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Determination of Carbonyl Compounds Found in Electronic Cigarettes

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Madison Hood
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Determination of Carbonyl Compounds Found in Electronic Cigarettes By: Madison Parker
Parker2 Abstract: Electronic Nicotine Delivery Systems (ENDS) and personal vaporizers are battery- powered devices that aerosolizes nicotine so that it is readily available to the user. Food-grade ingredients and traditional cigarette ingredients are used in these devices. There is very little analytical data available that informs the public to the possible health effects of ENDS on the user; however, it is known that these devices put out significant toxic carbonyl compounds. In one experiment, electronic cigarettes were tested to determine their carbonyl compound output. This was tested by testing 13 different brands of electronic cigarette solvent by capturing its vapor using coupled silica cartridges impregnated with hydroquinone and 2, 4- dinitrophenylhydrazine. They were then analyzed using high performance liquid chromatography. Of the 13 brands tested, 4 brands did not generate any carbonyl compounds and 9 generated various carbonyl compounds. From this experiment, there were not specific carbonyl compounds formed for every trial; however, it was determined that electronic cigarettes incidentally produce high concentrations of carbonyl compounds11 . In another study, the effect of nicotine solvent and voltage output on carbonyl compound formation were tested. To determine the effect of nicotine solvent on the carbonyl compound output, ten different electronic cigarette liquids were used for the experiment with concentrations of nicotine varying from 18-24 mg/ml. The ten different electronic cigarette liquids were placed in groupings based on the contents of their humectants. One group was made up of purely propylene glycol, one group purely vegetable glycerin, and another group a ratio of both propylene glycol and vegetable glycerin. In order to see how the base humectant effects the carbonyl compounds, three controls were also prepared for the experiment. In this experiment, it was observed that all electronic cigarette liquids contained at least one carbonyl compound in the vapors produced by the electronic
Parker3 cigarette. In this experiment, formaldehyde, butanol, acetone, and acetaldehyde were the most prevalent carbonyl compounds observed in the electronic cigarette vapors, while acrolein was not detected at all12 . In this same experiment, the effect of voltage on carbonyl compound formation was tested by observing the carbonyl compound generation when increasing the ENDS voltage to 3.2V, 4.0V, and 4.8V. From this experiment, it was observed that as voltage increases, so does the amount of carbonyl compounds formed within the vapors. The most significant increase in carbonyl compounds was observed in humectants that used propylene glycol as a base in the e-liquid. In order to determine the harmful effects of electronic cigarettes to its users, this paper evaluates the instrumentation of ENDS, analyzes the chemical action that occurs during its use, and reviews available evidence that evaluates how carbonyl compounds are generated during electronic cigarette usage.
Parker4 Introduction: Electronic Cigarettes have been around since the 1960’s. Hubert A. Gilbert, in 1963, filed a patent for the idea for the first electronic cigarette. At the time, smoking cigarettes in public was normal social behavior and the toxic side effects of smoking tobacco was not as extensively researched. At the time, there was not a need for “healthier” smoking options and smoking was fairly accepted in society. In 2003, Han Lik, a Chinese pharmacist and a smoker, developed the first usable electronic cigarette after his father passed away from lung cancer. Shortly after its invention, the Chinese and European markets were the first to accept electronic nicotine delivery systems. In 2007, the electronic cigarette was introduced into the American market3 . Over the years, the FDA and manufacturers have fought over the regulations of selling and producing electronic cigarettes, due to their unknown health effects on users. Import bans have been placed on the product and law suits have been filed to try and stop the spread of the popular product. To this day, electronic cigarettes are still banned in certain states. Originally, electronic cigarettes were created to help smokers quit their smoking addiction. Now electronic cigarette-use has evolved into a large community that utilizes personal vaporizers that can be modified to maximize the user’s smoking preferences. Electronic nicotine delivery systems are designed to look like traditional tobacco cigarettes in order to simulate the sensory, social, visual, and behavioral features of smoking4 . The models can be filled with any of the thousands of available “e-juice” flavors that range from traditional coffee, vanilla, cigar, or more unique flavorings such as watermelon, mango, or cotton candy17 . Some “e-juice” brands aim to simulate traditional cigarette brands such as Camel or Marlboro1 . Each “e-juice” contains varying amounts of nicotine, propylene glycol, vegetable glycerin, and food-grade flavorings.
Parker5 The “e-juice” is heated using a battery-powered device which aerosolizes the liquid mixture to the user for inhalation1 . There is little known about the long-term health risks associated with electronic cigarette usage or the “e-juice” that it utilized. Due to a lack of combustion, these products do not contain typical carcinogens that are known to be in tobacco products. In addition to the nicotine used to help curb a smoker’s addiction, other compounds that are added to the electronic cigarette liquid such as the humectant, flavoring, and other food-grade additives can cause problems. As this fad continues to increase, so does the need for regulation and the understanding of the long term effects. Electronic Nicotine Delivery System The electronic nicotine delivery system is a battery-powered alternative to cigarette smoking. The device utilizes an atomizer to heat up the liquid mixture of nicotine dissolved in propylene glycol. The propylene glycol acts as a humectant for the nicotine that users crave. Characteristically, propylene glycol is a sweet, colorless, and odorless substance. When mixed with the nicotine, it helps to preserve nicotine in the state needed for delivery. When it is inhaled by the user, the resultant is a white cloudy smoke similar to cigarette smoke; however, it’s odorless, which makes this form of smoking more attractive to its users. First generation electronic cigarettes consist of a cartridge that holds the nicotine and propylene glycol mixture and a battery that atomizes the liquid to be inhaled by the user. This electronic nicotine delivery system is disposable and is powered when the user inhales. A model of the first generation electronic cigarette can be seen in Figure I.
Parker6 Figure I. Model of a first generation electronic cigarette. Figure II. shows the general set up of the second generation electronic cigarette. The second generation electronic nicotine delivery system is powered by a lithium-ion battery. When the user presses the control button, the device activates the atomizer. There are two different types of atomizers: systems that are disposable and systems that can be rebuilt. Those that are disposable are classified as clearomizers or cartomizers. Those that can be rebuilt are referred to as rebuildable dripping atomizers (RDA) or rebuildable tank atomizers (RTA)2 . Inside the atomizer is a wick that soaks up the homogenous liquid. The wick is then wrapped around an internal coil. The internal coil is nichrome wire made up of 80% nickel and 20% chromium that is heated and incidentally heats the temperature of the electronic liquid to extremely high temperatures. At the vaporization point, the aqueous solution of vegetable glycerin, propylene glycol, flavoring, and/or nicotine within the tank is atomized to vapor. The vapor is then inhaled through the mouthpiece by the user.
Parker7 Figure II. Model of the second generation electronic cigarette. The newest generation of ENDS has progressed into box-mod devices that allow the user to have absolute control over their smoking experience and is sometimes referred to as a personal vaporizer. The personal vaporizer has LED displays and controls that allow the user to increase or decrease the voltage of the device. The flexibility of the device allows the user to customize their electronic liquid mixture to optimize their smoking capability. The box-mod/personal vaporizer model can be seen in Figure III. Figure III. Model of a box-mod personal vaporizer (3rd Generation).
Parker8 E-liquid The two most widely used electronic cigarette bases are propylene glycol and vegetable glycerin, usually referred to as glycerol. There are four main ingredients found in electronic liquids: (1) a propylene glycol or vegetable glycerin base, (2) water, (3) flavoring, and (4) nicotine. Propylene glycol and vegetable glycerin are commonly used as food additives and are known to be safe for consumption. They are non-toxic organic compounds that hold the nicotine and flavor in suspension. These particular bases are favored because they are characteristic for the white clouds of vapor that are exhaled by the user. Every electronic liquid contains propylene glycol, vegetable glycerin, or a customized ratio of both. The organic molecule propylene glycol is generated from propylene oxide. It is odorless, has low viscosity, and colorless. It is typically utilized to preserve foods, as solvents, pharmaceutical products, and tobacco products. Vegetable glycerin comes from naturally extracted plant oils such as coconut oil, palm oil, and soy. It is odorless, slightly tinted in color, sweet, and typically more viscous than propylene glycol. It is found in food production, cosmetics, and tobacco products. Electronic cigarettes are known for being customizable down to the flavor of their electronic liquid; however, the chemicals used to flavor electronic cigarettes may not be as safe as individuals’ believe5 . Third generation personal vaporizers allow for the user to choose a unique flavoring of electronic liquid to be vaporized. Flavorings can imitate common tobacco products such as Camel and Marlboro, and some manufacturers have developed dessert-like flavorings such as Pumpkin Spice, Watermelon, Swedish Fish, Marshmallow, or even Cotton Candy to name a few. Most of these flavorings are food-grade ingredients that have been deemed by the Federal Drug Administration as safe to consume; however, the FDA has not been able to
Parker9 state whether the food-grade ingredients are safe to inhale. These flavorings and additives make the nicotine also found in the electronic liquid more addicting and appealing to its users. Those who are regularly exposed to nicotine become dependent on the chemical16 . If exposure is discontinued, the user can experience withdrawal symptoms such as cravings, depression, anxiety, the feeling of emptiness, and irritability6 . In electronic cigarettes, nicotine is present in the liquid form and held in suspension by a humectant, which is then heated and aerosolized for the user to inhale. In its liquid form, nicotine is highly concentrated and exceedingly toxic13 . Users of personal vaporizers can also customize the concentrations of nicotine utilized within the electronic nicotine delivery system. Liquid concentrations of nicotine vary from 0 to 18 mg/ml and some were even found as high as 36-42 mg/ml. Dosing is inconsistent and fluctuates by manufacturer. E-liquids containing “low doses” of nicotine correspond to a concentration of 6-8 mg/mL, “Midrange” concentrations contain 10-14 mg/mL, “High” concentrations correspond to 16-18 mg/mL, and “Extra-high” concentrations correspond to 24-36 mg/mL of nicotine per mL of liquid1 . All doses of liquid nicotine have the numerical concentration printed on the container of the electronic liquid or on its original packaging; however, some studies have determined that the actual concentration of nicotine within the electronic liquid is hard to determine and often differs from what is stated on the packaging16 . Therefore, the user must be careful when loading their personal vaporizers due to the fact that nicotine toxicity can occur when the liquid is consumed or applied to the skin13 . An ENDS user has the option to determine which base they would like to utilize as a humectant in the third generation personal vaporizer. Users can use a pure propylene glycol base or vegetable glycerin base. Often times, users create differing ratios of propylene glycol and vegetable glycerin in order to maximize their smoking experience. Propylene glycol is utilized
Parker10 more often than vegetable glycerin as an e-liquid base for many reasons. Both structures can be seen in Figure IVa. and Figure IVb. Figure IVa. Structure of Propylene Glycol Figure IVb. Structure of Vegetable Glycerin Because propylene glycol is less viscous than vegetable glycerin it’s easier to load into the reusable drip tank and there is less build-up deposited on the nichrome wire coil after the liquid has been vaporized. Vegetable glycerin has a higher viscosity and density so it often creates build up on the nichrome coil that heats up the electronic liquid over time. Due to vegetable glycerin’s high viscosity, it takes more energy and a takes longer to reach the optimal temperature needed to vaporize; however, the density of the vegetable glycerin allows the user to create thicker vapor and tends to be a healthier option for the user.
Parker11 Chemical Reaction through which Propylene Glycol/Glycerol forms Carbonyl Compounds In order for the vaporizer to work, the propylene glycol, flavoring molecules, and nicotine molecules must be heated to their heat of vaporization without chemically degrading them. It is estimated that the theoretical vaporization temperature of an electronic cigarette could reach up to 350 ̊C. This temperature is high enough to cause physical alterations to the chemicals within electronic liquids and cause chemical reactions to occur within the solvent. At such high temperatures, the solution could undergo thermal decomposition which leads to the generation of toxic aldehydes6 . When glycerol (vegetable glycerin) is heated, it decomposes by a dehydration mechanism to acrolein and water. Eq. 1 C3H8O3 ∆ → C2H3CHO + 2H2O Acrolein is typically found in the environment and in food products. It can be formed from carbohydrates, animal fats, or by heating foods; however, when smoking tobacco products, the produced acrolein exceeds or equals the total human exposure to acrolein from all other sources. It is a colorless, poisonous, pungent, and the simplest unsaturated aldehyde. This volatile organic compound can cause burning of the nose and throat and can cause damage to the lungs. By a retro aldol condensation reaction, acrolein can further break down into acetaldehyde and formaldehyde. This reaction only occurs in the presence of a catalyst, such as the hot metal present in the e-liquid in the form of coils that heat the liquid. The nichrome wire present in the atomizer of the electronic cigarette is known to have a low heat tolerance and give a metallic taste to the user2 . Acids and bases can also catalyze the reaction and are present in the electronic liquid flavorings. Glycerol Acrolein
Parker12 Eq. 2 C3H8O ுశ ሱሮ H3CCHO + HCHO Eq. 3 C3H8O ௛௢௧ ௠௘௧௔௟ ሱۛۛۛۛۛۛሮ H3CCHO + HCHO Formaldehyde is a colorless, overpowering organic compound. The short term effect of this compound on the body could be irritation of the eyes, throat, and nose. If exposed to this toxic compound over a longer period of time, one could experience coughing, trouble breathing, rawness of the throat and interior of the nose. The respiratory system could also be effected. It has also been shown that with increased dosages of formaldehyde to the body, there is also an increase in developing specific types of cancer8 . In an electronic cigarette that utilizes propylene glycol, the propylene glycol boils when exposed to extremely high temperatures. With these specific conditions in the form of a catalyst, the electronic liquid could dehydrate to form propionaldehyde. Eq. 4 C3H8O2 ିுమை ሱۛۛሮ C2H5CHO Propionaldehyde is a colorless liquid that is accompanied by a fruity smell. When in contact with the body it can irritate the skin, nose, throat, and lungs. When inhaled it could cause shortness of breath, excessive coughing, and pulmonary edemas. Glycerol Glycerol Acetaldehyde Formaldehyde Acetaldehyde Formaldehyde PropionaldehydePropylene Glycol
Parker13 Effect of Aldehydes on the Body An aldehyde is an organic compound that contains a –CHO group. It is a simple carbonyl molecule that is formed by the oxidation of alcohol. The most common aldehydes are formaldehyde, formed from methanol, and acetaldehyde, which is generated from ethanol. Aldehydes such as acrolein, formaldehyde, acetaldehyde, and crotonaldehyde have been documented to have acute effects on the human body8 . Common aldehydes and their structures can be seen below in Figure V. Figure V. Common aldehydes and their chemical structures. acrolein Among these examples, acrolein was found to have the greatest impact7 . Acrolein is found to be 2 to 3 times more toxic formaldehyde7 . Occasional exposure to aldehydes may cause olfactory and ocular irritation. Long-term contact may cause extreme irritation to the mucous membranes and damage to respiration7 . Chronic exposure can even cause irreversible damage to the epithelial tissues lining the lungs and respiratory tract. A study was performed on rats to
Parker14 determine carcinogenicity of aldehydes. Rats were exposed to a concentration of formaldehyde for a period of time. After that period of time, 103 rats were observed to have induced squamous cell carcinoma. The same procedure was performed on mice. The mice were observed with nasal tumors. These studies all gave evidence to reversible and irreversible damage to epithelium cells lining the respiratory tract and the damage that can occur when exposed to aldehydes8 . Mechanism for Formation of Carbonyl Compounds by Glycerol and Propylene Glycol The electronic liquids in the electronic cigarette tank are vaporized when they come into contact with the nichrome wire and oxidized in the presence of oxygen from the surrounding air to form formaldehyde, acrolein, glyoxal, methylglyoxal, and acetaldehyde9 . The solid metal oxide wire is used as a catalyst in this reaction. Because the vegetable glycerin has a high boiling point, this is referred to as a heterogeneous catalyst9 . Figure VI. shows the reaction that occurs when the electronic liquid comes in contact with the heated nichrome wire. Figure VI. Oxidation of vegetable glycerin and propylene glycol with the nichrome wire as a catalyst
Parker15 The vegetable glycerin is oxidized to form acrolein. The propylene glycol is oxidized to form methylglyoxal and then further oxidized to form formaldehyde and acetaldehyde whose toxicity is well documented20 . Mechanism of Glycerin Dehydration Reaction to Carbonyl Compounds Glycerin acts as a humectant for a homogenous mixture of flavoring, nicotine, and water. Alcohols can undergo a variety of changes, most of which are either oxidation or reduction reactions. Primary alcohols can be oxidized to form an aldehyde structure. Oxidation is when there is a loss of hydrogen and an addition of an oxygen or halogen. Primary and secondary alcohols can be easily oxidized using catalysts such as acids and metals. The coil that is used to vaporize the electronic liquid is made up of nichrome wire. The hot metal catalyzes the oxidation reaction. The high temperatures that are reached within the electronic cigarette cause thermal degradation to occur, which is the probable catalyst for this oxidation reaction. The use of a heterogeneous catalyst significantly reduces the activation energy of the transition states and increases the rate of the reaction. Glycerin has been found to dehydrate to acrolein; however, the mechanism does not just produce acrolein but other carbonyl compounds such as acetaldehyde, propanal, and acetone. From the reaction, carbon dioxide and carbon monoxide were identified in small quantities10 . Glycerin readily forms a homogenous mixture with water due to its three hydroxyl groups that readily form a hydrogen bond with water molecules. When glycerin is in its purest form, its boiling point is 290 ̊ C. When water is mixed with glycerin to form a homogenous solvent, the boiling point decreases. Figure VII. shows the reaction mechanisms possible for the dehydration of glycerin.
