Inhalation Toxicology最新文献

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.

Introduction: Heated Tobacco Products (HTPs) are marketed as less harmful alternatives than cigarettes. While industry-funded studies suggest lower risks associated with HTP use compared with cigarettes, the health impacts of HTP use relative to non-use remain uncertain.

Methods: We reviewed tobacco industry-independent studies published between 2019 and 2024 investigating chemical composition of HTP sticks and emissions, and cardiovascular- and pulmonary health effects associated with their use in human subjects and relevant human in vitro models. Only original research articles were included. Studies on secondhand emissions, animal models and epidemiological studies were excluded.

Results: 74 studies met the inclusion criteria. HTP emissions contain lower levels of harmful tobacco-related chemicals (e.g. nicotine, Tobacco-Specific Nitrosamines and carbonyls) compared to cigarette smoke but higher concentrations of certain carcinogens. HTP-specific toxicants include formaldehyde cyanohydrin and plastic-derived compounds. Compared to smokers, HTP users show reduced levels of biomarkers of exposure (nicotine, exhaled CO, aromatic amines) and lower toxicity (oxidative stress, inflammation, DNA damage), although higher than in nonusers. Human studies reveal that HTP use adversely affects cardiovascular and pulmonary function. In vitro findings support these outcomes, showing cytotoxicity, oxidative stress, inflammation, and genotoxicity, often to a lesser extent compared to cigarette smoke.

Conclusions: HTP use exposes consumers to noxious chemicals and detrimentally impacts cardiovascular health and pulmonary function. Although the long-term harm of HTPs is unknown, current evidence suggests short-term toxicity comparable to cigarettes.

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.

Background: Ozone (O₃) and nitrogen dioxide (NO₂) are highly reactive gases associated with all cause-mortality. Epidemiology studies suggest that the risk from O₃ and NO₂ exposure is modified by sex. O₃ is more strongly associated with declines in pulmonary function in males, but females show stronger associations with cardiovascular disease (CVD). For NO₂ exposure, females show stronger associations for increased risk of CVD, loss of lung function, and mortality. It remains unclear if these differences stem from social constructs or underlying biologic responses.

Methods: To investigate sex differences after pollutant exposure, we used a single blind, randomized crossover, controlled exposure study to examine the pulmonary, inflammatory, and clotting/fibrinolysis response after exposure to O₃ and NO₂ relative to clean air. Healthy adult participants (n = 22 male = 10, female = 12) underwent separate two-hour exposures to clean air, 300 ppb O₃, and 500 ppb NO₂ exposures while exercising intermittently.

Results: Compared to air, exposure to O₃ resulted in a mean percent change in FEV₁ (-5.74%, 95%CI: -7.83, -3.65, p < 0.001), FVC (-3.94%, 95%CI: -5.59, -2.30, p < 0.001), and FEV₁/FVC (-1.90%, 95%CI: -3.54, -0.25, p < 0.01), and elevated IL-6 (16.3%, 95%CI: 0.51, 32.14, p < 0.01), C-Reactive Protein (CRP) (44.54%; 95%CI: 15.44, 73.65, p < 0.001), and Serum amyloid A (SAA) (33.6%; 95%CI: 7.30, 60.0, p < 0.01). NO₂ exposure resulted in a mean percent change of D-dimer (10.9%, 95%CI: -0.23, 21.93, p < 0.05). When stratified by sex, after O₃ exposure, males displayed greater decrements in FEV₁ (males; -7.81% (95%CI: -11.45, -4.19) females: -4.00% (95%CI: -6.20, -1.80; p < 0.05)) and CRP increased in males by 78.50% (95%CI: 27.50, 129.50) compared to 16.20% (95%CI: -10.43, 42.84) in females (p < 0.01) and SAA increased in males by 60.25% (95%CI: 12.02, 108.48) compared to 15.18% (95%CI: -14.53, 44.90) in females (p = 0.051). TNFα was elevated in females by an average of 10.9% (95%CI: 0.75, 21.23) compared to males (-2.29%, 95%CI: -12.32, 7.75) (p < 0.05). After NO₂, D-dimer was elevated in females by 18.98% (95%CI: 4.69, 33.26) compared to males (1.52%, 95%CI: -16.12,19.16) (p = 0.062).

