Lower or higher oxygenation targets in the intensive care unit: an individual patient data meta-analysis.

PURPOSE: Optimal oxygenation targets for patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are not clearly defined due to substantial variability in design of previous trials. This study aimed to perform a pre-specified individual patient data meta-analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) and the Handling Oxygenation Targets in coronavirus disease 2019 (COVID-19) (HOT-COVID) trials to compare targeting a partial pressure of arterial oxygen (PaO2) of 8-12 kPa in adult ICU patients, assessing both benefits and harms. METHODS: We assessed 90-day all-cause mortality and days alive without life support in 90 days using a generalised mixed model. Heterogeneity of treatment effects (HTE) was evaluated in 14 subgroups, and results graded using the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN). RESULTS: At 90 days, mortality was 40.4% (724/1792) in the 8 kPa group and 40.9% (733/1793) in the 12 kPa group (risk ratio, 0.99; 95% confidence interval [CI] 0.92-1.07; P = 0.80). No difference was observed in number of days alive without life support. Subgroup analyses indicated more days alive without life support in COVID-19 patients targeting 8 kPa (P = 0.04) (moderate credibility), and lower mortality (P = 0.03) and more days alive without life support (P = 0.02) in cancer-patients targeting 12 kPa (low credibility). CONCLUSION: This study reported no overall differences comparing a PaO2 target of 8-12 kPa on mortality or days alive without life support in 90 days. Subgroup analyses suggested HTE in patients with COVID-19 (moderate credibility) and cancer (low credibility).

Toxicity and biokinetics following pulmonary exposure to aluminium (aluminum): A review.

During the manufacture and use of aluminium (aluminum), inhalation exposure may occur. We reviewed the pulmonary toxicity of this metal including its toxicokinetics. The normal serum/plasma level based on 17 studies was 5.7 ± 7.7µg Al/L (mean ± SD). The normal urine level based on 15 studies was 7.7 ± 5.3µg/L. Bodily fluid and tissue levels during occupational exposure are also provided, and the urine level was increased in aluminium welders (43 ± 33µg/L) based on 7 studies. Some studies demonstrated that aluminium from occupational exposure can remain in the body for years. Excretion pathways include urine and faeces. Toxicity studies were mostly on aluminium flakes, aluminium oxide and aluminium chlorohydrate as well as on mixed exposure, e.g. in aluminium smelters. Endpoints affected by pulmonary aluminium exposure include body weight, lung function, lung fibrosis, pulmonary inflammation and neurotoxicity. In men exposed to aluminium oxide particles (3.2µm) for two hours, lowest observed adverse effect concentration (LOAEC) was 4mg Al2O3/m3 (= 2.1mg Al/m3), based on increased neutrophils in sputum. With the note that a similar but not statistically significant increase was seen during control exposure. In animal studies LOAECs start at 0.3mg Al/m3. In intratracheal instillation studies, all done with aluminium oxide and mainly nanomaterials, lowest observed adverse effect levels (LOAELs) started at 1.3mg Al/kg body weight (bw) (except one study with a LOAEL of ~0.1mg Al/kg bw). The collected data provide information regarding hazard identification and characterisation of pulmonary exposure to aluminium.

Evaluation of airborne asbestos concentrations associated with the maintenance of brakes on an industrial overhead crane.

OBJECTIVES: To evaluate potential airborne asbestos exposures during brake maintenance and repair activities on a P&H overhead crane, and during subsequent handling of the mechanic's clothing. METHODS: Personal (n = 27) and area (n = 61) airborne fiber concentrations were measured during brake tests, removal, hand sanding, compressed air use, removal and reattachment of chrysotile-containing brake linings, and reinstallation of the brake linings. The mechanic's clothing was used to measure potential exposure during clothes handling. RESULTS: All brake linings contained between 19.9% to 52.4% chrysotile asbestos. No amphibole fibers were detected in any bulk or airborne samples. The average full-shift airborne chrysotile concentration was 0.035 f/cc (PCM-equivalent asbestos-specific fibers, or PCME). Average task-based personal air samples collected during brake maintenance, sanding, compressed air use, and brake lining removal tasks ranged from 0 to 0.48 f/cc (PCME). The calculated 30-minute time-weighted average (TWA) airborne chrysotile concentration associated with 5-15 minutes of clothes handling was 0-0.035 f/cc PCME. CONCLUSION: The results indicated that personal and area TWA fiber concentrations measured during all crane brake maintenance and clothes handling tasks were below the current OSHA 8-h TWA Permissible Exposure Limit for asbestos of 0.1 f/cc. Further, no airborne asbestos fibers were measured during routine brake maintenance tasks following the manufacturer's maintenance manual procedures. All short-term airborne chrysotile concentrations measured during non-routine tasks were below the current 30-minute OSHA excursion limit for asbestos of 1 f/cc. This study adds to the available data regarding chrysotile exposure potential during maintenance on overhead cranes.