Parker16 Figure VII. Pathways of dehydration of glycerol and its proposed products. Figure VII. shows that there are two specific pathways of dehydration that glycerin can undergo-a 1-2 dehydration and a 1-3 dehydration. The 1-2 dehydration occurs when the secondary or primary hydroxyl group is protonated. If the secondary hydroxyl group is protonated, acrolein will be formed, if the terminal hydroxyl group is protonated, acetol will be formed. When the terminal hydroxyl group is protonated, has an unstable transition state is formed; however, this state is stabilized due to the conjugation of the weak basic sites4 . From this pathway, acetol is formed. If this product was dehydrated again, the product that would form would be thermodynamically unstable. Because of its unstability, acetol is the major product of this dehydration pathway. This unstable transition state is the reason that the dehydration pathway yields a large acrolein output. Acrolein is formed when the secondary hydroxyl group is protonated. The hydroxy propanal that is formed undergoes a second dehydration to form
Parker17 acrolein. If an aldol or retro aldol condensation reaction occurs, acetaldehyde, formaldehyde, and acrolein are favorable products. In a 1-3 dehydration of glycerin, the carbon backbone is deconstructed and the products formed are formaldehyde and vinyl alcohol. The mechanisms for the carbon backbone deconstruction and decomposition to formaldehyde and acetaldehyde can be seen in Figure VIII. The vinyl alcohol goes through keto-enol tautomerization to acetaldehyde, this aldehyde can further oxidized to form acetic acid. In the experiments performed, both acetaldehyde, formaldehyde, and acetic acid were present in the vapors produced by electronic cigarettes. Figure VIII. Mechanism for the deconstruction of the carbon backbone that occurs due to high temperatures Electronic cigarettes are heated to high temperatures in order to reach the vaporization temperature of the solvent so that it can be aerosolized to the user for inhalation. Formaldehyde is known to be unstable at such increased temperatures. When this occurs, formaldehyde
Parker18 thermally decomposes to carbon monoxide and hydrogen. The hydrogen that is formed at these high temperatures are responsible for reducing products formed in the reaction pathway. Mechanism of Propylene Glycol Dehydration to Carbonyl Compounds Propylene glycol decomposes at high temperatures via three different reaction pathways15 . These pathways can be seen below in Figure IX. Figure IX. Scheme of the three reaction pathways of propylene glycol In the first pathway, propylene glycol (1) dehydrates to an allyl alcohol (5). The reaction barrier for this pathway is fairly high compared to the other pathways15 . TDue to the higher reaction barrier, this pathway is not as favored as the other two. The allyl alcohol is further split into formaldehyde and acetaldehyde by bond scission. In the second pathway, Propylene glycol is dehydrated to form propylene oxide (2) as an intermediate; however, if a hydrogen shift occurs, propylene glycol will further decompose to acetone (3). The mechanism for this decomposition can be seen in Figure IX. in the first mechanism. In this mechanism, a hydrogen ion comes out and the propylene oxide structure
Parker19 rearranges it’s double dond to form acetone. Acetone was found in electronic cigarette vapors in multiple studies. This shows that this pathway can be favored at high temperatures. The propylene glycol can also decompose to propanal, or propionaldehyde (4). This can be seen in Figure X. below the first mechanism. In this mechanism, a hydride shift occurs and the propylene oxide rearranges it’s structure to form propionaldehyde.. The propylene glycol is in equilibrium with the protonated form; however, at high temperatures, entropy favors dehydration which will be stabilized by the formation of the enol15 . The reaction barrier to form propionaldehyde is the lowest among the pathways, therefore, this pathway is the most favorable and the main product formed in the thermal degradation of propylene glycol. Figure X. Mechanism of the rearrangement of propylene oxide in the event of a hydride shift Propylene glycol has been known to produce more carbonyl compounds than glycerol when vaporized. After reviewing both mechanisms, it can be assumed that this occurs due to the amount of carbonyl compounds produced for each molecule of humectant. The dehydration of propylene glycol has the possibility to yield formaldehyde and propionaldehyde. The propionaldehyde can further decompose to acetone. Therefore, this reaction mechanism presents
Parker20 the formation of two carbonyl species for every one molecule of propylene glycol. The glycerin only forms one carbonyl molecule when dehydrated. Determination of Carbonyl Compounds Generated from E-Cigarettes by HPLC In this experiment, carbonyl compounds from electronic cigarette vapor were captured using coupled silica cartridges impregnated with hydroquinone and 2, 4-dinitrophenylhydrazine and were analyzed using high performance liquid chromatography. A test group of 13 electronic cigarette brands were analyzed in this way. Of the 13 brands tested, 4 brands did not generate any carbonyl compounds and 9 generated various carbonyl compounds. From this experiment, there was not a prominent carbonyl compound that was always formed; however, it was determined that electronic cigarettes incidentally produce high concentrations of carbonyl compounds11 . An HPLC instrument was set up with two LC20AD pumps, photodiode array detector, and an auto-sampler. The column used allowed for a 2.7μm particle size and was 150mm x 4.6mm. The column temperature was set for 40 ̊C and the injection size was 10μL. The flow rate of the mobile phase was 0.7 mL/min. In order to generate vapor, a smoking machine was employed. Before the collection of the vapors from the electronic cigarette machine, a hydroquinone cartridge (HQ-cartridge) and a 2, 4-dinitrophenylhydrazine cartridge (DNPH- cartridge) were connected to the machine to capture the vapors in solid form. The cartridges were placed between the mouthpiece of the electronic cigarette and the smoking machine in order to collect the carbonyl compounds from the vapors. The smoking machine was set to 55mL puff volume, 2-s puff duration, 30-s puff interval, and 10 puffs. The cartridges were removed after each run and were rinsed with acetonitrile containing 1% phosphoric acid in the opposite
Parker21 direction the smoking machine was used until the total volume reached 4.5 mL. After 10 minutes, ethanol was added to the solution and it was then analyzed by HPLC11 . From this experiment, multiple simple carbonyl compounds were detected in the vapors of electronic cigarettes. Major carbonyl compounds found in electronic cigarette vapors were formaldehyde, acetone, propanol, glyoxal, acetaldehyde, and methylglyoxal11 . Figure XI. shows a sample chromatograph from one of the trials. Figure XI. Chromatogram of carbonyl compounds found in e-cigarette vapors. (Where FA=formaldehyde, AA=acetaldehyde, ACR=acrolein, GA=glyoxal, AC=acetone, MGA=methylglyoxal, and PA=propanol)11 The concentrations of each carbonyl compound that was found in the electronic cigarettes were compared against each other for each electronic cigarette brand. These comparisons can be seen in Figure XII.
Parker22 Figure XII. Graphs of the concentrations of carbonyl compounds found in 10 e-cigarettes using the same brand of e-liquid11 . The concentrations of all the major carbonyl compounds that were produced during the experiment from all 13 brands of e-liquid tested can be seen in Table I.
Parker23 Table I. The concentrations of key carbonyl compounds that were produced from the 13 e- cigarette brands tested11 From Figure XII. and Table I. the statistical analysis shows that there were large statistical differences in the carbonyl compounds produced among the different products and the carbonyl concentrations. Of the 13 e-cigarettes tested, nine produced carbonyl compound groups and the other four (J, K, L, M) did not. This evidence highly suggests that not one specific carbonyl group is produced; however, from the results it was noted that formaldehyde was measured at high concentrations in the electronic cigarette vapor. Two new carbonyl groups that were observed that are not prevalent in traditional cigarette smoke were glyoxal and methylglyoxal. Both are known to be mutagenic aldehydes. Methylglyoxal, also known as pyruvaldehyde, inhibits the metabolism of formaldehyde and increases the chance of formaldehyde-induced cytotoxicity11 .
Parker24 From this experiment, the cartomizer that was utilized was examined after the conclusion of the experiment. The cartomizers used in this experiment operated with a nichrome wire to heat the electronic liquid mixture to vaporization temperature so that it could be delivered in aerosol form. After the experiment, the nichrome wire was observed to have changed color from white to black. The cartomizer used in this experiment can be seen in Figure XII. Figure XII. The cartomizer used from the experiment with blackened deposits from thermal degradation of e-liquids used. The left shows a cartomizer that produced low concentrations of carbonyl compounds while the right shows a cartomizer that produced high concentrations of carbonyl compounds11 . From what is known about the contents of the electronic liquid used in electronic cigarettes, it can be assumed that the propylene glycol and glycerin came in contact with the metal, which catalyzed an oxidation reaction to form the carbonyl compounds acetone, acetaldehyde, formaldehyde, acrolein, glyoxal, and methylglyoxal.
Parker25 The Effect of Nicotine Solvent and Battery Output Voltage on Carbonyl Compounds Present in Electronic Cigarettes Previous experiments that determined the levels of carbonyl compounds found in e- cigarettes were performed on first generation electronic cigarettes. Since those experiments were performed, the electronic cigarette market continued to enhance the product and rapidly introduce the “second generation” electronic cigarette and “third generation” electronic cigarette which is also referred to as a personal vaporizer. This newest instrumentation allows the user to fully customize their smoking experience. The user can determine what ratio of propylene glycol to glycerin they would like to use in the tank, along with the concentration of nicotine. The individual can also increase the vaporization temperature by changing the battery output voltage. In this experiment, ten nicotine solvents and three control solutions made up of pure propylene glycol, pure glycerin, or a mixture of both solutions, were analyzed for twelve particular carbonyl compounds. The electronic cigarette voltage was slowly increased during the experiment from 3.2V to 4.8V. The carbonyl compounds were measured using HPLC method. The purpose of the experiment was to determine how battery output voltage and the nicotine solvent effect the concentration of carbonyl compounds produced in the vapors of the newest electronic cigarette model. Ten different electronic liquids were used for the experiment with concentrations of nicotine varying from 18-24 mg/ml. The ten different e-liquids were placed in groupings based on the contents of their humectants. Products A1-A3 were glycerin based, products A4-A6 were a mixture of glycerin and propylene glycol, and products A7-A10 were purely proplene glycol based. In order to see the how the base humectant effects the carbonyl compounds, three controls were also prepared for the experiment. The controls were made by dissolving liquid nicotine in
Parker26 analytical-grade solvents. Control 1 (C1) was a ratio of 88.2% glycerin, 10% redistilled water, and 1.8% nicotine. Control 2 (C2) was made up of 44.1% glycerin, 44.1% propylene glycol, 10% redistilled water, and 1.8% nicotine. Control 3 (C3) was composed of 88.2% propylene glycol, 10% redistilled water, and 1.8% nicotine. Each test was performed with a 70mL puff volume, 1.8s puff duration, and puff intervals of 17s. Each test consisted of 30 puffs from each electronic cigarette. The trial was ran in two series of 15 puffs with a 5 minute break in between series. For the experiment testing battery output voltage effect on carbonyl compounds found in electronic cigarettes, the electronic cigarette generated vapor at the battery voltages 3.2V, 4.0V, and 4.8V12 . The controls were utilized for this trial and each voltage was performed three times for each control for a total of nine runs. Table II. shows the electronic liquid brands, the label information, and nicotine content for each brand that was utilized for the experiment.
Parker27 Table II. Ingredient list with nicotine concentrations for each e-liquid product used12 . Silica gels were impregnated with 2, 4-dinitrophenylhydrazine in order to extract the carbonyl compounds from the aerosol phase to the solid phase to be examined. These gels were placed in
Parker28 between the mouthpiece of the electronic cigarette and the smoking machine in order to trap the carbonyl compounds that are present in the electronic cigarette vapors. The gels were rinsed with 1mL of acetonitrile. The solvent was then analyzed using HPLC. The elution gradient was made up of acetonitrile and water and the separation was carried out at 40 ̊ C. Table III. Shows the carbonyl compounds that were present in the vapors generated by the electronic cigarettes in the experiment12 . Table III. Carbonyl compounds present in the ten e-liquid solutions12 Table III. shows that all electronic liquids contained at least one carbonyl compound in the vapors generated by the electronic cigarette. This phenomena could have occurred due to the high temperatures needed to vaporize the electronic liquid. At these high temperatures, the solvents could have been catalyzed by the metal coil used to heat the liquid and the solvents could have undergone thermal decomposition. The humectants present in the bases, propylene glycol and glycerin, could have been oxidized to form the toxic carbonyl compounds. In this experiment, formaldehyde, butanol, acetone, and acetaldehyde were the most prevalent carbonyl compounds observed in the electronic cigarette vapors, while acrolein was not detected at all12 .
Parker29 The effect of battery output voltage on the carbonyls released in the electronic cigarette vapors were measured by increasing the battery voltage for each control and measuring the carbonyl groups using the silica gels saturated in DNPH. Each control was ran three times at each voltage. The amounts of acetone, acetaldehyde, and formaldehyde that were measure for each run and each control at each battery voltage output can be seen in Figure XIII. Figure XIII. The effect of the battery output voltage on carbonyl compound yields from e- cigarettes12 Figure XIII. shows that when the voltage was increased from 4.0V to 4.8V, the amount of formaldehyde in electronic cigarettes that used a propylene glycol and glycerin mixture base or purely propylene glycol increased significantly. The acetaldehyde was also significantly increased in those mixtures when the voltage was increased. Similarly, the amount of acetone produced experienced a statistically significant increase from 3.2V to 4.8V in the control that used the base mixture of glycerin and propylene glycol. Glycerin was not as affected by battery output as the base mixture propylene glycol; however, in this experiment, an increase in voltage
Parker30 showed an increase in carbonyl compound yield. Propylene glycol is known to be less viscous than glycerin. This means that it has a lower optimum temperature that it can be aerosolized. When voltage is increased, and temperature is increased faster, the reaction rate of the oxidation of propylene glycol will be increased, which produces more toxic carbonyl compounds. These results also propose that propylene glycol is more vulnerable to the thermal degradation than glycerin. Conclusion: The vaping community is quickly emerging. Between 2012-2013, the sale of electronic products increased 320% for disposable electronic cigarettes, 72% for starter kits, and 82% for cartridges18 .Within the next year, revenue from electronic cigarettes are expected to double to over $1.7 billion and projected to pass traditional cigarette sales by 204719 . With its increasing popularity, the electronic cigarette has rapidly evolving technology that gives the user more freedom with their personal vaporizing experience. There is still a lot to learn about the chemical reactions that are taking place within the electronic nicotine devices and how the by-products of these reactions could affect the user’s body short-term and long term. The refill solutions for these ever-evolving systems contain aldehydes, heavy metals, volatile organic compounds, food- grade flavoring, and humectants. Research has only scratched the surface of the chemical reactions that take place among all these additives. At the high temperatures that are required to vaporize these solutions, unpredictable behaviors among the compounds take place and carcinogenic carbonyl compounds are being formed and inhaled17 . The inconsistency of the carbonyl compounds that are formed from the electronic cigarette vapors suggests that at high temperatures there is a lot more interaction among the compounds within the solvents. From the studies performed it has been observed that at these high temperatures, the electronic liquid is
Parker31 catalyzed by the nichrome wire that incidentally touches the electronic liquid as it is heated to its vaporization temperature. By the metal coil, the solvent is oxidized to form formaldehyde, acetaldehyde, acrolein, and acetone. Increase in battery output voltage also proved that these toxic compounds can be produced in extremely high concentrations. The mechanism reaction for the oxidation of the solvent to form aldehydes has been determined; however, when food additives and flavorings are added to the solvent, there is a possibility of more interaction within the solvent and more toxic by-products being produced due to an acid catalyst being present. While it is known how the body is affected when these additives are consumed, it is not known how the body is affected when these additives are inhaled. Aldehydes have been identified as cytotoxic and carcinogenic and highly toxic to the body when exposed over a long period of time. In order to further the research on electronic cigarette reactions and obtain precise results, more research should be performed to determine the behaviors of electronic cigarette users. With this information, experiments can be ran similarly to the electronic cigarette user’s behavior so that results are more comparable. Also by standardizing the analysis of aerosol generation and collection of carbonyl compounds, this would allow for better comparisons of electronic cigarette vapor and cigarette smoke.
Parker32 References 1. VapeHit. E-liquid Facts. http://www.vapehit.co.uk/info.php?articles&articles_id=22 (accessed Oct. 25, 2015). 2. Info Electronic Cigarette. Electronic Cigarette GLossery.http://info-electronic- cigarette.com/electronic-cigarette-glossary/(accessed Oct. 21, 2015). 3. Eversmoke Electronic Cigarettes. History of the Electronic Cigarette. http://www.learn.eversmoke.com/history-of-electronic-cigarettes.html (accessed Oct. 21, 2015). 4. Nguyen, David and Aamodt Gail. Electronic Cigarettes the Past, Present, and Future. Continuing Education Course. DentalCare.com [Online] (October 1 2014). http://www.dentalcare.com/media/en-US/education/ce451/ce451.pdf (Accessed Oct. 15, 2015) 5. Sifferlin, Alexandra. E-cig Flavors May BE Dangerous, Study Says. Time. [Online] 2015. http://time.com/3822831/ecig-flavors/ (accessed Oct. 17, 2015) 6. Medical News Today. What is Nicotine? http://www.medicalnewstoday.com/articles/240820.php (Accessed Oct. 18, 2015) 7. Marnett, Lawrence J. Health Effects of Aldehydes and Alcohols in Mobile Source Emissions. In Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press, 1988. pp 580-585. (http://www.nap.edu/read/1033/chapter/25#583) (accessed Oct. 18, 2015) 8. Cassee, Flemming R; Groten, John P; Feron, Victor J. Changes in the Nasal Epithelium of Rates Exposed by Inhalation to Mixtures of Formaldehyde, Acetaldehyde, and Acrolein. Fundamental and Applied Toxicology. [Online] 1995, 29, 208-218. (http://toxsci.oxfordjournals.org/content/29/2/208.full.pdf+html) (accessed Oct. 23, 2015) 9. Laino, Teodoro; Tuma, Christian; Moor, Philippe; Martin, Elyette; Stolz, Steffen; Curioni, Alessandro. Mechanisms of Propylene Glycol and Triacetin Pyrolysis. J. Phys. Chem. A 2012, 116, 4602-4609 (http://eprints.eemcs.utwente.nl/22979/01/stolz1- jp300997d.pdf) (accessed Oct. 18, 2015) 10. Ulgen, Arda. Conversion of Glycerol to the Valuable Intermediates Acrolein and Allyl Alcohol in the Presence of Heterogeneous Catalysts. [online] (http://publications.rwth- aachen.de/record/63757/files/3078.pdf;) (accessed Oct. 19, 2015) 11. Uchiyama, Shigehisa; Ohta, Kuzushi; Inaba, Yohei; Kunugita, Naoki. Determination of Carbonyl Compounds Generated from the E-Cigarette Using Coupled Silica Cartridges Impregnated with Hydroquinone and 2, 4-Dinitrophenylhydrazine, Followed by High- Performance Liquid Chromatography. Analytical Sciences. December 2013, Vol. 29, 1219-1222. 12. Kosmider PharmD, Leon; Sobczak PhD, Andrzej; Fik PharmD, Maciej; Knysak PharmD, Jakub; Zaciera PharmD, Marzena; Kurek PharmD, Jolanta; Goniewicz PharmD, PhD, Maciej Lukasz. Carbonyl Compounds in Electronic Cigarette Vapors---Effects of Nicotine Solvent and Battery Output Voltage. Nicotine & Tobacco Advance Access. May 14, 2014.
Parker33 13. Centers for Disease Control and Prevention. Nicotine: Systematic Agent. http://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750028.html (accessed Oct. 17, 2015) 14. Geiss, Otmar; Bianchi, Ivana; Barahona, Francisco; Barrero-Moreno, Josefa. Characterization of Mainstream and Passive Vapours Emitted by Selected Electronic Cigarettes. International Journal of Hygiene and Environmental Health. Vol 218, Issue 1, January 2015, 172-180. 15. Schlaf, Marcel; Zhang, Z. Conrad; Cellulose Hydrogenolysis to Ethylene Glycol and 1,2- Propylene Glycol. Reaction Pathways and Mechanisms in Thermocatalytic Biomass Conversion I. Springer: New York, 2015; pp 242-247. 16. Cheng, Tianrong. Chemical Evaluation of Electronic Cigarettes. Center for Tobacco Products, Food, and Drug Administration. [Online]. 2014, 23, ii11-ii17. 17. Lim, Hyun-Hee; Shin, Ho-Sang. Measurement of Aldehydes in Replacement Liquids of Electronic Cigarettes by Headspace Gas Chromatography-Mass Spectrometry. Bull Korean Chem. Soc. 2013, Vol. 34, No. 9. Pp. 2691-2695. 18. Center for Disease Control and Prevention. Economic Facts About U.S. Tobacco Production and Use. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/economics/econ_facts/ (accessed Oct. 23, 2015) 19. Forbes. E-Cigarette Sales Surpass $1 Billion As Big Tobacco Moves In. http://www.forbes.com/sites/natalierobehmed/2013/09/17/e-cigarette-sales-surpass-1- billion-as-big-tobacco-moves-in/ (accessed Oct. 24, 2015) 20. Forbes. E-Cigarette Flavoring Chemicals May Pose Risks When Inhaled. http://www.forbes.com/sites/tarahaelle/2015/04/16/e-cigarette-flavoring-chemicals-may- pose-risks-when-inhaled/. (accessed Oct. 24, 2015).
