Short-term Inhalation Exposure Research Articles

Investigation of pulmonary inflammatory responses following intratracheal instillation of and inhalation exposure to polypropylene microplastics

BackgroundMicroplastics have been detected in the atmosphere as well as in the ocean, and there is concern about their biological effects in the lungs. We conducted a short-term inhalation exposure and intratracheal instillation using rats to evaluate lung disorders related to microplastics. We conducted an inhalation exposure of polypropylene fine powder at a low concentration of 2 mg/m3 and a high concentration of 10 mg/m3 on 8-week-old male Fischer 344 rats for 6 h a day, 5 days a week for 4 weeks. We also conducted an intratracheal instillation of polypropylene at a low dose of 0.2 mg/rat and a high dose of 1.0 mg/rat on 12-week-old male Fischer 344 rats. Rats were dissected from 3 days to 6 months after both exposures, and bronchoalveolar lavage fluid (BALF) and lung tissue were collected to analyze lung inflammation and lung injury.ResultsBoth exposures to polypropylene induced a persistent influx of inflammatory cells and expression of CINC-1, CINC-2, and MPO in BALF from 1 month after exposure. Genetic analysis showed a significant increase in inflammation-related factors for up to 6 months. The low concentration in the inhalation exposure of polypropylene also induced mild lung inflammation.ConclusionThese findings suggest that inhaled polypropylene, which is a microplastic, induces persistent lung inflammation and has the potential for lung disorder. Exposure to 2 mg/m3 induced inflammatory changes and was thought to be the Lowest Observed Adverse Effect Level (LOAEL) for acute effects of polypropylene. However, considering the concentration of microplastics in a real general environment, the risk of environmental hazards to humans may be low.

Short-term inhalation exposure to cigarette smoke induces oxidative stress and inflammation in lungs without systemic oxidative stress in mice.

Smoking is a well-established risk factor for various pathologies, including pulmonary diseases, cardiovascular disorders, and cancers. The toxic effects of cigarette smoke (CS) are mediated through multiple pathways and diverse mechanisms. A key pathogenic factor is oxidative stress, primarily induced by excessive formation of reactive oxygen species. However, it remains unclear whether smoking directly induces systemic oxidative stress or if such stress is a secondary consequence. This study aimed to determine whether short-term inhalation exposure to CS induces oxidative stress in extrapulmonary organs in addition to the lung in a murine model. In the experiment, 3R4F reference cigarettes were used to generate CS, and 8-week-old male BALB/c mice were exposed to CS at a total particulate matter concentration of either 0 or 800µg/L for four consecutive days. CS exposure led to an increase in neutrophils, eosinophils, and total cell counts in bronchoalveolar lavage fluid. It also elevated levels of lactate dehydrogenase and malondialdehyde (MDA), markers indicative of tissue damage and oxidative stress, respectively. Conversely, no significant changes were observed in systemic oxidative stress markers such as total oxidant scavenging capacity, MDA, glutathione (GSH), and the GSH/GSSG ratio in blood samples. In line with these findings, CS exposure elevated NADPH oxidase (NOX)-dependent superoxide generation in the lung but not in other organs like the liver, kidney, heart, aorta, and brain. Collectively, our results indicate that short-term exposure to CS induces inflammation and oxidative stress in the lung without significantly affecting oxidative stress in extrapulmonary organs under the current experimental conditions. NOX may play a role in these pulmonary-specific events.

Impact of inhalation exposure to cigarette smoke on the pathogenesis of pulmonary hypertension primed by monocrotaline in rats.