Genotoxicity of Formaldehyde: Effect of Whole-Body Exposure on Polychromatic Erythrocyte/Normochromatic Erythrocyte Ratio in Male and Female Rats.

Every day, millions of individuals are exposed to formaldehyde (FA) due to its extensive presence and versatile use. Many in vivoand in vitroexperiments revealed that the mechanism of genotoxicity induced by FA exposure is complex yet toxicity upon whole-body exposure (WBE) to FA is less. As teachers, students, and skilled assistants in the health care sectors are also extensively exposed to FA vapors, it might result in genotoxicity. However, the effects of subchronic exposure to FA at low concentrations are not clear. Hence, analysis of the micronucleus (MN) was necessary to study the genetic toxicity triggered by FA in the bone marrow of male and female experimental rats. The present study is a gender- and duration of exposure-based assessment of the geno- and cytotoxicity in bone marrow cells of Wistar rats to study the effect of WBE to 10% FA on polychromatic erythrocytes/normochromatic erythrocytes (PCE/NCE) ratio and micronucleated polychromatic erythrocytes (MnPCE) in experimental rats. The obtained result clearly showed that WBE to FA for 60 days at concentrations between 1 and 1.1 ppm (0, 1, and 1.5 h) induced genotoxic effects in both male and female rats by altering the MnPCE% and significantly increasing the ratio of PCE/NCE (1.07 ± 0.23, 1.20 ± 0.20, 1.22 ± 0.14). The PCE/NCE ratio in male rats was lesser (0.98, 1.12, and 1.18) when compared with female rats (1.17, 1.29, and 1.26) with 0, 1, and 1.5 h exposure, respectively. Thus, the genetic/cellular sensitivity to FA differs among the sexes and also depends on the exposure duration.

Real time monitoring of carbon dioxide levels in surgical helmet systems worn during hip and knee arthroplasty.

Background: Orthopaedic surgical helmet systems (SHS) rely on an intrinsic fan to force clean external air over the wearer. Carbon dioxide (CO2) is produced through aerobic metabolism and can potentially accumulate inside the SHS. Levels above 2500 ppm have previously been shown to affect cognitive and practical function. Maximum Health and Safety Executive (HSE) 8-h exposure limit is 5000 ppm. There is a paucity of data on real-world CO2 levels experienced during arthroplasty surgery whilst wearing a SHS. Objectives: To determine intra-operative levels of CO2 experienced within SHS. Methods: CO2 levels were continuously recorded during 30 elective arthroplasties, both primary and revision. Data was recorded at 0.5Hz throughout the procedure utilising a Bluetooth CO2 detector, worn inside a surgical helmet worn with a toga gown. Five surgeons contributed real time data to the study. Results: The average CO2 level across all procedures was 3006 ppm, with 23 of the cases measured within the surgeons' helmets having a mean above 2500 ppm, but none having a mean above 5000 ppm. For each procedure, the time spent above 2500 and 5000 ppm was calculated, with the means being 72.6 % and 5.4 % respectively. Minimum fan speed was associated with only a marginally higher mean CO2 value than maximum fan speed. Discussion: The use of surgical helmet systems for elective orthopaedic surgery, can result in CO2 levels regularly rising to a point which may affect cognitive function. Conclusion: Further research is needed to corroborate these findings however, we recommend that future designs of SHS include active management of exhaust gases, possibly returning to Charnley's original design principles of the body exhaust system.

Remission of hypersensitivity pneumonitis after allogeneic hematopoietic stem cell transplantation.

