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Algal blooms of Karenia brevis produce brevetoxins that lead to the natural phenomenon of red tide. Beyond monitoring the red tide concentration and forecasting future outbreaks, uncertainty exists in the field when examining these toxins in relation to the physiology of people. Contaminated air that results from outbreaks of K. brevis leads to inhalation of aerosolized brevetoxins, which directly impact the human respiratory system. This scoping review focused on the respiratory effects of red tide and was conducted by using a comparative method between 2 researchers. Relevant abstracts were collected, and full-text articles were reviewed by using PubMed, Science Direct, CINAHL Complete, and BioMed Central databases. Thirty articles were included in the final analysis and categorized by study design, location, and number and age of participants, and were also divided into assessment by respiratory effects, exposure, measurements of K. brevis, and asthma. The research indicates that respiratory health issues exist and can be compounded with exposure to red tide, specifically upper respiratory symptoms. Both symptomatic issues and pulmonary function tests were of concern when individuals were subjected to brevetoxin exposure. Even low levels of K. brevis resulted in negative respiratory health effects. Red tide is common in many areas of the world. The toxins released can cause adverse respiratory effects. This article provides a comprehensive summary of the scholarly literature focused on the respiratory system and red tide produced by K. brevis ., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2024 by Daedalus Enterprises.)

Background: Inhalation is a major pathway for phthalates (PAEs), an endocrine disruptor, to enter the human body. The actual internal exposure amount that participates in metabolism cannot be estimated by calculating total inhalation intake., Objective: To estimate the accumulation in each region of the respiratory tract after long-term exposure to PAEs in different populations., Methods: A mass transfer model was developed to simulate the long-term accumulation of PAEs in respiratory tract through inhalation. The model considered (1) mass transfer of PAEs in three phases across seven regions, (2) the effect of temperature differences on the mass transfer process. Based on this model, we simulated adult exposure to PAEs in a laboratory, identified key model parameters, and further simulated various scenarios for children, adults, and elders., Results: PAEs are not completely cleared from the respiratory tract after 16 hours, following 8 hours of daily exposure. Under regular laboratory environment, accumulation after 30 days is 3.8 times higher than that after the first day. The distribution of PAEs between the gas and mucus phases has a greater impact on the results than between the gas and particle phases. Children are at the highest risk to Diethyl phthalate (DEP) exposure compared with adults and elders. Nearly 80 % of DEP is exhaled, with 14 % accumulating in the alveolar region after an hour., Conclusion: This model links indoor air PAEs to human internal exposure, showing that most PAEs are exhaled, while the remainder accumulates in the respiratory tract and may participate in human metabolism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pyrethrin and pyrethroid are a relatively new class of pesticides with potent insecticidal properties. Pyrethrins are naturally occurring pesticides obtained from the Chrysanthemum cinerariaefolium flower, while pyrethroids are their synthetic derivatives. They are widely used as the insecticides of choice in agriculture, veterinary medicine, public health programs, and household activities. Pyrethrin, being a broad-spectrum insecticide kills a wide range of pests, while pyrethroids last longer in the environment owing to low susceptibility to sunlight, and greater stability and efficacy than parent molecules. Humans can be exposed through inhalation, ingestion, and dermal routes. Indoor usage of an insecticide poses a serious risk to human health, especially to women, children, and stay-at-home people. Although pyrethrin and pyrethroid are generally considered safe, sustained skin or inhalation exposure or direct contact with open wounds results in higher toxicity to mammals. There is a paucity of data on the impact of pyrethrin and pyrethroid on overall pulmonary health. The respiratory system, from the nose, nasal passages, airways, and bronchi to the pulmonary alveoli, is vulnerable to environmental contaminants such as pesticides because of its anatomical location as well as being a highly blood profused organ. Under and over-functioning of the respiratory system triggers diverse pathologies such as serious infections, allergies, asthma, metastatic malignancies, and auto-immune conditions. While the association between workplace-related pesticide exposures and respiratory diseases and symptoms is well documented, it is important to understand the adverse health impact of pyrethrin and pyrethroid on the general population for awareness and also for better regulation and implementation of the law., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The current study explores the effectiveness of drug particle deposition into human respiratory airways to cure various pulmonary-bound ailments. It has been assumed that drug solutions are inhaled in the form of tiny droplets or mist, which after striking create a thin layer along the inner surface of airways where the virus initially resides to infect the human body. A coupled Eulerian wall film (EWF) and discrete phase model (DPM) based simulation approach is used to capture these dynamics. Here, the Lagrangian DPM technique tracks the dynamics of tiny droplets, while the liquid layer formation after striking is captured using the Eulerian thin film approximations or the EWF model. Previous studies in this field primarily employed only the DPM method, which is inadequate to predict the poststriking dynamics of drug layer deposition and their spread to neutralize the respiratory virus. The drug delivery effectiveness is characterized by three different particle sizes, 1, 5, and 10 μm at the inhalation rates of 15, 30, and 60 L per minute (LPM). It has been found that the size of the drug particles significantly influences drug delivery effectiveness. The film thickness increases monotonically with particle sizes and inhalation rates. However, this increase in averaged film thickness is prominent in the range 5 to 10 μm (≈60%) compared to 1 to 5 μm (≈10%) droplet sizes at generation level 4 (G4). The other deposition parameters, e.g., deposition fraction, deposition density, and area coverage) roughly show similar behavior with the increase in droplet sizes. Therefore, it is recommended to vary the droplet sizes between 5 and 10 μm for better deposition effectiveness. The sizes of more than 10 μm mostly stuck into the oral cavity and cannot reach the targeted generations. In contrast, less than 5 μm may reach much deeper generations than the targeted one.