Extensive, long-term exposure to cigarette smoke (CS) was recently suggested to be a risk factor for pulmonary hypertension, although further validation is required. The vascular effects of CS share similarities with the etiology of pulmonary hypertension, including vascular inflammation and remodeling. Thus, we examined the influence of CS exposure on the pathogenesis of monocrotaline (MCT)-induced pulmonary hypertension, hypothesizing that smoking might accelerate the development of primed pulmonary hypertension. CS was generated from 3R4F reference cigarettes, and rats were exposed to CS by inhalation at total particulate matter concentrations of 100-300 μg/L for 4h/day, 7days/week for 4weeks. Following 1 week of initial exposure, rats received 60 mg/kg MCT and were sacrificed and analyzed after an additional 3weeks of exposure. MCT induced hypertrophy in pulmonary arterioles and increased the Fulton index, a measure of right ventricular hypertrophy. Additional CS exposure exacerbated arteriolar hypertrophy but did not further elevate the Fulton index. No significant alterations were observed in levels of endothelin-1 and vascular endothelial growth factor, or in hematological and serum biochemical parameters. Short-term inhalation exposure to CS exacerbated arteriolar hypertrophy in the lung, although this effect did not directly aggravate the overworked heart under the current experimental conditions.

Indoor dryness and humidification-induced arsenic inhalation exposure above 4200 m in Ngari, China.

Ngari Prefecture, Tibet, China, features its ultrahigh altitude above 4200 m, very little annual precipitation and extremely low relative humidity. Residents who have migrated to Tibet from the plains use indoor humidification to reduce the respiratory discomfort caused by prolonged exposure to dry indoor air. In this study, field investigations and analysis of residential indoor environments and humidification methods in Ngari Prefecture revealed that ninety-eight percent of humidifier consumers in the prefecture used low-cost ultrasonic humidifiers filled with indoor tap water. The results revealed that the arsenic (As) concentration of the tap water was 41.6μg/L, over four times China's standards for drinking water quality (10μg/L). The source As concentration in the air humidified by the tap water-filled ultrasonic humidifier is (619.8 ± 59.1) (ng/m3 ·air), while no As was detected in the air humidified by the evaporative humidifier. For ultrasonic humidifier with tap water-filled, the inhalation dose of a healthy adult was 45.4ng/d. The minute ventilation volume of migrated residents who had been in Ngari for less than two years (12.5 ± 4.3L/min) was greater than those of the long-term residents (10.0 ± 4.5L/min), which may exacerbate the short-term inhalation exposure risk for migrated residents. To reduce the health risks associated with As exposure, evaporative humidifiers are recommended for households using domestic water. If ultrasonic humidifiers are used, the tap water must be purified with terminal filters.

Short-term inhalation exposure evaluations of airborne antibiotic resistance genes in environments

Antibiotic resistance is a sword of Damocles that hangs over humans. In regards to airborne antibiotic resistance genes (AARGs), critical knowledge gaps still exist in the identification of hotspots and quantification of exposure levels in different environments. Here, we have studied the profiles of AARGs, mobile genetic elements (MGEs) and bacterial communities in various atmospheric environments by high throughput qPCR and 16S rRNA gene sequencing. We propose a new AARGs exposure dose calculation that uses short-term inhalation (STI). Swine farms and hospitals were high-risk areas where AARGs standardised abundance was more abundant than suburbs and urban areas. Additionally, resistance gene abundance in swine farm worker sputum was higher than that in healthy individuals in other environments. The correlation between AARGs with MGEs and bacteria was strong in suburbs but weak in livestock farms and hospitals. STI exposure analysis revealed that occupational intake of AARGs (via PM10) in swine farms and hospitals were 110 and 29 times higher than in suburbs, were 1.5 × 104, 5.6 × 104 and 5.1 × 102 copies, i.e., 61.9%, 75.1% and 10.7% of the overall daily inhalation intake, respectively. Our study comprehensively compares environmental differences in AARGs to identify high-risk areas, and forwardly proposes the STI exposure dose of AARGs to guide risk assessment.

Response biomarkers of inhalation exposure to cigarette smoke in the mouse lung.