Determination of Carbonyl Compounds Found in Electronic Cigarettes By: Madison Parker
Parker2 Abstract: Electronic Nicotine Delivery Systems (ENDS) and personal vaporizers are battery- powered devices that aerosolizes nicotine so that it is readily available to the user. Food-grade ingredients and traditional cigarette ingredients are used in these devices. There is very little analytical data available that informs the public to the possible health effects of ENDS on the user; however, it is known that these devices put out significant toxic carbonyl compounds. In one experiment, electronic cigarettes were tested to determine their carbonyl compound output. This was tested by testing 13 different brands of electronic cigarette solvent by capturing its vapor using coupled silica cartridges impregnated with hydroquinone and 2, 4- dinitrophenylhydrazine. They were then analyzed using high performance liquid chromatography. Of the 13 brands tested, 4 brands did not generate any carbonyl compounds and 9 generated various carbonyl compounds. From this experiment, there were not specific carbonyl compounds formed for every trial; however, it was determined that electronic cigarettes incidentally produce high concentrations of carbonyl compounds11 . In another study, the effect of nicotine solvent and voltage output on carbonyl compound formation were tested. To determine the effect of nicotine solvent on the carbonyl compound output, ten different electronic cigarette liquids were used for the experiment with concentrations of nicotine varying from 18-24 mg/ml. The ten different electronic cigarette liquids were placed in groupings based on the contents of their humectants. One group was made up of purely propylene glycol, one group purely vegetable glycerin, and another group a ratio of both propylene glycol and vegetable glycerin. In order to see how the base humectant effects the carbonyl compounds, three controls were also prepared for the experiment. In this experiment, it was observed that all electronic cigarette liquids contained at least one carbonyl compound in the vapors produced by the electronic
Parker3 cigarette. In this experiment, formaldehyde, butanol, acetone, and acetaldehyde were the most prevalent carbonyl compounds observed in the electronic cigarette vapors, while acrolein was not detected at all12 . In this same experiment, the effect of voltage on carbonyl compound formation was tested by observing the carbonyl compound generation when increasing the ENDS voltage to 3.2V, 4.0V, and 4.8V. From this experiment, it was observed that as voltage increases, so does the amount of carbonyl compounds formed within the vapors. The most significant increase in carbonyl compounds was observed in humectants that used propylene glycol as a base in the e-liquid. In order to determine the harmful effects of electronic cigarettes to its users, this paper evaluates the instrumentation of ENDS, analyzes the chemical action that occurs during its use, and reviews available evidence that evaluates how carbonyl compounds are generated during electronic cigarette usage.
Parker4 Introduction: Electronic Cigarettes have been around since the 1960’s. Hubert A. Gilbert, in 1963, filed a patent for the idea for the first electronic cigarette. At the time, smoking cigarettes in public was normal social behavior and the toxic side effects of smoking tobacco was not as extensively researched. At the time, there was not a need for “healthier” smoking options and smoking was fairly accepted in society. In 2003, Han Lik, a Chinese pharmacist and a smoker, developed the first usable electronic cigarette after his father passed away from lung cancer. Shortly after its invention, the Chinese and European markets were the first to accept electronic nicotine delivery systems. In 2007, the electronic cigarette was introduced into the American market3 . Over the years, the FDA and manufacturers have fought over the regulations of selling and producing electronic cigarettes, due to their unknown health effects on users. Import bans have been placed on the product and law suits have been filed to try and stop the spread of the popular product. To this day, electronic cigarettes are still banned in certain states. Originally, electronic cigarettes were created to help smokers quit their smoking addiction. Now electronic cigarette-use has evolved into a large community that utilizes personal vaporizers that can be modified to maximize the user’s smoking preferences. Electronic nicotine delivery systems are designed to look like traditional tobacco cigarettes in order to simulate the sensory, social, visual, and behavioral features of smoking4 . The models can be filled with any of the thousands of available “e-juice” flavors that range from traditional coffee, vanilla, cigar, or more unique flavorings such as watermelon, mango, or cotton candy17 . Some “e-juice” brands aim to simulate traditional cigarette brands such as Camel or Marlboro1 . Each “e-juice” contains varying amounts of nicotine, propylene glycol, vegetable glycerin, and food-grade flavorings.
Parker5 The “e-juice” is heated using a battery-powered device which aerosolizes the liquid mixture to the user for inhalation1 . There is little known about the long-term health risks associated with electronic cigarette usage or the “e-juice” that it utilized. Due to a lack of combustion, these products do not contain typical carcinogens that are known to be in tobacco products. In addition to the nicotine used to help curb a smoker’s addiction, other compounds that are added to the electronic cigarette liquid such as the humectant, flavoring, and other food-grade additives can cause problems. As this fad continues to increase, so does the need for regulation and the understanding of the long term effects. Electronic Nicotine Delivery System The electronic nicotine delivery system is a battery-powered alternative to cigarette smoking. The device utilizes an atomizer to heat up the liquid mixture of nicotine dissolved in propylene glycol. The propylene glycol acts as a humectant for the nicotine that users crave. Characteristically, propylene glycol is a sweet, colorless, and odorless substance. When mixed with the nicotine, it helps to preserve nicotine in the state needed for delivery. When it is inhaled by the user, the resultant is a white cloudy smoke similar to cigarette smoke; however, it’s odorless, which makes this form of smoking more attractive to its users. First generation electronic cigarettes consist of a cartridge that holds the nicotine and propylene glycol mixture and a battery that atomizes the liquid to be inhaled by the user. This electronic nicotine delivery system is disposable and is powered when the user inhales. A model of the first generation electronic cigarette can be seen in Figure I.
Parker6 Figure I. Model of a first generation electronic cigarette. Figure II. shows the general set up of the second generation electronic cigarette. The second generation electronic nicotine delivery system is powered by a lithium-ion battery. When the user presses the control button, the device activates the atomizer. There are two different types of atomizers: systems that are disposable and systems that can be rebuilt. Those that are disposable are classified as clearomizers or cartomizers. Those that can be rebuilt are referred to as rebuildable dripping atomizers (RDA) or rebuildable tank atomizers (RTA)2 . Inside the atomizer is a wick that soaks up the homogenous liquid. The wick is then wrapped around an internal coil. The internal coil is nichrome wire made up of 80% nickel and 20% chromium that is heated and incidentally heats the temperature of the electronic liquid to extremely high temperatures. At the vaporization point, the aqueous solution of vegetable glycerin, propylene glycol, flavoring, and/or nicotine within the tank is atomized to vapor. The vapor is then inhaled through the mouthpiece by the user.
Parker7 Figure II. Model of the second generation electronic cigarette. The newest generation of ENDS has progressed into box-mod devices that allow the user to have absolute control over their smoking experience and is sometimes referred to as a personal vaporizer. The personal vaporizer has LED displays and controls that allow the user to increase or decrease the voltage of the device. The flexibility of the device allows the user to customize their electronic liquid mixture to optimize their smoking capability. The box-mod/personal vaporizer model can be seen in Figure III. Figure III. Model of a box-mod personal vaporizer (3rd Generation).
Parker8 E-liquid The two most widely used electronic cigarette bases are propylene glycol and vegetable glycerin, usually referred to as glycerol. There are four main ingredients found in electronic liquids: (1) a propylene glycol or vegetable glycerin base, (2) water, (3) flavoring, and (4) nicotine. Propylene glycol and vegetable glycerin are commonly used as food additives and are known to be safe for consumption. They are non-toxic organic compounds that hold the nicotine and flavor in suspension. These particular bases are favored because they are characteristic for the white clouds of vapor that are exhaled by the user. Every electronic liquid contains propylene glycol, vegetable glycerin, or a customized ratio of both. The organic molecule propylene glycol is generated from propylene oxide. It is odorless, has low viscosity, and colorless. It is typically utilized to preserve foods, as solvents, pharmaceutical products, and tobacco products. Vegetable glycerin comes from naturally extracted plant oils such as coconut oil, palm oil, and soy. It is odorless, slightly tinted in color, sweet, and typically more viscous than propylene glycol. It is found in food production, cosmetics, and tobacco products. Electronic cigarettes are known for being customizable down to the flavor of their electronic liquid; however, the chemicals used to flavor electronic cigarettes may not be as safe as individuals’ believe5 . Third generation personal vaporizers allow for the user to choose a unique flavoring of electronic liquid to be vaporized. Flavorings can imitate common tobacco products such as Camel and Marlboro, and some manufacturers have developed dessert-like flavorings such as Pumpkin Spice, Watermelon, Swedish Fish, Marshmallow, or even Cotton Candy to name a few. Most of these flavorings are food-grade ingredients that have been deemed by the Federal Drug Administration as safe to consume; however, the FDA has not been able to
Parker9 state whether the food-grade ingredients are safe to inhale. These flavorings and additives make the nicotine also found in the electronic liquid more addicting and appealing to its users. Those who are regularly exposed to nicotine become dependent on the chemical16 . If exposure is discontinued, the user can experience withdrawal symptoms such as cravings, depression, anxiety, the feeling of emptiness, and irritability6 . In electronic cigarettes, nicotine is present in the liquid form and held in suspension by a humectant, which is then heated and aerosolized for the user to inhale. In its liquid form, nicotine is highly concentrated and exceedingly toxic13 . Users of personal vaporizers can also customize the concentrations of nicotine utilized within the electronic nicotine delivery system. Liquid concentrations of nicotine vary from 0 to 18 mg/ml and some were even found as high as 36-42 mg/ml. Dosing is inconsistent and fluctuates by manufacturer. E-liquids containing “low doses” of nicotine correspond to a concentration of 6-8 mg/mL, “Midrange” concentrations contain 10-14 mg/mL, “High” concentrations correspond to 16-18 mg/mL, and “Extra-high” concentrations correspond to 24-36 mg/mL of nicotine per mL of liquid1 . All doses of liquid nicotine have the numerical concentration printed on the container of the electronic liquid or on its original packaging; however, some studies have determined that the actual concentration of nicotine within the electronic liquid is hard to determine and often differs from what is stated on the packaging16 . Therefore, the user must be careful when loading their personal vaporizers due to the fact that nicotine toxicity can occur when the liquid is consumed or applied to the skin13 . An ENDS user has the option to determine which base they would like to utilize as a humectant in the third generation personal vaporizer. Users can use a pure propylene glycol base or vegetable glycerin base. Often times, users create differing ratios of propylene glycol and vegetable glycerin in order to maximize their smoking experience. Propylene glycol is utilized
Parker10 more often than vegetable glycerin as an e-liquid base for many reasons. Both structures can be seen in Figure IVa. and Figure IVb. Figure IVa. Structure of Propylene Glycol Figure IVb. Structure of Vegetable Glycerin Because propylene glycol is less viscous than vegetable glycerin it’s easier to load into the reusable drip tank and there is less build-up deposited on the nichrome wire coil after the liquid has been vaporized. Vegetable glycerin has a higher viscosity and density so it often creates build up on the nichrome coil that heats up the electronic liquid over time. Due to vegetable glycerin’s high viscosity, it takes more energy and a takes longer to reach the optimal temperature needed to vaporize; however, the density of the vegetable glycerin allows the user to create thicker vapor and tends to be a healthier option for the user.
Parker11 Chemical Reaction through which Propylene Glycol/Glycerol forms Carbonyl Compounds In order for the vaporizer to work, the propylene glycol, flavoring molecules, and nicotine molecules must be heated to their heat of vaporization without chemically degrading them. It is estimated that the theoretical vaporization temperature of an electronic cigarette could reach up to 350 ̊C. This temperature is high enough to cause physical alterations to the chemicals within electronic liquids and cause chemical reactions to occur within the solvent. At such high temperatures, the solution could undergo thermal decomposition which leads to the generation of toxic aldehydes6 . When glycerol (vegetable glycerin) is heated, it decomposes by a dehydration mechanism to acrolein and water. Eq. 1 C3H8O3 ∆ → C2H3CHO + 2H2O Acrolein is typically found in the environment and in food products. It can be formed from carbohydrates, animal fats, or by heating foods; however, when smoking tobacco products, the produced acrolein exceeds or equals the total human exposure to acrolein from all other sources. It is a colorless, poisonous, pungent, and the simplest unsaturated aldehyde. This volatile organic compound can cause burning of the nose and throat and can cause damage to the lungs. By a retro aldol condensation reaction, acrolein can further break down into acetaldehyde and formaldehyde. This reaction only occurs in the presence of a catalyst, such as the hot metal present in the e-liquid in the form of coils that heat the liquid. The nichrome wire present in the atomizer of the electronic cigarette is known to have a low heat tolerance and give a metallic taste to the user2 . Acids and bases can also catalyze the reaction and are present in the electronic liquid flavorings. Glycerol Acrolein
Parker12 Eq. 2 C3H8O ுశ ሱሮ H3CCHO + HCHO Eq. 3 C3H8O ௛௢௧ ௠௘௧௔௟ ሱۛۛۛۛۛۛሮ H3CCHO + HCHO Formaldehyde is a colorless, overpowering organic compound. The short term effect of this compound on the body could be irritation of the eyes, throat, and nose. If exposed to this toxic compound over a longer period of time, one could experience coughing, trouble breathing, rawness of the throat and interior of the nose. The respiratory system could also be effected. It has also been shown that with increased dosages of formaldehyde to the body, there is also an increase in developing specific types of cancer8 . In an electronic cigarette that utilizes propylene glycol, the propylene glycol boils when exposed to extremely high temperatures. With these specific conditions in the form of a catalyst, the electronic liquid could dehydrate to form propionaldehyde. Eq. 4 C3H8O2 ିுమை ሱۛۛሮ C2H5CHO Propionaldehyde is a colorless liquid that is accompanied by a fruity smell. When in contact with the body it can irritate the skin, nose, throat, and lungs. When inhaled it could cause shortness of breath, excessive coughing, and pulmonary edemas. Glycerol Glycerol Acetaldehyde Formaldehyde Acetaldehyde Formaldehyde PropionaldehydePropylene Glycol
Parker13 Effect of Aldehydes on the Body An aldehyde is an organic compound that contains a –CHO group. It is a simple carbonyl molecule that is formed by the oxidation of alcohol. The most common aldehydes are formaldehyde, formed from methanol, and acetaldehyde, which is generated from ethanol. Aldehydes such as acrolein, formaldehyde, acetaldehyde, and crotonaldehyde have been documented to have acute effects on the human body8 . Common aldehydes and their structures can be seen below in Figure V. Figure V. Common aldehydes and their chemical structures. acrolein Among these examples, acrolein was found to have the greatest impact7 . Acrolein is found to be 2 to 3 times more toxic formaldehyde7 . Occasional exposure to aldehydes may cause olfactory and ocular irritation. Long-term contact may cause extreme irritation to the mucous membranes and damage to respiration7 . Chronic exposure can even cause irreversible damage to the epithelial tissues lining the lungs and respiratory tract. A study was performed on rats to
Parker14 determine carcinogenicity of aldehydes. Rats were exposed to a concentration of formaldehyde for a period of time. After that period of time, 103 rats were observed to have induced squamous cell carcinoma. The same procedure was performed on mice. The mice were observed with nasal tumors. These studies all gave evidence to reversible and irreversible damage to epithelium cells lining the respiratory tract and the damage that can occur when exposed to aldehydes8 . Mechanism for Formation of Carbonyl Compounds by Glycerol and Propylene Glycol The electronic liquids in the electronic cigarette tank are vaporized when they come into contact with the nichrome wire and oxidized in the presence of oxygen from the surrounding air to form formaldehyde, acrolein, glyoxal, methylglyoxal, and acetaldehyde9 . The solid metal oxide wire is used as a catalyst in this reaction. Because the vegetable glycerin has a high boiling point, this is referred to as a heterogeneous catalyst9 . Figure VI. shows the reaction that occurs when the electronic liquid comes in contact with the heated nichrome wire. Figure VI. Oxidation of vegetable glycerin and propylene glycol with the nichrome wire as a catalyst
Parker15 The vegetable glycerin is oxidized to form acrolein. The propylene glycol is oxidized to form methylglyoxal and then further oxidized to form formaldehyde and acetaldehyde whose toxicity is well documented20 . Mechanism of Glycerin Dehydration Reaction to Carbonyl Compounds Glycerin acts as a humectant for a homogenous mixture of flavoring, nicotine, and water. Alcohols can undergo a variety of changes, most of which are either oxidation or reduction reactions. Primary alcohols can be oxidized to form an aldehyde structure. Oxidation is when there is a loss of hydrogen and an addition of an oxygen or halogen. Primary and secondary alcohols can be easily oxidized using catalysts such as acids and metals. The coil that is used to vaporize the electronic liquid is made up of nichrome wire. The hot metal catalyzes the oxidation reaction. The high temperatures that are reached within the electronic cigarette cause thermal degradation to occur, which is the probable catalyst for this oxidation reaction. The use of a heterogeneous catalyst significantly reduces the activation energy of the transition states and increases the rate of the reaction. Glycerin has been found to dehydrate to acrolein; however, the mechanism does not just produce acrolein but other carbonyl compounds such as acetaldehyde, propanal, and acetone. From the reaction, carbon dioxide and carbon monoxide were identified in small quantities10 . Glycerin readily forms a homogenous mixture with water due to its three hydroxyl groups that readily form a hydrogen bond with water molecules. When glycerin is in its purest form, its boiling point is 290 ̊ C. When water is mixed with glycerin to form a homogenous solvent, the boiling point decreases. Figure VII. shows the reaction mechanisms possible for the dehydration of glycerin.
