Phytol, not propylene glycol, causes severe pulmonary injury after inhalation dosing in Sprague-Dawley rats

Schwotzer, Daniela; Gigliotti, Andrew P.; Irshad, Hammad; Dye, Wendy W.; McDonald, Jacob D.

doi:10.1080/08958378.2020.1867260

Cited by 10 publications

(5 citation statements)

References 13 publications

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“…Little is known about the novel diterpene alcohol phytol found in Ecig products [ 24 ]. An extremely high dose (100%) of phytol was shown to be lethal to rats [ 25 ], but in our studies we find that even at a very low dose, 1%, phytol can induce significant changes to lung transcription, metabolites, and even function. Using analysis combining our results showing changes in transcriptomics, lipidomics, and metabolomics, we find that phytol increases acetylcholine.…”

Section: Discussioncontrasting

confidence: 61%

“…Alternatives to VEA include Phytol which is a diterpene alcohol that may naturally exist in cannabis products in small amounts, but it was an inexpensive diluent that many manufacturers of cannabis products were considering incorporating into products as a principal ingredient and was found in counterfeit cartridges [ 24 ]. An initial study highlighted significant pulmonary toxicity from phytol in rats and, for the most part, this finding quickly circulated to manufacturers who removed phytol from products [ 25 ]. That study used a high concentration incorporation of phytol and observed overt morbidity and mortality.…”

Section: Introductionmentioning

confidence: 99%

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Multi-omic assessment shows dysregulation of pulmonary and systemic immunity to e-cigarette exposure

et al. 2023

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Electronic cigarette (Ecig) use has become more common, gaining increasing acceptance as a safer alternative to tobacco smoking. However, the 2019 outbreak of Ecig and Vaping-Associated Lung Injury (EVALI) alerted the community to the potential for incorporation of deleterious ingredients such as vitamin E acetate into products without adequate safety testing. Understanding Ecig induced molecular changes in the lung and systemically can provide a path to safety assessment and protect consumers from unsafe formulations. While vitamin E acetate has been largely removed from commercial and illicit products, many Ecig products contain additives that remain largely uncharacterized. In this study, we determined the lung-specific effects as well as systemic immune effects in response to exposure to a common Ecig base, propylene glycol and vegetable glycerin (PGVG), with and without a 1% addition of phytol, a diterpene alcohol that has been found in commercial products. We exposed animals to PGVG with and without phytol and assessed metabolite, lipid, and transcriptional markers in the lung. We found both lung-specific as well as systemic effects in immune parameters, metabolites, and lipids. Phytol drove modest changes in lung function and increased splenic CD4 T cell populations. We also conducted multi-omic data integration to better understand early complex pulmonary responses, highlighting a central enhancement of acetylcholine responses and downregulation of palmitic acid connected with conventional flow cytometric assessments of lung, systemic inflammation, and pulmonary function. Our results demonstrate that Ecig exposure not only leads to changes in pulmonary function but also affects systemic immune and metabolic parameters.

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Section: Discussioncontrasting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Multi-omic assessment shows dysregulation of pulmonary and systemic immunity to e-cigarette exposure

et al. 2023

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“…Phytol is known both as a precursor for the synthesis of VE and vitamin K12 [32,33], as well as a byproduct of chlorophyll degradation [33,34]. Inhalation of aerosolized phytol has previously been shown to induce lung injury in exposed rats [35,36]. In addition, phytol is a long chain alkyl alcohol compound, meaning that it has the potential to induce damage to the membrane of cells in a biological system [37,38].…”

Section: Plos Onementioning

confidence: 99%

Temperature dependence of emission product distribution from vaping of vitamin E acetate

