Pulmonary Irritation Research Articles

Acute exposure to hydrazine reported to four United States regional poison centers: reconsidering a paradigm

Introduction Exposures to hydrazines occur during aeronautic and space operations and pose a potential risk to personnel. Historically, extensive preparatory countermeasures have been taken due to concern for severe toxicity. This study seeks to better understand manifestations of acute occupational exposures to hydrazine to guide recommendations for management. Materials and methods A retrospective database review of records from four United States regional poison centers was conducted of all human exposures to hydrazine, monomethylhydrazine, or 1,1-dimethylhydrazine over two decades. Following case abstraction, descriptive statistics were performed to characterize demographics, manifestations, treatments, and outcomes. Results One hundred and thirty-five cases were identified, and most were adult males exposed to inhaled hydrazine propellant vapors. Fifty-seven percent of patients were asymptomatic following exposure; otherwise, common symptoms were dyspnea, throat irritation, cough, ocular irritation, and headache. All patients were evacuated or received decontamination, with a few reports of symptomatic treatments, including oxygen supplementation and salbutamol (albuterol). Patients usually recovered quickly and were released after a brief healthcare facility evaluation or observed locally. No patients developed delayed symptoms. Symptoms of severe toxicity were not observed, and there were no deaths. Discussion Acute exposures to hydrazines during operations within the aerospace industry appear to be limited primarily to mucosal and mild pulmonary irritation without significant neurologic, hepatic, or hematologic toxicity. These findings are contrary to previously established expectations and may be related to low-level exposures or possibly due to current emergency countermeasures. Conclusions Care in occupational hydrazine exposure will focus on evacuation, decontamination, and symptomatic management of chemical irritant properties of hydrazines. It is reasonable to manage mild cases outside of a healthcare facility. Continued endeavors in human space exploration and habitation will increase the risk of these exposures, making it imperative that clinicians be comfortable with the care and management of these patients.

A rare case of acute eosinophilic pneumonia induced by vaping-associated lung injury: a case report

BackgroundAcute eosinophilic pneumonia (AEP) is well-known as one of the primary eosinophilic pulmonary diseases of unknown etiology. It’s defined as a febrile illness along with acute onset respiratory failure that is commonly misdiagnosed at the initial presentation as infectious pneumonia. Despite the fact that AEP sometimes classified as idiopathic as no exact cause can be identified in most cases, it has been suggested recently to be linked with electronic cigarette or vaping products and associated with electronic cigarette or vaping associated lung injury (EVALI). Therefore, history of recent tobacco smoking or vaping exposure along with peripheral eosinophilia are crucial clinical findings suggestive of AEP.Case presentationA previously healthy 17-year-old female presented to the Emergency Room with one day history of progressively worsening shortness of breath accompanied by left sided pleuritic chest pain and fever. She wasn’t taking any medications, denied traditional cigarette smoking, exposure to pulmonary irritants, recent travel and had no history of close contact with sick patient. She recently started vaping 20 days prior to the presentation. Initially, she was admitted with a presumptive diagnosis of atypical pneumonia but was found to have AEP due to a recent vaping exposure.ConclusionVaping is a well-known health hazard that has become a growing trend among adolescents and have been promoted as a safe and effective alternative to traditional cigarettes. The etiology of AEP remains unclear, but many studies suggest a possible link with recent tobacco smoking or vaping. A key challenge for this clinical entity is to reach the diagnosis after excluding all other pulmonary eosinophilia causes, and it has an excellent prognosis if diagnosed early and treated appropriately.

Surgical smoke and the orthopedic surgeon: a non-systematic review of the hazards and strategies for mitigating risk.

