Inhalation Toxicology最新文献

Background: Computational fluid dynamics (CFD) is widely used for studying nasal airflow but is rarely rigorously validated against experimental data. This study aimed to validate a subject-specific CFD model by comparing intranasal air pressure with measurements from a precise physical replica.

Methods: 1:1 scale resin model of a single healthy human nasal cavity was fabricated using high-precision 3D printing (0.1 mm tolerance). Static pressures at 63 checkpoints within the nasal cavity were measured under three steady-state flow rates (180, 560, and 1100 mL s^-1) corresponding to different respiratory intensities. These experimental data were compared with results from a standard k-ε CFD simulation.

Results: At low to moderate flow rates (180 and 560 mL s^-1), pressures showed excellent consistency between experimental and CFD data. Quantitative analysis confirmed a strong correlation (Pearson's r = 0.98) and low error margins (RMSE < 6 Pa). However, at the high flow rate of 1100 mL s^-1, a significant deviation (RMSE = 18.5 Pa) was observed in the posterior nasal cavity during expiration.

Conclusions: This study establishes a methodological framework for validating subject-specific nasal airflow simulations using high-fidelity 3D-printed replicas. Our findings confirm the accuracy of the standard k-ε turbulence model for this specific anatomy at low to moderate physiological flow rates. However, deviations at high flow rates highlight the limitations of standard turbulence models and experimental uncertainties in complex regimes. This validated methodology offers a robust tool for future clinical assessments of nasal resistance.

Background: Six years since the revised Test Guidelines 412 and 413 (TG412 and TG413) were issued, there are sufficient data to evaluate the relationship between bronchoalveolar lavage (BAL) cytology and biomarkers with histopathology.

Objective: This retrospective study evaluates the correlation between mandatory endpoints in the BAL fluid (LDH activity, concentration of total protein, inflammatory cell counts) and histopathological changes in the lungs following sub-chronic inhalation exposure in rats.

Materials and methods: Twenty-eight studies conducted across two Test Facilities from 2018 to 2023 were reviewed to identify trends.

Results: At baseline, there were no strain differences in BAL fluid total protein, but LDH activity was statistically different between sexes and ages. LDH activity and total protein in BALF at the lowest observed adverse effect concentration showed no pathological pattern following inhalation exposure to the tested chemicals, while immune cell counts shifted in Wistar Han rats. Specifically in studies with adverse lung histopathology, total protein and LDH activity were generally elevated, along with a shift in immune cells toward neutrophils and eosinophils, without correlation to the severity score of adverse microscopic findings.

Conclusion: These results suggest that BALF parameters are insufficient to independently characterize adversity but may be used in other ways to progress new approach methods.

Background: The rapid rise in e-cigarette use has generated increasing public health concern regarding its long-term effects on the cardiopulmonary system. Although e-cigarettes are often marketed as a safer alternative to traditional tobacco products, growing evidence suggests they may contribute to chronic respiratory and cardiovascular diseases.

Methods: This contemporary narrative review synthesizes current research published between 2015 and 2025 on the long-term respiratory and cardiovascular consequences of e-cigarette use, integrating findings from epidemiologic, clinical, and mechanistic studies.

Results and discussion: Evidence consistently links frequent e-cigarette use to elevated risks of chronic obstructive pulmonary disease (COPD), asthma exacerbation, impaired lung function, myocardial infarction, arrhythmias, and endothelial dysfunction. Mechanistic data reveal nicotine-induced sympathetic activation, oxidative stress, and vascular injury as key biological pathways underlying these effects. Older adults and daily users appear particularly vulnerable due to cumulative exposure and reduced physiological resilience. Despite these concerning trends, substantial gaps remain, including limited longitudinal data, inconsistent exposure characterization, and inadequate distinction between exclusive and dual users.

Conclusions: Addressing these gaps through well-designed cohort and mechanistic studies will be critical to refining clinical guidance, informing regulatory policy, and shaping evidence-based public health messaging.

Understanding particle deposition patterns in the pulmonary acinus is essential for early intervention and treatment in acinar diseases. This study numerically investigated the effects of respiratory modes and emphysematous alveolar wall ablation on airflow and particle deposition in a physiologically representative pulmonary acinar model. A heterogeneous acinar model was developed, incorporating alveolar expansion and contraction via the dynamic meshing method, and its validity was confirmed by comparison with published particle deposition data. Airflow and particle transport patterns were then analyzed under varying respiratory modes and degrees of alveolar wall ablation. For particles smaller than 1 μm, deposition decreased with higher breathing frequency and increased with larger tidal volume. Smaller particles penetrated deeper and deposited more uniformly due to strong airflow coupling. Compared with the normal acinus, the lesioned acinus exhibited reduced airflow variability, lower expansion capacity, and a decreased deposition fraction. Alveolar wall ablation impaired lung expansion and restricted distal airflow penetration, leading to localized particle deposition near the acinar entrance. As lesion severity increased, the deposition progressively declined due to altered flow patterns and a reduced surface-to-volume ratio. The particle deposition declined nonlinearly with lesion severity. A 30% wall ablation reduced total deposition by over 40%, whereas further increases to 60% and 90% caused only minor additional decreases, indicating a nonlinear response in which early structural damage disproportionately affects acinar particle deposition. These findings underscore the importance of early intervention to preserve alveolar drug deposition efficiency and improve therapeutic outcomes in patients with progressive pulmonary diseases such as emphysema.

