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Electronic nicotine delivery systems (ENDS) continue to rapidly evolve. Current products pose unique challenges and opportunities for researchers and regulators. This commentary aims to highlight research gaps, particularly in toxicity research, and provide guidance on priority research questions for the tobacco regulatory community. Disposable flavoured ENDS have become the most popular device class among youth and may contain higher nicotine levels than JUUL devices. They also exhibit enhanced harmful and potentially harmful constituents production, contain elevated levels of synthetic coolants and pose environmental concerns. Synthetic nicotine and flavour capsules are innovations that have recently enabled the circumvention of Food and Drug Administration oversight. Coil-less ENDS offer the promise of delivering fewer toxicants due to the absence of heating coils, but initial studies show that these products exhibit similar toxicological profiles compared with JUULs. Each of these topic areas requires further research to understand and mitigate their impact on human health, especially their risks to young users.

E-cigarette or vaping product use-associated lung injury (EVALI) is a severe pulmonary illness associated with the use of e-cigarettes or vaping products that was officially identified and named in 2019. This American Thoracic Society workshop was convened in 2021 to identify and prioritize research and regulatory needs to adequately respond to the EVALI outbreak and to prevent similar instances of disease associated with e-cigarette or vaping product use. An interdisciplinary group of 26 experts in adult and pediatric clinical care, public health, regulatory oversight, and toxicology were convened for the workshop. Four major topics were examined: 1) the public health and regulatory response to EVALI; 2) EVALI clinical care; 3) mechanisms contributing to EVALI; and 4) needed actions to address the health effects of EVALI. Oral presentations and group discussion were the primary modes used to identify top priorities for addressing EVALI. Initiatives including a national EVALI case registry and biorepository, integrated electronic medical record coding system, U.S. Food and Drug Administration regulation and enforcement of nicotine e-cigarette standards, regulatory authority over nontobacco-derived e-cigarettes, training in evaluating exogenous exposures, prospective clinical studies, standardized clinical follow-up assessments, ability to more readily study effects of cannabinoid e-cigarettes, and research to identify biomarkers of exposure and disease were identified as critical needs. These initiatives will require substantial federal investment as well as changes to regulatory policy. Overall, the workshop identified the need to address the root causes of EVALI to prevent future outbreaks. An integrated approach from multiple perspectives is required, including public health; clinical, basic, and translational research; regulators; and users of e-cigarettes. Improving the public health response to reduce the risk of another substantial disease-inducing event depends on coordinated actions to better understand the inhalational toxicity of these products, informing the public of the risks, and developing and enforcing regulatory standards for all e-cigarettes.

Some firms and marketers of electronic cigarettes (e-cigarettes; a type of electronic nicotine delivery system (ENDS)) and refill liquids (e-liquids) have made claims about the safety of ingredients used in their products based on the term "GRAS or Generally Recognized As Safe" (GRAS). However, GRAS is a provision within the definition of a food additive under section 201(s) (21 U.S.C. 321(s)) of the U.S. Federal Food Drug and Cosmetic Act (FD&C Act). Food additives and GRAS substances are by the FD&C Act definition intended for use in food, thus safety is based on oral consumption; the term GRAS cannot serve as an indicator of the toxicity of e-cigarette ingredients when aerosolized and inhaled (ie, vaped). There is no legal or scientific support for labeling e-cigarette product ingredients as "GRAS." This review discusses our concerns with the GRAS provision being applied to e-cigarette products and provides examples of chemical compounds that have been used as food ingredients but have been shown to lead to adverse health effects when inhaled. The review provides scientific insight into the toxicological evaluation of e-liquid ingredients and their aerosols to help determine the potential respiratory risks associated with their use in e-cigarettes. [ABSTRACT FROM AUTHOR]

Waterpipe tobacco (WPT) smoking is a public health concern, particularly among youth and young adults. The global spread of WPT use has surged because the introduction of pre-packaged flavored and sweetened WPT, which is widely marketed as a safer tobacco alternative. Besides flavorants and sugars, WPT additives include humectants, which enhance the moisture and sweetness of WPT, act as solvents for flavors, and impart smoothness to the smoke, thus increasing appeal to users. In the United States, unlike cigarette tobacco flavoring (with the exception of menthol), there is no FDA product standard or policy in place prohibiting sales of flavored WPT. Research has shown that the numerous fruit, candy, and alcohol flavors added to WPT entice individuals to experience those flavors, putting them at an increased risk of exposure to WPT smoke-related toxicants. Additionally, burning charcoal briquettes—used as a heating source for WPT—contributes to the harmful health effects of WPT smoking. This review presents existing evidence on the potential toxicity resulting from humectants, sugars, and flavorants in WPT, and from the charcoal used to heat WPT. The review discusses relevant studies of inhalation toxicity in animal models and of biomarkers of exposure in humans. Current evidence suggests that more data are needed on toxicant emissions in WPT smoke to inform effective tobacco regulation to mitigate the adverse impact of WPT use on human health. [ABSTRACT FROM AUTHOR]