Because of the disproportionate amount of time that people spend indoors and the complexities of air pollutant exposures found there, indoor air pollution is a growing concern for airway health. Both infiltration of outdoor air pollution into the indoor space and indoor sources (such as smoke from tobacco products, cooking or heating practices and combustion of associated fuels, and household materials) contribute to unique exposure mixtures. Although there is substantial literature on the chemistry of indoor air pollution, research focused on health effects is only beginning to emerge and remains an important area of need to protect public health. We provide a review of emerging literature spanning the past 3 years and relating indoor air exposures to airway health, with a specific focus on the impact of either individual pollutant exposures or common combustion sources on the lower airways. Factors defining susceptibility and/or vulnerability are reviewed with consideration for priority populations and modifiable risk factors that may be targeted to advance health equity., Competing Interests: Disclosure statement Supported by the National Institutes of Health (to M.R., H.K., and E.B.), US Department of Veteran Affairs (to H.K.), Canadian Institutes of Health Research (to E.B.), Michael Smith Health Research BC (to E.B.), National Sanitarium Association (to E.B.), BC Lung Foundation (to E.B.), Legacy for Airway Health (to E.B.), and the NIEHS center (ES05022 to H.K.). Disclosure of potential conflict of interest: E. Brigham reports an unrestricted award from AstraZeneca., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cadmium (Cd) poses a significant threat to human health. However, chronic toxicity parameters for inhalation exposure are lacking, especially for noncritical systemic toxic effects. A physiologically based toxicokinetic (PBTK) model can be used to extrapolate toxicity parameters across various exposure routes. We combined a PBTK model with a human respiratory tract (HRT) model, which is applicable to the general population and capable of simulating the deposition and clearance processes of various airborne Cd compounds in the respiratory tract. Monte Carlo analysis was used to simulate the distribution of sensitive parameters to reflect individual variability. Validation based on datasets from general and occupational populations showed that the improved model had acceptable or better predictive performance, outperforming the original model with a 14.45 % decrease in the root mean square error (RMSE). Using this PBTK-HRT model, we extrapolated toxicity parameters from oral exposure to inhalation exposure for four systemic toxic effects with doseresponse relationships but no known inhalation toxicity parameters, and ultimately recommended reference concentrations (RfCs) for four diseases (chronic kidney disease: 0.01 μg/m 3 , osteoporosis: 0.01 μg/m 3 , stroke: 0.04 μg/m 3 , diabetes mellitus: 0.13 μg/m 3 ), contributing to a comprehensive assessment of the health risks of Cd inhalation exposure. ENVIRONMENTAL IMPLICATION: Cadmium (Cd), a heavy metal, can cause lung cancer, chronic kidney disease, and osteoporosis and pose a significant threat to human health. We combined a physiologically based toxicokinetic (PBTK) model with a human respiratory tract (HRT) model to achieve better predictive performance and wider applicability; this model was subsequently employed for route-to-route extrapolation of toxicity parameters. Additionally, for the first time, we focused on multiple subchronic and chronic systemic toxic effects in addition to critical effects and derived their reference concentrations (RfCs), which can be used to assess the health risk of Cd inhalation exposure more comprehensively and accurately., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

At the end of the 2019 coronavirus pandemic (COVID-19), highly contagious variants of coronaviruses had emerged. Together with influenza viruses, different variants of the coronavirus currently cause most colds and require appropriate drug treatment. We have investigated the expression of important factors for the replication of these viruses, namely transmembrane protease serine subtype 2 (TMPRSS2), neuropilin1 (NRP1), and angiotensin converting enzyme 2 (ACE2) or tumor necrosis factor-α (TNF-α) after toll like receptor-3 (TLR-3) stimulation using RT-qPCR and flow cytometry (FC) analysis. As model served primary fibroblasts derived from the lung and nasal cavity, as well as epidermal stem cells and fully matured respiratory epithelium. The stimulated cell cultures were treated with pharmaceuticals (Dexamethasone and Enzalutamide) and the outcome was compared with the phytomedicine 1,8-Cineol. The stimulation of TLR3 is sufficient to induce the expression of exactly those targets that were highly expressed in the corresponding culture type, specifically ACE2 and TMPRSS2 in respiratory epithelial stem cells and NRP1 in fibroblast cells. It seems this self-perpetuating cycle of infection-driven upregulation of key viral replication factors by the innate immune system represents an evolutionary advantage for viruses using these transcripts as viral replication factors. Likewise, to the standard pharmaceuticals with proven clinical efficiency, 1,8-Cineol was able to disrupt this self-perpetuating cycle. Considering the minor side effects and negligible pharmacological interactions with other drugs, it is conceivable that an adjuvant or combinatorial therapy with 1,8-Cineol for respiratory diseases caused by corona- or influenza viruses would be beneficial., (© 2024 The Author(s). Phytotherapy Research published by John Wiley & Sons Ltd.)