Cigarette smoking is known to increase the risk of cancer and chronic obstructive pulmonary disease (COPD). In this study, we evaluated the effects of short-term nose-only inhalation exposure to cigarette smoke in mice. Male 10-week-old C57BL mice were exposed to clean air (control) or mainstream cigarette smoke for 1 h/day, 5 days/week, for 2 or 4 weeks. Exposure to cigarette smoke increased the number of inflammatory cells, especially neutrophils, in the bronchoalveolar lavage fluid, increased inflammatory cell infiltration foci, and caused an increase in the thickness of the peripheral bronchial epithelium. Microarray gene expression analysis indicated that smoke exposure induced inflammatory responses, including leukocyte migration and activation of phagocytes and myeloid cells, as early as two weeks after the initiation of exposure. Importantly, chemokine (C-C motif) ligand 17, resistin-like alpha, and lipocalin 2 were upregulated and may serve as useful markers of the toxic effects of exposure to cigarette smoke before pulmonary histological changes become evident.

Application of Meta-Analysis to Derivation of Points-of-Departure for Short-Term Inhalation Exposure Levels of Hazardous Chemicals

BACKGROUND AND AIM: For short-term chemical inhalation exposures to hazardous chemicals, the incidence of a health effect usually conforms to a generalized linear model with a bivariate probit link function dependent on inhalant concentration ({C}) and the duration of exposure ({t}). The National Academy’s Acute Exposure Guideline Levels (AEGLs) Committee relies on this model when deriving AEGLs. Threshold concentrations at AEGL durations are established by the toxic load equation, {C}^{n} x {t} = {constant}, which Toxic Load Exponent {n} (TLE or {n}-value) directly follows from the probit model. When multiple probit datasets are available, often they cannot be directly pooled together because of disparities in experimental design. METHODS: Recently, we reported both a meta-analytical framework for multiple studies and an application of the new methodology to dimethyl sulfide. The new methodology allows accurate TLE estimation even if multiple datasets are heterogenous. The utilized techniques include categorical regression, common-effect and random-effects models. The proposed framework was applied to multiple-study datasets from AEGL technical support documents. RESULTS:Using the framework, both new TLEs and confidence intervals on them were derived. The recalculated TLEs and points-of-departure include ammonia ({n} = 2.13, 95% CI: 1.98–2.27), allyl alcohol ({n} = 0.95, 95% CI: 0.76–1.15), 1,1,1-trichloroethane ({n} = 3.46, 95% CI: 2.85–4.07 ), carbon tetrachloride ({n} = 2.51, 95% CI: 2.27–2.76), and oxygen difluoride ({n} = 1.29, 95% CI: 0.26–2.32). CONCLUSIONS:The new TLEs and their confidence intervals were applied in calculations of short-term inhalation points of departure at five reference AEGL durations. Disclaimer: The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry and should not be construed to represent any agency determination or policy. KEYWORDS: Risk Assessment, Meta-analysis, Toxic Load Exponent (TLE), n-value, Probit, Categorical Regression

Identification, Quantification, and Imaging of the Biodistribution of Soot Particles by Mass Spectral Fingerprinting.

Soot is ubiquitous and has large detrimental effects on climate, air quality, and human health. However, identification of soot in carbonaceous media is very challenging due to its nanoscale carbon nature and complex sources. Due to the shortage in the methodology, until now, the fate and health effect of soot particles after inhalation are still poorly understood. Here, we report a new method for label-free identification, quantification, and imaging of soot particles in complex media based on laser desorption/ionization mass spectrometry fingerprinting. We found that soot particles from different origins and with different morphologies showed highly consistent mass spectral fingerprints deriving from peak ratios of small carbon cluster anions (C2--C10-), which enabled both accurate quantification of soot in fine particulate matter (PM2.5) samples and label-free imaging of soot particles in biological media. By using this technique, we tracked and imaged the suborgan distribution of soot particles in mice after exposure to PM2.5. The results showed that the lung is the main target organ for short-term inhalation exposure to soot particles. This study helps to better understand the inhalation toxicology of soot and also provides a practical novel methodological platform for identification, tracing, and toxicological studies of elemental carbon-based nanomaterials.