Agglomeration of nanoparticles (NP) is a key factor in the generation of aerosols from nano-powders and may represent an important parameter to consider in toxicological studies. For this reason, the characterization of NP aerosols (e.g., concentration, size, and structure of agglomerates) is a critical step in the determination of the relationship between exposure and effects. The aim of this study was to generate and characterize aerosols composed of TiO2 (5 nm) NP showing different agglomeration states. Two concentrations were tested: 2 and 7 mg/m3. Stable mass concentrations over 6 hr were successfully generated by a wet method using Collison and Delavan nebulizers that resulted in aerosols composed of smaller agglomerates (<100 nm), while aerosols composed of larger agglomerates (>100 nm) were obtained by dry generation techniques using either a Palas dust feeder or a Fluidized Bed. Particle size distributions in the aerosols were determined by an electrical low pressure impactor. Median number aerodynamic diameters corresponding to the aerosol with smaller and larger agglomerates were 30 and 185 nm, respectively, for the 2 mg/m3 concentration, and 31 and 194 nm for the 7 mg/m3 experiment. Image analysis by transmission electron microscopy showed the presence of compact or agglomerates with void spaces in the different nano-aerosols. These characterized nano-aerosols will be used in further experiments to study the influence of agglomerate size on NP toxicity. [ABSTRACT FROM AUTHOR]

Dysregulation of lung tissue collagen level plays a vital role in understanding how lung diseases progress. However, traditional scoring methods rely on manual histopathological examination introducing subjectivity and inconsistency into the assessment process. These methods are further hampered by inter-observer variability, lack of quantification, and their time-consuming nature. To mitigate these drawbacks, we propose a machine learning-driven framework for automated scoring of lung collagen content. Our study begins with the collection of a lung slide image dataset from adult female mice using second harmonic generation (SHG) microscopy. In our proposed approach, first, we manually extracted features based on the 46 statistical parameters of fibrillar collagen. Subsequently, we pre-processed the images and utilized a pre-trained VGG16 model to uncover hidden features from pre-processed images. We then combined both image and statistical features to train various machine learning and deep neural network models for classification tasks. We employed advanced unsupervised techniques like K-means, principal component analysis (PCA), t-distributed stochastic neighbour embedding (t-SNE), and uniform manifold approximation and projection (UMAP) to conduct thorough image analysis for lung collagen content. Also, the evaluation of the trained models using the collagen data includes both binary and multi-label classification to predict lung cancer in a urethane-induced mouse model. Experimental validation of our proposed approach demonstrates promising results. We obtained an average accuracy of 83% and an area under the receiver operating characteristic curve (ROC AUC) values of 0.96 through the use of a support vector machine (SVM) model for binary categorization tasks. For multi-label classification tasks, to quantify the structural alteration of collagen, we attained an average accuracy of 73% and ROC AUC values of 1.0, 0.38, 0.95, and 0.86 for control, baseline, treatment&#95;1, and treatment&#95;2 groups, respectively. Our findings provide significant potential for enhancing diagnostic accuracy, understanding disease mechanisms, and improving clinical practice using machine learning and deep learning models., Competing Interests: The authors affirm that they do not have any conflicts of interest., (© 2024 Optica Publishing Group.)

Airborne particulate matter (PM) is associated with an increased risk for cardiovascular diseases. Although the goal of thermal remediation is to eliminate organic wastes through combustion, when incomplete combustion occurs, organics chemisorb to transition metals to generate PM-containing environmentally persistent free radicals (EPFRs). Similar EPFR species have been detected in PM found in diesel and gasoline exhaust, woodsmoke, and urban air. Prior in vivo studies demonstrated that EPFRs reduce cardiac function secondary to elevations in pulmonary arterial pressures. In vitro studies showed that EPFRs increase ROS and cytokines in pulmonary epithelial cells. We thus hypothesized that EPFR inhalation would promote lung inflammation and oxidative stress, leading to systemic inflammation, vascular endothelial injury, and a decline in vascular function. Mice were exposed to EPFRs for either 4 h or for 4 h/day for 10 days and lung and vascular function were assessed. After a 4-h exposure, plasma nitric oxide (NO) was reduced while endothelin-1 (ET-1) was increased, however lung function was not altered. After 10 day, plasma NO and ET-1 levels were again altered and lung tidal volume was reduced. These time course studies suggested the vasculature may be an early target of injury. To test this hypothesis, an intermediate time point of 3 days was selected. Though the mice exhibited no marked inflammation in either the lung or the blood, we did note significantly reduced endothelial function concurrent with a reduction in lung tidal volume and an elevation in annexin V protein levels in the lung. Although vascular dysfunction was not dependent upon inflammation, it may be associated with an injury at the air-blood interface. Gene expression analysis suggested roles for oxidative stress and aryl hydrocarbon receptor (Ahr) signaling. Studies probing the relationship between pulmonary oxidative stress and AhR signaling at the air-blood interface with vascular dysfunction seem warranted. NEW & NOTEWORTHY Particulate matter (PM) resulting from the combustion of organic matter is known to contribute to cardiopulmonary disease. Despite hypotheses that cardiovascular dysfunction occurring after PM exposures is secondary to lung or systemic inflammation, these studies investigating exposures to PM-containing environmentally persistent free radicals (EPFRs) demonstrate that cardiovascular dysfunction precedes pulmonary inflammation. The cardiopulmonary health consequences of EPFRs have yet to be thoroughly evaluated, especially in healthy, adult mice. Our data suggest the vasculature as a direct target of PM exposure, and our studies aimed to elucidate the mechanisms contributing to EPFR-induced vascular dysfunction.