Drug development is a lengthy process that promotes and protects the health and safety of future patients. Nonclinical safety studies follow essentially similar designs that fulfill regulatory requirements but are amended based on factors including the mechanism of action, class of molecule, and route of administration. Clinical observations, clinical pathology, and macroscopic pathology in dose range-finding (DRF) studies generally provide sufficient information to select doses for pivotal studies by most delivery routes. Inhaled drug candidates are recognized for producing adverse effects on the respiratory system at the microscopic level that may otherwise be unpredictable; therefore, unlike other routes of administration, inhalation DRF studies typically include histopathology of the respiratory tract. Histopathology evaluations can add several weeks to the Investigational New Drug (IND) application timeline along with additional costs but have been considered necessary to support accurate dose selection for adequate safety margins, thereby potentially avoiding additional studies and animal usage by ensuring achievement of a NOAEL in the pivotal studies. Therefore, DRF inhalation studies initiated from 2018 to 2021 at Labcorp were reviewed to determine whether inclusion of histopathology on preliminary inhalation studies was necessary for subsequent dose selection. Histopathology findings in the DRF impacted dose selection in pivotal inhalation studies for approximately 45% of rat and dog studies. This review identified histopathology findings in rat and dog that support continued inclusion of respiratory tract histopathology in DRF studies. Future investigations will evaluate potential surrogate endpoints for these findings, which could reduce nonclinical drug development timelines by several weeks., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cold atmospheric plasma (CAP) devices generate reactive oxygen and nitrogen species, have antimicrobial and antiviral properties, but also affect the molecular and cellular mechanisms of eukaryotic cells. The aim of this study is to investigate CAP treatment in the upper respiratory tract (URT) to reduce the incidence of ventilator-associated bacterial pneumonia (especially superinfections with multi-resistant pathogens) or viral infections (e.g., COVID-19). For this purpose, the surface-microdischarge-based plasma intensive care (PIC) device was developed by terraplasma medical GmbH. This study analyzes the safety aspects using in vitro assays and molecular characterization of human oral keratinocytes (hOK), human bronchial-tracheal epithelial cells (hBTE), and human lung fibroblasts (hLF). A 5 min CAP treatment with the PIC device at the "throat" and "subglottis" positions in the URT model did not show any significant differences from the untreated control (ctrl.) and the corresponding pressurized air (PA) treatment in terms of cell morphology, viability, apoptosis, DNA damage, and migration. However, pro-inflammatory cytokines (MCP-1, IL-6, and TNFα) were induced in hBTE and hOK cells and profibrotic molecules (collagen-I, FKBP10, and αSMA) in hLF at the mRNA level. The use of CAP in the oropharynx may make an important contribution to the recovery of intensive care patients. The results indicate that a 5 min CAP treatment in the URT with the PIC device does not cause any cell damage. The extent to which immune cell activation is induced and whether it has long-term effects on the organism need to be carefully examined in follow-up studies in vivo., Competing Interests: Authors Lisa Gebhardt, Robert Schober were employed by the company Terraplasma Medical GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The company had no impact on the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The objective of the current study was to investigate the impact of human's height variability to the deposition percentage, the deposited and the retained dose of particulate matter in the respiratory tract. In addition, the dose to the oesophagus, blood and lymph nodes was evaluated after particle clearance. A methodology which correlates anatomical and physiological parameters with height was adopted into an existing particle dosimetry model (Exposure Dose Model 2, ExDoM2). Model results showed that deposition of particles with aerodynamic diameter (d ae ) ranging from 0.001 to 10 μm depends on the competition between anatomical/physiological parameters, with the maximum effect induced from height variability to be observed for particles in the size range of 0.30 μm ae <1.5 μm. Specifically, a decrease in the subject's height by 100 cm (from 175 to 75 cm) caused a 60.5 ± 6.8% increase in the total deposition percentage during light exercise. Contrarily, an increase in the subject's height by 100 cm (from 75 to 175 cm) caused a 376% increase in the daily deposited dose of PM 10 in the respiratory tract. Investigating the inter-subject variability of PM 10 dose showed that the extrathoracic region was characterized by lower variability (10.0%) compared to the thoracic region (16.2%). After clearance, the highest variability was observed for blood (15.7%), followed by the respiratory tract (12.1%), lymph nodes (10.4%) and oesophagus (10.1%). Results of the current study highlight the impact induced by incorporating height to scale the inter-subject variability in particle deposition and dose in the human body., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Airborne particulate matter (PM) is a global environmental risk factor threatening human health and is a major cause of cardiovascular and respiratory disease-associated death. Current studies on PM exposure have been limited to large-scale cohort and epidemiological investigations, emphasizing the need for detailed individual-level studies to uncover specific differentially expressed genes and their associated signaling mechanisms. Herein, we revealed that PM exposure significantly upregulated inflammatory and immune responses, such as cytokine-mediated signaling pathways, complement system, and the activation and migration of immune cells in gene set enrichment analysis of our RNA sequencing (RNAseq) data. Remarkably, we discovered that the broad gene expression and signaling pathways mediated by macrophages were predominantly expressed in the respiratory system following PM exposure. Consistent with these observations, individual PMs, classified by aerodynamic size and origin, significantly promoted macrophage recruitment to the lungs in the mouse lung inflammation model. Additionally, we confirmed that RNAseq observations from the respiratory system were reproduced in murine bone marrow-derived macrophages and the alveolar macrophage cell line MH-S after individual PM exposure. Our findings demonstrated that PM exposure augmented broad inflammatory and immune responses in the respiratory system and suggested the reinforcement of global strategies for reducing particulate air pollution to prevent respiratory diseases and their exacerbation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The presence of microplastics in the aquatic environment has attracted widespread attention. A large number of studies have assessed the effects of microplastics on the respiratory system of aquatic animals, but the results are not directly comparable across studies due to inconsistent evaluation criteria. Therefore, we adopted an integrated research approach that can integrate and parse complex data to improve reliability, conducted a systematic review and meta-analysis of 35 published studies, and elucidated the mechanisms of microplastic damage to cells. The results showed that PE had the greatest impact on aquatic animals, and fish were the most sensitive to the effects caused by microplastics, with oxidative stress induced by exposure concentrations exceeding 1000 µg/L or exposure times exceeding 28 days, leading to depletion of antioxidant defenses, cellular damage, inflammatory responses, and behavioral abnormalities. As this review is based on existing studies, there may be limitations in terms of literature quality, data availability and timeliness. In conclusion, we suggest to combat microplastic pollution by limiting plastic use, promoting plastic substitution and recycling, and enhancing microplastic capture degradation technologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin-deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N-acetylcysteine (NAC) has been shown to exert anti-inflammatory and anti-fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short-term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One-month-old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force-generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure-generating capacity. NAC treatment did not affect force-generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The objective of this study is to explore the transport, size growth, and deposition of Salbutamol Sulphate (SS) using Computational Fluid Dynamics (CFD). A CT-based realistic model of human airways from the oral cavity to the 5th generation of the lung was utilized as the computational domain. Four Test Cases (TC) with varying temperature and relative humidity (RH) under two inspiratory waveforms were considered to completely evaluate the impact of inhalation conditions on particle growth. Salbutamol Sulphate (SS) is a β2-adrenergic agonist and has been extensively used for asthma treatment. A monodispersed distribution of SS particles with an initial diameter of 167 nm was considered at the mouth inlet based on pharmaceutical data. Results indicated that inhalation of saturated/supersaturated air (RH>100%) leads to significant hygroscopic growth of SS particles with a factor of 10. In addition, the deposition efficiency of SS particles under the Quick and Deep (QD) inhalation profile was enhanced as the flow temperature and humidity increased. However, the implementation of Slow and Deep (SD) inspiratory waveform revealed that the same particle size growth is achieved in the respiratory system with lower deposition efficiency in the mouth-throat (less than 3%) and tracheobronchial airway (less than 2.18%). For the escaped particles form the right lung, in the SD waveform under TC 3, the maximum particle size distribution was for 600 nm particles with 25% probability. In the left lung, 30% of the particles were increased up to 950 nm in size. For the QD waveform in TC 3 and TC4, the most frequent particles were 800 nm with 36% probability. This holds practical significance in the context of deep lung delivery for asthmatic patients with enhanced deposition efficiency and large particle size. The findings of the present study can contribute to the development of targeted drug delivery strategies for the treatment of pulmonary diseases using hygroscopic dry powder formulations., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Cigarette smoking can lead to a host of adverse health effects such as lung and heart disease. Increased lung cancer risk is associated with inhalation of carcinogens present in a puff of smoke. These carcinogenic compounds deposit in the lung at different sites and trigger a cascade of events leading to adverse outcomes. Understanding the site-specific deposition of various smoke constituents will inform the study of respiratory diseases from cigarette smoking. We previously developed a deposition model for inhalation of aerosol from electronic nicotine delivery systems. In this study, the model was modified to simulate inhalation of cigarette smoke consisting of soluble and insoluble tar, nicotine, and cigarette-specific constituents that are known or possible human carcinogens., Materials and Methods: The deposition model was further modified to account for nicotine protonation and other cigarette-specific physics-based mechanisms that affect smoke deposition. Model predictions showed a total respiratory tract uptake in the lung for formaldehyde (99%), nicotine (80%), and benzo[a]pyrene (60%)., Results: The site of deposition and uptake depended primarily on the constituent's saturation vapor pressure. High vapor pressure constituents such as formaldehyde were preferentially absorbed in the oral cavity and proximal lung regions, while low vapor pressure constituents such as benzo[a]pyrene were deposited in the deep lung regions. Model predictions of exhaled droplet size, droplet retention, nicotine retention, and uptake of aldehydes compared favorably with experimental data., Conclusion: The deposition model can be integrated into exposure assessments and other studies that evaluate potential adverse health effects from cigarette smoking.