Pulmonary toxicity and gene expression changes after short-term inhalation exposure to surface-modified copper oxide nanoparticles

Copper oxide nanoparticles (CuO NPs) have previously been shown to cause dose-dependent pulmonary toxicity following inhalation. Here, CuO NPs (10 nm), coated with polyethylenimine (PEI) or ascorbate (ASC) resulting in positively or negatively charged NPs, respectively, were evaluated. Rats were exposed nose-only to similar exposure dose levels of ASC or PEI coated CuO NPs for 5 consecutive days. On day 6 and day 27 post-exposure, pulmonary toxicity markers in bronchoalveolar lavage fluid (BALF), lung histopathology and genome-wide transcriptomic changes in lungs, were assessed. BALF analyses showed a dose-dependent pulmonary inflammation and cell damage, which was supported by the lung histopathological findings of hypertrophy/hyperplasia of bronchiolar and alveolar epithelium, interstitial and alveolar inflammation, and paracortical histiocytosis in mediastinal lymph nodes for both types of CuO NPs. Transcriptomics analysis showed that pathways related to inflammation and cell proliferation were significantly activated. Additionally, we found evidence for the dysregulation of drug metabolism-related genes, especially in rats exposed to ASC-coated CuO NPs. Overall, no differences in the type of toxic effects and potency between the two surface coatings could be established, except with respect to the (regional) dose that initiates bronchiolar and alveolar hypertrophy. This disproves our hypothesis that differences in surface coatings affect the pulmonary toxicity of CuO NPs.

Meta-analysis of animal studies applied to short-term inhalation exposure levels of hazardous chemicals

For short-term chemical inhalation exposures to hazardous chemicals, the incidence of a health effect in biological testing usually conforms to a general linear model with a probit link function dependent on inhalant concentration C and the duration of exposure t. The National Academy's Acute Exposure Guideline Levels (AEGLs) Committee relies on these models when establishing AEGLs. Threshold concentrations at AEGL durations are established by the toxic load equation Cn x t = constant, which toxic load exponent n (TLE or n-value) directly follows from the bivariate probit model. When multiple probit datasets are available, the AEGL Committee routinely pools studies' incidence data. Such meta-analytical models are valid only when the pooled data are homogeneous, with similar sensitivities and equivalent responses to exposure concentrations and durations. In the present study, the homogeneity of datasets meta-analyzed by the AEGL Committee was examined, finding that 70% of datasets pooled by the AEGL Committee are heterogeneous. In these instances, data pooling leads to a statistically invalid model and TLE estimate, potentially resulting in under- or over-estimated inhalation guidance levels. When data pooling is inappropriate, other meta-analysis options include categorical regression, fixed-effect and random-effects models, or even designation of a key study based on scientific judgement. In the present work, options of TLE meta-analysis are summarized in a decision tree contingent on statistical testing.

Volatile Organic Compound (VOC) Emissions from a Personal Care Polymer-Based Item: Simulation of the Inhalation Exposure Scenario Indoors under Actual Conditions of Use

Polymer-based items may release Volatile Organic Compounds (VOCs) and odors indoors, contributing to the overall VOC inhalation exposure for end users and building occupants. The main objective of the present study is the evaluation of short-term inhalation exposure to VOCs due to the use of a personal care polymer-based item, namely, one of three electric heating bags, through a strategic methodological approach and the simulation of a ‘near-to-real’ exposure scenario. Seventy two-hour test chamber experiments were first performed to characterize VOC emissions with the items on ‘not-heating mode’ and to derive related emission rates. The polyester bag was revealed to be responsible for the highest emissions both in terms of total VOC and naphthalene emissions (437 and 360 µg/m3, respectively), compared with the other two bags under investigation. Complementary investigations on ‘heating mode’ and the simulation of the exposure scenario inside a 30 m3 reference room allowed us to highlight that the use of the polyester bag in the first life-cycle period could determine a naphthalene concentration (42 µg/m3) higher than the reference Lowest Concentration of Interest (LCI) value (10 µg/m3) reported in European evaluation schemes. The present study proposes a strategic methodological approach highlighting the need for the simulation of a realistic scenario when potential hazards for human health need to be assessed.