Surgical smoke generated through the use of electrical surgical devices poses a risk to the surgeon, medical personnel in the operating room, and the patient by exposing them to environmentally hazardous particulate matter. Previous investigation has shown that surgical smoke leads to an increased risk of pulmonary conditions, circulatory disorders, and irritation of the eyes, nose, and throat. Transmission of infectious disease can occur through inhalation of viral particles, and the presence of carcinogens are also of major concern. The deleterious effects of surgical smoke are well documented in several subspecialties, namely dermatology and general surgery, but there has been little discussion on the topic amongst orthopedic surgeons. A non-systematic review of the literature was completed with the aim of identifying the major categories of adverse health effects associated with surgical smoke inhalation and offering recommendations to reduce these hazards in the orthopedic surgical community. Three primary categories of risk associated with surgical smoke inhalation were identified: inflammation, viral/bacterial transmission, and carcinogenicity. In addition, strategies for mitigating risk and best practice recommendations were explored. Surgical smoke is an under-recognized occupational hazard within the orthopedic surgery literature. There are several strategies which can be employed to reduce risk. Further investigation is needed to understand the long-term impact of these risks, as well as what can be done to improve the practicality and compliance with protective measures.

Association between exposure to combustion-related air pollution and multiple sclerosis risk.

Smoking and occupational pulmonary irritants contribute to multiple sclerosis (MS) development. We aimed to study the association between ambient air pollution and MS risk and potential interaction with the human leukocyte antigen (HLA)-DRB1*15:01 allele. Exposure to combustion-related air pollution was estimated as outdoor levels of nitrogen oxides (NOx) at the participants' residence locations, by spatially resolved dispersion modelling for the years 1990-18. Using two population-based case-control studies (6635 cases, 8880 controls), NOx levels were associated with MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) using logistic regression models. Interaction between high NOx levels and the HLA-DRB1*15:01 allele regarding MS risk was calculated by the attributable proportion due to interaction (AP). In addition, a register study was performed comprising all MS cases in Sweden who had received their diagnosis between 1993 and 2018 (n = 22 173), with 10 controls per case randomly selected from the National Population register. Residential air pollution was associated with MS risk. NOx levels (3-year average) exceeding the 90th percentile (24.6 µg/m3) were associated with an OR of 1.37 (95% CI 1.10-1.76) compared with levels below the 25th percentile (5.9 µg/m3), with a trend of increasing risk of MS with increasing levels of NOx (P <0.0001). A synergistic effect was observed between high NOx levels (exceeding the lower quartile among controls) and the HLA-DRB1*15:01 allele regarding MS risk (AP 0.26, 95% CI 0.13-0.29). Our findings indicate that moderate levels of combustion-related ambient air pollution may play a role in MS development.

Abstract 13745: Electronic Cigarette-Derived Aerosols Induce Endothelial Dysfunction: Role of Aldehydes and Transient Receptor Potential Ankyrin-1 in Mice

Introduction: Electronic cigarettes (e-cigs) threaten to reverse the decline in rates of nicotine dependence and smoking. While some believe that e-cigarettes are less harmful than combustible cigarettes, e-cig use is associated with respiratory symptoms (cough, wheeze) and endothelial dysfunction (ED) indicating a potential to increase the risk of cardiovascular disease (CVD) with chronic use. ED is sine qua non of multiple CVD, yet the mechanism of e-cig-induced ED is unknown. Hypothesis: E-cigs generate levels of irritants that activate the Transient Receptor Potential Ankyrin-1 (TRPA1) to trigger nocifensive reflexes and induce ED in mice. Methods: Wild type (WT) and TRPA1-null C57BL/6J male and female mice were exposed to: filtered air (control), aerosols of JUUL e-cig liquid, e-cig solvents without nicotine (propylene glycol:glycerin, PG:G), or irritant gases alone (acrolein, formaldehyde). Urinary levels of nicotine and aldehyde metabolites were measured by UPLC-MS/MS. During acute exposures, respiratory irritant responses were monitored by radiotelemetry. Following short-term exposure (4d), aortic endothelial function, blood/plasma markers of organ toxicity, and platelet activation were measured. Results: Exposure of WT mice to e-cig aerosols increased urine levels of the acrolein, but not formaldehyde, metabolite (3HPMA), to that of exposures to 1 ppm acrolein alone. In WT mice, exposure to either PG:G (30:70), formaldehyde (5 ppm), or acrolein (1 ppm) induced respiratory braking. In female WT mice (n=5-18), exposure to PG:G (-61.8±4.2 % ACh relaxation) and formaldehyde (–56.3 ± 4.5 %) but not acrolein (-80.0±3.2 %) induced ED vs control group (-77.8±1.5 %). In female TRPA1-null mice (n=5-14), neither PG:G (-77.6±3.6 %), formaldehyde (-85.9±7.8 %) nor acrolein (-86.6±2.8 %) exposure induced ED vs control (-81.3±5.4 %). Acrolein exposure enhanced aortic sensitivity to an NO donor similarly in female WT and TRPA1-null mice. Conclusions: Formaldehyde and acrolein generated from the PG:G in e-cigs provoked pulmonary irritant reflexes, and formaldehyde exposure alone induced ED in female mice. Irritant aldehydes in e-cig-derived aerosols activate the TRPA1 receptor to promote ED that could increase CVD risk.