A 50-year-old man was diagnosed with hypersensitivity pneumonitis caused by the environment of his bar owing to worsening symptoms, laboratory test results, and computed tomography images after an environmental inhalation challenge test. His hypersensitivity pneumonitis exacerbated despite receiving prednisolone 20 mg/day. The patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor for myelodysplastic syndrome. No exacerbation of hypersensitivity pneumonitis was observed after HSCT. An environmental inhalation challenge test involving exposure to his bar confirmed the remission of hypersensitivity pneumonitis after HSCT. This case demonstrates that hypersensitivity pneumonitis can be remitted by HSCT.

Targeting LINC070974 inhibits lung adenocarcinoma cell proliferation and progression by interacting with Y-box binding protein 1.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Increasing evidence suggests that long noncoding RNAs play crucial roles in lung cancer pathogenesis. We previously identified a novel lncRNA, LINC070974, which is associated with tumor cell proliferation. In the present study, we find that knockdown of LINC070974 inhibits cell proliferation, migration and invasion as well as tumor formation both in vitro and in nude mice. LINC070974 silencing also improves cisplatin efficacy in A549/DDP cells. The function of LINC070974 may depend on its interaction with YBX1. Knockdown of LINC070974 reduces the recruitment of YBX1 to the CCND1 promoter and delays tumor progression through its coregulatory genes, which are mainly involved in the p53 signaling pathway. We utilize nebulized inhalation to deliver siRNAs targeting LINC070974 and find that LINC070974 significantly prevents tumor metastasis and growth in lung tissues. These findings reveal the role of LINC070974 in lung cancer and suggest a promising therapeutic approach involving siRNA inhalation.

A National Mandate for Thermal Fuses for Home Oxygen Users is Cost-effective in the Prevention of Burn Morbidity, Mortality and Property Loss.

Smoking while using home oxygen leads to explosions which cause cutaneous burns, death, and loss of property. Thermal fuses interrupt the propagation of ignited oxygen-lines and reduce the risk of injury. Prior to mandating thermal fuses for all home oxygen users in the US, cost-effectiveness analysis should be performed. A Markov model was constructed for suffering thermal injury while smoking on home oxygen. Societal and Medicare perspectives were adopted evaluating the costs of a federal policy including purchasing/shipping thermal fuses to all home oxygen users. Costs included the healthcare required to treat burn patients and extending lives in advanced chronic obstructive pulmonary disease. Cost savings included the avoided property loss. Effectiveness was measured in gains in quality adjusted life years (QALYS). In the status quo, the 10-year societal cost was $28.67 billion compared to $28.36 billion in the policy mandate (saving $305.40 million at ten years). 1,812 QALYs were gained with the policy mandate, yielding and ICER of -$160,317. For the Medicare payor perspective, the incremental cost-effectiveness ratio (ICER) was $64,981. Deterministic and probabilistic sensitivity analyses showed little variation in the ICER under multiple scenarios. The discrepancy between the dominant ICER for societal perspective and cost-effective ICER for Medicare perspective reflected savings from averted property loss not realized by Medicare. A national policy mandating and paying for thermal fuses for all home oxygen users is dominant from a societal perspective and cost-effective from a Medicare perspective. The US government should adopt such a policy.

Adherence to inhaled corticosteroid therapy and treatment escalation in the Swedish adult asthma population.

BACKGROUND: Patients with uncontrolled asthma should be evaluated for medication adherence. This study aimed to identify characteristics associated with poor adherence to inhaled corticosteroids (ICS) and to explore adherence prior to treatment escalation. METHODS: This nationwide longitudinal cohort study included adult asthma patients (n = 30880) with a healthcare visit including Asthma Control Test (ACT) and registered in the Swedish National Airway Register between 1 July 2017 and 28 February 2019 (index date). Patient data was crosslinked to other national registers. Treatment steps two years pre- and one year post-index, were identified by prescribed drugs. Poor adherence was defined as Medication Possession Ratio <80 %. RESULTS: Poor adherence was identified in 73 % of patients in treatment steps 2-5, where of 35 % had uncontrolled asthma (ACT≤19). In adjusted models, poor adherence was associated with better disease control; ACT≤19 (OR 0.78, 95 % CI 0.71-0.84), short-acting ß2-agonist (SABA) overuse (0.69, 0.61-0.79) and exacerbations (0.79, 0.70-0.89) in steps 2-3. Among patients with uncontrolled asthma, poor adherence was associated with SABA overuse (1.71, 1.50-1.95), exacerbations (1.29, 1.15-1.46), current smoking (1.38, 1.21-1.57) and inversely associated with asthma management education (0.85, 0.78-0.93. Similar results were observed in steps 4-5. When investigating post-index treatment, 53 % remained stationary, 30 % stepped down and 17 % escalated treatment. Prior to escalation, 49 % had poor adherence. CONCLUSIONS: Poor ICS adherence was associated with better asthma control. Among uncontrolled patients, poor adherence was associated with SABA overuse and exacerbations. Our result highlights the importance of asthma management education to improve adherence in uncontrolled patients.