Appearance of Alveolar Macrophage Subpopulations in Correlation With Histopathological Effects in Short-Term Inhalation Studies With Biopersistent (Nano)Materials.

Following inhalation and deposition in the alveolar region at sufficient dose, biopersistent (nano)materials generally provoke pulmonary inflammation. Alveolar macrophages (AMs) are mediators of pulmonary immune responses and were broadly categorized in pro-inflammatory M1 and anti-inflammatory M2 macrophages. This study aimed at identifying AM phenotype as M1 or M2 upon short-term inhalation exposure to different (nano)materials followed by a postexposure period. Phenotyping of AM was retrospectively performed using immunohistochemistry. M1 (CD68+iNOS+) and M2 (CD68+CD206+ and CD68+ArgI+) AMs were characterized in formalin-fixed, paraffin-embedded lung tissue of rats exposed for 6 hours/day for 5 days to air, 100 mg/m3 nano-TiO2, 25 mg/m3 nano-CeO2, 32 mg/m3 multiwalled carbon nanotubes, or 100 mg/m3 micron-sized quartz. During acute inflammation, relative numbers of M1 AMs were markedly increased, whereas relative numbers of M2 were generally decreased compared to control. Following an exposure-free period, changes in iNOS or CD206 expression correlated with persistence, regression, or progression of inflammation, suggesting a role of M1/M2 AMs in the pathogenesis of pulmonary inflammation. However, no clear correlation of AM subpopulations with qualitatively distinct histopathological findings caused by different (nano)materials was found. A more detailed understanding of the processes underlaying these morphological changes is needed to identify biomarkers for different histopathological outcomes.

Selective memory and behavioral alterations after ambient ultrafine particulate matter exposure in aged 3xTgAD Alzheimer\u2019s disease mice

BackgroundA growing body of epidemiological literature indicates that particulate matter (PM) air pollution exposure is associated with elevated Alzheimer’s disease (AD) risk and may exacerbate AD-related cognitive decline. Of concern is exposure to the ultrafine PM (UFP) fraction (≤100 nm), which deposits efficiently throughout the respiratory tract, has higher rates of translocation to secondary organs, like brain, and may induce inflammatory changes. We, therefore, hypothesize that exposure to UFPs will exacerbate cognitive deficits in a mouse model of AD. The present study assessed alterations in learning and memory behaviors in aged (12.5 months) male 3xTgAD and non-transgenic mice following a 2-week exposure (4-h/day, 4 days/week) to concentrated ambient UFPs using the Harvard ultrafine concentrated ambient particle system (HUCAPS) or filtered air. Beginning one month following exposure, locomotor activity, spatial learning and memory, short-term recognition memory, appetitive motivation, and olfactory discrimination were assessed.ResultsNo effects on locomotor activity were found following HUCAPS exposure (number concentration, 1 × 104–4.7 × 105 particles/cm3; mass concentration, 29–132 μg/m3). HUCAPS-exposed mice, independent of AD background, showed a significantly decreased spatial learning, mediated through reference memory deficits, as well as short-term memory deficits in novel object recognition testing. AD mice displayed diminished spatial working memory, potentially a result of olfactory deficits, and short-term memory. AD background modulated HUCAPS-induced changes on appetitive motivation and olfactory discrimination, specifically enhancing olfactory discrimination in NTg mice. Modeling variation in appetitive motivation as a covariate in spatial learning and memory, however, did not support the conclusion that differences in motivation significantly underlie changes in spatial learning and memory.ConclusionsA short-term inhalation exposure of aged mice to ambient UFPs at human-relevant concentrations resulted in protracted (testing spanning 1–6.5 months post-exposure) adverse effects on multiple memory domains (reference and short-term memory) independent of AD background. Impairments in learning and memory were present when accounting for potential covariates like motivational changes and locomotor activity. These results highlight the need for further research into the potential mechanisms underlying the cognitive effects of UFP exposure in adulthood.