Pulmonary Oxygen Toxicity Through Exhaled Breath Markers After Hyperbaric Oxygen Treatment Table 6.

Introduction: The hyperbaric oxygen treatment table 6 (TT6) is widely used to manage dysbaric illnesses in divers and iatrogenic gas emboli in patients after surgery and other interventional procedures. These treatment tables can have adverse effects, such as pulmonary oxygen toxicity (POT). It is caused by reactive oxygen species’ damaging effect in lung tissue and is often experienced after multiple days of therapy. The subclinical pulmonary effects have not been determined. The primary aim of this study was to measure volatile organic compounds (VOCs) in breath, indicative of subclinical POT after a TT6. Since the exposure would be limited, the secondary aim of this study was to determine whether these VOCs decreased to baseline levels within a few hours. Methods: Fourteen healthy, non-smoking volunteers from the Royal Netherlands Navy underwent a TT6 at the Amsterdam University Medical Center—location AMC. Breath samples for GC-MS analysis were collected before the TT6 and 30 min, 2 and 4 h after finishing. The concentrations of ions before and after exposure were compared by Wilcoxon signed-rank tests. The VOCs were identified by comparing the chromatograms with the NIST library. Compound intensities over time were tested using Friedman tests, with Wilcoxon signed-rank tests and Bonferroni corrections used for post hoc analyses. Results: Univariate analyses identified 11 compounds. Five compounds, isoprene, decane, nonane, nonanal and dodecane, showed significant changes after the Friedman test. Isoprene demonstrated a significant increase at 30 min after exposure and a subsequent decrease at 2 h. Other compounds remained constant, but declined significantly 4 h after exposure. Discussion and Conclusion: The identified VOCs consisted mainly of (methyl) alkanes, which may be generated by peroxidation of cell membranes. Other compounds may be linked to inflammatory processes, oxidative stress responses or cellular metabolism. The hypothesis, that exhaled VOCs would increase after hyperbaric exposure as an indicator of subclinical POT, was not fulfilled, except for isoprene. Hence, no evident signs of POT or subclinical pulmonary damage were detected after a TT6. Further studies on individuals recently exposed to pulmonary irritants, such as divers and individuals exposed to other hyperbaric treatment regimens, are needed.

Exposure to Sodium Hypochlorite or Cigarette Smoke Induces Lung Injury and Mechanical Impairment in Wistar Rats.

Pulmonary irritants, such as cigarette smoke (CS) and sodium hypochlorite (NaClO), are associated to pulmonary diseases in cleaning workers. We examined whether their association affects lung mechanics and inflammation in Wistar rats. Exposure to these irritants alone induced alterations in the lung mechanics, inflammation, and remodeling. The CS increased airway cell infiltration, acid mucus production, MMP-12 expression, and alveolar enlargement. NaClO increased the number of eosinophils and macrophages in the bronchoalveolar lavage fluid, with cells expressing IL-13, MMP-12, MMP-9, TIMP-1, and iNOS in addition to increased IL-1β and TNF-α levels. Co-exposure to both irritants increased epithelial and smooth muscle cell area, acid mucus production, and IL-13 expression in the airways, while it reduced the lung inflammation. In conclusion, the co-exposure of CS with NaClO reduced the pulmonary inflammation, but increased the acidity of mucus, which may protect lungs from more injury. A cross-resistance in people exposed to multiple lung irritants should also be considered.