Monitoring cystic fibrosis airway infections with Pseudomonas aeruginosa with anti-OprF serum antibodies.

BACKGROUND: The management of cystic fibrosis (CF) requires knowledge of the patient's microbiological status. The serology of anti-Pseudomonas aeruginosa antibodies against exoenzymes or water-soluble antigens has gained diagnostic value, particularly to detect the onset of colonization with P. aeruginosa. However, the diversity and variable expression of these antigens, which was unknown when the ELISAs became common diagnostic procedures at CF clinics, prohibits the quantitative evaluation of bacterial antigen load during intermittent and chronic infection. METHODS: An ELISA was developed to measure the serum IgG antibody levels against P. aeruginosa porin OprF, a species-specific, conserved, immunogenic and constitutively expressed protein present in the outer membrane and extracellular vesicles. RESULTS: Serial serum samples were collected from 310 people with CF (pwCF) over a period of up to 15 years. Compared to a reference of P. aeruginosa - negative CF sera set to 1, OprF antibody titers ranged from 0.3 to 13.2 (median: 1.7) in 56 intermittently colonized patients and from 0.5 to 51.2 (median: 11.8) in 176 chronically colonized pwCF showing higher anti-OprF antibody levels during chronic than during intermittent colonization with P. aeruginosa (P = 0, Z = - 21.7, effect size 0.62). Inhalation with twice daily 80 mg tobramycin decreased OprF antibody titers (P = 5 × 10-5), particularly during the third and fourth year of chronic colonization. CONCLUSION: The OprF ELISA should be an appropriate tool to monitor Pseudomonas serology at all stages of infection and disease severity and to study the impact of short- and long-term therapeutic interventions.

Characterization of Wildland Firefighters' Exposure to Coarse, Fine, and Ultrafine Particles; Polycyclic Aromatic Hydrocarbons; and Metal(loid)s, and Estimation of Associated Health Risks.

Firefighters' occupational activity causes cancer, and the characterization of exposure during firefighting activities remains limited. This work characterizes, for the first time, firefighters' exposure to (coarse/fine/ultrafine) particulate matter (PM) bound polycyclic aromatic hydrocarbons (PAHs) and metal(loid)s during prescribed fires, Fire 1 and Fire 2 (210 min). An impactor collected 14 PM fractions, the PM levels were determined by gravimetry, and the PM-bound PAHs and metal(loid)s were determined by chromatographic and spectroscopic methodologies, respectively. Firefighters were exposed to a total PM level of 1408.3 and 342.5 µg/m3 in Fire 1 and Fire 2, respectively; fine/ultrafine PM represented more than 90% of total PM. Total PM-bound PAHs (3260.2 ng/m3 in Fire 1; 412.1 ng/m3 in Fire 2) and metal(loid)s (660.8 ng/m3 versus 262.2 ng/m3), distributed between fine/ultrafine PM, contained 4.57-24.5% and 11.7-12.6% of (possible/probable) carcinogenic PAHs and metal(loid)s, respectively. Firefighters' exposure to PM, PAHs, and metal(loid)s were below available occupational limits. The estimated carcinogenic risks associated with the inhalation of PM-bound PAHs (3.78 × 10-9 - 1.74 × 10-6) and metal(loid)s (1.50 × 10-2 - 2.37 × 10-2) were, respectively, below and 150-237 times higher than the acceptable risk level defined by the USEPA during 210 min of firefighting activity and assuming a 40-year career as a firefighter. Additional studies need to (1) explore exposure to (coarse/fine/ultrafine) PM, (2) assess health risks, (3) identify intervention needs, and (4) support regulatory agencies recommending mitigation procedures to reduce the impact of fire effluents on firefighters.

