A full guide to vape aerosols. Post 6: organic byproducts
Aldehydes, reactions, yields, comparisons with tobacco smoke & air pollution. Free radicals and carbon monoxide
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Summary
This is the sixth Substack post of a series of posts describing vaping aerosols, their properties, their optimal regime of operation and comparisons with tobacco smoke and other aerosols.
Summary of previous posts:
Post 1. Basics: what is an aerosol? Vapes and kettles. Byproducts of the heating process. Post 2. Physical processes in vaping. Essentials of laboratory testing. Optimal Regime. Post 3. Overheating: exponential production of toxic byproducts and the “dry puff”. Post 4. Laboratory testing. The CORESTA standard and the evolution of the vape market. Post 5 Metals in vapee aerosols. Emission studies detecting metals. Our review of metal studies
Post 6: Organic byproducts in vape aerosols
Under normal vaping conditions (Optimal Regime, coil temperatures 180-290 °C) vape aerosols contain around 100-150 compounds. Besides the solvents PG and VG, nicotine and water, the remaining compounds appear (if they are detected) in minute trace level concentrations (tiny « 1 % of the aerosol mass, basically they are impurities).
Three aldehydes: formaldehyde, acetaldehyde and acrolein are the main villains, typically the most abundant byproducts (or biggest impurities), other organic compounds (including free radicals and flavoring byproducts) are also found under normal conditions, but at lower or much lower levels than the 3 villains.
Under Overheating Conditions coil temperatures rise, all byproduct levels increase and new byproducts are found, all this because of the reactions that form them depend exponentially on the temperature (see graphs in Post 3). Some of the emerging compounds are produced by flavor chemicals, some by the pyrolysis (heat degradation) of the organic material (cellulose) in the cotton wick, which becomes energetic at temperatures above 300 °C. Another Frankenstein compound that awakes under overheating is carbon monoxide.
Part of the content of this post will be based on a published extensive literature review by Sebastien Soulet and myself, looking in detail at 36 emission studies published between 2017 and 2022 In 2022 focused on organic byproducts, SPOILER: Our review shows that all studies reporting high toxicity from organic byproducts in vape aerosols are totally or partially unreliable: they generated aerosol under overheating conditions and/or exhibited other methodological flaws.
Aldehydes
Organic compounds containing the group —CHO (carbon-hydrogen-oxygen). They form by the oxidation of alcohols. Typical aldehydes include methanal (formaldehyde) and ethanal (acetaldehyde). Aldehydes belong (together with ketones) to the class of organic compounds called carbonyls, characterized by a carbon double bounded with oxygen (C=O). The abundance of aldehydes in vape aerosols depends exponentially on the coil temperature by Arhenious law (see Post 1), but at normal coil temperatures (180-290 °C) this function has a slow growth, with significant exponential growth at the Overheating Regime.
The main pathway for aldehydes to form in vape aerosols as byproducts of PG and VG is of low energy pyrolysis or thermal degradation (including heat induced dehydration) of the solvents PG and VG. Although there is another pathway to form aldehydes from PG and VG: H-abstraction by OH radicals, it is only efficient at temperatures above 360°C, well above normal coil temperatures of vaping (180-290 °C). This can be appreciated from the low growth linear profile in normal vaping temperatures of aldehydes (e.g. glyceraldehyde) formed through this alternative pathway. All this is explained in detail and in didactic form in the comprehensive study by Y. LI at al
The following diagrams in Figure 2 depict the main thermal degradation reactions and their byproducts that occur in vape aerosols
The mass of the most abundant aldehydes in the aerosol was measured by Li et al as a function of the coil temperature
Notice the exponential dependence on temperature of the mass (micrograms per puff). For temperatures above 266 °C (approximately the boiling temperature of the PG/VG: 30/70 mixture) the curves grow very rapidly.
The PG/VG rate of the e-liquid also influences the mass amount of quantified aldehydes. Figure 4 below displays the proportion of the aldehyde mass with respect to the total aerosol mass as a function of the ratio PG/VG
Notice that proportion of aerosol mass of formaldehyde is relatively insensitive to the ratio PG/VG , while acetaldehyde is dominant at higher PG content and acrolein at higher VG content. Although total aerosol mass decreases with usage, these tendencies in PG/VG content roughly remain. Also, since boiling temperatures are higher for pure VG than for pure PG (288 °C vs 188°C), in general e-liquid mixtures with majority VG content produce more and more abundant byproducts.
