to the lone pair about the oxygen, overcoming the solute-solute attractive forces of the other molecules - particularly the nicotine salt. This polarisation of the hydrogens of the hydroxyl group also give rise to the greater boiling points of glycerol and propylene glycol in comparison to water. Incidentally, the attractions formed between adjacent molecules are stronger than those between water due to the hydrogen bonding of the hydrogen and the lone pair of electrons from the oxygen. Hence, these solvents’ boiling points are greater than that of water.
Nicotine benzoate
The addictive chemical in cigarettes and vapes alike is known as being nicotine. Nicotine in its general form is more complex than the aforementioned chemicals. It is this chemical that once in the brain biochemically triggers the release of dopamine via the neuronal nicotinic acetylcholine receptors, and addicts users to the practice of nicotine consumption.
In traditional products (cigarettes), nicotine is found in the form extracted from tobacco. In more modern vaping products, however, it is found in the form of the salt, nicotine benzoate. This compound is used to mask the bitter (and often tobacco-tainted) flavour of nicotine and is formed by the reaction of benzoic acid with nicotine. The proton transfer from the acid protonates the tertiary amine group, and results in the formation of the organic salt nicotine benzoate. This protonated form of nicotine prompts the same dopamine-releasing receptor channel as the ordinary molecule.
Menthol
Menthol - 2-isopropyl-5-methylcyclohexanol - is a common compound in mint vapes. Having been used in tobacco products for over a century, menthol is known for its flavour and its soothing properties: masking the harshness of tobacco within the throat. In vaping products, it is utilised much more for its flavour as opposed to its soothing/masking abilities. Menthol occurs naturally in mint plants, but can also be synthesised via a variety of methods. These processes involve numerous steps and a collection of catalysts. Similar compounds can be made from the menthol molecule with very similar physical/olfactorial properties. For example, menthone can be produced by oxidation of menthol’s hydroxyl group to a ketone group. With a similar smell, menthone differs in its significantly more bitter taste. Menthol has three chiral centres, meaning that it exists in eight distinct enantiomers. Only one of these enantiomers is commercially distributed as “menthol”, due to the different tastes and properties of each enantiomer.
Ethyl maltol
Another flavour amongst the most popular found in vapes is tobacco. The tobacco flavour found in cigarettes derives directly from the tobacco plant, and as such its complex taste is the product of hundreds of organic compounds which vary in abundance across plants, geographies and genetic varieties. In vaping products, this complexity of flavour can't be achieved, and so the use of a few chemicals achieves the synthetic tobacco flavour. One of the primary compounds used for this is ethyl maltol. Ethyl maltol is created from the naturally occurring compound maltol, by replacement of the methyl group with an ethyl group. Ethyl maltol (or 3-hydroxy-2-ethyl-4-pyrone) has a much stronger taste than its naturally occurring precursor maltol, hence the industrial preference for its use.
In the body
Once the vape juice has been vaporised by the coil, the inhalation generated by the user’s diaphragmatic contraction continues to draw the vapour into the lungs. From the trachea, into the bronchi, to the bronchioles and finally into the alveoli, the vapour recondenses in the microscopic terminals of the airways (with residue also condensing along the path to these alveoli). Once in the alveoli, the vape juice settles. The general function of the alveoli is to act as the interface for the exchange of gases between the bloodstream and the airway: oxygen diffuses through the membrane of the alveoli into the capillary beds that surround it, and carbon dioxide diffuses outwards, into the alveoli to be exhaled. The membrane interface of the alveoli is composed of a lipid bilayer. This comprises two layers of phospholipid molecules. Each molecule in this bilayer has a polar phosphate group at the head and a non-polar carboxylic acid tail facing inwards from both sides of the lipid layer. This layer surrounds the cells which enclose the alveoli, and makes permeation by large polar molecules difficult. While minimal literature exists to say for certain what the rate of diffusion of propylene glycol/glycerol/nicotine benzoate/flavouring agents into the surrounding capillary beds from the alveoli is, it is known that glycerol - due to its polarity and size - diffuses extremely slowly through the lipid bilayer. With other aforementioned compounds being of similar size/polarity or larger, it is reasonable to infer that their diffusion rates through the bilayer are similarly slow. It is known also that, generally, only small lipid-soluble (hydrophobic) molecules are able to efficiently diffuse through the phospholipid bilayer - none of the above compounds satisfy this requirement. When vaping, therefore, an accumulation of the chemicals within vape juice is inevitable.