Neuroinflammation is dependent on sex and ovarian hormone presence following acute woodsmoke exposure.

Woodsmoke (WS) exposure is associated with significant health-related sequelae. Different populations can potentially exhibit varying susceptibility, based on endocrine phenotypes, to WS and investigating neurological impacts following inhaled WS is a growing area of research. In this study, a whole-body inhalation chamber was used to expose both male and female C57BL/6 mice (n = 8 per group) to either control filtered air (FA) or acute WS (0.861 ± 0.210 mg/m3) for 4 h/d for 2 days. Neuroinflammatory and lipid-based biological markers were then assessed. In a second set of studies, female mice were divided into two groups: one group was ovariectomized (OVX) to simulate an ovarian hormone-deficient state (surgical menopause), and the other underwent Sham surgery as controls, to mechanistically assess the impact of ovarian hormone presence on neuroinflammation following FA and acute WS exposure to simulate an acute wildfire episode. There was a statistically significant impact of sex (P ≤ 0.05) and statistically significant interactions between sex and treatment in IL-1ß, CXCL-1, TGF-ß, and IL-6 brain relative gene expression. Hippocampal and cortex genes also exhibited significant changes in acute WS-exposed Sham and OVX mice, particularly in TGF-ß (hippocampus) and CCL-2 and CXCL-1 (cortex). Cortex GFAP optical density (OD) showed a notable elevation in male mice exposed to acute WS, compared to the control FA. Sham and OVX females demonstrated differential GFAP expression, depending on brain region. Overall, targeted lipidomics in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) serum and brain lipids demonstrated more significant changes between control FA and acute WS exposure in female mice, compared to males. In summary, male and female mice show distinct neuroinflammatory markers in response to acute WS exposure. Furthermore, ovarian hormone deficiency may impact the neuroinflammatory response following an acute WS event.

In utero chronic intermittent nicotine aerosol exposure increases ischemic heart injury in adult offspring via programming of Angiotensin II receptor-derived TGFß/ROS/Akt signaling pathway.

BACKGROUND: In utero cigarette smoking/nicotine exposure during pregnancy significantly affects fetal development and increases the risk of cardiovascular disease late in life. However, the underlying molecular mechanisms remain largely unknown. We tested the hypothesis that fetal nicotine aerosol exposure reprograms ischemia-sensitive gene expressions, resulting in increased heart susceptibility to ischemic injury and cardiac dysfunction in adulthood. METHODS: Pregnant rats were exposed to chronic intermittent nicotine aerosol (CINA) or saline aerosol control from gestational day 4 to day 21. Experiments were performed on 6-month-old adult offspring. RESULTS: CINA exposure increased ischemia-induced cardiac injury and cardiac dysfunction compared to the control group, which was associated with over- expression of angiotensin II receptor (ATR) protein in the left ventricle (LV) of adult offspring. Meanwhile, CINA exposure up-regulated cardiac TGF-ß/SMADs family proteins in the LV. In addition, CINA exposure enhanced cardiac reactive oxygen species (ROS) production and increased the DNA methylation level. The levels of phosphorylated-Akt were upregulated but LC3B-II/I protein abundances were downregulated in the hearts isolated from the CINA-treated group. CONCLUSION: Fetal nicotine aerosol exposure leads to cardiac dysfunction in response to ischemic stimulation in adulthood. Two molecular pathways are implicated. First, fetal CINA exposure elevates cardiac ATR levels, affecting the TGFß-SMADs pathway. Second, heightened Angiotensin II/ATR signaling triggers ROS production, leading to DNA hypermethylation, p-Akt activation, and autophagy deficiency. These molecular shifts in cardiomyocytes result in the development of a heart ischemia-sensitive phenotype and subsequent dysfunction in adult offspring.

Challenges in current inhalable tobacco toxicity assessment models: A narrative review.