Note. The study by Li et al is an excellent source to understand the chemical reactions, their dependence on temperature and the effects of the PG/VG ratio, but its puffing protocol is not representative of consumer usage (sub-ohm puffed with insufficient airflow), therefore aldehyde yields (specially formaldehyde) are abnormally high.
Comparison with tobacco smoke and air pollution
Small molecular weight aldehydes provide the largest proportional contribution to cancer risks from smoking (see figure 2 of this review on cancer risks by Fowles and Dybing). In particular, from Table 2 in this review, acetaldehyde and formaldehyde respectivlely rank 4 and 11 among 158 chemicals in cigarette smoke. Both (as well as acrolein) also show high rankings in non-cancer risks (see Table 3 of Fowles and Dybing).
The International Agency for Research on Cancer (IARC) classifies formaldehyde as a human carcinogen (Group 1), acetaldehyde as possibly carcinogenic (Group 2 B) and acrolein as probably carcinogenic (Group 2A).
Since formaldehyde, acetaldehyde and acrolein are the most abundant byproducts in vape aerosols, their significant reduction of yields with respect to tobacco smoke should be an important factor in the reduction of cancer and non-cancer risks when switching from smoking to vaping. For the purpose of comparison, the laboratory ISO tests (in microgams) per cigarette (source) are 500-1500 for aldehyde, 75 - 125 for formaldehyde and 75 - 150 for acroleine.
We published a review of 14 emission studies (4 from industry) targeting carbonyls. Assuming 10 vape puffs = 1 cigarette, the formaldehyde, acetaldehyde and acrolein yields reported clustered around 1-10 micrograms, which is well below levels in tobacco smoke mentioned above (the exception was an outlier reporting 126 and 56 micrograms of formaldehyde and acetaldehyde, but only at the highest power). Figure 5 below displays a table of aldehyde yields in 9 recent studies: Mollock, Talih1, Talih2, Chen, Bitzer, Talih3, Talih4 and Xu:
Notice that in some studies (Bitzer at al (2019), Talih et al (2022) and (2023)) the upper end of the formaldehyde and aldehyde yields reached relatively high values. This reflects the wide variability in quality and design in the devices and also the fact that puffing parameters are in some studies unrepresentative of consumer usage. For example, Talih at al (2022) and (2023) puffed the devices every 10 seconds, which might overestimate aldehyde yields because 10 seconds might be insufficient time to dissipate residual heat. However, even the relatively high yields of (11.0 and 38.4 micrograms) are still well below levels in tobacco smoke (75-125 and 500-1500 micrograms). Without the outliers, yields are below 1% (formaldehyde) and below 0.1% (acetaldehyde) with respect to tobacco smoke.
To compare with indoor air pollution, we consider for formaldehyde the WHO guidelines for indoor air quality (50 micrograms per cubic meter) and for acetaldehyde the EU INDEX proyect upper safety limit of 200 micrograms per cubic meter. As daily dose from vaping we use the highest 10 puff values in Figure 5 multiplied times 20 (to get 200 daily puffs). The result is
Formaldehyde and aldehyde daily doses (even for the outliers) are below these safety thresholds. For the yields of tobacco smoke the daily dose of these aldehydes would be well above safety limits.
Free radicals
Organic molecules are known as free radicals when an electron in the outer energy shells is not paired, making it unstable and very reactive (ie triggering fast reactions) to obtain the electron pairing from other molecules. The "attacked" molecules loose their electron pairing and become free radicals, triggering a reaction cascade above the molecular scale into cells and organs.
Free radicals are also involved in natural biological processes (immunity), but can can also cause harm and disease, specially when their formation involves oxygen (the "reactive oxygen species" ROS) and produces "oxidative stress", an imbalance between free radicals and antioxidants at cellular level. In articular, the ROS hydroxyl OH(-) can cause more biological damage than other ROS.
Exposure to smoke and other carcinogens (also air pollution) exacerbates oxidative stress. In vaping hydroxyls can be produced during the dehydration steps of PG and GLY on the reaction pathway to aldehydes, potentially producing levels comparable to those of the aldehyde byproducts. Given the instability of the ROS and the rapidity and low energy of these reactions, a much lesser presence of hydroxyls is expected in vaping in comparison with smoking.