Salvianolic acid B dry powder inhaler for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a serious and fatal pulmonary inflammatory disease with an increasing incidence worldwide. The drugs nintedanib and pirfenidone, are listed as conditionally recommended drugs in the “Evidence-Based Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis”. However, these two drugs have many adverse reactions in clinical application. Salvianolic acid B (Sal B), a water-soluble component of Salvia miltiorrhiza, could alleviate bleomycin-induced peroxidative stress damage, and prevent or delay the onset of IPF by regulating inflammatory factors and fibrotic cytokines during the disease's progression. However, Sal B is poorly absorbed orally, and patient compliance is poor when administered intravenously. Therefore, there is an urgent need to find a new non-injection route of drug delivery. In this study, Sal B was used as model drug and l-leucine (LL) as excipient to prepare Sal B dry powder inhaler (Sal B-DPI) by spray drying method. Modern preparation evaluation methods were used to assess the quality of Sal B-DPI. Sal B-DPI is promising for the treatment of IPF, according to studies on pulmonary irritation evaluation, in vivo and in vitro pharmacodynamics, metabolomics, pharmacokinetics, and lung tissue distribution.

Çocuklarda Akut Klor Zehirlenmesinin Klinik Spektrumu

Objective: Chlorine gas (Cl2) is a common substance used in industry, which causes toxic inhalation as a potent pulmonary irritant. Herein, we aimed to investigate the findings of pediatric cases accidentally exposed to Cl2 gas.

Sodium Houttuyfonate Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice.

Pulmonary fibrosis (PF) could severely disrupt the normal lung architecture and function with fatal consequences. Currently, there is no effective treatment for PF or idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the effects of Sodium Houttuyfonate (SH) on bleomycin (BLM) induced PF mice model. Our results indicated that SH could attenuate BLM induced lung injury by reducing the inflammation, fibrogenesis and lung/body weight ratio. The proposed mechanisms for the protective effects of SH include: 1) improvement of pulmonary function in BLM mice, for instance, it can elevate the vital capacity (VC), increase the forced expiratory flow at 50% of forced vital capacity (FEF50) and improve other pulmonary function indices; 2) inhibition of collagen formation in BLM mice; 3) attenuation of the elevation of inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), which are triggered by BLM administration; 4) reduction of the mRNA level and protein production of transforming growth factor-β1 (TGF-β1) in BLM mice. Furthermore, it was found that the protective effects of SH against BLM induced PF in mice was comparable to that of prednisone acetate (PA) tablets, a widely used drug for immunological diseases. Although Houttuynia Cordata Thunb has been widely used in China for lung infection and inflammation, the mechanism has not yet been fully elucidated. Our study provides the evidence that SH is an effective compound against pulmonary injury, irritation and fibrogenesis.

Electronic cigarette solvents, pulmonary irritation, and endothelial dysfunction: role of acetaldehyde and formaldehyde.