Parker16 Figure VII. Pathways of dehydration of glycerol and its proposed products. Figure VII. shows that there are two specific pathways of dehydration that glycerin can undergo-a 1-2 dehydration and a 1-3 dehydration. The 1-2 dehydration occurs when the secondary or primary hydroxyl group is protonated. If the secondary hydroxyl group is protonated, acrolein will be formed, if the terminal hydroxyl group is protonated, acetol will be formed. When the terminal hydroxyl group is protonated, has an unstable transition state is formed; however, this state is stabilized due to the conjugation of the weak basic sites4 . From this pathway, acetol is formed. If this product was dehydrated again, the product that would form would be thermodynamically unstable. Because of its unstability, acetol is the major product of this dehydration pathway. This unstable transition state is the reason that the dehydration pathway yields a large acrolein output. Acrolein is formed when the secondary hydroxyl group is protonated. The hydroxy propanal that is formed undergoes a second dehydration to form
Parker17 acrolein. If an aldol or retro aldol condensation reaction occurs, acetaldehyde, formaldehyde, and acrolein are favorable products. In a 1-3 dehydration of glycerin, the carbon backbone is deconstructed and the products formed are formaldehyde and vinyl alcohol. The mechanisms for the carbon backbone deconstruction and decomposition to formaldehyde and acetaldehyde can be seen in Figure VIII. The vinyl alcohol goes through keto-enol tautomerization to acetaldehyde, this aldehyde can further oxidized to form acetic acid. In the experiments performed, both acetaldehyde, formaldehyde, and acetic acid were present in the vapors produced by electronic cigarettes. Figure VIII. Mechanism for the deconstruction of the carbon backbone that occurs due to high temperatures Electronic cigarettes are heated to high temperatures in order to reach the vaporization temperature of the solvent so that it can be aerosolized to the user for inhalation. Formaldehyde is known to be unstable at such increased temperatures. When this occurs, formaldehyde
Parker18 thermally decomposes to carbon monoxide and hydrogen. The hydrogen that is formed at these high temperatures are responsible for reducing products formed in the reaction pathway. Mechanism of Propylene Glycol Dehydration to Carbonyl Compounds Propylene glycol decomposes at high temperatures via three different reaction pathways15 . These pathways can be seen below in Figure IX. Figure IX. Scheme of the three reaction pathways of propylene glycol In the first pathway, propylene glycol (1) dehydrates to an allyl alcohol (5). The reaction barrier for this pathway is fairly high compared to the other pathways15 . TDue to the higher reaction barrier, this pathway is not as favored as the other two. The allyl alcohol is further split into formaldehyde and acetaldehyde by bond scission. In the second pathway, Propylene glycol is dehydrated to form propylene oxide (2) as an intermediate; however, if a hydrogen shift occurs, propylene glycol will further decompose to acetone (3). The mechanism for this decomposition can be seen in Figure IX. in the first mechanism. In this mechanism, a hydrogen ion comes out and the propylene oxide structure
Parker19 rearranges it’s double dond to form acetone. Acetone was found in electronic cigarette vapors in multiple studies. This shows that this pathway can be favored at high temperatures. The propylene glycol can also decompose to propanal, or propionaldehyde (4). This can be seen in Figure X. below the first mechanism. In this mechanism, a hydride shift occurs and the propylene oxide rearranges it’s structure to form propionaldehyde.. The propylene glycol is in equilibrium with the protonated form; however, at high temperatures, entropy favors dehydration which will be stabilized by the formation of the enol15 . The reaction barrier to form propionaldehyde is the lowest among the pathways, therefore, this pathway is the most favorable and the main product formed in the thermal degradation of propylene glycol. Figure X. Mechanism of the rearrangement of propylene oxide in the event of a hydride shift Propylene glycol has been known to produce more carbonyl compounds than glycerol when vaporized. After reviewing both mechanisms, it can be assumed that this occurs due to the amount of carbonyl compounds produced for each molecule of humectant. The dehydration of propylene glycol has the possibility to yield formaldehyde and propionaldehyde. The propionaldehyde can further decompose to acetone. Therefore, this reaction mechanism presents
Parker20 the formation of two carbonyl species for every one molecule of propylene glycol. The glycerin only forms one carbonyl molecule when dehydrated. Determination of Carbonyl Compounds Generated from E-Cigarettes by HPLC In this experiment, carbonyl compounds from electronic cigarette vapor were captured using coupled silica cartridges impregnated with hydroquinone and 2, 4-dinitrophenylhydrazine and were analyzed using high performance liquid chromatography. A test group of 13 electronic cigarette brands were analyzed in this way. Of the 13 brands tested, 4 brands did not generate any carbonyl compounds and 9 generated various carbonyl compounds. From this experiment, there was not a prominent carbonyl compound that was always formed; however, it was determined that electronic cigarettes incidentally produce high concentrations of carbonyl compounds11 . An HPLC instrument was set up with two LC20AD pumps, photodiode array detector, and an auto-sampler. The column used allowed for a 2.7μm particle size and was 150mm x 4.6mm. The column temperature was set for 40 ̊C and the injection size was 10μL. The flow rate of the mobile phase was 0.7 mL/min. In order to generate vapor, a smoking machine was employed. Before the collection of the vapors from the electronic cigarette machine, a hydroquinone cartridge (HQ-cartridge) and a 2, 4-dinitrophenylhydrazine cartridge (DNPH- cartridge) were connected to the machine to capture the vapors in solid form. The cartridges were placed between the mouthpiece of the electronic cigarette and the smoking machine in order to collect the carbonyl compounds from the vapors. The smoking machine was set to 55mL puff volume, 2-s puff duration, 30-s puff interval, and 10 puffs. The cartridges were removed after each run and were rinsed with acetonitrile containing 1% phosphoric acid in the opposite
Parker21 direction the smoking machine was used until the total volume reached 4.5 mL. After 10 minutes, ethanol was added to the solution and it was then analyzed by HPLC11 . From this experiment, multiple simple carbonyl compounds were detected in the vapors of electronic cigarettes. Major carbonyl compounds found in electronic cigarette vapors were formaldehyde, acetone, propanol, glyoxal, acetaldehyde, and methylglyoxal11 . Figure XI. shows a sample chromatograph from one of the trials. Figure XI. Chromatogram of carbonyl compounds found in e-cigarette vapors. (Where FA=formaldehyde, AA=acetaldehyde, ACR=acrolein, GA=glyoxal, AC=acetone, MGA=methylglyoxal, and PA=propanol)11 The concentrations of each carbonyl compound that was found in the electronic cigarettes were compared against each other for each electronic cigarette brand. These comparisons can be seen in Figure XII.
Parker22 Figure XII. Graphs of the concentrations of carbonyl compounds found in 10 e-cigarettes using the same brand of e-liquid11 . The concentrations of all the major carbonyl compounds that were produced during the experiment from all 13 brands of e-liquid tested can be seen in Table I.
Parker23 Table I. The concentrations of key carbonyl compounds that were produced from the 13 e- cigarette brands tested11 From Figure XII. and Table I. the statistical analysis shows that there were large statistical differences in the carbonyl compounds produced among the different products and the carbonyl concentrations. Of the 13 e-cigarettes tested, nine produced carbonyl compound groups and the other four (J, K, L, M) did not. This evidence highly suggests that not one specific carbonyl group is produced; however, from the results it was noted that formaldehyde was measured at high concentrations in the electronic cigarette vapor. Two new carbonyl groups that were observed that are not prevalent in traditional cigarette smoke were glyoxal and methylglyoxal. Both are known to be mutagenic aldehydes. Methylglyoxal, also known as pyruvaldehyde, inhibits the metabolism of formaldehyde and increases the chance of formaldehyde-induced cytotoxicity11 .
Parker24 From this experiment, the cartomizer that was utilized was examined after the conclusion of the experiment. The cartomizers used in this experiment operated with a nichrome wire to heat the electronic liquid mixture to vaporization temperature so that it could be delivered in aerosol form. After the experiment, the nichrome wire was observed to have changed color from white to black. The cartomizer used in this experiment can be seen in Figure XII. Figure XII. The cartomizer used from the experiment with blackened deposits from thermal degradation of e-liquids used. The left shows a cartomizer that produced low concentrations of carbonyl compounds while the right shows a cartomizer that produced high concentrations of carbonyl compounds11 . From what is known about the contents of the electronic liquid used in electronic cigarettes, it can be assumed that the propylene glycol and glycerin came in contact with the metal, which catalyzed an oxidation reaction to form the carbonyl compounds acetone, acetaldehyde, formaldehyde, acrolein, glyoxal, and methylglyoxal.
Parker25 The Effect of Nicotine Solvent and Battery Output Voltage on Carbonyl Compounds Present in Electronic Cigarettes Previous experiments that determined the levels of carbonyl compounds found in e- cigarettes were performed on first generation electronic cigarettes. Since those experiments were performed, the electronic cigarette market continued to enhance the product and rapidly introduce the “second generation” electronic cigarette and “third generation” electronic cigarette which is also referred to as a personal vaporizer. This newest instrumentation allows the user to fully customize their smoking experience. The user can determine what ratio of propylene glycol to glycerin they would like to use in the tank, along with the concentration of nicotine. The individual can also increase the vaporization temperature by changing the battery output voltage. In this experiment, ten nicotine solvents and three control solutions made up of pure propylene glycol, pure glycerin, or a mixture of both solutions, were analyzed for twelve particular carbonyl compounds. The electronic cigarette voltage was slowly increased during the experiment from 3.2V to 4.8V. The carbonyl compounds were measured using HPLC method. The purpose of the experiment was to determine how battery output voltage and the nicotine solvent effect the concentration of carbonyl compounds produced in the vapors of the newest electronic cigarette model. Ten different electronic liquids were used for the experiment with concentrations of nicotine varying from 18-24 mg/ml. The ten different e-liquids were placed in groupings based on the contents of their humectants. Products A1-A3 were glycerin based, products A4-A6 were a mixture of glycerin and propylene glycol, and products A7-A10 were purely proplene glycol based. In order to see the how the base humectant effects the carbonyl compounds, three controls were also prepared for the experiment. The controls were made by dissolving liquid nicotine in
Parker26 analytical-grade solvents. Control 1 (C1) was a ratio of 88.2% glycerin, 10% redistilled water, and 1.8% nicotine. Control 2 (C2) was made up of 44.1% glycerin, 44.1% propylene glycol, 10% redistilled water, and 1.8% nicotine. Control 3 (C3) was composed of 88.2% propylene glycol, 10% redistilled water, and 1.8% nicotine. Each test was performed with a 70mL puff volume, 1.8s puff duration, and puff intervals of 17s. Each test consisted of 30 puffs from each electronic cigarette. The trial was ran in two series of 15 puffs with a 5 minute break in between series. For the experiment testing battery output voltage effect on carbonyl compounds found in electronic cigarettes, the electronic cigarette generated vapor at the battery voltages 3.2V, 4.0V, and 4.8V12 . The controls were utilized for this trial and each voltage was performed three times for each control for a total of nine runs. Table II. shows the electronic liquid brands, the label information, and nicotine content for each brand that was utilized for the experiment.
Parker27 Table II. Ingredient list with nicotine concentrations for each e-liquid product used12 . Silica gels were impregnated with 2, 4-dinitrophenylhydrazine in order to extract the carbonyl compounds from the aerosol phase to the solid phase to be examined. These gels were placed in
Parker28 between the mouthpiece of the electronic cigarette and the smoking machine in order to trap the carbonyl compounds that are present in the electronic cigarette vapors. The gels were rinsed with 1mL of acetonitrile. The solvent was then analyzed using HPLC. The elution gradient was made up of acetonitrile and water and the separation was carried out at 40 ̊ C. Table III. Shows the carbonyl compounds that were present in the vapors generated by the electronic cigarettes in the experiment12 . Table III. Carbonyl compounds present in the ten e-liquid solutions12 Table III. shows that all electronic liquids contained at least one carbonyl compound in the vapors generated by the electronic cigarette. This phenomena could have occurred due to the high temperatures needed to vaporize the electronic liquid. At these high temperatures, the solvents could have been catalyzed by the metal coil used to heat the liquid and the solvents could have undergone thermal decomposition. The humectants present in the bases, propylene glycol and glycerin, could have been oxidized to form the toxic carbonyl compounds. In this experiment, formaldehyde, butanol, acetone, and acetaldehyde were the most prevalent carbonyl compounds observed in the electronic cigarette vapors, while acrolein was not detected at all12 .
Parker29 The effect of battery output voltage on the carbonyls released in the electronic cigarette vapors were measured by increasing the battery voltage for each control and measuring the carbonyl groups using the silica gels saturated in DNPH. Each control was ran three times at each voltage. The amounts of acetone, acetaldehyde, and formaldehyde that were measure for each run and each control at each battery voltage output can be seen in Figure XIII. Figure XIII. The effect of the battery output voltage on carbonyl compound yields from e- cigarettes12 Figure XIII. shows that when the voltage was increased from 4.0V to 4.8V, the amount of formaldehyde in electronic cigarettes that used a propylene glycol and glycerin mixture base or purely propylene glycol increased significantly. The acetaldehyde was also significantly increased in those mixtures when the voltage was increased. Similarly, the amount of acetone produced experienced a statistically significant increase from 3.2V to 4.8V in the control that used the base mixture of glycerin and propylene glycol. Glycerin was not as affected by battery output as the base mixture propylene glycol; however, in this experiment, an increase in voltage
Parker30 showed an increase in carbonyl compound yield. Propylene glycol is known to be less viscous than glycerin. This means that it has a lower optimum temperature that it can be aerosolized. When voltage is increased, and temperature is increased faster, the reaction rate of the oxidation of propylene glycol will be increased, which produces more toxic carbonyl compounds. These results also propose that propylene glycol is more vulnerable to the thermal degradation than glycerin. Conclusion: The vaping community is quickly emerging. Between 2012-2013, the sale of electronic products increased 320% for disposable electronic cigarettes, 72% for starter kits, and 82% for cartridges18 .Within the next year, revenue from electronic cigarettes are expected to double to over $1.7 billion and projected to pass traditional cigarette sales by 204719 . With its increasing popularity, the electronic cigarette has rapidly evolving technology that gives the user more freedom with their personal vaporizing experience. There is still a lot to learn about the chemical reactions that are taking place within the electronic nicotine devices and how the by-products of these reactions could affect the user’s body short-term and long term. The refill solutions for these ever-evolving systems contain aldehydes, heavy metals, volatile organic compounds, food- grade flavoring, and humectants. Research has only scratched the surface of the chemical reactions that take place among all these additives. At the high temperatures that are required to vaporize these solutions, unpredictable behaviors among the compounds take place and carcinogenic carbonyl compounds are being formed and inhaled17 . The inconsistency of the carbonyl compounds that are formed from the electronic cigarette vapors suggests that at high temperatures there is a lot more interaction among the compounds within the solvents. From the studies performed it has been observed that at these high temperatures, the electronic liquid is
Parker31 catalyzed by the nichrome wire that incidentally touches the electronic liquid as it is heated to its vaporization temperature. By the metal coil, the solvent is oxidized to form formaldehyde, acetaldehyde, acrolein, and acetone. Increase in battery output voltage also proved that these toxic compounds can be produced in extremely high concentrations. The mechanism reaction for the oxidation of the solvent to form aldehydes has been determined; however, when food additives and flavorings are added to the solvent, there is a possibility of more interaction within the solvent and more toxic by-products being produced due to an acid catalyst being present. While it is known how the body is affected when these additives are consumed, it is not known how the body is affected when these additives are inhaled. Aldehydes have been identified as cytotoxic and carcinogenic and highly toxic to the body when exposed over a long period of time. In order to further the research on electronic cigarette reactions and obtain precise results, more research should be performed to determine the behaviors of electronic cigarette users. With this information, experiments can be ran similarly to the electronic cigarette user’s behavior so that results are more comparable. Also by standardizing the analysis of aerosol generation and collection of carbonyl compounds, this would allow for better comparisons of electronic cigarette vapor and cigarette smoke.
Parker32 References 1. VapeHit. E-liquid Facts. http://www.vapehit.co.uk/info.php?articles&articles_id=22 (accessed Oct. 25, 2015). 2. Info Electronic Cigarette. Electronic Cigarette GLossery.http://info-electronic- cigarette.com/electronic-cigarette-glossary/(accessed Oct. 21, 2015). 3. Eversmoke Electronic Cigarettes. History of the Electronic Cigarette. http://www.learn.eversmoke.com/history-of-electronic-cigarettes.html (accessed Oct. 21, 2015). 4. Nguyen, David and Aamodt Gail. Electronic Cigarettes the Past, Present, and Future. Continuing Education Course. DentalCare.com [Online] (October 1 2014). http://www.dentalcare.com/media/en-US/education/ce451/ce451.pdf (Accessed Oct. 15, 2015) 5. Sifferlin, Alexandra. E-cig Flavors May BE Dangerous, Study Says. Time. [Online] 2015. http://time.com/3822831/ecig-flavors/ (accessed Oct. 17, 2015) 6. Medical News Today. What is Nicotine? http://www.medicalnewstoday.com/articles/240820.php (Accessed Oct. 18, 2015) 7. Marnett, Lawrence J. Health Effects of Aldehydes and Alcohols in Mobile Source Emissions. In Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press, 1988. pp 580-585. (http://www.nap.edu/read/1033/chapter/25#583) (accessed Oct. 18, 2015) 8. Cassee, Flemming R; Groten, John P; Feron, Victor J. Changes in the Nasal Epithelium of Rates Exposed by Inhalation to Mixtures of Formaldehyde, Acetaldehyde, and Acrolein. Fundamental and Applied Toxicology. [Online] 1995, 29, 208-218. (http://toxsci.oxfordjournals.org/content/29/2/208.full.pdf+html) (accessed Oct. 23, 2015) 9. Laino, Teodoro; Tuma, Christian; Moor, Philippe; Martin, Elyette; Stolz, Steffen; Curioni, Alessandro. Mechanisms of Propylene Glycol and Triacetin Pyrolysis. J. Phys. Chem. A 2012, 116, 4602-4609 (http://eprints.eemcs.utwente.nl/22979/01/stolz1- jp300997d.pdf) (accessed Oct. 18, 2015) 10. Ulgen, Arda. Conversion of Glycerol to the Valuable Intermediates Acrolein and Allyl Alcohol in the Presence of Heterogeneous Catalysts. [online] (http://publications.rwth- aachen.de/record/63757/files/3078.pdf;) (accessed Oct. 19, 2015) 11. Uchiyama, Shigehisa; Ohta, Kuzushi; Inaba, Yohei; Kunugita, Naoki. Determination of Carbonyl Compounds Generated from the E-Cigarette Using Coupled Silica Cartridges Impregnated with Hydroquinone and 2, 4-Dinitrophenylhydrazine, Followed by High- Performance Liquid Chromatography. Analytical Sciences. December 2013, Vol. 29, 1219-1222. 12. Kosmider PharmD, Leon; Sobczak PhD, Andrzej; Fik PharmD, Maciej; Knysak PharmD, Jakub; Zaciera PharmD, Marzena; Kurek PharmD, Jolanta; Goniewicz PharmD, PhD, Maciej Lukasz. Carbonyl Compounds in Electronic Cigarette Vapors---Effects of Nicotine Solvent and Battery Output Voltage. Nicotine & Tobacco Advance Access. May 14, 2014.
Parker33 13. Centers for Disease Control and Prevention. Nicotine: Systematic Agent. http://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750028.html (accessed Oct. 17, 2015) 14. Geiss, Otmar; Bianchi, Ivana; Barahona, Francisco; Barrero-Moreno, Josefa. Characterization of Mainstream and Passive Vapours Emitted by Selected Electronic Cigarettes. International Journal of Hygiene and Environmental Health. Vol 218, Issue 1, January 2015, 172-180. 15. Schlaf, Marcel; Zhang, Z. Conrad; Cellulose Hydrogenolysis to Ethylene Glycol and 1,2- Propylene Glycol. Reaction Pathways and Mechanisms in Thermocatalytic Biomass Conversion I. Springer: New York, 2015; pp 242-247. 16. Cheng, Tianrong. Chemical Evaluation of Electronic Cigarettes. Center for Tobacco Products, Food, and Drug Administration. [Online]. 2014, 23, ii11-ii17. 17. Lim, Hyun-Hee; Shin, Ho-Sang. Measurement of Aldehydes in Replacement Liquids of Electronic Cigarettes by Headspace Gas Chromatography-Mass Spectrometry. Bull Korean Chem. Soc. 2013, Vol. 34, No. 9. Pp. 2691-2695. 18. Center for Disease Control and Prevention. Economic Facts About U.S. Tobacco Production and Use. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/economics/econ_facts/ (accessed Oct. 23, 2015) 19. Forbes. E-Cigarette Sales Surpass $1 Billion As Big Tobacco Moves In. http://www.forbes.com/sites/natalierobehmed/2013/09/17/e-cigarette-sales-surpass-1- billion-as-big-tobacco-moves-in/ (accessed Oct. 24, 2015) 20. Forbes. E-Cigarette Flavoring Chemicals May Pose Risks When Inhaled. http://www.forbes.com/sites/tarahaelle/2015/04/16/e-cigarette-flavoring-chemicals-may- pose-risks-when-inhaled/. (accessed Oct. 24, 2015).