This study was the first attempt to visualize pulmonary retention of nanocarriers (NCs) with the use of the P2 probe, a new water-initiated aggregation-caused fluorescent-quenching (ACQ) dye, for the development of NCs with long-lasting retention in the respiratory system (RS). Flash nanoprecipitation was used to fabricate mucopenetrating NCs (MP/NCs) and mucoadhesive NCs (MA/NCs). Both NCs were labeled with the P2 probe, and their distribution and retention in RS were visualized after intratracheal administration to rats. MP/NCs and MA/NCs had a mean diameter below 200 nm and ζ-potential of 0 and 48 mV, respectively. MA/NCs showed three times stronger interactions with mucin than MP/NCs, resulting in significantly lower diffusiveness in mucus. The P2 probe exhibited an ACQ effect with negligible rekindling in simulated lung fluid, and the spectroscopic data suggested applicability to reliable imaging of insufflated NCs. In confocal laser scanning microscopic and in vivo imaging system images of the rat RS, MA/NCs were locally deposited in the respiratory tract and transported toward the pharynx by mucocilliary clearance (MCC). In contrast, MP/NCs diffused in the respiratory mucus were less subject to the influence of MCC. Based on the results from the bioimaging study using the P2 probe, MP/NCs could offer enhanced pulmonary retention of drugs compared with MA/NCs.

Inhalation is a critical route through which substances can exert adverse effects in humans; therefore, it is important to characterize the potential effects that inhaled substances may have on the human respiratory tract by using fit for purpose, reliable, and human relevant testing tools. In regulatory toxicology testing, rats have primarily been used to assess the effects of inhaled substances as they-being mammals-share similarities in structure and function of the respiratory tract with humans. However, questions about inter-species differences impacting the predictability of human effects have surfaced. Disparities in macroscopic anatomy, microscopic anatomy, or physiology, such as breathing mode (e.g., nose-only versus oronasal breathing), airway structure (e.g., complexity of the nasal turbinates), cell types and location within the respiratory tract, and local metabolism may impact inhalation toxicity testing results. This review shows that these key differences describe uncertainty in the use of rat data to predict human effects and supports an opportunity to harness modern toxicology tools and a detailed understanding of the human respiratory tract to develop testing approaches grounded in human biology. Ultimately, as the regulatory purpose is protecting human health, there is a need for testing approaches based on human biology and mechanisms of toxicity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Co-author is on the editorial board of Regulatory Toxicology and Pharmacology - A.L. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: While evidence continues to emerge on the negative health effects of electronic cigarettes (e-cigarettes) on the lungs, little is known regarding their deleterious effects on the upper airway. The purpose of this review is to summarize the toxicological effects of e-cigarettes, and their components, on the upper airway., Data Sources: PubMed, SCOPUS, EMBASE databases., Review Methods: Systematic searches were performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines from 2003 to 2023. Studies were included if they investigated the toxicological effects of e-cigarette exposure on human or animal upper airway tissue. Two authors independently screened, reviewed, and appraised all included articles., Results: A total of 822 unique articles were identified, of which 53 met inclusion criteria and spanned subsites including the oral cavity (22/53 studies), nasal cavity/nasopharynx (13/53), multiple sites (10/53), larynx (5/53), trachea (2/53), and oropharynx (1/53). The most commonly observed consequences of e-cigarette use on the upper airway included: proinflammatory (15/53 studies), histological (13/53), cytotoxicity (11/53), genotoxicity (11/53), and procarcinogenic (6/53). E-cigarette humectants independently induced toxicity at multiple upper airway subsites, however, effects were generally amplified when flavoring(s) and/or nicotine were added. Across almost all studies, exposure to cigarette smoke exhibited increased toxicity in the upper airway compared with exposure to e-cigarette vapor., Conclusion: Current data suggest that while e-cigarettes are generally less harmful than traditional cigarettes, they possess a distinct toxicological profile that is enhanced upon the addition of flavoring(s) and/or nicotine. Future investigations into underexamined subsites, such as the oropharynx and hypopharynx, are needed to comprehensively understand the effects of e-cigarettes on the upper airway., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

This comprehensive review focuses on various dimensions of nanoparticle toxicity, emphasizing toxicological characteristics, assessment techniques, and examinations of relevant studies on the effects on biological systems. The primary objective is to comprehend the potential risks associated with nanoparticles and to provide efficient strategies for mitigating them by consolidating current research discoveries. For in-depth insights, the discussions extend to crucial aspects such as toxicity associated with different nanoparticles, human exposure, and nanoparticle deposition in the human respiratory tract. The analysis utilizes the multiple-path particle dosimetry (MPPD) modeling for computational simulation. The SiO 2 nanoparticles with a volume concentration of 1% and a particle size of 50 nm are used to depict the MPPD modeling of the Left upper (LU), left lower (LL), right upper (RU), right middle (RM), and right lower (RL) lobes in the respiratory tract. The analysis revealed a substantial 67.5% decrease in the deposition fraction as the particle size increased from 10 nm to 100 nm. Graphical representation emphasizes the significant impact of exposure path selection on nanoparticle deposition, with distinct deposition values observed for nasal, oral, oronasal-mouth breather, oronasal - normal augmenter, and endotracheal paths (0.00291 μg, 0.00332 μg, 0.00297 μg, 0.00291 μg, and 0.00383 μg, respectively). Consistent with the focus of the review, the article also addresses crucial mitigation strategies for managing nanoparticle toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, the toxicity effects on circulatory system and respiratory system, and the acute toxicity test of recombinant neorudin (EPR-hirudin, EH) in cynomolgus monkeys were evaluated to provide reference information for clinical studies. Eighteen cynomolgus monkeys were randomly divided into three groups for single intravenous administration of 3, 30 mg/kg EH and normal saline, respectively. The changes of respiratory frequency, respiratory intensity, blood pressure and electrocardiogram before and after administration were recorded. In acute toxicity test, six cynomolgus monkeys were intravenously received EH at a single dose of 171, 257, 385, 578, 867 and 1300 mg/kg respectively. The vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of the animals were determined before administration and on the 7th and 14th day after administration. As the results showed that there were no significant abnormal changes in respiratory frequency, respiratory intensity, blood pressure or electrocardiogram in cynomolgus monkeys after receiving EH at 3 mg/kg and 30 mg/kg, and there was no statistical difference between the treated groups and normal saline group. In the acute toxicity test, no significant abnormalities were observed in vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of six cynomolgus monkeys at day 7 and 14 after EH administration. Furthermore, autopsies of all cynomolgus monkeys showed no abnormalities. The results of toxicokinetics showed that AUClast of the drug increased in proportion to the EH dose in the range of 171-578 mg/kg, and increased in over proportion to the EH dose in the range of 578-1300 mg/kg. The variation of Cmax was basically consistent with AUClast. In a sum, A single intravenous injection of 3 and 30 mg/kg of EH did not affect the circulatory system and respiratory system in cynomolgus monkeys and the maximum tolerated dose of EH in cynomolgus monkey is over 1300 mg/kg (equivalent to 619-1300 times of the proposed clinical equivalent dose).

