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E-cigarette aerosol emission studies typically focus on benchmarking toxicant levels versus those of cigarettes. However, such studies do not fully account for the distinct chemical makeup of e-liquids and their unique properties. These approaches often conclude that there are fewer and lower levels of toxins produced by e-cigarettes than by cigarettes. In 2015, we reported the discovery of new hemiacetals derived from the reaction of formaldehyde and the e-liquid solvents. The main finding was that they constituted a significant proportion of potentially undetected formaldehyde. Moreover, unlike gaseous formaldehyde, the hemiacetals reside in the aerosol particulate phase, and thus are capable of delivering formaldehyde more deeply into the lungs. However, the findings were criticized by those claiming that some of the results were obtained under conditions that are averse to vapers. A “reinvestigation” of our study was recently published addressing this latter issue. However, this reinvestigation ignored major details, including no mention of the formaldehyde hemiacetals. Herein, we isolated both gaseous formaldehyde and formaldehyde hemiacetals at an intermediate power level claimed, in the “reinvestigation”, to be relevant to “non-averse,” “normal” usage. The results were that both gaseous formaldehyde and formaldehyde from hemiacetals were produced at levels above OSHA workplace limits.

Flavoring chemicals in electronic nicotine delivery systems have been shown to cause cellular inflammation; meanwhile, the effects of fruit and tobacco flavors on lung inflammation by nose-only exposures to mice are relatively unknown. We hypothesized that exposure to flavored e-cigarettes would cause lung inflammation in C57BL/6 J mice. The mice were exposed to air, propylene glycol/vegetable glycerin, and flavored e-liquids: Apple, Cherry, Strawberry, Wintergreen, and Smooth & Mild Tobacco, one hour per day for three days. Quantification of flavoring chemicals by proton nuclear magnetic resonance spectroscopy (1H NMR), differential cell counts by flow cytometry, pro-inflammatory cytokines/chemokines by ELISA, and matrix metalloproteinase levels by western blot were performed. Exposure to PG/VG increased neutrophil cell count in lung bronchoalveolar lavage fluid (BALF). KC and IL6 levels were increased by PG/VG exposure and female mice exposed to Cherry flavored e-cigarettes, in lung homogenate. Mice exposed to PG/VG, Apple, Cherry, and Wintergreen increased MMP2 levels. Our results revealed flavor- and sex-based e-cigarette effects in female mice exposed to cherry-flavored e-liquids and male mice exposed to tobacco-flavored e-liquids, namely, increased lung inflammation.

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Pine rosin (colophony) has been identified as a potentially new adulterant in cannabis oil. Its inhalation toxicity poses a significant health concern to users. For example, pine rosin fumes are released during soldering, and have been cited as a causative agent of occupational asthma. Symptoms also include desquamation of bronchial epithelium, which has also been observed in e-cigarette or vaping product used-associated lung injury (EVALI) patients. The sample analyzed herein was acquired from a cannabis industry source, also contains medium chain triglycerides and oleamide, the latter of which is a hypnotic that is commonly found in the synthetic marijuana product Spice, or K2. A combination of proton nuclear magnetic resonance (1H NMR) and high pressure liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESIMS) was used to unambiguously identify major pine rosin ingredients such as abietic and other resin acids. Comparison to commercial samples of pure pine rosin confirmed the assignment.

•Pine rosin was identified as component in a sample of cannabis extract adulterant.•The inhalation toxicology of pine rosin is well-studied.•Current analytical methods may misidentify pine rosin as an additive.•The prevalence of this additive is unknown. Pine rosin (colophony) has been identified as a potentially new adulterant in cannabis oil. Its inhalation toxicity poses a significant health concern to users. For example, pine rosin fumes are released during soldering, and have been cited as a causative agent of occupational asthma. Symptoms also include desquamation of bronchial epithelium, which has also been observed in e-cigarette or vaping product used-associated lung injury (EVALI) patients. The sample analyzed herein was acquired from a cannabis industry source, also contains medium chain triglycerides and oleamide, the latter of which is a hypnotic that is commonly found in the synthetic marijuana product Spice, or K2. A combination of proton nuclear magnetic resonance (1H NMR) and high pressure liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESIMS) was used to unambiguously identify major pine rosin ingredients such as abietic and other resin acids. Comparison to commercial samples of pure pine rosin confirmed the assignment.

Observations that copper and homocysteine levels are simultaneously elevated in patients with cardiovascular disease has generated interest in investigating the interactions between copper and homocysteine. Several prior studies have shown that complexes of copper and homocysteine are toxic, leading to cardiovascular damage in vitro. It is not clear, however, why related effects do not occur with other structurally similar, more abundant cellular thiols such as glutathione and cysteine. Herein, a mechanism for a selective redox interaction between copper and homocysteine is demonstrated. It involves a kinetically favored intramolecular hydrogen atom transfer that results in an alpha-amino carbon-centered radical known to promote biomolecular damage.