Propylene glycol
In the bloodstream, propylene glycol doesn’t pose a threat to human health - especially in doses such as those found in vapes. In the body, propylene glycol undergoes a simple pathway with the end product lactic acid. After the initial removal of the terminal hydroxyl group of propylene glycol by the enzyme dehydrogenase, lactaldehyde is formed (which exists as enantiomers). Lactaldehyde then is converted to lactate, either directly, or via methylglyoxal (Scheme 1).
While propylene glycol, lactaldehyde and lactic acid are all very benign, methylglyoxal is known to cause damage to the epithelial lining of the lungs. Epithelial necrosis can occur wherein cells enclosing the alveoli and bronchi rupture as a direct result of exposure to methylglyoxal.
Bronchiolitis obliterans can arise from severe or numerous instances of pulmonary epithelial necrosis - i.e. caused by chronic vape usage - more commonly referred to as popcorn lung. Popcorn lung received its name from the disease acquired by popcorn factory workers who inhaled large amounts of diacetyl. Diacetyl is very similar to methylglyoxal, being distinguished only by one methyl group. Their shared relation to the necrosis of the pulmonary epithelia is therefore not surprising.
Methylglyoxal is as damaging to the body as it is to the lungs.2 Particular research has found that methylglyoxal accumulation in the bloodstream can cause damage to the blood-brain barrier, causing increased apoptotic action by these cells, loss of integrity and a decrease in the detoxification rate of further methylglyoxal. Due to the known biochemical and physiological fragility of the blood-brain barrier, and its involvement in the development of neuropathological diseases such as dementia, methylglyoxal’s dangers shouldn’t be overlooked. While it is likely that the increase in the amount of methylglyoxal in the bloodstream consequent to vaping is minimal (due to its minimal permeation into the bloodstream from the alveoli) there is no certainty that the neurological risk is nonexistent.
Methylglyoxal’s dangers may well extend further. The final product, lactic acid, can be slowly assimilated into surrounding tissue (or more rapidly by protein channels: monocarboxylate transporters), and converted to pyruvate by lactate dehydrogenase to be used within the mitochondria of the host cells in the citric acid cycle. While alcohol and aldehyde dehydrogenase, glyoxalase and lactate dehydrogenase are all found in particular abundance in the liver, these necessary enzymes are also found in lung tissue, and thus this pathway can occur in the lungs as well as in the body.
Glycerol
Similar to propylene glycol, glycerol is found commonly in the bloodstream and has no known negative effect on the general, somatic, body. In fact, much of our bodily energy reserves are found in triacylglycerols (triols with three fatty acid chains). In a process referred to as gluconeogenesis, select non-hexose molecules (such as glycerol) are able to be biochemically converted into glucose for use in pyruvate generation, followed by the citric acid cycle and then the electron transport chain - ultimately resulting in the production of ATP and the provision of energy to the body.
Alternatively, in the final stages of glycerol gluconeogenesis, glycogen or pyruvate can be formed. Glycogen is a stable, composite form of glucose that is stored in cells for belated conversion back to glucose when energy demands increase, and pyruvate is a precursor to the krebs cycle - needing to be oxidised to acetyl coenzyme A prior to its biochemical role in this cycle. Of the other chemical intermediaries involved in this pathway, none pose any pathological - particularly necrotic - threat to the pulmonary and somatic tissues it encounters, as methylglyoxal does.
Menthol
Menthol has been a common ingredient in inhalants for many years - prior to the emergence of vaping, menthol was commonly found in cigarettes, to mask the flavour of the bitter tobacco present. For this reason, it’s thought to be a reinforcer for addiction to nicotine (when used in combination) increasing nicotine reward-related behaviour.3 It is also commonly used as a soothing chemical for pain and inflammation local to the mid pharynx and nasal passage. Generally such medical applications are swallowed as opposed to inhaled, but not all of them (i.e. nasal sprays to reduce congestion - this, however, results in little pulmonary deposition).
While menthol is an approved comestible, its effects on the respiratory system aren’t necessarily benign. Studies have shown that the interaction of particularly menthol-containing vape juices with the surfactant layer of the alveoli reduces the function of the surfactant in its biophysical role in reducing friction and collapse within the alveoli.4 While these experiments used bovine lipid extract surfactant (BLES), as opposed to a human surfactant extract, due to the similar properties of the two extracts, a similar relationship is seen in human pulmonary tissue. Maintenance of alveolar integrity is essential to our pulmonary function, and our longevity in general. With decrease in respiratory capacity comes greater metabolic strain and broader effects regarding the biochemical equilibria within our bodies. This correlation, then, is deeply concerning.