Respiratory irritation is an important human health endpoint in chemical risk assessment. There are two established modes of action of respiratory irritation, 1) sensory irritation mediated by the interaction with sensory neurons, potentially stimulating trigeminal nerve, and 2) direct tissue irritation. The aim of our research was to, develop a QSAR method to predict human respiratory irritants, and to potentially reduce the reliance on animal testing for the identification of respiratory irritants. Compounds are classified as irritating based on combined evidence from different types of toxicological data, including inhalation studies with acute and repeated exposure. The curated project database comprised 1997 organic substances, 1553 being classified as irritating and 444 as non-irritating. A comparison of machine learning approaches, including Logistic Regression (LR), Random Forests (RFs), and Gradient Boosted Decision Trees (GBTs), showed, the best classification was obtained by GBTs. The LR model resulted in an area under the curve (AUC) of 0.65, while the optimal performance for both RFs and GBTs gives an AUC of 0.71. In addition to the classification and the information on the applicability domain, the web-based tool provides a list of structurally similar analogues together with their experimental data to facilitate expert review for read-across purposes., (Copyright © 2021. Published by Elsevier Inc.)

Asthma is a respiratory disease with complex pathogenesis. Sterol-responsive element-binding proteins 2 (SREBP2) was found to bind to promoter sequences of ABCA1 to suppress ABCA1 promoter activity. This study aimed to explore the expression level of SREBP2 and ATP-binding cassette transporter A1 (ABCA1), and their effects on the development of airway smooth muscle cells (ASMCs) in asthma. ASMCs were treated with different concentrations of TGF-β1 (0, 0.5, 1, 5 and 10 ng/mL). Short hairpin SREBP2 (shSREBP2), SREBP2, shABCA1 or ABCA1 were transfected into ASMCs. Cell viability, proliferation, apoptosis, migration, and the expression of SREBP2, ABCA1 and related pathway proteins were detected by MTT assay, Brdu staining, flow cytometer, Transwell assay, qRT-PCR, and Western blotting, respectively. The results showed that TGF-β1 increased the viability, proliferation, migration and inhibited apoptosis in ASMCs. Moreover, TGF-β1 also decreased the expression of ABCA1, cleaved caspase-3, cleaved PARP, E-cadherin, and increased the expression of vimentin, TLR2, p-p65 and NFATc1. SREBP2 knockdown alleviated these TGF-β1-induced changes. SREBP2 overexpression inhibited ABCA1 expression and apoptosis, and promoted cell migration and the expression of TLR2, p-p65, NFATc1 in ASMCs. ABCA1 overexpression alleviated these SREBP2-induced promoting and inhibition effects. In conclusion, SREBP2 activates TLR2/NF-κB/NFATc1 regulatory network and promotes TGF-β1-induced cell movement through inhibiting ABCA1 expression.

While a considerable body of literature has characterized the clinical features induced by organophosphate pesticides, the field lacks scrutiny into cardio-respiratory changes in different phases of poisoning. Herein, we evaluated the impact of chlorpyrifos (CPF) and its active metabolite chlorpyrifos-oxon (CPO) on the cardiorespiratory system during acute and subacute phases of poisoning using an in situ experimental rodent model. CPF (30 mg/kg) was injected intraperitoneally to rats beforehand (24 h) whereas CPO (15 mg/kg) was added into the perfusate reservoir to evaluate the effects on the motor outputs throughout the three phases of the respiratory cycle: inspiration, post-inspiration and late expiration. Phrenic, recurrent laryngeal (RLN) and thoracic sympathetic nerve activity (tSNA) were recorded. Heart rate was derived from the electrocardiogram (ECG) and the baro- and chemo-reflexes tested. CPF and CPO led to a time-dependent change in cardiorespiratory motor outputs. In the acute phase, the CPO induced bradypnea, transiently reduced the inspiratory time (TI), and increased the amplitude of phrenic. Post-inspiratory (PI) discharge recorded from the RLN was progressively reduced while tSNA was increased. CPO significantly depressed the chemoreflex but had no effect on baroreflex. During subacute phase, CPF prolongated T I with no effect on respiratory rate. Both the RLN PI discharge, the chemoreflex and the baroreflex sympathetic gain were reduced. In addition, both CPF and CPO shifted the cardiac sympatho-vagal balance towards sympathetic dominance. Our data show that different phases of poisoning are associated with specific changes in the cardio-respiratory system and might therefore demand distinct approaches by health care providers., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl - currents and intracellular Ca 2+ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca 2+ activated Cl - channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca 2+ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application.

The existing information supports the use of this material as described in this safety assessment. 5,8-Methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 5,8-methano-2H-1-benzopyran-2-one, 6- ethylideneoctahydro- (CAS # 69486-14-2) show that 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class III material, and the exposure to 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). Data provided 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- a NESIL of 8200 μg/cm 2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on human study data and UV/Vis spectra; 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The existing information supports the use of this material as described in this safety assessment. Phenethyl phenylacetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that phenethyl phenylacetate is not genotoxic. Data provide a calculated MOE >100 for the repeated dose toxicity endpoint. Data on read-across analog benzyl benzoate (CAS # 120-51-4) provide an MOE >100 for the developmental toxicity endpoint. The fertility and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to phenethyl phenylacetate is below the TTC (0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from analog benzyl phenylacetate (CAS # 102-16-9) show that there are no safety concerns for phenethyl phenylacetate for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV/Vis spectra; phenethyl phenylacetate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; phenethyl phenylacetate was found not to be PBT as per the IFRA Environmental Standards and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The existing information supports the use of this material as described in this safety assessment. β-Caryophyllene was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that β-caryophyllene is not genotoxic. Data on β-caryophyllene provided a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and fertility endpoints. The developmental and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to β-caryophyllene is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively. Data show that there are no safety concerns for β-caryophyllene for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on data and ultraviolet/visible (UV/Vis) spectra; β-caryophyllene is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; β-caryophyllene was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