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Dr Konstantinos Farsalinos - E-Cigarette Summit 2014
Dr Konstantinos Farsalinos - E-Cigarette Summit 2014Dr Konstantinos Farsalinos - E-Cigarette Summit 2014
Dr Konstantinos Farsalinos - E-Cigarette Summit 2014
 

Determination of Carbonyl Compounds Found in Electronic Cigarettes

  • 1. Determination of Carbonyl Compounds Found in Electronic Cigarettes By: Madison Parker
  • 2. Parker2 Abstract: Electronic Nicotine Delivery Systems (ENDS) and personal vaporizers are battery- powered devices that aerosolizes nicotine so that it is readily available to the user. Food-grade ingredients and traditional cigarette ingredients are used in these devices. There is very little analytical data available that informs the public to the possible health effects of ENDS on the user; however, it is known that these devices put out significant toxic carbonyl compounds. In one experiment, electronic cigarettes were tested to determine their carbonyl compound output. This was tested by testing 13 different brands of electronic cigarette solvent by capturing its vapor using coupled silica cartridges impregnated with hydroquinone and 2, 4- dinitrophenylhydrazine. They were then analyzed using high performance liquid chromatography. Of the 13 brands tested, 4 brands did not generate any carbonyl compounds and 9 generated various carbonyl compounds. From this experiment, there were not specific carbonyl compounds formed for every trial; however, it was determined that electronic cigarettes incidentally produce high concentrations of carbonyl compounds11 . In another study, the effect of nicotine solvent and voltage output on carbonyl compound formation were tested. To determine the effect of nicotine solvent on the carbonyl compound output, ten different electronic cigarette liquids were used for the experiment with concentrations of nicotine varying from 18-24 mg/ml. The ten different electronic cigarette liquids were placed in groupings based on the contents of their humectants. One group was made up of purely propylene glycol, one group purely vegetable glycerin, and another group a ratio of both propylene glycol and vegetable glycerin. In order to see how the base humectant effects the carbonyl compounds, three controls were also prepared for the experiment. In this experiment, it was observed that all electronic cigarette liquids contained at least one carbonyl compound in the vapors produced by the electronic
  • 3. Parker3 cigarette. In this experiment, formaldehyde, butanol, acetone, and acetaldehyde were the most prevalent carbonyl compounds observed in the electronic cigarette vapors, while acrolein was not detected at all12 . In this same experiment, the effect of voltage on carbonyl compound formation was tested by observing the carbonyl compound generation when increasing the ENDS voltage to 3.2V, 4.0V, and 4.8V. From this experiment, it was observed that as voltage increases, so does the amount of carbonyl compounds formed within the vapors. The most significant increase in carbonyl compounds was observed in humectants that used propylene glycol as a base in the e-liquid. In order to determine the harmful effects of electronic cigarettes to its users, this paper evaluates the instrumentation of ENDS, analyzes the chemical action that occurs during its use, and reviews available evidence that evaluates how carbonyl compounds are generated during electronic cigarette usage.
  • 4. Parker4 Introduction: Electronic Cigarettes have been around since the 1960’s. Hubert A. Gilbert, in 1963, filed a patent for the idea for the first electronic cigarette. At the time, smoking cigarettes in public was normal social behavior and the toxic side effects of smoking tobacco was not as extensively researched. At the time, there was not a need for “healthier” smoking options and smoking was fairly accepted in society. In 2003, Han Lik, a Chinese pharmacist and a smoker, developed the first usable electronic cigarette after his father passed away from lung cancer. Shortly after its invention, the Chinese and European markets were the first to accept electronic nicotine delivery systems. In 2007, the electronic cigarette was introduced into the American market3 . Over the years, the FDA and manufacturers have fought over the regulations of selling and producing electronic cigarettes, due to their unknown health effects on users. Import bans have been placed on the product and law suits have been filed to try and stop the spread of the popular product. To this day, electronic cigarettes are still banned in certain states. Originally, electronic cigarettes were created to help smokers quit their smoking addiction. Now electronic cigarette-use has evolved into a large community that utilizes personal vaporizers that can be modified to maximize the user’s smoking preferences. Electronic nicotine delivery systems are designed to look like traditional tobacco cigarettes in order to simulate the sensory, social, visual, and behavioral features of smoking4 . The models can be filled with any of the thousands of available “e-juice” flavors that range from traditional coffee, vanilla, cigar, or more unique flavorings such as watermelon, mango, or cotton candy17 . Some “e-juice” brands aim to simulate traditional cigarette brands such as Camel or Marlboro1 . Each “e-juice” contains varying amounts of nicotine, propylene glycol, vegetable glycerin, and food-grade flavorings.
  • 5. Parker5 The “e-juice” is heated using a battery-powered device which aerosolizes the liquid mixture to the user for inhalation1 . There is little known about the long-term health risks associated with electronic cigarette usage or the “e-juice” that it utilized. Due to a lack of combustion, these products do not contain typical carcinogens that are known to be in tobacco products. In addition to the nicotine used to help curb a smoker’s addiction, other compounds that are added to the electronic cigarette liquid such as the humectant, flavoring, and other food-grade additives can cause problems. As this fad continues to increase, so does the need for regulation and the understanding of the long term effects. Electronic Nicotine Delivery System The electronic nicotine delivery system is a battery-powered alternative to cigarette smoking. The device utilizes an atomizer to heat up the liquid mixture of nicotine dissolved in propylene glycol. The propylene glycol acts as a humectant for the nicotine that users crave. Characteristically, propylene glycol is a sweet, colorless, and odorless substance. When mixed with the nicotine, it helps to preserve nicotine in the state needed for delivery. When it is inhaled by the user, the resultant is a white cloudy smoke similar to cigarette smoke; however, it’s odorless, which makes this form of smoking more attractive to its users. First generation electronic cigarettes consist of a cartridge that holds the nicotine and propylene glycol mixture and a battery that atomizes the liquid to be inhaled by the user. This electronic nicotine delivery system is disposable and is powered when the user inhales. A model of the first generation electronic cigarette can be seen in Figure I.
  • 6. Parker6 Figure I. Model of a first generation electronic cigarette. Figure II. shows the general set up of the second generation electronic cigarette. The second generation electronic nicotine delivery system is powered by a lithium-ion battery. When the user presses the control button, the device activates the atomizer. There are two different types of atomizers: systems that are disposable and systems that can be rebuilt. Those that are disposable are classified as clearomizers or cartomizers. Those that can be rebuilt are referred to as rebuildable dripping atomizers (RDA) or rebuildable tank atomizers (RTA)2 . Inside the atomizer is a wick that soaks up the homogenous liquid. The wick is then wrapped around an internal coil. The internal coil is nichrome wire made up of 80% nickel and 20% chromium that is heated and incidentally heats the temperature of the electronic liquid to extremely high temperatures. At the vaporization point, the aqueous solution of vegetable glycerin, propylene glycol, flavoring, and/or nicotine within the tank is atomized to vapor. The vapor is then inhaled through the mouthpiece by the user.
  • 7. Parker7 Figure II. Model of the second generation electronic cigarette. The newest generation of ENDS has progressed into box-mod devices that allow the user to have absolute control over their smoking experience and is sometimes referred to as a personal vaporizer. The personal vaporizer has LED displays and controls that allow the user to increase or decrease the voltage of the device. The flexibility of the device allows the user to customize their electronic liquid mixture to optimize their smoking capability. The box-mod/personal vaporizer model can be seen in Figure III. Figure III. Model of a box-mod personal vaporizer (3rd Generation).
  • 8. Parker8 E-liquid The two most widely used electronic cigarette bases are propylene glycol and vegetable glycerin, usually referred to as glycerol. There are four main ingredients found in electronic liquids: (1) a propylene glycol or vegetable glycerin base, (2) water, (3) flavoring, and (4) nicotine. Propylene glycol and vegetable glycerin are commonly used as food additives and are known to be safe for consumption. They are non-toxic organic compounds that hold the nicotine and flavor in suspension. These particular bases are favored because they are characteristic for the white clouds of vapor that are exhaled by the user. Every electronic liquid contains propylene glycol, vegetable glycerin, or a customized ratio of both. The organic molecule propylene glycol is generated from propylene oxide. It is odorless, has low viscosity, and colorless. It is typically utilized to preserve foods, as solvents, pharmaceutical products, and tobacco products. Vegetable glycerin comes from naturally extracted plant oils such as coconut oil, palm oil, and soy. It is odorless, slightly tinted in color, sweet, and typically more viscous than propylene glycol. It is found in food production, cosmetics, and tobacco products. Electronic cigarettes are known for being customizable down to the flavor of their electronic liquid; however, the chemicals used to flavor electronic cigarettes may not be as safe as individuals’ believe5 . Third generation personal vaporizers allow for the user to choose a unique flavoring of electronic liquid to be vaporized. Flavorings can imitate common tobacco products such as Camel and Marlboro, and some manufacturers have developed dessert-like flavorings such as Pumpkin Spice, Watermelon, Swedish Fish, Marshmallow, or even Cotton Candy to name a few. Most of these flavorings are food-grade ingredients that have been deemed by the Federal Drug Administration as safe to consume; however, the FDA has not been able to
  • 9. Parker9 state whether the food-grade ingredients are safe to inhale. These flavorings and additives make the nicotine also found in the electronic liquid more addicting and appealing to its users. Those who are regularly exposed to nicotine become dependent on the chemical16 . If exposure is discontinued, the user can experience withdrawal symptoms such as cravings, depression, anxiety, the feeling of emptiness, and irritability6 . In electronic cigarettes, nicotine is present in the liquid form and held in suspension by a humectant, which is then heated and aerosolized for the user to inhale. In its liquid form, nicotine is highly concentrated and exceedingly toxic13 . Users of personal vaporizers can also customize the concentrations of nicotine utilized within the electronic nicotine delivery system. Liquid concentrations of nicotine vary from 0 to 18 mg/ml and some were even found as high as 36-42 mg/ml. Dosing is inconsistent and fluctuates by manufacturer. E-liquids containing “low doses” of nicotine correspond to a concentration of 6-8 mg/mL, “Midrange” concentrations contain 10-14 mg/mL, “High” concentrations correspond to 16-18 mg/mL, and “Extra-high” concentrations correspond to 24-36 mg/mL of nicotine per mL of liquid1 . All doses of liquid nicotine have the numerical concentration printed on the container of the electronic liquid or on its original packaging; however, some studies have determined that the actual concentration of nicotine within the electronic liquid is hard to determine and often differs from what is stated on the packaging16 . Therefore, the user must be careful when loading their personal vaporizers due to the fact that nicotine toxicity can occur when the liquid is consumed or applied to the skin13 . An ENDS user has the option to determine which base they would like to utilize as a humectant in the third generation personal vaporizer. Users can use a pure propylene glycol base or vegetable glycerin base. Often times, users create differing ratios of propylene glycol and vegetable glycerin in order to maximize their smoking experience. Propylene glycol is utilized
  • 10. Parker10 more often than vegetable glycerin as an e-liquid base for many reasons. Both structures can be seen in Figure IVa. and Figure IVb. Figure IVa. Structure of Propylene Glycol Figure IVb. Structure of Vegetable Glycerin Because propylene glycol is less viscous than vegetable glycerin it’s easier to load into the reusable drip tank and there is less build-up deposited on the nichrome wire coil after the liquid has been vaporized. Vegetable glycerin has a higher viscosity and density so it often creates build up on the nichrome coil that heats up the electronic liquid over time. Due to vegetable glycerin’s high viscosity, it takes more energy and a takes longer to reach the optimal temperature needed to vaporize; however, the density of the vegetable glycerin allows the user to create thicker vapor and tends to be a healthier option for the user.
  • 11. Parker11 Chemical Reaction through which Propylene Glycol/Glycerol forms Carbonyl Compounds In order for the vaporizer to work, the propylene glycol, flavoring molecules, and nicotine molecules must be heated to their heat of vaporization without chemically degrading them. It is estimated that the theoretical vaporization temperature of an electronic cigarette could reach up to 350 ̊C. This temperature is high enough to cause physical alterations to the chemicals within electronic liquids and cause chemical reactions to occur within the solvent. At such high temperatures, the solution could undergo thermal decomposition which leads to the generation of toxic aldehydes6 . When glycerol (vegetable glycerin) is heated, it decomposes by a dehydration mechanism to acrolein and water. Eq. 1 C3H8O3 ∆ → C2H3CHO + 2H2O Acrolein is typically found in the environment and in food products. It can be formed from carbohydrates, animal fats, or by heating foods; however, when smoking tobacco products, the produced acrolein exceeds or equals the total human exposure to acrolein from all other sources. It is a colorless, poisonous, pungent, and the simplest unsaturated aldehyde. This volatile organic compound can cause burning of the nose and throat and can cause damage to the lungs. By a retro aldol condensation reaction, acrolein can further break down into acetaldehyde and formaldehyde. This reaction only occurs in the presence of a catalyst, such as the hot metal present in the e-liquid in the form of coils that heat the liquid. The nichrome wire present in the atomizer of the electronic cigarette is known to have a low heat tolerance and give a metallic taste to the user2 . Acids and bases can also catalyze the reaction and are present in the electronic liquid flavorings. Glycerol Acrolein
  • 12. Parker12 Eq. 2 C3H8O ுశ ሱሮ H3CCHO + HCHO Eq. 3 C3H8O ௛௢௧ ௠௘௧௔௟ ሱۛۛۛۛۛۛሮ H3CCHO + HCHO Formaldehyde is a colorless, overpowering organic compound. The short term effect of this compound on the body could be irritation of the eyes, throat, and nose. If exposed to this toxic compound over a longer period of time, one could experience coughing, trouble breathing, rawness of the throat and interior of the nose. The respiratory system could also be effected. It has also been shown that with increased dosages of formaldehyde to the body, there is also an increase in developing specific types of cancer8 . In an electronic cigarette that utilizes propylene glycol, the propylene glycol boils when exposed to extremely high temperatures. With these specific conditions in the form of a catalyst, the electronic liquid could dehydrate to form propionaldehyde. Eq. 4 C3H8O2 ିுమை ሱۛۛሮ C2H5CHO Propionaldehyde is a colorless liquid that is accompanied by a fruity smell. When in contact with the body it can irritate the skin, nose, throat, and lungs. When inhaled it could cause shortness of breath, excessive coughing, and pulmonary edemas. Glycerol Glycerol Acetaldehyde Formaldehyde Acetaldehyde Formaldehyde PropionaldehydePropylene Glycol
  • 13. Parker13 Effect of Aldehydes on the Body An aldehyde is an organic compound that contains a –CHO group. It is a simple carbonyl molecule that is formed by the oxidation of alcohol. The most common aldehydes are formaldehyde, formed from methanol, and acetaldehyde, which is generated from ethanol. Aldehydes such as acrolein, formaldehyde, acetaldehyde, and crotonaldehyde have been documented to have acute effects on the human body8 . Common aldehydes and their structures can be seen below in Figure V. Figure V. Common aldehydes and their chemical structures. acrolein Among these examples, acrolein was found to have the greatest impact7 . Acrolein is found to be 2 to 3 times more toxic formaldehyde7 . Occasional exposure to aldehydes may cause olfactory and ocular irritation. Long-term contact may cause extreme irritation to the mucous membranes and damage to respiration7 . Chronic exposure can even cause irreversible damage to the epithelial tissues lining the lungs and respiratory tract. A study was performed on rats to
  • 14. Parker14 determine carcinogenicity of aldehydes. Rats were exposed to a concentration of formaldehyde for a period of time. After that period of time, 103 rats were observed to have induced squamous cell carcinoma. The same procedure was performed on mice. The mice were observed with nasal tumors. These studies all gave evidence to reversible and irreversible damage to epithelium cells lining the respiratory tract and the damage that can occur when exposed to aldehydes8 . Mechanism for Formation of Carbonyl Compounds by Glycerol and Propylene Glycol The electronic liquids in the electronic cigarette tank are vaporized when they come into contact with the nichrome wire and oxidized in the presence of oxygen from the surrounding air to form formaldehyde, acrolein, glyoxal, methylglyoxal, and acetaldehyde9 . The solid metal oxide wire is used as a catalyst in this reaction. Because the vegetable glycerin has a high boiling point, this is referred to as a heterogeneous catalyst9 . Figure VI. shows the reaction that occurs when the electronic liquid comes in contact with the heated nichrome wire. Figure VI. Oxidation of vegetable glycerin and propylene glycol with the nichrome wire as a catalyst
  • 15. Parker15 The vegetable glycerin is oxidized to form acrolein. The propylene glycol is oxidized to form methylglyoxal and then further oxidized to form formaldehyde and acetaldehyde whose toxicity is well documented20 . Mechanism of Glycerin Dehydration Reaction to Carbonyl Compounds Glycerin acts as a humectant for a homogenous mixture of flavoring, nicotine, and water. Alcohols can undergo a variety of changes, most of which are either oxidation or reduction reactions. Primary alcohols can be oxidized to form an aldehyde structure. Oxidation is when there is a loss of hydrogen and an addition of an oxygen or halogen. Primary and secondary alcohols can be easily oxidized using catalysts such as acids and metals. The coil that is used to vaporize the electronic liquid is made up of nichrome wire. The hot metal catalyzes the oxidation reaction. The high temperatures that are reached within the electronic cigarette cause thermal degradation to occur, which is the probable catalyst for this oxidation reaction. The use of a heterogeneous catalyst significantly reduces the activation energy of the transition states and increases the rate of the reaction. Glycerin has been found to dehydrate to acrolein; however, the mechanism does not just produce acrolein but other carbonyl compounds such as acetaldehyde, propanal, and acetone. From the reaction, carbon dioxide and carbon monoxide were identified in small quantities10 . Glycerin readily forms a homogenous mixture with water due to its three hydroxyl groups that readily form a hydrogen bond with water molecules. When glycerin is in its purest form, its boiling point is 290 ̊ C. When water is mixed with glycerin to form a homogenous solvent, the boiling point decreases. Figure VII. shows the reaction mechanisms possible for the dehydration of glycerin.
