By Dr. V. A. Gyarmathy and Dr. G. Z. Xantus
Although the electronic cigarette or vaping product-use associated lung injury (EVALI) epidemic in the US seems to have stopped, various epidemiological and medical questions remain open. We have come to a shocking conclusion after discussing the following topics:
In the summer of 2019, the Centers for Disease Control and Prevention (CDC) declared an emergency in the United States of electronic cigarette or vaping product-use associated lung injury (EVALI).
The numbers were the highest in September of 2019, when almost 1,000 patients were admitted to the hospital and almost 120 people per one million visited the emergency room because of e-cigarettes. By February of 2020, over 2,800 patients were hospitalized and 68 people died.
EVALI patients typically vaped multiple products: 82% used any THC and 33% used only THC, and 57% used any nicotine and 14% used only nicotine. The CDC claimed to have established a link between Vitamin E acetate (VEA) and EVALI, especially in connection with THC containing products, and recommended the people refrain from vaping and that VEA should not be added to vaping liquids.
By the beginning of February 2020, however, the EVALI epidemic was considered to be over. The CDC attributed the end of the epidemic to – among other things – the removal of VEA from vape juices.
Although the EVALI epidemic in the US seems to have stopped, various epidemiological and medical questions remain open.
In this review, we are attempting to address these three questions.
Vaping has become increasingly popular all over the world. There are no commercial restrictions on devices or fluids, and they are freely accessible in online stores like Amazon and Ali Express, not to mention other online retailers.
Still, one of the most striking characteristics of the EVALI epidemic was that only the United States reported a severe upsurge in cases. There were only 17 cases in Canada, two in Thailand, and one in Mexico, but the latter one was somebody form the US who happened to be diagnosed in Mexico. In addition, the 3 cases in Brazil reported that they had used vape juices from the United States.
Is this an issue of disease reporting characteristic of the United States but not of other countries? There is no major difference in the disease surveillance systems of the United States and, for example, that of the United Kingdom and Australia. As such, the EVALI outbreak is probably not the product of differential reporting due to differences in the reporting systems.
In addition, even within the United States, the EVALI outbreak did now show a clear geographic pattern that would have reflected local legislative patterns of cannabis decriminalization.
Could it be cultural differences? Users often tweak vaping devices to change manufacturers’ settings. This tweaking obviously has an effect on the physical and chemical characteristics of vaped juices. It is difficult to imagine that it is only Americans that tweak and no other nations, especially given the busy social media contacts of cannabis and e-cigarette aficionados.
Alternatively, vaping juices that caused EVALI might have contained bad quality unregulated THC products, which appeared in the United States as a result of a sudden legalization wave across states and the following “green rush”.
In September of 2019, the CDC found a link between EVALI and Vitamin E acetate. They established this link based on a small report from a forensic laboratory. This report was not only small and unrepresentative of the entire United States, but also analyzed vape juices in general and not from those patients that succumbed to EVALI.
In addition, another study found no Vitamin E acetate in vape juices before the outbreak only after the outbreak. The vape juice that the scientists examined were from confiscated pods. As such, they were probably not stored in accordance with strict laboratory standards, and as we know, chemicals break down in temperatures higher than 70F (20C). Is it a possibility that Vitamin E acetate degraded over time in those pre-epidemic pods, and this is why they did not contain any traceable amounts?
Even if it is indeed true that there was Vitamin E acetate only afterwards, does that really mean that evaporated Vitamin E acetate is dangerous for one’s health? According to our knowledge, there are no studies specifically assessing Vitamin E acetate vapors on human health.
The CDC noted that heightened user awareness and most probably the removal of Vitamin E acetate from vape juices lead to the end of the EVALI epidemic in the United States. In addition, the CDC also warned against counterfeit products, which apparently make up the majority of vaping products.
The primary motivation of black-market players is profits and not public health concerns. As such, it is unrealistic to expect that counterfeit producers would stop using an adulterant (Vitamin E acetate in this case) as a response to public uproar or ill health effects.
It is also possible that while THC and Vitamin E Acetate alone might not be a health hazard, but they interact at high temperatures and exert a synergistic ill effect.
We know little about the long-term effects of vaping. Vaping-related emergency room visits have been on the rise parallel with the increasing popularity of vaping. As such, Vitamin E acetate and/or counterfeit vape juices may (or may not) have been the reason of the EVALI outbreak. However, there is still something about vaping that makes people sick.
One reason might be repeated exposure of people who vape to metal fumes. Most vaping devices heat a metal coil to about 1800F (1000C) by means of a rechargeable 3-6 V battery. This high temperature is above the boiling point of a number of metals, including cadmium and zinc.
To our knowledge, no requirements exist about the labeling of the coil alloys of vaping pens. As such, only the producers know what the coils are made up of. In addition, vape coil manufacturing probably follows cost effectiveness rather than public health concerns.