No treatment-related effects at the low and mid doses were observed in gestation, viability and lactation indices, duration of gestation, parturition, sex ratio, maternal care, litter size, and early postnatal pup development consisting of mortality, clinical signs, anogenital distance, areola/nipple retention, T4 thyroid hormone levels, or macroscopic examination. However, the number of litters (N = 5) at the high dose was considered too low for toxicological evaluation. Thus, based on insufficient data at 120 mg/kg/day, the NOAEL for this study was considered to be 60 mg/kg/day (RIFM, 2020d)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The following paper presents the method of determination of the percolation threshold in cement composites with expanded graphite by impedance spectroscopy. Most of the applications of cement composites with conductive additives require exceeding the percolation threshold. The ionic conductivity of cement matrix below the percolation threshold has a major impact on the conductivity of the composite, as a result, it significantly hinders the exploitation of these composites. The electric properties of cement composites with expanded graphite were evaluated by DC measurements and impedance spectroscopy (IS). Based on Nyquist plots, two equivalent circuits were adopted for the composites. Next, the values of capacitance and inductance of cement composites with expanded graphite were calculated from the fitted equivalent circuits. The analysis of the results shows that the percolation threshold occurs when the reactance of the composite changes from captative to inductive. Comparison between the values of percolation threshold obtained from DC measurements and IS shows that the method is effective for cement composites with conductive additives., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The existing information supports the use of this material as described in this safety assessment. Tetrahydro-6-(3-pentenyl)-2H-pyran-2-one was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that tetrahydro-6-(3-pentenyl)-2H-pyran-2-one is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class II material, and the exposure to tetrahydro-6-(3-pentenyl)-2H-pyran-2-one is below the TTC (0.009 mg/kg/day, 0.009 mg/kg/day, and 0.47 mg/day, respectively). Data and read-across to 5-hydroxy-7-decenoic acid δ-lactone (CAS # 25,524-95-2) show that there are no safety concerns for tetrahydro-6-(3-pentenyl)-2H-pyran-2-one for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on data and ultraviolet/visible (UV/Vis) spectra; tetrahydro-6-(3-pentenyl)-2H-pyran-2-one is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; tetrahydro-6-(3-pentenyl)-2H-pyran-2-one was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The airway epithelium is a dynamic tissue that undergoes slow but constant renewal. Dysregulation of airway epithelial function related to cigarette smoke exposure plays an important role in the pathophysiology of COPD. Oct4 is a transcription factor responsible for maintaining cellular self-renewal and regeneration, and CD146 and CD105/Endoglin are adhesion molecules involved in cell proliferation, differentiation, epithelial-mesenchymal-transition and tissue remodeling. Bronchial biopsy specimens (BBs) were obtained from 7 healthy controls (HC) and 10 COPD and subjected to paraffin embedding; BBs from HC were also used for epithelial cell expansion and pHBEC/ALI (air-liquid interface) culture. pHBEC/ALI were exposed to cigarette smoke extract (CSE) for 7, 14 and 21 days. In BBs, Oct4, CD146 and CD105 were evaluated by immunohistochemistry. In pHBEC/ALI, the expression of Oct4, CD146, CD105 and acetyl-αtubulin was evaluated by Western Blot, MUC5AC and IL-8 measurements by ELISA. The Oct4 epithelial immunoreactivity was lower in COPD than in HC, whilst CD146 and CD105 expression was higher in COPD than in HC. In pHBEC/ALI, Transepithelial Electrical Resistance values, measured over 7 to 21 days of differentiation, decreased by 18% (2.5% CSE) and 29% (5% CSE) compared to untreated samples. Oct4 and acetyl-αtubulin were induced after one-week differentiation and downregulated by CSE in reconstituted epithelium; CD146, CD105, MUC5AC and IL-8 were increased by CSE. Oct4 de-regulation and CD146 and CD105 overexpression, induced by cigarette smoke exposure, might play a role in airway epithelial dysfunction by causing changes in self-renewal and mesenchymal transition mechanisms, leading to alteration of epithelium homeostasis and abnormal tissue remodeling involved in progression of COPD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Exposure to spray cleaning products constitutes a potential risk for asthma induction. We set out to review whether substances in such products are potential inducers of asthma. We identified 101 spray cleaning products for professional use. Twenty-eight of their chemical substances were selected. We based the selection on (a) positive prediction for respiratory sensitisation in humans based on quantitative structure activity relationship (QSAR) in the Danish (Q)SAR Database, (b) positive QSAR prediction for severe skin irritation in rabbits and (c) knowledge on the substances' physico-chemical characteristics and toxicity. Combining the findings in the literature and QSAR predictions, we could group substances into four classes: (1) some indication in humans for asthma induction: chloramine, benzalkonium chloride; (2) some indication in animals for asthma induction: ethylenediaminetetraacetic acid (EDTA), citric acid; (3) equivocal data: hypochlorite; (4) few or lacking data: nitriloacetic acid, monoethanolamine, 2-(2-aminoethoxy)ethanol, 2-diethylaminoethanol, alkyldimethylamin oxide, 1-aminopropan-2-ol, methylisothiazolinone, benzisothiazolinone and chlormethylisothiazolinone; three specific sulphonates and sulfamic acid, salicylic acid and its analogue sodium benzoate, propane-1,2-diol, glycerol, propylidynetrimethanol, lactic acid, disodium malate, morpholine, bronopol and benzyl alcohol. In conclusion, we identified an asthma induction potential for some of the substances. In addition, we identified major knowledge gaps for most substances. Thus, more data are needed to feed into a strategy of safe-by-design, where substances with potential for induction of asthma are avoided in future (spray) cleaning products. Moreover, we suggest that QSAR predictions can serve to prioritise substances that need further testing in various areas of toxicology., (© 2021 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.)

Respiratory system injury is the main cause of mortality for nitrogen mustard (NM)-induced damage. Previous studies indicate that reactive oxygen species (ROS) participates in NM-mediated respiratory injuries, but the detailed mechanism is not quite clear. Human bronchial epithelial cell lines 16HBE and BEAS-2B were treated with HN2, a type of NM. In detail, it was shown that HN2 treatment induced impaired cell viability, excessive mitochondrial ROS production and enhanced cellular apoptosis in bronchial epithelial cells. Moreover, impaired Sirt3/SOD2 axis was observed upon HN2 treatment, with decreased Sirt3 and increased acetylated SOD2 expression levels. Sirt3 overexpression partially ameliorated HN2-induced cell injury. Meanwhile, vitamin D3 treatment partially attenuated HN2-induced apoptosis and improved the mitochondrial functions upon HN2 intervention. In addition, HN2 exposure decreased VDR expression, thus inhibiting the Nrf2 phosphorylation and Sirt3 activation. Inhibition of Nrf2 or Sirt3 could decrease the protective effects of vitamin D3 and enhance mitochondrial ROS production via modulating mitochondrial redox balance. In conclusion, impaired VDR/Nrf2/Sirt3 axis contributed to NM-induced apoptosis, while vitamin D3 supplementation provides protective effects via the activation of VDR and the improvement of mitochondrial functions. This study provides novel mechanism and strategy for NM exposure-induced pulmonary injuries., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Over 40 million people use e-cigarettes worldwide, but the impact of chronic e-cigarette use on health has not been adequately defined. In particular, effects of e-cigarette aerosol inhalation on inflammation and host defenses across the body are not fully understood. We conducted a longitudinal cohort pilot study to explore changes in the inflammatory state and monocyte function of e-cigarette users ( n = 20) versus healthy controls ( n = 13) and to evaluate effects of e-cigarette use reduction on the same. Saliva, sputum, and blood were obtained from e-cigarette users at baseline and after a 2-wk intervention of decreased e-cigarette use. Overall, across 38 proteins quantified by multiplex, airway samples from e-cigarette users tended to have decreased levels of immunomodulatory proteins relative to healthy controls, whereas levels of cytokines, chemokines, and growth factors in the circulation tended to be elevated. Specifically, e-cigarette users had lower levels of IL-1 receptor antagonist (IL-1Ra) in saliva ( P < 0.0001), with higher IL-1Ra and growth-regulated oncogene (GRO) levels in sputum ( P < 0.01 and P < 0.05, respectively), and higher levels of both TNFβ ( P < 0.0001) and VEGF ( P < 0.0001) in plasma. Circulating monocytes from e-cigarette users had alterations in their inflammatory phenotype in response to reduced e-cigarette use, with blunted IL-8 and IL-6 release upon challenge with bacterial lipopolysaccharide ( P < 0.001 and P < 0.05, respectively), suggesting a decreased ability to appropriately respond to bacterial infection. Based on these findings, chronic inhalation of e-cigarette aerosols alters the inflammatory state of the airways and systemic circulation, raising concern for the development of both inflammatory and infectious diseases in chronic users of e-cigarettes.