Emerging tobacco products such as electronic nicotine delivery systems (ENDS) and heated tobacco products (HTPs) have a dynamic landscape and are becoming widely popular as they claim to offer a low-risk alternative to conventional smoking. Most pre-clinical laboratories currently exploit in vitro, ex vivo, and in vivo experimental models to assess toxicological outcomes as well as to develop risk-estimation models. While most laboratories have produced a wide range of cell culture and mouse model data utilizing current smoke/aerosol generators and standardized puffing profiles, much variation still exists between research studies, hindering the generation of usable data appropriate for the standardization of these tobacco products. In this review, we discuss current state-of-the-art in vitro and in vivo models and their challenges, as well as insights into risk estimation of novel products and recommendations for toxicological parameters for reporting, allowing comparability of the research studies between laboratories, resulting in usable data for regulation of these products before approval by regulatory authorities.

Inhaled polystyrene microplastics impaired lung function through pulmonary flora/TLR4-mediated iron homeostasis imbalance.

Microplastics (MPs) have been found in the air, human nasal cavity, and lung, suggesting that the respiratory tract is one of the important exposure routes for MPs. The lung is a direct target organ for injury from inhaled MPs, but data on lung injury from longer-term exposure to environmental doses of MPs are limited, and the mechanisms remain unclear. Here, C57BL/6 J mice were treated with 5 µm polystyrene (PS)-MPs by intratracheal instillation (0.6, 3, and 15 mg/kg) for 60 days to establish MPs exposure model. We found that PS-MPs lead to increased collagen fibers and decreased lung barrier permeability and lung function in lung tissue. Mechanistically, the abundance of gram-negative bacteria in the pulmonary flora increased after inhalation of PS-MPs, causing lipopolysaccharide (LPS) release. The expression of Toll-like receptor 4 (TLR4), the key receptor of LPS, was increased, and ferroptosis occurred in lung tissue cells. Further in vitro intervention experiments were performed, pulmonary flora/TLR4-induced imbalance of lung iron homeostasis is an important mechanism of PS-MPs-induced lung injury. Our study provides new evidence for lung injury caused by environmental doses of MPs and strategies to prevent it through longer-term dynamic observation.

Effect of volatile versus propofol anaesthesia on major complications and mortality after cardiac surgery: a multicentre randomised trial.

BACKGROUND: The comparative effectiveness of volatile anaesthesia and total intravenous anaesthesia (TIVA) in terms of patient outcomes after cardiac surgery remains a topic of debate. METHODS: Multicentre randomised trial in 16 tertiary hospitals in China. Adult patients undergoing elective cardiac surgery were randomised in a 1:1 ratio to receive volatile anaesthesia (sevoflurane or desflurane) or propofol-based TIVA. The primary outcome was a composite of predefined major complications during hospitalisation and mortality 30 days after surgery. RESULTS: Of the 3123 randomised patients, 3083 (98.7%; mean age 55 yr; 1419 [46.0%] women) were included in the modified intention-to-treat analysis. The composite primary outcome was met by a similar number of patients in both groups (volatile group: 517 of 1531 (33.8%) patients vs TIVA group: 515 of 1552 (33.2%) patients; relative risk 1.02 [0.92-1.12]; P=0.76; adjusted odds ratio 1.05 [0.90-1.22]; P=0.57). Secondary outcomes including 6-month and 1-yr mortality, duration of mechanical ventilation, length of ICU and hospital stay, and healthcare costs, were also similar for the two groups. CONCLUSIONS: Among adults undergoing cardiac surgery, we found no difference in the clinical effectiveness of volatile anaesthesia and propofol-based TIVA. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IOR-17013578).

Bis-(2-Chloroisopropyl) ether.