After more than a decade of electronic cigarette (E-cig) use in the United States, uncertainty persists regarding E-cig use and long-term cardiopulmonary disease risk. As all E-cigs use propylene glycol and vegetable glycerin (PG-VG) and generate abundant saturated aldehydes, mice were exposed by inhalation to PG-VG-derived aerosol, formaldehyde (FA), acetaldehyde (AA), or filtered air. Biomarkers of exposure and cardiopulmonary injury were monitored by mass spectrometry (urine metabolites), radiotelemetry (respiratory reflexes), isometric myography (aorta), and flow cytometry (blood markers). Acute PG-VG exposure significantly affected multiple biomarkers including pulmonary reflex (decreased respiratory rate, -50%), endothelium-dependent relaxation (-61.8 ± 4.2%), decreased WBC (-47 ± 7%), and, increased RBC (+6 ± 1%) and hemoglobin (+4 ± 1%) versus air control group. Notably, FA exposure recapitulated the prominent effects of PG-VG aerosol on pulmonary irritant reflex and endothelial dysfunction, whereas AA exposure did not. To attempt to link PG-VG exposure with FA or AA exposure, urinary formate and acetate levels were measured by GC-MS. Although neither FA nor AA exposure altered excretion of their primary metabolite, formate or acetate, respectively, compared with air-exposed controls, PG-VG aerosol exposure significantly increased post-exposure urinary acetate but not formate. These data suggest that E-cig use may increase cardiopulmonary disease risk independent of the presence of nicotine and/or flavorings. This study indicates that FA levels in tobacco product-derived aerosols should be regulated to levels that do not induce biomarkers of cardiopulmonary harm. There remains a need for reliable biomarkers of exposure to inhaled FA and AA.NEW & NOTEWORTHY Use of electronic cigarettes (E-cig) induces endothelial dysfunction (ED) in healthy humans, yet the specific constituents in E-cig aerosols that contribute to ED are unknown. Our study implicates formaldehyde that is formed in heating of E-cig solvents (propylene glycol, PG; vegetable glycerin, VG). Exposure to formaldehyde or PG-VG-derived aerosol alone stimulated ED in female mice. As ED was independent of nicotine and flavorants, these data reflect a "universal flaw" of E-cigs that use PG-VG.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/e-cigarettes-aldehydes-and-endothelial-dysfunction/.

Compiling Evidence for EVALI: A Scoping Review of In Vivo Pulmonary Effects After Inhaling Vitamin E or Vitamin E Acetate.

Vitamin E acetate (VEA) has come under significant scrutiny due to its association with E-cigarette or vaping product use-associated lung injury (EVALI). Various theoretical mechanisms have been proposed for toxicity, including tocopherol (vitamin E)-mediated surfactant damage, recruitment of inflammation, and pyrolysis of acetate to the pulmonary irritant ketene. Characterize studies in mammals evaluating inhaled VEA, vitamin E analogues, or pyrolyzed acetate that describe subsequent effects on the lung. Research in all languages from time of inception to October 1, 2020, regarding mammals (human or animal) exposed to inhaled vitamin E analogues, or any compound containing acetate administered via inhalation after pyrolysis, and subsequent description of pulmonary effect. Ovid MEDLINE, Scopus, and Web of Science Core Collection. In total, 786 unique articles were identified. After duplicate reviewer screening, 16 articles were eligible for inclusion. Tocopherol was evaluated in 68.8% (11/16) of the studies, VEA in 18.8% (3/16), and both VEA and tocopherol were evaluated in 12.5% (2/16). Of the five studies evaluating VEA, it was given by pyrolysis in 60.0% (3/5). No human studies were identified. All included trials were conducted on non-human mammals: 75.0% (12/16) rodent models and 25.0% (4/16) sheep models. Outcomes assessed were heterogeneous and included 57 unique outcomes. Several questions still exist regarding the pulmonary toxicity of inhaled tocopherol and VEA. More studies are needed to determine whether tocopherol alone (i.e., without acetate) can cause pulmonary injury. Additionally, further studies of VEA should evaluate the impact that pyrolysis and co-administration with other compounds, such as tetrahydrocannabinol, have on the toxic potential of VEA.

Safety, Tolerability, and Pharmacokinetics of RT234 (Vardenafil Inhalation Powder): A First-in-Human, Ascending Single- and Multiple-Dose Study in Healthy Subjects.