Nocturnal asthma is characterized by heightened bronchial reactivity at night, and plasma melatonin concentrations are higher in patients with nocturnal asthma symptoms. Numerous physiological effects of melatonin are mediated via its specific G protein-coupled receptors (GPCRs) named the MT 1 receptor, which couples to both G q and G i proteins, and the MT 2 receptor, which couples to G i . We investigated whether melatonin receptors are expressed on airway smooth muscle; whether they regulate intracellular cyclic AMP (cAMP) and calcium concentrations ([Ca 2+ ] i ), which modulate airway smooth muscle tone; and whether they promote airway smooth muscle cell proliferation. We detected the mRNA and protein expression of the melatonin MT 2 but not the MT 1 receptor in native human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by RT-PCR, immunoblotting, and immunohistochemistry. Activation of melatonin MT 2 receptors with either pharmacological concentrations of melatonin (10-100 µM) or the nonselective MT 1 /MT 2 agonist ramelteon (10 µM) significantly inhibited forskolin-stimulated cAMP accumulation in HASM cells, which was reversed by the Gα i protein inhibitor pertussis toxin or knockdown of the MT 2 receptor by its specific siRNA. Although melatonin by itself did not induce an initial [Ca 2+ ] i increase and airway contraction, melatonin significantly potentiated acetylcholine-stimulated [Ca 2+ ] i increases, stress fiber formation through the MT 2 receptor in HASM cells, and attenuated the relaxant effect of isoproterenol in guinea pig trachea. These findings suggest that the melatonin MT 2 receptor is expressed in ASM, and modulates airway smooth muscle tone via reduced cAMP production and increased [Ca 2+ ] i .

Antibiotic-induced host health imbalance during upper respiratory tract infection (URTI) treatment is an emerging issue. Studies have confirmed that Lactobacillus casei 431 and Lactobacillus fermentum PCC alleviate gut microbiome dysbiosis and improve immune response. However, their effect on the upper respiratory tract (URT) microbial structure and the correlation between the URT microbiota and immunological indicators remain unclear. To evaluate the effects of Lactobacillus strains on restoring penicillin-induced imbalance in the URT microbiome and on immune response, Lactobacillus fermentum PCC and Lactobacillus casei 431 were individually administered to penicillin-pretreated mice, and their effects were assessed. The results revealed that L. casei 431 and L. fermentum PCC could regulate the systemic immune response imbalance, but the regulation direction of L. fermentum PCC was closer to that of the control group. Moreover, the Lactobacillus strains could restore penicillin-induced URT dysbacteriosis in the microbial community structure, but no significant change in alpha diversity was observed. The key bacterial taxa modulated by L. casei 431 were Faecalibaculum , Lactococcus , and Ralstonia . L. fermentum PCC enhanced biofilms and facultatively anaerobic bacteria. Different regulation pathways were observed in the two strains, and RDA revealed that both L. casei 431 and L. fermentum PCC groups were correlated with IL-17 and IL-1α, while the L. casei 431 group was also correlated with IL-6. In conclusion, L. casei 431 and L. fermentum PCC could beneficially and differentially ameliorate penicillin-induced imbalance in the URT microbial composition structure and functional metabolic pathways and modulate immune response, reflecting strain-specific regulation.

The existing information supports the use of this material as described in this safety assessment. Dihydrocarvyl acetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs dihydrocarveol (isomer unspecified) (CAS # 619-01-2) and acetic acid (CAS # 64-19-7) show that dihydrocarvyl acetate is not expected to be genotoxic. Data on read-across analogs isopulegol (CAS # 89-79-2) and acetic acid (CAS # 64-19-7 provide a calculated MOE >100 for the repeated dose toxicity endpoint. The reproductive and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to dihydrocarvyl acetate is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). Data from read-across analog 4-methyl-8-methylenetricyclo [3.3.1.(3,7)]decan-2-yl acetate (CAS # 122,760-85-4) provided dihydrocarvyl acetate a NESIL of 2500 μg/cm 2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on UV/Vis spectra; dihydrocarvyl acetate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; dihydrocarvyl acetate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The existing information supports the use of this material as described in this safety assessment. cis-3-Hexenyl tiglate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs 2-methyl-trans-2-butenoic acid (CAS # 80-59-1) and cis-3-hexenol (CAS # 928-96-1) show that cis-3-hexenyl tiglate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold for Toxicological Concern (TTC) for a Cramer Class I material; exposure to cis-3-hexenyl tiglate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day and 1.4 mg/day, respectively). Data from analog 2-hexenoic acid, 2-methyl-, methyl ester, (2E)- (CAS # 16493-96-2) provided cis-3-hexenyl tiglate a No Expected Sensitization Induction Level (NESIL) of 1100 μg/cm 2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; cis-3-hexenyl tiglate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; cis-3-hexenyl tiglate was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The existing information supports the use of this material as described in this safety assessment. 4,8-Decadienal, (4Z,8Z)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs 4,7-decadienal (CAS # 934534-30-2) and nona-2-trans-6-cis-dienal (CAS # 557-48-2) show that 4,8-decadienal, (4Z,8Z)- is not expected to be genotoxic. Data on analog 10-undecenal (CAS # 112-45-8) provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and fertility endpoints and a No Expected Sensitization Induction Level (NESIL) of 1700 μg/cm 2 for the skin sensitization endpoint. The developmental toxicity and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for Cramer Class I materials; exposure is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 4,8-decadienal, (4Z,8Z)- is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 4,8-decadienal, (4Z,8Z)- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. Its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Contemporary approaches to human health risk assessment for respiratory tract irritants are variable and controversial. This manuscript provides an in-depth analysis and assessment of the applicability of the classical respiratory depression 50 % (RD 50 ) assay with focus on the Log-linear extrapolation of the non-sensory irritant threshold (RD 0 or RD 10 ) relative to the contemporary Point of Departure (POD) U.S.-EPA benchmark approach. Three prototypic volatile chemically reactive irritants are used to exemplify the pros and cons of this alternative approach. These irritants differ in physicochemical properties affecting water-solubility and lipophilicity. Depending on these variables, a vapor may preferentially be retained in the extrathoracic region (ET), the tracheobronchial region (TB), and the pulmonary region (PU); although a smooth transition between these regions occurs at increasingly high concentrations. Each region has its specific nociceptors sensing irritants and regional-specific response to injury. The alternative approach using rats identified the chemical-specific critical region of respiratory tract injury. Statistically derived PODs on ET-TB related sensory irritation provide important information for ET-TB irritants but not for PU irritants. The POD of ET-TB irritants from acute and repeated studies decreased substantially. In summary, statistically derived PODs improve the risk assessment of respiratory tract irritants; however, those from repeated exposures should be given preference to those from acute exposures., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic-COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature'-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development., Competing Interests: The authors have declared that no competing interests exist.