Consumption of cannabis concentrates using the relatively novel non-combustion methods dabbing and vaping has steadily grown in popularity as cannabis legalization in North America has allowed increased access to sophisticated cannabis products and technology. In order to assess the safety of these products, it is necessary to gain a chemical understanding of the decomposition reactions that occur when the active ingredients are heated in the conditions seen when dabbing or vaping. This dissertation contains a manuscript that details efforts to structurally characterize a toxic cannabis concentrate adulterant, and three manuscripts that studied the chemical decomposition of the two primary cannabis concentrate ingredients, the psychoactive ∆9-tetrahydrocannabinol (THC) and aromatic terpenoids. The known airway toxicant pine rosin or colophony was identified as a major component of a cannabis extract adulterant using liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy (NMR). Though this agent has previously been identified as a hashish adulterant in Europe, this was the first report of its use in North America. THC and cannabis terpenoids were shown to decompose to generate potentially harmful levels of known toxicants such as methyl vinyl ketone, 1,3-butadiene, methacrolein, benzene, toluene, and a slew of other volatile organic compounds (VOCs) with unknown health impacts. Characterization and quantification methods for such VOCs using NMR and automated thermal desorption-gas chromatography-mass spectrometry are presented. Given the lack of previous understanding related to THC and cannabis terpenoid (e.g. β-myrcene) decomposition when heated to the temperatures seen during dabbing and vaping (250–400 °C), special attention is paid to the chemical mechanisms that occur. β-Myrcene decomposition was studied by characterizing the VOCs released when dabbing a site-specifically deuterated isotopologue of this molecule. THC decomposition was studied by characterizing its dabbing and vaping-released VOCs, and comparing these to a structurally similar cannabinoid, cannabinol. Chemical mechanisms that account for large shares of the VOCs released by these molecules are described. Curiously, THC and β-myrcene share a common reactive intermediate that is the source of isoprene, 2-methyl-2-butene, 3- methylcrotonaldehyde, and 3-methyl-1-butene, and it was shown that the relative proportions of these four VOCs is temperature dependent. It was shown that the ratio of the two primary cannabis concentrate ingredients, THC and terpenoids, impacts the release of VOCs and transfer of active ingredients. Specifically, increasing the mass percent of β-myrcene in THC for a synthetic cannabis oil from 7% to 14% led to significant decreases in the the release of degradants and carcinogens such as benzene, 1,3-butadiene, and isoprene, and more efficient transfer of THC when vaping. However, the opposite effect was observed for dabbing: increased mass percent of this terpene led to an increased release of degradation products. In addition to these insights, a novel quantitative risk assessment model for cannabis inhalation was described that allowed for preliminary determination of the relative cancer and non- cancer chronic health risks associated with dabbing, vaping, and smoking cannabis. Further chemical and toxicological characterization of other aerosol components will allow the expansion of this model to provide an accurate description of the chronic health impacts associated with these cannabis consumption modalities.

Flavoring chemicals utilized in electronic nicotine delivery systems (ENDS) have been shown to result in an increase in cellular inflammation, meanwhile, the effects of fruit and tobacco flavors on lung inflammation by nose-only exposures to mice are relatively unknown. We hypothesized that C57BL/6J mice exposed to flavored e-cigarettes would result in an increase in lung inflammation. C57BL/6J mice were exposed to air, propylene glycol/vegetable glycerin (PG/VG), and e-liquids “Apple”, “Cherry”, “Strawberry”, “Wintergreen”, and “Smooth & Mild Tobacco”, for one hour per day for a three day exposure. Quantification of flavoring chemicals was measured by proton nuclear magnetic resonance spectroscopy (1H NMR), differential cell counts by flow cytometry, pro-inflammatory cytokines/chemokines by ELISA, and matrix metalloproteinase levels by western blot. Exposure to PG/VG, Apple, and Smooth & Mild Tobacco resulted in an increase in neutrophil cell count in lung bronchoalveolar lavage fluid (BALF). Strawberry exposure increased KC levels in BALF while in lung homogenate KC levels were increased in PG/VG, Cherry, and Smooth & Mild Tobacco exposure. Exposure to PG/VG and Cherry increased IL-6 levels and in all exposed mice there was a male-specific decrease in MCP-1 levels in lung homogenate. Mice exposed to PG/VG, Apple, Cherry, and Wintergreen resulted in an increase in MMP2 levels. Our results indicate that female mice exposed to cherry flavored e-liquids and male mice exposed to tobacco flavored e-liquids resulted in an increase in inflammation, while exposure to mint flavored e-liquids resulted in a decrease in inflammatory cytokine and an increase in tissue repair proteins. This study revealed that flavored-based e-cigarette exposure elicited sex-specific alterations in lung inflammation, with cherry flavors/benzaldehyde eliciting female-specific increases in inflammation. This highlights the toxicity of flavored chemicals and the further need for regulation of flavoring chemicals.