In addition to the potential melting of the metal vaping coils, new and potentially hazardous molecules might form at these high temperatures. Moreover, unknown added hazardous materials might also contribute to the risks of vaping. An analogous example is the addition of bright boat paint to tattoo inks that scientists found caused severe health reactions.
How do the health effects of smoking compare to those of vaping? To our knowledge, nobody has ever performed a scientific study contrasting tobacco-related illnesses and deaths among tobacco smokers with vaping related illnesses and deaths among vapers. It could be a very interesting assessment.
Research related to and therefore conclusions about the health effects of vaping are difficult. In vitro experiments might not adequately reflect real-life conditions due to the unregulated nature of vaping liquids as well as users potentially tweaking their vaping pens.
What is more, there is not just one type of vaping pen, but most pens are different. Therefore, even if the pens are not tweaked, there is no consensus regarding how a “typical” vaping pen works.
In addition, it is difficult to model the environment in the human lungs. Moreover, certain components in the vape juice might interact with other components and have synergistic effects that they alone would not have.
Vaping is a multidimensional issue. Quality control of vaping products, transparency considering the legality, are necessary thorough international research to understand the health aspects of vaping. Having accomplished that, proper user education is essential to prevent similar epidemics in the future and determine safe vaping and/or whether safe vaping exists.
Speaking of safe vaping, is the American only EVALI epidemic the result of an upsurge of bad quality THC products due to a sudden legalization wave in the US, and is the subsequent vilification and widespread e-cigarette and vaping ban a conspiracy by the tobacco industry to eliminate the competition? Watch this stunning investigative video by The Economist.
Abdala-Valencia H., Berdnikovs S., Cook-Mills J.: Vitamin E Isoforms as Modulators of Lung Inflammation. 2016. Nutrients. 5, 4347-4363
Bergfeld WF., Belsito VD., Hill AR., et al.: Safety Assessment of Tocopherols and Tocotrienols as Used in Cosmetics. 2014. Cosmetics Ingredients Review. [Online] Available at: https://www.cir-safety.org/sites/default/files/tocoph032014FR.pdf
Blount B., Karwowski M., Shields PG., et al.: Vitamin E Acetate in Bronchoalveolar-Lavage Fluid Associated with EVALI. NEJM. 2019. [Online] Available at: DOI: 10.1056/NEJMoa1916433
Chatham-Stephens K., Roguski K., Jang Y., et al. Characteristics of Hospitalized and Nonhospitalized Patients in a Nationwide Outbreak of E-cigarette, or Vaping, Product Use–Associated Lung Injury — United States, November 2019. 2019. MMWR 68(46);1076-1080
Chow C., Herrera Abreu MT., Suzuki T., et al. Oxidative Stress and Acute Lung Injury. 2003. Am J Resp Cell and Molecular Biology. 2003. [Online] Available at: https://www.atsjournals.org/doi/full/10.1165/rcmb.F278
Cook-Mills J., Gebretsadik T., Abdaba V et al.: Interaction of vitamin E isoforms on asthma and allergic airway disease. Thorax 71(10) 954-956
Cook-Mills JM., Abdala-Valencia H., Hartert T: Two Faces of Vitamin E in the Lung [Online] Available at: https://www.atsjournals.org/doi/full/10.1164/rccm.201303-0503ED
Effect of Gamma Tocopherol Enriched Supplementation on Response to Inhaled LPS [Online] Available at: https://clinicaltrials.gov/ct2/show/NCT02104505
Ghinai I., Navon L., Gunn KL., et al: Characteristics of Persons Who Report Using Only Nicotine-Containing Products Among Interviewed Patients with E-cigarette, or Vaping, Product Use–Associated Lung Injury — Illinois, August–December 2019 Morbidity and Mortality Weekly Report. The CDC. 69(3);84–89
Hajimahmodi M., Mojtahedzadeh M., GaffarNatanzi N., et al.: Effects of vitamin E administration on APACHE II Score in ARDS patients. 2009. [Online] Available at: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.615.4953&rep=rep1&type=pdf
Hernandez M., Wagner GJ., Kala A., et al.: Vitamin E Gamma-tocopherol Reduces Airway Neutrophil Recruitment after Inhaled Endotoxin Challenge in Rats and in Healthy Volunteers. 2013. Free Radic Biol Med [Online] Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654053/
Huang JF., Zhu DM., Zhong M.: Acute respiratory distress syndrome due to exposure to high-concentration mixture of ethenone and crotonaldehyde. 2015. Toxicol Ind Health 31(7):585-7
Hybertson BM., Chung JH., Fini MA., et al: Aerosol-administered alpha-tocopherol attenuates lung inflammation in rats given lipopolysaccharide intratracheally. 2005. Exp Lung Res 31(3):283-94.