Conclusions: Sex modified the pulmonary and inflammatory response to O₃ and NO₂, a finding consistent with epidemiological observations of sex differences after O3 and NO2 exposure.

Objective: Ammonia (NH₃) inhalation is a common occupational exposure, causing injuries similar to acute lung injury (ALI). Medical management is limited to supportive care, as no specific antidotes are currently available. This study aimed to evaluate the efficacy of potential therapeutic interventions to mitigate NH₃-induced damage using both in vivo (mouse) and in vitro (A549 alveolar epithelial cells) models.

Methods: BALB/c mice received 91.0 mg/kg NH₃ via intratracheal instillation, followed by intraperitoneal dexamethasone (100 mg/kg) at 1, 5, and 23 h post-exposure to assess therapeutic effects. Analyses were performed on days 1 and 7. The complementary studies in A549 cells examined whether therapeutic interventions could counteract NH₃-induced toxicity affecting cell viability and function.

Results: Dexamethasone-treatment did not counteract the lethal damage in mice or significantly reduce the severity of ALI that intensified over time, including increased lung inflammatory cell infiltration, lung hemorrhages, and coagulation abnormalities. However, treatment reduced methacholine-induced AHR, and MMP-9 and SP-D levels at 20h post-exposure. Most treatments in A549 cells failed to prevent apoptotic and necrotic cell death, oxidative stress, mitochondrial dysfunction, and membrane damage caused by NH₃ exposure however, the membrane stabilizer Poloxamer 188 (P188) highlighted the importance of stabilizing the cellular membrane damage to prevent further damages.

Conclusions: While standard treatment with corticosteroids offered limited protection in NH₃-exposed mice, the study's complementary in vitro investigations on new medical counter measures highlighted the complexity and severity of NH₃-induced lung injury. Together, the in vivo and in vitro findings emphasize the urgent need for effective medical countermeasures.

Objective: Vaping's perception as a safe method of nicotine consumption has contributed to its widespread use among American youth. Research indicates that serious lung disease termed EVALI (E-cigarette or Vaping Product Use-Associated Lung Injury) can develop from vaping. However, the broader consequences on lung health remain less understood.

Methods: We evaluated the effects of vaping on college students' lungs using fractional exhaled nitric oxide (FeNO) scores, metal concentrations, and microbiota composition collected over three months.

Results and discussion: Mass spectrometry analysis of vape coils revealed that ceramic coils contained higher levels of metals Mg, Al, Cr, Mn, Fe, Ni, As, Sr, Ag, and Ti, while mesh coils had elevated concentrations of Cu, Cd, Pb, and Sn. Corresponding metals were detected in participants' exhaled breath, with vaping status and coil type significantly influencing heavy metal profiles, and FeNO contributing among vapers. FeNO levels positively correlated with vaping duration, indicating effects on airway inflammation. Analysis of exhaled microbiota showed that temporal variation (sampling month) and, among vapers, duration of vaping had stronger influences on microbial composition than vaping status or coil type, while FeNO had minimal impact. Specific metals, including Al, Fe, Co, Zn, and Zr, were modestly associated with microbial patterns, with Zn and Fe showing the strongest effects.

Conclusions: These findings identified three interconnected effects of vaping: lung inflammation, heavy metal exposure from heating coils, and changes in lung microbiota. This highlights the need for further research to clarify the mechanisms linking these outcomes.

Objective: Phosgene is a highly toxic asphyxiating gas and also an important chemical raw material. Phosgene has been regarded as an environmental pollutant, and the accidental leakage of phosgene in the process of industrial production has posed a serious threat to related occupational groups. Phosgene exposure may lead to acute lung injury (ALI), marked by inflammation, heightened vascular permeability, and potentially life-threatening pulmonary edema. BML-111 is a lipid A4 receptor agonist which is compound with anti-inflammatory and antioxidant properties. The involvement of BML-111 in mitigating phosgene-induced ALI and the underlying mechanisms remain unclear.