Ractopamine (RAC) is a beta-adrenoceptor agonist that is used to promote lean and increased food conversion efficiency in livestock. This compound has been considered to be causing behavioral and physiological alterations in livestock like pig. Few studies have addressed the potential non-target effect of RAC in aquatic animals. In this study, we aimed to explore the potential physiological response after acute RAC exposure in zebrafish by evaluating multiple endpoints like locomotor activity, oxygen consumption, and cardiovascular performance. Zebrafish larvae were subjected to waterborne RAC exposure at 0.1, 1, 2, 4, or 8 ppm for 24 h, and the corresponding cardiovascular, respiratory, and locomotion activities were monitored and quantified. In addition, we also performed in silico molecular docking for RAC with 10 zebrafish endogenous β-adrenergic receptors to elucidate the potential acting mechanism of RAC. Results show RAC administration can significantly boost locomotor activity, cardiac performance, oxygen consumption, and blood flow rate, but without affecting the cardiac rhythm regularity in zebrafish embryos. Based on structure-based flexible molecular docking, RAC display similar binding affinity to all ten subtypes of endogenous β-adrenergic receptors, from adra1aa to adra2db , which are equivalent to the human one. This result suggests RAC might act as high potency and broad spectrum β-adrenergic receptors agonist on boosting the locomotor activity, cardiac performance, and oxygen consumption in zebrafish. To validate our results, we co-incubated a well-known β-blocker of propranolol (PROP) with RAC. PROP exposure tends to minimize the locomotor hyperactivity, high oxygen consumption, and cardiac rate in zebrafish larvae. In silico structure-based molecular simulation and binding affinity tests show PROP has an overall lower binding affinity than RAC. Taken together, our studies provide solid in vivo evidence to support that RAC plays crucial roles on modulating cardiovascular, respiratory, and locomotory physiology in zebrafish for the first time. In addition, the versatile functions of RAC as β-agonist possibly mediated via receptor competition with PROP as β-antagonist.

Nowadays, caffeine is one of the most commonly consumed substances, which presents in many plants and products. It has both positive and negative effects on the human body, and its activity concerns a variety of systems including the central nervous system, immune system, digestive system, respiratory system, urinary tract, etc. These effects are dependent on quantity, the type of product in which caffeine is contained, and also on the individual differences among people (sex, age, diet etc.). The main aim of this review was to collect, present, and analyze the available information including the latest discoveries on the impact of caffeine on human health and the functioning of human body systems, taking into account the role of caffeine in individual disease entities. We present both the positive and negative sides of caffeine consumption and the healing properties of this purine alkaloid in diseases such as asthma, Parkinson's disease, and others, not forgetting about the negative effects of excess caffeine (e.g., in people with hypertension, children, adolescents, and the elderly). In summary, we can conclude, however, that caffeine has a multi-directional influence on various organs of the human body, and because of its anti-oxidative properties, it was, and still is, an interesting topic for research studies including those aimed at developing new therapeutic strategies.

The Adverse Outcome Pathway (AOP) framework is serving as a basis to integrate new data streams in order to enhance the power of predictive toxicology. AOP development for engineered nanomaterials (ENM), including silver nanoparticles (AgNP), is currently lagging behind other chemicals of regulatory interest due to our limited understanding of the mechanism by which underlying genetics or diseases directly modify host response to AgNP exposures. This also highlights the importance of considering the Aggregate Exposure Pathway (AEP) framework, which precedes the AOP framework and outlines source to target site exposure. The AEP and AOP frameworks interface at the target site, where a molecular initiating event (MIE) occurs and is followed by key events (KE) for adverse cellular and organ responses along a biological pathway and ends with the adverse organism response. The primary goal of this study is to use AgNP to interrogate the AEP-AOP framework by organizing and integrating in vitro dose-response data and in vivo exposure-response data from previous studies to evaluate the effects of interactions between host genetic and acquired factors, or gene × environment interactions (G × E), on AgNP toxicity in the respiratory system. Using this framework will help us to identify plausible key event relationships (KER) between MIE and adverse organism responses when KE are not measured using the same assay in order to derive future predictive models, guide research, and support development of tools for making risk-based, regulatory decisions on ENM. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine., (© 2021 Wiley Periodicals LLC.)

Bitter taste receptors (TAS2Rs) and their signaling elements are detected throughout the body, and bitter tastants induce a wide variety of biological responses in tissues and organs outside the mouth. However, the roles of TAS2Rs in these responses remain to be tested and established genetically. Here, we employed the CRISPR/Cas9 gene-editing technique to delete three bitter taste receptors-Tas2r143/Tas2r135/Tas2r126 (i.e., Tas2r triple knockout [TKO]) in mice. The fidelity and effectiveness of the Tas2r deletions were validated genetically at DNA and messenger RNA levels and functionally based on the tasting of TAS2R135 and TAS2R126 agonists. Bitter tastants are known to relax airways completely. However, TAS2R135 or TAS2R126 agonists either failed to induce relaxation of pre-contracted airways in wild-type mice and Tas2r TKO mice or relaxed them dose-dependently, but to the same extent in both types of mice. These results indicate that TAS2Rs are not required for bitter tastant-induced bronchodilation. The Tas2r TKO mice also provide a valuable model to resolve whether TAS2Rs mediate bitter tastant-induced responses in many other extraoral tissues., (© 2021 Wiley Periodicals LLC.)

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-β1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-β1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-β1 and urinary LTE4. The function of TGF-β1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-β1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-β1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-β1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-β1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-β1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation., Competing Interests: The authors declare that this is an investigator-initiated study therefore Dong-A ST Co. and MD Healthcare Inc. have no issues that lead to conflicts of interests in this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.