Since its market launch in the mid-2000s, e-cigarette devices have become more and more popular, especially among teenagers and young people. According to the National Youth Tobacco Survey of the US Centers for Disease Control and Prevention, more than 53% of high school students report having tried tobacco products, of which e-cigarettes (also known as e-cigarettes, vape pens, and hookah pens) are the most popular. The design of these products is similar to traditional tobacco cigarettes, containing flavors, solvents, and usually nicotine. With the increasing popularity of e-cigarette devices, the number of lung injuries and hospitalizations has increased, as well as concerns about potential long-term health effects. One of the main reasons for the popularity of these products among teenagers and young people is the variety of fruits, candies and other flavors to choose from. Although many of these chemicals are considered safe for ingestion, their inhalation toxicology and effects on human health are now being investigated. At the Inhalation Flavor Toxicology Center of the University of Rochester Medical Center (CIFT), CIFT Director Dr. Irfan Rahman and his colleagues are conducting research to understand these effects.

E-cigarette devices usually contain nicotine, and recently also contain tetrahydrocannabinol (THC), as well as flavoring chemicals such as pulegone and eucalyptol (mint flavor), diacetyl (butter flavor) and cinnamaldehyde (cinnamon)​​ Flavor), and propylene glycol and vegetable glycerin as the base liquid. These flavoring chemicals and base fluids are generally considered safe-can be ingested. Inhalation is not always the case.

"Due to the different enzymes (CYP enzyme system), the lungs cannot metabolize and eliminate these products like intestinal-liver metabolism," Rahman explained. Cytochrome P450 (CYPs) enzymes metabolize xenobiotics, such as these flavoring chemicals. CYP3A and CYP2C9 are most widely expressed in the small intestine, while CYP2E is ubiquitous in the respiratory tract.

Rahman also explained that e-cigarette devices are designed to heat propylene glycol, vegetable glycerin, and products containing THC oil. Thermal degradation produces many toxic compounds, including aldehydes (formaldehyde, benzaldehyde, and acrolein) that exceed safe exposure levels. To make matters worse, "products produced from adulterated e-cigarettes include vitamin E acetate, silicon conjugated products, butane derivatives, terpenes and heavy metals," he said.

Rahman explained that once inhaled, these toxic compounds promote oxidative stress and inflammation in the lung epithelium and alveoli where gas exchange occurs, leading to a type of pneumonia characterized by "lung air leakage, accompanied by ground-glass opacity and scales." Is the plaque of EVALI". EVALI (pulmonary injury associated with the use of e-cigarettes or e-cigarette products) is a relatively new term caused by a lung disease outbreak in the United States in August 2019. Symptoms include shortness of breath, cough, chest pain, fever, diarrhea, vomiting, tachycardia, and shortness of breath.

"During the EVALI epidemic, many patients were diagnosed with lipoid pneumonia, organizing pneumonia, and eosinophilic pneumonia," Rahman said. "These cases are mainly related to the illegal use of e-cigarettes." However, with The health risks associated with e-cigarettes are not limited to illegal or adulterated products, because the ingredients of legal and widely used products are also related to adverse health effects.

Rahman explained that exposure to flavoring chemicals (such as 2,3-pentanedione and diacetyl) can have a range of health effects, from mild respiratory tract irritation to more severe lung effects, such as bronchiolitis obliterans (popcorn pulmonary disease). "Our research shows that cinnamaldehyde, menthol, and vanillin-containing e-cigarette liquids are significantly toxic," he said.

Rahman and his colleagues at CIFT aim to understand the inhalation toxicology of flavoring chemicals used in e-cigarette products, so as to provide the FDA and NIH with the latest toxicity information of emerging flavoring chemicals, and inform schools and researchers of the risks. This is achieved through a combination of preclinical and clinical research. The center works closely with various experts and pulmonologists in the fields of inhalation toxicology, environmental science, lung biology, cancer research, and public health science.