Background: RT234 (vardenafil inhalation powder) is being developed for pulmonary administration “as needed”, to acutely improve exercise tolerance and symptoms in patients with pulmonary arterial hypertension (PAH).Methods: This single-center, open-label, randomized study in 32 healthy adult subjects evaluated single and multiple inhalation doses of RT234, for safety, tolerability, and pharmacokinetics (PKs).Results: RT234 was generally safe and well tolerated at single doses of 0.2–2.4 mg and after repeated dose administration of up to 2.4 mg q4h for four doses daily for 9 days. The most common treatment-emergent adverse events were mild-to-moderate headaches. There was no evidence of pulmonary irritation or inflammation. Vardenafil was absorbed very rapidly after inhalation as RT234, independent of dose level and number of doses administered. The tmax occurred at the time that the first blood sample following completion of dosing. After Cmax was achieved, plasma vardenafil concentrations declined rapidly in an exponential fashion that appeared to be parallel among dose levels. Vardenafil plasma concentrations and PK parameters increased in a dose-proportional manner. Vardenafil systemic exposure was notably greater after oral administration of 20 mg vardenafil tablets (Levitra®) than after administration of any dose level of RT234. During repeated dose administration of RT234, Cmax was attained rapidly following each dose and in a pattern similar to that observed after single-dose administration. Minor accumulation, characterized by very low mean morning predose vardenafil concentrations (<0.5 ng/mL), occurred after q4h dosing of up to four doses per day for 9 days. Taken together, these findings show that no clinically important vardenafil accumulation is likely after repeated-dose administration of RT234. Mean vardenafil t1/2 values were comparable after single- and repeated-dose administration.Conclusions: Comparative plasma vardenafil bioavailability data from this study provide scientific justification for reliance on Food and Drug Administration findings for Levitra tablets. These findings support further evaluation of RT234 for as-needed treatment of patients with PAH. The Clinical Trials Registration number is ACTRN12618001077257.

Regulation of Lung Macrophage Activation and Oxidative Stress Following Ozone Exposure by Farnesoid X Receptor.

Inflammatory macrophages are known to contribute to ozone toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating bile acid and lipid homeostasis; it also exerts anti-inflammatory activity by suppressing macrophage NF-κB. Herein, we analyzed the role of FXR in regulating macrophage activation in the lung following ozone exposure. Treatment of wild-type (WT) mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory (F4/80+CD11c+CD11b+Ly6CHi) and anti-inflammatory (F4/80+CD11c+CD11b+Ly6CLo) macrophages in the lung. The accumulation of proinflammatory macrophages was increased in FXR-/- mice compared with WT mice; however, anti-inflammatory macrophage activation was blunted as reflected by reduced arginase and mannose receptor expression, a response correlated with decreased Nur77. This was associated with prolonged oxidative stress, as measured by 4-hydroxynonenal-modified proteins in the lung. Loss of FXR was accompanied by protracted increases in lung NF-κB activity and its target, inducible nitric oxide synthase in response to ozone. Levels of Tnf-α, Il-1β, Ccr2, Ccl2, Cx3cr1, and Cx3cl1 were also increased in lungs of FXR-/- relative to WT mice; conversely, genes regulating lipid homeostasis including Lxrα, Apoe, Vldlr, Abcg1, and Abca1 were downregulated, irrespective of ozone exposure. In FXR-/- mice, ozone caused an increase in total lung phospholipids, with no effect on SP-B or SP-D. Dyslipidemia was correlated with blunting of ozone-induced increases in positive end-expiratory pressure-dependent quasi-static pressure volume curves indicating a stiffer lung in FXR-/- mice. These findings identify FXR as a regulator of macrophage activation following ozone exposure suggesting that FXR ligands may be useful in mitigating inflammation and oxidative stress induced by pulmonary irritants.

Toxicological assessment of chlorine concentration in atmospheric particulate matter in Benin City, Nigeria

Chlorine gas is widely known as obnoxious gas in the environment. It is well documented that little amount of chlorine gas in the atmosphere can cause pulmonary edema, pneumonitis, emphysema, bronchitis, and irritation of eyes, throat, and nose, just to mention a few. The thrust of this work is to investigate the breathing disease and health hazard emanating from the inhalation of chlorine concentration in particulate matter during job activities. This work was conducted among 120 employers from nine (9) industries. Information of the various ailments were gathered by using questionnaires and spirometry. The spirometry has an opening in which one blows in air to determine the lung volume. The commonest symptoms in the work were cough 47.5%, phlegm expectoration 50.0%, wheeze 5.8%, chest tightness 10.0%, chest pain 5.7%, breathlessness 8.3%, and cough with phlegm 8.3%. The concentration of chlorine in the total suspended particle ranged from 0.005 to 0.189 ppm, while the mean concentration of chlorine in the inhalable particle ranged from 0.112 to 0.270 ppm, and the concentration of chlorine gas in respirable particle ranged from 0.070 to 0.266 ppm. Further study should be conducted to enable establishment of reference level for the state.