  • 16. Parker16 Figure VII. Pathways of dehydration of glycerol and its proposed products. Figure VII. shows that there are two specific pathways of dehydration that glycerin can undergo-a 1-2 dehydration and a 1-3 dehydration. The 1-2 dehydration occurs when the secondary or primary hydroxyl group is protonated. If the secondary hydroxyl group is protonated, acrolein will be formed, if the terminal hydroxyl group is protonated, acetol will be formed. When the terminal hydroxyl group is protonated, has an unstable transition state is formed; however, this state is stabilized due to the conjugation of the weak basic sites4 . From this pathway, acetol is formed. If this product was dehydrated again, the product that would form would be thermodynamically unstable. Because of its unstability, acetol is the major product of this dehydration pathway. This unstable transition state is the reason that the dehydration pathway yields a large acrolein output. Acrolein is formed when the secondary hydroxyl group is protonated. The hydroxy propanal that is formed undergoes a second dehydration to form
  • 17. Parker17 acrolein. If an aldol or retro aldol condensation reaction occurs, acetaldehyde, formaldehyde, and acrolein are favorable products. In a 1-3 dehydration of glycerin, the carbon backbone is deconstructed and the products formed are formaldehyde and vinyl alcohol. The mechanisms for the carbon backbone deconstruction and decomposition to formaldehyde and acetaldehyde can be seen in Figure VIII. The vinyl alcohol goes through keto-enol tautomerization to acetaldehyde, this aldehyde can further oxidized to form acetic acid. In the experiments performed, both acetaldehyde, formaldehyde, and acetic acid were present in the vapors produced by electronic cigarettes. Figure VIII. Mechanism for the deconstruction of the carbon backbone that occurs due to high temperatures Electronic cigarettes are heated to high temperatures in order to reach the vaporization temperature of the solvent so that it can be aerosolized to the user for inhalation. Formaldehyde is known to be unstable at such increased temperatures. When this occurs, formaldehyde
  • 18. Parker18 thermally decomposes to carbon monoxide and hydrogen. The hydrogen that is formed at these high temperatures are responsible for reducing products formed in the reaction pathway. Mechanism of Propylene Glycol Dehydration to Carbonyl Compounds Propylene glycol decomposes at high temperatures via three different reaction pathways15 . These pathways can be seen below in Figure IX. Figure IX. Scheme of the three reaction pathways of propylene glycol In the first pathway, propylene glycol (1) dehydrates to an allyl alcohol (5). The reaction barrier for this pathway is fairly high compared to the other pathways15 . TDue to the higher reaction barrier, this pathway is not as favored as the other two. The allyl alcohol is further split into formaldehyde and acetaldehyde by bond scission. In the second pathway, Propylene glycol is dehydrated to form propylene oxide (2) as an intermediate; however, if a hydrogen shift occurs, propylene glycol will further decompose to acetone (3). The mechanism for this decomposition can be seen in Figure IX. in the first mechanism. In this mechanism, a hydrogen ion comes out and the propylene oxide structure
  • 19. Parker19 rearranges it’s double dond to form acetone. Acetone was found in electronic cigarette vapors in multiple studies. This shows that this pathway can be favored at high temperatures. The propylene glycol can also decompose to propanal, or propionaldehyde (4). This can be seen in Figure X. below the first mechanism. In this mechanism, a hydride shift occurs and the propylene oxide rearranges it’s structure to form propionaldehyde.. The propylene glycol is in equilibrium with the protonated form; however, at high temperatures, entropy favors dehydration which will be stabilized by the formation of the enol15 . The reaction barrier to form propionaldehyde is the lowest among the pathways, therefore, this pathway is the most favorable and the main product formed in the thermal degradation of propylene glycol. Figure X. Mechanism of the rearrangement of propylene oxide in the event of a hydride shift Propylene glycol has been known to produce more carbonyl compounds than glycerol when vaporized. After reviewing both mechanisms, it can be assumed that this occurs due to the amount of carbonyl compounds produced for each molecule of humectant. The dehydration of propylene glycol has the possibility to yield formaldehyde and propionaldehyde. The propionaldehyde can further decompose to acetone. Therefore, this reaction mechanism presents
  • 20. Parker20 the formation of two carbonyl species for every one molecule of propylene glycol. The glycerin only forms one carbonyl molecule when dehydrated. Determination of Carbonyl Compounds Generated from E-Cigarettes by HPLC In this experiment, carbonyl compounds from electronic cigarette vapor were captured using coupled silica cartridges impregnated with hydroquinone and 2, 4-dinitrophenylhydrazine and were analyzed using high performance liquid chromatography. A test group of 13 electronic cigarette brands were analyzed in this way. Of the 13 brands tested, 4 brands did not generate any carbonyl compounds and 9 generated various carbonyl compounds. From this experiment, there was not a prominent carbonyl compound that was always formed; however, it was determined that electronic cigarettes incidentally produce high concentrations of carbonyl compounds11 . An HPLC instrument was set up with two LC20AD pumps, photodiode array detector, and an auto-sampler. The column used allowed for a 2.7μm particle size and was 150mm x 4.6mm. The column temperature was set for 40 ̊C and the injection size was 10μL. The flow rate of the mobile phase was 0.7 mL/min. In order to generate vapor, a smoking machine was employed. Before the collection of the vapors from the electronic cigarette machine, a hydroquinone cartridge (HQ-cartridge) and a 2, 4-dinitrophenylhydrazine cartridge (DNPH- cartridge) were connected to the machine to capture the vapors in solid form. The cartridges were placed between the mouthpiece of the electronic cigarette and the smoking machine in order to collect the carbonyl compounds from the vapors. The smoking machine was set to 55mL puff volume, 2-s puff duration, 30-s puff interval, and 10 puffs. The cartridges were removed after each run and were rinsed with acetonitrile containing 1% phosphoric acid in the opposite
  • 21. Parker21 direction the smoking machine was used until the total volume reached 4.5 mL. After 10 minutes, ethanol was added to the solution and it was then analyzed by HPLC11 . From this experiment, multiple simple carbonyl compounds were detected in the vapors of electronic cigarettes. Major carbonyl compounds found in electronic cigarette vapors were formaldehyde, acetone, propanol, glyoxal, acetaldehyde, and methylglyoxal11 . Figure XI. shows a sample chromatograph from one of the trials. Figure XI. Chromatogram of carbonyl compounds found in e-cigarette vapors. (Where FA=formaldehyde, AA=acetaldehyde, ACR=acrolein, GA=glyoxal, AC=acetone, MGA=methylglyoxal, and PA=propanol)11 The concentrations of each carbonyl compound that was found in the electronic cigarettes were compared against each other for each electronic cigarette brand. These comparisons can be seen in Figure XII.
  • 22. Parker22 Figure XII. Graphs of the concentrations of carbonyl compounds found in 10 e-cigarettes using the same brand of e-liquid11 . The concentrations of all the major carbonyl compounds that were produced during the experiment from all 13 brands of e-liquid tested can be seen in Table I.
  • 23. Parker23 Table I. The concentrations of key carbonyl compounds that were produced from the 13 e- cigarette brands tested11 From Figure XII. and Table I. the statistical analysis shows that there were large statistical differences in the carbonyl compounds produced among the different products and the carbonyl concentrations. Of the 13 e-cigarettes tested, nine produced carbonyl compound groups and the other four (J, K, L, M) did not. This evidence highly suggests that not one specific carbonyl group is produced; however, from the results it was noted that formaldehyde was measured at high concentrations in the electronic cigarette vapor. Two new carbonyl groups that were observed that are not prevalent in traditional cigarette smoke were glyoxal and methylglyoxal. Both are known to be mutagenic aldehydes. Methylglyoxal, also known as pyruvaldehyde, inhibits the metabolism of formaldehyde and increases the chance of formaldehyde-induced cytotoxicity11 .
  • 24. Parker24 From this experiment, the cartomizer that was utilized was examined after the conclusion of the experiment. The cartomizers used in this experiment operated with a nichrome wire to heat the electronic liquid mixture to vaporization temperature so that it could be delivered in aerosol form. After the experiment, the nichrome wire was observed to have changed color from white to black. The cartomizer used in this experiment can be seen in Figure XII. Figure XII. The cartomizer used from the experiment with blackened deposits from thermal degradation of e-liquids used. The left shows a cartomizer that produced low concentrations of carbonyl compounds while the right shows a cartomizer that produced high concentrations of carbonyl compounds11 . From what is known about the contents of the electronic liquid used in electronic cigarettes, it can be assumed that the propylene glycol and glycerin came in contact with the metal, which catalyzed an oxidation reaction to form the carbonyl compounds acetone, acetaldehyde, formaldehyde, acrolein, glyoxal, and methylglyoxal.
  • 25. Parker25 The Effect of Nicotine Solvent and Battery Output Voltage on Carbonyl Compounds Present in Electronic Cigarettes Previous experiments that determined the levels of carbonyl compounds found in e- cigarettes were performed on first generation electronic cigarettes. Since those experiments were performed, the electronic cigarette market continued to enhance the product and rapidly introduce the “second generation” electronic cigarette and “third generation” electronic cigarette which is also referred to as a personal vaporizer. This newest instrumentation allows the user to fully customize their smoking experience. The user can determine what ratio of propylene glycol to glycerin they would like to use in the tank, along with the concentration of nicotine. The individual can also increase the vaporization temperature by changing the battery output voltage. In this experiment, ten nicotine solvents and three control solutions made up of pure propylene glycol, pure glycerin, or a mixture of both solutions, were analyzed for twelve particular carbonyl compounds. The electronic cigarette voltage was slowly increased during the experiment from 3.2V to 4.8V. The carbonyl compounds were measured using HPLC method. The purpose of the experiment was to determine how battery output voltage and the nicotine solvent effect the concentration of carbonyl compounds produced in the vapors of the newest electronic cigarette model. Ten different electronic liquids were used for the experiment with concentrations of nicotine varying from 18-24 mg/ml. The ten different e-liquids were placed in groupings based on the contents of their humectants. Products A1-A3 were glycerin based, products A4-A6 were a mixture of glycerin and propylene glycol, and products A7-A10 were purely proplene glycol based. In order to see the how the base humectant effects the carbonyl compounds, three controls were also prepared for the experiment. The controls were made by dissolving liquid nicotine in
  • 26. Parker26 analytical-grade solvents. Control 1 (C1) was a ratio of 88.2% glycerin, 10% redistilled water, and 1.8% nicotine. Control 2 (C2) was made up of 44.1% glycerin, 44.1% propylene glycol, 10% redistilled water, and 1.8% nicotine. Control 3 (C3) was composed of 88.2% propylene glycol, 10% redistilled water, and 1.8% nicotine. Each test was performed with a 70mL puff volume, 1.8s puff duration, and puff intervals of 17s. Each test consisted of 30 puffs from each electronic cigarette. The trial was ran in two series of 15 puffs with a 5 minute break in between series. For the experiment testing battery output voltage effect on carbonyl compounds found in electronic cigarettes, the electronic cigarette generated vapor at the battery voltages 3.2V, 4.0V, and 4.8V12 . The controls were utilized for this trial and each voltage was performed three times for each control for a total of nine runs. Table II. shows the electronic liquid brands, the label information, and nicotine content for each brand that was utilized for the experiment.
  • 27. Parker27 Table II. Ingredient list with nicotine concentrations for each e-liquid product used12 . Silica gels were impregnated with 2, 4-dinitrophenylhydrazine in order to extract the carbonyl compounds from the aerosol phase to the solid phase to be examined. These gels were placed in
  • 28. Parker28 between the mouthpiece of the electronic cigarette and the smoking machine in order to trap the carbonyl compounds that are present in the electronic cigarette vapors. The gels were rinsed with 1mL of acetonitrile. The solvent was then analyzed using HPLC. The elution gradient was made up of acetonitrile and water and the separation was carried out at 40 ̊ C. Table III. Shows the carbonyl compounds that were present in the vapors generated by the electronic cigarettes in the experiment12 . Table III. Carbonyl compounds present in the ten e-liquid solutions12 Table III. shows that all electronic liquids contained at least one carbonyl compound in the vapors generated by the electronic cigarette. This phenomena could have occurred due to the high temperatures needed to vaporize the electronic liquid. At these high temperatures, the solvents could have been catalyzed by the metal coil used to heat the liquid and the solvents could have undergone thermal decomposition. The humectants present in the bases, propylene glycol and glycerin, could have been oxidized to form the toxic carbonyl compounds. In this experiment, formaldehyde, butanol, acetone, and acetaldehyde were the most prevalent carbonyl compounds observed in the electronic cigarette vapors, while acrolein was not detected at all12 .
  • 29. Parker29 The effect of battery output voltage on the carbonyls released in the electronic cigarette vapors were measured by increasing the battery voltage for each control and measuring the carbonyl groups using the silica gels saturated in DNPH. Each control was ran three times at each voltage. The amounts of acetone, acetaldehyde, and formaldehyde that were measure for each run and each control at each battery voltage output can be seen in Figure XIII. Figure XIII. The effect of the battery output voltage on carbonyl compound yields from e- cigarettes12 Figure XIII. shows that when the voltage was increased from 4.0V to 4.8V, the amount of formaldehyde in electronic cigarettes that used a propylene glycol and glycerin mixture base or purely propylene glycol increased significantly. The acetaldehyde was also significantly increased in those mixtures when the voltage was increased. Similarly, the amount of acetone produced experienced a statistically significant increase from 3.2V to 4.8V in the control that used the base mixture of glycerin and propylene glycol. Glycerin was not as affected by battery output as the base mixture propylene glycol; however, in this experiment, an increase in voltage
  • 30. Parker30 showed an increase in carbonyl compound yield. Propylene glycol is known to be less viscous than glycerin. This means that it has a lower optimum temperature that it can be aerosolized. When voltage is increased, and temperature is increased faster, the reaction rate of the oxidation of propylene glycol will be increased, which produces more toxic carbonyl compounds. These results also propose that propylene glycol is more vulnerable to the thermal degradation than glycerin. Conclusion: The vaping community is quickly emerging. Between 2012-2013, the sale of electronic products increased 320% for disposable electronic cigarettes, 72% for starter kits, and 82% for cartridges18 .Within the next year, revenue from electronic cigarettes are expected to double to over $1.7 billion and projected to pass traditional cigarette sales by 204719 . With its increasing popularity, the electronic cigarette has rapidly evolving technology that gives the user more freedom with their personal vaporizing experience. There is still a lot to learn about the chemical reactions that are taking place within the electronic nicotine devices and how the by-products of these reactions could affect the user’s body short-term and long term. The refill solutions for these ever-evolving systems contain aldehydes, heavy metals, volatile organic compounds, food- grade flavoring, and humectants. Research has only scratched the surface of the chemical reactions that take place among all these additives. At the high temperatures that are required to vaporize these solutions, unpredictable behaviors among the compounds take place and carcinogenic carbonyl compounds are being formed and inhaled17 . The inconsistency of the carbonyl compounds that are formed from the electronic cigarette vapors suggests that at high temperatures there is a lot more interaction among the compounds within the solvents. From the studies performed it has been observed that at these high temperatures, the electronic liquid is
  • 31. Parker31 catalyzed by the nichrome wire that incidentally touches the electronic liquid as it is heated to its vaporization temperature. By the metal coil, the solvent is oxidized to form formaldehyde, acetaldehyde, acrolein, and acetone. Increase in battery output voltage also proved that these toxic compounds can be produced in extremely high concentrations. The mechanism reaction for the oxidation of the solvent to form aldehydes has been determined; however, when food additives and flavorings are added to the solvent, there is a possibility of more interaction within the solvent and more toxic by-products being produced due to an acid catalyst being present. While it is known how the body is affected when these additives are consumed, it is not known how the body is affected when these additives are inhaled. Aldehydes have been identified as cytotoxic and carcinogenic and highly toxic to the body when exposed over a long period of time. In order to further the research on electronic cigarette reactions and obtain precise results, more research should be performed to determine the behaviors of electronic cigarette users. With this information, experiments can be ran similarly to the electronic cigarette user’s behavior so that results are more comparable. Also by standardizing the analysis of aerosol generation and collection of carbonyl compounds, this would allow for better comparisons of electronic cigarette vapor and cigarette smoke.
  • 32. Parker32 References 1. VapeHit. E-liquid Facts. http://www.vapehit.co.uk/info.php?articles&articles_id=22 (accessed Oct. 25, 2015). 2. Info Electronic Cigarette. Electronic Cigarette GLossery.http://info-electronic- cigarette.com/electronic-cigarette-glossary/(accessed Oct. 21, 2015). 3. Eversmoke Electronic Cigarettes. History of the Electronic Cigarette. http://www.learn.eversmoke.com/history-of-electronic-cigarettes.html (accessed Oct. 21, 2015). 4. Nguyen, David and Aamodt Gail. Electronic Cigarettes the Past, Present, and Future. Continuing Education Course. DentalCare.com [Online] (October 1 2014). http://www.dentalcare.com/media/en-US/education/ce451/ce451.pdf (Accessed Oct. 15, 2015) 5. Sifferlin, Alexandra. E-cig Flavors May BE Dangerous, Study Says. Time. [Online] 2015. http://time.com/3822831/ecig-flavors/ (accessed Oct. 17, 2015) 6. Medical News Today. What is Nicotine? http://www.medicalnewstoday.com/articles/240820.php (Accessed Oct. 18, 2015) 7. Marnett, Lawrence J. Health Effects of Aldehydes and Alcohols in Mobile Source Emissions. In Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press, 1988. pp 580-585. (http://www.nap.edu/read/1033/chapter/25#583) (accessed Oct. 18, 2015) 8. Cassee, Flemming R; Groten, John P; Feron, Victor J. Changes in the Nasal Epithelium of Rates Exposed by Inhalation to Mixtures of Formaldehyde, Acetaldehyde, and Acrolein. Fundamental and Applied Toxicology. [Online] 1995, 29, 208-218. (http://toxsci.oxfordjournals.org/content/29/2/208.full.pdf+html) (accessed Oct. 23, 2015) 9. Laino, Teodoro; Tuma, Christian; Moor, Philippe; Martin, Elyette; Stolz, Steffen; Curioni, Alessandro. Mechanisms of Propylene Glycol and Triacetin Pyrolysis. J. Phys. Chem. A 2012, 116, 4602-4609 (http://eprints.eemcs.utwente.nl/22979/01/stolz1- jp300997d.pdf) (accessed Oct. 18, 2015) 10. Ulgen, Arda. Conversion of Glycerol to the Valuable Intermediates Acrolein and Allyl Alcohol in the Presence of Heterogeneous Catalysts. [online] (http://publications.rwth- aachen.de/record/63757/files/3078.pdf;) (accessed Oct. 19, 2015) 11. Uchiyama, Shigehisa; Ohta, Kuzushi; Inaba, Yohei; Kunugita, Naoki. Determination of Carbonyl Compounds Generated from the E-Cigarette Using Coupled Silica Cartridges Impregnated with Hydroquinone and 2, 4-Dinitrophenylhydrazine, Followed by High- Performance Liquid Chromatography. Analytical Sciences. December 2013, Vol. 29, 1219-1222. 12. Kosmider PharmD, Leon; Sobczak PhD, Andrzej; Fik PharmD, Maciej; Knysak PharmD, Jakub; Zaciera PharmD, Marzena; Kurek PharmD, Jolanta; Goniewicz PharmD, PhD, Maciej Lukasz. Carbonyl Compounds in Electronic Cigarette Vapors---Effects of Nicotine Solvent and Battery Output Voltage. Nicotine & Tobacco Advance Access. May 14, 2014.