Graphene Nanobuds: A New Second-Generation Phosgene Sensor with Ultralow Detection Limit in Aqueous Solution.

Selective and sensitive detection of highly toxic chemicals by a suitable, fast, inexpensive, and trustworthy method is vital due to its serious health threats to humankind and breach of public security caused by unexpected terrorist attacks and industrial accidents. Phosgene or carbonyl dichloride is widely employed in many chemical industries and pharmaceuticals, and in pesticide production, which is extremely toxic by severe (short-term) inhalation exposure. Because of the non-existence of a phosgene sensor in aqueous solution and the immense emphasis gained by nanomaterials, especially carbonaceous materials, augmented attention has been given to the development of a fluorophore-functionalized carbon-based method to detect this noxious substance. In this study, surfactant free 1,8-diaminonaphthalene (DAN)-functionalized graphene quantum dots (DAN-GQDs) were prepared to detect phosgene in aqueous solution. The FESEM (field emission scanning electron microscopy) and HRTEM (high-resolution transmission electron microscopy) analyses confirm the as-prepared DAN-GQD morphology as nanobuds (NBs) with an average diameter of ca. 35-40 nm. The crystalline nature, elemental composition, and chemical state of DAN-GQDs were analyzed by standard physiochemical techniques. The edge-termination at the carboxyl functional group of GQDs with DAN was examined by XPS, Raman, FT-IR, and 1H NMR spectroscopy analyses. The aqueous solution of DAN-GQDs (4.89 × 10-9 M) exhibits a strong emission peak at 423 nm upon excitation at 328 nm. The addition of the phosgene molecule (0 → 88 μL) quenches the initial fluorescence intensity of DAN-GQDs (ΦF 53.6 → 34.6%) through the formation of a stable six-membered cyclized product. The DAN-GQDs displayed excellent selectivity and sensitivity for phosgene ( Ka = 3.84 × 102 M-1 and LoD (limit of detection) = 2.26 ppb) over other competing toxic pollutants in water. The time-resolved fluorescence analysis confirms that the quenching of DAN-GQDs follows nonradiative relaxation of excited electrons. Furthermore, bioimaging experiments of phosgene in living human breast cancer (HeLa) cells and cell viability test successfully demonstrated the practicability of DAN-GQDs.

Тhe experimental assessment of NiO nanoparticles toxicity in inxalation exposure

Introduction.Nanoparticles of NiO pollute air of workplace in metallurgic production of nickel and alloyed steel (during their use in electric welding). Toxicity of NiO nanoparticles was studied in some experiments, but mechanisms underlying their toxic eff ects are not understood and require wider base of experimental data.Objective. To study toxic eff ects of NiO nanoparticles in chronic inhalation exposure.Materials and methods.Outbred female rats were subjected to repeated low-level inhalation exposure to NiO nanoparticles of 99.99% purity, measured 23±5 nm, 4 hours per day, 5 days per week, up to 10-month duration in an “only nose” device with concentration 0.2±0.01 mg/m3. To select this concentration, preliminary pilot experiment included 5-fold exposure with concentration 1.00±0.12 mg/m3.Results.NiO nanoparticles in short-term and chronic inhalation exposure aff ect lipids peroxidation, red blood parameters, liver and kidney functions, oxidation-reduction balance. All three terms of chronic inhalation experiment cause active alveolar phagocytosis reaction, and their high cytotoxicity is proved by relation of neutrophils to alveolar macrophages and by enzymes levels in bronchoalveolar lavage.Conclusions.NiO nanoparticles if inhaled in concentration 0.2 mg/m3 cause moderate toxic eff ect in experimental animals.