Review of Health Consequences of Electronic Cigarettes and the Outbreak of Electronic Cigarette, or Vaping, Product Use-Associated Lung Injury.

Electronic cigarettes (e-cigarettes) are battery-operated devices to insufflate nicotine or other psychoactive e-liquid aerosols. Despite initial claims of e-cigarettes as a nicotine-cessation device, aggressive marketing of e-cigarettes has led to an explosion in adolescents' and young adults' use over the last few years. Coupled with a lack of adequate investigation and regulation of e-cigarettes, the USA is facing an outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) starting in mid-2019. While little long-term health hazard data are available, the components and constituents of e-cigarettes may adversely impact health. Propylene glycol and glycerin are humectants (water-retaining excipients) that generate pulmonary irritants and carcinogenic carbonyl compounds (e.g., formaldehyde, acetaldehyde, and acrolein) when heated in e-cigarettes. Metals contained in heating coils and cartridge casings may leach metals such as aluminum, chromium, iron, lead, manganese, nickel, and tin. Flavoring agents are considered safe for ingestion but lack safety data for inhalational exposures. Diacetyl, a common buttery flavoring agent, has known pulmonary toxicity with inhalational exposures leading to bronchiolitis obliterans. In 2019, clusters of lung injury associated with e-cigarette use were identified in Wisconsin and Illinois. Patients with EVALI present with a constellation of respiratory, gastrointestinal, and constitutional symptoms. Radiographically, patients have bilateral ground glass opacifications. As of February 18, 2020, the Centers for Disease Control has identified 2807 hospitalized patients diagnosed with either "confirmed" or "probable" EVALI in the US. Currently, vitamin E acetate (VEA) used as a diluent in tetrahydrocannabinol vape cartridges is implicated in EVALI. VEA cuts tetrahydrocannabinol oil without changing the appearance or viscosity. When inhaled, pulmonary tissue lacks the mechanism to metabolize and absorb VEA, which may lead to its accumulation. While most EVALI patients were hospitalized, treatment remains largely supportive, and use of corticosteroids has been associated with clinical improvement. The outbreak of EVALI highlights the need for regulation of e-cigarette devices and e-liquids. Clinicians need to be aware of the health hazards of e-cigarettes and be vigilant in asking about vaping.

Indoor air chemistry: Terpene reaction products and airway effects.

Reactive chemistry is ubiquitous indoors with a wealth of complex oxidation reactions; some of these are initiated by both homogeneous and heterogeneous reaction of ozone with unsaturated organic compounds and subsequent the hydroxyl radical, either in the gas-phase or on reactive surfaces. One major focus has been the reaction of common and abundant terpene-based fragrances in indoor air emitted from many wood-based materials, a variety of consumer products, and citrus fruits and flowers. Inhalation of the terpenes themselves are generally not considered a health concern (both acute and long-term) due to their low indoor air concentrations; however, their gas- and surface reactions with ozone and the hydroxyl radical produce a host of products, both gaseous, i. a. formaldehyde, and ultrafine particles formed by condensation/nucleation processes. These reaction products may be of health concern. Human cell bioassays with key reaction products from ozone-initiated terpene reactions have shown some inflammatory reactions, but results are difficult to interpret for human exposure and risk assessment. Acute effects like sensory irritation in eyes and airways are unlikely or present at very low intensity in real life conditions based on rodent and human exposure studies and known thresholds for sensory irritation in eyes and airways and derived human reference values for airflow limitation and pulmonary irritation. Some fragrances and their ozone-initiated reaction products may possess anti-inflammatory properties. However, long-term effects of the reaction products as ultrafine particles are poorly explored. Material and product surfaces with high ozone deposition velocities may significantly impact the perceived air quality by altered emissions from both homogeneous and heterogeneous surface reactions.