  • 33. Parker33 13. Centers for Disease Control and Prevention. Nicotine: Systematic Agent. http://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750028.html (accessed Oct. 17, 2015) 14. Geiss, Otmar; Bianchi, Ivana; Barahona, Francisco; Barrero-Moreno, Josefa. Characterization of Mainstream and Passive Vapours Emitted by Selected Electronic Cigarettes. International Journal of Hygiene and Environmental Health. Vol 218, Issue 1, January 2015, 172-180. 15. Schlaf, Marcel; Zhang, Z. Conrad; Cellulose Hydrogenolysis to Ethylene Glycol and 1,2- Propylene Glycol. Reaction Pathways and Mechanisms in Thermocatalytic Biomass Conversion I. Springer: New York, 2015; pp 242-247. 16. Cheng, Tianrong. Chemical Evaluation of Electronic Cigarettes. Center for Tobacco Products, Food, and Drug Administration. [Online]. 2014, 23, ii11-ii17. 17. Lim, Hyun-Hee; Shin, Ho-Sang. Measurement of Aldehydes in Replacement Liquids of Electronic Cigarettes by Headspace Gas Chromatography-Mass Spectrometry. Bull Korean Chem. Soc. 2013, Vol. 34, No. 9. Pp. 2691-2695. 18. Center for Disease Control and Prevention. Economic Facts About U.S. Tobacco Production and Use. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/economics/econ_facts/ (accessed Oct. 23, 2015) 19. Forbes. E-Cigarette Sales Surpass $1 Billion As Big Tobacco Moves In. http://www.forbes.com/sites/natalierobehmed/2013/09/17/e-cigarette-sales-surpass-1- billion-as-big-tobacco-moves-in/ (accessed Oct. 24, 2015) 20. Forbes. E-Cigarette Flavoring Chemicals May Pose Risks When Inhaled. http://www.forbes.com/sites/tarahaelle/2015/04/16/e-cigarette-flavoring-chemicals-may- pose-risks-when-inhaled/. (accessed Oct. 24, 2015).
  • 34. Determination of Carbonyl Compounds Found in Electronic Cigarettes By: Madison Parker
  • 35. Parker2 Abstract: Electronic Nicotine Delivery Systems (ENDS) and personal vaporizers are battery- powered devices that aerosolizes nicotine so that it is readily available to the user. Food-grade ingredients and traditional cigarette ingredients are used in these devices. There is very little analytical data available that informs the public to the possible health effects of ENDS on the user; however, it is known that these devices put out significant toxic carbonyl compounds. In one experiment, electronic cigarettes were tested to determine their carbonyl compound output. This was tested by testing 13 different brands of electronic cigarette solvent by capturing its vapor using coupled silica cartridges impregnated with hydroquinone and 2, 4- dinitrophenylhydrazine. They were then analyzed using high performance liquid chromatography. Of the 13 brands tested, 4 brands did not generate any carbonyl compounds and 9 generated various carbonyl compounds. From this experiment, there were not specific carbonyl compounds formed for every trial; however, it was determined that electronic cigarettes incidentally produce high concentrations of carbonyl compounds11 . In another study, the effect of nicotine solvent and voltage output on carbonyl compound formation were tested. To determine the effect of nicotine solvent on the carbonyl compound output, ten different electronic cigarette liquids were used for the experiment with concentrations of nicotine varying from 18-24 mg/ml. The ten different electronic cigarette liquids were placed in groupings based on the contents of their humectants. One group was made up of purely propylene glycol, one group purely vegetable glycerin, and another group a ratio of both propylene glycol and vegetable glycerin. In order to see how the base humectant effects the carbonyl compounds, three controls were also prepared for the experiment. In this experiment, it was observed that all electronic cigarette liquids contained at least one carbonyl compound in the vapors produced by the electronic
  • 36. Parker3 cigarette. In this experiment, formaldehyde, butanol, acetone, and acetaldehyde were the most prevalent carbonyl compounds observed in the electronic cigarette vapors, while acrolein was not detected at all12 . In this same experiment, the effect of voltage on carbonyl compound formation was tested by observing the carbonyl compound generation when increasing the ENDS voltage to 3.2V, 4.0V, and 4.8V. From this experiment, it was observed that as voltage increases, so does the amount of carbonyl compounds formed within the vapors. The most significant increase in carbonyl compounds was observed in humectants that used propylene glycol as a base in the e-liquid. In order to determine the harmful effects of electronic cigarettes to its users, this paper evaluates the instrumentation of ENDS, analyzes the chemical action that occurs during its use, and reviews available evidence that evaluates how carbonyl compounds are generated during electronic cigarette usage.
  • 37. Parker4 Introduction: Electronic Cigarettes have been around since the 1960’s. Hubert A. Gilbert, in 1963, filed a patent for the idea for the first electronic cigarette. At the time, smoking cigarettes in public was normal social behavior and the toxic side effects of smoking tobacco was not as extensively researched. At the time, there was not a need for “healthier” smoking options and smoking was fairly accepted in society. In 2003, Han Lik, a Chinese pharmacist and a smoker, developed the first usable electronic cigarette after his father passed away from lung cancer. Shortly after its invention, the Chinese and European markets were the first to accept electronic nicotine delivery systems. In 2007, the electronic cigarette was introduced into the American market3 . Over the years, the FDA and manufacturers have fought over the regulations of selling and producing electronic cigarettes, due to their unknown health effects on users. Import bans have been placed on the product and law suits have been filed to try and stop the spread of the popular product. To this day, electronic cigarettes are still banned in certain states. Originally, electronic cigarettes were created to help smokers quit their smoking addiction. Now electronic cigarette-use has evolved into a large community that utilizes personal vaporizers that can be modified to maximize the user’s smoking preferences. Electronic nicotine delivery systems are designed to look like traditional tobacco cigarettes in order to simulate the sensory, social, visual, and behavioral features of smoking4 . The models can be filled with any of the thousands of available “e-juice” flavors that range from traditional coffee, vanilla, cigar, or more unique flavorings such as watermelon, mango, or cotton candy17 . Some “e-juice” brands aim to simulate traditional cigarette brands such as Camel or Marlboro1 . Each “e-juice” contains varying amounts of nicotine, propylene glycol, vegetable glycerin, and food-grade flavorings.
  • 38. Parker5 The “e-juice” is heated using a battery-powered device which aerosolizes the liquid mixture to the user for inhalation1 . There is little known about the long-term health risks associated with electronic cigarette usage or the “e-juice” that it utilized. Due to a lack of combustion, these products do not contain typical carcinogens that are known to be in tobacco products. In addition to the nicotine used to help curb a smoker’s addiction, other compounds that are added to the electronic cigarette liquid such as the humectant, flavoring, and other food-grade additives can cause problems. As this fad continues to increase, so does the need for regulation and the understanding of the long term effects. Electronic Nicotine Delivery System The electronic nicotine delivery system is a battery-powered alternative to cigarette smoking. The device utilizes an atomizer to heat up the liquid mixture of nicotine dissolved in propylene glycol. The propylene glycol acts as a humectant for the nicotine that users crave. Characteristically, propylene glycol is a sweet, colorless, and odorless substance. When mixed with the nicotine, it helps to preserve nicotine in the state needed for delivery. When it is inhaled by the user, the resultant is a white cloudy smoke similar to cigarette smoke; however, it’s odorless, which makes this form of smoking more attractive to its users. First generation electronic cigarettes consist of a cartridge that holds the nicotine and propylene glycol mixture and a battery that atomizes the liquid to be inhaled by the user. This electronic nicotine delivery system is disposable and is powered when the user inhales. A model of the first generation electronic cigarette can be seen in Figure I.
  • 39. Parker6 Figure I. Model of a first generation electronic cigarette. Figure II. shows the general set up of the second generation electronic cigarette. The second generation electronic nicotine delivery system is powered by a lithium-ion battery. When the user presses the control button, the device activates the atomizer. There are two different types of atomizers: systems that are disposable and systems that can be rebuilt. Those that are disposable are classified as clearomizers or cartomizers. Those that can be rebuilt are referred to as rebuildable dripping atomizers (RDA) or rebuildable tank atomizers (RTA)2 . Inside the atomizer is a wick that soaks up the homogenous liquid. The wick is then wrapped around an internal coil. The internal coil is nichrome wire made up of 80% nickel and 20% chromium that is heated and incidentally heats the temperature of the electronic liquid to extremely high temperatures. At the vaporization point, the aqueous solution of vegetable glycerin, propylene glycol, flavoring, and/or nicotine within the tank is atomized to vapor. The vapor is then inhaled through the mouthpiece by the user.
  • 40. Parker7 Figure II. Model of the second generation electronic cigarette. The newest generation of ENDS has progressed into box-mod devices that allow the user to have absolute control over their smoking experience and is sometimes referred to as a personal vaporizer. The personal vaporizer has LED displays and controls that allow the user to increase or decrease the voltage of the device. The flexibility of the device allows the user to customize their electronic liquid mixture to optimize their smoking capability. The box-mod/personal vaporizer model can be seen in Figure III. Figure III. Model of a box-mod personal vaporizer (3rd Generation).
  • 41. Parker8 E-liquid The two most widely used electronic cigarette bases are propylene glycol and vegetable glycerin, usually referred to as glycerol. There are four main ingredients found in electronic liquids: (1) a propylene glycol or vegetable glycerin base, (2) water, (3) flavoring, and (4) nicotine. Propylene glycol and vegetable glycerin are commonly used as food additives and are known to be safe for consumption. They are non-toxic organic compounds that hold the nicotine and flavor in suspension. These particular bases are favored because they are characteristic for the white clouds of vapor that are exhaled by the user. Every electronic liquid contains propylene glycol, vegetable glycerin, or a customized ratio of both. The organic molecule propylene glycol is generated from propylene oxide. It is odorless, has low viscosity, and colorless. It is typically utilized to preserve foods, as solvents, pharmaceutical products, and tobacco products. Vegetable glycerin comes from naturally extracted plant oils such as coconut oil, palm oil, and soy. It is odorless, slightly tinted in color, sweet, and typically more viscous than propylene glycol. It is found in food production, cosmetics, and tobacco products. Electronic cigarettes are known for being customizable down to the flavor of their electronic liquid; however, the chemicals used to flavor electronic cigarettes may not be as safe as individuals’ believe5 . Third generation personal vaporizers allow for the user to choose a unique flavoring of electronic liquid to be vaporized. Flavorings can imitate common tobacco products such as Camel and Marlboro, and some manufacturers have developed dessert-like flavorings such as Pumpkin Spice, Watermelon, Swedish Fish, Marshmallow, or even Cotton Candy to name a few. Most of these flavorings are food-grade ingredients that have been deemed by the Federal Drug Administration as safe to consume; however, the FDA has not been able to
  • 42. Parker9 state whether the food-grade ingredients are safe to inhale. These flavorings and additives make the nicotine also found in the electronic liquid more addicting and appealing to its users. Those who are regularly exposed to nicotine become dependent on the chemical16 . If exposure is discontinued, the user can experience withdrawal symptoms such as cravings, depression, anxiety, the feeling of emptiness, and irritability6 . In electronic cigarettes, nicotine is present in the liquid form and held in suspension by a humectant, which is then heated and aerosolized for the user to inhale. In its liquid form, nicotine is highly concentrated and exceedingly toxic13 . Users of personal vaporizers can also customize the concentrations of nicotine utilized within the electronic nicotine delivery system. Liquid concentrations of nicotine vary from 0 to 18 mg/ml and some were even found as high as 36-42 mg/ml. Dosing is inconsistent and fluctuates by manufacturer. E-liquids containing “low doses” of nicotine correspond to a concentration of 6-8 mg/mL, “Midrange” concentrations contain 10-14 mg/mL, “High” concentrations correspond to 16-18 mg/mL, and “Extra-high” concentrations correspond to 24-36 mg/mL of nicotine per mL of liquid1 . All doses of liquid nicotine have the numerical concentration printed on the container of the electronic liquid or on its original packaging; however, some studies have determined that the actual concentration of nicotine within the electronic liquid is hard to determine and often differs from what is stated on the packaging16 . Therefore, the user must be careful when loading their personal vaporizers due to the fact that nicotine toxicity can occur when the liquid is consumed or applied to the skin13 . An ENDS user has the option to determine which base they would like to utilize as a humectant in the third generation personal vaporizer. Users can use a pure propylene glycol base or vegetable glycerin base. Often times, users create differing ratios of propylene glycol and vegetable glycerin in order to maximize their smoking experience. Propylene glycol is utilized
  • 43. Parker10 more often than vegetable glycerin as an e-liquid base for many reasons. Both structures can be seen in Figure IVa. and Figure IVb. Figure IVa. Structure of Propylene Glycol Figure IVb. Structure of Vegetable Glycerin Because propylene glycol is less viscous than vegetable glycerin it’s easier to load into the reusable drip tank and there is less build-up deposited on the nichrome wire coil after the liquid has been vaporized. Vegetable glycerin has a higher viscosity and density so it often creates build up on the nichrome coil that heats up the electronic liquid over time. Due to vegetable glycerin’s high viscosity, it takes more energy and a takes longer to reach the optimal temperature needed to vaporize; however, the density of the vegetable glycerin allows the user to create thicker vapor and tends to be a healthier option for the user.
  • 44. Parker11 Chemical Reaction through which Propylene Glycol/Glycerol forms Carbonyl Compounds In order for the vaporizer to work, the propylene glycol, flavoring molecules, and nicotine molecules must be heated to their heat of vaporization without chemically degrading them. It is estimated that the theoretical vaporization temperature of an electronic cigarette could reach up to 350 ̊C. This temperature is high enough to cause physical alterations to the chemicals within electronic liquids and cause chemical reactions to occur within the solvent. At such high temperatures, the solution could undergo thermal decomposition which leads to the generation of toxic aldehydes6 . When glycerol (vegetable glycerin) is heated, it decomposes by a dehydration mechanism to acrolein and water. Eq. 1 C3H8O3 ∆ → C2H3CHO + 2H2O Acrolein is typically found in the environment and in food products. It can be formed from carbohydrates, animal fats, or by heating foods; however, when smoking tobacco products, the produced acrolein exceeds or equals the total human exposure to acrolein from all other sources. It is a colorless, poisonous, pungent, and the simplest unsaturated aldehyde. This volatile organic compound can cause burning of the nose and throat and can cause damage to the lungs. By a retro aldol condensation reaction, acrolein can further break down into acetaldehyde and formaldehyde. This reaction only occurs in the presence of a catalyst, such as the hot metal present in the e-liquid in the form of coils that heat the liquid. The nichrome wire present in the atomizer of the electronic cigarette is known to have a low heat tolerance and give a metallic taste to the user2 . Acids and bases can also catalyze the reaction and are present in the electronic liquid flavorings. Glycerol Acrolein
  • 45. Parker12 Eq. 2 C3H8O ுశ ሱሮ H3CCHO + HCHO Eq. 3 C3H8O ௛௢௧ ௠௘௧௔௟ ሱۛۛۛۛۛۛሮ H3CCHO + HCHO Formaldehyde is a colorless, overpowering organic compound. The short term effect of this compound on the body could be irritation of the eyes, throat, and nose. If exposed to this toxic compound over a longer period of time, one could experience coughing, trouble breathing, rawness of the throat and interior of the nose. The respiratory system could also be effected. It has also been shown that with increased dosages of formaldehyde to the body, there is also an increase in developing specific types of cancer8 . In an electronic cigarette that utilizes propylene glycol, the propylene glycol boils when exposed to extremely high temperatures. With these specific conditions in the form of a catalyst, the electronic liquid could dehydrate to form propionaldehyde. Eq. 4 C3H8O2 ିுమை ሱۛۛሮ C2H5CHO Propionaldehyde is a colorless liquid that is accompanied by a fruity smell. When in contact with the body it can irritate the skin, nose, throat, and lungs. When inhaled it could cause shortness of breath, excessive coughing, and pulmonary edemas. Glycerol Glycerol Acetaldehyde Formaldehyde Acetaldehyde Formaldehyde PropionaldehydePropylene Glycol
  • 46. Parker13 Effect of Aldehydes on the Body An aldehyde is an organic compound that contains a –CHO group. It is a simple carbonyl molecule that is formed by the oxidation of alcohol. The most common aldehydes are formaldehyde, formed from methanol, and acetaldehyde, which is generated from ethanol. Aldehydes such as acrolein, formaldehyde, acetaldehyde, and crotonaldehyde have been documented to have acute effects on the human body8 . Common aldehydes and their structures can be seen below in Figure V. Figure V. Common aldehydes and their chemical structures. acrolein Among these examples, acrolein was found to have the greatest impact7 . Acrolein is found to be 2 to 3 times more toxic formaldehyde7 . Occasional exposure to aldehydes may cause olfactory and ocular irritation. Long-term contact may cause extreme irritation to the mucous membranes and damage to respiration7 . Chronic exposure can even cause irreversible damage to the epithelial tissues lining the lungs and respiratory tract. A study was performed on rats to
  • 47. Parker14 determine carcinogenicity of aldehydes. Rats were exposed to a concentration of formaldehyde for a period of time. After that period of time, 103 rats were observed to have induced squamous cell carcinoma. The same procedure was performed on mice. The mice were observed with nasal tumors. These studies all gave evidence to reversible and irreversible damage to epithelium cells lining the respiratory tract and the damage that can occur when exposed to aldehydes8 . Mechanism for Formation of Carbonyl Compounds by Glycerol and Propylene Glycol The electronic liquids in the electronic cigarette tank are vaporized when they come into contact with the nichrome wire and oxidized in the presence of oxygen from the surrounding air to form formaldehyde, acrolein, glyoxal, methylglyoxal, and acetaldehyde9 . The solid metal oxide wire is used as a catalyst in this reaction. Because the vegetable glycerin has a high boiling point, this is referred to as a heterogeneous catalyst9 . Figure VI. shows the reaction that occurs when the electronic liquid comes in contact with the heated nichrome wire. Figure VI. Oxidation of vegetable glycerin and propylene glycol with the nichrome wire as a catalyst
  • 48. Parker15 The vegetable glycerin is oxidized to form acrolein. The propylene glycol is oxidized to form methylglyoxal and then further oxidized to form formaldehyde and acetaldehyde whose toxicity is well documented20 . Mechanism of Glycerin Dehydration Reaction to Carbonyl Compounds Glycerin acts as a humectant for a homogenous mixture of flavoring, nicotine, and water. Alcohols can undergo a variety of changes, most of which are either oxidation or reduction reactions. Primary alcohols can be oxidized to form an aldehyde structure. Oxidation is when there is a loss of hydrogen and an addition of an oxygen or halogen. Primary and secondary alcohols can be easily oxidized using catalysts such as acids and metals. The coil that is used to vaporize the electronic liquid is made up of nichrome wire. The hot metal catalyzes the oxidation reaction. The high temperatures that are reached within the electronic cigarette cause thermal degradation to occur, which is the probable catalyst for this oxidation reaction. The use of a heterogeneous catalyst significantly reduces the activation energy of the transition states and increases the rate of the reaction. Glycerin has been found to dehydrate to acrolein; however, the mechanism does not just produce acrolein but other carbonyl compounds such as acetaldehyde, propanal, and acetone. From the reaction, carbon dioxide and carbon monoxide were identified in small quantities10 . Glycerin readily forms a homogenous mixture with water due to its three hydroxyl groups that readily form a hydrogen bond with water molecules. When glycerin is in its purest form, its boiling point is 290 ̊ C. When water is mixed with glycerin to form a homogenous solvent, the boiling point decreases. Figure VII. shows the reaction mechanisms possible for the dehydration of glycerin.