An important aspect of this research is the characterization of the gas and aerosol phase components, which is achieved by gas chromatography and mass spectrometry (GC-MS). The physical and chemical properties of aerosols, including particle concentration and size distribution, and lung deposition are also important.

Using a real-time live cell analyzer, CIFT researchers can evaluate cell barrier function, reactive oxygen species production, and mitochondrial function. The assay is also used to quantify inflammatory mediators, such as interleukin-6 and interleukin-8 released by cells exposed to flavoring chemicals.

To examine the effects of in vivo exposure, the team used a compact inhalation exposure device to expose the nose or whole body to aerosols.​​​ After exposure, several lung function parameters were evaluated, including compliance, elasticity, and resistance, as well as lipidomics assessment of bronchoalveolar lavage fluid. Lung imaging using luminescence and fluorescence-based techniques was also performed.

Using non-invasive technology, researchers can evaluate the health effects of e-cigarette products on human subjects. "In human studies, spirometry is used to evaluate the lung function of e-cigarette/bomb users and normal subjects," Rahman said. "The breath condensate, plasma, saliva, and urine they exhale is used to determine exposure and disease biomarkers." For example, nitric oxide measured in a subject's breath is an indicator of lung inflammation, especially in asthma .

The combination of CIFT's in vitro and in vivo studies has provided valuable insights into the inhalation toxicology and human health effects of emerging flavoring chemicals used in e-cigarette products, which has had an impact on consumers and regulatory agencies.

In a study aimed at evaluating the immunotoxicology and oxidative stress effects of flavoring chemicals on human monocyte cell lines, the team determined that cinnamaldehyde, vanillin, and pentadione had the most toxic effects on monocytes and stimulated Secretion of pro-inflammatory cytokines.

Rahman pointed out that these are not the only flavoring chemicals of concern. "During the three-day acute menthol and tobacco flavor exposure, we saw significant changes in the differential cell counts of neutrophils and T cells, as well as changes in inflammatory mediators," he said. "These data indicate that taste can cause lung inflammation and lead to acute lung injury and pathogenesis."

There is also evidence that these harmful effects are amplified when individuals inhale various tastes, which is not uncommon in social environments. When the CIFT team exposed the cells to 10 different flavors of e-liquid in equal proportions, the cytotoxic effect was enhanced.

These and other harmful cellular effects can translate into serious health effects on consumers. "Our data shows that exposure to spices, flavoring chemicals and e-cigarette bombs can cause changes in immune cell function," he said, which suppresses the immune system and inflammation. According to Rahman, adverse airway and respiratory system effects such as lung dysfunction and lung remodeling (a form of fibrosis) are also possible, as well as the development of respiratory diseases such as asthma, bronchitis, and interstitial lung disease , Acute Respiratory Distress Syndrome or EVALI.

As the world battles the ongoing COVID-19 pandemic, many epidemiological studies aim to determine factors and pre-existing conditions related to susceptibility to COVID-19, as well as serious disease outcomes and mortality. Unfortunately, there are several mechanisms that may increase the susceptibility of smokers and e-cigarettes to COVID-19.

Smoking and e-cigarettes will affect the tight barrier connections, resulting in enhanced epithelial permeability and increased susceptibility to infection. By increasing oxidative stress, smoking and e-cigarettes can also adversely affect the expression of angiotensin-converting enzyme 2 (ACE2) receptors, thereby increasing the number of potential binding sites for SARS-CoV-2. A weakened immune response may also lead to an excessive inflammatory response to infection and a greater risk of lung remodeling, leading to lung tissue damage.

In view of the widespread use and increasing popularity of e-cigarette products, understanding the inhalation toxicology and health effects associated with the flavoring chemicals contained in these products is essential to reduce the risk of acute injury and the development of respiratory diseases. CIFT's ongoing research aims to provide regulators with accurate data and inform consumers (especially teenagers and young adults) that attractive tastes do not necessarily guarantee product safety.

Tags: Cannabis Research, Clinical Flavor Product Resources: Insights into Respiratory Diseases THC Vaping

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