Methods: In this study, we established a phosgene induced ALI rat model, examined the effects of phosgene exposure on lung tissue and bronchoalveolar lavage fluid (BALF) of rats, and evaluated the lung tissue pathology, lung wet weight, lung coefficient and respiratory function of phosgene exposed rats after intervention with BML-111. The levels of pro-inflammatory cytokines and oxidative stress markers were measured in BALF and lung tissue.

Results: This study showed that BML-111 notably enhanced respiratory function, mitigated ALI severity, and reduced pulmonary edema in phosgene-exposed rats. Mechanistically, these protective effects were attributed to a reduction in pro-inflammatory cytokines and oxidative stress, alongside an enhancement of overall antioxidant capacity. Furthermore, it was found that the activation of ACE2 is a key mechanism through which BML-111 exerts its protection.

Conclusion: The findings suggest that BML-111 can alleviate phosgene-induced ALI in rats by activating ACE2, thereby inhibiting inflammatory responses and oxidative stress. BML-111 shows promise as a preventive candidate for treating phosgene-induced ALI.

Objective: To investigate the associations between long-term exposure to ambient air pollutants and incident cardiovascular disease (CVD) in a high-exposure setting and to evaluate whether multimorbidity affects this relationship in middle-aged and older Chinese individuals.

Methods: Data from 7,692 adults in the China Health and Retirement Longitudinal Study (CHARLS), with up to 8 years of follow-up, were used. Long-term exposure to particulate matter ≤1 μm (PM₁), ≤2.5 μm (PM₂.₅), ≤10 μm (PM₁₀), nitrogen dioxide (NO₂), and ozone (O₃) was analyzed using high-resolution satellite-based estimates. Next, a least absolute shrinkage and selection operator regression multipollutant index was constructed. Hazard ratios for incident CVD were estimated using Cox proportional hazards models, and effect modification by multimorbidity was examined.

Results: During follow-up, a total of 1,759 participants developed CVD. Compared with those in the lowest quartile, participants in the highest quartile of PM₁, PM₂.₅, PM₁₀, and NO₂ exposure had hazard ratios of 1.35 (95% CI: 1.18-1.54), 1.58 (95% CI: 1.38-1.81), 1.63 (95% CI: 1.42-1.87), and 1.25 (95% CI: 1.09-1.44), respectively. Combined multipollutant exposure had the strongest effect, with an HR of 2.05 (95% CI: 1.78-2.37). The corresponding HRs were 2.27 (95% CI: 1.89-2.72) among participants without multimorbidity and 3.02 (95% CI: 2.44-3.73) among those with multimorbidity (P for interaction = 0.029).

Conclusion: Long-term exposure to ambient air pollutants is associated with a substantially increased risk of CVD, particularly among individuals with multimorbidity. These findings highlight the need for multipollutant control strategies and targeted prevention efforts among clinically vulnerable populations.

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.

Electronic nicotine delivery systems (ENDS) arrived on the U.S. market in 2007 and rapidly grew in popularity as a harm reduction tool for traditional cigarette users. While initially marketed as a healthier alternative to combustible cigarettes, the unique mixture of chemical constituents in ENDS products and their emissions have led to rising concern about their safety and the long-term health implications. Given the lack of long-term, epidemiological research on the health effects of these products, recent research has sought to understand the impacts on cellular components and gain understanding of acute effects to inform potential chronic health implications. Studies have demonstrated the deleterious effects the use of ENDS has on the oral cavity, respiratory, and cardiovascular systems. ENDS use has been linked to gingival inflammation and alterations in the oral microbiome contributing to periodontal disease. Further, the presence of heavy metals and other constituents in ENDS emissions contribute to aberrant oxidative stress and inflammation within the lung, contributing to alterations in functional lung capacity and respiratory symptoms in ENDS users. In addition, harmful components of ENDS emissions make their way to the circulatory system, leading to detrimental impacts in cardiovascular functioning such as a rise in blood pressure, impaired vascular functioning, and increased heart rate, all of which are known to underscore long-term cardiovascular ailments. This review will provide an in-depth discussion of the current literature available on the consequences of ENDS use on the oral cavity, respiratory, and cardiovascular systems as well as provide insight into long-term implications that may result.