Objective: The presence of fine dusts in the industrial working environment has significant implications for occupational safety. As a result, legislators have implemented regulations to protect employees from adverse lung effects. The establishment of limits aims to prevent health hazards, particularly lung diseases, even with prolonged exposure. Niobium, a chemical element widely used in the industry, is commonly found as an additive in various alloy products.

Materials and methods: Given the inhalation potential during manufacturing and the substantial volume of niobium used, a 90-day-nose-only inhalation study of diniobium pentaoxide (Nb₂O₅) was conducted in rats. Following exposure of rats to 1.5, 6, and 24 mg/m³ Nb₂O₅, various endpoints were examined to assess potential lung toxicity and exposure-concentration-response relationships associated with the inhaled test substance.

Results: Analysis of polymorphonuclear neutrophils (PMNs) in bronchoalveolar lavage fluid (BALF) in the treated groups showed levels close to clean air control levels. Histopathological analysis revealed the presence of particle-laden macrophages in lung alveoli, bronchus- and nose-associated lymphoid tissue, and lung-associated lymph nodes in the group exposed to the highest concentration. Additionally, activation of pneumocytes type 2 was observed.

Discussion and conclusions: All findings were interpreted as adaptive and non-adverse. Therefore, no adverse effects were observed in any of the endpoints, including the group exposed to the highest concentration. Under the conditions of this study, a NOAEC (no observed adverse effect concentration) of 24 mg/m³ was determined. Diniobium pentaoxide is thus considered a newly discovered nuisance dust.

Objective: Pulmonary surfactant proteins (SP-A, SP-B, SP-C, and SP-D) are essential regulators of alveolar surface tension and pulmonary immune defense, forming a critical frontline barrier against airborne xenobiotics. This study aimed to evaluate the molecular interactions between environmentally prevalent airborne pollutants and human surfactant proteins.

Materials and methods: A multi-tiered computational framework assessed interactions between 87 airborne pollutants and surfactant proteins. Structure-based molecular docking using AutoDock Vina identified benzo[a]pyrene and crotonic acid as highest-affinity ligands (binding energies up to -8.1 kcal/mol). The top ligands underwent 200 ns molecular dynamics simulations with SP-A, SP-B, SP-C, and SP-D using the CHARMM36 force field in GROMACS. Structural metrics (RMSD, RMSF, SASA, and Rg), principal component analysis (PCA), and MM-GBSA binding free energy calculations were performed.

Results and discussion: Analyses demonstrated sustained ligand-protein interactions and moderate conformational shifts, particularly within SP-A and SP-C domains. PCA revealed ligand-induced conformational changes, while MM-GBSA confirmed thermodynamic favorability (ΔGbind -26.5 to -32.8 kcal/mol). These findings suggest a novel mechanism of respiratory toxicity via molecular disruption of surfactant proteins.

Conclusions: This integrated in-silico approach highlights pollutant-induced surfactant protein alterations as potential biomarkers of pulmonary toxicant exposure and underscores the need for experimental validation and further mechanistic studies.

Objective: Volatile organic compounds (VOCs) are prevalent in both indoor and outdoor environments and have been linked to health effects. This study aimed to assess VOC-induced effects on the respiratory epithelium using an in vitro human bronchial epithelial air-liquid interface (ALI) model.

Methods: A human bronchial epithelial cell line, 16HBE, was cultured at ALI and exposed to relevant concentrations of two representative VOCs, acrolein or formic acid, and matched filtered air (control) in a CelTox exposure system for two hours to replicate an acute inhalation exposure. Cells were allowed to recover for 24 h before cell lysate and culture media were collected for analysis.

Results: Cytotoxicity, based on LDH activity, significantly increased at the highest doses tested for both VOCs. A dose-dependent increase in barrier permeability was observed for confluent cells exposed to acrolein and formic acid. Acrolein and formic acid exposure induced IL-8, TNFα, and HMOX-1 expression, genes indicative of proinflammatory signaling and oxidative stress, respectively. Formic acid, but not acrolein, exposure also increased expression of PINK1, a gene indicative of mitophagy. Benchmark concentration (BMC) modeling of in vitro acrolein data yielded a BMCL (benchmark concentration lower confidence limit) that substantiates the stringency of OSHA's 8-hour permissible exposure limit (PEL). In contrast, BMC modeling of in vitro formic acid data produced BMCLs below existing regulatory exposure thresholds.

Conclusion: Collectively, these findings demonstrate that this model is a plausible in vitro tool to investigate VOC-induced effects on the airway and supports its utility in VOC safety evaluation.