Risk Analysis of Cellulose Nanomaterials by Inhalation: Current State of Science.

Cellulose nanomaterials (CNs) are emerging advanced materials with many unique properties and growing commercial significance. A life-cycle risk assessment and environmental health and safety roadmap identified potential risks from inhalation of powdered CNs in the workplace as a key gap in our understanding of safety and recommended addressing this data gap to advance the safe and successful commercialization of these materials. Here, we (i) summarize the currently available published literature for its contribution to our current understanding of CN inhalation hazard and (ii) evaluate the quality of the studies for risk assessment purposes using published study evaluation tools for nanomaterials to assess the weight of evidence provided. Our analysis found that the quality of the available studies is generally inadequate for risk assessment purposes but is improving over time. There have been some advances in knowledge about the effects of short-term inhalation exposures of CN. The most recent in vivo studies suggest that short-term exposure to CNs results in transient inflammation, similarly to other poorly soluble, low toxicity dusts such as conventional cellulose, but is markedly different from fibers with known toxicity such as certain types of multiwalled carbon nanotubes or asbestos. However, several data gaps remain, and there is still a lack of understanding of the effects from long-term, low-dose exposures that represent realistic workplace conditions, essential for a quantitative assessment of potential health risk. Therefore, taking precautions when handling dry forms of CNs to avoid dust inhalation exposure is warranted.

Inhalation of iron-abundant gas metal arc welding-mild steel fume promotes lung tumors in mice

Welding fumes were reclassified as a Group 1 carcinogen by the International Agency for Research on Cancer in 2017. Gas metal arc welding (GMAW) is a process widely used in industry. Fume generated from GMAW-mild steel (MS) is abundant in iron with some manganese, while GMAW-stainless steel (SS) fume also contains significant amounts of chromium and nickel, known carcinogenic metals. It has been shown that exposure to GMAW-SS fume in A/J mice promotes lung tumors. The objective was to determine if GMAW-MS fume, which lacks known carcinogenic metals, also promotes lung tumors in mice. Male A/J mice received a single intraperitoneal injection of corn oil or the initiator 3-methylcholanthrene (MCA; 10 μg/g) and, one week later, were exposed by whole-body inhalation to GMAW-MS aerosols for 4 hours/day x 4 days/week x 8 weeks at a mean concentration of 34.5 mg/m3. Lung nodules were enumerated by gross examination at 30 weeks post-initiation. GMAW-MS fume significantly increased lung tumor multiplicity in mice initiated with MCA (21.86 ± 1.50) compared to MCA/air-exposed mice (8.34 ± 0.59). Histopathological analysis confirmed these findings and also revealed an absence of inflammation. Bronchoalveolar lavage analysis also indicated a lack of lung inflammation and toxicity after short-term inhalation exposure to GMAW-MS fume. In conclusion, this study demonstrates that inhalation of GMAW-MS fume promotes lung tumors in vivo and aligns with epidemiologic evidence that shows MS welders, despite less exposure to carcinogenic metals, are at an increased risk for lung cancer.

Transcriptional profiling reveals gene expression changes associated with inflammation and cell proliferation following short-term inhalation exposure to copper oxide nanoparticles.