Effect of dibenz(b,f)-1,4-oxazepine aerosol on the breathing pattern and respiratory variables by continuous recording and analysis in unanaesthetised mice

A riot control agent has to be a sensory irritant of a reversible type without pulmonary irritation as the later can cause lung injury. The aim of the present study is to continuously record and analyse breathing pattern and respiratory variables of dibenz (b,f)-1,4-oxazepine (CR) in unanaesthetised mice during and after exposure. The lowest concentration of 0.65 mg/m3 did not produce any effect on the breathing pattern. As high as 500 fold increase (315.9 mg/m3) in the concentration was used and no mortality was observed. CR produced a concentration dependent sensory irritation, without pulmonary irritation or airflow obstruction, showing that it may not cause any lung injury. The sensory irritation was initiated within 5 min of exposure due to the activation of TRPA1 receptors of the upper respiratory tract. Immediate recovery of normal breath without sensory irritation was observed in all the concentrations except the highest concentration of 315.9 mg/m3. Corresponding to the sensory irritation there was concentration dependent respiratory depression. The 50 percent respiratory depression (RD50) in this experiment was 152 mg/m3 and the estimated threshold limit value for occupational exposure was 4.56 mg/m3. The present study shows that CR causes sensory irritation only which is completely recoverable.

Differential Activation of TRPA1 by Diesel Exhaust Particles: Relationships between Chemical Composition, Potency, and Lung Toxicity.

Diesel exhaust particulate (DEP) causes pulmonary irritation and inflammation, which can exacerbate asthma and other diseases. These effects may arise from the activation of transient receptor potential ankyrin-1 (TRPA1). This study shows that a representative DEP can activate TRPA1-expressing pulmonary C-fibers in the mouse lung. Furthermore, DEP collected from idling vehicles at an emissions inspection station, the tailpipe of an on-road “black smoker” diesel truck, waste DEP from a diesel exhaust filter regeneration machine, and NIST SRM 2975 can activate human TRPA1 in lung epithelial cells to elicit different biological responses. The potency of the DEP, particle extracts, and selected chemical components was compared in TRPA1 over-expressing HEK-293 and human lung cells using calcium flux and other toxicologically relevant end-point assays. Emission station DEP was the most potent and filter DEP the least. Potency was related to the percentage of ethanol extractable TRPA1 agonists and was equivalent when equal amounts of extract mass was used for treatment. The DEP samples were further compared using scanning electron microscopy, energy-dispersive X-ray spectroscopy, gas chromatography–mass spectrometry, and principal component analysis as well as targeted analysis of known TRPA1 agonists. Activation of TRPA1 was attributable to both particle-associated electrophiles and non-electrophilic agonists, which affected the induction of interleukin-8 mRNA via TRPA1 in A549 and IMR-90 lung cells as well as TRPA1-mediated mucin gene induction in human lung cells and mucous cell metaplasia in mice. This work illustrates that not all DEP samples are equivalent, and studies aimed at assessing mechanisms of DEP toxicity should account for multiple variables, including the expression of receptor targets such as TRPA1 and particle chemistry.

Activation of TRPA1 by volatile organic chemicals leading to sensory irritation.

Many volatile organic chemicals (VOCs) have not been tested for sensory pulmonary irritation. Development of in vitro non-animal sensory irritation assay suitable for a large number of chemicals is needed to replace the mouse assay. An adverse outcome pathway (AOP) is designed to provide a clear description of the biochemical and cellular processes leading to toxicological effects or an adverse outcome. The AOP for chemical sensory pulmonary irritation was developed according to the Organization for Economic Co-operation and Development guidance including the Bradford Hill criteria for a weight of evidence to determine the confidence of the AOP. The proposed AOP is based on an in-depth review of the relevant scientific literature to identify the initial molecular event for respiratory irritation. The activation of TRPA1 receptor (transient receptor potential cation channel, subfamily A, member 1) is the molecular initial event (MIE) leading to sensory irritation. A direct measure of TRPA1 activation in vitro should identify chemical sensory irritants and provide an estimate of potency. Fibroblasts expressing TRPA1 are used to determine TRPA1 activation and irritant potency. We report a linear relationship between the in vivo RD₅₀ and the in vitro pEC₅₀ values (R=0.81) to support this hypothesis. We propose that this in vitro assay after additional analysis and validation could serve as a suitable candidate to replace the mouse sensory irritation assay.