Menthol is disposed of via a metabolic pathway, a simplified version of which is shown in Scheme 2. Conversion of menthol to menthol glucuronide by the enzyme diphosphate glucuronyl transferase occurs, and menthol glucuronide is excreted in the urine of the user.5 Menthol glucuronide has no known pathological effects on the body.
Ethyl maltol
Ethyl maltol is not found in the human body as commonly as one would find menthol, glycerol or propylene glycol. Due to its infrequency in household and consumable items, little literature exists detailing its biochemical metabolism and removal from the body.
What is known of ethyl maltol, however, is its ability to form complexes with the metals found commonly in the atomisers of vaping devices. Iron and copper are large constituents of the heating component of vaping devices (the atomiser). The formation of copper and iron hydroxypyranone complexes specifically can occur upon reaction of ethyl maltol with the iron and copper containing atomiser. Transition metal complexes are abundant in the human body, with uses ranging from intercellular communication to regulating DNA transcription. Specificity of the complexes enables their various and differentiated functions.
While hydroxypyranone complexes are not heavily researched on a health front, free radicals (of which hydroxypyranone complexes are an example) on the whole are known to pose considerable threat to the function of pulmonary epithelial tissue. Associated with a decrease in pulmonary function due to damage to the epithelial tissue, the issues posed by ethyl maltol’s propensity to transition metal complex formation is a concerning one.6,7 Ethyl maltol is one of vape juice constituents’ most free radical generative compounds.7 The potential the hydroxypyranone complexes have to degrade pulmonary tissue function is only one of the various threats it poses. The specific chemistry of the complexes and their interaction with their biomolecular environments is still largely unknown.
Conclusions
The process and chemistry of vaping is not as simple as users may assume. The variety of compounds found in vape juices - only a few of which are mentioned in this paper - have unique and disparate chemistries, the effects and function of which vary greatly. From before the vaporised juice even reaches the mouth of the user, gaseous complexes have formed. In the mouth, many of these compounds bind to taste buds, eliciting the sensation of flavour. In the throat, select compounds can soothe epithelial inflammation and pain, while upon reaching the alveoli and more superficial structures of the lungs, severe damage to the lungs can be done by the chemicals to the tissue.
After all of this, the chemical constituents of the vape juice are biochemically altered to engender a whole new raft of chemicals and biochemical interactions with surrounding tissues. Some give rise to a dangerous pathology within the pulmonary tissue and external to that, and some are entirely benign. Removal or reuse of these compounds then occurs. Upon consideration of the vagaries and varieties of the chemical journeys of vape juice constituents, it’s easy to see why extensive research is required to be done to fully gauge the effects of vaping on the user. In isolation, these chemicals’ effects may have overt consequences, but in cooperation, we’re yet to be certain of vaping’s true impact.
References
- NZ Ministry of Health. Smoking Status of Daily Vapers: New Zealand Health Survey 2017/18 to 2021/22. 6 June 2023. www.health.govt.nz/publication/smoking-status-daily-vapers-new-zealand-health-survey-2017-18-2021-22#:~:text=Key%20findings (accessed 02/04/2024).
- Berends, E. et al. Fluids and Barriers of the CNS 2023, 20(1) https://doi.org/10.1186/s12987-023-00477-6
- Henderson, B.J. et al. Neuropsychopharmacology, 2017, 42(12), 2285–2291 www.nature.com/articles/npp201772,
- Xu, L. et al. American Journal of Physiology-Lung Cellular and Molecular Physiology, 2022, 323(2), L165–L177 https://doi.org/10.1152/ajplung.00015.2022.
- Silva, H. Frontiers in Physiology 2020 (11) https://doi.org/10.3389/fphys.2020.00298.
- Harmon, A.C. et al. American Journal of Physiology-Heart and Circulatory Physiology 2021, 321(4), H667–H683 https://doi.org/10.1152/ajpheart.00725.2020.
- Blitzer, Z.T. et al. Science Direct, 20 May 2018 www.sciencedirect.com/science/article/abs/pii/S0891584918301230 (accessed 02/04/2024).