Our recent studies revealed a dose-dependent proinflammatory response to copper oxide nanoparticles (CuO NPs) in rats following short-term inhalation exposure for five consecutive days. Here transcriptomics approaches were applied using the same model to assess global gene expression in lung tissues obtained 1 day post-exposure and after a recovery period of 22 days from rats exposed to clean air or 6 hour equivalent doses of 3.3 mg m-3 (low dose) and 13.2 mg m-3 (high dose). Microarray analyses yielded about 1000 differentially expressed genes in the high-dose group and 200 in low-dose compared to the clean air control group, and less than 20 after the recovery period. Pathway analysis indicated cell proliferation/survival and inflammation as the main processes triggered by exposure to CuO NPs. We did not find significant perturbations of pathways related to oxidative stress. Upregulation of epithelial cell transforming protein 2 (Ect2), a known oncogene, was noted and ECT2 protein was upregulated in the lungs of exposed animals. Proliferation of alveolar epithelial cells was demonstrated based on Ki67 expression. The gene encoding monocyte chemoattractant protein 1 (or CCL2) was also upregulated and this was confirmed by immunohistochemistry. However, no aberrant DNA methylation of inflammation-associated genes was observed. In conclusion, we have found that inhalation of CuO NPs in rats causes upregulation of the oncoprotein ECT2 and the chemokine CCL2 and other proinflammatory markers as well as proliferation in bronchoalveolar epithelium after a short-term inhalation exposure. Thus, pathways known to be associated with neoplastic processes and inflammation were affected in this model.

Comparison of airway response in naïve and ovalbumin-sensitized mice during short-term inhalation exposure to chlorine

Objective: It has been suggested that asthmatics are more susceptible than healthy individuals to airborne irritating chemicals in general. However, there is limited human data available to support this hypothesis due to ethical and practical difficulties. We explored a murine model of ovalbumin (OVA)-induced airway inflammation to study susceptibility during acute exposure to chemicals with chlorine as a model substance.Methods: Naïve and OVA sensitized female BALB/c mice were exposed to chlorine at four different concentrations (0, 5, 30 and 80 ppm) for 15 minutes with online recording of the respiratory function by plethysmography. The specific effects on respiratory mechanics, inflammatory cells and inflammatory mediators (cytokines and chemokines) of the airways were measured 24 hours after the chlorine exposure as well as histopathological examination of the lungs.Results: Similar concentration-dependent reductions in respiratory frequency were seen in the two groups, with a 50% reduction (RD50) slightly above 5 ppm. Decreased body weight 24 hours after exposure to 80 ppm was also observed in both groups. Naïve, but not OVA-sensitized, mice showed increased bronchial reactivity and higher number of neutrophils in bronchoalveolar lavage fluid at 80 ppm.Conclusions: The results do not support an increased susceptibility to chlorine among OVA-sensitized mice. This animal model, which represents a phenotype of eosinophilic airway inflammation, seems unsuitable to study susceptibility to inhalation of irritants in relation to asthma.

Assessing Inhalation Exposures Associated with Contamination Events in Water Distribution Systems.

When a water distribution system (WDS) is contaminated, short-term inhalation exposures to airborne contaminants could occur as the result of domestic water use. The most important domestic sources of such exposures are likely to be showering and the use of aerosol-producing humidifiers, i.e., ultrasonic and impeller (cool-mist) units. A framework is presented for assessing the potential effects of short-term, system-wide inhalation exposures that could result from such activities during a contamination event. This framework utilizes available statistical models for showering frequency and duration, available exposure models for showering and humidifier use, and experimental results on both aerosol generation and the volatilization of chemicals during showering. New models for the times when showering occurs are developed using time-use data for the United States. Given a lack of similar models for how humidifiers are used, or the information needed to develop them, an analysis of the sensitivity of results to assumptions concerning humidifier use is presented. The framework is applied using network models for three actual WDSs. Simple models are developed for estimating upper bounds on the potential effects of system-wide inhalation exposures associated with showering and humidifier use. From a system-wide, population perspective, showering could result in significant inhalation doses of volatile chemical contaminants, and humidifier use could result in significant inhalation doses of microbial contaminants during a contamination event. From a system-wide perspective, showering is unlikely to be associated with significant doses of microbial contaminants. Given the potential importance of humidifiers as a source of airborne contaminants during a contamination event, an improved understanding of the nature of humidifier use is warranted.