As shown in Figure 7 below, we reviewed 4 studies targeting ROS (hydroxyl) in vape aerosols. Three of the 4 studies involved puffing protocols unrepresentative of consumer usage (high power with low airflow with high likelihood of overheating). In one study (Son et al) puffing protocols were more realistic, with ROS levels below the levels of cigarete smoke, only approaching the latter under extreme unrealistic conditions (puffing 1000 per day with 100% VG e-liquids).
Carbon monoxide
This volatile gas is seldom detected in vape aerosols. While it can be produced from the thermal decomposition reactions of PG and VG, this only happens under overheating conditions. This is the case in thre studies that we reviewed (see Figure 7 below).
Our extensive literature review
Excess aldehyde (carbonyls in general) content in vape aerosols has been reported since 2015. As shown in several replications by Farsalinos and his team of this emission scare (see summaries in our review), all studies published before 2017 that reported extreme levels of aldehydes (higher than in tobacco smoke) generated aerosols under dry hit conditions. Our review continues early revisions of emission studies and (essentially) reaches the same conclusion as those early replications.
As with metals (see our review), it is necessary and important to verify that emission experiments have an appropriate design, with supplied power and puffing protocols based as much as possible on consumer usage. Sebastien Soulet and I published an extensive reviewhttps://doi.org/ 10.3390/toxics10120714 of 36 studies focusing on organic byproducts in vape aerosols.
We examined the experimental quality of the studies in terms of 4 conditions:
Experimental consistency in setting up puffing protocols (vaping regime)
Experimental consistency in setting up the Power range,
Reproducibility of aerosol generation and analytic methods
Toxicological consistency (correct exposure computation)
We graded 30 studies in Figure 7 below, with tick marks in three levels (approval, failure and partial aproval/failure). The final grade is given in a traffic light system to grade them as “reliable” (GREEN, at least 3 of the 4 conditions), “partially reliable” (to be taken with skepticism) (ORANGE, 2 conditions) and “unreliable” (RED, zero or one condition). We did not classify 6 studies that only dealt with chemical issues. Of the 30 classified studies 9 (32%) were reliable (GREEN), 9 (32%) were partially reliable (ORANGE) and 12 (36%) were NOT reliable (RED). In particular, sudies focusing on free radicals and CO were the less reliable.
The comments in the last column are:
(1) sub-ohm device with CORESTA at high powers (certain overheating),
(2) sub-ohm device with CORESTA recommended powers (likely overheating),
(3) other forms of inconsistent protocol,
(4) incorrect computation of exposure,
(5) outliers not properly identified,
(6) devices not fully identified (unreproducible),
(7) testing power not identified (unreproducible),
(8) too frequent puffs,
(9) too long puffs,
(10) used too old devices (corrosion)
As in the review of metal studies, a significant proportion of studies (10, 33%) found excessive levels of byproducts for puffing high powered devices with CORESTA or CORESTA-like airflows (number (1) above), which is certain to occur under overheating conditions.
This is an easily avoidable experimental flaw that comes from testing high powered devices completely ignoring that consumers use them for the “Direct to Lung” puffing style that involves large airflow rates. We have found this flaw also in pre-clinical studies that expose cell lines and rodents to aerosols generated under these overheating conditions (currently under peer review, see preprint).
Unfortunately, there are many articles and several literature reviews on toxic contents (organic or metal) of vape aerosols that uncritically cite outcomes of emission studies that generated overheated aerosols and had other experimental flaws. Evidently, uncritically citing these articles contributes to an overestimation of the risks involved in vaping.
Conclusions & further posts.
This post extends the conclusions of the previous post (Post 5) on metals. All studies reporting organic byproducts above toxicological safety markers were conducted under unrealistic and abnormal conditions that produce aerosols repellent to users. Some were carried with other flaws in their experimental design. Alarming statements on health risks from metals and organic byproducts in the aerosol are not supported by high quality studies.
In the following Substack posts I will describe our research on preclinical studies that have exposed cell lines and rodents to overheated and toxin laden aerosols generated by puffing sub-ohm devices with low airflow rates (which the authors mistakenly regard as “normal” usage). A review of such studies is currently under peer review. There is full certainty of overheating in at least 14 studies and we have identified other 67 studies with same experimental flaw.
Yet again, excellent information, vital to proper testing and regulation.
Regulation must work to protect consumers from undue risk, corner-cutting in construction, contamination, and other hazards. Honest information is key to making that work!