Bis-(2-Chloroisopropyl) ether (BCIPE) was used as a solvent for fats, greases, paint, varnish removers, and in spotting and cleaning solutions. However, BCIPE has not been commercially manufactured or used for numerous years. In experimental animal studies, BCIPE is moderately toxic following acute oral, dermal, and inhalation routes of exposure. BCIPE is a severe eye irritant but not a dermal irritant or dermal sensitizer. BCIPE was not genotoxic or mutagenic in in vitro and in vivo assays; it was not toxic in a 3-generation reproductive dietary study in rats. Short-term, repeated inhalation and oral exposure in rats produced increased liver and kidney weights and congestion; dermal exposure in rabbits did not produce any observable adverse effects. BCIPE did not produce a statistically significant increase in tumors in two different 2-year dietary studies in mice and rats. In mice, technical grade BCIPE produced increased incidences of alveolar/bronchiolar adenomas in females, hepatocellular carcinomas in males, and a low incidence of forestomach hyperplasia (in both sexes at the high-dose). Further investigation with technical grade BCIPE concluded that these effects were species- and dose-specific with limited, if any, relevance to humans. The NOAEL of 400 ppm (15 mg/kg/day) from the 2-year dietary study in female rats was considered the point of departure for the health-based WEEL derivation. After adjustment for duration of exposure, interindividual variability, and intraindividual variability, an 8-h time-weighted average (TWA) WEEL value of 3 ppm (21 mg/m3) was derived. This exposure limit is expected to provide a significant margin of safety against any potential adverse health effects in workers.

The fate of an inhaled cigarette puff in the human respiratory tract.

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.

Phospholipids of inhaled liposomes determine the in vivo fate and therapeutic effects of salvianolic acid B on idiopathic pulmonary fibrosis.

Since phospholipids have an important effect on the size, surface potential and hardness of liposomes that decide their in vivo fate after inhalation, this research has systematically evaluated the effect of phospholipids on pulmonary drug delivery by liposomes. In this study, liposomes composed of neutral saturated/unsaturated phospholipids, anionic and cationic phospholipids were constructed to investigate how surface potential and the degree of saturation of fatty acid chains determined their mucus and epithelium permeability both in vitro and in vivo. Our results clearly indicated that liposomes composed of saturated neutral and anionic phospholipids possessed high stability and permeability, compared to that of liposomes composed of unsaturated phospholipids and cationic phospholipids. Furthermore, both in vivo imaging of fluorescence-labeled liposomes and biodistribution of salvianolic acid B (SAB) that encapsulated in liposomes were performed to estimate the effect of phospholipids on the lung exposure and retention of inhaled liposomes. Finally, inhaled SAB-loaded liposomes exhibited enhanced therapeutic effects in a bleomycin-induced idiopathic pulmonary fibrosis mice model via inhibition of inflammation and regulation on coagulation-fibrinolytic system. Such findings will be beneficial to the development of inhalable lipid-based nanodrug delivery systems for the treatment of respiratory diseases where inhalation is the preferred route of administration.

A review of the toxicity of ingredients in e-cigarettes, including those ingredients having the FDA's "Generally Recognized as Safe (GRAS)" regulatory status for use in food.

INTRODUCTION: Some firms and marketers of electronic cigarettes (e-cigarettes; a type of electronic nicotine delivery system (ENDS)) and refill liquids (e-liquids) have made claims about the safety of ingredients used in their products based on the term "GRAS or Generally Recognized As Safe" (GRAS). However, GRAS is a provision within the definition of a food additive under section 201(s) (21 U.S.C. 321(s)) of the U.S. Federal Food Drug and Cosmetic Act (FD&C Act). Food additives and GRAS substances are by the FD&C Act definition intended for use in food, thus safety is based on oral consumption; the term GRAS cannot serve as an indicator of the toxicity of e-cigarette ingredients when aerosolized and inhaled (i.e., vaped). There is no legal or scientific support for labeling e-cigarette product ingredients as "GRAS". This review discusses our concerns with the GRAS provision being applied to e-cigarette products and provides examples of chemical compounds that have been used as food ingredients but have been shown to lead to adverse health effects when inhaled. The review provides scientific insight into the toxicological evaluation of e-liquid ingredients and their aerosols to help determine the potential respiratory risks associated with their use in e-cigarettes. IMPLICATIONS: The rise in prevalence of e-cigarette use and emerging evidence of adverse effects, particularly on lung health, warrant assessing all aspects of e-cigarette toxicity. One development is manufacturers' stated or implied claims of the safety of using e-cigarette products containing ingredients determined to be "Generally Recognized As Safe" (GRAS) for use in food. Such claims, typically placed on e-cigarette product labels and used in marketing, are unfounded, as pointed out by the United States Food and Drug Administration (FDA)1 and the Flavor and Extract Manufacturers Association (FEMA)2. Assessment of inhalation health risks of all ingredients used in e-liquids, including those claimed to be GRAS, is warranted.