  • 49. Parker16 Figure VII. Pathways of dehydration of glycerol and its proposed products. Figure VII. shows that there are two specific pathways of dehydration that glycerin can undergo-a 1-2 dehydration and a 1-3 dehydration. The 1-2 dehydration occurs when the secondary or primary hydroxyl group is protonated. If the secondary hydroxyl group is protonated, acrolein will be formed, if the terminal hydroxyl group is protonated, acetol will be formed. When the terminal hydroxyl group is protonated, has an unstable transition state is formed; however, this state is stabilized due to the conjugation of the weak basic sites4 . From this pathway, acetol is formed. If this product was dehydrated again, the product that would form would be thermodynamically unstable. Because of its unstability, acetol is the major product of this dehydration pathway. This unstable transition state is the reason that the dehydration pathway yields a large acrolein output. Acrolein is formed when the secondary hydroxyl group is protonated. The hydroxy propanal that is formed undergoes a second dehydration to form
  • 50. Parker17 acrolein. If an aldol or retro aldol condensation reaction occurs, acetaldehyde, formaldehyde, and acrolein are favorable products. In a 1-3 dehydration of glycerin, the carbon backbone is deconstructed and the products formed are formaldehyde and vinyl alcohol. The mechanisms for the carbon backbone deconstruction and decomposition to formaldehyde and acetaldehyde can be seen in Figure VIII. The vinyl alcohol goes through keto-enol tautomerization to acetaldehyde, this aldehyde can further oxidized to form acetic acid. In the experiments performed, both acetaldehyde, formaldehyde, and acetic acid were present in the vapors produced by electronic cigarettes. Figure VIII. Mechanism for the deconstruction of the carbon backbone that occurs due to high temperatures Electronic cigarettes are heated to high temperatures in order to reach the vaporization temperature of the solvent so that it can be aerosolized to the user for inhalation. Formaldehyde is known to be unstable at such increased temperatures. When this occurs, formaldehyde
  • 51. Parker18 thermally decomposes to carbon monoxide and hydrogen. The hydrogen that is formed at these high temperatures are responsible for reducing products formed in the reaction pathway. Mechanism of Propylene Glycol Dehydration to Carbonyl Compounds Propylene glycol decomposes at high temperatures via three different reaction pathways15 . These pathways can be seen below in Figure IX. Figure IX. Scheme of the three reaction pathways of propylene glycol In the first pathway, propylene glycol (1) dehydrates to an allyl alcohol (5). The reaction barrier for this pathway is fairly high compared to the other pathways15 . TDue to the higher reaction barrier, this pathway is not as favored as the other two. The allyl alcohol is further split into formaldehyde and acetaldehyde by bond scission. In the second pathway, Propylene glycol is dehydrated to form propylene oxide (2) as an intermediate; however, if a hydrogen shift occurs, propylene glycol will further decompose to acetone (3). The mechanism for this decomposition can be seen in Figure IX. in the first mechanism. In this mechanism, a hydrogen ion comes out and the propylene oxide structure
  • 52. Parker19 rearranges it’s double dond to form acetone. Acetone was found in electronic cigarette vapors in multiple studies. This shows that this pathway can be favored at high temperatures. The propylene glycol can also decompose to propanal, or propionaldehyde (4). This can be seen in Figure X. below the first mechanism. In this mechanism, a hydride shift occurs and the propylene oxide rearranges it’s structure to form propionaldehyde.. The propylene glycol is in equilibrium with the protonated form; however, at high temperatures, entropy favors dehydration which will be stabilized by the formation of the enol15 . The reaction barrier to form propionaldehyde is the lowest among the pathways, therefore, this pathway is the most favorable and the main product formed in the thermal degradation of propylene glycol. Figure X. Mechanism of the rearrangement of propylene oxide in the event of a hydride shift Propylene glycol has been known to produce more carbonyl compounds than glycerol when vaporized. After reviewing both mechanisms, it can be assumed that this occurs due to the amount of carbonyl compounds produced for each molecule of humectant. The dehydration of propylene glycol has the possibility to yield formaldehyde and propionaldehyde. The propionaldehyde can further decompose to acetone. Therefore, this reaction mechanism presents
  • 53. Parker20 the formation of two carbonyl species for every one molecule of propylene glycol. The glycerin only forms one carbonyl molecule when dehydrated. Determination of Carbonyl Compounds Generated from E-Cigarettes by HPLC In this experiment, carbonyl compounds from electronic cigarette vapor were captured using coupled silica cartridges impregnated with hydroquinone and 2, 4-dinitrophenylhydrazine and were analyzed using high performance liquid chromatography. A test group of 13 electronic cigarette brands were analyzed in this way. Of the 13 brands tested, 4 brands did not generate any carbonyl compounds and 9 generated various carbonyl compounds. From this experiment, there was not a prominent carbonyl compound that was always formed; however, it was determined that electronic cigarettes incidentally produce high concentrations of carbonyl compounds11 . An HPLC instrument was set up with two LC20AD pumps, photodiode array detector, and an auto-sampler. The column used allowed for a 2.7μm particle size and was 150mm x 4.6mm. The column temperature was set for 40 ̊C and the injection size was 10μL. The flow rate of the mobile phase was 0.7 mL/min. In order to generate vapor, a smoking machine was employed. Before the collection of the vapors from the electronic cigarette machine, a hydroquinone cartridge (HQ-cartridge) and a 2, 4-dinitrophenylhydrazine cartridge (DNPH- cartridge) were connected to the machine to capture the vapors in solid form. The cartridges were placed between the mouthpiece of the electronic cigarette and the smoking machine in order to collect the carbonyl compounds from the vapors. The smoking machine was set to 55mL puff volume, 2-s puff duration, 30-s puff interval, and 10 puffs. The cartridges were removed after each run and were rinsed with acetonitrile containing 1% phosphoric acid in the opposite
  • 54. Parker21 direction the smoking machine was used until the total volume reached 4.5 mL. After 10 minutes, ethanol was added to the solution and it was then analyzed by HPLC11 . From this experiment, multiple simple carbonyl compounds were detected in the vapors of electronic cigarettes. Major carbonyl compounds found in electronic cigarette vapors were formaldehyde, acetone, propanol, glyoxal, acetaldehyde, and methylglyoxal11 . Figure XI. shows a sample chromatograph from one of the trials. Figure XI. Chromatogram of carbonyl compounds found in e-cigarette vapors. (Where FA=formaldehyde, AA=acetaldehyde, ACR=acrolein, GA=glyoxal, AC=acetone, MGA=methylglyoxal, and PA=propanol)11 The concentrations of each carbonyl compound that was found in the electronic cigarettes were compared against each other for each electronic cigarette brand. These comparisons can be seen in Figure XII.
  • 55. Parker22 Figure XII. Graphs of the concentrations of carbonyl compounds found in 10 e-cigarettes using the same brand of e-liquid11 . The concentrations of all the major carbonyl compounds that were produced during the experiment from all 13 brands of e-liquid tested can be seen in Table I.
  • 56. Parker23 Table I. The concentrations of key carbonyl compounds that were produced from the 13 e- cigarette brands tested11 From Figure XII. and Table I. the statistical analysis shows that there were large statistical differences in the carbonyl compounds produced among the different products and the carbonyl concentrations. Of the 13 e-cigarettes tested, nine produced carbonyl compound groups and the other four (J, K, L, M) did not. This evidence highly suggests that not one specific carbonyl group is produced; however, from the results it was noted that formaldehyde was measured at high concentrations in the electronic cigarette vapor. Two new carbonyl groups that were observed that are not prevalent in traditional cigarette smoke were glyoxal and methylglyoxal. Both are known to be mutagenic aldehydes. Methylglyoxal, also known as pyruvaldehyde, inhibits the metabolism of formaldehyde and increases the chance of formaldehyde-induced cytotoxicity11 .
  • 57. Parker24 From this experiment, the cartomizer that was utilized was examined after the conclusion of the experiment. The cartomizers used in this experiment operated with a nichrome wire to heat the electronic liquid mixture to vaporization temperature so that it could be delivered in aerosol form. After the experiment, the nichrome wire was observed to have changed color from white to black. The cartomizer used in this experiment can be seen in Figure XII. Figure XII. The cartomizer used from the experiment with blackened deposits from thermal degradation of e-liquids used. The left shows a cartomizer that produced low concentrations of carbonyl compounds while the right shows a cartomizer that produced high concentrations of carbonyl compounds11 . From what is known about the contents of the electronic liquid used in electronic cigarettes, it can be assumed that the propylene glycol and glycerin came in contact with the metal, which catalyzed an oxidation reaction to form the carbonyl compounds acetone, acetaldehyde, formaldehyde, acrolein, glyoxal, and methylglyoxal.
  • 58. Parker25 The Effect of Nicotine Solvent and Battery Output Voltage on Carbonyl Compounds Present in Electronic Cigarettes Previous experiments that determined the levels of carbonyl compounds found in e- cigarettes were performed on first generation electronic cigarettes. Since those experiments were performed, the electronic cigarette market continued to enhance the product and rapidly introduce the “second generation” electronic cigarette and “third generation” electronic cigarette which is also referred to as a personal vaporizer. This newest instrumentation allows the user to fully customize their smoking experience. The user can determine what ratio of propylene glycol to glycerin they would like to use in the tank, along with the concentration of nicotine. The individual can also increase the vaporization temperature by changing the battery output voltage. In this experiment, ten nicotine solvents and three control solutions made up of pure propylene glycol, pure glycerin, or a mixture of both solutions, were analyzed for twelve particular carbonyl compounds. The electronic cigarette voltage was slowly increased during the experiment from 3.2V to 4.8V. The carbonyl compounds were measured using HPLC method. The purpose of the experiment was to determine how battery output voltage and the nicotine solvent effect the concentration of carbonyl compounds produced in the vapors of the newest electronic cigarette model. Ten different electronic liquids were used for the experiment with concentrations of nicotine varying from 18-24 mg/ml. The ten different e-liquids were placed in groupings based on the contents of their humectants. Products A1-A3 were glycerin based, products A4-A6 were a mixture of glycerin and propylene glycol, and products A7-A10 were purely proplene glycol based. In order to see the how the base humectant effects the carbonyl compounds, three controls were also prepared for the experiment. The controls were made by dissolving liquid nicotine in
  • 59. Parker26 analytical-grade solvents. Control 1 (C1) was a ratio of 88.2% glycerin, 10% redistilled water, and 1.8% nicotine. Control 2 (C2) was made up of 44.1% glycerin, 44.1% propylene glycol, 10% redistilled water, and 1.8% nicotine. Control 3 (C3) was composed of 88.2% propylene glycol, 10% redistilled water, and 1.8% nicotine. Each test was performed with a 70mL puff volume, 1.8s puff duration, and puff intervals of 17s. Each test consisted of 30 puffs from each electronic cigarette. The trial was ran in two series of 15 puffs with a 5 minute break in between series. For the experiment testing battery output voltage effect on carbonyl compounds found in electronic cigarettes, the electronic cigarette generated vapor at the battery voltages 3.2V, 4.0V, and 4.8V12 . The controls were utilized for this trial and each voltage was performed three times for each control for a total of nine runs. Table II. shows the electronic liquid brands, the label information, and nicotine content for each brand that was utilized for the experiment.
  • 60. Parker27 Table II. Ingredient list with nicotine concentrations for each e-liquid product used12 . Silica gels were impregnated with 2, 4-dinitrophenylhydrazine in order to extract the carbonyl compounds from the aerosol phase to the solid phase to be examined. These gels were placed in
  • 61. Parker28 between the mouthpiece of the electronic cigarette and the smoking machine in order to trap the carbonyl compounds that are present in the electronic cigarette vapors. The gels were rinsed with 1mL of acetonitrile. The solvent was then analyzed using HPLC. The elution gradient was made up of acetonitrile and water and the separation was carried out at 40 ̊ C. Table III. Shows the carbonyl compounds that were present in the vapors generated by the electronic cigarettes in the experiment12 . Table III. Carbonyl compounds present in the ten e-liquid solutions12 Table III. shows that all electronic liquids contained at least one carbonyl compound in the vapors generated by the electronic cigarette. This phenomena could have occurred due to the high temperatures needed to vaporize the electronic liquid. At these high temperatures, the solvents could have been catalyzed by the metal coil used to heat the liquid and the solvents could have undergone thermal decomposition. The humectants present in the bases, propylene glycol and glycerin, could have been oxidized to form the toxic carbonyl compounds. In this experiment, formaldehyde, butanol, acetone, and acetaldehyde were the most prevalent carbonyl compounds observed in the electronic cigarette vapors, while acrolein was not detected at all12 .
  • 62. Parker29 The effect of battery output voltage on the carbonyls released in the electronic cigarette vapors were measured by increasing the battery voltage for each control and measuring the carbonyl groups using the silica gels saturated in DNPH. Each control was ran three times at each voltage. The amounts of acetone, acetaldehyde, and formaldehyde that were measure for each run and each control at each battery voltage output can be seen in Figure XIII. Figure XIII. The effect of the battery output voltage on carbonyl compound yields from e- cigarettes12 Figure XIII. shows that when the voltage was increased from 4.0V to 4.8V, the amount of formaldehyde in electronic cigarettes that used a propylene glycol and glycerin mixture base or purely propylene glycol increased significantly. The acetaldehyde was also significantly increased in those mixtures when the voltage was increased. Similarly, the amount of acetone produced experienced a statistically significant increase from 3.2V to 4.8V in the control that used the base mixture of glycerin and propylene glycol. Glycerin was not as affected by battery output as the base mixture propylene glycol; however, in this experiment, an increase in voltage
  • 63. Parker30 showed an increase in carbonyl compound yield. Propylene glycol is known to be less viscous than glycerin. This means that it has a lower optimum temperature that it can be aerosolized. When voltage is increased, and temperature is increased faster, the reaction rate of the oxidation of propylene glycol will be increased, which produces more toxic carbonyl compounds. These results also propose that propylene glycol is more vulnerable to the thermal degradation than glycerin. Conclusion: The vaping community is quickly emerging. Between 2012-2013, the sale of electronic products increased 320% for disposable electronic cigarettes, 72% for starter kits, and 82% for cartridges18 .Within the next year, revenue from electronic cigarettes are expected to double to over $1.7 billion and projected to pass traditional cigarette sales by 204719 . With its increasing popularity, the electronic cigarette has rapidly evolving technology that gives the user more freedom with their personal vaporizing experience. There is still a lot to learn about the chemical reactions that are taking place within the electronic nicotine devices and how the by-products of these reactions could affect the user’s body short-term and long term. The refill solutions for these ever-evolving systems contain aldehydes, heavy metals, volatile organic compounds, food- grade flavoring, and humectants. Research has only scratched the surface of the chemical reactions that take place among all these additives. At the high temperatures that are required to vaporize these solutions, unpredictable behaviors among the compounds take place and carcinogenic carbonyl compounds are being formed and inhaled17 . The inconsistency of the carbonyl compounds that are formed from the electronic cigarette vapors suggests that at high temperatures there is a lot more interaction among the compounds within the solvents. From the studies performed it has been observed that at these high temperatures, the electronic liquid is
  • 64. Parker31 catalyzed by the nichrome wire that incidentally touches the electronic liquid as it is heated to its vaporization temperature. By the metal coil, the solvent is oxidized to form formaldehyde, acetaldehyde, acrolein, and acetone. Increase in battery output voltage also proved that these toxic compounds can be produced in extremely high concentrations. The mechanism reaction for the oxidation of the solvent to form aldehydes has been determined; however, when food additives and flavorings are added to the solvent, there is a possibility of more interaction within the solvent and more toxic by-products being produced due to an acid catalyst being present. While it is known how the body is affected when these additives are consumed, it is not known how the body is affected when these additives are inhaled. Aldehydes have been identified as cytotoxic and carcinogenic and highly toxic to the body when exposed over a long period of time. In order to further the research on electronic cigarette reactions and obtain precise results, more research should be performed to determine the behaviors of electronic cigarette users. With this information, experiments can be ran similarly to the electronic cigarette user’s behavior so that results are more comparable. Also by standardizing the analysis of aerosol generation and collection of carbonyl compounds, this would allow for better comparisons of electronic cigarette vapor and cigarette smoke.
  • 65. Parker32 References 1. VapeHit. E-liquid Facts. http://www.vapehit.co.uk/info.php?articles&articles_id=22 (accessed Oct. 25, 2015). 2. Info Electronic Cigarette. Electronic Cigarette GLossery.http://info-electronic- cigarette.com/electronic-cigarette-glossary/(accessed Oct. 21, 2015). 3. Eversmoke Electronic Cigarettes. History of the Electronic Cigarette. http://www.learn.eversmoke.com/history-of-electronic-cigarettes.html (accessed Oct. 21, 2015). 4. Nguyen, David and Aamodt Gail. Electronic Cigarettes the Past, Present, and Future. Continuing Education Course. DentalCare.com [Online] (October 1 2014). http://www.dentalcare.com/media/en-US/education/ce451/ce451.pdf (Accessed Oct. 15, 2015) 5. Sifferlin, Alexandra. E-cig Flavors May BE Dangerous, Study Says. Time. [Online] 2015. http://time.com/3822831/ecig-flavors/ (accessed Oct. 17, 2015) 6. Medical News Today. What is Nicotine? http://www.medicalnewstoday.com/articles/240820.php (Accessed Oct. 18, 2015) 7. Marnett, Lawrence J. Health Effects of Aldehydes and Alcohols in Mobile Source Emissions. In Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press, 1988. pp 580-585. (http://www.nap.edu/read/1033/chapter/25#583) (accessed Oct. 18, 2015) 8. Cassee, Flemming R; Groten, John P; Feron, Victor J. Changes in the Nasal Epithelium of Rates Exposed by Inhalation to Mixtures of Formaldehyde, Acetaldehyde, and Acrolein. Fundamental and Applied Toxicology. [Online] 1995, 29, 208-218. (http://toxsci.oxfordjournals.org/content/29/2/208.full.pdf+html) (accessed Oct. 23, 2015) 9. Laino, Teodoro; Tuma, Christian; Moor, Philippe; Martin, Elyette; Stolz, Steffen; Curioni, Alessandro. Mechanisms of Propylene Glycol and Triacetin Pyrolysis. J. Phys. Chem. A 2012, 116, 4602-4609 (http://eprints.eemcs.utwente.nl/22979/01/stolz1- jp300997d.pdf) (accessed Oct. 18, 2015) 10. Ulgen, Arda. Conversion of Glycerol to the Valuable Intermediates Acrolein and Allyl Alcohol in the Presence of Heterogeneous Catalysts. [online] (http://publications.rwth- aachen.de/record/63757/files/3078.pdf;) (accessed Oct. 19, 2015) 11. Uchiyama, Shigehisa; Ohta, Kuzushi; Inaba, Yohei; Kunugita, Naoki. Determination of Carbonyl Compounds Generated from the E-Cigarette Using Coupled Silica Cartridges Impregnated with Hydroquinone and 2, 4-Dinitrophenylhydrazine, Followed by High- Performance Liquid Chromatography. Analytical Sciences. December 2013, Vol. 29, 1219-1222. 12. Kosmider PharmD, Leon; Sobczak PhD, Andrzej; Fik PharmD, Maciej; Knysak PharmD, Jakub; Zaciera PharmD, Marzena; Kurek PharmD, Jolanta; Goniewicz PharmD, PhD, Maciej Lukasz. Carbonyl Compounds in Electronic Cigarette Vapors---Effects of Nicotine Solvent and Battery Output Voltage. Nicotine & Tobacco Advance Access. May 14, 2014.
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