et al. 2022

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Nearly two years after vitamin E acetate (VEA) was identified as the potential cause of the 2019–2020 outbreak of e-cigarette, or vaping product-associated lung injuries (EVALI), the toxicity mechanisms of VEA vaping are still yet to be fully understood. Studies since the outbreak have found that e-liquids such as VEA undergo thermal degradation during the vaping process to produce various degradation products, which may pose a greater risk of toxicity than exposure to unvaped VEA. Additionally, a wide range of customizable parameters–including the model of e-cigarette used, puffing topography, or the applied power/temperature used to generate aerosols–have been found to influence the physical properties and chemical compositions of vaping emissions. However, the impact of heating coil temperature on the chemical composition of VEA vaping emissions has not been fully assessed. In this study, we investigated the emission product distribution of VEA vaping emissions produced at temperatures ranging from 176 to 356°C, corresponding to a variable voltage vape pen set at 3.3 to 4.8V. VEA degradation was found to be greatly enhanced with increasing temperature, resulting in a shift towards the production of lower molecular weight compounds, such as the redox active duroquinone (DQ) and short-chain alkenes. Low temperature vaping of VEA resulted in the production of long-chain molecules, such as phytol, exposure to which has been suggested to induce lung damage in previous studies. Furthermore, differential product distribution was observed in VEA degradation products generated from vaping and from pyrolysis using a tube furnace in the absence of the heating coil at equivalent temperatures, suggesting the presence of external factors such as metals or oxidation that may enhance VEA degradation during vaping. Overall, our findings indicate that vaping behavior may significantly impact the risk of exposure to toxic vaping products and potential for vaping-related health concerns.

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“…Aromatic/volatile hydrocarbons and oils consisting of MCT, terpenes and mineral oil in cannabis vaping fluids are suspected to cause oxidative stress and inflammatory responses in the lung ( Chand et al, 2020 ). Recent studies in rats of phytol, one of the terpenes identified in commercial additives in this study, showed significant toxicity in respiratory tissue including dose-responsive tissue degeneration and necrosis in exposed animals that were in some instances associated with mortality ( Schwotzer et al, 2021 ). These authors recommended that phytol not be used as an excipient in vaping products, as a safe exposure range for the compound has not been established.…”

Section: Discussionmentioning

confidence: 82%

Investigation of Vaping Fluids Recovered From New York State E-Cigarette or Vaping Product Use-Associated Lung Injury Patients

Duffy

et al. 2021

Front. Chem.

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E-cigarette or vaping product use-associated lung injury (EVALI) is a serious pulmonary condition that is associated with the extended use of certain vaping products. EVALI was first characterized in the summer of 2019 and has since been reported in all 50 U.S. states. From August 2019 through June 2021, the New York State Department of Health has reported more than 197 confirmed cases emanating from all regions of the state. The Wadsworth Center at the New York State Department of Heath received vaping cartridges recovered from EVALI patients for chemical analysis of their contents. Untargeted analytical methods using gas chromatography-mass spectrometry and liquid chromatography-high-resolution mass spectrometry as well as targeted analyses for a variety of analytes including cannabinoids, pesticides, vitamin E acetate (VEA) and mycotoxins were used to characterize the composition of the vaping fluids and several commercial vaping fluid additives. From the analyses of the 284 e-cigarette devices recovered from patients, 82 were found to be nicotine-containing pods, and 202 devices containing cannabis oil, apparently from unauthorized or black-market dealers. The fluids from the cannabis-oil cartridges tended to have lower levels of THCs (Δ9-tetrahydrocannabinol + Δ8-tetrahydrocannabinol) and total cannabinoids compared with those of commercially produced formulations and contained significant levels of diluents including VEA, medium-chain triglycerides, polyethylene glycol, and castor oil. VEA was the diluent most frequently detected, which was present in 132 (65.3%) of the vaping fluids that contained cannabis oil. When present, VEA ranged from 2.0 to 67.8% of the total mass of the oil with a mean content of 37.0%. In some cases, two or three diluents were detected in the same sample. The ratio of VEA to THCs varied widely, from 0.07 to 5.34. VEA and specifically the high ratios of VEA to THCs in black-market vaping fluids may be causative in EVALI. The safety of additional components and additives that are present in vaping fluids are likewise of concern.

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Phytol, not propylene glycol, causes severe pulmonary injury after inhalation dosing in Sprague-Dawley rats

Cited by 10 publications

References 13 publications

Multi-omic assessment shows dysregulation of pulmonary and systemic immunity to e-cigarette exposure

Multi-omic assessment shows dysregulation of pulmonary and systemic immunity to e-cigarette exposure

Temperature dependence of emission product distribution from vaping of vitamin E acetate

Investigation of Vaping Fluids Recovered From New York State E-Cigarette or Vaping Product Use-Associated Lung Injury Patients

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