King BA., Jones MC., Baldwin MC., et al.: The EVALI and Youth Vaping Epidemics — Implications for Public Health. 2020. NEJM. [Online] Available at: https://www.nejm.org/doi/full/10.1056/NEJMp1916171
Kosari P., Alikhan A., Sockolov M., et al. Vitamin E and allergic contact dermatitis 2010. Dermatitis. 21(3):148-53
Krishnasami VP., Hallowell BD., Ko YJ., et al.: Update: Characteristics of a Nationwide Outbreak of E-cigarette, or Vaping, Product Use–Associated Lung Injury — United States, August 2019–January 2020. MMWR 69(3);90–94
Lozier M., Wallace B., Anderson K., et al. Update: Demographic, Product, and Substance-Use Characteristics of Hospitalized Patients in a Nationwide Outbreak of E-cigarette, or Vaping, Product Use–Associated Lung Injuries — United States, MMWR. December 2019. 2019. 68(49);1142–1148
Lodge JK. Vitamin E bioavailability in humans. 2005. J Plant Physiol 162(7):790-6
Massey JB, She HS, Pownall HJ. Interaction of vitamin E with saturated phospholipid bilayers. Biochem Biophys Res Commun 1982;106:842-847.
Meehan-Atrash J., Luo WT., McWhirter KJ., et al. Aerosol Gas-Phase Components from Cannabis E-Cigarettes and Dabbing: Mechanistic Insight and Quantitative Risk Analysis,” Acs Omega 2019, 4, 16111-16120.
Mendoza-Morales RC., Camberos-Nava MB., Luna-Rosa A., et al. A fatal case of systemic fat embolism resulting from gluteal injections of vitamin e for cosmetic enhancement. 2015. Forensic Sci Int. 259:e1-4,
Mills HK., Burbank AJ. et al.: A Study of Gamma Tocopherol-enriched Supplement on Lower Airway Responses to Inhaled Wood Smoke in Healthy Adults. ICH GCP Trial Registry. 2018. [Online] Available at: https://ichgcp.net/clinical-trials-registry/NCT03444298
Morita N., Traber RG., Enkhbataar P., et al. Aerosolized alpha-tocopherol ameliorates acute lung injury following combined burn and smoke inhalation injury in sheep. 2006. Shock. [Online] Available at: DOI:10.1097/01.shk.0000208805.23182.a7
Mulder et al. 2019 The Effect of Electronic Cigarette User Modifications and E-liquid Adulteration on the Particle Size Profile of an Aerosolized Product Nature [Online] Available at: https://www.nature.com/articles/s41598-019-46387-2.pdf
Olmedo P., Goessler W., Rule M., et al. Metal Concentrations in e-Cigarette Liquid and Aerosol Samples: The Contribution of Metallic Coils. Envir Health Perspectives [Online] Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066345/
Palmer KT., McNeill-Love R., Poole JR. et al. Inflammatory responses to the occupational inhalation of metal fume. 2016. Eur Respir J. 27: 366-373
Scmiedt R., Luboienski P., Markart C., et al.: Alveolar antioxidant status in patients with acute respiratory distress syndrome. Eur Respirat J. [Online] Available at: https://erj.ersjournals.com/content/24/6/994
Shu-Hong Z., Jessica ZY., Bonnevie E., et al: Four hundred and sixty brands of e-cigarettes and counting: implications for product regulation. 2014. Tobacco Control. 23 (3): iii3–iii9.
Surveillance systems evaluation: a systematic review of the existing approaches. 2015 BMC Public Health [Online]. Available at: doi: 10.1186/s12889-015-1791-5
Taylor J., Wiens T., Peterson J., et al.: Characteristics of E-cigarette, or Vaping, Products Used by Patients with Associated Lung Injury and Products Seized by Law Enforcement — Minnesota, 2018 and 2019. Morbidity and Mortality Weekly Report. The CDC. 68(47);1096-1100
Vreeke S., Peyton DH., Strongin RM.: “Triacetin Enhances Levels of Acrolein, Formaldehyde Hemiacetals, and Acetaldehyde in Electronic Cigarette Aerosols,” Acs Omega 2018, 3, 7165-7170.
Wu D. and O’She D. Potential to release of pulmonary toxic ketene from vaping pyrolysis of Vita min E acetate. 2019 ChemRxiv. [Online] Available at https://chemrxiv.org/articles/Potential_for_Release_of_Pulmonary_Toxic_Ketene_from_Vaping_Pyrolysis_of_Vitamin_E_Acetate/10058168
Xantus GZ Vaping-associated lung injury-VALI facts, assumptions and opportunities: review of the present situation. 2019. Postgrad Med J. doi: 10.1136/postgradmedj-2019-137185
Yamamoto Y., Enkhbataar P., Sousse L., et al: Nebulization with Gamma-Tocopherol Ameliorates Acute Lung Injury after Burn and Smoke Inhalation in the Ovine Model. Shock. 2012 37(4): 408–414
Zhou Y., Li J., Duan L., Acute exposure of ozone induced pulmonary injury and the protective role of vitamin E through the Nrf2 pathway in Balb/c mice. 2016. Toxicol Research [Online] Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062352/pdf/TX-005-C5TX00259A.pdf