Currently, more than 9 million American adults, including women of childbearing age, use electronic-cigarettes (e-cigs). Further, the prevalence of maternal vaping now approaching 10% is similar to that of maternal smoking. Little, however, is known about the effects of fetal exposures to nicotine-rich e-cig aerosols on lung development. In this study, we assessed whether in utero exposures to e-cig aerosols compromised lung development in mice. A third-generation e-cig device was used to expose pregnant BALB/c mice by inhalation to 36 mg/mL of nicotine cinnamon-flavored e-cig aerosols for 14-31 days. This included exposures for either 12 days before mating plus during gestation (preconception groups) or only during gestation (prenatal groups). Respective control mice were exposed to filtered air. Subgroups of offspring were euthanized at birth or at 4 wk of age. Compared with respective air-exposed controls, both preconception and prenatal exposures to e-cig aerosols significantly decreased the offspring birth weight and body length. In the preconception group, 7 inflammation-related genes were downregulated, including 4 genes common to both dams and fetuses, denoting an e-cig immunosuppressive effect. Lung morphometry assessments of preconception e-cig-exposed offspring showed a significantly increased tissue fraction at birth. This result was supported by the downregulation of 75 lung genes involved in the Wnt signaling, which is essential to lung organogenesis. Thus, our data indicate that maternal vaping impairs pregnancy outcomes, alters fetal lung structure, and dysregulates the Wnt signaling. This study provides experimental evidence for future regulations of e-cig products for pregnant women and developmentally vulnerable populations.

Background: The exact role of primary nanoparticle (NP) size and their degree of agglomeration in aerosols on the determination of pulmonary effects is still poorly understood. Smaller NP are thought to have greater biological reactivity, but their level of agglomeration in an aerosol may also have an impact on pulmonary response. The aim of this study was to investigate the role of primary NP size and the agglomeration state in aerosols, using well-characterized TiO₂ NP, on their relative pulmonary toxicity, through inflammatory, cytotoxic and oxidative stress effects in Fisher 344 male rats., Methods: Three different sizes of TiO₂ NP, i.e., 5, 10-30 or 50 nm, were inhaled as small (SA) (< 100 nm) or large agglomerates (LA) (> 100 nm) at 20 mg/m³ for 6 hours., Results: Compared to the controls, bronchoalveolar lavage fluids (BALF) showed that LA aerosols induced an acute inflammatory response, characterized by a significant increase in the number of neutrophils, while SA aerosols produced significant oxidative stress damages and cytotoxicity. Data also demonstrate that for an agglomeration state smaller than 100 nm, the 5 nm particles caused a significant increase in cytotoxic effects compared to controls (assessed by an increase in LDH activity), while oxidative damage measured by 8-isoprostane concentration was less when compared to 10-30 and 50 nm particles. In both SA and LA aerosols, the 10-30 nm TiO₂ NP size induced the most pronounced pro-inflammatory effects compared to controls., Conclusions: Overall, this study showed that initial NP size and agglomeration state are key determinants of nano-TiO₂ lung inflammatory reaction, cytotoxic and oxidative stress induced effects.

Agglomeration of nanoparticles (NP) is a key factor in the generation of aerosols from nano-powders and may represent an important parameter to consider in toxicological studies. For this reason, the characterization of NP aerosols (e.g., concentration, size, and structure of agglomerates) is a critical step in the determination of the relationship between exposure and effects. The aim of this study was to generate and characterize aerosols composed of TiO₂ (5 nm) NP showing different agglomeration states. Two concentrations were tested: 2 and 7 mg/m³. Stable mass concentrations over 6 hr were successfully generated by a wet method using Collison and Delavan nebulizers that resulted in aerosols composed of smaller agglomerates (<100 nm), while aerosols composed of larger agglomerates (>100 nm) were obtained by dry generation techniques using either a Palas dust feeder or a Fluidized Bed. Particle size distributions in the aerosols were determined by an electrical low pressure impactor. Median number aerodynamic diameters corresponding to the aerosol with smaller and larger agglomerates were 30 and 185 nm, respectively, for the 2 mg/m³ concentration, and 31 and 194 nm for the 7 mg/m³ experiment. Image analysis by transmission electron microscopy showed the presence of compact or agglomerates with void spaces in the different nano-aerosols. These characterized nano-aerosols will be used in further experiments to study the influence of agglomerate size on NP toxicity.