Objective: Nebulizers are medical devices that convert liquid solutions, such as saline or medication, into aerosols for direct airway delivery. Their effectiveness relies on interfaces, typically made from polymeric materials containing additives to enhance functionality and durability. This study aimed to characterize emissions of volatile organic compounds (VOCs) and semi-volatile organic compounds (SVOCs) from different components of five nebulizers, considering two exposure routes: inhalation and dermal contact.

Materials and methods: Five nebulizers were assessed by analyzing emissions from individual components and from complete system configurations. VOC and SVOC emissions were quantified and short-term exposure (20 minutes) was assessed for infants and children. Estimated exposure levels were compared with toxicological reference values, including inhalation Derived No-Effect Levels (DNELs), to evaluate potential health risks via inhalation and dermal contact.

Results: All tested components emitted VOCs, with the highest concentrations detected in masks and whole-system configurations. Some identified compounds, including toluene, styrene, siloxane D4, and 2-ethylhexanoic acid, are suspected or recognized reproductive toxicants. Although measured levels were very low, inhalation represents a potential exposure route warranting a precautionary approach. Phenol, a suspected mutagen, reached concentrations up to 65.9 μg/m³, corresponding to 11.7% of the inhalation DNEL for a 20-minute exposure in infants and children. Dermal exposure levels were very low compared with toxicological reference values. Nevertheless, compounds such as benzyl alcohol and 2-ethylhexyl acrylate, both recognized as EU-classified skin sensitizers, were detected. Cyclic siloxanes D5, D6, and D7 were also detected, with D6 showing the highest dermal intake. As these siloxanes are classified as Persistent, Bioaccumulative and Toxic (PBT) in the EU, long-term effects from bioaccumulation and environmental persistence should be considered.

Discussion and conclusions: Although measured VOC and SVOC concentrations were low and below established toxicological thresholds, these findings underscore the need for preventive measures, particularly for sensitive populations such as infants and children. Inhalation appears to be the most relevant exposure pathway during use, while dermal exposure, though minimal, may contribute to sensitization risks. The presence of PBT-classified siloxanes further emphasizes the need to consider long-term human health and environmental implications. Overall, these findings support the implementation of preventive strategies and continued monitoring of material emissions in medical devices intended for vulnerable users.

Background: The use of alternative and renewable fuels in the transport sector is growing rapidly due to increasing demand for sustainable energy solutions, however implying an increased risk for human exposure to emissions from these new fuels.

Methods: In this study, we examined the effects on BEAS-2B cells of particulate matter (PM) emissions, derived from the use of petroleum diesel (SD10) and rapeseed methyl ester (RME100) in a truck engine. We assessed several endpoints, including the induction of apoptotic and necrotic cell death, reactive oxygen species generation inside cells, inflammatory response, and cell cycle alterations.

Results: The characteristics of the exhaust PM varied between the two fuels, where the RME100-derived PM contained lower levels of polycyclic aromatic hydrocarbons and elemental carbon compared to SD10. Toxicological analyses revealed that PM from RME100 induced weaker oxidative stress and cell death responses than SD10. However, unlike SD10, RME100 PM caused a notable arrest in the S-G2/M phase of the cell cycle.

Conclusions: In summary, fuel type clearly influenced the characteristics of PM emissions from a heavy-duty diesel engine, which in turn affected the particles' biological activity. Overall, RME100 exhaust PM exhibited lower toxicity compared to petroleum diesel PM in the BEAS-2B cell model.

Objective: Carbon nanotubes (CNTs) are increasingly applied in industrial and biomedical fields, yet their fiber-like geometry and structural durability raise concerns about inhalation risks in occupational settings. This review synthesizes current evidence on neutrophil recruitment, activation, and extracellular trap (NET) formation in CNT-induced lung injury, with emphasis on biomarker discovery, therapeutic strategies, and worker protection.

Methods: A narrative synthesis integrating mechanistic, experimental, and translational studies on CNT-induced neutrophil activation and NETosis was conducted.

Results and discussion: Experimental data show that CNT deposition in distal airways rapidly recruits and activates neutrophil, initiating the release of reactive oxygen species (ROS), proteolytic enzymes, and chromatin-based NETs. While these responses contribute to host defense, sustained activation promotes epithelial injury and fibrotic remodeling. Translational studies in exposed workers reveal elevated myeloperoxidase (MPO), neutrophil elastase, neutrophil gelatinase-associated lipocalin (NGAL), and circulating DNA, supporting their value as early biomarkers of pulmonary injury. Remaining challenges include the absence of long-term human cohort data, heterogeneity in CNT physicochemical features, and technical limitations in detecting biologically meaningful exposure endpoints.

Conclusions: Neutrophil activation and NETosis represent important contributing pathways in CNT-induced inflammation and fibrosis, although current evidence does not establish NETosis as a central or predictive mechanism. Future strategies should focus on safer CNT design, strengthened occupational controls, biomarker-based surveillance, and mechanism-targeted interventions to minimize health risks while advancing sustainable nanotechnology.